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RELATED APPLICATIONS
This application is a continuation-in-part of U.S. patent application Ser. No. 12/462,384, now U.S. Pat. No. 8,463,383, filed 3 Aug. 2009, and entitled “Portable Assemblies, Systems, and Methods for Providing Functional or Therapeutic Neurostimulation,” which is incorporated herein by reference in its entirety and which claims the benefit of U.S. Provisional Patent Application Ser. No. 61/137,652, filed 1 Aug. 2008, and entitled “Portable Assemblies, Systems, and Methods for Providing Functional or Therapeutic Neurostimulation.”
This application is also a continuation-in-part of U.S. patent application Ser. No. 12/653,029, filed 7 Dec. 2009, and entitled “Systems and Methods To Place One or More Leads in Tissue for Providing Functional and/or Therapeutic Stimulation,” which is incorporated herein by reference in its entirety and which claims the benefit of U.S. Provisional Patent Application Ser. No. 61/201,030, filed 5 Dec. 2008, and entitled “Systems and Methods To Place One or More Leads in Tissue for Providing Functional and/or Therapeutic Stimulation.”
This application is also a continuation-in-part of U.S. patent application Ser. No. 12/653,023, filed 7 Dec. 2009, and entitled “Systems and Methods To Place One or More Leads in Tissue to Electrically Stimulate Nerves of Passage to Treat Pain,” which is incorporated herein by reference in its entirety and which claims the benefit of U.S. Provisional Patent Application Ser. No. 61/201,030, filed 5 Dec. 2000, and entitled “Systems and Methods To Place One or More Leads in Tissue for Providing Functional and/or Therapeutic Stimulation.”
This application is also a continuation-in-part of U.S. patent application Ser. No. 13/323,152, now abandoned, filed 12 Dec. 2011, and entitled “Systems and Methods for Percutaneous Electrical Stimulation,” which is a continuation of U.S. patent application Ser. No. 13/095,616, now abandoned, filed 27 Apr. 2011, and entitled “Systems and Methods for Percutaneous Electrical Stimulation,” which is incorporated herein by reference in its entirety and which claims the benefit of U.S. Provisional Patent Application Ser. No. 61/343,325, filed 27 Apr. 2010, and entitled “Systems and Methods for Percutaneous Electrical Stimulation.”
Every combination of the various embodiments contained in the incorporated reference applications may be formed so as to carry out the intention of embodiments of the invention described below.
BACKGROUND OF THE INVENTION
Approximately 185,000 individuals in the U.S. undergo an amputation each year. The majority of new amputations result from vascular disorders such as diabetes, with other causes including cancer and trauma. Almost all amputees (95%) have intense pain during the recovery period following their amputation, either sensed in the portion of the limb that remains (residual limb pain) or in the portion of the limb that has been removed (phantom pain). It is critical to treat this sub-chronic pain condition quickly and effectively to avoid the significant social, economic, and rehabilitation issues associated with severe post-amputation pain. Other types of neuropathic pain affect over 6 million Americans.
Almost all amputees (95%) have pain related to their amputation: approximately 68-76% of amputees have residual limb pain (RLP) and 72-85% of amputees have phantom limb pain (PLP). Their severity and prevalence make them significant medical problems. Pain can lead to discouragement, anger, depression, and general suffering. PLP and RLP frequently cause further disability and greatly reduce quality of life (QOL). In amputees with severe pain, it is frequently the pain rather than the loss of a limb that most impacts daily activities and employment. Amputee pain has a significant economic impact on the patient and society. For the patient, the median cost of medications exceeds $3,000/year and the median cost for a treatment regimen provided by a pain management center is over $6,000/year. The annual cost in the U.S. to manage post-amputation pain is estimated to be over $1.4 billion for medications and over $2.7 billion for pain center treatment programs. When the overall costs of pain management care are summed, the annual cost can exceed $30,000/patient for a cost of over $13 billion/year to treat amputees with severe pain in the US.
Present methods of treatment are unsatisfactory in reducing pain, have unwanted side effects, and are not suited for temporary use. Electrical stimulation of nerves can provide significant (>50%) pain relief, but present methods of implementation are either inappropriate for sub-chronic pain due to their invasiveness, or are uncomfortable and inconvenient to use. We have developed an innovative, minimally invasive method of delivering temporary electrical stimulation to target nerves. Preliminary data on treating amputee pain using methods according to the present invention are promising, but there is a significant need for a stimulation system that overcomes the technical and clinical barriers of presently available devices, including imprecise programming (requiring precise lead placement which is impractical for widespread use) and lack of moisture ingress protection (requiring removal of system during some daily activities).
PLP and RLP are severe and debilitating to a large proportion of amputees, who often progress through a series of treatments without finding relief. Most patients are managed with medications. Non-narcotic analgesics, such as non-steroidal anti-inflammatory drugs (NSAIDS), are commonly used but are rarely sufficient in managing moderate to severe pain. Trials of narcotics have failed to show significant reduction in PLP, and they carry the risk of addiction and side effects, such as nausea, confusion, vomiting, hallucinations, drowsiness, headache, agitation, and insomnia. Other medications such as antidepressants are used for neuropathic pain, but their use for post-amputation pain is based primarily on anecdotal evidence and there are few controlled clinical trials to support their efficacy for post-amputation pain. Physical treatments (e.g., acupuncture, massage, heating/cooling of the residual limb) have limited data to support their use and are not well accepted. Psychological strategies, such as biofeedback and psychotherapy, may be used as an adjunct to other therapies but are seldom sufficient on their own, and there are few studies demonstrating their efficacy. Mirror-box therapy has demonstrated mixed results and is not widely used. Few surgical procedures are successful and most are contraindicated for the majority of the amputee patients 11. Studies have shown that pain resolves over the first 6 months following amputation for some patients. Within 6 months, RLP resolves for 60% of patients and PLP resolves for 10% of patients, with another 40% experiencing a significant reduction in pain intensity, making it inappropriate to use invasive methods before establishing that the pain is long-term (>6 months).
Prior electrical stimulation has been attempted. Transcutaneous electrical nerve stimulation (TENS, i.e., surface stimulation) is a commercially available treatment and has been demonstrated at being at least partially successful in reducing post-amputation pain. However, TENS has a low (<25%) success rate due to low patient compliance. Patients are non-compliant because the stimulus intensity required to activate deep nerves from the skin surface can activate cutaneous pain fibers leading to discomfort, the electrodes must be placed by skilled personnel daily, and the cumbersome systems interferes with daily activities. Spinal cord stimulation (SCS), motor cortex stimulation, and deep brain stimulation (DBS) have evidence of efficacy, but their invasiveness, high cost, and risk of complications makes them inappropriate for patients who may only need a temporary therapy. High frequency nerve block has been shown to decrease transmission of pain signals in the laboratory, but the therapy has not been developed for clinical use. Historically, peripheral nerve stimulation (PNS) for pain has not been widely used due to the complicated approach of dissecting nerves in an open surgical procedure and placing leads directly in contact with these target nerves. Such procedures are time consuming and complex (greatly limiting clinical use outside of academic institutions), have risks of damaging nerves, and often (27%) have electrode migration or failure. Other groups are developing percutaneous electrode placement methods, but their methods still require delicate, placement and intimate contact with the nerve, making them prone to complications and migration (up to 43%) because the technology lacks sufficient anchoring systems, leading to loss of pain relief and rapid failure (averaging 1-2 revisions/patient).
SUMMARY OF THE INVENTION
A system according to the present invention relates to a novel, non-surgical, non-narcotic, minimally-invasive, peripheral nerve stimulation pain therapy intended to deliver up to 6 months or more of therapy to patients that may be experiencing pain, such as post-amputation pain. In one embodiment, system components are an external stimulator, preferably a 2-channel stimulator that connects to up to two percutaneous leads, a charging pad for recharging the stimulator, and wireless controllers used by the patient and the clinician.
Systems and methods according to the present invention overcome at least the limitations or drawbacks of conventional TENS systems, such as cutaneous pain and low compliance, thought to be at least partially due to the cumbersome nature of prior systems. Systems and methods according to the present invention also overcome at least some of the limitations or drawbacks of conventional surgical options such as SCS, DBS, and surgically-implemented PNS, such as invasiveness, cost, and risk of complications. Systems and methods according to the present invention relate to delivering stimulation percutaneously (electrical current traveling through a lead placed through the skin) which has significant advantages. Such stimulation may be provided using methods that are minimally invasive and reversible (making it ideal for treating temporary pain), easy for pain specialists to perform (due to its similarity to common procedures such as injections), and can be trialed without long-term commitment. In addition, the electrodes of the electrical leads only need to be placed within centimeters of the nerve, reducing the risk of nerve injury (as the electrode does not touch the nerve) and making the lead placement procedure simple for non-surgeons. Finally, improved percutaneous leads have a proven anchoring system, reducing susceptibility to electrode migration. At the conclusion of use, the lead is removed by gentle traction. Systems and methods according to the present invention may employ a percutaneous lead with a long history of successful use is multiple pain indications including amputee pain. Data suggest that systems and methods according to the present invention will have a low risk of complications. For instance, in a long-term study of 1713 leads placed in the lower extremities and trunk, there were 14 (0.9%) electrode fragment-associated tissue reactions that resolved when the fragments were removed with forceps, and 14 (0.9%) superficial infections that resolved when treated with antibiotics and/or the lead was removed.
Ongoing studies are being used to investigate the safety & efficacy of treating amputee pain using percutaneous leads connected to surface stimulators to deliver safe stimulation percutaneously, and the results are promising. Five subjects with amputations have received in-clinic (i.e., trial) therapy. Three subjects had amputations due to trauma, one due to cancer, and one due to vascular disease. The subjects had used various combinations of medications (narcotic and non-narcotic), physical therapy, injections, and nerve blocks in the past without success. Stimulation was delivered to the femoral nerve (n=1), the sciatic nerve (n=1), or both (n=3) depending on the location of pain. Of the three subjects who reported RLP at baseline, the average reduction in pain during in-clinic trial was 64%. The two subjects who reported PLP at baseline reported a 60% reduction in pain during the in-clinic testing. One subject did not report pain relief due to vascular dysfunction in the amputated limb. It was determined that the nerves would not respond to stimulation during the in-clinic testing and remove the lead through gentle traction. If this patient had received a trial stage system for SCS, the leads would have required open surgery for removal. The present approach allows for minimally-invasive screening of patients to determine responders. Thus far, three subjects have received the therapy at home for ≦2 weeks. All three subjects reported significant pain relief for the duration of therapy use. There have been no adverse events to date. Results are promising, but using prior available surface stimulators to deliver stimulation through percutaneous leads has significant limitations (e.g., per pulse charges that can be unsafe with percutaneous leads if not limited by a technical modification, lack of moisture ingress protection forcing subjects to remove the system when showering, burdensome cables that can snag), making it unfeasible to deliver therapy, under methods according to the present invention, using existing systems for a full 6-month period. Systems and methods according to the present invention address unfortunate shortcomings of prior systems, as they may be used to deliver optimal safe and effective percutaneous stimulation that will maximize clinical benefit.
Prior systems and methods fail to provide an effective and minimally invasive treatment option for patients with post-amputation pain, forcing many of them to suffer with severe pain during their initial recovery or resort to an invasive therapy that may not be necessary in the long-term. Systems and methods according to the present invention have the capability to provide a therapy that has the potential for a high rate of efficacy with minimal side effects, has a simple procedure performed in an outpatient setting, is temporary & reversible, and has established reimbursement coding and coverage policies (existing codes and coverage policies reimburse the therapy cost and make the procedure profitable for the hospital % physician). Systems and methods according to the present invention may be used to treat other types of neuropathic pain, such as complex regional pain syndrome (CRPS). CRPS is challenging to treat due to its poorly understood pathophysiology, and few patients receive pain relief from available treatments. PNS produces dramatic pain relief in most patients with CRPS, but existing methods require surgically placing the lead in intimate contact with the nerve. These procedures are time consuming & complex (greatly limiting clinical use outside of academic institutions), have risks of nerve damage, and often (27%) have lead migration or failure. Another neuropathic pain that may be treated with systems and methods according to the present invention is post-herpetic neuralgia, which is severe but often temporary, making invasive surgeries inappropriate. Pain due to diabetic neuropathy, which is poorly controlled using medications, may also be treated using systems and methods according to the present invention. As indicated, over 6 million Americans suffer from neuropathic pain, resulting in a negative impact on quality of life (QOL) and profound economic costs. Systems and methods according to the present invention may change how neuropathic pain is managed by providing clinicians with a minimally-invasive, simple, reversible, and effective treatment option, resulting in a significant, decrease in the socioeconomic consequences of neuropathic pain and an improvement in the QOL of millions of Americans.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1-7 depict a preferred external stimulator according to the present invention.
FIGS. 8-11 depict a preferred mounting patch according to the present invention.
FIG. 12 shows a partial assembly view of an external stimulator and mounting patch according to the present invention.
FIGS. 13-19 depict the stimulator from FIGS. 1-7 coupled to the mounting patch from FIGS. 8-11 , including the mechanical and/or electrical engagement of the snap receptacles provided on the stimulator with the snaps provided on the mounting patch.
FIG. 20 depicts a first stimulator controller according to the present invention, which may be used by a patient or clinician to preferably wirelessly program and/or control the stimulator of FIGS. 1-7 before or after the stimulator is supported on a patient, such as by the mounting patch of FIGS. 8-11 .
FIG. 21 depicts a second stimulator controller according to the present invention, which may be used by a patient or clinician to preferably wirelessly program and/or control the stimulator of FIGS. 1-7 before or after the stimulator is supported on a patient, such as by the mounting patch of FIGS. 8-11 .
FIG. 22 is a partial assembly view including an external stimulator, mounting patch, and stimulating lead according to the present invention. The stimulating lead may have one or more stimulating electrodes supported thereby.
FIG. 23 is an assembled view of the embodiment of FIG. 22 .
FIG. 24 is a perspective view of the stimulator of FIGS. 1-7 resting on an inductive charging mat, which is preferably connected to a power mains.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Although the disclosure hereof is detailed and exact to enable those skilled in the art to practice the invention, the physical embodiments herein disclosed merely exemplify the invention which may be embodied in other specific structures. While the preferred embodiment has been described, the details may be changed without departing from the invention, which is defined by the claims.
Systems, components, or methods according to the present invention may provide safety improvements, such as electrical safety improvements that may be provided by improved moisture ingress protection.
Systems, components, or methods according to the present invention may provide stimulation output improvements, such as direct-to-nerve stimulation and current-controlled output.
Systems, components, or methods according to the present invention may provide stimulation usability improvements, such as decreased physical size, wireless stimulation control, and decreased maintenance requirements.
A system according to the present invention may include one or more of the following components: an external stimulator, percutaneous leads, a patient controller, a charging pad, and a clinician controller. The external stimulator is a preferably small, lightweight pod that may be selectively mountable to a replaceable adhesive patch that may function as a return electrode. The external stimulator is preferably less than four centimeters wide, less than six centimeters long, and less than one centimeter thick. More preferably, the external stimulator is about 3.6 centimeters wide, about 5.8 centimeters long, and about 0.8 centimeters thick. The external stimulator weighs preferably less than 30 grams, and more preferably less than 24 grams. The external stimulator may include or not include a power source. If the external stimulator does not include a power source, electrical power is provided to electrical stimulation circuitry housed within the stimulator by a battery that is preferably provided in the adhesive patch. If the external stimulator does house a power source, the power source is preferably a battery that may be inductively recharged.
The external stimulator may be physically mounted to and supported by an adhesive patch that may be adhered to the skin spaced from, but preferably near (preferably less than fifteen centimeters) the exit site of the percutaneous leads (preferably proximal to a prosthetic limb, if used). The adhesive patch may provide a mounting location for the external stimulator, but may also function as a surface electrode for either stimulating, as an active electrode, or serving as a non-stimulating return electrode. Thus, the mounting mechanism between the patch and the external stimulator is preferably electrically conductive, such as one or more metallic snap structures that are mateable with corresponding seat structures provided on the external stimulator. The patch may provide an additional, alternate, and/or back-up power supply for electrical stimulation circuitry contained in the external stimulator. A preferred smooth and low profile design of the housing of the external stimulator, helps reduce a majority of common problems associated with existing external stimulators, including accidental button activation and snagging on clothes (which can disconnect or break the electrodes). Wireless control, such as with a remote controller, allows further miniaturization of the stimulator, decreasing the footprint of the device on the skin surface and allowing it to be worn almost imperceptibly under clothing, in contrast to commercially available stimulators which are typically worn outside of clothing due to their large size and the need to view the display screen. Using a system according to the present invention, a patient may utilize a controller, such as a key-fob like device, to adjust the intensity of each percutaneous stimulation channel within a safe and effective range. Recharging the power source of the stimulator may be performed in a variety of ways. If a power source is provided in the stimulator housing, the power source is preferably a battery that may be inductively recharged, preferably within 2 hours by placing it on a charging pad. A clinician controller may be provided in the form of a notepad computer with custom software and a wireless communications interface or adaptor for programming stimulus parameters in the external stimulator or the controller used by the patient, and reading patient compliance data from the external stimulator or from the controller used by the patient.
Systems according the present invention are preferably designed to meet preferred safety, output, and usability goals that are not met by presently available devices, see Table b.1, below. Safety features such as maximum per pulse charge safe for percutaneous stimulation, moisture ingress protection for safe use during daily activities including showering, and limited programming by patients, may be incorporated. Design mechanisms to deliver minimally-invasive and effective therapy, such as bypassing cutaneous pain fibers and current-controlled output, may also be included. Features that improve comfort and usability may also be incorporated, such as miniaturization and low maintenance.
TABLE B.1
Systems and methods according to the presert invention address limitations of prior available devices.
Preferred features of
Possible limitations of available
embodiments of
technology (surface stimulators
systems according to
and trial SCS stimulators)
present invention
SAFETY
Output safe for
Surface stimulators can be adjusted
Full parameter range is
stimulus
to per pulse charges that can damage
safe for use with
delivery via
tissue when used with percutaneous
percutaneous leads
percutaneous
leads, which would be an off-label
(preferred maximum per
leads
use
pulse charge injection of
4 μC = 0.4 μC/mm 2 )
Moisture
Most surface stimulators rated as
Rated as IP44
ingress
IPX0 (ordinary equipment). Must be
(protection from water
protection
removed during daily activities such
sprayed from all
suitable for
as showering.
directions). Remains safe
wearing on the
and reliable despite
skin during all
perspiration, showering,
daily activities
etc.
Patient
Surface stimulators allow unrestricted
Allows patient to select
adjustment of
adjustment, resulting in stimulus
from a safe and effective
stimulus
output that can be ineffective or
range of intensities with
intensity within
unsafe
minimal clinician
a safe &
programming.
effective range
Minimally
Trial SCS leads are placed via open
percutaneous leads are
invasive lead
procedures requiring imaging
placed through the skin
placement
by non-surgeons
OUTPUT
Comfortable
Surface stimulation can activate
Therapy is delivered
therapy (for high
cutaneous pain fibers leading to
directly to the nerves,
compliance)
discomfort/pain
bypassing cutaneous
pain fibers.
Current-
Many surface stimulators are voltage-
Current-controlled
controlled
controlled: the output current
output, eliminating output
output to
depends on surface electrode-to-
variability.
minimize
tissue impedance which varies over
variability
time and by surface, electrode
among patients
adhesion and cleanliness of skin
USABILITY
Minimization of
Surface stimulators typically worn on
Elimination of cable
cables, low
the waist due to their large size
connecting anode.
profile, and
(typical dimensions of 6 cm × 10 cm ×
Minimization of cable
small size
2.5 cm), requiring cables connecting
connecting cathode by
the stimulator to the electrodes on the
placing system on skin
skin. Cables interfere with daily
near lead site. Preferably
activities and restrict movement.
sized approx. 3.6 cm ×
5.8 cm × 0.8 cm and 24 g.
Ease of
Patients must open the battery
Recharged by placing it
recharging and
compartment of surface stimulators
on a recharging pad, an
low
and replace the battery regularly. This
action that can he done
maintenance
can be difficult for patients with
with one hand.
impairments. Surface electrodes must
Percutaneous lead is
be placed by skilled personnel daily.
placed once.
Previous and ongoing studies suggest that PNS can significantly reduce post-amputation pain, but a system capable of delivering minimally invasive therapy safely and effectively does not exist. Systems and methods according to the present invention provide an innovative PNS system that addresses deficiencies in presently available devices in addition to introducing features that will improve the experience for the patient and clinician. Such systems and methods will improve clinical practice for pain management by providing clinicians with a therapy that can significantly reduce pain following amputation and improve QOL during the first 6 months of recovery without systemic side-effects or invasive procedures. For many amputees, pain subsides over time and the systems and methods according to the present invention may be the only pain therapy necessary. For patients who continue to experience pain, either the therapy can be re-dosed or a fully implantable electrical stimulation system can be considered.
Preferred technical features of a system according to the present invention include preferred stimulation parameters, electrical safety (including reduction of moisture ingress), physical characteristics, and operational functionality. Regarding stimulation parameters, a preferred stimulation amplitude is in a preferred range of about 0-30 milliamps, and more preferably in a preferred range of 0.1 mA-20 mA, +/−7%. A preferred pulse duration is about 0-500 microseconds, and more preferably is a range of 10-300 microseconds, +/−2-30%, but more preferably +/−2%. The pulse duration is preferably adjustable in increments of a single microsecond, though a coarser adjustment such as 10's of microseconds may be provided. A preferred stimulation frequency is in the range of about 0-500 Hz, and more preferably in a range of 1-200 Hz, +/−1-30%, but more preferably +/−1%.
Preferred electrical safety features include single-fault condition safety conditions that are generally standard to neurostimulation systems, but may also include improved, reduced moisture ingress resistance, which allows the external stimulator to be worn at all times, even during a shower, for example, and yet remain safe and reliable.
Preferred physical characteristics include relatively small size and mass for an external electrical stimulator. Preferred dimensions of the stimulator housing are about 3.6 centimeters×about 5.8 centimeters×about 0.8 centimeters. A preferred mass is about 24 grams.
Regarding operational functionality, an external stimulator according to the present invention is preferably controllable and/or programmable via a wireless interface that may be a radio interface, such as a Bluetooth interface or other RF interface, or an infrared communications interface. Whatever wireless protocol is selected, it is preferred that, upon command to transmit a control signal to the stimulator, such as from a controller manipulated by a patient or clinician, the action may be performed by the stimulator within one second. Wireless programmability and/or control allows for stimulator miniaturization. Stimulator miniaturization allows a low profile housing to enable a user to carry on and perform daily activities with limited concern of interfering with therapy provided by the stimulator, and further allows the user to keep the stimulator out of view, such as under clothing. Also regarding operational functionality, preferred stimulators according to the present invention have an operating life of at least one week at maximum settings used for RLP and PLP with stimulation settings at 5 mA amplitude, 20 microsecond pulse width and 100 Hz frequency. Such preferred operational functionality provides a user with at least one week without the need to recharge or replace a power source of the stimulator. Additionally, as already mentioned an operationally complete battery charge is preferred to occur in less than or equal to two hours of time.
Optimal stimulation of peripheral nerves for pain relief using percutaneous leads is most efficient through the generation and use of a controlled current, biphasic stimulus output with no net direct current (DC) and accurate stimulus parameters with precise programming. This may be accomplished through the use of circuit topologies and components capable of the required precision and stability despite changes in battery voltage, operating temperature, and aging. These requirements are easily achieved with conventional instrumentation design methods; however, these design methods are often at conflict with miniaturization and minimal power consumption (i.e., maximum battery life), which are both key features of a comfortable and easy to maintain external stimulator. To overcome this issue, precision circuit components and topologies may be used to ensure that the required accuracy and precision are achieved. Also, multiple power reduction methods may be used, such as disabling the portions of stimulation circuitry responsible for controlling the stimulus current between stimulus pulses, specifying fast turn-on voltage reference semiconductors, enabling them only shortly before use, and disabling them as soon as their measuring or output function is completed. These power minimization features may be implemented in the embedded software of the stimulator (i.e., in firmware of a microcontroller of the circuit board assembly).
Regarding an aspect of electrical safety, the electrical stimulation circuitry in the external stimulator preferably monitors total current drawn from the stimulus power supply. An excessive load, indicated by a high current draw, on this power supply may be caused by a component failure or a failure of the enclosure to isolate the circuitry from moisture and hazard currents through the compromised enclosure. When a high current or an excessive load is detected, the stimulator and/or power supply are shutdown, preferably within 100 milliseconds, and more preferably within 50 ms. confirming appropriate failsafe response.
Also related to electrical safety, and general reliability, is moisture ingress protection. It is preferable to ensure that the stimulator circuitry not damaged or made unsafe by moisture ingress. The technical challenges of packaging electronics for reliable operation in moist environments have been solved in numerous scientific, military, industrial and commercial applications, but the additional requirements of minimizing size and weight increase the technical burden. To achieve a safe reliable stimulator in a potentially moist environment, it is preferable to 1) eliminate or substantially reduce unnecessary seams in the molded plastic enclosure (e.g., switches, displays, battery access panel); 2) use sealed electrical connectors for the two-channel percutaneous lead receptacle and the snap connectors to the surface return electrode; and 3) provide a mechanism to allow venting the enclosure without providing a path for the ingress of fluids. A preferred stimulator housing is capable of preventing the ingress of water when sprayed from any direction at the housing for 10 minutes with specified flow rates and pressure. Note that the electrical safety function provided by the enclosure is single fault tolerant given the fail-safe stimulation power supply circuitry described above. Additional moisture control mechanisms may be employed such as conformal coating the circuit board and/or using a moisture getter (desiccant) inside the stimulator housing.
Patient comfort may be optimized by a stimulator and/or controller that are as small and light as possible. The stimulator preferably is approximately 3.6×5.8×0.8 cm and about 24 g. One way that such size may be achieved is by employing a button-less stimulator. Rather than having controls on the stimulator, a key-fob like controller containing a display and controls may be used by a patient or clinician to operate and/or program the stimulator, eliminating the size and weight associated with these elements (and increasing its integrity against moisture ingress). Lustran 348 ABS plastic is an exemplary material for the stimulator housing material for an optimal strength to weight ratio, durability and impact resistance, ease of fabrication, and evidence of biocompatibility. Internal rib structures may be incorporated into the device top housing to position and support the rechargeable lithium ion battery, circuit assembly, and recharging coil. The housing preferably has a smooth surface that is tapered at the periphery to minimize the potential for snagging. The top and bottom housing are preferably joined using an ultrasonic welding operation in order to ensure protection against water ingress, which may have the added features of eliminating the presence of thru-holes or lock-tabs frequently used for assembly of plastic housings of prior external stimulators. The size of the circuit assembly is preferably minimized through high-density circuit design and fabrication methods. FIG. 12 shows the internal construction of the stimulator, adapted to fit within a preferred target stimulator size.
Regarding control and/or programmability of the external stimulator, the use of a limited range wireless personal area network (PAN) communications system may be used to the utility of the stimulator because it eliminates the need for the patient to access the stimulator to start, stop, or adjust the intensity of the stimulation. The patient uses a small (i.e., 5.2×3.0×0.8 cm) wireless controller to control the stimulator and retrieve information from the stimulator (e.g., battery charge status, stimulus intensity). The clinician controller, such as a tablet PC, also uses the wireless link to retrieve usage information and to program stimulus settings. Driven by the rapid growth of short range wireless PANs in personal devices (e.g., cell phone head sets, remote controls for televisions, personal fitness and health monitoring devices), a number of micro-power wireless radio chip sets (i.e., integrated circuits specifically designed for short range communications at very low power levels) have become available with software for several low power communications protocols. Various chip sets and/or protocols may be used to implement a wireless telemetry link. The use of readily available chip sets and reference designs may significantly reduce the design effort required and the associated technology risks and ensure a ready source of low cost integrated circuits. Preferred are parameters such as performance levels (communications range (1 m in front of patient with stimulator anywhere on patient), interference recovery (using the standard test methods and limits of the protocol selected), peak and average current consumption (consistent with the selected battery capacity and operating life), and message quality and latency time (i.e., preferably at least 95% of all patient initiated commands axe received and acted on by the stimulator within 1 second).
Using a computer model of stimulator battery current consumption, the battery capacity was estimated for the stimulation circuitry to operate at the maximum optimal levels used to date during clinical trial investigations of peripheral nerve stimulation for post-amputation pain (5 mA, 20 μsec, and 100 Hz on each of the two stimulation channels). With a battery capacity of 100 mA-hours, the stimulator preferably has no need to be recharged more than once every eight days or so. The rechargeable battery may be formed from one or more Lithium Ion Polymer cells, preferably each that has 120 mA-hr or more of capacity, meet the package constraints, and preferably uses less than 25% of the available package volume. A commercially available charging pad compliant with the Wireless Power Consortium standard such as the Energizer® Inductive Charger may be used.
Preferably, the external stimulator with adhesive patch may be comfortable to wear on the body for 24 hours/day. The adhesive patch preferably adheres securely to a skin surface of a human body for at least 24 hours.
The foregoing is considered as illustrative only of the principles of the invention. Furthermore, since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the invention to the exact construction and operation shown and described. While the preferred embodiment has been described, the details may be changed without departing from the invention, which is defined by the claims.
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Systems and methods according to the present invention relate to a novel peripheral nerve stimulation system for the treatment of pain, such as pain that exists after amputation.
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TECHNICAL FIELD
The invention generally relates to electrical switches and more particularly relates to steering column switches of a vehicle.
BACKGROUND OF THE INVENTION
EP-A-0 845 389 discloses a steering column switch with a housing, in which at least one operating lever is mounted to pivot and/or move, for which different types of operating levers with the corresponding contact device can be used during assembly. A mating contact device with a predefined number of switch functions that cooperates with the contact device of the operating lever is arranged in the housing of the steering column switch. The available choice of switch functions is a function of the type of operating lever to be installed and its contact device.
DE-A-43 32 748 also shows a steering column switch with a switch lever mounted to move, at least in one plane relative to the steering column, in a housing, which is in connection with switch elements arranged on a printed-circuit board for its activation. At least one of its switch elements is designed as a light-transmitting or light-receiving element in optical connection with a corresponding optical switch, operable by the switch lever.
DE 44 28 883 C1 discloses a steering column switch with a housing having mounts for single switches. The single switches comprise a switch housing, in which a switch lever is mounted to pivot. Guide elements are molded onto the switch housing for alignment in the correct position and holding in a mounting chamber of the housing. The switch housing also has clip elements for fastening of the switch in the corresponding mounting chambers. The switch is provided with function elements and is equipped with a printed-circuit board that is connected to a central circuit board of the steering column switch.
Steering column switches are also known, whose switches, integrated in a switch lever, are connected by corresponding wiring to a circuit board of the steering column switch, on which the switch lever is mounted in a two-part housing of the steering column switch, whose separation runs in the region of the switch lever. This type of switch lever must have corresponding free space available in its interior, in order to permit passage of the wiring, which requires relatively large dimensioning of the switch lever. Significant assembly expense is required for wiring within the switch lever, as well as from the switch lever to the corresponding circuit board. The steering column switches are pre-mounted together with the corresponding switch lever and then installed in the vehicle, so that a significant risk of damage to the switch lever exists during handling of the steering column switches.
The object of the invention is to devise a steering column switch of the initially mentioned type, which has various applications, in terms of functions, is inexpensive to manufacture and easy to handle during assembly.
The objective is realized according to the invention in that the switch lever is assembled from a foot cooperating with the switch element and a grip piece inserted into the foot.
Because of the two-part design of the switch lever, the switch mechanics of the steering column switch can be made cost effectively in a large number of pieces, regardless of its switching functions. Coordination of the switching functions to the steering column switch, provided with a central printed-circuit board, occurs by means of corresponding programming of the computer system of the vehicle. More specifically, the switch lever (grip piece) is coupled to the foot of the switch lever. Insertion of the grip piece into the foot can occur at the end of assembly of the steering column switch in the vehicle, for which reason the grip piece is only exposed to limited risk of damage during assembly. In addition, the arrangement of a one-part housing for the steering column switch is possible, which need only be provided with a corresponding opening for the grip piece. A visually pleasing effect is achieved with the one-part housing.
In a steering column switch of the initially mentioned type, with at least one additional switch integrated in the switch lever of the single switch, the objective according to the invention is realized in that the switch lever is assembled from a foot cooperating with the switch element and a grip piece inserted into the foot, wherein the end of the grip piece inserted into the foot has contact traces, which transmit the functions of the switch to the terminal contacts via a contact unit.
Because of these advantages, prefabrication of the switch mechanism of the steering column switch, together with the contact unit and the foot of the switch lever, is ensured in a relatively large number of pieces. Different grip pieces, insertable into the foot of the switch lever, each can be equipped with at least one arbitrarily designed switch. For example, a switch for interval functions of the windshield wiper is connected to the grip piece for a windshield wiper/washer switch. In addition or as an alternative, a switch to control a computer system is provided, in which the switch or switches cooperate with the contact traces integrated in the grip piece, and the electrical connection to the terminal contacts for the switch or switches is achieved by simple insertion of the grip piece into the foot over the contact unit.
In order to achieve rapid, permanent assembly, and also several degrees of freedom of the switch lever, the foot of the switch lever is preferably mounted as a swivel joint and provided with two opposite clip arms that engage in corresponding clip openings of the grip piece.
For simple swivel mounting of the switch lever and to achieve switching functions, the foot of the switch lever is expediently mounted to pivot in an opening of an arm of an L-shaped rotary switch element, where the rotary switch element is inserted into an arm of a Z-shaped support fixed to the housing. Arrangement of additional mounts with a switch lever therefore is unnecessary, since corresponding support sites are integrated in the rotary switch element.
The arm of the rotary switch element running parallel to the connector of the support is preferably provided with a terminating locating curved element that cooperates with a spring-loaded locating sleeve in the arm of the support facing the end of the rotary switch element. Thus, an initial position of the swivel-mounted switch lever is defined and a desired switching sensation is created during its operation. The arm of the support carrying the locating sleeve for the rotary switching element expediently comprises an additional spring-loaded locating sleeve that cooperates with a locating curve in the free end of the foot. Thus, the switch lever is held in a certain initial position. Pivoting of the switch lever from the initial position occurs against the spring force, to which the locating sleeve is exposed, so that a corresponding switch sensation is produced.
According to an advantageous modification of the invention, the arm of the support carrying the locating sleeves supports a sliding switch element, acted upon by the foot of the switch lever. The support therefore represents an essential component to accommodate the sliding switch element, as well as the rotary switch element, and forms a separate assembly with the connected switch element, which is simple to install and replace.
The switch contacts of the rotary switch element and the sliding switch element are expediently designed as contact springs and act on corresponding contact traces of the support that are connected to the terminal contacts. The contact springs are components of a punched grid inserted into the rotary switch element and the sliding switch element, which is simultaneously injection molded during production of the switch elements in the injection molding process, so that an additional assembly step can be eliminated. In order to avoid damage to the grip piece and the foot during assembly, the grip piece has a centering shoulder on the end inserted into the foot, which engages in a corresponding centering hole of the foot.
According to an advantageous embodiment of the concept of the invention, the contact traces of the grip piece are exposed regions of a punched grid integrated in the grip piece connected to the switch. Relatively costly wiring of the switch with the contact traces is therefore eliminated and a number of switching functions to be transmitted are possible by appropriate coding of the punched grid introduced to the grip piece.
In order to produce a cost-effective contact unit having relatively high functional safety and that ensures tolerance and movement compensation, the contact unit preferably has contact arms designed as leaf springs, where one end of each contact arm is connected to the corresponding contact trace of the punched grid of the grip piece and the other end of the contact arm is connected to a corresponding contact trace of the support. The contact arms of the contact unit that act on the contact traces of the support extend through a recess of the rotary switch element mounted in the support.
According to a modification of the invention, the contact unit has limiting arms on the side that extend essentially parallel to the contact arms. Each arm of the contact unit has a cylindrical shoulder on the end, where the opposite shoulders on one end of the contact unit engage in a corresponding recess of the rotary switch element and the shoulders on the other end of the contact unit engage in a corresponding recess of the foot. The contact unit therefore represents a compact assembly that can be fixed relatively simply between the rotary switch unit and the foot.
The recesses in the rotary switch element, in which the shoulders of the arm of the contact unit engage, are, advantageously, cylindrical holes. The recesses in the foot of the switch lever, into which the shoulders of the arm of the contact unit engage, are also elongated holes. In this way, a compensatory movement of the contact unit is guaranteed during the pivoting of the switch lever to act on the sliding switch element. The sliding of the contact arms of the contact unit on the corresponding contact traces of the grip piece and the contact traces of the support effects the self-cleaning of the support.
It is understood that the aforementioned features and those still to be explained can be used not only in the stated combination, but also in other combinations without departing from the scope of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows an exploded view of a steering column switch according to the invention;
FIG. 2 shows an enlarged view of a detail II according to FIG. 1 ;
FIG. 3 shows a view in the direction of arrow III according to FIG. 2 ;
FIG. 4 shows an exploded view of a detail II according to FIG. 1 ; and
FIG. 5 shows another exploded view of a detail II according to FIG. 1 .
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Now referring to FIG. 1 , the steering column switch comprises a housing 1 that consists of a cover 2 and a support module 3 , and an individual switch 6 designed as a blinker switch 4 and a wiper/washer switch 5 , as well as a circuit board 7 . On the side facing the steering wheel (not shown), a transfer element 8 to control the functions of an airbag in cover 2 of housing 1 is inserted, which is connected to circuit board 7 . The cover 2 is provided with clip openings 9 on its periphery that engage with corresponding clip arms 10 of support module 3 . The support module 3 also contains a mount 11 for an ignition key and a fastening device 12 to attach the steering column switch to a jacket tube of a steering column of the vehicle.
The blinker switch 4 and the wiper/washer switch 5 are designed identically, and each consists essentially of a support 13 with terminal contacts 14 that engage in corresponding holes 15 of circuit board 7 , a rotary 16 and sliding switch element 17 and a swivel-mounted switch lever 18 . The switch lever 18 is designed in two parts and consists of a foot 19 and a grip piece 20 .
The support 13 is designed essentially Z-shaped and holds, in the arm 21 facing switch lever 18 , two superimposed, spring-loaded, locating sleeves 22 , 23 in the center, which are components of the locating elements 24 of the corresponding single switch 6 . For this purpose, a dome 25 is molded onto the arm 21 of support 13 , into which corresponding compression springs 26 are inserted that act on locating sleeves 22 , 23 . The arm 21 also has opposite grooves 27 to guide the sliding switch element 17 , as well as contact traces 61 .
The second arm 28 of support 13 , designed as a centering shoulder, is fixed in the support module 3 of housing 1 in a corresponding recess 29 . The connector 30 that connects arms 21 , 28 comprises a mounting hole 31 inserted into the centering shoulder in the region of arm 28 to support the rotary switch element 16 .
The essentially L-shaped rotary switch element 16 has switch contacts 33 assigned to the long arm 32 , which are designed as contact springs and cooperate with contract traces 34 in connector 30 of support 13 . The switch contacts 33 extend into a recess 35 of arm 32 and are provided on their free end with a V-shaped angle 36 , the point of which acts on the corresponding contact trace 34 . An additional recess 37 is provided in arm 32 of the rotary switch element 16 , parallel to the recess 35 for the switch contacts 33 . A locating curve 60 is introduced to the end of the arm 32 of rotary switch element 16 , which cooperates with the locating sleeve 23 of support 13 .
The short arm 38 of the rotary switch element 16 contains a bearing pin 40 , formed on the ends and on the opposite side, in which the end bearing pin 40 engages in a corresponding bearing hole in cover 2 of housing 1 and the opposite bearing pin 40 engages in the bearing hole 31 of support 13 . An opening 39 is formed in the short arm 38 , into which the foot 19 of switch lever 18 is inserted to pivot. For this purpose, foot 19 has axial pins 41 on the side that are mounted in corresponding holes 42 of arm 38 .
The foot 19 of switch lever 18 also contains a V-shaped, locating curve 43 on its free end facing arm 21 of support 13 , which cooperates with the upper locating sleeve 22 , as well as an operating shoulder 44 that limits the locating curve 43 that acts on the sliding switch element 17 . By cooperation of the locating sleeve 22 with the locating curve 43 of switch lever 18 , it is held in a center position, so that the sliding switch element 17 assumes an equivalent position. The switch contacts 59 that cooperate with the contact traces 61 in arm 21 of support 13 are connected to sliding switch element 17 .
A blind hole 46 with a rectangular cross section to accommodate the grip piece 20 is inserted in the longitudinal axis 45 of foot 19 of switch lever 18 . The side walls of the blind hole 46 are formed in areas by two opposite clip arms 47 that engage in corresponding clip openings 48 of grip piece 20 .
The grip piece 20 of the single switch 6 , designed as a blinker switch 4 , is provided with an additional switch 49 that serves as a push-button to control a computer system (not shown). For electrical contact transmission, a punched grid is integrated with the switch 49 in the grip piece 20 , having exposed contact traces 50 in the end region inserted into foot 19 . In the region of contact traces 50 , the foot 19 has a perforation 58 , penetrated by contact arms 51 of a contact unit 52 , in which the contact arms 51 , on the one hand, are connected to contact traces 50 of the punched grid of grip piece 20 and, on the other hand, pass through the recess 37 of the rotary switch element 16 , and are connected to corresponding contact traces 53 of support 13 .
Arms 54 are arranged parallel to contact arms 51 of the contact unit 52 for fastening of the contact unit on the foot 19 and on the rotary switch element 16 . For this purpose, each arm 54 has a cylindrical shoulder 55 on the end, in which the opposite shoulders 55 on one end of the contact unit 52 engage in corresponding holes 56 of the rotary switch element 16 , and the shoulders 55 on the other end of the contact unit 52 engage in corresponding elongated holes 57 of foot 19 . The required freedom of movement of the switch lever 18 is guaranteed by this mounting of the contact unit 52 with simultaneously ensured transfer of the functions of switch 49 .
After switch 49 is acted upon in any position of the switch lever 18 of the corresponding single switch 6 , the transfer of the switch signal occurs via punched grids integrated in the grip piece 20 and its exposed contact traces 50 to one end of the contact arms 51 of the contact unit 52 . The connection to the contact traces 53 of support 13 , and thus to the terminal contacts 14 coupled to the contact traces 53 , is produced via the contact arms 51 . The terminal contacts 14 again contact the circuit board 7 connected to the electrical system. To transmit complex switching functions or for assignment of switching functions to the corresponding single switch 6 , the punched grid of grip piece 20 can be coded, in which transmission occurs according to the coded signals.
LIST OF REFERENCE NUMBERS
1 Housing
2 Cover
3 Support module
4 Blinker switch
5 Wiper/washer switch
6 Single switch
7 Circuit board
8 Transmission element
9 Clip opening
10 Clip arm
11 Mount
12 Fastening device
13 Support
14 Terminal contact
15 Hole
16 Rotary switch element
17 Sliding switch element
18 Switch lever
19 Foot
20 Grip piece
21 Arm
22 Locating sleeve
23 Locating sleeve
24 Locating elements
25 Dome
26 Compression springs
27 Groove
28 Arm
29 Recess
30 Connector
31 Bearing hole
32 Arm
33 Switch contact
34 Contact trace
35 Recess
36 Angle
37 Recess
38 Arm
39 Opening
40 Bearing pin
41 Axial pin
42 Hole
43 Locating curve
44 Operating shoulder
45 Longitudinal axis
46 Blind hole
47 Clip arm
48 Clip opening
49 Switch
50 Contact trace
51 Contact arm
52 Contact unit
53 Contact trace
54 Arm
55 Shoulder
56 Hole
57 Elongated hole
58 Perforation
59 Switch contact
60 Locating curve
61 Contact trace
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A steering column switch having a switch element and a switch lever, wherein the switch lever is designed from first and second modules. Because of the modular design, different grip pieces can be accommodated by the same switch element.
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STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
[0001] N/A
RELATED APPLICATIONS
[0002] N/A
BACKGROUND OF THE DISCLOSURE
[0003] 1. Field of the Disclosure
[0004] The present disclosure relates to feminine hygiene kits. More particularly, the invention relates to improved feminine hygiene kits designed for females during or for unexpected menstruation. These kits provide underwear, feminine wipes and a feminine sanitary towel.
[0005] 2. Discussion of the Background
[0006] Fertile female humans and other female primates goes through a process called menstrual cycle. Menstrual cycle is a cycle that occurs in the uterus and ovary for the purpose of sexual reproduction. One of the steps during the menstrual cycle is call menstruation. Menstruation is a periodic discharge of blood and some mucosal tissue from the uterus and vagina. Usually during this period the females wears a feminine sanitary towel or any absorbent item outside the vaginal area in order to absorb the blood and some mucosal tissue without damaging the female underwear.
[0007] However females, more often younger females cannot predict the exact date when they are going to have their periods. Dealing with an unexpected menstruation can be tough and uncomfortable. Sometime the period even start during typically daily events. Mainly during the unexpected period underwear is damaged by blood. Therefore there is a need to provide a kit, easy to carry, that offers a greater degree of discretion, convenience, and portability to females.
SUMMARY
[0008] The present invention relates to the packaging and dispensing of a female care product, and in particular to a feminine hygiene kit that offers a greater degree of discretion, convenience, and portability to consumers during the event of unexpected periods.
[0009] In general, the present disclosure overcomes the disadvantages and shortcomings of prior art by disclosing feminine hygiene kit comprising at least underwear, at least a feminine wipes and at least a feminine sanitary towel.
[0010] In one embodiment, the feminine hygiene kit includes a shaped base, compacted underwear, a feminine wipe and at least a feminine sanitary towel in an individual compacted sealed pouch.
[0011] Another object of this disclosure is to provide a feminine hygiene kit with basic item for the event of unexpected periods.
[0012] Another object of this disclosure is to provide a compact feminine hygiene kit easy to carry.
[0013] Still another object of the present disclosure is to provide a light weight feminine hygiene kit with basic items for the event of unexpected periods.
[0014] Yet another object of the present disclosure is to provide a feminine hygiene kit shaped for convenient handling of the product.
[0015] The disclosure itself, both as to its configuration and its mode of operation will be best understood, and additional objects and advantages thereof will become apparent, by the following detailed description of a preferred embodiment taken in conjunction with the accompanying drawings.
[0016] The Applicant hereby asserts, that the disclosure of the present application may include more than one invention, and, in the event that there is more than one invention, that these inventions may be patentable and non-obvious one with respect to the other.
[0017] Further, the purpose of the accompanying abstract is to enable the U.S. Patent and Trademark Office and the public generally, and especially the scientists, engineers, and practitioners in the art who are not familiar with patent or legal terms or phraseology, to determine quickly from a cursory inspection the nature and essence of the technical disclosure of the application. The abstract is neither intended to define the disclosure of the application, which is measured by the claims, nor is it intended to be limiting as to the scope of the disclosure in any way.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] The accompanying drawings, which are incorporated herein, constitute part of the specification and illustrate the preferred embodiment of the disclosure.
[0019] FIG. 1 shows a general structure in accordance with the principles of the present disclosure.
[0020] FIG. 2 shows a general structure of the feminine hygiene kit in accordance with the principles of the present disclosure.
[0021] FIG. 3 shows a general structure of the compression cycle for the underwear in accordance with the principles of the present disclosure.
[0022] FIG. 4 shows a flowchart exemplary embodiment of the compression cycle for the feminine sanitary towel in accordance with the principles of the present disclosure.
[0023] FIGS. 5A-5B shows a first exemplary embodiment of the underwear, feminine sanitary towel and feminine wipe assembly in accordance with the principles of the present disclosure.
[0024] FIG. 6 shows a first exemplary embodiment of the underwear, feminine sanitary towel, feminine wipe and shaped base in accordance with the principles of the present disclosure.
[0025] FIG. 7 shows a first exemplary embodiment of the underwear, feminine sanitary towel, feminine wipe and shaped base in accordance with the principles of the present disclosure.
[0026] FIG. 8 shows a first exemplary embodiment of the compacted underwear, compacted feminine sanitary towel, feminine wipe and shaped base embedded in a bag of transparent and shrinkage characteristics in accordance with the principles of the present disclosure.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0027] FIG. 1 shows a general structure in accordance with the principles of the present disclosure. The feminine hygiene kit 1 comprises at least a shaped base 5 , at least underwear 4 , at least sanitary towel 3 , more particularly a feminine sanitary towel, and at least wipe 2 .
[0028] Further the underwear 4 , sanitary towel 3 and the wipe 2 are positioned on top of the rigid base 5 and emended in a transparent material 6 with shrinkage characteristics, as shown in FIG. 2 .
[0029] As discussed above, the object of the present invention is to provide a compact light weigh feminine hygiene kit 1 comprising the basic items for the event of unexpected periods. The basic items comprise, as mentioned before, an underwear, a sanitary towel and a feminine wipe. The underwear, more particularly the female underwear comprises a waistband, such as an elastic waistband, a crotch panel to cover the genital area and a pair of leg openings which. Different materials can be used, however compactable breathable material, such as cotton, is preferred. The sanitary towel is an absorbent item preferably made of a compactable absorbent material, such as cotton and hemp. The feminine wipes are cleansing cloths meant to clean the female genital area. The feminine wipe may include antibacterial properties, fragrance or any type of substance or medicine direct to female genital area.
[0030] FIG. 3 shows a general structure of the compression cycle for the underwear. The process of compression comprises a compressing machine, wherein said compressing machine comprises a mold 8 and a pressing arm 7 . The mold 8 is placed directly below the pressing arm 7 . The mold 8 is fixed to a surface in such way it does not move during the pressing process. Further after ensuring the mold is placed and firm at the surface, the female underwear 4 is placed inside the mold at a shaped cavity 80 . In the instant case the cavity 80 is configured to have the shape similar to the shaped base 5 . Before pressing the underwear material is well distributed in the mold 8 inside cavity 80 . Then we placed the compressing plate 70 above the underwear which is inside the mold's cavity 80 . The compressing plate 70 is configured to travel inside the cavity in such way that compresses the underwear between the compressing plate 70 and the cavity 80 bottom surface. The underwear 4 is compressed for several seconds at maximum pressure. After a first compression cycle the compression plate 70 is removed.
[0031] After removing the compression plate 70 the sanitary towel 3 , as shown in FIG. 4 , is placed inside cavity 80 . The sanitary towel 3 is folded to fit inside cavity 80 . It is important to understand that the compacted underwear still inside cavity 80 while the sanitary towel 3 is positioned on top inside the cavity 80 . Once the sanitary towel 3 is well placed inside the cavity the sanitary towel 3 is compressed. In the instant case, the sanitary towel 3 is compressed with less pressure for several seconds when compared to the first cycle. One of the reasons is to avoid damages to the pre-fabricated sanitary towel 3 . After the compression of the underwear 4 in combination with the sanitary towel 3 is performed the second cycle is completed. When the second cycle of compression is finished the compressed material, including the underwear 4 in combination with the sanitary towel 3 , is removed from the mold 8 for the packing process.
[0032] FIGS. 5A-5B shows a first exemplary embodiment of the underwear, feminine sanitary towel and feminine wipe assembly as part of packing process in accordance with the principles of the present disclosure. The feminine wipe 2 is placed on top or at the bottom of the compacted underwear 4 and compacted sanitary towel 3 . The assembly of the compacted underwear 4 and compacted sanitary towel 3 and feminine wipe 2 is the result of the basic items.
[0033] Further the basic items are positioned over the shaped base 5 , as shown in FIG. 6 . As mentioned the compacted underwear and compacted sanitary towel 3 is configured to comprise a shape similar or smaller to shaped base 5 perimeters in such way that do not exceed the shaped base perimeter once it is located on top of the shaped base 5 . For example, in the instant case the compacted underwear 4 and compacted sanitary towel 3 comprises a square shape similar to shaped base 5 not exceeding the shaped base perimeters once each piece is located on top of the shaped base 5 . The shaped base 5 comprises a rigid body providing stability to the feminine hygiene kit 1 .
[0034] After the basic items 2 , 3 , 4 and shaped base 5 are aligned and placed together said assembly is covered with a heat-shrinkable material, as shown in FIG. 7 . The heat-shrinkable material 6 is preferred to be transparent and with shrinkable characteristics when heat is applied. In the instant case once the assembly is covered with the heat-shrinkable material 6 heat is applied in order to seal the package including the basic items 2 , 3 , 4 and shaped base 5 . The heat may be applied using an oven or a heat blower gun or any other device of providing heat regulation capability.
[0035] As mentioned the shrinkable material 6 is preferred to be transparent in order to use the shaped base 5 as a promotional means. A display 50 may be included as part of the back part of the shaped base 5 , which is the part not covered by the basic items, as shown in FIG. 8 . Several designs or any visual form of communication for marketing may be located at the display 50 .
[0036] The disclosure is not limited to the precise configuration described above. While the disclosure has been described as having a preferred design, it is understood that many changes, modifications, variations and other uses and applications of the subject disclosure will, however, become apparent to those skilled in the art without materially departing from the novel teachings and advantages of this disclosure after considering this specification together with the accompanying drawings. Accordingly, all such changes, modifications, variations and other uses and applications which do not depart from the spirit and scope of the disclosure are deemed to be covered by this disclosure as defined in the following claims and their legal equivalents. In the claims, means-plus-function clauses, if any, are intended to cover the structures described herein as performing the recited function and not only structural equivalents but also equivalent structures.
[0037] All of the patents, patent applications, and publications recited herein, and in the Declaration attached hereto, if any, are hereby incorporated by reference as if set forth in their entirety herein. All, or substantially all, the components disclosed in such patents may be used in the embodiments of the present disclosure, as well as equivalents thereof. The details in the patents, patent applications, and publications incorporated by reference herein may be considered to be incorporable at applicant's option, into the claims during prosecution as further limitations in the claims to patently distinguish any amended claims from any applied prior art.
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A compacted feminine hygiene kit comprising basic items such as at least underwear, at least a feminine wipes and at least a feminine sanitary towel. Further the compacted feminine hygiene kit comprises a shaped base for keeping the feminine hygiene kit assembly rigid body while providing a kit, easy to carry, that offers a greater degree of discretion, convenience, and portability to females.
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RELATED APPLICATIONS
This application is a continuation of U.S. patent application Ser. No. 09/698,537, filed Oct. 26, 2000, now issued as U.S. Pat. No. 6,521,248, which claims the benefit of priority of prior U.S. provisional application 60/161,546, filed Oct. 26, 1999. This aforementioned application is explicitly incorporated herein by reference in its entirety and for all purposes.
FIELD OF THE INVENTION
The invention relates generally to micro-cluster liquids and methods of making and using them. The present invention provides a process of making micro-cluster liquid and methods of use thereof.
BACKGROUND OF THE INVENTION
Water is composed of individual H 2 O molecules that may bond with each other through hydrogen bonding to form clusters that have been characterized as five species: un-bonded molecules, tetrahedral hydrogen bonded molecules comprised of five (5) H 2 O molecules in a quasi-tetrahedral arrangement and surface connected molecules connected to the clusters by 1, 2 or 3 hydrogen bonds, (U.S. Pat. No. 5,711,950 Lorenzen; Lee H.). These clusters can then form larger arrays consisting of varying amounts of these micro-cluster molecules with weak long distance van der Waals attraction forces holding the arrays together by one or more of such forces as; (1) dipole-dipole interaction, i.e., electrostatic attraction between two molecules with permanent dipole moments; (2) dipole-induced dipole interactions in which the dipole of one molecule polarizes a neighboring molecule; and (3) dispersion forces arising because of small instantaneous dipoles in atoms. Under normal conditions the tetrahedral micro-clusters are unstable and reform into larger arrays from agitation, which impart London Forces to overcome the van der Waals repulsion forces. Dispersive forces arise from the relative position and motion of two water molecules when these molecules approach one another and results in a distortion of their individual envelopes of intra-atomic molecular orbital configurations. Each molecule resists this distortion resulting in an increased force opposing the continued distortion, until a point of proximity is reached where London Inductive Forces come into effect. If the velocities of these molecules are sufficiently high enough to allow them to approach one another at a distance equal to van der Waals radii, the water molecules combine.
There is currently a need for a process whereby large molecular arrays of liquids can be advantageously fractionated. Furthermore, there is a desire for smaller molecular (e.g., micro-clusters) of water for consumption, medicinal and chemical processes.
SUMMARY OF THE INVENTION
The inventors have discovered that liquids, which form large molecular arrays, such as through various electrostatic and van der Waal forces (e.g., water), can be disrupted through cavitation into fractionated or micro-cluster molecules (e.g., theoretical tetrahedral micro-clusters of water). The inventors have further discovered a method for stabilizing newly created micro-clusters of water by utilizing van der Waals repulsion forces. The method involves cooling the micro-cluster water to a desired density, wherein the micro-cluster water may then be oxygenated. The micro-cluster water is bottled while still cold. In addition, by overfilling the bottle and capping while the micro-cluster oxygenated water is dense (i.e., cold), the London forces are slowed down by reducing the agitation which might occur in a partially filled bottle while providing a partial pressure to the dissolved gases (e.g., oxygen) in solution thereby stabilizing the micro-clusters for about 6 to 9 months when stored at 40 to 70 degrees Fahrenheit.
The present invention provides a process for producing a micro-cluster liquid, such as water, comprising subjecting a liquid to cavitation such that dissolved entrained gases in the liquid form a plurality of cavitation bubbles; and subjecting the liquid containing the plurality of cavitation bubbles to a reduced pressure, wherein the reduction in pressure causes breakage of large liquid molecule matrices into smaller liquid molecule matrices. In another embodiment the liquid is substantially free of minerals and can be water which may also be substantially free of minerals. The embodiment provides for a process which is repeated until the water reaches about 140° F. (about 60° C.) The cavitation can be provided by subjecting the liquid to a first pressure followed by a rapid depressurization to a second pressure to form cavitation bubbles. The pressurization can be provided by a pump. In one embodiment the first pressure is about 55 psig to more than 120 psig. In another embodiment the second pressure is about atmospheric pressure. The embodiment can be carried out such that the pressure change caused the plurality of cavitation bubbles to implode or explode. The pressure change may be performed to create a plasma which dissociates the local atoms and reforms the atom at a different bond angle and strength. In another embodiment the liquid is cooled to about 4° C. to 15° C. A further embodiment comprises providing gas to the micro-cluster liquid, such as where the gas is oxygen. In a further embodiment the oxygen is provided for about 5 to about 15 minutes.
In a further embodiment, the invention provides a process for producing a micro-cluster liquid, comprising subjecting a liquid to a pressure sufficient to pressurize the liquid; emitting the pressurized liquid such that a continuous stream of liquid is created; subjecting the continuous stream of liquid to a multiple rotational vortex having a partial vacuum pressure such that dissolved and entrained gases in the liquid form a plurality of cavitation bubbles; and subjecting the liquid containing the plurality of cavitation bubbles to a reduced pressure, wherein the plurality of cavitation bubbles implode or explode causing shockwaves that break large liquid molecule matrices into smaller liquid molecule matrices. In a further embodiment the liquid is substantially free of minerals and in an additional embodiment the liquid is water, preferably substantially free of minerals. The invention provides that the process can be repeated until the water reaches about 140° F. (about 60° C.). In another embodiment the cavitation is provided by subjecting the liquid to a first pressure followed by a rapid depressurization to a second pressure to form cavitation bubbles. Further the invention provides that the pressurization is provided by a pump. In a further embodiment the first pressure is about 55 psig to more than 120 psig and, in another embodiment the second pressure is about atmospheric pressure, including embodiments where the second pressure is less than 5 psig. The invention also provides for micro-cluster liquid where the pressure change causes the plurality of cavitation bubbles to implode or explode. In a further embodiment, the pressure change creates a plasma which dissociates the local atoms and reforms the atoms at a different bond angle and strength. The invention also provides a process where the liquid is cooled to about 4° C. to 15° C. In another embodiment, the invention provides subjecting a gas to the micro-cluster liquid. Preferably, the gas is oxygen, especially oxygen administered for about 5 to 15 minutes and more preferably at pressure from about 15 to 20 psig.
The present invention also provides for a composition comprising a micro-cluster water produced according to the procedures noted above.
Still another aspect of the invention is a micro-cluster water which has any or all of the properties of a conductivity of about 3.0 to 4.0 μmhos/cm, a FTIR spectrophotometric pattern with a major sharp feature at about 2650 wave numbers, a vapor pressure between about 40° C. and 70° C. as determined by thermogravimetric analysis, and an 17 O NMR peak shift of at least about +30 Hertz, preferably at least about +40 Hertz relative to reverse osmosis water.
The present invention further provides for the use of the micro-cluster water of the invention for such purposes as modulating cellular performance and lowering free radical levels in cells by contacting the cell with the micro-cluster water.
The present invention further provides a delivery system comprising a micro-cluster water (e.g., an oxygenated microcluster water) and an agent, such as a nutritional agent, a medication, and the like.
Further, the micro-cluster water of the invention can be used to remove stains from fabrics by contacting the fabric with the micro-cluster water.
The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
All publications, patents and patent applications cited herein are hereby expressly incorporated by reference for all purposes.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a water molecule and the resulting net dipole moment.
FIG. 2 shows a large array of water molecules.
FIG. 3 shows a micro-cluster of water having 5 water molecules forming a tetrahedral shape. FIG. 4 shows an example of a system useful in creating cavitation in a liquid, including a cavitation device with four volutes.
FIG. 5 shows FTIR spectra for RO water ( FIG. 5( a )) and processed micro-cluster water ( FIG. 5( b )).
FIG. 6 shows TGA plots for RO water and oxygenated micro-cluster water.
FIG. 7 shows NMR spectra for RO water ( FIG. 7( a )), micro-cluster water without oxygenation ( FIG. 7( b )) and micro-cluster water with oxygenation ( FIG. 7( c )).
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Liquids, including for example, alcohols, water, fuels and combinations thereof, are comprised of atoms and molecules having complex molecular arrangements. Many of these arrangements result in the formation of large molecular arrays of covalently bonded atoms having non-covalent interactions with adjacent molecules, which in turn interact via additional non-covalent interactions with yet other molecules. These large arrays, although stable, are not ideal for many applications due to their size. Accordingly it is desirable to create and provide liquids having smaller arrays by reducing the number of non-covalent interactions. These smaller molecules are better able to penetrate and react in biological and chemical systems. In addition, the smaller molecular arrays provide novel characteristics that are desirable.
As used herein, “covalent bonds” means bonds that result when atoms share electrons. The term “non-covalent bonds” or “non-covalent interactions” means bonds or interactions wherein electrons are not shared between atoms. Such non-covalent interactions include, for example, ionic (or electrovalent) bonds, formed by the transfer of one or more electrons from one atom to another to create ions, interactions resulting from dipole moments, hydrogen bonding, and van der Waals forces. Van der Waals forces are weak forces that act between non-polar molecules or between parts of the same molecule, thus bringing two groups together due to a temporary unsymmetrical distribution of electrons in one group, which induces an opposite polarity in the other. When the groups are brought closer than their van der Waals radii, the force between them becomes repulsive because their electron clouds begin to interpenetrate each other.
Numerous liquids are applicable to the techniques described herein. Such liquids include water, alcohols, petroleum and fuels. Liquids, such as water, are molecules comprising one or more basic elements or atoms (e.g., hydrogen and oxygen). The interaction of the atoms through covalent bonds and molecular charges form molecules. A molecule of water has an angular or bent geometry. The H—O—H bond angle in a molecule of water is about 104.5° to 105°. The net dipole moment of a molecule of water is depicted in FIG. 1 . This dipole moment creates electrostatic forces that allow for the attraction of other molecules of water. Recent studies by Pugliano et al., ( Science, 257: 1937, 1992) have suggested the relationship and complex interactions of water molecules. These studies have revealed that hydrogen bonding and oxygen—oxygen interactions play a major role in creating large clusters of water molecules. Substantially purified water forms complex structures comprising multiple water molecules each interacting with an adjacent water molecule (as depicted in FIG. 2 ) to form large arrays. These large arrays are formed based upon, for example, non-covalent interactions such as hydrogen bond formation and as a result of the dipole moment of the molecule. Although highly stable, these large molecules have been suggested to be detrimental in various chemical and biological reactions. Accordingly, in one embodiment, the present invention provides a method of forming fractionized or micro-cluster water as depicted in FIG. 3 having as few as about 5 molecules of water.
The present invention provides small micro-cluster liquids (e.g., micro-cluster water molecules) a method for manufacturing fractionized or micro-cluster water and methods of use in the treatment of various biological conditions.
Accordingly, the present invention provides a method for manufacturing fractionized or micro-cluster liquids (e.g., water) comprising pressurizing a starting liquid to a first pressure followed by rapid depressurization to a second pressure to create a partial vacuum pressure that results in release of entrained gases and the formation of cavitation bubbles. The thermo-physical reactions provided by the implosion and explosion of the cavitation bubbles results in an increase in heat and the breaking of non-covalent interactions holding large liquid arrays together. This process can be repeated until a desired physical-chemical trait of the fractionized liquid is obtained. Where the liquid is water, the process is repeated until the water temperature reaches about 140° F. (about 60° C.). The resulting smaller or fractionized liquid is cooled under conditions that prevent reformation of the large arrays. As used herein, “water” or “a starting water” includes tap water, natural mineral water, and processed water such as purified water.
Any number of techniques known to those of skill in the art can be used to create cavitation in a liquid so long as the cavitating source is suitable to generate sufficient energy to break the large arrays. The acoustical energy produced by the cavitation provides energy to break the large liquid arrays into smaller liquid clusters. For example, the use of acoustical transducers may be utilized to provide the required cavitation source. In addition, cavitation can be induced by forcing the liquid through a tube having a constriction in its length to generate a high pressure before the constriction, which is rapidly depressurized following the constriction. Another example, includes forcing a liquid through a pump in reverse direction through a rotational volute.
In one embodiment, water to be fractionized is pressurized into a rotational volute to create a vortex that reaches partial vacuum pressures releasing entrained gases as cavitation bubbles when the rotational vortex exits through a tapered nozzle at or close to atmospheric pressure. This sudden pressurization and decompression causes implosion and explosion of cavitation bubbles that create acoustical energy shockwaves. These shockwaves break the covalent and non-covalent bonds on large liquid arrays, breaking the weak array bonds, and form micro-cluster or fractiomzed liquid consisting of, for example, about five (5) H 2 O molecules in a quasi tetrahedral arrangement (as depicted in FIG. 3 ), and impart an electron charge to the micro-cluster liquid, thus producing electrolyte properties in the liquid. The micro-cluster liquid is recycled until the desired number of micro-cluster liquid molecules are formed to reach a given surface tension and electron charge, as determined by the temperature rise of the fluid over time as cavitation bubbles impart kinetic heat to the processed liquid. Once the desired surface tension and electron charge are reached, the micro-cluster liquid is cooled until the liquid density increases. The desired surface tension and electron charge can be measured in any number of ways but are preferably detected by temperature. Once the liquid reaches a desired density, typically at about 4° to 15° C., a gas, such as, for example, molecular oxygen is introduced for a sufficient amount of time to attain the desired quantity of oxygen in the micro-cluster liquid. The micro-cluster liquid is then aliquoted into a container or bottle, preferably filled to maximum capacity and capped while the oxygenated micro-cluster water is still cool, thus applying a partial pressure to the gassed micro-cluster liquid as the temperature reaches room temperature. This enables larger quantities of dissolved gas to be maintained in solution due to increased partial pressure on the bottle's contents.
The present invention provides a method for making a micro-cluster or fractionized water or liquid, for ease of explanation water will be used as the liquid being described, however any type liquid may be substituted for water. A starting water such as, for example, purified or distilled water is preferably used as a base material since it is relatively free of mineral content. The water is then placed into a food grade stainless steel tank for processing. By subjecting the starting water to a pump capable of supplying a continuous pressure of between about 55 and 120 psig or higher a continuous stream of water is created. This stream of water is then applied to a suitable device (see for example FIG. 4 ) capable of establishing a multiple rotational vortex reaching partial vacuum pressures of about 27″ Hg, thereby reaching the vapor pressure of dissolved entrained gases in the water. These gases form cavitation bubbles that travel down multiple acceleration tubes exiting into a common chamber at or close to atmospheric pressure. The resultant shock waves produced by the imploding and exploding cavitation bubbles breaks the large water arrays into smaller water molecules by repeated re-circulation of the water. The recycling of the water creates increases results in an increase in temperature of the water. The heat produced by the imploding and exploding cavitation bubbles release energy as seen in sonoluminescence, in which the temperature of sonoluminance bubbles are estimated to range from 10 to 100 eV or 2,042.033 degrees Fahrenheit at 19,743,336 atmospheres. However the heat created is at a sub micron size and is rapidly absorbed by the surrounding water imparting its kinetic energy. The inventors have determined that the breaking of these large arrays into smaller water molecules can be manipulated through a sinusoidal wave utilizing cavitation, and by monitoring the rise in temperature one can adjust the osmotic pressure and surface tension of the water under treatment. The inventors have determined that the ideal temperature for oxygenated micro-cluster water (Penta-hydrate™) is about 140 degrees F. (about 60° C.). This can be accomplished by using four opposing vortex volutes with a 6-degree acceleration tube exiting into a common chamber at or close to atmospheric pressure, less than 5 pounds backpressure.
As mentioned above, the inventors have also discovered that liquids undergo a sinusoidal fluctuation in heat/temperature under the process described herein. Depending upon the desired physical-chemical traits, the process is repeated until a desired point in the sinusoidal curve is established at which point the liquid is collected and cooled under conditions to inhibit the formation of large molecular arrays. For example, and not by way of limitation, the inventors have discovered that water processed according to the methods described herein undergoes a sinusoidal heating process. During the production of this water a high negative charge is created and imparted to the water. Voltages of −350 mV to −1 volt have been measured with a superimposed sinusoidal wave with a frequency of 800 cycles or higher depending on operating pressures and subsequent water velocities. The inventors have found that the third sinusoidal peak in temperature provides an optimal number of micro-cluster structures for water. Although the inventors are under no duty to provide the mechanism or theory of action, it is believed that the high negative ion production serves as a ready source of donor electrons to act as antioxidants when consumed and further act to stabilize the water micro-clusters and help prevent reformation of the large arrays by aligning the water molecules exposed to the electrostatic field of the negative charge. While not wanting to be bound to a particular theory, it is believed that the high temperatures achieved during cavitation may form a plasma in the water which dissociates the H 2 O atoms and which then reform at a different bond association, as evidenced by the FTIR and NMR test data, to generate a different structure.
It will be recognized by those skilled in the art that the water of the present invention can be further modified in any number of ways. For example, following formation of the micro-cluster water, the water may be oxygenated as described herein, further purified, flavored, distilled, irradiated, or any number of further modifications known in the art and which will become apparent depending on the final use of the water.
In another embodiment, the present invention provides methods of modulating the cellular performance of a tissue or subject. The micro-cluster water (e.g., oxygenated microcluster water) can be designed as a delivery system to deliver hydration, oxygenation, nutrition, medications and increasing overall cellular performance and exchanging liquids in the cell and removing edema. Tests accomplished utilizing an RJL Systems Bio-Electrical Impedance Analyzer model BIA101Q Body Composition Analysis System™ demonstrated substantial intracellular and extracellular hydration changes in as little as 5 minutes. Tests were accomplished on a 58-year-old male 71.5″ in height 269 lbs, obese body type. Baseline readings were taken with Bio-Electrical Impedance Analyzer™ as listed below.
As described in the Examples below it is contemplated that the micro-cluster water of the present invention provides beneficial effects upon consumption by a subject. The subject can be any mammal (e.g, equine, bovine, porcine, murine, feline, canine) and is preferably human. The dosage of the micro-cluster water or oxygenated micro-cluster water (Penta-hydrate™) will depend upon many factors recognized in the art, which are commonly modified and adjusted. Such factors include, age, weight, activity, dehydration, body fat, etc. Typically 0.5 liters of the oxygenated micro-cluster water of the invention provide beneficial results. In addition, it is contemplated that the micro-cluster water of the invention may be administered in any number of ways known in the art, including, for example, orally and intravenously alone or mixed with other agents, compounds and chemicals. It is also contemplated that the water of the invention may be useful to irrigate wounds or at the site of a surgical incision. The water of the invention can have use in the treatment of infections, for example, infections by anaerobic organisms may be beneficially treated with the micro-cluster water (e.g., oxygenated microcluster water).
In another embodiment, the micro-cluster water of the invention can be used to lower free radical levels and, thereby, inhibit free radical damage in cells.
In still another embodiment the micro-cluster water of the invention can be used to remove stains from fabrics, such as cotton.
The following examples are meant to illustrate but no limit the present invention. Equivalents of the following examples will be recognized by those skilled in the art and are encompassed by the present disclosure.
EXAMPLE 1
How to Make Micro-Cluster Water
Described below is one example of a method for making micro-cluster liquids. Those skilled in the art will recognize alternative equivalents that are encompassed by the present invention. Accordingly, the following examples is not to be construed to limit the present invention but are provided as an exemplary method for better understanding of the invention.
325 gallons of steam distilled water from Culligan Water or purified in 5 gallon bottles at a temperature about 29 degrees C. ambient temperature, was placed in a 316 stainless steel non-pressurized tank 40 with a removable top for treatment. The tank was connected by bottom feed 2¼″ 316 stainless steel pipe that is reduced to 1″ NPT into a 20″ U.S. filter housing 42 containing a 5 micron fiber filter, the filter serves to remove any contaminants that may be in the water. Output of the 20″ filter is connected to a Teel model 1V458 316 stainless steel Gear pump 44 driven by a 3HP 1740 RPM 3 phase electric motor by direct drive. Output of the gear pump 44 1″ NPT was directed to a cavitation device via 1″ 316 stainless steel pipe fitted with a 1″ stainless steel ball valve used for isolation only and past a pressure gauge. Output of the pump 44 delivers a continuous pressure of 65 psig to the cavitation device.
The cavitation device 10 , illustrated in FIG. 4 , provides inlets for a liquid, wherein the liquid is then subjected to multiple rotational vortexes. The device was composed of four small inverted pump volutees 11 – 14 made of Teflon® (polyterafluoroethylene) without impellers, housed in a 316 stainless steel pipe housing 16 that are tangentially fed by a common water source. The common water source fed by the 1V458 Gear pump at 65 psig, through a ¼″ hole 21 – 24 that, although normally used as the discharge of a pump, is utilized as the input for the purpose of establishing a rotational vortex. The water entering the four volutes 11 – 14 is directed in a circle 360 degrees and discharged by means of an 1″ long acceleration tube 31 – 34 with a ⅜″ discharge hole. The discharge hole would normally be the suction side of a pump volute but, in this case, is utilized as the discharge side of the device. The four reverse fed volutes 11 – 14 establish rotational vortices that spin the water through one 360 degree rotation 18 , where it reaches partial vacuum pressures of about 27″ Hg, then discharge the water down the acceleration tubes 31 – 34 , which are at a 5 degree decreasing angle from center line. The accelerated water is discharged into a common chamber 30 at point A) at a lower pressure than within the device, i.e., at or close to atmospheric pressure. The common chamber 30 is connected to a 1″ stainless steel discharge line 38 that feeds back into the top of the 325-gallon tank containing the distilled water. At this point, the water has made one treatment pass through the device 10 .
The process described above is repeated continuously until the energy created by the implosions and explosions of the cavitation (e.g., due to the acoustical energy) have imparted sufficient kinetic heat to the water to raise the water temperature to about 60 degrees Celsius.
Although the inventors are under no duty to explain the theory of the invention, the inventors provide the following theory in the way of explanation and are not to be bound by this theory. The inventors believe that the acoustical energy created by the cavitation brakes the static electric bonds holding a single tetrahedral Micro-Clusters of five H 2 O molecules together in larger arrays, thus decreasing their size and/or create a localized plasma in the water restructuring the normal bond angles into a different structure of water.
The temperature was detected by a hand held infrared thermal detector through a stainless steel thermo well. Other methods of assessing the temperature will be recognized by those of skill in the art. Once the temperature of 60 degrees C. has been reached the pump motor is secured and the water is left to cool. An 8 foot by 8 foot insulated room fitted with a 5,000 Btu. air conditioner is used to expedite cooling, but this is not required. It is important that the processed water not be agitated for cooling it should be moved as little as possible.
A cooling temperature of 4 degrees C. can be used, however 15 degrees C. is sufficient and will vary depending upon the quantity of water being cooled. Once sufficiently cooled to about 4 to 15 degrees C. the water can be oxygenated.
Once the water is cooled to desired temperature, the processed water is removed from the 325 gallon stainless steel tank into 5-gallon polycarbonate bottles for oxygenation.
Oxygenation is accomplished by applying gas O 2 at a pressure of 20 psig fed through a ¼″ ID plastic line fitted with a plastic air diffuser utilized to make fine air bubbles (e.g., Lee's Catalog number 12522). The plastic tube is run through a screw on lid of the 5 gallon bottle until it reaches the bottom of the bottle. The line is fitted with the air diffuser at its discharge end. The Oxygen is applied at 20 psig flowing pressure to insure a good visual flow of oxygen bubbles. In one embodiment (Penta-hydrate™) the water is oxygenated for about five minutes and in another embodiment (Penta-hydrate Pro™) the water is oxygenated for about ten minutes.
Immediately after oxygenation the water is bottled in 500 ml PET bottles, filled to overflowing and capped with a pressure seal type plastic cap with inserted seal gasket. In one embodiment, the 0.5 L bottle is over filled so when the temperature of the water increases to room temperature it will self pressurize the bottle retaining a greater concentration of dissolved oxygen at partial pressure. This step not only keeps more oxygen in a dissolved state but also for preventing excessive agitation of the water during shipping.
EXAMPLE 2
The following are reports from individuals who used the water of the invention.
Elimination Of Edema:
Patient A: A 66-year-old Male presenting with (ALS) Amyothrophic Lateral Sclerosis (Lou Gherig's Disease) exhibited a shoulder hand syndrome with marked swelling of the left hand. This hand being the predominately affected limb. After consuming 500 ml of Penta-hydrate™ micro-cluster water the swelling of the left hand was dramatically reduced to normal state. Additional tests were accomplished over several weeks noting the same reduction of edema after consuming Penta-hydrate™ micro-cluster water. When Penta-hydrate™ was discontinued edema reoccurred overnight, upon consuming 500 ml of Penta-hydrate™ micro-cluster water edema was reduced within 4 to 6 hours.
Patient B: Is a 53 year old female with multijoint Acute Rheumatoid Arthritis of 6 year duration. She has been taking diuretics for dependent edema on a daily basis for 4 years. She began taking Penta-hydrate™ Micro-Cluster Water, 5 months ago in place of diuretics, consuming three (3) 500 ml bottles daily. Within one day the edema of the feet/legs and hands cleared. When Penta-hydrate™ was discontinued during a trip, the edema promptly returned. Upon resumption of Penta-hydrate™ Micro-Cluster Water the edema quickly cleared.
Increased Physical Endurance:
A 56-year-old woman diagnosed with “severe emphysema” and retired on full disability underwent experimental lung reduction surgery in December 1998 at St Elizabeth's Hospital in Boston. Each of the lungs upper lobes were removed and re-sectioned. While the surgery was deemed successful the patient had begun to deteriorate. The depression and loss of stamina was overcome by Oxy-Hi-drate Pro™. A 2⅓ increase in endurance is usually seen in response to subject taking Penta-hydrate™ and is caused by increased delivery of hydration to the cells, which is the delivery system for increased oxygenation and cellular energy production. Tests on numerous test subjects show marked increase in cellular hydration within 10 minutes of consuming Penta-hydrate™ micro-cluster water.
Decreased Lactic Acid Soreness from Exercise:
The inventors have received reports of reduced or eliminated soreness caused by lactic acid buildup during exercise as well as increased endurance and performance after consuming Penta-hydrate™ micro-cluster water. This includes elderly fibromyalgia patients. Penta-hydrate™ micro-cluster is thought to delay or prevent the on set of anaerobic cellular function by increasing cellular water and oxygen exchange keeping the cells operating aerobic condition for a longer time period during strenuous exercise, thus preventing or delaying the buildup of lactic acid in the body.
Increased Athletic Performance:
Test accomplished on three high performance athletes have demonstrated a marked increase in overall performance.
A 29 year old male Tri-athlete competing in the 1999 Coronado Calif. 21 st annual Super Frog Half Iron Man Triathlon consumed (6) six 500 ml bottles of Penta-hydrate™ Micro-Cluster the day prior to the race and (6) six 500 ml bottles of Penta-hydrate™ during the race posted a finish time of 4:19:37 winning the overall male winner, finishing over 24 minutes ahead of the second place finisher in his age group and beating the combined time of the Navy SEAL Relay Team One's time of 4:26:09 which had a fresh man for each leg of the three events. Normally after such a demanding race this athlete would be extremely sore the next day, however drinking the Penta-hydrate™ Micro-Cluster Water he was not sore and competed in a 20 K cycle qualifier the following day. Subject Tri-Athlete has won numerous Triathlons' and qualified for the 1999 World-Championships in Australia.
A 39 year old male Tri-athlete competing in the San Diego Second Annual Duadrome World Championships on Aug. 8 th 1999 at the Morley Field Velodrome. Subject athlete was pre hydrated with Penta-hydrate™ Micro-Cluster Water set a new world record winning the 35–39 age group division, beating his own best time by 26 seconds in the male relay division and the course record by 3 seconds
Both of the above Tri-athletes report dramatic increase in endurance and rapid recovery after strenuous exercise not experienced with conventional water and an ability to hydrate during the running portion of a triathlon, normally hydration is only accomplished during the cycling portion of a triathlon, due to normal water causing the subject to regurgitate, this problem is not encountered drinking Penta-hydrate™ Micro-Cluster Water due to its rapid absorption.
45-year-old woman TV 10 News anchor in San Diego, that also competes in rough ocean swimming. Consumed 500 ml of Penta-hydrate™ just prior to entering the water in a swim meet in Hawaii, won the gold medal in 45-year-old age division. Returned to San Diego and competed in the La Jolla rough water swim and won a gold medal. Next competed in the. US Nationals held at Catalina Island in California and won the US National Gold Medal after drinking 500 ml of Penta-hydrate™ just prior to entering the water. She was not considered a contender for the Gold in the US Nationals.
Congestive Heart Failure:
The inventors have had several reports from subjects with congestive heart failure report ten minutes after consuming 500 ml of Penta-hydrate Pro™ their shortness of breath had gone away and their energy was increased.
Muscular Sclerosis MS:
A woman with Muscular Sclerosis was rushed to the hospital in San Antonio Tex. having passed out from severe dehydration. The MS subject drank×500 ml bottles of Penta-hydrate™ their and was re-hydrated.
Colds, Flu, Sinus Infections and Energy:
58-year-old male with loss of spleen and 20-year sufferer of fibromyalgia, suffered from chronic sinus infections and annual bouts of the flu and reoccurring bouts of pneumonia. He started drinking 6–500 ml bottles of Penta-hydrate™ Micro-Cluster Water per day 19 months ago. At that time he had a severe sinus infection that would have normally required antibiotics. While taking the Penta-hydrate™ Micro-Cluster Water, the sinus infection was cleared within three days and subject has not had a single sinus infection in 19 months. In addition he has not experienced any colds, flu or allergy conditions and is now for the first time in 20-years able to work with out fatigue.
Elimination of Edema:
In numerous test cases Penta-hydrate™ has eliminated edema in all test subjects from both chronic health conditions as well as surgically caused edema. In all cases edema was dramatically reduced after consuming as little as one 500 ml bottle of Penta-hydrate™ Micro-Cluster Water but no more than two 500 ml bottles were required. One such case was a middle-aged woman that had broken her forearm in two places. The forearm was in a cast and suffering severs edema, subject was given two 500 ml bottles of Penta-hydrate™ Micro-Cluster Water that she consumed from 3:00 pm until bedtime. Swelling was so bad that she could not insert a business card between her swollen arm and the cast. When she awoke at 7:00 am the next morning the swelling was reduced to where she was endanger of loosing the cast and had to return to the orthopedic surgeon to have the cast redone.
Liquid Nutritional Analyzer Results.
Liquid nutritional analyzer results utilizing a RJL Systems BIA101Q™ FDA registered analyzer for assessing cellular hydration and health. The following measurements were preformed on a 58 year-old male subject.
Time: 7:59 am Oct. 9, 1999 Baseline Test:
Measured: Resistance: 413 ohms Reactance: 53 ohms Calculated: Impedance 416 ohms Phase Angle: 7.3 degrees Parallel Model: Resistance: 419.8 ohms Capacitance: 973.0 pF Fluid Assessment: Status: (Edema) Results: Percent: Normal Range: Deviation: Total Body Water 63.3 L 52% (WT) 40%–50% +2 Intracellular Water 37.5 L 59% (TBW) 51%–60% +0 Extracellular Water 25.8 L 41% (TBW) 39%–51% +0
Nutrition Assessment:
Basal Metabolism 2069 Kcal Body Cell Mass 90.6 lbs. 34% (WT) Fat Free Mass 190.2 lbs. 71% Fat 78.8 lbs. 29% ECT 99.6 lbs. 52% Impedance Index 1437 Normal
Time: 8:02 am consumed 500 ml Penta-hydrate Pro™
Time: 8:12 am Oct. 9, 1999
Measured: Resistance: 436 ohms Reactance: 57 ohms Calculated: Impedance 439.7 ohms Phase Angle: 7.4 degrees Parallel Model: Resistance: 443.5 ohms Capacitance: 938.4 pF Fluid Assessment: Status: (Edema) Results: Percent: Normal Range: Deviation: Total Body Water 63.3 L 51% (WT) 40%–50% +1 Intracellular Water 37.1 L 60% (TBW) 51%–60% +0 Extracellular Water 25.2 L 40% (TBW) 39%–51% +0
Nutrition Assessment:
Basal Metabolism 2060 Kcal Body Cell Mass 89.6 lbs. 33% (WT) Fat Free Mass 188.0 lbs. 70% Fat 81.0 lbs. 30% ECT 99.6 lbs. 52% Impedance Index 1469 Normal
Time: 8:38 am Oct. 9, 1999
Measured: Resistance: 442 ohms Reactance: 56 ohms Calculated: Impedance 445.5 ohms Phase Angle: 7.2 degrees Parallel Model: Resistance: 449.1 ohms Capacitance: 898.0 pF Fluid Assessment: Status: (Edema) Results: Percent: Normal Range: Deviation: Total Body Water 62.0 L 51% (WT) 40%–50% +1 Intracellular Water 36.6 L 60% (TBW) 51%–60% +0 Extracellular Water 25.4 L 40% (TBW) 39%–51% +0
Nutrition Assessment:
Basal Metabolism 2048 Kcal Body Cell Mass 88.4 lbs. 33% (WT) Fat Free Mass 187.5 lbs. 70% Fat 81.5 lbs. 30% ECT 99.1 lbs. 53% Impedance Index 1426 Normal
Time: 8:43 am Oct. 9, 1999
Measured: Resistance: 453 ohms Reactance: 57 ohms Calculated: Impedance 456.6 ohms Phase Angle: 7.2 degrees Parallel Model: Resistance: 460.2 ohms Capacitance: 870.4 pF Fluid Assessment: Status: (Edema) Results: Percent: Normal Range: Deviation: Total Body Water 63.6 L 50% (WT) 40%–50% +0 Intracellular Water 36.2 L 59% (TBW) 51%–60% +0 Extracellular Water 25.3 L 41% (TBW) 39%–51% +0
Nutrition Assessment:
Basal Metabolism 2040 Kcal Body Cell Mass 87.6 lbs. 33% (WT) Fat Free Mass 186.5 lbs. 69% Fat 82.5 lbs. 31% ECT 99.0 lbs. 53% Impedance Index 1421 Normal
Time: 8:45 Consumed additional 500 ml Penta-hydrate Pro™
Time: 8:48 am Oct. 9, 1999
Measured: Resistance: 431 ohms Reactance: 60 ohms Calculated: Impedance 435.2 ohms Phase Angle: 7.9 degrees Parallel Model: Resistance: 439.4 ohms Capacitance: 1008.6 pF Fluid Assessment: Status: (Edema) Results: Percent: Normal Range: Deviation: Total Body Water 62.5 L 51% (WT) 40%–50% +1 Intracellular Water 37.9 L 61% (TBW) 51%–60% +1 Extracellular Water 24.5 L 39% (TBW) 39%–51% +0
Nutrition Assessment:
Basal Metabolism 2078 Kcal Body Cell Mass 91.7 lbs. 34% (WT) Fat Free Mass 188.4 lbs. 70% Fat 80.6 lbs. 30% ECT 96.8 lbs. 52% Impedance Index 1561 Normal
Time: 9:07 am Oct. 9, 1999
Measured: Resistance: 442 ohms Reactance: 57 ohms Calculated: Impedance 445.7 ohms Phase Angle: 7.3 degrees Parallel Model: Resistance: 449.4 ohms Capacitance: 913.5 pF Fluid Assessment: Status: (Edema) Results: Percent: Normal Range: Deviation: Total Body Water 62.0 L 51% (WT) 40%–50% +1 Intracellular Water 36.8 L 59% (TBW) 51%–60% +0 Extracellular Water 25.2 L 41% (TBW) 39%–51% +0
Nutrition Assessment:
Basal Metabolism 2053 Kcal Body Cell Mass 88.9 lbs. 33% (WT) Fat Free Mass 187.5 lbs. 70% Fat 81.5 lbs. 30% ECT 98.6 lbs. 53% Impedance Index 1452 Normal
Time: 9:27 am Oct. 9, 1999
Measured: Resistance: 427 ohms Reactance: 56 ohms Calculated: Impedance 430.7 ohms Phase Angle: 7.5 degrees Parallel Model: Resistance: 434.3 ohms Capacitance: 961.1 pF Fluid Assessment: Status: (Edema) Results: Percent: Normal Range: Deviation: Total Body Water 62.7 L 51% (WT) 40%–50% +1 Intracellular Water 37.4 L 60% (TBW) 51%–60% +0 Extracellular Water 25.3 L 40% (TBW) 39%–51% +0
Nutrition Assessment:
Basal Metabolism 2066 Kcal Body Cell Mass 90.3 lbs. 34% (WT) Fat Free Mass 188.8 lbs. 70% Fat 80.2 lbs. 30% ECT 98.5 lbs. 52% Impedance Index 1471 Normal
Time: 9:38 Consumed 500 ml Penta-hydrate™
Time: 9:46 am Oct. 9, 1999
Measured: Resistance: 430 ohms Reactance: 59 ohms Calculated: Impedance 434.0 ohms Phase Angle: 7.8 degrees Parallel Model: Resistance: 438.1 ohms Capacitance: 996.9 pF Fluid Assessment: Status: (Edema) Results: Percent: Normal Range: Deviation: Total Body Water 62.0 L 51% (WT) 40%–50% +1 Intracellular Water 37.8 L 60% (TBW) 51%–60% +0 Extracellular Water 24.7 L 40% (TBW) 39%–51% +0
Nutrition Assessment:
Basal Metabolism 2075 Kcal Body Cell Mass 91.3 lbs. 34% (WT) Fat Free Mass 188.5 lbs. 70% Fat 80.5 lbs. 30% ECT 97.2 lbs. 52% Impedance Index 1539 Normal
Time: 10:32 am Oct. 9, 1999
Measured: Resistance: 437 ohms Reactance: 57 ohms Calculated: Impedance 440.7 ohms Phase Angle: 7.4 degrees Parallel Model: Resistance: 444.4 ohms Capacitance: 934.2 pF Fluid Assessment: Status: (Edema) Results: Percent: Normal Range: Deviation: Total Body Water 62.2 L 51% (WT) 40%–50% +1 Intracellular Water 37.0 L 60% (TBW) 51%–60% +0 Extracellular Water 25.2 L 40% (TBW) 39%–51% +0
Nutrition Assessment:
Basal Metabolism
2058
Kcal
Body Cell Mass
89.5
lbs.
33% (WT)
Fat Free Mass
187.9
lbs.
70%
Fat
81.1
lbs.
30%
ECT
98.4
lbs.
52%
Impedance Index
1466
Normal
Although test subjects were well hydrated prior to testing, the results were dramatic. Analysis of the above tests clearly show rapid cellular fluid exchange not possible with current hydrating fluid hydrating technology, including intravenous hydration methods. Similar tests utilizing tap and purified water demonstrated no change in cellular fluid exchanges over the same time frames. Note even though over-hydration increased total body water, the intercellular and extracellular remained within normal range with rapid noted in and out exchanges seen in both intercellular and extracellular fluids. And a 1.0% decrease in edema is noted after consuming only 500 ml of Penta-hydrate™ micro-cluster water. It is worth noting that the base micro-cluster water without oxygen is even more dramatic, hydrating the cells in less time than the oxygenated version micro-cluster water. The overall change in the Impedance Index of 124 points is utilized by the RJA System as an overall indication of health. Changes of this magnitude are not seen in a 90 day period of monitoring in the absence of oxygenated micro-cluster water (Penta-hydrate™ Micro-Cluster Water). However, when Penta-hydrate™ Micro-Cluster Water was consumed the 124 point change occurred within a 2.5 hour period.
EXAMPLE 3
A novel water prepared by the method of the invention was characterized with respect to various parameters.
A. Conductivity
Conductivity was tested using the USP 645 procedure that specifies conductivity measurements as criteria for characterizing water. In addition to defining the test protocol, USP 645 sets performance standards for the conductivity measurement system, as well as validation and calibration requirements for the meter and conductivity. Conductivity testing was performed by West Coast Analytical Service, Inc. in Santa Fe Springs, Calif.
Conductivity Test Results
Micro-cluster
Micro-cluster
w/O 2
RO water
water
water
Conductivity at 25° C.*
5.55
3.16
3.88
(μmhos/cm)
*Conductivity values are the average of two measurements.
The conductivity observed for the micro-cluster water is reduced by slightly more than half compared to the RO water. This is highly significant and indicates that the micro-cluster water exhibits significantly different behavior and is therefore substantively different, relative to RO unprocessed water.
B. Fourier Transform Infra Red Spectroscopy (FTIR)
Water, a strong absorber in the IR spectral region, has been well-characterized by FTIR and shows a major spectral line at approximately 3000 wave numbers corresponding to O—H bond vibrations. This spectral line is characteristic of the hydrogen bonding structure in the sample. An unprocessed RO water sample, Sample A, and a unoxygenated micro-cluster water sample, Sample B, were each placed between silver chloride plates, and the film of each liquid analyzed by FTIR at 25° C. The FTIR tests were performed by West Coast Analytical Service, Inc. in Santa Fe Springs, Calif. using a Nicolet Impact 400D™ benchtop FTIR. The FTIR spectra are shown in FIG. 5 .
In comparing the FTIR spectra for the unoxygenated micro-cluster and RO waters, it is clear that the two samples have a number of features in common, but also significant differences. A major sharp feature at approximately 2650 wave numbers in the FTIR spectrum is observed for the micro-cluster water ( FIG. 5( b )). The RO water has no such feature ( FIG. 5( a )). This indicates that the bonds in the water sample are behaving differently and that their energetic interaction has changed. These results suggest that the unoxygenated micro-cluster water is physically and chemically different than RO unprocessed water.
C. Simulated Distillation
Simulated distillations were carried out on RO water and unoxygenated micro-cluster water without oxygenation by West Coast Analytical Service, Inc. in Santa Fe Springs, Calif.
Simulated Distillation Test Results
RO Water
Unoxygenated Micro-cluster water
Boiling Point range*
98–100
93.2–100
(deg. C.)
*Corrected for barometric pressure.
These results show a significant lowering of the boiling temperature of the lowest boiling fraction in the unoxygenated micro-cluster water sample. The lowest boiling fraction for micro-cluster water is observed at 93.2° C. compared with a temperature of 98° C. for the lowest boiling fraction of RO water. This suggests that the process has significantly changed the compositional make-up of molecular species present in the sample. Note that lower boiling species are typically smaller, which is consistent with all observed data and the formation of micro-clusters.
D. Thermogravimetric Analysis
In this test, one drop of water was placed in a disc sample pan and sealed with a cover in which a pin-hole was precision laser-drilled. The sample was subject to a temperature ramp increase of 5 degrees every 5 minutes until the final temperature. TGA profiles were run on both unoxygenated micro-cluster water and RO water for comparison.
The TGA analysis was performed on a TA Instruments Model TFA2950™ by Analytical Products in La Canada, Calif. The TGA test results are shown in FIG. 6 . Three test runs utilizing three different samples are shown. The RO water sample is designated, “Purified Water” on the TGA plot. The unoxygenated micro-cluster water was run in duplicate, designated Super Pro 1 st test and Super Pro 2 nd Test. The unoxygenated micro-cluster water and the unprocessed RO water showed significantly greater weight loss dynamics. It is evident that the RO water began losing mass almost immediately, beginning at about 40° C. until the end temperature. The micro-cluster water did not begin to lose mass until about 70° C. This suggests that the processed water has a greater vapor pressure between 40 and 70° C. compared to unprocessed RO water. The TGA results demonstrated that the vapor pressure of the unxoygenated micro-cluster water was lower when the boiling temperature was reached. These data once again show that the unoxygenated micro-cluster water is significantly changed compared to RO water. These data once again show that the unoxygenated micro-cluster water also shows more features between the temperatures of 75 and 100+deg. C. These features could account for the low boiling fraction(s) observed in the simulated distillation.
E. Nuclear Magnetic Resonance (NMR) Spectroscopy
NMR testing was performed by Expert Chemical Analysis, Inc. in San Diego, Calif. utilizing a 600 MHz Bruker AM500™ instrument. NMR studies were performed on micro-cluster water with and without oxygen and on RO water. The results of these studies are shown in FIG. 7 . In 17 O NMR testing a single expected peak was observed for RO water ( FIG. 7( a )). For micro-cluster water without oxygen ( FIG. 7( b )), the single peak observed was shifted +54.1 Hertz relative to the RO water, and for the micro-cluster water with oxygen ( FIG. 7( c )), the single peak was shifted +49.8 Hertz relative to the RO water. The shifts of the observed NMR peaks for the micro-cluster water and RO water. Also of significance in the NMR data is the broadening of the peak observed with the micro-cluster water sample compared to the narrower peak of the unprocessed sample.
|
The system for producing a micro-cluster liquid from a starting liquid utilizes a cavitation device with a plurality of reverse-fed pump volutes within a housing, where each volute establishes a rotational vortex for spinning the liquid in a circle and directing a liquid stream into a common chamber at a center of the housing. The starting liquid is pumped into the cavitation device at a first pressure and tangentially fed into each volute. The rotational vortex creates a partial vacuum within the spinning liquid so that cavitation bubbles are formed when the liquid exits the volute. The common chamber is maintained at a lower pressure so that the bubbles explode or implode upon exit from the volute to generate shock waves that break molecular bonds in the liquid. The volutes are oriented so that the liquid streams collide with each other within the common chamber, facilitating breakdown of molecular bonds. A discharge line connected to the common chamber carries the liquid out of the housing and into a tank for further processing.
| 2 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application Serial No. 61/891,766, filed Oct. 16, 2013, and which is herein incorporated by reference in its entirety.
BACKGROUND
[0002] 1. Technical Field
[0003] This disclosure relates to powdered automatic dishwashing detergents. More particularly, this disclosure relates to powdered automatic dishwashing detergent packets with superior environmental and human safety as well as superior cleaning efficacy and stability.
[0004] 2. Background
[0005] Many automatic dishwashing detergents currently available are suitable for their intended purposes, i.e., effectively cleaning and leaving previously soiled eating and cooking utensils in a generally spot-free, clean condition. Known automatic dishwashing detergents, however, often contain some combination of one or more of three ingredients, including bleach, caustic soda, and phosphates. These substances can be deleterious, for various reasons. For example, phosphates are minerals that act as water softeners and are considered by some to be among the worst pollutants found in detergents. Phosphates are a nutrient, and can act as a fertilizer for algae. Thus, when phosphates enter waterways, they promote the growth of algae and other plants. In the presence of large amounts of phosphates and other similar nutrients, excessive algae growth occurs. This causes odors and creates hypoxic conditions. Some states have banned the use of phosphates in all detergents, other than automatic dishwasher detergents.
SUMMARY
[0006] Provided herein are powdered detergent compositions for use in automatic dishwashing machines. For example, the powder compositions provided herein can contain one or more of a low foaming nonionic surfactant, a non-phosphate detergent builder, a detergent enzyme, and a sheeting polymer. In some cases, compositions provided herein can contain less than about 1% by weight of water or other solvent and lack phosphate builders and bleach or other bleaching agents. In addition, compositions provided herein can be contained within a water-soluble film container to prepare a monophasic automatic dishwashing detergent packet.
[0007] Provided herein is a powder detergent composition including:
[0008] (a) about 0.5 to about 15% by weight of a surfactant, wherein said surfactant is a low foaming nonionic surfactant;
[0009] (b) about 30 to about 90% by weight of a non-phosphate detergent builder,
[0010] wherein said non-phosphate detergent builder is selected from the group consisting of citric acid or a soluble salt form of citric acid;
[0011] (c) about 0.02 to about 5% by weight of a detergent enzyme; and
[0012] (d) about 0.05 to about 3% by weight of a sheeting polymer; wherein the composition includes less than about 1% by weight of water or other solvent.
[0013] In some embodiments, the low foaming nonionic surfactant is selected from the group consisting of:
[0014] (a) first condensation products, wherein said first condensation products are condensates from a first mixture containing about one mole of a straight or branched chain fatty alcohol or fatty acid and from about four to about forty moles of ethylene oxide, wherein said alcohol or acid is saturated or unsaturated, and wherein the chain of said alcohol or acid contains from about ten to about twenty carbon atoms;
[0015] (b) second condensation products, wherein said second condensation products are condensates from a second mixture containing about one mole of alkyl phenol and from about four to about fifty moles of ethylene oxide, wherein the alkyl chain of said alkyl phenol contains from about eight to about eighteen carbon atoms;
[0016] (c) polyoxypropylene, polyoxyethylene condensates having the formula R 1 O(CH 2 CH 2 O) x (CH(CH 3 )CH 2 O) y R 2 , wherein R 1 is H or an alkyl group having from one to four carbon atoms, wherein R 2 is H or an alkyl group having from one to four carbon atoms, wherein x is an integer greater than or equal to one, wherein y is an integer greater than or equal to one, wherein the total C 2 H 4 O content is from about 20 percent to about 90 percent of the total weight of said polyoxypropylene, polyoxyethylene condensates, and wherein the molecular weight of said polyoxypropylene, polyoxyethylene condensates is from about 2000 Daltons to about 10,000 Daltons; and
[0017] (d) capped condensates, wherein said capped condensates comprise said polyoxypropylene, polyoxyethylene condensates capped with at least one capping molecule, said capping molecule being selected from the group consisting of propylene oxide, butylene oxide, short chain alcohols, and short chain fatty acids.
[0018] In some embodiments, the surfactant is a polyoxypropylene polyoxyethylene condensate.
[0019] In some embodiments, the non-phosphate detergent builder is a soluble salt of citric acid. For example, the non-phosphate detergent builder can be an alkali metal salt of citric acid, an ammonium salt of citric acid, or a mixture thereof. In some embodiments, the non-phosphate detergent builder is a sodium salt of citric acid. For example, the non-phosphate detergent builder is sodium citrate dihydrate.
[0020] In some embodiments, the detergent enzyme is selected from lipases, mannanases, cellulases, zylenases, proteases, amylases, and mixtures of two or more thereof. For example, the detergent enzyme is selected from a protease, an amylase, or mixtures thereof.
[0021] In some embodiments, the sheeting polymer is diallyldimethylammonium chloride.
[0022] In some embodiments, the compositions provided herein can be free of phosphate builders and/or bleach and other bleaching agents.
[0023] In some embodiments, the composition further comprises from about 0.001 to about 5% by weight of one or more essential oils. For example, the one or more essential oils can be selected from the group consisting of: abies, bitter, seed, angelica, anise, balsam, basil, bay, benzoin, bergamot, birch, rose, cajuput, calamus, cananga, capsicum, caraway, cardamon, cassia, Japanese cinnamon, acacia, cedarwood, celery, camomile, hay podge, cinnamon, citronella, clove, coriander, costus, cumin, dill, elemi, estragon, eucalyptus, fennel, galbanum, garlic, geranium, ginger, ginger grass, grapefruit, guaiac wood, white cedar, hinoki, hop, hyacinth, Jasmine, jonquil, juniper berry, laurel, lavandin, lavender, lemon, lemongrass, lime, linaloe, richea cubeb, lovage, mandarin, Melaleuca alternifolia leaf oil, mint, minosa, mustard, myrrh, myrtle, narcissus, neroli, nutmeg, oak moss, ocotea, olibanum, onion, opopanax, orange, oris, parsley, patchouli, palmarosa, pennyroyal, pepper, perilla, petitgrain, pimento, pine, rose, rosemary, camphor, clary sage, sage, sandalwood, spearmint, spike, star anise, styrax, thyme, tonka, tuberose, terpin, vanilla, vetiver, violet, wintergreen, worm wood, and ylang ylang. In some embodiments, the essential oils are selected from the group consisting of: Melaleuca alternifolia leaf oil and orange oil.
[0024] In some embodiments, the composition further includes from about 0.05 to about 5% by weight of a preservative. For example, a preservative can be selected from the group consisting of propylene glycol, sorbitol, fructose, sucrose, glucose, short chain carboxylic acids, salt forms of short chain carboxylic acids, polyhydroxyl compounds, boric acid, soluble salt forms of boric acid, boronic acid, soluble salt forms of boronic acid, sorbic acid, soluble salt forms of sorbic acid, calcium ions, and mixtures thereof. In some embodiments, the preservative is selected from sorbic acid, soluble salt forms of sorbic acid, calcium ions, and mixtures thereof.
[0025] In some embodiments, the composition further includes from about 0.5 to about 5% by weight of a flow aid. For example, the flow aid can be selected from the group consisting of: silica and aluminosilicate.
[0026] In some embodiments, the composition further includes from about 0.05 to about 2% by weight of fragrance.
[0027] In some embodiments, the composition includes:
[0028] (a) about 0.5 to about 15% by weight of a surfactant, wherein said surfactant is a low foaming nonionic surfactant;
[0029] (b) about 30 to about 90% by weight of a non-phosphate detergent builder, wherein said non-phosphate detergent builder is selected from the group consisting of citric acid or a salt form thereof;
[0030] (c) about 0.02 to about 5% by weight of a detergent enzyme;
[0031] (d) about 0.05 to about 3% by weight of a sheeting polymer;
[0032] (e) about 0 to about 5% by weight of a preservative;
[0033] (f) about 0.5 to about 5% by weight of a flow aid;
[0034] (g) from 0 to about 5% by weight of one or more essential oils; and
[0035] (h) from 0 to about 2% by weight of fragrance;
[0036] wherein the composition includes less than about 1% by weight of water or other solvent.
[0037] In some embodiments, the composition includes:
[0038] (a) about 1 to about 10% by weight of a surfactant, wherein said surfactant is a low foaming nonionic surfactant;
[0039] (b) about 80 to about 90% by weight of a non-phosphate detergent builder, wherein said non-phosphate detergent builder is selected from the group consisting of citric acid or a salt form thereof;
[0040] (c) about 0.5 to about 2% by weight of a detergent enzyme; and
[0041] (d) about 0.1 to about 1% by weight of a sheeting polymer;
[0042] wherein the composition includes less than about 1% by weight of water or other solvent.
[0043] For example, the composition can include:
[0044] (a) about 1 to about 10% by weight of a surfactant, wherein said surfactant is a low foaming nonionic surfactant;
[0045] (b) about 80 to about 90% by weight of a non-phosphate detergent builder, wherein said non-phosphate detergent builder is selected from the group consisting of citric acid or a salt form thereof;
[0046] (c) about 0.5 to about 2% by weight of a detergent enzyme;
[0047] (d) about 0.1 to about 1% by weight of a sheeting polymer;
[0048] (e) about 0 to about 5% by weight of a preservative;
[0049] (f) about 0.5 to about 5% by weight of a flow aid;
[0050] (g) from 0 to about 1% by weight of one or more essential oils; and
[0051] (h) from 0 to about 2% by weight of fragrance;
[0052] wherein the composition includes less than about 1% by weight of water or other solvent.
[0053] In some embodiments, the composition includes:
[0054] (a) about 1 to about 10% by weight of a polyoxypropylene polyoxyethylene condensate;
[0055] (b) about 80 to about 90% by weight of sodium citrate dihydrate;
[0056] (c) about 0.5 to about 2% by weight of a mixture of amylase and protease enzymes; and
[0057] (d) about 0.1 to about 1% by weight of diallyldimethylammonium chloride; wherein the composition includes less than about 1% by weight of water or other solvent.
[0058] For example, the composition can include:
[0059] (a) about 1 to about 10% by weight of a polyoxypropylene polyoxyethylene condensate;
[0060] (b) about 80 to about 90% by weight of sodium citrate dihydrate;
[0061] (c) about 0.5 to about 2% by weight of a mixture of amylase and protease enzymes;
[0062] (d) about 0.1 to about 1% by weight of diallyldimethylammonium chloride;
[0063] (e) about 0 to about 5% by weight of a mixture of sorbic acid, citric acid, and calcium chloride;
[0064] (f) about 0.5 to about 5% by weight of silica;
[0065] (g) from 0 to about 1% by weight of Melaleuca alternifolia leaf oil; and
[0066] (h) from 0 to about 2% by weight of fragrance;
[0067] wherein said composition comprises less than about 1% by weight of water or other solvent.
[0068] In some embodiments, the composition includes:
[0069] (a) about 6% by weight of a polyoxypropylene polyoxyethylene condensate;
[0070] (b) about 87% by weight of sodium citrate dihydrate;
[0071] (c) about 1% by weight of a mixture of amylase and protease enzymes; and
[0072] (d) about 0.5% by weight of diallyldimethylammonium chloride; wherein the composition includes less than about 1% by weight of water or other solvent.
[0073] For example, the composition can include:
[0074] (a) about 6% by weight of a polyoxypropylene polyoxyethylene condensate;
[0075] (b) about 87% by weight of sodium citrate dihydrate;
[0076] (c) about 1% by weight of a mixture of amylase and protease enzymes;
[0077] (d) about 0.5% by weight of diallyldimethylammonium chloride;
[0078] (e) about 3.4% by weight of a mixture of sorbic acid, citric acid, and calcium chloride;
[0079] (f) about 2% by weight of silica;
[0080] (g) about 0.003% by weight of Melaleuca alternifolia leaf oil; and
[0081] (h) about 0.2% by weight of fragrance;
[0082] wherein the composition comprises less than about 1% by weight of water or other solvent.
[0083] Also provided herein is an automatic dishwashing detergent packet including:
[0084] (a) a water soluble container comprising a water-soluble film; and
[0085] (b) a powder detergent composition of claim 1 within said container.
[0086] In some embodiments, the container includes a single-layer of said water-soluble film wherein the water-soluble film has an internal surface directly contacting the powder detergent composition and an external surface which is an outermost portion of the packet. In some embodiments, the water-soluble film comprises polyvinyl alcohol. In some embodiments, the container consists essentially of said water-soluble film and said water-soluble film consists essentially of polyvinyl alcohol. In some embodiments, the automatic dishwashing detergent packet is a monophasic automatic dishwashing detergent packet.
[0087] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.
[0088] Other features and advantages of the invention will be apparent from the following detailed description and from the claims.
DETAILED DESCRIPTION
[0089] Provided herein are powdered detergent compositions for use in automatic dishwashing machines. For example, the powder compositions provided herein can contain one or more of a low foaming nonionic surfactant, a non-phosphate detergent builder, a detergent enzyme, and a sheeting polymer. In some cases, compositions provided herein can contain less than about 1% by weight of water or other solvent and lack phosphate builders and bleach or other bleaching agents. In addition, compositions provided herein can be contained within a water-soluble film container to prepare a monophasic automatic dishwashing detergent packet.
Surfactant
[0090] A powder detergent composition provided herein can include a surfactant, specifically, a low foaming nonionic surfactant. Surfactants lower the surface tension between food residue and the dishes they are on and act as a detergent to assist in cleaning. A low-foaming nonionic surfactant is a surfactant that foams little, if at all, during the wash cycle of an automatic dishwashing appliance. In addition, a low-foaming nonionic surfactant can function to suppress foaming during the wash cycle caused by food residues.
[0091] Examples of nonionic surfactants include, without limitation, various condensation products. For example, the condensation product from a mixture of about one mole of a fatty alcohol or fatty acid and about four to about forty moles of ethylene oxide can be used. The fatty alcohol or fatty acid can be saturated or unsaturated while the chain can be straight or branched. In addition, the chain can contain from ten to twenty carbon atoms. Another nonionic surfactant can be the condensation product from a mixture of about one mole of alkyl phenol and about four to about fifty moles of ethylene oxide. The alkyl chain of the alkyl phenol can contain from eight to eighteen carbon atoms.
[0092] Further, polyoxypropylene, polyoxyethylene condensates can be used as nonionic surfactants. Polyoxypropylene, polyoxyethylene condensates can have a chemical formula of R 1 O(CH 2 CH 2 O) x (CH(CH 3 )CH 2 O) y R 2 where R 1 can be H or an alkyl group having from one to four carbon atoms, where R 2 can be H or an alkyl group having from one to four carbon atoms, where x is an integer greater than or equal to one, where y is an integer greater than or equal to one, and where the total C 2 H 4 O content equals about 20 percent to about 90 percent (e.g., about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90 percent) of the total weight of the condensation product. In addition, the molecular weight of the polyoxypropylene, polyoxyethylene condensates can be from about 2,000 Daltons to about 10,000 Daltons. Polyoxypropylene, polyoxyethylene condensates can be capped or uncapped. For example, polyoxypropylene, polyoxyethylene condensates can be capped with propylene oxide, butylene oxide, short chain alcohols, short chain fatty acids, or combinations thereof. In some cases, a polyoxypropylene, polyoxyethylene condensate can be MEROXAPOL® 252 (CAS No. 9003-11-6) or PLURONIC® 25R2.
[0093] Other nonionic surfactants include, without limitation, those described in McCutcheon's Emulsifiers and Detergents, 1999 North American Edition.
[0094] In some cases, a composition provided herein can contain between about 0.5% to about 15% by weight of a polyoxypropylene, polyoxyethylene condensate. For example, about 0.5% to about 14% by weight, about 0.5% to about 12% by weight, about 0.5% to about 10% by weight, about 0.5% to about 8% by weight, about 0.5% to about 7% by weight, about 0.5% to about 6% by weight, about 0.5% to about 4%, about 0.5% to about 2% by weight, about 1% to about 15% by weight, about 3% to about 15% by weight, about 4% to about 15% by weight, about 5% to about 15% by weight, about 8% to about 15% by weight, about 10% to about 15% by weight, about 1% to about 10% by weight, about 2% to about 8% by weight, about 3% to about 7% by weight, and about 4% to about 6% by weight of a polyoxypropylene, polyoxyethylene condensate. In some cases, a composition provided herein can contain about 6% by weight of a polyoxypropylene, polyoxyethylene condensate. For example, a composition can include about 5.941% by weight of a polyoxypropylene, polyoxyethylene condensate such as MEROXAPOL® 252 (CAS No. 9003-11-6) or PLURONIC® 25R2.
[0095] In some cases, a composition provided herein can contain between about 0.5% to about 15% by weight of a surfactant. For example, about 0.5% to about 14% by weight, about 0.5% to about 12% by weight, about 0.5% to about 10% by weight, about 0.5% to about 8% by weight, about 0.5% to about 7% by weight, about 0.5% to about 6% by weight, about 0.5% to about 4%, about 0.5% to about 2% by weight, about 1% to about 15% by weight, about 3% to about 15% by weight, about 4% to about 15% by weight, about 5% to about 15% by weight, about 8% to about 15% by weight, about 10% to about 15% by weight, about 1% to about 10% by weight, about 2% to about 8% by weight, about 3% to about 7% by weight, and about 4% to about 6% by weight of a surfactant. In some cases, a composition provided herein can contain about 6% by weight of a surfactant. For example, a composition can include about 5.941% by weight of a low foaming non-ionic surfactant.
[0096] In some cases, compositions provided herein do not contain other types of surfactants. For example, compositions provided herein can lack anionic or amphoteric surfactants.
[0000] Non phosphate detergent builder
[0097] A powder detergent composition provided herein can include a non-phosphate detergent builder. Detergent builders are compounds that remove calcium ions by complexation or precipitation. Examples of non-phosphate builders include, without limitation, citric acid, soluble salt forms of citric acid, nitrilotriacetic acid, soluble salt forms of nitrilotriacetic acid, sodium carboxymethyl oxymalonate, sodium carboxymethyl oxysuccinate, polymers of acrylic acid, copolymers of acrylic acid, polymers of maleic acid, copolymers of maleic acid, soluble salt forms of carbonate, soluble salt forms of bicarbonate, and soluble salt forms of percarbonate. In some embodiments, a non-phosphate detergent builder can be selected from citric acid, a soluble salt form of citric acid, a soluble salt form of carbonate, a soluble salt form of bicarbonate, and a soluble salt form of percarbonate. For example, the salt form can be a sodium salt such as sodium citrate, sodium carbonate, sodium bicarbonate, and sodium percarbonate. In some embodiments, a non-phosphate detergent builder can include citric acid or a soluble salt form of citric acid. For example, the non-phosphate detergent builder can be a soluble salt of citric acid such as an alkali metal salt of citric acid, an ammonium salt of citric acid, or a mixture thereof. In some cases, the non-phosphate detergent builder can be a sodium salt of citric acid such as sodium citrate dihydrate.
[0098] In some cases, compositions provided herein can contain about 30% to about 90% by weight of a non-phosphate detergent builder. For example, about 30% to about 80% by weight, about 30% to about 60% by weight, about 30% to about 50% by weight, about 40% to about 90% by weight, about 50% to about 90% by weight, about 60% to about 90% by weight, about 70% to about 90% by weight, about 80% to about 90% by weight, about 40% to about 80% by weight, and about 50% to about 70% by weight of a non-phosphate detergent builder. In some cases, a composition provided herein contains about 70% to about 90% by weight or about 80% to about 90% by weight of a non-phosphate detergent builder. In some embodiments, a composition provided herein can contain about 80% to about 90% by weight of a non-phosphate detergent builder. For example, a composition can contain about 87% by weight of a non-phosphate detergent builder.
[0099] In some cases, compositions provided herein can contain about 30% to about 90% by weight of a sodium salt of citric acid. For example, about 30% to about 80% by weight, about 30% to about 60% by weight, about 30% to about 50% by weight, about 40% to about 90% by weight, about 50% to about 90% by weight, about 60% to about 90% by weight, about 70% to about 90% by weight, about 80% to about 90% by weight, about 40% to about 80% by weight, and about 50% to about 70% by weight of a sodium salt of citric acid. In some cases, a composition provided herein contains about 70% to about 90% by weight or about 80% to about 90% by weight of a sodium salt of citric acid. In some embodiments, a composition provided herein can contain about 80% to about 90% by weight of a sodium salt of citric acid. For example, a composition can contain about 87% by weight of a sodium salt of citric acid such as sodium citrate dihydrate.
Detergent Enzyme
[0100] The term “detergent enzyme” as used herein refers to any enzyme preparation having the ability to aid in the cleaning process including, without limitation, the removal of debris (e.g., proteinaceous organic food soils and starch-containing food residues), the degradation of debris, and the removal and prevention of spots and film after the wash cycle. Detergent enzymes can be selected from lipases, mannanases, cellulases, zylenases, proteases, amylases, and mixtures of two or more detergent enzymes. In some embodiments, the detergent enzymes can be proteases, amylases, or a mixture thereof. Examples of protease enzyme detergents include, without limitation, Savinase™, Alcalase™, Esperase™, Maxatase™, Maxacal™ and Maxapem™. Examples of amylase enzyme detergents include, without limitation, Maxamyl™ (a bacterial amylase), Termamyl™ (a bacterial amylase), and BAN™ (a bacterial amylase). In some cases, compositions provided herein can include a mixture of protease and amylase detergent enzymes.
[0101] In some cases, compositions provided herein can contain about 0.02% to about 10% by weight of a detergent enzyme. For example, about 0.2% to about 8% by weight, about 0.2% to about 6% by weight, about 0.02% to about 5% by weight, about 0.02% to about 4% by weight, about 0.02% to about 3% by weight, about 0.02% to about 2% by weight, about 0.1% to about 10% by weight, about 0.5% to about 10% by weight, about 1% to about 10% by weight, about 3% to about 10% by weight, about 5% to about 10% by weight, about 7% to about 10% by weight, about 0.1% to about 5% by weight, about 0.5% to about 5% by weight, about 1% to about 5% by weight, about 3% to about 5% by weight, about 0.1% to about 3% by weight, about 2% to about 8% by weight, about 3% to about 7% by weight, about 4% to about 8% by weight, about 3% to about 6% by weight, about 0.5% to about 2% by weight, and about 0.75% to about 1.5% by weight of a detergent enzyme. In some cases, compositions provided herein can contain about 0.5% to about 2% by weight or about 0.75% to about 1.5% by weight of a detergent enzyme. For example, compositions provided herein can contain about 0.5% to about 2% by weight or about 0.75% to about 1.5% by weight of a mixture of detergent enzymes such as a mixture of two or more enzymes selected from the group including lipases, mannanases, cellulases, zylenases, proteases, and amylases. In some embodiments, compositions provided herein can contain about 0.5% to about 2% by weight or about 0.75% to about 1.5% by weight of a mixture of amylase and protease enzymes. Mixtures of the enzymes can contain the same or different amounts of each type of enzyme. In some cases, compositions provided herein can contain about 0.5% of an amylase enzyme and 0.5% of a protease enzyme.
[0000] Sheeting polymer
[0102] A sheeting polymer can be included in the compositions provided herein to provide a layer on the surfaces of the dishes and afford a sheeting action in the aqueous rinse step. In some cases, the inclusion of a sheeting polymer can obviate the need to include a rinse aid and/or a descaling agent in the composition.
[0103] Without wishing to be bound by theory, it is believed that the sheeting polymer adsorbs on the surfaces of the dishes, during the cleaning process. The layer of adsorbed sheeting polymer generally makes these surfaces more hydrophilic. The sheeting polymer thus should be capable to adsorb on the surfaces of the dishes to provide a layer thereon so as to afford a sheeting action in the aqueous rinse step. Water droplets getting into contact with these hydrophilically modified surfaces during rinsing will wet better implying that a continuous thin water film is formed instead of separate droplets. This thin water film will generally dry more uniformly without leaving water marks behind. Therefore, a good visual appearance is obtained without the need to use a rinse aid and/or a descaling agent in the composition.
[0104] In some cases, the sheeting polymer is a powder. A non-limiting example of sheeting polymer includes diallyldimethylammonium chloride.
[0105] In some cases, compositions provided herein can contain about 0.05% to about 3% by weight of a sheeting polymer. For example, about 0.05% to about 2% by weight, about 0.05% to about 1% by weight, about 0.05% to about 0.75% by weight, about 0.05% to about 0.5% by weight, about 0.05% to about 0.1% by weight, about 0.1% to about 3% by weight, about 0.25% to about 3% by weight, about 0.5% to about 3% by weight, about 1% to about 3% by weight, about 0.1% to about 1% by weight, and about 0.25% to about 0.75% by weight of a sheeting polymer. In some cases, composition provided herein can contain about 0.1% to about 1% by weight, and about 0.25% to about 0.75% by weight of a sheeting polymer. For example, compositions provided herein can contain about 0.5% by weight of a sheeting polymer.
[0106] In some cases, compositions provided herein can contain about 0.05% to about 3% by weight of diallyldimethylammonium chloride. For example, about 0.05% to about 2% by weight, about 0.05% to about 1% by weight, about 0.05% to about 0.75% by weight, about 0.05% to about 0.5% by weight, about 0.05% to about 0.1% by weight, about 0.1% to about 3% by weight, about 0.25% to about 3% by weight, about 0.5% to about 3% by weight, about 1% to about 3% by weight, about 0.1% to about 1% by weight, and about 0.25% to about 0.75% by weight of diallyldimethylammonium chloride. In some cases, composition provided herein can contain about 0.1% to about 1% by weight, and about 0.25% to about 0.75% by weight of diallyldimethylammonium chloride. For example, compositions provided herein can contain about 0.5% by weight of diallyldimethylammonium chloride.
Preservative
[0107] A powder detergent composition provided herein can include a preservative. The term “preservative” as used herein refers to any compound that acts as one or more of the following: as an enzyme stabilizer, a pH adjuster, an antimicrobial, an antifungal, or a chelator in a composition provided herein. An “enzyme stabilizer” as used herein refers to a compound that enhances or maintains the stability of a detergent enzyme within a composition provided herein. Examples of preservatives include, without limitation, calcium ions, propylene glycol, sorbitol, boric acid, soluble salts of boric acid, boronic acids, soluble salts of boronic acids, citric acid, soluble salts of citric acid, polyhydroxy compounds, carboxylic acids having from one to six carbon atoms (short chain carboxylic acids), and salt forms of carboxylic acids having from one to six carbon atoms (salt forms of short chain carboxylic acids), sorbic acid, soluble salt forms of sorbic acid, and mixtures thereof. In some cases, the preservative is selected from sorbic acid, soluble salt forms of sorbic acid, calcium ions, and mixtures thereof.
[0108] Any source can be used to provide calcium ions. For example, soluble salts of calcium such as calcium chloride, bromide, iodide, and nitrate can be used. Typically, the source of calcium ions has a moderate degree of solubility such that the calcium ions become available. Calcium ions can also be provided by slightly soluble salts (e.g., calcium sulfate). In addition, calcium ions can be introduced as the salt of another preservative (e.g., sorbic acid, formic acid or acetic acid) or as the salt of a non-phosphate builder (e.g., citric acid). In some cases, a soluble salt of calcium is calcium chloride.
[0109] In some cases, a preservative can be included in the compositions provided herein from about 0.05% to about 6% by weight. For example, about 0.05% to about 4% by weight, about 0.05% to about 3% by weight, about 0.05% to about 2% by weight, about 0.05% to about 1% by weight, about 0.1% to about 6% by weight, about 0.25% to about 6% by weight, about 0.5% to about 6% by weight, about 1% to about 6% by weight, about 3% to about 5% by weight, about 0.25% to about 1% by weight, about 0.5% to about 1% by weight, about 1% to about 4% by weight, and about 2% to about 4% by weight of a preservative. In some cases, compositions provided herein can include about 0.25% to about 1% by weight or about 0.5% to about 1% by weight of a preservative. For example, compositions provided herein can include about 0.25% to about 1% by weight of a mixture of one or more of sorbic acid, soluble salt forms of sorbic acid, and calcium ions. In some cases, compositions provided herein can include about 0.25% to about 1% by weight of a mixture of sorbic acid and calcium ions. For example, compositions provided herein can include a mixture of 0.4% by weight of sorbic acid and 0.3% by weight of calcium chloride. In some cases, compositions provided herein can include about 1% to about 6% by weight or about 2% to about 4% by weight of a preservative. For example, compositions provided herein can include about 2% to about 4% by weight of a mixture of one or more of sorbic acid, soluble salt forms of sorbic acid, citric acid, soluble salts of citric acid, and calcium ions. In some cases, compositions provided herein can include about 2% to about 4% by weight of a mixture of sorbic acid, citric acid, and calcium ions. For example, compositions provided herein can include a mixture of 0.4% by weight of sorbic acid, 2.6% citric acid, and 0.3% by weight of calcium chloride.
[0110] In some cases, compositions provided herein can contain from about 0.05% to about 6% by weight of a mixture of one or more of sorbic acid, soluble salts of sorbic acid, citric acid, soluble salts of citric acid, and calcium ions. For example, about 0.05% to about 4% by weight, about 0.05% to about 3% by weight, about 0.05% to about 2% by weight, about 0.05% to about 1% by weight, about 0.1% to about 6% by weight, about 0.25% to about 6% by weight, about 0.5% to about 6% by weight, about 1% to about 6% by weight, about 3% to about 5% by weight, about 0.25% to about 1% by weight, about 0.5% to about 1% by weight, about 1% to about 4% by weight, and about 2% to about 4% by weight of a mixture of one or more of sorbic acid, soluble salts of sorbic acid, citric acid, soluble salts of citric acid, and calcium ions. In some cases, compositions provided herein can include about 1% to about 6% by weight or about 2% to about 4% by weight of a mixture of one or more of sorbic acid, soluble salts of sorbic acid, citric acid, soluble salts of citric acid, and calcium ions.
Flow Aid
[0111] Powdered detergent compositions provided herein can include a flow aid. A flow aid can help to reduce the stickiness of the powdered detergent granules. Non-limiting examples of flow aids include silica, silicates, and phosphates. In some embodiments, a flow aid can include a precipitated amorphous silica, fumed silica, silicon dioxide, calcium silicates (e.g., tricalcium silicate and dicalcium silicate), aluminosilicate, and/or tricalcium phosphate. In some embodiments, the flow aid can be a sodium aluminosilicate or precipitated amorphous silica.
[0112] In some cases, compositions provided herein can include from about 0.5% to about 5% by weight of a flow aid. For example, about 0.5% to about 4% by weight, about 0.5% to about 3% by weight, about 0.5% to about 2.5% by weight, about 0.5% to about 2% by weight, about 0.5% to about 1% by weight, about 1% to about 5% by weight, about 1.5% to about 5% by weight, about 2% to about 5% by weight, about 3% to about 5% by weight, about 1% to about 4% by weight, about 1.5% to about 2.5% by weight, and about 1% to about 3% by weight of a flow aid. In some cases, compositions provided herein can include about 1% to about 3% by weight or about 1.5% to about 2.5% by weight of a flow aid. For example, compositions provided herein can contain about 2% by weight of a flow aid. In some cases, compositions provided herein can contain about 2% by weight of silica such as precipitated amorphous silica.
[0113] In some cases, compositions provided herein can include from about 0.5% to about 5% by weight of silica. For example, about 0.5% to about 4% by weight, about 0.5% to about 3% by weight, about 0.5% to about 2.5% by weight, about 0.5% to about 2% by weight, about 0.5% to about 1% by weight, about 1% to about 5% by weight, about 1.5% to about 5% by weight, about 2% to about 5% by weight, about 3% to about 5% by weight, about 1% to about 4% by weight, about 1.5% to about 2.5% by weight, and about 1% to about 3% by weight of silica. In some cases, compositions provided herein can include about 1% to about 3% by weight or about 1.5% to about 2.5% by weight of silica. For example, compositions provided herein can contain about 2% by weight of silica. In some cases, compositions provided herein can contain about 2% by weight of precipitated amorphous silica.
Essential Oils
[0114] Compositions provided herein can also include one or more essential oils. Such oils can provide a boost in the cleaning power of the compositions and/or a fragrance to the composition. In some cases, an essential oil can be used in place of a fragrance in the compositions. Non-limiting examples of essential oils include: abies, bitter, seed, angelica, anise, balsam, basil, bay, benzoin, bergamot, birch, rose, cajuput, calamus, cananga, capsicum, caraway, cardamon, cassia, Japanese cinnamon, acacia, cedarwood, celery, camomile, hay podge, cinnamon, citronella, clove, coriander, costus, cumin, dill, elemi, estragon, eucalyptus, fennel, galbanum, garlic, geranium, ginger, ginger grass, grapefruit, guaiac wood, white cedar, hinoki, hop, hyacinth, Jasmine, jonquil, juniper berry, laurel, lavandin, lavender, lemon, lemongrass, lime, linaloe, richea cubeb, lovage, mandarin, Melaleuca alternifolia leaf oil, mint, minosa, mustard, myrrh, myrtle, narcissus, neroli, nutmeg, oak moss, ocotea, olibanum, onion, opopanax, orange, oris, parsley, patchouli, palmarosa, pennyroyal, pepper, perilla, petitgrain, pimento, pine, rose, rosemary, camphor, clary sage, sage, sandalwood, spearmint, spike, star anise, styrax, thyme, tonka, tuberose, terpin, vanilla, vetiver, violet, wintergreen, worm wood, and ylang ylang. In some cases, the essential oils are selected from Melaleuca alternifolia leaf oil and orange oil. In some cases, compositions provided herein include from about 0.001% to about 5% by weight of one or more essential oils. For example, about 0.001% to about 4% by weight, about 0.001% to about 3% by weight, about 0.001% to about 2% by weight, about 0.001% to about 1% by weight, about 0.001% to about 0.5% by weight, about 0.001% to about 0.25% by weight, about 0.001% to about 0.1% by weight, about 0.001% to about 0.05% by weight, about 0.001% to about 0.01% by weight, about 0.001% to about 0.005% by weight, about 0.002% to about 5% by weight, about 0.003% to about 5% by weight, about 0.01% to about 5% by weight, about 0.1% to about 5% by weight, about 0.5% to about 5% by weight, about 1% to about 5% by weight, about 2% to about 5% by weight, about 3% to about 5% by weight, about 4% to about 5% by weight, about 0.002% to about 1% by weight, about 0.003% to about 1% by weight, about 0.01% to about 1% by weight, about 0.1% to about 1% by weight, about 0.5% to about 1% by weight, about 0.002% to about 0.005% by weight, about 2% to about 4% by weight, about 1% to about 3% by weight, about 0.5 to about 2.5% by weight, about 0.005% to about 0.01% by weight, about 0.01% to about 0.05% by weight, and about 0.1% to about 0.5% by weight of one or more essential oils. In some cases, compositions provided herein can contain about 0.002% to about 0.005% by weight of one or more essential oils. For example, compositions provided herein can contain about 0.003% by weight of one or more essential oils such as Melaleuca alternifolia leaf oil or orange oil. In some cases, compositions provided herein can contain about 0.003% by weight of Melaleuca alternifolia leaf oil.
[0115] In some cases, compositions provided herein include from about 0.001% to about 5% by weight of Melaleuca alternifolia leaf oil or orange oil. For example, about 0.001% to about 4% by weight, about 0.001% to about 3% by weight, about 0.001% to about 2% by weight, about 0.001% to about 1% by weight, about 0.001% to about 0.5% by weight, about 0.001% to about 0.25% by weight, about 0.001% to about 0.1% by weight, about 0.001% to about 0.05% by weight, about 0.001% to about 0.01% by weight, about 0.001% to about 0.005% by weight, about 0.002% to about 5% by weight, about 0.003% to about 5% by weight, about 0.01% to about 5% by weight, about 0.1% to about 5% by weight, about 0.5% to about 5% by weight, about 1% to about 5% by weight, about 2% to about 5% by weight, about 3% to about 5% by weight, about 4% to about 5% by weight, about 0.002% to about 1% by weight, about 0.003% to about 1% by weight, about 0.01% to about 1% by weight, about 0.1% to about 1% by weight, about 0.5% to about 1% by weight, about 0.002% to about 0.005% by weight, about 2% to about 4% by weight, about 1% to about 3% by weight, about 0.5 to about 2.5% by weight, about 0.005% to about 0.01% by weight, about 0.01% to about 0.05% by weight, and about 0.1% to about 0.5% by weight of Melaleuca alternifolia leaf oil or orange oil. In some cases, compositions provided herein can contain about 0.002 to about 0.005% by weight of Melaleuca alternifolia leaf oil or orange oil. For example, compositions provided herein can contain about 0.003% by weight of Melaleuca alternifolia leaf oil.
Fragrance
[0116] Compositions provided herein can include one or more fragrances. Fragrances and fragrant ingredients useful in the present compositions include a wide variety of natural and synthetic chemical ingredients, including, but not limited to, aldehydes, ketones, esters, and the like.
[0117] In some cases, compositions provided herein include from about 0.05 to about 2% by weight of fragrance. For example, about 0.05 to about 1% by weight, about 0.05 to about 0.5% by weight, about 0.05 to about 0.3% by weight, about 0.05 to about 0.1% by weight, about 0.1 to about 2% by weight, about 0.15 to about 2% by weight, about 0.3 to about 2% by weight, about 0.5 to about 2% by weight, about 1 to about 2% by weight, about 0.1 to about 0.3% by weight, about 0.05 to about 0.5% by weight, and 0.15% to about 0.25% by weight of fragrance. In some cases, compositions provided herein can contain about 0.1 to about 0.3% by weight or 0.15% to about 0.25% by weight of fragrance. For example, compositions provided herein can contain about 0.2% by weight of fragrance.
Phosphate Builders, Bleach, Bleaching Agents, Water, and Solvents
[0118] In some cases, the compositions provided herein lack one or more of phosphate builders, bleach, and bleaching agents. Phosphate builders can include, for example, orthophosphates such as trisodium phostate and disodium phosate, and complex (or condensed) phosphates such as tetrasodium pyrophosphate, sodium tripolyphosphate, sodium tetraphosphate, and sodium hexametaphosphate. In some cases, compositions provided herein can lack chlorine bleaches such as sodium hypochlorite and calcium hypochlorite. Bleaching agents can include peroxides, such as hydrogen peroxide, sodium percarbonate, sodium perborate, sodium dithionite, and sodium borohydride.
[0119] Compositions provided herein can also include less than about 1% by weight of water or other solvent. Solvents, as used herein, include organic and inorganic solvents such as alcohols (e.g., ethanol, isopropanol, methanol), dimethyl glyoxime, and polyols. In some cases, solvents include non-polar, polar, and polar aprotic solvents. In some cases, compositions provided herein include no or negligible amounts of water or other solvents.
[0120] As used herein, a “soluble salt” refers to a salt form of a compound that is soluble in water or other aqueous solution. Such salt forms are readily known to those having ordinary skill in the art. Examples of suitable cations of soluble salts include sodium, potassium, calcium, and magnesium salts. Examples of suitable anions of soluble salts include chloride, bromide, iodide, and nitrate.
Powdered Detergent Compositions
[0121] As described above, compositions provided herein can contain one or more of a low foaming nonionic surfactant, a non-phosphate detergent builder, a detergent enzyme, and a sheeting polymer. In some cases, the compositions can further include one or more of a preservative, a flow aid, an essential oil, and a fragrance. For example, compositions can include a low foaming nonionic surfactant, a non-phosphate detergent builder, a detergent enzyme, a sheeting polymer, and a preservative; a low foaming nonionic surfactant, a non-phosphate detergent builder, a detergent enzyme, a sheeting polymer, and a flow aid; a low foaming nonionic surfactant, a non-phosphate detergent builder, a detergent enzyme, a sheeting polymer, and an essential oil; a low foaming nonionic surfactant, a non-phosphate detergent builder, a detergent enzyme, a sheeting polymer, and a fragrance; a low foaming nonionic surfactant, a non-phosphate detergent builder, a detergent enzyme, a sheeting polymer, a preservative, and a flow aid; a low foaming nonionic surfactant, a non-phosphate detergent builder, a detergent enzyme, a sheeting polymer, a preservative, and an essential oil; a low foaming nonionic surfactant, a non-phosphate detergent builder, a detergent enzyme, a sheeting polymer, a preservative, and a fragrance; a low foaming nonionic surfactant, a non-phosphate detergent builder, a detergent enzyme, a sheeting polymer, a flow aid, and an essential oil; a low foaming nonionic surfactant, a non-phosphate detergent builder, a detergent enzyme, a sheeting polymer, a flow aid, and a fragrance; a low foaming nonionic surfactant, a non-phosphate detergent builder, a detergent enzyme, a sheeting polymer, an essential oil, and a fragrance; a low foaming nonionic surfactant, a non-phosphate detergent builder, a detergent enzyme, a sheeting polymer, a preservative, and a flow aid; a low foaming nonionic surfactant, a non-phosphate detergent builder, a detergent enzyme, a sheeting polymer, a preservative, a flow aid, and an essential oil; a low foaming nonionic surfactant, a non-phosphate detergent builder, a detergent enzyme, a sheeting polymer, a preservative, a flow aid, an essential oil, and a fragrance; a low foaming nonionic surfactant, a non-phosphate detergent builder, a detergent enzyme, a sheeting polymer, a flow aid, an essential oil, and a fragrance; and a low foaming nonionic surfactant, a non-phosphate detergent builder, a detergent enzyme, a sheeting polymer, a preservative, an essential oil, and a fragrance.
[0122] For example, provided herein is a powder detergent composition comprising or consisting of:
[0123] (a) about 0.5 to about 15% by weight of a surfactant, wherein said surfactant is a low foaming nonionic surfactant;
[0124] (b) about 30 to about 90% by weight of a non-phosphate detergent builder;
[0125] (c) about 0.02 to about 5% by weight of a detergent enzyme; and
[0126] (d) about 0.05 to about 3% by weight of a sheeting polymer.
[0127] In some cases, the above composition further comprises from about 0.001 to about 5% by weight (e.g., 0.001 to about 1% by weight) of one or more essential oils. For example, Melaleuca alternifolia leaf oil or orange oil. In some cases, the above composition can also include from about 0.5 to about 5% by weight of a flow aid. In some cases, the above composition further includes from about 0.05 to about 2% by weight of fragrance.
[0128] For example, a composition provided herein can include or consist of:
[0129] (a) about 0.5 to about 15% by weight of a surfactant, wherein said surfactant is a low foaming nonionic surfactant;
[0130] (b) about 30 to about 90% by weight of a non-phosphate detergent builder, wherein said non-phosphate detergent builder is selected from the group consisting of citric acid or a salt form thereof;
[0131] (c) about 0.02 to about 5% by weight of a detergent enzyme;
[0132] (d) about 0.05 to about 3% by weight of a sheeting polymer;
[0133] (e) about 0 to about 5% by weight of a preservative;
[0134] (f) about 0.5 to about 5% by weight of a flow aid;
[0135] (g) from 0 to about 5% by weight of one or more essential oils; and
[0136] (h) from 0 to about 2% by weight of fragrance.
[0137] In some embodiments, a composition provided herein includes or consists of: (a) about 1 to about 10% by weight of a surfactant, wherein said surfactant is a low foaming nonionic surfactant;
[0138] (b) about 80 to about 90% by weight of a non-phosphate detergent builder, wherein said non-phosphate detergent builder is selected from the group consisting of citric acid or a salt form thereof;
[0139] (c) about 0.5 to about 2% by weight of a detergent enzyme; and
[0140] (d) about 0.1 to about 1% by weight of a sheeting polymer;
[0141] (e) wherein the composition comprises less than about 1% by weight of water or other solvent.
[0142] In some cases, the above composition further comprises from about 0.001 to about 5% by weight (e.g., about 0.001 to about 1% by weight) of one or more essential oils. For example, Melaleuca alternifolia leaf oil or orange oil. In some cases, the above composition can also include from about 0.5 to about 5% by weight of a flow aid. In some cases, the above composition further includes from about 0.05 to about 2% by weight of fragrance.
[0143] For example, a composition can include or consist of:
[0144] (a) about 1 to about 10% by weight of a surfactant, wherein said surfactant is a low foaming nonionic surfactant;
[0145] (b) about 80 to about 90% by weight of a non-phosphate detergent builder, wherein said non-phosphate detergent builder is selected from the group consisting of citric acid or a salt form thereof;
[0146] (c) about 0.5 to about 2% by weight of a detergent enzyme;
[0147] (d) about 0.1 to about 1% by weight of a sheeting polymer;
[0148] (e) about 0 to about 5% by weight of a preservative;
[0149] (f) about 0.5 to about 5% by weight of a flow aid;
[0150] (g) from 0 to about 1% by weight of one or more essential oils; and
[0151] (h) from 0 to about 2% by weight of fragrance.
[0152] In some cases, a composition provided herein includes or consists of:
[0153] (a) about 1 to about 10% by weight of a polyoxypropylene polyoxyethylene condensate;
[0154] (b) about 80 to about 90% by weight of sodium citrate dihydrate;
[0155] (c) about 0.5 to about 2% by weight of a mixture of amylase and protease enzymes; and
[0156] (d) about 0.1 to about 1% by weight of diallyldimethylammonium chloride. In some cases, the above composition further comprises from about 0.001 to about 5% by weight (e.g., about 0.001 to about 1% by weight) of one or more essential oils. For example, Melaleuca alternifolia leaf oil or orange oil. In some cases, the above composition can also include from about 0.5 to about 5% by weight of a flow aid. In some cases, the above composition further includes from about 0.05 to about 2% by weight of fragrance.
[0157] For example, a composition provided herein can include or consist of:
[0158] (a) about 1 to about 10% by weight of a polyoxypropylene polyoxyethylene condensate;
[0159] (b) about 80 to about 90% by weight of sodium citrate dihydrate;
[0160] (c) about 0.5 to about 2% by weight of a mixture of amylase and protease enzymes;
[0161] (d) about 0.1 to about 1% by weight of diallyldimethylammonium chloride;
[0162] (e) about 0.05 to about 5% by weight of a mixture of sorbic acid, citric acid, and calcium chloride;
[0163] (f) about 0.5 to about 5% by weight of silica;
[0164] (g) from 0 to about 1% by weight of Melaleuca alternifolia leaf oil; and
[0165] (h) from 0 to about 2% by weight of fragrance.
[0166] In some cases, a composition provided herein includes or consists of:
[0167] (a) about 6% by weight of a polyoxypropylene polyoxyethylene condensate;
[0168] (b) about 87% by weight of sodium citrate dihydrate;
[0169] (c) about 1% by weight of a mixture of amylase and protease enzymes; and
[0170] (d) about 0.5% by weight of diallyldimethylammonium chloride.
[0171] In some cases, the above composition further comprises from about 0.001 to about 1% by weight of one or more essential oils. For example, Melaleuca alternifolia leaf oil or orange oil. In some cases, the above composition can also include from about 0.5 to about 5% by weight of a flow aid. In some cases, the above composition further includes from about 0.05 to about 2% by weight of fragrance.
[0172] For example, a composition provided herein can include or consist of:
[0173] (a) about 6% by weight of a polyoxypropylene polyoxyethylene condensate;
[0174] (b) about 87% by weight of sodium citrate dihydrate;
[0175] (c) about 1% by weight of a mixture of amylase and protease enzymes;
[0176] (d) about 0.5% by weight of diallyldimethylammonium chloride;
[0177] (e) about 3.4% by weight of a mixture of sorbic acid, citric acid, and calcium chloride;
[0178] (f) about 2% by weight of silica;
[0179] (g) about 0.003% by weight of Melaleuca alternifolia leaf oil; and
[0180] (h) about 0.2% by weight of fragrance.
[0181] In any of the above compositions, the composition can include less than about 1% by weight of water or other solvent. In some cases, any of the above compositions can be free of phosphate builders, bleach, and/or bleaching agents.
[0182] Further provided herein is an automatic dishwashing detergent packet. This packet can include a water soluble container comprising a water-soluble film; and a powder detergent composition provided herein within the container. In some embodiments, the automatic dishwashing detergent packet can be a monophasic automatic dishwashing detergent packet. As used herein, the term “monophasic” refers to the presence of a single composition (e.g., a single powdered composition) within the water-soluble container. In some embodiments, the compositions provided herein can be included in multi-pocketed (e.g., two pockets, three pockets, or four pockets) automatic dishwashing detergent packets, where different powdered or liquid compositions can be contained in separate pockets created by layers or compartments made with the water-soluble films.
[0183] Packets as provided herein contain powder compositions which are compatible with the water-soluble containers in which they are stored. For example, the powdered compositions do not substantially degrade the containers or breach their containment.
[0184] The packets are suitable for cleaning a variety of materials, and enable relatively safe and efficient handling of concentrates by both skilled and unskilled laborers.
[0185] The container provided herein comprises a water-soluble material. As used herein, a water-soluble material is defined as a material which substantially dissolves in response to being contacted with water. In some cases, the water-soluble material can be in the form of a film. Suitable materials for the film include polyvinyl alcohol and partially hydrolyzed polyvinyl acetate and alginates. In some cases, the films include polyvinyl alcohol. For example, the container can consists essentially of or consist of a water-soluble film and the water-soluble film consists essentially of or consists of polyvinyl alcohol. Other water-soluble materials can include materials having water-solubilities ranging from partial solubility in hot water to complete solubility in cold water. For example, in the case of a packet containing automatic dishwashing powder, it is sufficient that water at wash temperatures will cause enough disintegration of the film to allow release of the contents from the package into the wash water.
[0186] The thickness of the film itself should be sufficient to give it the required mechanical strength. Typically, the thickness of the film will lie within the range of from 0.5 to 10 mil (12.7 μm to 254 μm). For example, from 1 to 5 mil, from 1 to 3 mil, from 1.5 to 3 mil, and from 1 to 4 mil. In some embodiments, the film thickness is 3 mil (76 μm). The films can also have a high bursting strength. The film is also capable of undergoing high heat-sealing, since heat-sealing represents a convenient and inexpensive method of making packets as described herein.
[0187] In some embodiments, the film can include Monosol® having a thickness of about 1.5 to about 3 mil. In some embodiments, the top and the bottom film have different thicknesses. For example, the top film can be 2 mil and the bottom film can be 3 mil.
[0188] The film or container can be uncoated. In most cases, the compositions provided herein are compatible with the water-soluble container, and thus, protective coatings may not be necessary to provide adequate stability to the packet.
[0189] In some cases, the packets provided herein are conveniently in the form of a bag or sachet. The packet may be formed from one or more sheets of a packaging film or from a tubular section of such film. For example, the packet can be formed from a single folded sheet or from two sheets, sealed together at the edge regions either by means of an adhesive or by heat-sealing. In some cases, a packet provided herein can be a rectangular one formed from a single folded sheet sealed on three sides, with the fourth side sealed after filling the packet with a powder composition provided herein. Accordingly, the packet will have a single-layer of a water-soluble film wherein the water-soluble film has an internal surface directly contacting a powder detergent composition and an external surface which is an outermost portion of the packet.
[0190] The compositions provided herein can be used in an automatic dishwashing machine. For example, provided herein are methods of cleaning non-textile surfaces such as tableware (e.g., plates, cups, flatware, etc.) using an effective amount of a composition provided herein. In some cases, an effective amount of a composition is one or more packets as described herein. For example, one packet can be used to effectively clean tableware in an automatic dishwashing machine. In some cases, one packet is effective to clean tableware without the addition of a separate rinse aid.
EXAMPLES
[0191] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.
Example 1
[0192]
[0000]
Component
% by weight
Sodium Citrate dihydrate
87
Sorbic acid
0.4
Citric Acid
2.6
Calcium chloride
0.3
Meroxapol 252; Pluronic 25R2 (low foaming
6
non-ionic surfactant - see below)
Diallyldimethylammonium chloride - (sheeting
0.500
polymer)
Amylase Enyzme
0.500
Protease Enzyme
0.500
Precipitated amorphous silica (flow aid)
2.000
Melaleuca alternifolia Leaf oil
0.003
Fragrance
0.200
OTHER EMBODIMENTS
[0193] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.
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This disclosure relates to powdered automatic dishwashing detergents. More particularly, this disclosure relates to powdered automatic dishwashing detergent packets with superior environmental and human safety as well as superior cleaning efficacy and stability.
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BACKGROUND OF THE INVENTION
The invention relates to a radial press with a press axis and with a plurality of outer cam surfaces which are disposed at an angle to one another and have surface normals aimed at the press axis, and which are disposed in sets of two press yokes movable radially against one another by a driving system, the planes of symmetry of the cam surfaces disposed in the same press yoke running parallel to the drive direction, and having several outer cam follower bodies, each lying between two of the outer cam surfaces, for the radial advancement of press jaws toward the press axis.
Such radial presses serve for the shaping or machining of workpieces having rotationally symmetrical external surfaces, such as pipes, tubes, thimbles etc. An especially wide field of application of such radial presses is the manufacture of hoses by the radial pressing of hollow cylindrical hose sleeves, provided as a rule with an internal bead, onto a hose end having an armature of steel wire, from which the elastomeric outer layer has been removed. In the end of the hose in this case is a coupling piece consisting of metal, against which the hose end is to be pressed under high pressure by means of the sleeve. Such hose lines must be able to withstand pressures of up to 1,000 bar and more under fluctuating stress over a long period of time. Any failure of such a hose with a discharge of hydraulic fluid can lead to fatal injuries, and therefore the radial presses in question must satisfy stringent requirements.
The term, "rotationally symmetrical outside surfaces", is to be understood to mean workpiece shapes with circular cross sections and cross sections in the form of regular polygons, such as those to be found in hexagonal cross sections. The outer surfaces of the workpiece can be straight, barrel-shaped or stepped. Such workpiece surfaces can be provided for by shaping the press jaws accordingly.
Another problem is based on the fact that neither the press manufacturer nor the user can anticipate the numerous shapes of metal couplings for the hoses in question. A large number of the couplings are in the form of elbows, for example, and coupling parts with long tubular pieces are known. Such coupling units necessitate a great amount of free space on the back of the press facing away from the operator's side, and likewise a very short axial depth in the press. Both requirements militate against the design needs of such presses, in which high pressing forces and reaction forces must be reckoned with. Furthermore, the presses in question must be as small as possible and for many applications they must also be transportable without great complications, for example for use on large construction sites. Special machines have, as a rule, a large number of high-pressure hose lines which also have to be replaced and repaired in the field, by separating the hose from the still usable coupling parts. The re-use of the coupling parts is practiced even for the sake of reducing industrial waste.
A radial press of the kind described above pertains to the state of the art due to public use, and its principles of design and action will be further explained in a detailed description in conjunction with FIG. 1. At this point it will only be said that the press in question has a large and heavy one-piece press frame completely encompassing the hydraulic cylinder for reasons of strength.
German patent disclosure document OS 35 13 129 discloses a radial press with four hydraulic drivers disposed star-wise, in which twice the number of press jaws, namely eight, can be actuated synchronously by the interaction of four outer and four inner cam follower bodies. This press too has a large and heavy press frame, which is ring-like.
It is the object of the invention, on the other hand, to provide a radial press of the kind described above, which will be smaller and lighter, have an extremely short depth, and on the back of the press facing away from the operator's side, it will have virtually unlimited room both for the insertion of fittings with elbows and for the processing of fittings with long pipes and of endless tubing.
The solution of the problem is accomplished in accordance with the invention in the radial press described above in that the one press yoke is moved against the other press yoke by traction posts which are disposed parallel to the direction of action and pass through the guiding press yoke at the ends of the yoke outside of the yoke's cam faces, are affixed to the other, guided press yoke, and are connected on the other side of the guiding press yoke to a driver having a pulling action.
A radial press thus configured combines an extremely small size and especially small depth with low weight and an extremely simple construction.
The drivers with pulling action might be, for example, threaded spindles; it is especially advantageous, however, if a hydraulic jack could be associated with each traction post. Since the radial press does not require a circular press frame as in the state of the art, there is no need for components subject to traction and/or flexure to be mounted around the hydraulic jack, so that substantially larger piston faces can be used without interfering with a press frame, so that either the pressing force can be increased or the driving capacity of the hydraulic jack can be reduced. Further particulars on this will be set forth in the detailed description.
An especially advantageous design of such a press is characterized, pursuant to additional development, in that the press axis is horizontal, that the bottom, guiding press yoke is disposed on a platform beneath which the hydraulic jacks are in a case containing hydraulic fluid, and that the bottom press yoke and the hydraulic jacks are mounted on opposite sides of the platform.
In such a design the positive forces and reaction forces are directly engaged with one another and cancel one another within a minimum of space. Therefore it is not even necessary to provide the platform with any special rigidity.
The term, "platform," as used herein refers to all components which absorb the contrary forces of the press yoke and the hydraulic jack. In the simplest case it can be a horizontal steel plate serving as the cover or top of the case.
It is especially advantageous that each press yoke has an approximately parallelepipedal envelope surface with one long axis and two cam faces set at a right angle to one another and separated by a planar surface parallel to the long axis of the parallelepiped, the bisectors of the angle being parallel to the direction of the press action; that four outer cam follower bodies and four inner cam follower bodies are present, which alternate on the circumference; that the outer cam follower bodies lying above and below the press axis are supported motionless on the said planar surfaces of the press yokes; that the press yokes have additional planar boundary surfaces radially outside of the cam faces, which are parallel to one another and perpendicular to the direction of the press action, and that the bores in line with one another in pairs that are provided for two traction posts are brought through these planar boundary surfaces.
Additional advantageous configurations of the subject matter of the invention will be found in the secondary claims.
SUMMARY OF THE INVENTION
In accordance with the invention, a radial press comprises a set of movable press yokes (18, 19), a press axis (A) and a plurality of outer cam surfaces (1, 2, 3, 4) which are disposed at an angle to one another and have surface normals aimed at the press axis, and which are disposed in the set of movable press yokes (18, 19), a driving system for moving the set of two press yokes in a drive direction (17) radially against one another, cam surfaces (1-2, and 3-4, respectively) disposed in the same press yoke having planes of symmetry running parallel to the drive direction, several outer cam follower bodies (31, 32, 33, 34), each lying between two of the outer cam surfaces, for the radial advancement of press jaws (30, 41) toward the press axis, traction posts (25, 26) for guiding one guided press yoke (18) with respect to the other guiding press yoke (19), the traction posts running parallel to the drive direction and passing through the guiding press yoke (19) on a side at its ends lying outside of the cam surfaces (1, 2, 3, 4), and fixedly joined to the other, guided, press yoke (18), and joined on an other side of the guiding press yoke to a driver having a pulling action (52).
BRIEF DESCRIPTION OF THE DRAWING
The state of the art, as well as an embodiment of the subject matter of the invention, will be further explained with the aid of FIGS. 1 to 7.
FIG. 1 shows the principle of construction and operation of a radial press according to the generic idea and according to the state of the art, respectively,
FIG. 2 shows the principle of action of the control surfaces with respect to the individual press jaws,
FIG. 3 represents a radial press in accordance with the invention with the details according to FIG. 2, with the press jaws in the open state,
FIG. 4 shows the radial press according to FIG. 3 with the press jaws in the closed state,
FIG. 5 shows the right half of FIG. 2 with additionally placed guide plates,
FIG. 6 is a side view of the subject of FIG. 4 seen in the direction of arrow VI in FIG. 5, and
FIG. 7 is a variant of the subject of FIG. 2.
In FIG. 1 there is shown a radial press according to the state of the art, wherein four cam faces 1, 2, 3 and 4 are in pairs at right angles to one another. The cam faces 1 and 2 are disposed in the upper yoke 5 of a press frame 6 that is continuous all around and which also surrounds a double-acting hydraulic cylinder 7 with a piston 8. A very thick piston rod 9 designed for pressure connects the hydraulic jack 10 to a bottom yoke 11 in which the cam faces 3 and 4 are disposed.
The cam faces 1 to 4, as seen in projection onto the plane of drawing, are on the sides of a square. To avoid excessive weakening of the yokes 5 and 11, however, two corners of this square are set back, so that the pair of cam faces 3 and 4 are separated by an additional planar surface 13. Thus a bridging portion of the thickness A 2 is formed in the upper yoke 5. The bridging portion of the bottom yoke 11 is not further identified. The bridging portion A 2 , however, must nevertheless be of adequate thickness, because in the center of the yoke 5 great flexural moments occur, which are due to the great distance B 2 between the center lines 14a and 15a of the sides 14 and 15 of the press frame 6. Overall, the press frame 6 has a considerable height H 2 which is due to the design of the cam faces 1 to 4, the hydraulic drive 10 and the necessary thicknesses in the upper yoke 5, in the bottom yoke 11, and in the base yoke 16 of the press frame. It is obvious that such a press frame is large and heavy, and means must additionally be provided for guiding the bottom yoke 11 in the press frame 6, which are not shown here for the sake of simplicity. The rest of the hydraulic units for supplying the hydraulic jack 10 must be housed outside of the press frame 6, which again are not shown here for the sake of simplicity.
Here let it be explained once again that the press axis A is perpendicular to the plane of drawing, and that the direction of drive is indicated by the broken line 17 which passes through the axis of the piston rod 9. The bisectors of the angles of the cam faces 1 and 2 and of the cam faces 3 and 4 run in the direction of line 17 through the press axis A.
DESCRIPTION OF THE PREFERRED EMBODIMENT
FIG. 2 shows an upper yoke 18 and a bottom yoke 19 in accordance with the invention. Each of these yokes has an approximately parallelepipedal envelope surface with a longitudinal axis, not shown here, running perpendicular to the direction of driver 17 and parallel to the plane of drawing. The two press yokes 18 and 19 have the planar cam faces 1 to 4 described above, which in the present case are provided with facings 20 of a permanently lubricating material. The explanations given above apply with regard to the geometrical arrangement of the cam faces and to the separation created between them by the planar surfaces 12 and 13 which are parallel to the long axes of the parallelepiped.
The press yokes 18 an 19 have additional planar boundary surfaces 21, 22, 23 and 24, which are parallel to one another in pairs 21/23 and 22/24, and run perpendicular to the direction of drive 17. The identical spacings between the boundary surfaces 21/23 and 22/24 define a stroke H which the upper press yoke 18 can execute against the bottom, fixed press yoke 19. Between the press yokes 18 and 19 can be seen sections of tension armatures 25 and 26 whose longitudinal axes are indicated by the broken lines 25a and 26a, respectively. On the bottom yoke 19 there is a microswitch 27 and on the upper yoke 18 an adjusting spindle 28 with a pusher plate 28a for the microswitch 27. The arrangement in question forms an adjustable stroke limiter for the total stroke of the press jaws, starting from the maximum possible opening corresponding to the double arrow 29.
Four outer control bodies 31, 32, 33 and 34 are supported against the cam faces 1 to 4 and each has a press jaw 30 in its center. Each of these outer control bodies has in mirror-image symmetry with its axis of symmetry on both sides an inner cam face 35 and 36, and on two adjacent cam faces 35 and 36 of each pair of outer control bodies is an inner cam follower body 37, 38, 39 and 40, each bearing a press jaw 41 of the same configuration as press jaw 30. The inside surfaces of all the press jaws are at the same distance from the press axis A. The outside surfaces of the inner control bodies 37 to 40 which are at an angle of 135 degrees likewise bear a facing 20a of a permanently lubricating material. The attitude angle of the individual cam faces to one another is selected so that the inner cam follower body borne by the inner cam faces 35 and 36 can be moved at the same radial speed and over the same radial distance as the outer control bodies 31 and 34.
It can be seen that the outer control bodies 31 and 33 situated directly over and under the press axis A remain stationary on the planar surfaces 12 and 13, while the outer control bodies 32 and 34 between them perform a movement toward the press axis A under the action of the cam faces 1 to 4 when the yokes 18 and 19 come together. During this pressing stroke the press axis A performs a downward movement of the magnitude of one-half of the movement of the upper yoke 18.
It can be seen that the outer and inner control bodies alternate on the circumference. It can also be understood that the bores for the two tension armatures 25 and 26, which are not especially highlighted here, run all the way through the boundary surfaces 21 to 24 of the yokes 18 and 19.
In the figures that follow the same parts as before are identified by the same reference numbers. FIG. 2 shows an enlarged detail of FIG. 3, so that the parts lying within the cam faces 1 to 4 do not have to be discussed again. It can be understood that the upper ends of the tension armatures 25 and 26 bear nuts 42 and 43 resting on the upper press yoke 18. The bottom ends of the tension armatures 25 and 26 pass through a platform 44 consisting of a thin steel plate and simultaneously forming the cover of a case 45 containing a hydraulic fluid 46. While the bottom press yoke 19 is supported on the top of the platform 44, two hydraulic cylinders 47 and 48 are held on the bottom of the platform 44. The bottom ends of the tension armatures 25 and 26 reach into these hydraulic cylinders 47 and 48 through bores 49 of which only one is represented by a radial section through the hydraulic cylinder 48. The bottom ends of the tension armatures 25 and 26 are joined to single-acting pistons 50 and 51, which are represented in FIG. 4.
The hydraulic cylinders 47 and 48 together with the pistons 50 and 51, which are driven on one side only, form a drawing mechanism 52.
The hydraulic cylinders 47 and 48 are situated side by side leaving a small gap in which a tensionally stressed piston rod 53 of a hydraulic jack 54 is located. The upper end of the piston rod 53 is screwed to the bottom yoke 19, while the bottom end bears a piston 54a which is encompassed by a hydraulic cylinder 54b (especially FIG. 4). The cylinder 54b is in contact with the pistons 50 and 51 and, when the annular space above the piston 54a is pressurized it forces them upwardly to the position shown in FIG. 3. This movement is followed, through the tension armatures 25 and 26, by the upper press yoke 18, while the bottom press yoke 19 remains on the platform 44. Thus the cam faces and 4, and 2 and 3, respectively, move apart, and the press jaws return under the action of compression springs 55 to their open position, which is indicated by the double arrow 29.
In back of the plane of drawing according to FIG. 3, the platform 44 has a circular opening 56 on which a motor 57 is fastened by means of a flange 57a. Underneath the recess 56 a hydraulic pump 58, in the form of a submersible pump, is flange-mounted to the motor 57. This pump is connected by a control valve 59 and by hydraulic tubing indicated by broken lines to the individual hydraulic drives. All of the hydraulic drive elements are contained within the case 45, as represented in FIG. 3, so that not only is an extremely simple routing of the lines possible, but also leakage can be disregarded.
FIG. 4 shows the radial press with the press jaws in the closed position. The distances between diametrically opposite press jaws, whose working surfaces in this case make up a cylindrical surface, are at a distance apart (diameter) that is indicated by the double arrow 60. It can also be seen that the upper cam follower body 31 and the bottom cam follower body 33 remain steady on the corresponding planar surfaces 12 and 13, respectively, while the other two control bodies 32 and 34 have been pushed toward the press axis A under the action of the cam faces 1/4 and 2/3, respectively.
It can furthermore be seen that the tension armature 26 has a shoulder 61 which is situated in the seam between the two press yokes. With this shoulder the upper end of reduced diameter of the tension armature 26 is drawn by means of the nut 43 against the upper press yoke 18. Fitted bores 62 serve to accommodate the said reduced ends. The same applies, of course, to the situation of tension armature 25. The larger-diameter section of each of the tension armatures 25 and 26 is held with clearance and with the interposition of a bearing material if desired, in bores 63 of the bottom press yoke 19, as shown on the right side of FIG. 4. Therefore the upper press yoke 18 is the guided part and the bottom press yoke 19 the guiding part.
It can also be learned from FIG. 4 that the distance B 1 between the axes 25a and 26a of the tension armatures is less than the distance B 2 between the so-called "neutral axes" of the press frame according to FIG. 1 in the area of the frame opening for the hydraulic driver 10 and the press yoke 11 (FIGS. 1, 3 and 4 are comparable in scale). In this manner it is possible to keep the cross section at the weakest point of the upper press yoke 18, which is characterized by the dimension A 1 , considerably smaller than is the case in the state of the art according to FIG. 1 with the dimension A 2 . Also in regard to the total height of the parts essential to the operation of the press, a lower structural height is achieved in the subject matter of the invention with the dimension H 1 than in the state of the art with the dimension H 2 . Lastly, in the subject matter of the invention, a definitely larger piston cross section can be contained underneath the press yokes 18 and 19, because the sum of two piston areas with the diameter D 1 is definitely greater, even after deducting the cross-sectional areas for the tension armature, than the cross-sectional area of a single piston with the diameter D 2 according to FIG. 1. Lastly, as regards the use of material, the two tension armatures can be configured with a decidedly smaller diameter d 1 than is the case in a piston rod under compressive stress in accordance with FIG. 1. Also, a beam on two bearings, as in the subject matter of the invention, is always subjected to much less stress than a beam supported in the center as in the state of the art with the bottom press yoke 11.
In FIG. 5 it is shown that guide bars 64 are fastened releasably by screws 65 in a mirror-image relationship on the plane-parallel side faces of the upper yoke 18 and lower yoke 19, and they contain between them the inner control bodies 37 to 40 and thereby prevent them from slipping out axially. This assumes that the width of the yokes 18 and 19 is wider by the necessary clearance of the control bodies than the axial length of these control bodies. The boundary surfaces 64a parallel to the direction of press action 17 do not reach as far as a plane of symmetry passing through the press axis A--A, but instead leave a space between them which facilitates the pressing of armatures with pipe elbows.
FIG. 6 shows the situation in the direction of the arrow VI in FIG. 5.
FIG. 7 shows a variant of the subject of FIG. 2. In this case the uppermost cam follower body 31 and the lowermost cam follower body 33 are made integral or in one piece with the press yoke 18 and 19. This makes the formation of the press yokes 18 and 19 more difficult, but the one-piece outer control bodies 31 and 32 serve to increase the moment of resistance of the press yokes 18 and 19. Of course, the subject of FIG. 7 also has the guide bars 64 shown in FIGS. 5 and 6, which are omitted from FIG. 7 for the sake of simplicity.
While there has been described what is at present considered to be the preferred embodiment of this invention, it will be obvious to those skilled in the art that various changes and modifications may be made therein without departing from the invention, and it is, therefore, aimed to cover all such changes and modifications as fall within the true spirit and scope of the invention.
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In a radial press having a press axis (A) , a plurality of outer cam surfaces (1, 2, 3, 4) at an angle to one another are grouped in two press yokes (18, 19) which are driven radially against one another. The planes of symmetry of the cam surfaces (1-2 and 3-4) disposed in the same press yoke are parallel with the drive direction. A number of outer cam follower bodies (31) lying between each pair of the outer cam surfaces serve for the radial advancement of press jaws (30) toward the press axis. Inner cam follower bodies (37) with additional press jaws (41) are driven synchronously by the outer cam follower bodies (31). To reduce weight and size the one press yoke (18) is guided with respect to the other press yoke (19) by traction posts (25, 26) which pass through the guiding press yoke (19) at its extremities lying outside of the cam surfaces (1, 2, 3, 4 ), are fixedly joined to the other, guided, press yoke (18), and are joined on the other side of the guiding press yoke to a traction-producing drive (52) which is preferably in the form of a hydraulic jack (47/51, 48/50) associated with each traction post.
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TECHNICAL FIELD OF THE INVENTION
[0001] The present invention concerns methods and manually adjustable devices for ultrasound processing of a strip or a web of material, in particular textile material strips or webs based on thermofusible materials.
[0002] Ultrasound is routinely used to process thermofusible materials, for example to effect cutting, welding, lamination.
[0003] A machine for this requiring manual adjustment is already known. This machine generally comprises a sonotrode, functionally associated with an ultrasound converter that applies to it a vibration at ultrasound frequency. The sonotrode is held opposite an anvil on respective opposite sides of a working area into which the material to be processed is introduced. The sonotrode is carried by a first device body part and the anvil is held by a second device body part. The first and second device body parts are articulated to each other about a transverse axis to modify the distance between the sonotrode and the anvil by relative rotation of the first and second device body parts about the transverse axis. Elastic means elastically urge rotation of the first and second device body parts in the direction of relative movement of the sonotrode and the anvil toward each other in the working area.
[0004] Such a machine requiring manual adjustment as defined hereinabove is described in the document WO 01/12422. In that machine, the transverse axis of rotation between the first and second device body parts is close to the working area so that a relative rotation about the transverse axis through a given angle produces only a small relative displacement of the sonotrode and the anvil. A thumbwheel enables adjustment of the bearing force of the elastic means and thus the force with which the material to be processed is compressed between the sonotrode and the anvil. The thumbwheel and the elastic means are placed between the first and second device body parts at the level of the sonotrode, i.e. not far from the pivot axis. This makes the relative positioning of the sonotrode and the anvil inaccurate.
[0005] In another machine requiring manual adjustment, described in the document U.S. Pat. No. 4,410,383, the transverse axis of rotation between the first and second device body parts is remote from the working area, in the middle of a lever the first end whereof carries the anvil and the second end whereof is provided with a vertical tie-rod acted on by spring providing the relative movement toward each other between the sonotrode and the anvil. A nut screwed onto the tie-rod enables adjustment of the bearing force exerted by the spring. A transverse screw engaged in a hole in the lever abuts against a fixed block to limit the rotation of the lever and therefore the relative movement toward each other between the sonotrode and the anvil, in an adjustable manner. Because of the large distance between the rotation axis and the working area, the relative positioning of the sonotrode and the anvil is inaccurate in this device.
[0006] Also, screwing the transverse screw abutting against the fixed block further in or out to adjust the limit of the relative movement toward each other between the sonotrode and the anvil significantly modifies the compression state of the spring and the elastic bearing force of the sonotrode and the anvil on the material to be welded. The adjustments of the bearing force and the relative position between the sonotrode and the anvil are interdependent, which complicates the use of the device and degrades the accuracy and the reproducibility of the adjustments.
[0007] In all cases, the ultrasonic vibrations of the sonotrode cause total or partial melting of the part of the material disposed between the sonotrode and the anvil. The result obtained depends on a number of parameters, and in particular on the speed of movement of the material between the sonotrode and the anvil, the amplitude of the ultrasonic vibrations applied to the sonotrode by the ultrasound converter, the bearing pressure of the sonotrode in the direction of the anvil, the shape of the sonotrode and the shape of the anvil.
[0008] In a first application, the anvil is a circular blade. The melting of the material by the ultrasound then produces a cut at the level of the edge of the circular blade, together with a continuous partial welding of the textile material fibers to each other on either side of the cutting line.
[0009] In a second application, the tool is a rotary roller with a textured surface. The ultrasound then produces spot welds in the region between the sonotrode and the roller and the machine includes a mechanical blade that cuts the textile material on the downstream side of the welded area.
[0010] These known devices produce a result of random quality. Usually insufficient melting is found, and therefore insufficient welding, with the risk of the textile material fraying after cutting. Conversely, excessive melting of the material is often noted, which causes plasticization of the welded areas, making them stiffer and more fragile, introducing a risk of subsequent tearing of the textile material.
[0011] The result also depends on the nature of the material to be processed. It is therefore very difficult to control the result obtained.
[0012] Furthermore, premature wear of the anvils and the sonotrodes is regularly observed, which necessitates maintenance operations to change these parts, failing which the result obtained becomes even more random.
[0013] Also known are more complex devices in which the sonotrode is moved relative to the anvil by hydraulic or pneumatic means, with sensors for monitoring the result obtained and controlling the relative displacement of the sonotrode with respect to the anvil. Such a machine is very complex and costly, however, and necessitates a source of pneumatic or hydraulic energy, which renders it inapplicable under many conditions of use, for example at the exit from circular weaving looms.
SUMMARY OF THE INVENTION
[0014] A first problem addressed by the present invention is to conceive of improvements to ultrasound processing devices with manual adjustment means with a view to guaranteeing the regularity of the result of welding or cutting a thermofusible material to be processed, in particular a textile thermofusible material to be processed, without recourse to the use of exterior pneumatic or hydraulic energy sources.
[0015] The invention aims in particular to avoid excessive melting of a thermofusible fabric, any such excessive melting degrading or even destroying the technical qualities of the fabric. It also aims to avoid insufficient melting.
[0016] Another problem addressed by the invention is eliminating the risk of a thermofusible fabric fraying on either side of the cutting line after ultrasound cutting.
[0017] Simultaneously, the invention reduces the wear of the sonotrodes and the anvils.
[0018] The invention results from the detailed analysis of the possible causes of the defects noted when using known manual adjustment devices.
[0019] When the material advances between the sonotrode and the anvil, the ultrasound vibrations cause progressive melting of the thermofusible material and thus relative penetration of the sonotrode and/or the tool into the thermofusible material. The melting is efficacious provided that the pressure exerted on the thermofusible material between the sonotrode and the anvil is high. In contrast, if this pressure disappears, there is no longer any significant transmission of ultrasound energy into the material and melting is interrupted. As a result, the sonotrode and/or the anvil penetrate(s) progressively into the thermofusible material until reaching a non-null minimum relative separation which may be rendered adjustable by abutment means for limiting convergent movement like those described in the document U.S. Pat. No. 4,410,383. If they are correctly adjusted, these means enable controlled melting to be obtained. This therefore avoids excessive melting of the thermofusible fabric, so that the technical qualities of the fabric are consequently preserved. It simultaneously avoids all risk of contact between the sonotrode and the anvil, which is liable to cause wear of the two components because of the rubbing effect of the ultrasound vibrations.
[0020] However, in such a known device, a first difficulty stems from the interdependence of the adjustment of the bearing or pressure force and the adjustment of the minimum relative separation by the transverse screw. In fact this makes the pressure exerted on the thermofusible material between the sonotrode and the anvil inaccurate, and this parameter significantly affects the quality and the regularity of the weld produced.
[0021] With the aim of solving the problem addressed by the invention, namely guaranteeing regular welding or cutting of a thermofusible material to be processed, in accordance with the invention, means are provided whereby modification of the minimum separation by the member for manual adjustment of the minimum separation does not modify the elastic bearing force produced by the elastic means and therefore does not modify the pressure exerted on the thermofusible material by the sonotrode and the anvil.
[0022] The adjustment that the operator must effect most frequently is in fact an adjustment of the minimum separation value. The determination of an appropriate adjustment as a function of the product to be processed is simplified by the fact that the minimum separation adjustment is rendered independent of the adjustment of the bearing force of the elastic means. It is also possible to adjust these two parameters, namely the elastic bearing force and the minimum separation, successively.
[0023] The adjustment of the elastic bearing force enables the device to be adapted to different natures or thicknesses of the strip or web of material to be processed: the operator may choose an elastic bearing force that is just sufficient for the sonotrode and the anvil to move toward each other until the minimum separation is reached when the material is melted in the working area. As a result, in the case of a momentary overthickness of the strip or web of material to be processed, for example, the latter can easily and without damage push the sonotrode and the anvil as far apart as necessary by compressing the elastic means.
[0024] In practice, these effects will be obtained by a device as defined in claim 1 , comprising:
a sonotrode functionally associated with an ultrasound converter and carried by a first device body part on a first side of a working area, an anvil held opposite the sonotrode by a second device body part on the other side of the working area, the first and second device body parts being displaceable relative to each other with a movement producing relative displacement of the sonotrode and of the anvil toward or away from each other, manually adjustable mechanical means disposed between a first connecting portion on the first device body part and a second connecting portion on the second device body part, having elastic means for spring-loading relative displacement the first and second connecting portions in the direction of relative movement toward each other of the sonotrode and the anvil in the working area, elastic bearing force adjustment means in the manually adjustable mechanical means for modifying the state of compression of the elastic means, abutment means in the manually adjustable mechanical means for limiting convergent movement which oppose relative displacement between the first and second connecting portions in the direction of relative movement toward each other of the sonotrode and the anvil short of a minimum separation whilst allowing displacement thereof in the opposite direction, a manual minimum separation adjustment member in the manually adjustable mechanical means for adjusting the position of the abutment for limiting convergent movement and thus adjusting the minimum separation, in the manually adjustable mechanical means, the abutment means for limiting convergent movement and the elastic means are in direct or indirect bearing engagement against the manual minimum separation adjustment member so that operation of the minimum separation adjustment member to modify the minimum separation does not modify the elastic bearing force produced by the elastic means.
[0033] In one advantageous embodiment, such a device according to the invention may be such that:
the means for limiting convergent movement include an abutment in selected bearing engagement against one of the connecting portions and are carried by the manual minimum separation adjustment member, the manual minimum separation adjustment member is mounted to be mobile along the other connecting portion, the elastic means are functionally engaged between the manual minimum separation adjustment member and said one connecting portion.
[0037] In this case, in the mechanical means requiring manual adjustment, for example there can be provided that:
the abutment means for limiting convergent movement comprise a tie-rod slidably engaged in at least one of the connecting portions on the first and second device body parts, the tie-rod having a first end head in axial bearing engagement against said one connecting portion, the tie-rod may include a threaded body passing through an axial hole in a threaded thumbwheel for manual adjustment of the minimum separation and receiving an adjuster nut in axial bearing engagement against said threaded adjustment thumbwheel, the threaded adjustment thumbwheel may be functionally screwed into a threaded bore in the other connecting portion, and at least one compression spring may be engaged axially around the tie-rod between the threaded adjustment thumbwheel and said one connecting portion on the opposite side to the bearing engagement of the first end head.
[0042] Such a structure is simple, reliable and robust.
[0043] Said one connecting portion is preferably the first connecting portion on the first body part and said other connecting portion is preferably the second connecting part on the second body part. As a result, during adjustment, the user operates on members carried by the fixed part of the device, which guarantees a more accurate adjustment.
[0044] The first and second device body parts are preferably rotationally articulated to each other about a transverse axis close to the working area, whereas the connecting portions on the first and second device body parts, which receive the manually adjustable mechanical means, are on the opposite side of the transverse axis to the working area and are remote from the transverse axis, in the vicinity of the distal part of the ultrasound converter. This therefore increases very significantly the accuracy of adjustment of the minimum separation, where accuracy is necessary to adapt to the generally small thicknesses of thermofusible fabrics and to guarantee more regular welding.
[0045] The compression spring or springs may advantageously be positioned at substantially the same distance from the transverse axis as the abutment means for limiting convergent movement, in order to improve further the accuracy of adjustment.
[0046] To improve the accuracy of adjustment still further, the compression spring may preferably be engaged around the tie-rod.
[0047] In a simple embodiment, the threaded adjustment thumbwheel is selectively locked in position on the corresponding connecting portion by a locknut screwed onto a threaded section.
[0048] A further improvement in the regularity of welding may be obtained by improving the member for manual adjustment of the minimum separation to take up slack continuously, by providing for:
the threaded adjustment thumbwheel to be selectively locked in position on the corresponding connecting portion by a transverse screw screwed into a transverse threaded hole in the corresponding connecting portion and in radial bearing engagement on the interior section of the threaded adjustment thumbwheel, elastic means for taking up slack to be engaged between the threaded adjustment thumbwheel and the corresponding connecting portion to push the threaded adjustment thumbwheel at all times away from the other connecting portion.
[0051] The device defined hereinabove may be adapted to cut or weld continuously moving thermofusible products.
[0052] According to a first application, it can be provided that:
the anvil may comprise a rotary roller with a transverse axis and having appropriate raised patterns on its active surface, and the sonotrode may have a cylindrical active surface with a transverse axis.
[0055] Such a device can produce a continuous line of spot welds around a median line.
[0056] According to another application, it can be provided that:
the anvil may have an active surface with a circular ridge with a transverse axis and may be fixed to the second device body part, and the sonotrode may have a cylindrical active surface with a transverse axis.
[0059] Such a device produces a longitudinal cut or groove by ultrasound and welds the two lateral areas close to the cutting line.
[0060] In either of the above applications, the device may include a cutting blade placed on the downstream side of the working area. This results in a machine that cuts a thermofusible fabric in a median area of a welding area.
[0061] According to another aspect, the invention proposes a method for ultrasound processing of a strip or web of material by means of a device as defined hereinabove, wherein a bearing force is adjusted first by operating elastic bearing force adjustment means, after which a non-null minimum separation is adjusted by operating the manual minimum separation adjustment member, so that a separation greater than the non-null minimum separation is maintained between the sonotrode and the anvil whilst maintaining a particular elastic bearing force from the sonotrode toward the anvil against the strip or web of material if the separation is greater than the non-null minimum separation.
[0062] Preferably, in such a method:
a continuous melted area is produced by ultrasound in the strip or web of material to be processed with a longitudinal groove that may be bordered by one or two spot weld areas, the strip or web of material is cut mechanically in the continuous melted area that is reduced in thickness in this way, while it is still hot.
[0065] To solve another problem of fraying, a device may be provided wherein:
the anvil comprises a narrow fixed or rotary central part oriented longitudinally in the direction of forward movement of the strip or web of material to be processed and having a central ridge in the longitudinal plane containing the axial direction of the sonotrode, the anvil comprises two cylindrical rotary parts with appropriate raised patterns on either side of the central part, the central ridge extends slightly beyond the top generatrix of the cylindrical rotary parts in the working area, a fixed cutting blade is disposed on the downstream side of the working area and on the axis of the central part.
[0070] As a result, the narrow central part with the central ridge produces a longitudinal median groove that may be considered as a partial ultrasound cut, leaving a reduced thickness of material along the cutting line which is then very easy to separate by means of the fixed downstream cutting blade. Simultaneously, the narrow central part with the central ridge ensures continuous welding of the two edges of the cutting line over a width of about 1 mm, which complements the spot welding effected by the lateral cylindrical rotary parts over a width that can range from a few millimeters to about 20 to 25 millimeters his eliminates the risk of the thermofusible fabric fraying on either side of the cutting line whilst preserving the flexibility and the technical qualities of the fabric.
[0071] The raised patterns are preferably pips having a section less than or equal to 1 mm 2 and distributed with a pitch of about 1 mm 2 mm.
DESCRIPTION OF THE DRAWINGS
[0072] Other objects, features and advantages of the present invention will emerge from the following description of particular embodiments, given with reference to the appended figures, in which:
[0073] FIG. 1 is a diagrammatic side view of a device according to a first embodiment of the present invention;
[0074] FIG. 2 is a front view of the device from FIG. 1 ;
[0075] FIG. 3 is a diagrammatic side view of a device according to a second embodiment of the present invention;
[0076] FIG. 4 is a front view of the device from FIG. 3 ;
[0077] FIG. 5 is a side view of a device according to another embodiment of the invention including a tapered sonotrode;
[0078] FIG. 6 is a front view of the device from FIG. 5 ;
[0079] FIG. 7 is a partial side view in longitudinal section of the manually adjustable mechanical means according to one embodiment of the present invention, with the device against the abutment with a first adjustment of the minimum separation;
[0080] FIG. 8 is a view similar to FIG. 7 , with the device remote from the abutment, with a separation greater than the minimum separation that is the effect of a force applied to the sonotrode;
[0081] FIG. 9 is a view similar to FIG. 7 , with the device against the abutment but with another, smaller adjustment of the minimum separation;
[0082] FIG. 10 is a diagrammatic side view of the working area showing the possibilities of adjustment and relative movement of a sonotrode and an anvil;
[0083] FIG. 11 is a diagrammatic side view of a particular anvil structure according to one embodiment of the invention adapted for partial ultrasound cutting and multiple ultrasound spot welding;
[0084] FIG. 12 is a top view of the anvil from FIG. 11 ;
[0085] FIG. 13 is a front view in partial cross-section of the anvil from FIG. 11 with the sonotrode and the material to be processed;
[0086] FIG. 14 shows in perspective the result obtained with an anvil from FIGS. 11 to 13 associated with a fixed blade on the downstream side;
[0087] FIG. 15 is a front view in cross-section of an anvil according to the embodiment of FIGS. 3 and 4 with the sonotrode and the material to be processed;
[0088] FIG. 16 shows in perspective the result obtained with an anvil from FIG. 15 associated with a fixed blade on the downstream side;
[0089] FIG. 17 is a view similar to FIG. 7 , with the device against the abutment but with a different elastic bearing force adjustment;
[0090] FIG. 18 is a side view of an anvil according to a variant of the FIG. 11 embodiment for partial ultrasound cutting and multiple ultrasound spot welding;
[0091] FIG. 19 is a top view of the anvil from FIG. 18 ; and
[0092] FIG. 20 is a partial side view in longitudinal section of the mechanical adjustment means according to another embodiment of the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0093] FIGS. 1 to 6 show, by way of illustrative but nonlimiting example, three embodiments of a device in accordance with the present invention for ultrasound processing of strips of material.
[0094] The device from FIGS. 1 and 2 is a continuous ultrasound spot welding machine with integrated mechanical cutting which produces two lateral spot welds over a width of several millimeters followed by a mechanical cut in the median area between the welds.
[0095] The device from FIGS. 3 and 4 is a continuous ultrasound cutting and welding machine which produces a welding cut with two continuous welds each over a width of approximately 1 mm on either side of the cutting line.
[0096] The device from FIGS. 5 and 6 is another continuous ultrasound cutting and welding device.
[0097] In each of the three embodiments, most of the structural elements recur, and the corresponding elements are identified by the same numerical references.
[0098] In each case, the device is in principle intended to process a strip or web 23 of thermofusible material that is fed, in a direction of forward movement indicated by the arrow 1 , toward a working area 2 situated between a sonotrode 3 and an anvil 4 .
[0099] The device therefore includes the sonotrode 3 , functionally associated with an ultrasound converter 5 and carried by a first device body part 6 .
[0100] The device includes the anvil 4 , held opposite the sonotrode 3 by a second device body part 7 on the other side of the working area 2 .
[0101] The sonotrode 3 , the ultrasound converter 5 and the anvil 4 are aligned in an axial direction I-I passing through the working area 2 and generally perpendicular to the forward direction 1 . The ultrasound converter 5 produces axial vibrations at ultrasound frequencies in the direction I-I, which vibrations are transmitted to the sonotrode 3 by a transmitter and/or amplifier unit 9 , for example a booster.
[0102] The first device body part 6 and the second device body part 7 are articulated to each other about a transverse axis 8 .
[0103] The transverse axis 8 is preferably close to the working area 2 and offset laterally in the forward direction 1 . D 1 denotes the distance between the working area 2 and the transverse axis 8 .
[0104] In this embodiment, the first device body part 6 and the second device body part 7 are movable relative to each other with a rotation movement that produces the relative displacement of the sonotrode 3 and the anvil 4 toward or away from each other in the working area 2 .
[0105] Manually adjusted mechanical means 10 are disposed between a connecting portion 11 on the first device body part 6 and a connecting portion 12 on the second device body part 7 . As seen in the figures, the connecting portions 11 and 12 on the first device body part 6 and the second device body part 7 are remote from the transverse axis 8 , in the vicinity of the distal part 5 a of the ultrasound converter 5 . D 2 denotes the distance between the rotation axis 8 and the connecting portions 11 and 12 .
[0106] Also, as shown in the figures, the manually adjustable mechanical means 10 are on the opposite side of the transverse axis 8 to the working area 2 .
[0107] As a result, a given relative displacement D between the connecting portions 11 and 12 on the first device body part 6 and the second device body part 7 causes relative pivoting of the first device body part 6 and the second device body part 7 relative to each other about the transverse axis 8 which produces a simultaneous displacement d of the sonotrode 3 relative to the anvil 4 in the axial direction I-I.
[0108] By choosing to place the transverse axis 8 in a position close to the working area 2 and to place the connecting portions 11 and 12 remote from the transverse axis 8 , i.e. by choosing a distance D 2 significantly greater than the distance D 1 , the displacement d between the sonotrode 3 and the anvil 4 will have a much smaller amplitude than the displacement D of the two connecting portions 11 and 12 on the first device body part 6 and the second device body part 7 , and so the accuracy of adjustment of the distance d will be significantly increased. The person skilled in the art will be able to choose the ratio D 2 /D 1 according to the accuracy required.
[0109] In the embodiment shown in FIGS. 1 and 2 , the sonotrode 3 has a cylindrical active surface 3 a with a transverse axis and with a width L ( FIG. 2 ) that may be relatively small, for example a few millimeters, or 20 to 25 mm as a function of requirements, and the anvil 4 includes a rotary roller 4 a with a transverse axis and the active surface 4 b whereof includes pips or raised patterns of appropriate shape for producing, in the material to be processed, spot welds facing the active surface 3 a of the sonotrode 3 .
[0110] The device further comprises a fixed cutting blade 13 , placed on the downstream side of the working area 2 in the forward direction 1 of movement of the material to be processed. The fixed cutting blade 13 is aligned with the median plane II-II ( FIG. 2 ) of the sonotrode 3 .
[0111] In the embodiment of FIGS. 3 and 4 , the sonotrode 3 has substantially the same shape as in the embodiment of FIGS. 1 and 2 , with a cylindrical active surface 3 a having a transverse axis, and the anvil 4 includes an active surface with a circular edge 4 c having a transverse axis 4 d . In operation, the anvil 4 is fixed against rotation about its transverse axis 4 d so as to split the material to be processed on its passage between the sonotrode 3 and the anvil 4 .
[0112] In a variant, the embodiment of FIGS. 3 and 4 may be associated with a cutting blade 13 , shown in dashed line in FIG. 3 , disposed on the downstream side of the working area 2 in the median plane II-II.
[0113] In the embodiment of FIGS. 5 and 6 , the anvil 4 includes a cylindrical active surface 4 e having a transverse axis and of narrow width L 1 , and the sonotrode 3 includes a tapered semicircular active surface 3 b with a transverse axis.
[0114] In the embodiments of FIGS. 1 , 2 , 5 and 6 , the second device body part 7 is conformed to be fixed to a support such as a machine frame, thus carrying the anvil 4 in a fixed position, and the sonotrode 3 and the first device body part 6 pivot about the transverse axis 8 .
[0115] In the embodiment of FIGS. 3 and 4 , it is conversely the first device body part 6 that is conformed to be fixed to a support such as a machine frame, the sonotrode 3 also being fixed, whereas the anvil 4 and the second device body part 7 pivot about the transverse axis 8 .
[0116] In all the embodiments of the invention, the manually adjustable mechanical means 10 comprise on the one hand elastic means, such as a spring 22 ( FIG. 7 ), for spring-loading relative displacement of the first device body part 6 and the second device body part 7 in the direction of relative movement toward each other of the sonotrode 3 and the anvil 4 in the working area 2 in the axial direction I-I ( FIG. 10 ) and on the other hand abutment means for limiting convergent movement, such as a tie-rod 20 ( FIG. 7 ), which prohibit the relative displacement of the connecting portions 11 and 12 relative to each other in the direction of relative movement toward each other of the sonotrode 3 and the anvil 4 in the working area 2 short of a minimum separation E. Thus the limiter abutment means 20 maintain the axial distance between the sonotrode 3 and the anvil 4 greater than a particular minimum separation E, prohibiting relative displacement between the sonotrode 3 and the anvil 4 in the direction of convergent movement short of the minimum separation E, whilst allowing their relative displacement in the direction of movement away from each other.
[0117] As a result, a relatively thick strip or web of material 23 presented in the working area 2 in the forward direction 1 can push the sonotrode 3 and the anvil 4 elastically apart, whereas the elastic means 22 press on the strip or web of material 23 to be processed between the sonotrode 3 and the anvil 4 to transmit ultrasonic vibratory energy. This therefore causes the softening or partial melting of the material in the working area 2 , but without allowing physical contact between the sonotrode 3 and the anvil 4 .
[0118] In all embodiments, the manually adjustable mechanical means 10 further include a manual member for adjusting the minimum separation E, such as a threaded adjustment thumbwheel 17 , which itself carries the abutment means 20 for limiting convergent relative movement and the elastic means or spring 22 .
[0119] There will now be described in more detail the manually adjustable mechanical means 10 according to one possible embodiment of the present invention, as shown in FIGS. 7 to 9 and 17 , during four steps of operation.
[0120] These figures show the first device body part 6 , the second device body part 7 and the transverse axis 8 as well as the connecting portion 11 on the first device body part 6 and the connecting portion 12 on the second device body part 7 between which the manually adjustable mechanical means 10 are disposed.
[0121] The connecting portion 11 on the first device body part 6 includes a through-hole 14 . The connecting portion 12 on the second device body part 7 has a tubular shape the interior housing 15 whereof includes a threaded bore 16 in its part away from the connecting portion 11 , which threaded bore 16 has a threaded adjustment thumbwheel 17 screwed into it. The adjustment thumbwheel 17 includes an axial hole 18 in alignment with the hole 14 in the connecting portion 11 . The thumbwheel 17 has a projecting external part 19 for holding it and rotating it manually about the axis III-III. A tie-rod 20 is slidably engaged in the hole 14 in the first connecting portion 11 and in the hole 18 in the adjustment thumbwheel 17 , and therefore also slides in the interior housing 15 of the connecting portion 12 on the second device body part 7 .
[0122] The tie-rod 20 has a first end head 20 a in axial bearing engagement against the external face of the connecting portion 11 on the first device body part 6 . The tie-rod 20 includes a threaded body 20 b which passes freely through the axial hole 18 of the thumbwheel 17 and receives an adjuster nut 21 . The adjuster nut 21 normally bears axially against the external face 19 a of the thumbwheel 17 . The tie-rod 20 therefore bears indirectly against the thumbwheel 17 . A helicoidal compression spring 22 is engaged axially between the adjustment thumbwheel 17 and the connecting portion 11 on the first device body part 6 , around the threaded body 20 b of the tie-rod 20 . The spring 22 therefore bears against the thumbwheel 17 .
[0123] Operation is as follows: in the rest state, shown in FIG. 7 , the compression spring 22 urges the two connecting portions 11 and 12 and therefore the two device body parts 6 and 7 apart, thus tending to move the sonotrode 3 ( FIGS. 1 to 6 ) and the anvil 4 toward each other in the axial direction I-I. This convergent movement is nevertheless limited by the fact that the tie-rod 20 limits the separation of the connecting portions 11 and 12 , its head 20 a continuing to bear against the portion 11 and the nut 21 continuing to bear against the thumbwheel 17 . The tie-rod 20 , in association with the thumbwheel 17 and the nut 21 , constitutes the means for limiting movement of the sonotrode 3 and the anvil 4 toward each other.
[0124] Assuming a force between the sonotrode 3 and the anvil 4 , for example by virtue of the engagement of a thick strip or web of material 23 between the sonotrode 3 and the anvil 4 , the sonotrode 3 can move away from the anvil 4 , compressing the compression spring 22 , as shown in FIG. 8 . In this case, the tie-rod 20 slides in the connecting portion 11 on the first device body part 6 . The spring 22 determines the return force on the sonotrode 3 in the direction of the anvil 4 and therefore determines the pressure force exerted on the strip or web of material 23 to be processed. When the material to be processed is melted between the sonotrode 3 and the anvil 4 , the sonotrode 3 penetrates into the material to be processed and the device may return to the position shown in FIG. 7 , the tie-rod 20 then limiting penetration of the sonotrode 3 and the anvil 4 into the material to be processed.
[0125] The depth of penetration of the sonotrode 3 and the anvil 4 into the strip or web of material 23 to be processed can be adjusted by screwing the thumbwheel 17 in or out, for example as shown in FIG. 9 . As seen in that figure, screwing the thumbwheel 17 further in has displaced the thumbwheel 17 and the connecting portion 11 on the first device body part 6 toward the left, causing relative movement of the sonotrode 3 and the anvil 4 toward each other, and thus producing a smaller minimum separation.
[0126] As a result, the tie-rod 20 prevents relative movement of the two connecting portions 11 and 12 on the first and second device body parts 6 and 7 away from each other beyond a maximum separation value adjustable by the thumbwheel 17 . Simultaneously, the spring 22 urges the two connecting portions 11 and 12 on the first device body part 6 and the second device body part 7 away from each other.
[0127] The tie-rod 20 constitutes abutment means for limiting convergent movement which limit the possible movement toward each other of the sonotrode 3 and the anvil 4 . The abutment means therefore maintain the distance between the sonotrode 3 and the anvil 4 greater than a minimum separation E.
[0128] The thumbwheel 17 constitutes a manual minimum separation adjustment member by means of which the minimum separation E may be adjusted.
[0129] On considering the figures, it is seen that the mechanical manual adjustment means 10 are arranged so that the displacement of the thumbwheel 17 by turning it, which modifies the minimum separation between the sonotrode 3 and the anvil 4 , does not modify the spring-loading in pivoting produced by the elastic means or spring 22 , in that the spring 22 is not compressed differently during the change from FIG. 7 to FIG. 9 . This effect is obtained by virtue of the fact that the abutment means 20 for limiting convergent movement and the elastic means 22 bear directly or indirectly against the manual minimum separation adjustment member or thumbwheel 17 , for example when they are carried by the thumbwheel 17 as shown in the figures.
[0130] As is clear in FIGS. 7 to 9 and 17 , the abutment means for limiting convergent movement consisting of the tie-rod 20 prevent relative displacement of the two connecting portions 11 and 12 on the first device body part 6 and the second device body part 7 away from each other beyond a maximum value adjustable by the thumbwheel 17 . Simultaneously, the elastic means consisting of the spring 22 urge the two connecting portions 11 and 12 on the first device body part 6 and the second device body part 7 away from each other to move the sonotrode 3 and the anvil 4 toward each other.
[0131] It may nevertheless be useful to modify the force exerted by the spring 22 , by providing elastic bearing force adjustment means consisting of the adjuster nut 21 screwed onto the tie-rod 20 and bearing against the thumbwheel 17 .
[0132] For this purpose the adjuster nut 21 is turned, which compresses the spring 22 more or less. Reducing the compression of the spring 22 by unscrewing the adjuster nut 21 to move it from the position shown in FIG. 7 to the position shown in FIG. 17 for example reduces the return force exerted by the spring 22 for convergent movement between the sonotrode 3 and the anvil 4 . Screwing in the adjuster nut 21 produces the opposite effect.
[0133] The device described hereinabove works by pressing the sonotrode 3 and the anvil 4 onto respective opposite sides of the material to be processed, as occurs in the known devices. However, according to the invention, the device works with an accurate and adjustable separation between the sonotrode 3 and the anvil 4 . The minimum separation E may be determined by the user as a function of the thickness and the nature of the material to be processed. The result of melting the material can be easily controlled and becomes virtually independent of the speed of movement of the material in the forward direction 1 .
[0134] This results in very regular ultrasound welding and cutting. The device avoids excessive melting of the thermofusible fabric, which for certain materials signifies the destruction of the technical qualities of the fabric.
[0135] Improved productivity and reduced wastage are obtained.
[0136] The particular arrangement of the mechanical manual adjustment means 10 , in the vicinity of the distal part 5 a of the converter 5 , i.e. with a relatively large distance D 2 , combined with a relatively small distance D 1 , achieves highly accurate movement of the sonotrode 3 toward the anvil 4 and great accuracy of the minimum separation E. This accuracy is necessary for optimum control of the result of welding or cutting a strip or web of material that is generally thin. The accuracy obtained is equal to or less than the amplitude of the ultrasound vibrations of the sonotrode 3 .
[0137] Simultaneously, in case of excess thickness of the strip or web of material 23 to be processed, the sonotrode 3 can be retracted automatically thanks to the possibility of crushing the spring 22 .
[0138] The force exerted by the spring 22 can be adjusted by turning the adjuster nut 21 or by replacing the spring 22 with a spring of different stiffness.
[0139] To guarantee good accuracy and good reproducibility of the minimum separation E, it may be useful to lock selectively the position of the manual minimum separation adjustment threaded thumbwheel 17 .
[0140] For this, in the embodiment of FIGS. 1 to 9 and 17 , the thumbwheel 17 may be locked by a locknut 17 a screwed onto the threaded section of the thumbwheel 17 . The locknut 17 a comes to bear axially against the end of the tubular connecting portion 12 .
[0141] It will be noted that the clamping effect of the locknut 17 a presses one of the faces of the threads of the thumbwheel 17 against the corresponding thread faces of the screwthread 16 , which, given a certain functional clearance that is necessary, modifies very little the adjustment of the minimum separation E.
[0142] To reduce this effect, and thus to improve further the accuracy of the minimum separation E adjustment, the embodiment shown in FIG. 20 may be preferred, in which the manual minimum separation adjustment threaded thumbwheel 17 is selectively locked in position on the corresponding connecting portion 12 by a transverse screw 17 b screwed into a transverse threaded hole 12 a in the corresponding connection portion 12 and bearing radially on the interior section of the adjustment threaded thumbwheel 17 .
[0143] Simultaneously, elastic means for taking up slack, such as a helicoidal spring 17 c stronger than the spring 22 , are engaged between the manual minimum separation adjustment threaded thumbwheel 17 and the corresponding connection portion 12 , to push the manual minimum separation adjustment threaded thumbwheel 17 at all times away from the other connecting portion 11 . The spring 17 c therefore presses the threads of the thumbwheel 17 at all times against the same thread faces of the screwthread 16 , whether the transverse screw 17 b is tightened or not.
[0144] FIG. 10 shows diagrammatically the operation of the device when working. The sonotrode 3 and the anvil 4 are seen. At rest, i.e. in the absence of material to be processed, the sonotrode 3 can be moved toward and away from the anvil 4 , over a travel C, by maneuvering the adjuster thumbwheel 17 ( FIG. 7 ).
[0145] The minimum separation E, or the separation between the sonotrode 3 and the anvil 4 at rest, is chosen in this way.
[0146] By loading the sonotrode 3 with ultrasound vibrations produced by the converter 5 , it is then possible to process a strip or web of thermofusible material 23 introduced into the working area 2 in the forward direction 1 . Because of the effect of the ultrasound vibrations, which heat the material and tend to soften it to the melting point, the strip or web of material 23 is made thinner as it passes into the working area 2 . For a longitudinal cutting of the strip or web of material 23 , a small minimum separation E is chosen.
[0147] A larger minimum separation E will be chosen to effect a weld: the minimum separation E must be less than the initial thickness of the strip or web of material 23 to press on the material sufficiently to melt it in the working area 2 ; but the minimum separation E must not be too small, to avoid exaggerated reduction of the thickness of the strip or web of material 23 during operation.
[0148] Spot welding may be effected by providing an anvil 4 in the form of a cylindrical roller having appropriate raised patterns on its active surface 4 b.
[0149] If the strip or web of material 23 is very thick, or assuming insufficient melting of the material, the sonotrode 3 may be moved away from the anvil 4 by the pivoting means and the spring 22 .
[0150] In the foregoing description, the strip or web of material 23 is displaced in the forward direction 1 shown in the figures, i.e. a direction perpendicular to the transverse axis 8 . The device could nevertheless be used, in accordance with the invention, to process a strip or web of material moving in the direction of forward movement parallel to the transverse axis, for example by pivoting the sonotrode 3 and/or the anvil 4 by 90° if necessary. This enables a fabric selvedge to be processed, for example.
[0151] Consider now FIGS. 11 to 14 , which show a particular anvil structure according to the invention.
[0152] This particular anvil structure has the benefit of very significantly reducing the risk of fraying of a thermofusible material fabric during longitudinal cutting in the strip or web of fabric.
[0153] To obtain this effect, the anvil 4 comprises a fixed narrow central part 24 oriented longitudinally in the forward direction 1 of movement of the strip or web of material 23 to be processed, with a central ridge 24 a oriented facing the sonotrode 3 in the longitudinal plane containing the axial direction I-I.
[0154] The anvil 4 further comprises two cylindrical rotary parts 25 a and 25 b with appropriate raised patterns on respective opposite sides of the fixed central part 24 , the cylindrical rotary parts 25 a and 25 b being mounted to rotate freely about a transverse axis 25 c.
[0155] The central ridge 24 a of the fixed central part 24 projects slightly beyond the top generatrix of the two cylindrical rotary parts 25 a and 25 b of the working area 2 , so as to be slightly closer to the sonotrode 3 .
[0156] The fixed central part 24 may advantageously be adjustable in position toward and away from the sonotrode 3 by adjustment means shown diagrammatically, for example lifting screws 24 b and 24 c.
[0157] The adjustment means may also adjust the lateral position of the fixed central part 24 , for example by means of centering screws 24 d and 24 e , to prevent any rubbing against the cylindrical rotary parts 25 a and 25 b.
[0158] In practice, the cylindrical rotary parts 25 a and 25 b are fastened together, mounted on the same hub and separated by a groove 25 d in which the fixed central part 24 of the anvil 4 is engaged.
[0159] FIG. 14 shows the result obtained by the use of this kind of anvil: a strip or web of woven thermofusible material 23 advances in the forward direction 1 and slides over the fixed central part 24 of the anvil, facing the fixed sonotrode 3 , so that the fixed central part 24 penetrates into the material forming a longitudinal groove 26 . The edges of the groove 26 consist of material that has been melted continuously, ensuring continuous welding of the edges of the groove 26 over a width of approximately 1 mm on each side of the cutting line. Simultaneously, the two cylindrical rotary parts 25 a and 25 b have formed two lateral areas 27 and 28 , over a width that may be of a few millimeters, or may be of the order of 20 to 25 mm, as a function of requirements, in which lateral areas the raised patterns of the cylindrical rotary parts 25 a and 25 b produce spot welds, ensuring cohesion of the thermofusible fibers of the strip or web of woven material 23 without affecting the flexibility.
[0160] Thanks to the device for limiting penetration of the sonotrode 3 and the anvil 4 into the strip or web of material 23 , the groove 26 is sure to have a depth slightly less than the thickness of the strip of material 23 .
[0161] This task can then easily be combined with cutting by a cutting blade 13 ( FIG. 1 or 3 ) disposed on the downstream side of the working area 2 and on the axis of the fixed central part 24 , the cutting blade 13 having only a very small thickness of material to cut in the bottom of the groove 26 .
[0162] Good results may be obtained if the cylindrical rotary parts 25 a and 25 b have raised patterns in the form of pyramidal pips with a section less than or equal to 1 mm 2 and distributed with a pitch of about 1 mm to 2 mm.
[0163] FIGS. 18 and 19 show a variant anvil 4 according to the invention for reducing the risk of fraying of a thermofusible material fabric. There are two cylindrical rotary parts 25 a and 25 b with appropriate raised patterns mounted to rotate freely about a transverse axis 25 c , as in FIGS. 11 to 13 . The difference lies in the central part 24 , which is also a rotary part, fastened to the cylindrical rotary parts 25 a and 25 b . The central part 24 includes a circular central ridge 24 a in the longitudinal plane containing the axial direction I-I. The central ridge 24 a project slightly beyond the top generatrix of the cylindrical rotary parts 25 a and 25 b in the working area 2 . FIG. 14 shows in a similar way the result obtained by the use of this kind of anvil.
[0164] It will be understood that the invention therefore provides a method for ultrasound processing of a strip or web of thermofusible material by means of a device defined hereinabove in which there are effected successively the adjustment of the bearing force and then the adjustment of the non-null minimum separation E, so as to maintain between the sonotrode 3 and the anvil 4 a separation greater than the non-null minimum separation E whilst maintaining a particular elastic bearing force of the sonotrode 3 and the anvil 4 on the strip or web of material 23 if the separation is greater than the non-null minimum separation E.
[0165] Cutting may advantageously be effected in two successive, closely spaced steps:
there is produced by ultrasound, in the strip or web of material 23 , a continuous fused area, i.e. the area of the groove 26 , bordered by two areas of spot welds, i.e. the two lateral areas 27 and 28 , the strip or web of material 23 is cut mechanically in the fused area produced in this way i.e. in the bottom of the groove 26 , this area still being hot, which further facilitates cutting.
[0168] The anvil 4 according to FIGS. 11 to 13 may be used in a device as shown in FIGS. 1 and 2 in particular.
[0169] It may in particular prove advantageous to use this anvil with mechanical manual adjustment means 10 that effectively limit the depth of penetration of the sonotrode 3 and of the anvil 4 into the material to be processed, leaving the fixed cutting blade 13 to finish the cut.
[0170] However, the anvil 4 according to FIGS. 11 to 13 may find useful applications, independently of the use of other mechanical manual adjustment means 10 , and thereby constitute an independent invention.
[0171] FIGS. 15 and 16 show a variant of the method according to the invention. In this case, a device as represented in FIGS. 3 and 4 is used, for example. FIG. 15 is a partial front view to a larger scale, in the vicinity of the working area 2 , in cross section. The anvil 4 with the circular ridge 4 c is seen.
[0172] FIG. 16 shows the result obtained by the use of this kind of anvil 4 : the strip or web of thermofusible material 23 advances in the forward direction 1 and slides over the circular ridge 4 c which forms the groove 26 the edges whereof consist of molten material, ensuring a continuous weld. A fixed cutting blade 13 disposed on the downstream side of the working area 2 completes the cutting of the strip or web of material 23 in the bottom of the groove 26 .
[0173] In all the embodiments described hereinabove including an anvil 4 having at least one element rotating about the transverse axis 4 a , it may be advantageous to mount the rotary element on bearing. Such mounting facilitates the passage of the strip or web of material 23 through improved rolling, and thus contributes to an improved quality of the weld both in terms of geometry and in terms of intensity.
[0174] In fact, the rolling encouraged by the bearings prevents loading of the welding area in traction, which area is weakened during the ultrasound heating, thus guaranteeing less geometrical deformation of the imprints left by the pips or raised patterns of the anvil 4 in the material to be processed. Furthermore, this rolling then being more fluid and less subject to jerks, the fabric may be pulled more regularly, thus preventing a particular area of the weld, by remaining slightly too long under the sonotrode, being subjected to overheating, affecting the quality and/or uniformity of the weld.
[0175] The present invention is not limited to the embodiments that have been described explicitly, but includes diverse variants and generalizations thereof falling within the scope of the following claims.
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A sonotrode and an anvil have a spacing determined by a manually adjustable mechanical device. The adjustable mechanical device includes an abutment device which maintains the distance between the sonotrode and the anvil greater than the minimum space, and which is provided with an elastic device for elastically attracting the sonotrode and the anvil to each other. Thus, it is possible to control efficiently the melting of material between the sonotrode and the anvil, for reliable welding, or for efficient cutting, or for welding along the cutting line.
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TECHNICAL FIELD OF THE INVENTION
This invention refers to a valve which is adapted for integration in the suction duct of a vacuum gripper, the valve configured for closing of the suction duct except for a limited leak flow when the vacuum gripper does not contact an object, while opening the suction duct when the vacuum gripper is placed in contact with an object.
BACKGROUND AND PRIOR ART
Vacuum gripping means which are arranged to permit a limited leakage and in-flow of air at ambient pressure via a restriction to the flow in a suction duct are previously known. These vacuum gripping means are often used in grippers that include a plurality of suction mouths which are distributed over an area and which are supplied from a common vacuum source. The suction mouths may be arranged in rows and columns in the form of an array, e.g., or in the shape of concentric rings, or may be arranged in a singular row. A set of suction mouths are this way connected to a common vacuum chamber in the vacuum gripper which may be realized in different embodiments of plates or beams, e.g.
Vacuum gripping means of this type are suitable for handling of objects which may vary in shape and/or size, e.g., or in the simultaneous handling of several objects such as sets of objects which are to be picked up and released at regular interspaced relation. The restriction to the suction duct flow ensures that a useful work pressure is generated in the vacuum gripper also in a case where one or several suction mouths are inactive and therefore admit a leak flow of ambient pressure into the vacuum chamber.
This technical approach requires surplus capacity with the vacuum source, which typically operates at oversized effect and energy consumption in order to compensate for the loss in efficiency which is caused by the leak flow.
The restriction to flow in the suction duct may be of fixed and invariable type, and thus insensitive to the presence of an object. A drawback in this kind of solution is that evacuation of air from between the gripper and the object via a restricted flow through the suction duct will be relatively time-consuming. Another drawback in relation to a flow that is reduced by means of a fixed restriction in the suction duct is a resulting delay in the process of releasing the object from the gripper. In order to improve the dynamics of the system and to shorten work cycle times, the fixed restriction may be dimensioned to permit a larger leak flow which would obviously require a correspondingly increase in consumption of energy in the vacuum generator.
Another approach aimed to improve the dynamics of the system would be to integrate an object-sensing valve in the suction duct, a valve that on one hand is configured to allow only a limited flow of air in the suction duct when the vacuum gripper is not in contact with an object, and which on the other hand is configured to open the suction duct for unrestricted flow of air when the vacuum gripper is brought into contact with an object, or upon release of an object from the vacuum gripper, respectively.
A previously known object-sensing valve for a vacuum gripper comprises a ball which seals only incompletely against a seat when the ball is sucked towards the seat by an inwardly directed flow, and which falls out from the seat to open the suction duct when the gripper is brought into contact with an object and the flow in result thereof is reduced or ceased. A drawback in relation to this known leak flow valve is that its operation is dependent on the valve's position in space, since the ball is caused by gravitational force to fall out from the seat.
SUMMARY OF THE INVENTION
In general, the invention aims at providing a dynamic vacuum system characterized by short work cycle times and an optimized energy consumption.
The invention particularly aims at providing an object-sensing valve for a vacuum gripper, wherein the valve avoids the drawbacks discussed above in relation to prior art solutions.
The object is met in the form of an object-sensing valve that is configured for integration into the suction duct of a vacuum gripper, the valve comprising a flexible and elastic tongue one end of which is anchored by the side of the suction duct, the other end of which extends freely outside the mouth of the suction duct, wherein the tongue is dimensioned to bend towards the mouth of the suction duct from the load of an air flow that is directed towards the suction duct, the tongue in its loaded condition incompletely covering the mouth of the suction duct.
Through the inherent elasticity of the valve tongue, a biasing force is applied on the tongue which is urged thereby to assume an open position permitting unrestricted flow of air through the valve. On the other hand, the flow of air into the suction duct creates a drop in pressure on this side of the tongue, which acts to draw the tongue towards the mouth of the suction duct. Accordingly, the valve is not dependent on its orientation in space in order to function. Since in the loaded condition the tongue covers the mouth of the suction duct only incompletely, a leak flow and a pressure differential is maintained that keeps the tongue in the loaded state, until the gripper is brought in contact with an object whereupon the flow and pressure difference ceases and the tongue springs back to its original, unloaded position.
It will be realized that the functionality is partly dependent on the elasticity of the tongue, and dimensions and choice of material in the tongue are parameters which need to be considered from case to case in order to ensure the desired operation. However, since operating pressure and flow are both parameters which may vary from one vacuum system to another it is not meaningful to provide herein a detailed specification which would be valid for a chosen implementation of the invention. Commercially available qualities in material include a number of candidates which would be suitable for the purpose. It can be foreseen that a skilled person, having knowledge about mechanical properties and behavior of these materials when used in suction cups and bellows, e.g., will have the skills and facilities required to try out and to choose the material and dimensions which would ensure the function of the tongue in a particular application.
It is preferred that the leak flow is introduced via a gap which is formed as the length of a flexible portion of the tongue, when viewed in a direction towards the tongue's free end, is shorter than the extent of the mouth of the suction duct in the same direction. A leak flow may however be alternatively created via a gap that is formed in other way, such as along the side of the tongue, as the tongue covers only partly the suction duct mouth.
Furthermore, the suction duct may advantageously be arranged to open in a convexly curved or arcuate surface that provides, on each side of the mouth, a support surface for the tongue in its loaded state. This way, the tongue will undergo a gradual and controlled deformation in to and out from the loaded state, and the embodiment reduces the risk for fracture in the tongue due to fatigue.
The embodiment which includes a supporting surface curved outwardly from the suction duct also permits increasing the length of the tongue, and increasing the dimensions of the supporting surface and the mouth of the suctions duct as well, as viewed in a plane that shows the actual length of the tongue. This may be advantageous if the invention is implemented in vacuum grippers of smaller sizes, e.g. The tongue may be arranged by the side of the suction duct to extend in a direction at which the free end of the tongue reaches into an imaginary extension of the suction duct outwardly of the suction duct mouth, as viewed in the aforementioned plane.
In one advantageous embodiment of the invention, the mouth of the suction duct is realized in the form of one or more slots which have a reducing width, transversely to the flow direction, from that end of the mouth which is adjacent to a point of attachment of the tongue by the side of the suction duct and towards the opposite end where the gap for the leak flow is created in the incompletely covering state of the tongue. The embodiment results in a leak flow which gradually reduces in relation to a gradually increasing pressure drop over the valve, via a suction duct mouth which provides a flow area that is reducing gradually in the length direction of the tongue. An effect hereof, resulting from the gradually reducing flow area in the length direction of the tongue, is that the ability of the valve to react upon the presence of an object is improved since the tongue's sensitivity and spring back motion in response to a decrease in the pressure drop over the valve is increased, proportionally to the degree of bending deformation of the tongue.
It is further of advantage when the tongue is formed with reinforcements that provide increased resistance against bending and added rigidity to the tongue transversely to the desired bending direction upon loading/bending of the tongue. These enforcements may in alternative embodiments include elements of more rigid material that is integrated in the tongue, or may include stiffening ridges formed in one side of the tongue, e.g.
The object-sensing valve can be configured for integration into a vacuum gripper's suction duct as a unit, including the suction mouth and the associated tongue. This unit can be mounted into the suction duct where the suction duct opens in the vacuum gripper, or be inserted in the suction duct, or integrated in the suction duct as a part thereof.
Further advantageous and details of the invention will appear from the following detailed description.
SHORT DESCRIPTION OF THE DRAWINGS
Embodiments of the invention will be explained more closely below with reference made to the accompanying schematic drawings, wherein
FIG. 1 shows a partially broken away sectional view through a vacuum gripper with a suction cup and an object-sensing valve according to the present invention integrated in a suction duct through the vacuum gripper;
FIG. 2 shows a side view of the valve of FIG. 1 , and
FIG. 3 shows the same valve in a view from above.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
For illustrating purposes, FIG. 1 shows a vacuum gripper means here comprising a holder 1 for a suction cup 2 . Vacuum is supplied to the suction cup via a suction duct 3 which opens in the holder. The suction duct is in flow communication with a vacuum source P, not further illustrated in the drawing. An object-sensing valve 4 in accordance with the present invention is arranged in the holder 1 .
The valve 4 comprises a body 5 having a through passage 6 . The valve body 5 is accommodated in the holder 1 in such way that the passage 6 through the valve body forms an extension of the suction duct 3 , whereas air flow from the valve body and the holder is prevented in result of a tight fit between the valve body and the holder, or alternatively by means of a sealing element 7 inserted as illustrated schematically in FIG. 1 .
In its mounted position, the valve 4 with the through passage 6 can be seen as a unit that is integrated in the suction duct 3 . The suction duct is this way provided a mouth 8 in the outer face of the valve body 5 . In the illustrated embodiment the suction duct mouth 8 is defined between outwardly curved or arcuate surfaces 9 in the end of the valve body, the surfaces 9 forming supporting faces for a tongue 10 which is anchored by the side of the suction duct. Since the suction duct opens in a convex surface that is curved outwardly as illustrated, the length of the tongue and the length of the suction duct mouth and of the supporting surfaces as well, can be extended as viewed in the sectional plane A-A, i.e. within the subject diameter of the suction duct. In its unloaded state, the tongue 10 may be arranged to extend in a direction at which the free end of the tongue reaches inside of an imaginary extension of the suction duct, outwardly of the mouth 8 .
As already mentioned, the tongue 10 is made of an elastic material which in a deformed and bended condition strives to return to its original shape. The tongue 10 , which may have four-sided, rectangular shape, is anchored in the valve body 5 by the side of the suction duct through the valve body. In the illustrated embodiment, an end region 11 of the tongue is inserted laterally into a seat 12 that is formed in the valve body (see FIG. 3 , wherein end portions of the seat 12 are visible outside the tongue 10 which is indicated by dash-dot lines). The tongue 10 may be secured in the seat 12 in any suitable way. In the illustrated embodiment, the tongue is secured in a seat having a sectional profile that is adapted to a ridge or rib 13 , running along a transverse edge of the tongue. Several ridges 13 may be distributed over the same side of the tongue, running in parallel in the width direction of the tongue to form reinforcements that provide increased resistance to bending of the tongue in other directions than the desired closing direction.
In the unloaded state of the tongue, the free end 14 of the tongue extends outside the mouth 8 of the suction duct. Upon connecting the vacuum gripper to a vacuum source P, an air stream F into the suction duct will generate a drop in pressure P SUB /P ATM over the tongue, forcing the tongue to bend into the air stream. When a certain sub-pressure level is reachee in the suction duct, the full length of the tongue will be sucked towards the suction duct mouth. Restriction of the air flow to the suction duct is this way accomplished gradually in proportion to an increase of the differential pressure over the tongue.
In the fully bended state of the tongue, the tongue is supported against the curved supporting surfaces 9 in a way illustrated through dashed lines in FIG. 1 . In this state, the tongue covers the mouth of the suction duct with exception for a gap 15 that is formed in result of the tongue having a length, in the sectional plane A-A, which is less than the length of the mouth of the suction duct in the same plane.
A constant and controllable flow is this way established via the gap 15 at the vacuum level which is required to fully bend the tongue 10 in its bendable total length. The amount of leak flow in a valve of a given gap area can be controlled by proper choice of elasticity in the tongue 10 : a more rigid tongue will result in higher flow at a given vacuum level since it will increase the force that is required to “close” the valve.
In a particularly preferred embodiment of the valve 4 , see FIG. 3 , the sensitivity and ability to react upon the presence of an object can be improved if the mouth of the suction duct is realized in the form of one or several slots 8 , 8 ′, having a width w transversally to the flow direction F which is successively reducing from that end of the mouth which is adjacent to the tongue's point of attachment 12 by the side of the suction duct, towards the opposite end in which the leak flow gap is formed in the incompletely covering state of the tongue.
The valve 4 can this way be adapted to different flows and vacuum levels without changing the physical dimensions of the valve. Nevertheless, no conclusions should be made from the accompanying drawings with regard to installation dimensions, the drawings being merely schematic representations of embodiment examples of the invention. In particular, in some applications the valve 4 may be dimensioned to permit installation into the suction duct of a vacuum gripper, instead of being mounted in a holder for a suction cup as illustrated in FIG. 1 . Nevertheless, the valve can be seen as an integrated unit since in both cases the valve provides a mouth to the suction duct.
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An object-sensing valve configured for integration in the suction duct ( 3 ) of a vacuum gripper includes a flexible and back-springing tongue ( 10 ), one end ( 11 ) of which is anchored by the side of the suction duct and the other end ( 14 ) of which extends freely outside a mouth ( 8; 8 ′) to the suction duct, the tongue dimensioned to be forced by an air flow (F) to bend towards the mouth of the suction duct and to cover the mouth incompletely in the loaded state of the tongue.
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RELATED APPLICATION DATA
This application is related to application Ser. No. 09/213,100 filed Dec. 17, 1998, which is a continuation-in-part of application Ser. No. 09/150,966 filed Sep. 10, 1998, now U.S. Pat. No. 6,145,796 which is a continuation-in-part of application Ser. No. 09/050, 533 filed Mar. 30, 1998, now U.S. Pat. No. 6,062,467 which claims priority from provisional application Serial No. 60/069,859 filed Dec. 17, 1997, each of which are incorporated herein by reference.
BACKGROUND
This invention relates to the packaging of dry particulate foods such as ready-to-eat (“RTE”) cereal. More specifically, this invention relates to production of bagin-a-box cartons using induction heating.
Cartons for dry particulate products such as RTE cereal are usually formed from a blank of paperboard or similar material comprising sidewalls with top and bottom flaps. The liner is a plastic or coated paper bag to preserve the particulate product. The liner can be filled and sealed before or after being placed inside an open carton, the flaps of which are then folded and sealed.
In U.S. patent application Ser. No. 09/213,100 filed Dec. 17, 1998, the use of induction heating and a vacuum is disclosed to seal a filled and sealed liner along weakened seal or tear lines without breaking the seal of the liner to a dispensing panel or door forming a dispensing opening. The present application is directed to other applications of the technology described in the '100 application to prepare alternative containers and other products, including, e.g., single-serving type containers.
SUMMARY
The present invention is directed towards a method for affixing filled and sealed liner bags in bag-in-box cartons wherein the liner is filled and sealed before being inserted into the carton and is thereafter induction sealed to the interior of the carton without breaking the seal of the liner. The carton may be open or sealed when the liner is adhered to the carton interior. Preferably a weakened tear line is formed in the liner corresponding to a pour spout or opening of the carton so that upon initial opening, the liner separates from the reminder of the liner along the weakened tear line to provide access to the contents of the carton.
Cartons made according to the invention have a filled and sealed liner which contacts an adhesive that is activated in situ by induction heating, preferably under vacuum, such that the liner adheres to the interior of the carton or a selected portion or portions thereof without breaking the seal of the liner.
The present invention is also directed to single serving “bag-in-bowl” containers, having a filled and sealed bag that is adhesively bonded to a rim or peripheral edge of a disposable bowl made of paper, cardboard or plastic. The bag-in-bowl is made in a manner similar to the process described above in that it relies on induction heating to bond the bag to the bowl using a heat activated adhesive without breaking the seal of the bag.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention is more fully understood from the following description and the accompanying drawings wherein:
FIG. 1 is a flow diagram showing an embodiment for preparing a single serving, bag-in-box carton having perforated flaps in a side wall that fold out to provide access to the contents of the bag;
FIG. 2 is a flow diagram of a method to affix the liner of a bag-in-box carton to the carton interior;
FIG. 3 is a flow diagram an alternative method to affix the liner of a bag-in-box carton to the carton interior;
FIG. 4 is a flow diagram of a method for preparing a bag-in-bowl carton according to the invention.
DESCRIPTION
According to the present invention, a filled and sealed liner or bag is bonded to a side panel or panels and/or end wall or walls of a carton blank without breaking the seal of the liner. One purpose is to maintain the bag in a fixed position relative to the carton after it is opened and he bag seal broken to gain access to the contents. The liner bag is formed, filled and sealed using means known in the art.
Prior attempts to affix a filled and sealed lines to a carton interior after insertion of the liner have led to inconsistent results and have interfered with the insertion of the filled liner into the carton.
FIG. 2 is a flow diagram of the general process for preparing the cartons of the invention. The method begins by providing a carton blank 9 in step 40 . Blank 9 is conventional and has side panels 22 , end panels 24 and corresponding top flaps 21 and 23 and bottom flaps 21 ′ and 23 ′. A strip of a radio frequency adhesive 20 is applied in step 12 to a transverse section of side panel 22 of blank 9 . An RF adhesive useful herein is normally untacky but activated into an adhesive state when heated remotely by RF heating.
Carton 9 is then erected in step 44 leaving one end open to receive a filled and sealed bag 15 which is separately prepared as is known in the art. Filled and sealed bag is inserted into the open end of erected carton 9 which is closed and sealed in step 46 . The sealed carton is then introduced into an induction heating chamber in step 20 , where the carton is exposed to induction (RF) heating under vacuum and conditions such that the bag expands and contacts the side walls of the carton. The sealed bag contains air at ambient pressure which causes the bag to expand and press against the carton in a low pressure environment. The application of radio frequency activates adhesive strip 20 to therapy bonding and affixing the bag to the carton interior without breaking the seal of the bag 15 . Alternatively, the bonding energy may be applied to activate the adhesive and bond the liner to the carton prior to sealing the carton, with the carton being sealed thereafter.
Known RF activatable adhesives can be used as well as known vacuum chambers and induction heating units or devices. Suitable adhesives include known hot melt adhesives that are not tacky at ambient temperatures so as to not interfere with liner insertion.
A preferred multi chamber device with intake and discharge locks for handling (sealing) cartons on a high-speed continuous basis is disclosed in copending application Ser. No. 09/213,100 filed Dec. 17, 1998, which is incorporated herein by reference.
RF adhesive can be applied in any desired pattern such as strips, dots, squares and the like to the side and/or end walls of blank 9 or to the entire area of the side and end walls 22 an 24 (reference number 28 , FIG. 3) to create a linerless-type carton normally obtained by laminating or coating stock before cutting blanks. RF adhesive can also be applied to bag 15 with or without adhesive applied to the interior of blank 9 .
The amount and location of the adhesive will be determined in part by the contents of the carton and the intended use of the carton. An RTE cereal liner can be affixed with a strip 20 as shown in FIG. 2 to maintain bag 15 upright in the carton after opening. One or more strips or dots will be sufficient in the case of light contents like RTE cereal whereas more dots, strips or a full coating of adhesive may be needed for heavier contents such as pet foods, soaps or lawn care products. The invention is especially useful for maintaining liner alignment when a pour spout is employed as disclosed in U.S. Ser. No. 09/213,100 filed Dec. 17, 1998.
FIG. 1 shows an embodiment wherein a known single serving bag-in-box type carton having perforated access flaps 11 a and 11 b in a side wall of blank 9 is prepared with a radio frequency adhesive applied to the flaps 11 a and 11 b and to an adjacent area of the inner side wall 22 of blank 9 . The carton is then erected in step 14 , leaving the top open to receive a filled and sealed single serving bag 15 in step 16 . The carton is sealed step 18 and is then introduced into an induction heating unit 32 under vacuum. The vacuum causes the bag 15 to expand and contact the adhesive area 25 which is activated by induction heating therapy bonding the bag to flaps 11 a and 11 b and to adjacent areas of side panel 22 .
In FIG. 3, RF adhesive 28 is applied to substantially the entire inner surface of the carton blank 9 in step 62 . The carton is then erected in step 64 , and the separately prepared filled and sealed liner bag is inserted into the erect carton through an open end thereof in step 66 . As before, the carton is sealed in step 68 and introduced into an induction sealer as described above.
FIG. 4 shows a “bag-in-bowl” useful for single or multiple servings. A six-sided bowl 100 made of paper, plastic, composite or other suitable disposable material has a peripheral lip or rim 101 on which an RF adhesive or other activatable adhesive is applied. The RF adhesive may also be applied to an interior region of bowl 100 . A sealed and filled bag 103 is positioned on bowl 100 in such a manner that the end seams 104 of bag 103 contact the adhesive on rim 101 and/or bowl 100 . Pressure is applied to the bag, e.g. by a plunger 103 in unit 32 to compress the bag so that end seams 104 contact the adhesive areas. While pressure is applied, the adhesive is inductively heated or otherwise activated to bond end seams 104 to the bowl.
Liner bags used with the products of the invention can be prepared and filled by any means known in the art. For example, liner material is cut into sized sheets, wrapped around a mandrel and longitudinally and transversely sealed before and after filling.
In an alternative embodiment, the bowl may be filled with the desired contents and a liner placed over the bowl and bonded thereto using the techniques described above.
Multiple activatable adhesive systems such as hot melt (which might further employ any variety of heating methodologies such as conduction, convection, or by activation with electromagnetic or sonic energy) as well as RF induction heating may be used to prepare the bag and to adhere the filled bag to the back of carton.
Hot-melt adhesives are 100% solids and are applied in hot, molten form. They set fast when heat is removed and can be preapplied and reactivated later by the application of heat. Hot melt adhesives are typically formulated with a backbone polymer such as ethylene-vinyl acetate or polyethylene. The main polymer is usually let down with a diluent such as wax to improve melt flow properties. Antioxidants may be added since the adhesive is applied hot and is subject to oxidation. Tackifiers can also be added to improve hot tack and viscosity. Other materials can be added to influence the melt temperature, and colorants may be added to make the adhesive more visible.
Hot-melt adhesives are readily available from numerous sources. INSTANT LOK® hot melt adhesives from National Starch and Chemical Corporation of Bridgewater N.J. 08807 are suitable for use in the invention.
In a preferred embodiment, the hot melt adhesive is activated by induction heating. In this embodiment, an activatable hot melt adhesive is applied to the carton interior and/or the bag and heat is applied to the interface between the liner and the carton such as by induction heating after creating or forcing contact at the interface by employing a vacuum and/or compressing the filled and sealed bag. Such a bag normally has “head space” created by under filling a bag which allows the bag to be compressed without crushing the contents.
Activation of the hot melt adhesive can also be accomplished by inclusion of a heat generating substance in or positioned such that the hot melt adhesive to generate the heat necessary to activate the hot melt adhesive to bond the liner to the carton. Such heat generating substances include metal foils such as aluminum foil, which may be laminated on one or both sides to a hot melt adhesive, metal salts such as magnesium chloride, chromium nitrate, aluminum chloride and the like, which are mixed with the hot melt adhesive; and metal particles such as iron or aluminum powder mixed with or flocked onto the hot melt adhesive applied to the carton interior and/or bag.
When using magnetic particles such as iron, a magnet can be employed to orient the particles and promote bonding with the liner. The metal salts and metal particles are used in amounts sufficient to activate the adhesive when external bonding energy is applied.
Metal foil laminates are easy to apply and activate. A typical metal foil laminate includes aluminum foil, generally vacuum metalized aluminum on a polyester film, with a linear low density polyethylene adhesive on one or both sides. Curwood Inc., of Oshkosh, WI. 54903, provides CURLAM® Grade 5432 film which has an adhesive on one side of the film. It is preferred to coat both sides of the film with an adhesive which enables the use of induction heating to bond the foil laminate to the carton and the liner at the same time. The metal foil laminate is preferably aligned corresponding to an area of the carton that will be opened for use, e.g., along a perforated access panel, so that when the liner bonds to the foil laminate a weakened tear line is formed in the liner corresponding to the carton opening. The weakened tear line allows for easy access to the carton contents while maintaining a seal prior to opening. Upon initial opening, the liner will separate along the weakened tear line to allow access to the inner contents.
Induction heating equipment is widely used in the packaging field and suitable units for use in the invention are available from Lepel Corporation of Edgewood, N.Y. 11717 and Amertherm, Inc. of Scottsville, N.Y. 14546.
The intensity and duration of the induction field required to bond the liner to the carton depends on the composition of the heat activatable adhesive. For example, an aluminum foil laminated with linear, low density polyethylene generally achieves its sealing temperature in 0.9 to 1.2 seconds when exposed to a Lepel, LEPAK, Jr. 750 watt induction sealer. An adhesive having a resin base including about 5 to 10 weight percent metallic salt, such as chromium nitrate or aluminum chloride, generally reaches its sealing temperature in under 2.0 seconds when placed in an 800 watt GE microwave oven operating at 900 to 1100 kHz.
Other induction heating systems and heat activatable adhesives can be used. For example, an induction heating system for sealing packages using magnetic susceptible particles and heat softenable adhesives and high frequency alternating magnetic fields is disclosed in U.S. Pat. No. 3,879,247 which is incorporated herein by reference. Polymer systems for sealing containers which can be activated by electromagnetic energy frequencies of 0.1-30,000 MHZ, including radio frequency and microwave heating, are disclosed in U.S. Pat. No. 4,787,194 which is incorporated herein by reference. RF sealable, non-foil acrylate based polymers for packaging applications are disclosed in U.S. Pat. No. 4,660,354 and WO 95/03939 which are also incorporated herein by reference.
It is particularly advantageous to use the invention along with a pour spout as disclosed in copending application Ser. No. 09/213,100 filed Dec. 17, 1998, wherein heat sealing a liner to a flap or front panel of a pour spout locally weakens the liner to facilitate separation of a portion of the liner upon initial opening of the pour spout or flap. In one embodiment, this can be accomplished by attaching a metal foil laminate to the front panel of the pour spout or to a fitment which defines the dispensing opening. The foil can be configured so as to concentrate heat at the edges of the dispensing opening which crates a weakened or thinned tear line without breaking the seal of the bag.
A preferred liner is biaxially oriented, laminated high density polyethylene film. Such films will tear easily in the longitudinal or machine direction and to impart better tearability in the transverse direction, fillers such as finely divided calcium carbonate, silica, diatomaceous earth and the like can be added to the film. A suitable film can have two high density polyethylene layers containing 15% by weight finely divided silica in the inner layer and 10% in the outer layer.
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Processes for preparing cartons, including bag in the box type cartons, using inductive heating are disclosed. Methods for preparing bowl-type single serving containers having filled bags therein and methods for using inductive heating to bond pour spouts to cartons are also disclosed.
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[0001] This application is a Divisional of co-pending Application Ser. No. 12/549,208, filed on Aug. 27, 2009, which is a continuation-in-part of application Ser. No. 10/547,336 filed on Sep. 1, 2005; which is the 35 U.S.C. 371 national stage of International application PCT/CH2004/000109 filed on Mar. 1, 2004; which claimed priority to Switzerland application 328/03 filed Mar. 3, 2003. The entire contents of each of the above-identified applications are hereby incorporated by reference.
TECHNICAL FIELD
[0002] The present invention relates to the field of medical aids. It includes both a device and method for analgesic immobilization of fractured ribs (thorax immobilization device). Such a device is known from, e.g., U.S. Pat. No. 4,312,334.
BACKGROUND ART
[0003] Rib fractures are very painful, especially if multiple ribs are fractured simultaneously. This is especially true while breathing, and as a result the patient tends to breathe flatly (reduced forced vital capacity, FVC), or, in case of multiple fractures on the same rib, forcing the patient to breath in an unusual way, in which the chest parts participating in breathing move in the opposite direction as usual. In most rib fracture cases, no surgical intervention is performed, and natural healing occurs. It is desirable to administer some medicine for controlling the pain of the patient in order to achieve better breathing.
[0004] The immobilization of fractured ribs presents an unique splinting challenge due to their localization. Proper splinting technique teaches that a splint should extend to include the joint on either side of the injury. Applying this general rule to the case of rib fractures would mean a circumferential brace or belt which wraps around the body. This technique was introduced by Malgaine (1859), however it is medically rather contraindicated today. This is because—due to the inhibition of the breathing—the risk of pneumonia is greatly increased in such cases. The various trials after Malgaine with taping or surgical approaches were all failures, owing to either a lack of any therapeutic advantage or the costs (e.g., with surgical approaches).
[0005] In the fact, the target of splinting is an immobilized limb in the classic bone fracture case. This lies in stark contrast to a chest injury, in which body part that moves steadily and three-dimensionally has to be splinted. In this regard, it is worth noting that the average human performs about 20,000 breathing cycles per day! This substantial difference has made it impossible even for experts to apply the results or observations of the usual splinting techniques the splinting of a rib fracture.
[0006] On one hand, a rib splint must be wide-based and must over-bridge the fracture region. As noted above, circular bandaging cannot be used without inhibiting the breathing capacity. On the other hand, the larger the splint, the stronger the forces exerted by each breathing cycle to diminish the effect of the adhesive at its periphery. The whole splint has to be rigid (and also formable at the same time) to reduce all the forces resulting from the different movements of the ribs. However, an appropriate degree of flexibility of the material may also be desirable for the patient's comfort. No known arrangement complies with these criteria before the present device and method.
[0007] It has already been known for a long time that for immobilizing fractured ribs, the side with the fracture in the thorax can be fixed by an adhesive plaster, in order to reduce the movement of the fractured rib. However, this is usually not sufficient. There is a suggestion (GB-A-624,425) to use bundle-like, stretchable stripes instead of the plaster, which can be prestreched by means of a releasable stretching device. However, those immobilizing devices ensure a limited mobility in the region of the fracture, but, at the same time, they hinder breathing to a large extent, as well.
[0008] The earlier mentioned description U.S. Pat. No. 4,312,334 suggests binding a frame around the patient. The front side of the frame consists of two vertical, arched supporting elements over the chest. The indented part of the thorax in the fracture area is drawn out by means of a wire fixed on its one end to the chest and on the other end to the supporting element. In this way, the fractured ribs can be kept in a position suitable for healing, easing the pain that reduces breathing.
[0009] The drawbacks of this arrangement include the necessary intervention, the difficulty in positioning the wire, and the hindering of the patient's movements by the stretched wire and the frame.
[0010] Shippert (1980; U.S. Pat. No. 4,213,452) describes a “compound” splint, primarily for use after nasal surgery. The splint is put together on the patient. Adhesive tapes are used as a basic layer for securing a secondary component followed by a malleable metal sheet and the closing layer(s). This reference makes no suggestion of possible use in rib fracture, and in fact concerns itself only with a small and immobilized area. It is entirely unsuitable for use in connection with a larger and moving area, such as the chest.
[0011] Groiso (1986; U.S. Pat. No. 4,852,556) describes an orthopedic rigid splint-plate orthesis of different sizes and forms depending on the target of the immobilization. One of the claimed targets is a rib fracture. The material used requires a curing process, and any mention of an adhesive in such reference is proposed only in connection with such curing period. Groiso acknowledges that for securing a bigger thermoplastic splint, adhesive attachment is not sufficient. Accordingly, he uses a circumferential wrapping around the body. In fact, the possible positive effect of his method is based on the circular bandaging of the thorax, a technique used since the middle of the nineteenth century.
[0012] Erickson (WO-A1-89/05620) provides a fixing plate for rib fractures being flexurally rigid in the longitudinal direction, and to a certain extent flexible in the direction perpendicular to this. In addition, it is to a certain extent also rotatable in the diagonal direction (being able to torsion). This arrangement serves for supporting and fixing the individual fractured ribs on the one hand, and at the same time, should make free breathing movement of the patient possible, on the other hand. This objective is achieved by using a plate made of a flexible, elastic material, such as rubber or plastic, in which several closed, long-shaped cavities parallel to the longitudinal, flexurally rigid direction are arranged. In each of these cavities, freely movable, as one-dimensional splint elements, rods made of an inelastic but deformable material are arranged. In case of a rib fracture, due to their deformability, these splints can be fitted to the contour of the rib. The plate with the splints will be stuck flat to the chest, in this position the splints run parallel to the ribs. Thus, the ribs are fixed in the longitudinal direction, whereas at normal breathing, the chest is able to expand without hindrance.
[0013] Though the one-dimensional splints fix the fractured ribs in the longitudinal direction, they allow for unhindered movement of the ribs relative to each other for breathing. This is partly due to the free movability of the splints in the cavities. Due to this movability of the ribs relative to each other during breathing, the distances between individual ribs change. As a result, the fractured sites of the ribs may rub on each other, causing pain for the patient. This pain may lead to a cramp in the intercostal musculature, which only exacerbates the pain.
[0014] Bolla et. al. (1996; U.S. Pat. No. 6,039,706) describes a medical splint, metal sheets for such a splint, and its use for securing and immobilizing movable body parts in particular extremities. The specially prepared material ensured “a high shapability and stiffness at the same time.” It is rigid and formable at the same time, a ready-to-use splinting material without the necessity of a curing process. This reference proposes the device for use only for conventional (e.g., limb) splinting. Splinting of the thorax (rib fracture) is not suggested as appropriate for such device. The breathing-related, nearly continuous movement of the thorax excludes such an application without a belt.
[0015] Singh et. al. (2000; U.S. Pat. No. 6,716,186 B1) describes curable adhesive splints and methods. The splints include at least a curable splinting layer (developing the requested stiffness) and an adhesive one. The declared target of the splinting is “Immobilization of smaller skeletal features, such as fingers or of oddly shaped skeletal features, such as noses . . . ” The use of the claimed technique for ribs is not mentioned. The inventors seemingly knew the substantial differences in the requirements between splinting an immobilized body part and a steadily moving one, such as the thorax. The device described in this patent could only be used in connection with a rib fracture (if at all) with an additional belt. This, however, is already the subject of the Groiso reference described above (1986; U.S. Pat. No. 4,852,556). The securing of the splint position with an adhesive layer, as Groiso describes, can be utilized for larger splints only with the additional wrapping necessitated thereby. He secures the rib splint from similar materials, with an adhesive used only during the curing process.
[0016] Rolnik et. al. (2004; U.S. Pat. No. 6,971,995) proposes an adhesive elastic splint construction for the treatment of rib injuries. He even disclaims the applying of an inelastic adherent patch even because it is asserted not to be appropriate for allowing the patient's comfort.
SUMMARY OF THE INVENTION
[0017] Based on the above, the task of the present invention is to create an analgesic immobilizing device for use in thorax fractures eliminating the drawbacks of the devices known, with a device that is simple to produce, easy to apply, quite safe to use and whose use results in a reduction of pain and improvement of breathing, without influencing significantly the free movement of the patient's chest.
[0018] It is proposed at the first time an adhesive, rigid, and yet formable splint for the treatment of rib fracture. The rigidity ensures the desired partial immobilization of the thorax, while the formability makes wearing of the splint comfortable for the patient and reduces the forces acting against the adhesive during breathing. To compensate, or at least reduce the effect of the forces occurring by each breath increasingly on the adhesive at the periphery of the splint, the fixation with the inherent adhesive layer is strengthened with a non rigid protective foil, which is larger than the splint element. The two fixations must be performed in two steps in different phases of the breathing cycle. The two-step fixation makes the use of a belt unnecessary.
[0019] The task is solved according to features described in further detail below and in the attached claims. The essence of the invention lies in a formable, flat splint element being rigid in itself covering the fracture area, including the fractured rib(s) and the neighboring, non-fractured ribs as well, which splint is provided with an adhesive layer on its side facing the body suitable for adhering the immobilizing device to the body. The splint element should be adhered to the fractured part of the thorax (fracture area) so that preferably the neighboring, non-fractured parts are also covered. The fractured ribs will thus be secured by the splint element being relatively rigid in itself, while nevertheless being formable at the same time, and is supported also by the uninjured ribs. This stabilization leads to reducing the pain and consequently improves the patient's breathing.
[0020] In a preferred embodiment of the invention the splint element can be fitted to the outside contour of the thorax particularly without any additional aid or tool, whereas it preferably contains a deformable plastic plate or a plastically deformable metal plate. This plate increases further the efficiency of the splint and makes its application simpler.
[0021] The plastically deformable metal plate is made preferably of aluminium, where the plastically deformable metal plate is corrugated in order to improve local deformability with increasing at the same time the rigidity, and the crests of corrugations of the plate are essentially parallel to the ribs to be treated. Such a splint material has already successful applications for different purposes (WO-A1-97/22312 resp. U.S. Pat. No. 6,039,706).
[0022] The wear of such a splint element can be made more comfortable so that the upper and/or lower side of the splint element is provided with a covering, made preferably of some tissue, or of an elastic foam material. In addition, some perforation can also be made in the splint element in order to achieve better permeability of the immobilizing device.
[0023] In order to protect the immobilizing device against external effects, such as water or similar substances, it is preferable to use a protecting foil for covering the upper side of the splint element. This protecting foil should be adhered onto the splint element and also to the chest after applying the splint on the body. A protection of the sides can also be achieved easily so that the foil over the splint element sticks out on the sides, and forms a continuous rimstrip, whereas the lower side of the protecting foil is also provided with an adhesive layer in the field of the rimstrip.
[0024] In order to reduce further the pain caused by rib fractures it is preferred if the immobilizing device is provided additionally also with some local analgesic substance. For this purpose, pain killers may be contained in a smaller pad or cushion coupled to the immobilizing device by a releasable bond. Another possibility is that parts of or the total of the adhesive layer contains a pain killer
BRIEF DESCRIPTION OF THE FIGURES
[0025] The invention will be explained on the basis of figures showing some embodiments.
[0026] FIG. 1 illustrates a very simplified perspective view of a first embodiment of the immobilizing device of the invention for putting to rest position the injured ribs,
[0027] FIG. 2 shows a top view of the immobilizing device shown in FIG. 1 ,
[0028] FIG. 3 is a top view from the front of an example of rib fracture showing four ribs from among which the second from the top is fractured,
[0029] FIG. 4 shows the rib fracture in FIG. 3 in a simplified section along the line IV-IV with the fracture area,
[0030] FIG. 5 is a top view from the front of a second embodiment of the invention showing the immobilizing device adhered to the rib fracture shown in FIG. 3 ,
[0031] FIG. 6 illustrates the effect of the adhered immobilizing device in a view similar to that in FIG. 4 ,
[0032] FIG. 7 shows an enlarged view of a section through the immobilizing device shown in FIGS. 5 and 6 .
DETAILED DESCRIPTION OF THE INVENTION
[0033] The device according to the invention is applied to fractured ribs (thorax fractures). In these cases the object is to reduce the movement of the injured ribs in the chest.
[0034] An embodiment of such an immobilizing device and its application are shown in a significantly simplified way in FIGS. 1 and 2 . FIG. 1 shows the scheme of four ribs 15 - 18 from one side of a chest 13 , from among which the second rib from the top, rib 16 has a fracture 14 . The tissue and skin layers of the body over ribs 15 - 18 are not shown for simplicity reasons. The intercostal musculature is not shown either. A flat, splint-like immobilizing device 10 fitted to the arching of chest 13 is adhered to the area of chest 13 surrounding fracture 14 , on a large part of the total surface. The main component of the immobilizing device 10 consists of a splint element 12 ( FIG. 2 ) in form of a plate made of a suitably rigid, but at the same time plastically deformable, material. Adhering is achieved by applying an appropriate adhesive layer 11 on the inside of splint element 12 , similarly to plasters ( FIG. 2 ). The size (lateral dimension) of the immobilizing device 10 is chosen preferably so that the immobilizing device 10 covers not only the injured rib 16 , but also the neighboring ribs 15 and 17 in a sufficient manner.
[0035] Through adhering, the immobilizing device 10 is supported by the not fractured part of the injured rib(s) and by the uninjured neighboring ribs 15 and 17 and keeps the fractured rib 16 in a fixed position relative to the neighboring ribs 15 and 17 . This hinders to a great extent any painful movement of the injured rib 16 at breathing, coughing, laughing or in other similar situations eliminating or at least reducing thereby the pain caused by these movements.
[0036] Additionally, some means can also be applied locally to the inside of the immobilizing device 10 for reducing the pain caused by the injured rib 16 . Preferably pads or cushions impregnated with some analgesic material having its effect through the skin are used, which are connected to the inside of immobilizing device 10 by a releasable bond, e.g. by adhering or by hook and loop fastener. Another solution may be to impregnate parts of or the total adhesive layer 11 with a suitable pain killer.
[0037] The effect of the immobilizing device 10 according to the present invention may be explained on the basis of FIGS. 3-6 . In this case, we also have four parallel ribs 15 - 18 , from among which the second one from the top, rib 16 has a fracture 14 (of course, it is also possible that more fractured ribs are present). Considering the section of the chest along the line IV-IV in FIG. 3 , the configuration shown in FIG. 4 is obtained in a simplified form. Ribs 15 - 18 are embedded into intercostal musculature 21 serving, among other things, for breathing. This is covered by a multilayer consisting of skin and fat tissues which, in a simplified way, can be denoted as a skin/fat tissue layer 20 . In the area of fracture (fracture area 19 ), the fractured rib 16 looses at least in part its stability, and as a result, a frictional movement (marked in FIGS. 3 and 4 by double arrows) of the ends of the fracture relatively to each other may occur causing significant pain to the patient at any movement of the chest.
[0038] If, according to FIGS. 5 and 6 a flat immobilizing device 22 is adhered to fracture area 19 involving rib 16 and preferably to the not injured ribs 15 , 17 and 18 as well, fracture area 19 is stabilized so that rib 16 is immobilized in se and also relative to the other ribs 15 , 17 and 18 . This leads to a less painful breathing of the patient improving thereby the way of his/her breathing, as well.
[0039] Clinical experiments were carried out in 90 patients (72 of them using the immobilizing device, 18 being in the control group) which patients had fractures up to 5 neighboring ribs, in which experiments the intensity of pain was determined by an analogous scale before the admission of the patients to the study, and 1-2, 24, 48 and 72 hours after that. In comparing with the control group, the intensity of pain in rest (p<0,05), and especially at forced inspiration (p<0,01) was over the whole period significantly less than in the control patients. The reduction of pain owing to the use of immobilizing devices 10 or 22 was measurable already even 1 hour after putting them on, whereas the control patients experienced a measurable reduction of pain only after 2-3 days.
[0040] Spirometric measurements were carried out in 29 patients before, and 1-2, 24, 48 and 72 hours after the adhering of the immobilizing device (in several patients in all these periods). Two different sizes of immobilizing devices (12×17 cm and 17×17 cm) were used according to the size of the fracture area. In 12 further patients (control patients) was the fracture area covered only by operation pads. In these control patients the forced vital capacity (FVC) hindered by the fracture, was further reduced by 174 ml in the average after 1-2 hours, and improved within further 24 or 48 hours only by 4 or 34 ml. To the contrary, in patients treated with the immobilizing device, the FVC continuously and significantly improved (p<0.001), by 153 ml in the average already after 1-2 hours, and by 384, 474 and 616 ml after 24, 48 and 72 hours, after the application of the immobilizing device, respectively. Just like FVC, the spirometric parameters FEV1, IVC and PEF improved also by using the immobilizing device.
[0041] A preferred embodiment of immobilizing device 22 is shown in FIGS. 5-7 . The immobilizing device 22 comprises a flat splint element 24 as central component, in the present case made of a corrugated aluminum plate. The thickness and corrugation of the plate are chosen so that splint element 24 may be fitted easily to the area of the fracture to be treated in the arching of the chest by bare hands without any additional aid, and on the other hand, it is appropriately rigid for its function as support and immobilizing means for the fracture. Splint elements described in WO-A1-97/22312 are also suitable for this purpose (this is why the dates about the material used in that description are taken over in the present application).
[0042] In order to fit immobilizing device 22 best to the chest, the crests of the corrugations of splint element 24 are arranged parallel to the ribs. Splint element 24 is provided with a covering 25 on its lower side and covering 23 on its upper side for making its wearing more comfortable. Coverings 23 and 25 are preferably made of an elastic, foamed open-pored or perforated plastic material. Covering 25 at the lower side is provided with an adhesive layer 26 on its outer surface, by means of which the immobilizing device 22 can be adhered to the fracture area. As adhesive materials for the adhesive layer, every adhesive suitable for medical applications can be used. During application, the upper side of the immobilizing device 22 , e.g. the outer surface of covering 23 is adhered to a protecting foil 27 which is greater on the sides than the covering, thus forming a protruding rim 28 ( FIG. 5 ). If the protecting foil 27 with its protruding rim 28 is adhered to the skin of the patient, immobilizing device 22 is protected against external effects, thus the patient can e.g. take a shower without any negative consequence. The protecting foil is permeable for air (so called breathing foil) and water-tight. Splint elements 24 in the present invention may be made of other materials than corrugated aluminum plate, such as plastic plates or similar materials being rigid enough and at the same time, sufficiently plastically deformable. Splint element 24 is preferably provided with holes, e.g. in form of a perforation, in order to be permeable and being more comfortable to wear.
[0043] The inventor has also discovered that the present device offers a further improvement over any known prior art in the field of analgesic relief for rib fractures. As described in detail above the present device is preferably constructed with two adhesive areas. One of these areas is that of adhesive layer 26 . The other is that of the perimeter area of protecting foil 28 . In at least one embodiment, the adhesive layer 26 is surrounded by the perimeter adhesive area of layer 28 . The perimeter area of protecting foil 28 is adhered to the skin of the chest in a separate step from that of adhering adhesive layer 26 .
[0044] As described above, one of the beneficial effects of the perimeter adhesive area of layer 28 is to act as a barrier to things such as water. The presence of this layer allows the patient to engage in activities such as showering without adverse effect to the device.
[0045] The combination of these two separate adhesives has proven to have yet another, entirely different advantage, however.
[0046] One of the characteristics of rib fractures that makes their treatment considerably more difficult than fractures of other bones is the necessarily dynamic nature of ribs. By their very nature, ribs must be in nearly constant motion with respect to the remainder of the skeletal structure. The inhalation and exhalation of air required for breathing is, at its core, a fundamental mechanical operation.
[0047] Like a bellows, the lungs must be expanded and contracted to draw in oxygen-rich air in and expel the carbon dioxide produced by the respiration process. It is the skeletal-muscular structure of the ribcage that acts as the bellows.
[0048] Given this crucial function, a fractured rib or ribs cannot be rigidy fixed in place by a cast or other similar immobilizing device. To draw a contrast with the leg, as an example, the two elements of a fractured tibia can be set back into proper relationship with one another and then rigidly fixed in place by a cast or other immobilizing device. Such a cast can not only surround the lower part of the leg, but can extend down past the ankle. In so doing, such a cast holds several bones of the leg and foot in a fixed positional relationship with one another. While uncomfortable, this does not interfere with the overall health of the patient. It is only the activities of mobility that are affected while the cast is in place.
[0049] It is not, however, possible to hold the chest in place in a similar manner. To do so would bring to a halt the motion necessary for inhalation and exhalation, with obvious disastrous consequences.
[0050] While the present device makes a considerable advance in the possibilities for treatment of rib fractures by virtue of its ability to be secured to that area of the skin of a patient that overlies the fracture or fractures, the presence of the two different adhesive areas offers yet another considerable advance in treatment, insofar as it allows for yet further accommodation of the different positions that the ribcage must occupy during maximum and minimum lung volume at different times of the breathing cycle.
[0051] With this in mind, it has been discovered that considerable gains can be achieved by adhering the two different adhesive portions at two different point in the breathing cycle. Under one example, the adhesive portion 26 is first adhered to the skin that overlies the fracture or fractures when the patient is in a condition of minimum lung volume, namely when the patient has finished exhaling, or very nearly so. The other adhesive portion 28 of the perimeter is not attached to the surrounding skin at the same time, however. Instead, the patient is instructed to inhale, and the adhesive portion 28 is then adhered when the lung volume is at or near its maximum volume.
[0052] In this way, the inner area of adhesive 26 is secured to the skin at a time when the skin is relatively slack at the end of exhalation. The outer perimeter adhesive 28 is secured to the skin when the skin when the skin is relatively stretched at the end of inhalation. Accordingly, when one of the areas of adhesive is stressed by the movement of skin (and underlying structure) away from the relationship the adhesive had with the skin at the time it was adhered, the other area of adhesive is having a corresponding stress relieved as it moves back into the relationship it had with the skin and underlying structure at the time of adhesion.
[0053] This method of application greatly improves the ability of the device to provide an overall secure relationship of the rigid portion of the device with the fractured rib or ribs during the many tens of thousands of respiration cycles that will take place from the time that the device is attached to the time that it is removed after the rib or ribs have healed.
[0054] It is also possible that the relationship of the two can be reversed, so that the inner adhesive area 26 is secured when the lungs are at or near a condition of maximum volume, and the outer adhesive is attached at or near a condition of minimum volume.
[0055] It is also unnecessary that the attachment of either adhesive portion take place at the limit of either inhalation or exhalation. So long as the two steps of adhesion take place at different points in the cycle, an advantage will be had over a corresponding method and device in which all adhesion takes place at essentially a single point in the respiration cycle.
REFERENCE NUMBERS
[0056] 10 , 22 immobilizing device
[0057] 11 adhesive layer
[0058] 12 splint element (flat)
[0059] 13 chest
[0060] 14 fracture
[0061] 15 - 18 ribs
[0062] 19 fracture area
[0063] 20 skin/fat tissue layer
[0064] 21 intercostal musculature
[0065] 23 upper covering
[0066] 24 splint element (flat)
[0067] 25 lower covering
[0068] 26 adhesive layer
[0069] 27 protecting foil
[0070] 28 rim (protecting foil)
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A device ( 22 ) for analgesic immobilization in the event of thorax or rib fractures as well as a method for application of such a device are disclosed. The immobilization device ( 22 ) includes a flat splint element ( 24 ) which covers a large area of the region of the break ( 19 ), and is provided with an adhesive layer ( 26 ) which is located on the side thereof facing the body and is used to adhere the immobilization device ( 22 ) to the body. In a preferred method of application, two separate areas of adhesive are applied to the patient's skin over the fracture at two different points in the breathing cycle. This allows the device to remain in place more securely under the dynamic condition of the ribcage that results from constant inhalation and exhalation.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to an oil filling device, and in particular to an oil filling device that enables adjustment of relative direction and distance between an oil filling funnel of the device and an engine oil filling hole so as to allow the oil filling device to accommodate various models and types of engine.
2. The Related Arts
Vehicles, such as automobiles and motorcycles, comprise an engine that is provided with an oil pan having a small filling opening. It is often that over-filling of oil result in spillage or overflowing of the oil outside the engine, causing environmental pollution when falling to the ground. In addition, when a large amount of oil is filled into an oil tube in a short period, air bubbles are generated and stuck in the oil tube so that the air may not be discharged and thus block oil from being further filled. This affects the efficiency and smoothness of the operation of filling oil and may often lead to spillage of oil due to negligence.
Further, the location and direction of the oil filling opening are different from each other for different engines. Heretofore, oil filling devices are generally not adjustable and are thus not fit to the oil filling openings of various models and types of vehicles. Consequently, it is common to change the oil filling devices when it is attempted to fill oil to different models or types of vehicles. This is certainly very troublesome. Apparently, the conventional, non-adjustable oil filling devices can be further improved.
Thus, it is desired to provide an oil filling device that overcomes the above discussed problems.
SUMMARY OF THE INVENTION
An object of the present invention is to provides an oil filling device, which enables adjustment of direction of an oil filling funnel with respect to an oil filling hole of an engine and also enables adjustment of distance between the oil filling funnel and the engine oil filling hole, whereby the oil filling device is applicable to filling oil to various models and types of engines.
To achieve the above object, the present invention provides an oil filling device, which comprises an oil filling funnel, an extendable tube assembly, a direction adjustment assembly, and a coupling assembly. The oil filling funnel is mounted to a first end of the extendable tube assembly. The extendable tube assembly has a second end mounted to the direction adjustment assembly. The direction adjustment assembly is mounted to the coupling assembly that is attachable to an oil filling hole of an engine. The direction adjustment assembly enables adjustment of the direction of the extendable tube assembly and the oil filling funnel with respect to the engine, while the extendable tube assembly allows the oil filling funnel to be selectively moved toward or away from the oil filling hole. Thus, the oil filling device may accommodate various heights and angles of engine oil filling hole and allows filling of oil into the engine to be conducted in a smoother manner.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention will be apparent to those skilled in the art by reading the following description of a preferred embodiment thereof, with reference to the attached drawings, wherein:
FIG. 1 is an exploded view showing an oil filling device according to the embodiment of the present invention;
FIG. 2 is a perspective view, in an assembled form, of the oil filling device according to the present invention;
FIG. 3 is a cross-sectional view of a portion of the oil filling device of the present invention, particularly showing details of an extendable tube assembly of the oil filling device;
FIG. 4 is a cross-sectional view of a portion of the oil filling device of the present invention, particularly showing a direction adjustment assembly to which a coupling assembly is attached;
FIG. 5 is a cross-sectional view showing a locking cap of the coupling assembly of the oil filling device according to the present invention;
FIG. 6 is a side elevational view illustrating an extension operation of the oil filling device according to the present invention;
FIG. 7 is a side elevational view illustrating a direction adjustment operation of the oil filling device according to the present invention; and
FIG. 8 is a perspective view illustrating an application of the oil filling device according to the present invention to filling oil into an engine.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
With reference to the drawings and in particular to FIGS. 1 and 2 , the present invention provides an oil filling device, which comprises a oil filling funnel 10 , which has a lower end connected to an insertion connector 11 . The insertion connector 11 has a lower end connected to an angled fitting 12 .
An extendable tube assembly 20 comprises a first tubular member 21 that has a first end 211 . The angled fitting 12 has a free end that is fit into the first end 211 of the first tubular member 21 of the extendable tube assembly 20 . The first tubular member 21 has a free end to which an end connector 22 is mounted. The end connector 22 comprises a tapered bore 221 formed therein and the tapered bore 221 receives a second tubular member 23 to telescopically extend therethrough. The tapered bore 221 comprises a tapered section that receives and retains therein a conical wedge block 24 having a C-shaped cross-section. A fastening element 25 , which is internally threaded, is mounted to an external thread 222 . After the second tubular member 23 is telescopically received and sets a desired length, the fastening element 25 is rotated to urge the conical wedge block 24 further into the tapered bore 221 so as to get compressed and securely fix the first tubular member 21 and the second tubular member 23 to each other to thereby achieve the functions of extension for adjustment and also fixing at selected length.
A direction adjustment assembly 30 comprises a rotary adjustment knob 31 , a fastening knob 32 , and a T-shaped fitting 33 . The T-shaped fitting 33 has a top portion through which a lateral passage 331 is formed to receive the rotary adjustment knob 31 to extend therethrough in such a way as to maintain the rotary adjustment knob 31 rotatable. The rotary adjustment knob 31 has an end that receives, engages, and fixes an external thread 232 formed on a free end of the second tubular member 23 . The rotary adjustment knob 31 has an opposite free end forming an external thread 314 with which an internal thread 321 formed in the fastening knob 32 engages, whereby when the rotary adjustment knob 31 is rotated to a desired angular position, the fastening knob 32 is rotated to tightly abut the T-shaped fitting 33 so as to secure the position of the rotary adjustment knob 31 .
A coupling assembly 40 comprises a locking cap 41 , in which an axially extending insertion bore 411 is formed. The insertion bore 411 receives the T-shaped fitting 33 to inset therein. In operation, the insertion bore 411 is set in communication with an interior of an engine 50 (see FIG. 8 ). The locking cap 41 as a lower end forming an external thread 412 that is engageable with an internal thread 511 of an oil filling opening 51 of the engine 50 (see FIG. 8 ). The external thread 412 can be further provided with a gasket ring 42 set around an outer circumference of the external thread. The locking cap 41 has a side portion in which an inverted T-shaped vent hole 43 is formed, whereby a first opening 431 of the inverted T-shaped vent hole 43 is in communication with the interior of the engine 50 , a second opening 432 is formed in a side surface of the locking cap 41 to communicate with the outside atmosphere, and a third opening 433 is formed in a top of the locking cap 41 to communicate with the outside atmosphere so as to enable an oil filling operation to be done in a smoother manner without jamming.
Referring to FIGS. 3 and 4 , as discussed above, the oil filling device according to the present invention comprises an oil filling funnel 10 having a lower end to connect to an insertion connector 11 and the insertion connector 11 has a lower end connected to the angled fitting 12 , whereby a funnel hole 101 , a connector hole 111 , and an angled fitting hole 121 are in communication with each other. The angled fitting 12 has a free end that is fit to the first end 211 of the first tubular member 21 of the extendable tube assembly 20 in such a way that the angled fitting hole 121 is in communication with a first bore 212 of the first tubular member 21 . The first tubular member 21 has a free end to which an end connector 22 is mounted.
The end connector 22 comprises an internal tapered bore 221 , which telescopically receives the second tubular member 23 to extend therethrough. The tapered bore 221 comprises a tapering section that receives and retains the conical wedge block 24 therein. The fastening element 25 comprises an internally threaded hole 251 and the end connector 22 has an outer circumference that forms an external thread 222 engaging the internally threaded hole 251 of the fastening element 25 .
Once the second tubular member 23 is extended or retracted to a desired length, the fastening element 25 is rotated to drive the conical wedge block 24 further into the tapered bore 221 so as to compress the wedge block and thus fix the first tubular member 21 and the second tubular member 23 to each other to achieve the functions of extension for adjustment and also fixing at selected length.
The first bore 212 of the first tubular member 21 is in communication with a second bore 231 of the second tubular member 23 .
The direction adjustment assembly 30 that comprises the rotary adjustment knob 31 , the fastening knob 32 , and the T-shaped fitting 33 is structured so that the T-shaped fitting 33 has a top portion forming the lateral passage 331 to receive the rotary adjustment knob 31 to extend therethrough. The T-shaped fitting 33 also has a lower portion forming a vertical passage 332 extending from and in communication with the lateral passage 331 . The rotary adjustment knob 31 is rotatable and has an end (leading end) forming an internally-threaded hole 311 that engages an external thread 232 formed at a free end of the second tubular member 23 .
The rotary adjustment knob 31 has an opposite end (tailing end) forming a hole 312 in communication with the internally-threaded hole 311 . The rotary adjustment knob 31 has a circumferential wall in which a plurality of through holes 313 is formed to correspond to the vertical passage 332 to communicate with the vertical passage 332 . The rotary adjustment knob 31 comprises an external thread 314 formed at the tailing end to engage an internal thread 321 formed in the fastening knob 32 , whereby when the rotary adjustment knob 31 is set at a desired angular position, the fastening knob 32 is rotated to abut against the T-shaped fitting 33 and thus secure the rotary adjustment knob 31 in position.
The coupling assembly 40 comprises the locking cap 41 , which forms an axially extending insertion bore 411 to receive and retain the T-shaped fitting 33 in such a way that the vertical passage 332 is in communication with the insertion bore 411 . The insertion bore 411 is set in communication with the engine 50 (see FIG. 8 ). The locking cap 41 has a lower end forming an external thread 412 engageable with the internal thread 511 of the oil filling opening 51 of the engine 50 (see FIG. 8 ).
Oil is filled through the funnel hole 101 of the oil filling funnel 10 , passing through the connector hole 111 , the angled fitting hole 121 , the first bore 212 , the tapered bore 221 , the second bore 231 , the internally-threaded hole 311 , the hole 312 , the through holes 313 , the vertical passage 332 , and the insertion bore 411 to get into the interior of the engine 50 .
Referring to FIG. 5 , the locking cap 41 has a side portion forming the inverted T-shaped vent hole 43 , whereby the first opening 431 of the inverted T-shaped vent hole 43 is in communication with the engine 50 , the second opening 432 is formed in a side surface of the locking cap 41 to communicate with the outside atmosphere, and the third opening 433 is formed in the top of the locking cap 41 to communicate with the outside atmosphere so as to enable an oil filling operation to be done in a smoother manner without jamming.
Referring to FIG. 6 , the extendable tube assembly 20 has two opposite ends that are respectively connected to the oil filling funnel 10 and the direction adjustment assembly 30 . The second tubular member 23 of the extendable tube assembly 20 is telescopically received through the end connector 22 and the first tubular member 21 , whereby after being set to a desired length, the fastening element 25 is rotated to fix the first tubular member 21 and the second tubular member 23 to each other achieve the functions of extension for adjustment and also fixing at selected length.
Referring to FIGS. 1 and 7 , according to the present invention, the rotary adjustment knob 31 of the direction adjustment assembly 30 is kept in a selectively rotatable condition and the leading end of manner of the rotary adjustment knob 31 is coupled to the second tubular member 23 through mating engagement with the external thread 232 of the second tubular member. Further, the rotary adjustment knob 31 comprises an external thread 314 formed at the tailing end thereof to mate the internal thread 321 of the fastening knob 32 , whereby when the rotary adjustment knob 31 is rotated to a desired angular position, generally with respect to the T-shaped fitting 33 and the coupling assembly 40 , the fastening knob 32 can be fastened to abut the T-shaped fitting 33 and thus secure the rotary adjustment knob 31 in position.
Referring to FIGS. 1 and 8 , the coupling assembly 40 is provided for coupling to the oil filling opening 51 of an engine 50 and the relative angle (or direction) between the direction adjustment assembly 30 with respect to the coupling assembly 40 can be adjusted as desired to set the direction the extendable tube assembly 20 and the oil filling funnel 10 with respect to the coupling assembly and the engine. The extendable tube assembly 20 can be adjusted to set the relative distance between the oil filling funnel 10 and the oil filling opening 51 of the engine 50 to selectively make them approaching to each other or distant from each other. In this way, the oil filling device can accommodate various heights and angles of oil filling opening 51 to allow the filling of oil into an engine to be done more smoothly.
It is apparent that the oil filling device according to the present invention enables adjustment of position and direction thereof with respect to an engine where oil is to be filled with the oil filling device and such adjustment is done with a novel and unique structure and arrangement that has never been proposed and known.
Although the present invention has been described with reference to the preferred embodiment thereof, it is apparent to those skilled in the art that a variety of modifications and changes may be made without departing from the scope of the present invention which is intended to be defined by the appended claims.
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An oil filling device includes an oil filling funnel, an extendable tube assembly, a direction adjustment assembly, and a coupling assembly. The oil filling funnel is mounted to a first end of the extendable tube assembly. The extendable tube assembly has a second end mounted to the direction adjustment assembly. The direction adjustment assembly is mounted to the coupling assembly that is attachable to an oil filling hole of an engine. The direction adjustment assembly enables adjustment of the direction of the extendable tube assembly and the oil filling funnel with respect to the engine, while the extendable tube assembly allows the oil filling funnel to be selectively moved toward or away from the oil filling hole. Thus, the oil filling device may accommodate various heights and angles of oil filling hole of engine and allows filling of oil into the engine to be conducted in a smoother manner.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a method of cleaning a dust separator which has a raw gas shaft, through which raw gas flows from the top to the bottom, and filter elements protruding into the raw gas shaft transverse to the raw gas flow, by which filter elements the raw gas is deflected into a clean gas shaft under a corresponding separation of dust, and which filter elements are briefly subjected to compressed air one after the other for blowing off the dust particles deposited thereon into the raw gas shaft, where during the application of compressed air onto the filter elements their flow connection to the clean gas shaft is interrupted, as well as to an apparatus for performing the method.
2. Description of the Prior Art
In dust separators with a raw gas shaft, which accommodates filter elements, usually filter cartridges, that are connected to a clean gas shaft, the dust-laden raw gas introduced into the raw gas shaft flows through the filter surfaces into the filter elements, from where they are sucked off as clean gas via the common clean gas shaft. To be able to remove the dust particles retained during the passage of raw gas from the filter surfaces during the operation of the filter, it is known to briefly subject the clean gas shaft to compressed air in certain intervals, so that by means of the pulses of compressed air in the individual filter elements the dust particles are blown off from the filter surfaces of the filter elements into the raw gas shaft. To prevent in this connection that the dust particles blown off from the filter elements have to be discharged from the raw gas shaft in downward direction against the raw gas stream usually passed through the raw gas shaft from the bottom to the top, the filter elements of a known dust separator are arranged in groups one above the other in a horizontal orientation, so that in the case of a raw gas flow inside the raw gas shaft from the top to the bottom the coarse-grained fraction of the dust that has been blown off can be moved downwards by the raw gas stream. This is possible because the coarse-grained fraction of the dust is accelerated when it is blown off and due to its inertia is moved away from the filter surface so far that in the case of a flow reversal by the raw gas fraction again flowing through the filter surface after the pulse of compressed air, it is no longer attached to the cleaned filter surface. Due to the friction behavior relevant for the movement of the fine fraction of the dust, which is characterized by a small Reynolds number (e.g. Re particle <30), the movement of the fine dust particles is substantially determined by the gas flow. This means that the fine dust particles, which were blown off from the filter surfaces by the pulse of compressed air only to a comparatively small extent, are again attached to the filter surfaces of the filter elements by means of the raw gas stream directly subsequent to the pulses of compressed air, which leads to an increasing pressure loss and thus to a decreasing filter performance with the result that after certain operating periods the dust separator must be shut off for cleaning the filter elements. By means of a scavenging air flow through the filter elements against the raw gas flow the fine dust fraction can naturally be blown off from the filter surfaces of the filter elements and be discharged from the raw gas shaft without raw gas flow, but not during the operation of the filter.
Moreover, it is known (DE 31 11 502 A1, DE 43 34 699 C1) to block the filter elements against the clean gas shaft during the application of compressed air. Filter elements vertically lying one above the other are combined to groups, so that in the vicinity of such vertical group of filter elements there cannot be formed a raw gas flow from the top to the bottom. To make things worse, the filter elements which are disposed laterally beside the filter elements vertically lying one above the other and subjected to compressed air are likewise separated from the clean gas shaft during the application of compressed air onto the filter elements lying therebetween, which prevents the formation of a suction flow in the vicinity of these filter elements disposed one beside the other. This means that merely the coarse-grained fraction of the dust blown off can be discharged downwards due to a corresponding sinking speed, but not the fine-grained fraction, which during the subsequent connection of the filter elements to the suction of the clean gas shaft is again sucked towards the filter elements.
SUMMARY OF THE INVENTION
It is therefore the object underlying the invention to eliminate these deficiencies and provide a method of cleaning a dust separator as described above such that also the fine dust fraction can largely be removed from the filter elements during the operation of the filter.
This object is solved by the invention in that during the interruption of the flow connection between the filter elements and the clean gas shaft a raw gas stream having a flow component directed from the top to the bottom flows around the filter elements blocked against the clean gas shaft.
Since as a result of these measures the filter elements blocked against the clean gas shaft remain in a raw gas stream directed from the top to the bottom, not only the coarse dust particles flung off at a larger distance due to their greater inertia, but also the fine dust particles in the direct vicinity of the filter surfaces are downwardly entrained by the raw gas stream, which ensures the desired cleaning of the filter elements, because the fine dust particles are no longer sucked towards the filter elements during the connection of the cleaned filter elements to the clean gas shaft.
When the filter elements are at least arranged in groups one above the other, it is therefore recommended to apply compressed air onto the filter elements one after the other from the top to the bottom, so that the filter elements are progressively cleaned from the top to the bottom during the operation of the filter. Because of the downward flow of the raw gas decreasing in the vicinity of the bottommost filter elements, the cleaning effect described above can develop only incompletely in the bottommost filter elements. In these bottommost filter elements a higher dust loading must therefore be expected, which influences, however, the entire filter performance only to a comparatively small extent.
As has already been explained above, it is of decisive importance for the invention that the raw gas flow carries away the dust particles blown off during the pressurization of the filter elements from the cleaned filter surface, so that when the flow connection between the clean gas shaft and the filter elements blocked for the application of compressed air is opened, the raw gas fractions again flowing through the open filter elements can no longer deposit the dust particles blown off at the cleaned filter surfaces. To be able to satisfy this request even when the filter elements are disposed one beside the other, the raw gas stream is divided by means of partitions between the filter elements into partial streams associated to the filter elements at least in groups, which partial streams ensure a further downward movement of the dust particles blown off from the filter elements. In this connection it should be considered that despite the blocking of a filter element, a raw gas flow will be produced between the partitions fluidically delimiting this filter element against the filter elements disposed one beside the other, when the partitions form downwardly open flow passages, as this is absolutely necessary for discharging the dust particles blown off. In the vicinity of the flow passages having a flow connection at their lower end a negative pressure is produced as compared to the upper inflow side of these passages, which negative pressure effects a raw gas flow from the top to the bottom in the vicinity of the blocked filter element.
To improve the cleaning effect by applying compressed air onto the filter elements, the filter elements blocked against the clean gas shaft can be subjected to at least two successive pulses of compressed air, so that by means of the subsequent pulses of compressed air dust particles still adhering to the filter elements can likewise be blown off from the filter surfaces. The time of blocking the filter elements must be adjusted to the raw gas flow, which is produced during such blocking and flows around the filter elements from the top to the bottom, in order to ensure a sufficient transport of dust particles.
For performing the inventive method a known dust separator may be employed, which is provided with a raw gas shaft having a raw gas connection at its upper end, into which raw gas shaft filter elements protrude, which are disposed transverse to the raw gas flow and are attached to a clean gas shaft connected with a suction blower, with a compressed-air source for supplying pulses of compressed air to the groups of filter elements, with at least one shut-off means for successively closing the flow connections of the groups of filter elements to the clean gas shaft, and with at least one valve for connecting the filter elements to the compressed-air source. In such dust separator, the filter elements may be combined to groups disposed one above the other, in order to ensure the desired cleaning by blowing off the dust from the groups of filter elements into the raw gas stream, because the raw gas stream directed from the top to the bottom is maintained via the groups of filter elements not blocked against the clean gas shaft.
When the filter elements in the raw gas shaft are not disposed in groups one above the other, but are disposed one beside the other, the raw gas shaft must be divided into flow passages which are open at their upper and their lower end by means of partitions at least between groups of filter elements, in order to provide for a raw gas flow with a marked flow component from the top to the bottom. Due to the lower flow connection of the flow passages, a pressure differential becomes effective in the flow passage with the blocked filter element or the blocked group of filter elements, which pressure differential leads to a downwardly directed raw gas flow which is sufficient to entrain the dust particles blown off despite the missing sucking off of raw gas by the filter element or the group of filter elements.
When the filter elements inside groups should be actuated jointly, it is not necessary to provide each filter element with a separate shut-off means or with a separate valve for the connection of compressed air. The filter elements combined to groups may open in groups into a collecting passage, which on the one hand is connected to the clean gas shaft via a shut-off means and on the other hand is connected to the compressed-air source via a valve. By means of such measure, the construction of the dust separator is considerably simplified.
However, the filter elements combined to groups disposed one above the other or disposed one beside the other also provide for another simple construction, which consists in that to the filter elements or groups of filter elements a carriage is associated, which is guided in the clean gas shaft and can be moved from filter element to filter element or from group of filter elements to group of filter elements, and which has an actuatable shut-off means for a filter element or a group of filter elements and a compressed-air connection for the compressed-air source, which can be controlled via a valve and opens inside the shut-off means. By means of this carriage, the filter elements can thus be shut off individually or in groups and be subjected to compressed air, so that for the successive cleaning of the groups of filter elements the carriage must merely be moved from filter element to filter element or from group of filter elements to group of filter elements. When the filter elements are disposed one above the other, the carriage must be moved from the top to the bottom, and when the filter elements are disposed one beside the other, the carriage must be moved along the row of filter elements. The shut-off means for the filter elements of one group may consist in a comparatively simple way of a lock common to all filter elements of a group, which lock is sealingly urged against the partition between the clean gas shaft and the raw gas shaft. The filter elements protrude through this partition into the raw gas shaft.
To promote the discharge of dust particles blown off from the filter surfaces of the blocked filter elements, at least one blower for the raw gas stream to be switched on in dependence on the actuation of the shut-off means may be associated to the raw gas shaft, so that during the shut-off of a filter element the raw gas flow is reinforced by the blower at least in the vicinity of this filter element.
BRIEF DESCRIPTION OF THE DRAWING
The method in accordance with the invention will be explained in detail with reference to the drawing, wherein:
FIG. 1 shows an inventive dust separator in a simplified vertical section;
FIG. 2 shows a section along line II—II FIG. 1;
FIG. 3 shows a section along line III—III of FIG. 1;
FIG. 4 shows a vertical section through a modified embodiment of an inventive dust separator;
FIG. 5 shows the dust separator in accordance with FIG. 4 in a section along line V—V of FIG. 4;
FIG. 6 shows a section along line VI—VI of FIG. 4,
FIG. 7 shows a section along line VII—VII of FIG. 4 on an enlarged scale;
FIG. 8 shows an inventive dust separator in accordance with a further embodiment in a vertical section;
FIG. 9 shows a section along line IX—IX of FIG. 8, and
FIG. 10 shows a section along line X—X of FIG. 9 .
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The dust separator in accordance with the embodiment shown in FIGS. 1 to 3 substantially consists of a housing 1 , which by means of a partition 2 is divided into a raw gas shaft 3 and a clean gas shaft 4 . From the side of the clean gas shaft 4 , filter elements 5 have been inserted into the raw gas shaft 3 through the partition 2 , which filter elements are disposed in rows one above the other and for instance consist of filter cartridges. The shape of the filter elements 5 is, however, not decisive, but it is merely important that the raw gas stream, which enters through an upper raw gas connection 6 into the raw gas shaft 3 , can get into the filter elements 5 only through the filter surfaces enclosing the filter elements 5 and into the clean gas shaft 4 through the filter elements 5 , from which clean gas shaft the clean gas stream is withdrawn via a suction blower 7 , in order to leave the housing 1 through a clean gas outlet 8 . During the passage of the raw gas flow through the filter surfaces of the filter elements 5 , the dust particles are retained by the filter surfaces, which are thus increasingly clogged by the deposited dust particles. For this reason, the filter surfaces of the filter elements 5 must be cleaned in certain intervals. The time intervals between such cleaning of the filter may be chosen in dependence on the respectively occurring pressure losses, when a greatly varying dust loading of the raw gases must be expected. When the dust loading of the raw gases remains approximately the same, the cleaning of the filter may also be performed in predetermined intervals.
To avoid that the operation of the filter must be interrupted during the cleaning of the filter, the filter elements 5 are combined to groups row by row, and via a valve 10 are briefly connected in groups with a compressed-air source 9 , for instance a compressed-air cylinder, so that by means of the pulses of compressed air, which become effective in the filter elements 5 , the attached dust particles are blown off from the filter surfaces against the raw gas flow. During the brief pressurization of the filter elements 5 , the flow connection between the filter elements 5 and the clean gas shaft 4 is interrupted, namely by means of a shut-off means 11 , so that the fine dust particles blown off from the filter surfaces only to a small extent are entrained by the raw gas stream flowing around the outside of the filter elements 5 because the filter elements 5 are blocked, and are moved away from the filter surfaces of the blocked filter elements 5 with the effect that after the shut-off means 11 has been opened, the dust particles blown off can no longer be carried to the cleaned filter surfaces with the partial raw gas streams now again flowing through the previously blocked filter elements 5 . Since the raw gas flows through the raw gas shaft 3 from the top to the bottom, the dust particles blown off from the blocked filter elements 5 of one row are moved downwards, where they partly attach to the filter surfaces of the filter elements 5 of the rows of filter elements disposed below. When the filter elements 5 are cleaned row by row from the top to the bottom in the manner described above, the dust particles blown off from the filter surfaces of the filter elements 5 are moved downwards in the raw gas shaft 3 step by step, until they settle in the vicinity of the ground of the raw gas shaft 3 in dust collecting tanks 12 . With such an arrangement of the filter elements 5 it is thus decisive for the cleaning of the filter that the filter elements 5 are progressively dedusted at least in groups one after the other from the top to the bottom through the filter elements 5 with blocked raw gas flow.
For the constructive solution of this object a carriage 13 is provided in accordance with the embodiment shown in FIGS. 1 to 3 , which carriage is vertically movably mounted in the clean gas shaft 4 on a vertical guideway 14 . This carriage 13 carries the shut-off means 11 for the filter elements 5 of a row of filter elements as well as the compressed-air source 9 with the compressed-air connection 15 extending through the shut-off means 11 and connected with the compressed-air source 9 via the valve 10 , as is indicated in FIG. 1 . In the carriage position in accordance with FIG. 1, the uppermost of the rows of filter elements can be cleaned. For this purpose, the shutoff means 11 is actuated, which consists for instance of a lock 16 extending over the entire row of filter elements, which lock is sealingly urged against the partition 2 by means of an actuator not represented, so that the flow connection between the filter elements 5 of the uppermost row of filter elements and the clean gas shaft 4 is interrupted. Since the pressure connection 15 extends through the lock 16 and therefore opens inside the shut-off means 11 , the filter elements 5 of the uppermost row can briefly be subjected to compressed air by opening the valve 10 .
After the uppermost row of filter elements has been cleaned, the carriage 13 is moved further downwards by one row of filter elements after the shut-off means 11 has been opened, in order to clean the filter elements 5 of this row in the same way. The rows of filter elements are thus progressively liberated from dust from the top to the bottom, which dust is moved downwards step by step. Upon dedusting the filter elements 5 of the bottommost row of filter elements, the carriage 13 is lowered to a waiting position below the bottommost row of filter elements, so as not to impair the operation of the filter. To this end, the clean gas shaft 4 has been expanded downwards to form a receiving space 17 for the carriage 13 .
In the embodiment shown in FIGS. 4 to 7 , the cleaning of the filter elements 5 row by row has been solved in a different way. The filter elements 5 of a row do not open directly into a clean gas shaft adjoining the partition 2 , but into collecting passages 18 associated to each row of filter elements, which collecting passages adjoin the end face of the clean gas shaft 4 , namely each via a shut-off means 11 . In accordance with FIG. 7, these shut-off means 11 consist of a lock 20 covering the through holes 19 between the collecting passage 18 and the clean gas shaft 4 , which lock can sealingly be urged against the through hole 19 by means of an actuator 21 , for instance an electromagnet. To the individual collecting passages 18 there should also be associated one compressed-air connection 15 each to be actuated via a valve 10 , in order to be able to connect the collecting passage 18 and the filter elements 5 attached thereto with a compressed-air source via the valve 10 .
The mode of function of the dust separator in accordance with the embodiment shown in FIGS. 4 to 7 corresponds to the one shown in FIGS. 1 to 3 . For cleaning the filter, the collecting passage 18 for the uppermost row of filter elements is first of all separated from the clean gas shaft 4 via the shut-off means 11 associated to this collecting passage 18 , before via the associated valve 10 and the compressed-air connection 15 compressed air is briefly applied onto the filter elements 5 attached to this collecting passage 18 . After the dust particles have been blown off from the filter elements 5 of the uppermost row of filter elements, the uppermost collecting passage 18 is again connected to the clean gas shaft and the shut-off means 11 of the collecting passage 18 disposed below is actuated, in order to again progressively clean the rows of filter elements from the top to the bottom by individually actuating one after the other the shut-off means 11 or the valves 10 of the collecting passages 18 via a corresponding control means. The dust blown off is collected in dust collecting tanks 12 .
In the embodiment shown in FIGS. 8 to 10 no filter cartridges are used, but plate-shaped filter elements 5 are inserted in the partition 2 between the raw gas shaft 3 and the clean gas shaft 4 . By means of partitions 22 between the filter elements 5 , the raw gas shaft 3 is divided into flow passages 3 a , which are associated to these filter elements 5 and are open at the top and at the bottom, as can be taken in particular from FIG. 10 . Correspondingly, the clean gas shaft 4 is divided into clean gas passages 4 a associated to the individual filter elements 5 , which clean gas passages are connected to the common clean gas shaft 4 via one shut-off means 11 each. Since compressed air from a compressed-air source can also be applied individually to the clean gas passages 4 a via compressed-air connections 15 and control valves 10 , an application of compressed air onto the filter elements 5 is again possible during the closure of the flow connection between the respective filter element 5 and the clean gas shaft 4 . For this purpose it is merely necessary to actuate the shut-off means 11 of the filter element 5 to be cleaned and to open the valve 10 for the compressed-air connection 15 , so that the related pressurization of the filter element 5 effects a blowing off of dust particles from the filter surfaces of this filter element 5 . Although the flow of raw gas through the blocked filter element 5 is prevented, a raw gas flow directed from the top to the bottom is obtained inside the flow passage 3 a of the blocked filter element 5 , because the flow passages 3 a are in flow connection with each other at their lower end, so that the decrease in pressure in the flow passages 3 a adjacent the blocked filter element 5 also reaches the flow passage 3 a of the blocked filter element 5 and effects a corresponding raw gas flow along the blocked filter element 5 , as it was indicated by corresponding flow arrows for the filter element 5 to the extreme right in FIG. 10 . By means of this raw gas flow, the dust particles blown off are moved downwards to the dust collecting tanks 12 .
It need probably not be emphasized particularly that the successive shut-off of the filter elements 5 disposed one beside the other and the pressurization thereof can also be performed via a carriage similar to the embodiment shown in FIGS. 1 to 3 . The carriage must, however, be moved in horizontal direction from filter element 5 to filter element 5 along the row of filter elements.
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There is described a method and an apparatus for cleaning a dust separator which has a raw gas shaft ( 3 ), through which raw gas flows from the top to the bottom, and filter elements ( 5 ) protruding into the raw gas shaft ( 3 ) transverse to the raw gas flow, by which filter elements the raw gas is deflected into a clean gas shaft ( 4 ) under a corresponding separation of dust, and which filter elements are briefly subjected to compressed air one after the other for blowing off the dust particles deposited on the same into the raw gas shaft ( 3 ), where during the application of compressed air onto the filter elements ( 5 ) their flow connection to the clean gas shaft ( 4 ) is interrupted. To ensure a good cleaning effect, it is proposed that during the interruption of the flow connection between the filter elements ( 5 ) and the clean gas shaft ( 4 ) a raw gas stream having a flow component directed from the top to the bottom flows around the filter elements ( 5 ) blocked against the clean gas shaft ( 4 ).
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FIELD OF INVENTION
[0001] The present invention relates to a nutraceutical with significant phytoestrogenic property. The disclosed comestible composition can lengthen the estrus phase of the estrous cycle and have phytoestrogenic properties that protect against oxidative stress, retarding hormone related cancer, affecting fertility and effective to hinder or prevent ailments or conditions resulting from, or exacerbated by, a decrease in endogenous estrogen including: reproductive organ ailments, cardiovascular disease, osteoporosis, loss of cognitive function, urinary incontinence, body fat increase, post menopausal syndromes and vasomotor symptoms, and contains extract from palm leaf.
BACKGROUND OF INVENTION
[0002] Phytoestrogens, [phyto (plant), estrus (period of fertility for female mammals)+gen (to generate)] are non steroidal plant compounds that are structurally similar to estradiol (17β-estradiol), and have the ability to cause estrogenic or/and antiestrogenic effects. Phytoestrogens are protective against diverse health disorders such as prostate, breast, bowel, and other cancers, cardiovascular disease, brain function disorders, menopausal symptoms and osteoporosis. Phytoestrogens interact with Estrogen Receptors (ER), and may modulate the endogenous estrogens concentration by binding or inactivating some enzymes, thus may affect the bioavailability of sex hormones through binding or stimulating the sex hormone binding globuline (SHBG) synthesis. Seeds contained the highest phytoestrogen contents. In human beings, phytoestrogens are readily absorbed, circulated in plasma and excreted in the urine. Theoretically, men exposed to high levels of phytoestrogens may have altered hypothalamic-pituitary-gonadal axis, however, such hormonal effects are small. Dietary phytoestrogen have no effect in sperm count or mobility or on testicular or ejaculate volume. Phytoestrogens may prevent prostate cancer. Epidemiological evidence showed phytoestrogens are protective against breast cancer. In cell line studies, low concentration of genistein supported tumor cell growth, but higher concentrations produced inhibitory effects. Phytoestrogens have different effects on fertility with different animals. Metabolic influence is different between ruminants, birds and monogastric mammals.
[0003] Metabolites from some plants have been proven to possess phytoestrogenic enhancing properties. A few phytoestrogenic enhancing products containing plant metabolites as the active ingredients have been developed. For example, U.S. Pat. No. 7,045,155 provides compositions enriched with natural phyto-oestrogens or analogues thereof selected from Genistein, Daidzein, Formononetin and Biochanin A. These may be used as food additives, tablets or capsules for promoting health in cases of cancer, pre-menstrual syndrome, menopause or hypercholesterolaemia.
[0004] U.S. Pat. No. 6,861,079 discloses a fertility kit and method for enhancing the natural fertility process. The kit includes a vaginal douche that is used prior to intercourse to enhance the sperm transportation and sustaining properties of the cervical mucous. The douche contains a balanced electrolyte solution, polysaccharides, and pH buffers. The kit also includes nutraceuticals specifically formulated for both the male and female which include amino acids, minerals, vitamins, herbs, phytoestrogens, and antioxidants along with a specified dosing regimen. A basal body temperature thermometer and chart is provided with instructions to confirm when and if ovulation will/did occur. Commercially available urinary chemical reagent strips are provided with instructions so as to predict/confirm if and when ovulation will occur. A lubricating medium will also be provided and utilized at the time of intercourse which is nonspermicidal and which contains polysaccharides which influence natural sperm motility. A detailed instruction book regarding the method and practice is provided along with dietary and lifestyle recommendations which have been shown to affect natural fertility.
[0005] KR0039720050214, provides a therapeutic agent for osteoporosis, comprising Ginkgo biloba leaf extract as an active ingredient. The Ginkgo biloba leaf extract contains a large amount of phytoestrogen such as quercetin and kaempferol and thus can be usefully utilized as a therapeutic agent for treatment of osteoporosis without having adverse effects of causing breast cancer due to capability to function as a selective estrogen receptor modulator.
[0006] US 20080167278 claims a composition comprising a progestin, a phytoestrogen compound, and an estrogen, in which the phytoestrogen is preferably an isoflavone compound selected from the group consisting of daidzein, genistein, and glycitein and their conjugated forms. The progestin is preferably selected from the group consisting of norgestimate, levonorgestrel, norgestrel, norethindrone, desogestrel, gestodene, dienogest, drospirenone, and medroxy-progesterone acetate. The estrogen is preferably from the group consisting of ethinyl estradiol, 17.alpha.-ethinylestradiol, and 17 beta-estradiol and conjugated estrogens.
[0007] EP1453827 provides methods for preparing an estrogenic preparation and isolating estrogenic compounds from a plant, such as an Epimedium plant, are provided. Also provided are estrogenic compounds from Epimedium plant that have been isolated and characterized and methods for their use in modulating estrogen receptors and in treating conditions mediated by estrogen receptors, such as menopause and estrogen-dependent cancers. Also provided are preparations from Epimedium that are enriched for estrogenic compounds, and methods for their use in modulating estrogen receptors and preventing and treating conditions that are mediated by estrogen receptors.
[0008] U.S. Pat. No. 6,326,366 discloses a hormone replacement therapy and a composition useful for women having reduced levels of endogenous estrogen. A mammalian estrogen and an isoflavone which is incapable of being metabolized to equol are co-administered to a woman having a reduced level of endogenous estrogen. The hormone replacement therapy is effective to inhibit or prevent diseases or conditions resulting from, or exacerbated by, a reduction in endogenous estrogen including: coronary heart disease, cardiovascular disease, osteoporosis, loss of cognitive function, urinary incontinence, weight gain, fat mass gain, and vasomotor symptoms. A composition for use in the hormone replacement therapy of the present invention contains a mammalian estrogen and at least one isoflavone, where the isoflavone is incapable of being metabolized to equol by a human and where the composition contains less than 10% by weight of isoflavones and phytoestrogens capable of being metabolized to equol by a human.
SUMMARY OF INVENTION
[0009] The present invention aims to provide a nutraceutical composition which is effective in lengthening the estrus period of the estrous cycle and have phytoestrogenic properties that protect against oxidative stress, retarding hormone related cancer and effective to hinder or prevent ailments or conditions resulting from, or exacerbated by, a decrease in endogenous estrogen including: reproductive organ ailments, cardiovascular disease, osteoporosis, loss of cognitive function, urinary incontinence, body fat increase, and vasomotor symptoms which contains extract from palm leaf.
[0010] At least one of the preceding objects is met, in whole or in part, by the present invention, in which one of the embodiment of the present invention a composition with phytoestrogenic property comprising aqueous or alcoholic extract from palm leaf.
[0011] The present invention consists of several novel features and a combination of parts hereinafter fully described and illustrated in the accompanying description and drawings, it being understood that various changes in the details may be made without departing from the scope of the invention or sacrificing any of the advantages of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] The present invention will be fully understood from the detailed description given herein below and the accompanying drawings which are given by way of illustration only, and thus are not limitative of the present invention, wherein:
[0013] FIG. 1 is a graph showing the effect of PALM LEAVES EXTRACT on estrous cycle and estrus phase.
[0014] FIG. 2 is a table showing the dose-dependent effect of PALM LEAVES EXTRACT on the uterine weight.
[0015] FIG. 3 is a graph showing the effect of PALM LEAVES EXTRACT on vaginal cornification.
[0016] FIG. 4 is a graph showing a comparison of the estrogenic activity of PLE and Premarin, by vaginal cytology assay in ovariectomized rats.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0017] The present invention relates to a nutraceutical with significant phytoestrogenic property. Hereinafter, this specification will describe the present invention according to the preferred embodiments of the present invention. However, it is to be understood that limiting the description to the preferred embodiments of the invention is merely to facilitate discussion of the present invention and it is envisioned that those skilled in the art may devise various modifications and equivalents without departing from the scope of the appended claims.
[0018] The following detailed description of the preferred embodiments will now be described in accordance with the attached drawings, either individually or in combination.
[0019] One skilled in the art will readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The embodiment describes herein is not intended as limitations on the scope of the invention.
[0020] The term “pharmaceutically effective amount” used herein through out the specification refers to the amount of the active ingredient, the extract, to be administered orally to the subject to trigger the desired effect without or causing minimal toxic adverse effect against the subject. One skilled in the art should know that the effective amount can vary from one individual to another due to the external factors such as age, sex, diseased state, races, body weight, formulation of the extract, availability of other active ingredients in the formulation and so on.
[0021] It is important to note that the extract used in the disclosed method in this embodiment is derived from the plant species of Arecaceae family. The extracts obtained from the abovementioned plant species are suitable to be incorporated into edible or topical products, or as capsules, ointments, lotions and tablets.
[0022] The desired compounds to be extracted from the alcohol/aqueous extracts of are mainly constituted of, but not limited to, biophenols, proteins, lipids, saccharides, minerals and small peptides. Due to polarity of these compounds, the polar solvent such as water, alcohol or acetone is found to be effective in extracting these desired compounds from the plant matrix.
[0023] Another embodiment of the present invention involves a comestible and topical composition with phytoestrogenic property comprising alcohol/aqueous extracts derived from the leaves of Palmae family using an appropriate extraction solvent. The comestibles mentioned herein can be any common daily consumed processed food such as bread, noodles, confections, chocolates, beverages, and the like. One skilled in the art shall appreciate the fact that the aforesaid extract can be incorporated into the processed comestibles, capsules, tablets or topical medicine during the course of processing. Therefore, any modification thereon shall not depart from the scope of the present invention.
[0024] As setting forth in the above description, the composition with phytoestrogenic properties comprising alcoholic extract from leaves of Palm species. Apart from that the composition may further comprise extract derived from the leaves of Palm species. Preferably, the plant is any one or combination of the plant species of, Elaeis guineensis, Elaeis oleifera, Phoenix dactylifera and Cocos nucifera . The inventors of the present invention found that the alcohol extract derived from the aforementioned species possesses both acceptable taste that confers the derived extract to be comfortably incorporated with the comestibles product, capsules, tablets or topical medicine with minimal additional refining process.
[0025] According to the preferred embodiment, the extract to be incorporated into the comestibles and medicine can be acquired from any known method not limited only to the foregoing disclosed method. Following another embodiment, the extract is prepared in a concentrated form, preferably paste or powdery form which enables the extract to be incorporated in various formulations of the comestibles, capsules, tablets or topical products.
[0026] In line with the preferred embodiment, the extract shall be the plant metabolites which are susceptible to an extraction solvent. The compounds and small peptides with the phytoestrogenic enhancing and reproductive system health-promoting properties are those metabolites with polarity in the alcohol/aqueous extracts. Therefore, the alcohol/aqueous extracts of leaves of Palmae family is preferably derives from the extraction solvent of water, alcohol, acetone, chloroform, liquid CO 2 and any combination thereof.
[0027] In view of the prominent property of promoting phytoestrogenic activity and general healthcare of the reproductive system by the extracts in a subject, further embodiment of the present invention includes a method comprising the step of administrating orally or topically to the subject an effective amount of an extract derived from palm spp. leaves.
[0028] The following examples are intended to further illustrate the invention, without any intent for the invention to be limited to the specific embodiments described therein.
Example 1
[0029] Adult female Sprague Dawley rats were randomly divided into three groups containing eight animals in each group: a vehicle control, a low dose (150 mg/kg), and a high dose (300 mg/kg) of palm Leaf extract (PLE) were measured and fed daily in the morning using a 2-g fresh apple wedge as vehicle. The apple vehicle eliminated stress associated with gavage, and rats eagerly ate the apple and the PLE in this manner, making it easy to monitor and ensure complete deliverance of the PLE. Vaginal smears from each rat were monitored daily between 09:00 and 10:00 h using staging criteria described by Everett (Evert. 1989). The vaginal epithelium cells observed under the microscope were classified into three types: leukocyte cells (L), nucleated cells (O) and cornified cells (Co). The representative cell type was determined by choosing the majority of cells. The results of examined vaginal smear cells from five rats in each treatment group were expressed as a mode value (the most frequently occurring cell type in five rats). After 4 week, all rats were removed from treatment.
[0000]
Stage
Cell-Types
Proestrus
nucleated epithelia
Estrus
cornified
Metestrus
cornified + leukocytes
Diestrus
nucleated + leukocytes
[0030] Based on distribution and density of cell types, each daily vaginal smear was assigned one of four estrous cycle stages: proestrus, estrus, metestrus, and diestrus. Untreated female rats displayed estrus stage for 0.5 days every 4 to 5 d. Both dose of PLE employed produced increased duration of the estrus phase to 2 days (during which ovulation occur) in 75% of the PLE fed animals.
[0031] The estrous cycle in females involves many histological, physiological, and morphological and biochemical changes within the ovary. During the estrous cycle the maturation and ovulation of preovulatory follicles takes place under the combined and balanced influence of ovarian and extraovarian hormones. Any imbalance in these hormones leads to irregularity in the function of the ovary and irregular changes in the duration of estrous cycle. Any increase in the duration of estrus phases in the rats indicates further increase of estrogen and FSH levels upon administration of a compound.
Example 2
[0032] Phytoestrogenic enhancing activities of PLE were evaluated in normal and ovariectomised rats at 150 and 300 mg/kg doses. Estrogenic activity of the alcoholic extract was assessed in bilaterally ovarectomized female Sprague-Dawley rats taking percentage vaginal cornification, and uterine wet weight as parameters of assessment. Ovarectomized female rats (9 rats per group) given distilled water were used as a negative control, while rats gavaged daily with 5 mg/kg BW diethylstilbesterol were used as a positive control. At the end of treatment period of 14 days, rats were euthanized; the uteri were dissected and weighed, thereafter.
[0033] All rats had only L-type cells throughout the pre-treatment period after ovariectomy which confirmed that the ovaries were completely removed and no endogenous ovarian estrogens were produced. The administration of distilled water did not influence the vaginal epithelium, and only L-type cells were found. In contrast, synthetic estrogen induced a cornification of the vaginal epithelium as early as the third day of treatment. The occurrence of vaginal cornification in rats was dependent the PLE doses with the higher dose showing an earlier response.
[0034] Vaginal cytology assay is particularly useful to determine the estrogenic activity of the phytoestrogens, synthetic estrogens or xenoestrogens, based on the specific action of estrogens on specific receptors. Ovariectomised rats, treated orally with estradiol (0.5 mg/day/animal) show vaginal cornification, whereas the sham-treated animals have unestrous vaginal smear. Miroestrol produced cornification of the vaginal epithelium in the immature female mice. Dietary supplementation with phytoestrogens led to increased vaginal cytological maturation in women. Six-month treatment of soy-rich diet to the asymptomatic post-menopausal women increased vaginal cornification of epithelium, karyopycnotic index (KI) and maturation value (MV), identical to those found in the hormonal replacement women.
[0035] The increment of uterus weight at the end of treatment period in both PLE groups of rats agreed with changes of vaginal epithelium, with the higher doses of PLE producing the heavier uterus weight ( FIG. 2 ).
Example 3
[0036] Forty rats were randomly divided into 5 groups consist of eight rats in each group, control group (normal diet) was considered as negative control. Rats were allowed for acclimatization a week before the induction. Rat mammary gland tumour cells were grown to 80% confluence, harvested using 0.25% Trypsin-EDTA, counted for cell viability using a trypan blue exclusion test, and then resuspended in serum-free media. Cells were inoculated subcutaneously into mammary fat pad (right flank) of female Sprague-Dawley rats with a 200 μl of cell mixture (total 6×10 7 cells) using a 26-gavage needle. PLE were dissolved in water and administered orally. On day 14, the rats were sacrificed.
[0037] All animals were inspected daily, while body weights were recorded weekly. Rats were palpated weekly to monitor tumor development. The diameters of each tumor were measured with calipers and tumor volume was calculated using the following formula:
[0000] largest diameter×(smallest diameter) 2 ×0.4 (Li-Qiang et al., 2007).
[0000]
TABLE 1
Experimental procedures and mammary tumors in Female Sprague Dawley
rats with PLE supplements
Post-
Pre-inoculation
inoculation
Total tumour
Acclimation
Treatment
Treatment
Incidence
Volume
Group
(1 week)
(4 week)
Inoculation
(2 week)
(%)
(cm3)
Control
+
−
+
−
87.5%
10.7
Pre + post
+
+
+
+
25%
1.4
inoculation low
PLE
(150 mg/kg)
Pre + Post
+
+
+
+
12.5%
0.8
inoculation high
PLE
(300 mg/kg)
Post-Inoculation
+
−
+
+
37.5%
2.6
low PLE
(150 mg/kg)
Post-Inoculation
+
−
+
+
25%
0.9
high PLE
(300 mg/kg)
[0038] The anticancer activities of the PLE were investigated using a MTT assay on human Breast cancer cell lines (MCF-7). A mitochondrial enzyme in living cells, succinate-dehydrogenase, cleaves the tetrazolium ring, converting the MIT to an insoluble purple formazan.
[0039] Cells were exposed to various concentrations of PLE (0-1200 μg/ml) for 48 h. Cells treated with 0.1% DMSO were used as control. The PLE led to proliferation of the MCF-7 cells at 17.5 μg/ml (p<0.05) and an anti-proliferation effect at 150 μg/ml (p<0.05) and 1200 μg/ml (p<0.01) with an IC50 value of 678.5 μg/ml.
Example 4
[0040] PLE enhanced the antioxidant defence system. The hypercholesterol diet triggered a drop in GSH, an increase in lipid peroxidation, and reductions in key antioxidant enzymes activities in the brain, kidney and erythrocytes. In rats, PLE upregulated at least two antioxidant enzymes (SOD and catalase). Although exposure to hypercholesterol diet resulted in oxidative damage of brain, heart, kidney, liver and erythrocyte, PLE counteracted these deleterious effects. PLE administration is associated with an increase antioxidant capacity in blood and organ of rats and also prevented the changes induced by hypercholesterolemia. The reduction in MDA level in hypercholesterolemic rats by PLE showed that PLE prevented lipid peroxidation and this can contribute to a reduction of cardiovascular risk and atherosclerosis.
Example 5
Effect of PLE on the Estradiol Levels
[0041] Following the 150 mg/kgBW treatment, mean serum estradiol levels were increased from 20.80±4.43 to 33.78±3.2 pg/ml (p=0.09) for 2 wk and to 42.17±6.37 pg/ml (p=0.01) after 4 wk. At a high dose treatment (300 mg/kgBW) mean serum estradiol levels increased from 21.46±2.88 to 35.42±6.37 pg/ml (p=0.05) after 2 wk and to 72.10±8.87 pg/ml (p=0.001) after 4 wk, suggesting a dose dependent effect.
[0000]
TABLE 2
Antioxidant enzyme level in erythrocyte of Normal and hypercholesterol diet in
Male Sprague Dawley rats with PLE supplements
Diets
Normal (N)
N + PLE
High Fat + 1% cholesterol (C)
C + PLE
Catalase (U/min/mL)
Week 0
0.012 ± 0.003
0.008 ± 0.004
0.013 ± 0.016
0.005 ± 0.002
2
0.011 ± 0.002
0.012 ± 0.003
0.013 ± 0.003
0.020 ± 0.002
4
0.009 ± 0.001
0.008 ± 0.003
0.007 ± 0.004
0.009 ± 0.002
6
0.010 ± 0.003
0.010 ± 0.002
0.014 ± 0.001*
0.011 ± 0.004
8
0.0087 ± 0.003
0.010 ± 0.002
0.010 ± 0.0005
0.010 ± 0.004
10
0.012 ± 0.004
0.017 ± 0.004*
0.010 ± 0.005
0.012 ± 0.003
12
0.011 ± 0.003
0.005 ± 0.003*
0.010 ± 0.004
0.011 ± 0.003
Superoxide Dismutase (U/min/mL)
Week 0
0.018 ± 0.005
0.041 ± 0.038
0.025 ± 0.027
0.031 ± 0.029
2
0.016 ± 0.002
0.029 ± 0.007
0.025 ± 0.009
0.071 ± 0.011
4
0.013 ± 0.010
0.011 ± 0.009
0.015 ± 0.003
0.014 ± 0.001
6
0.010 ± 0.004
0.007 ± 0.002
0.004 ± 0.003*
0.008 ± 0.005
8
0.003 ± 0.003
0.004 ± 0.003
0.003 ± 0.002
0.007 ± 0.005 #
10
0.003 ± 0.004
0.007 ± 0.003
0.009 ± 0.002*
0.007 ± 0.005
12
0.008 ± 0.006
0.012 ± 0.006
0.013 ± 0.004
0.007 ± 0.003 #
Gluthathione Peroxidase (U/min/mL)
Week 0
13.15 ± 1.60
22.10 ± 7.48*
8.77 ± 4.04
5.799 ± 3.45*
2
1.02 ± 0.93
4.447 ± 1.23*
11.91 ± 2.87*
3.69 ± 0.92*
4
13.79 ± 3.36
6.34 ± 0.48*
14.43 ± 3.7
20.08 ± 3.59*
6
39.40 ± 8.59
16.37 ± 2.73
14.55 ± 4.72
7.91 ± 2.43
8
16.23 ± 3.23
7.67 ± 1.66
18.54 ± 7.85
9.56 ± 7.5
10
11.11 ± 3.89
9.11 ± 2.23
17.13 ± 4.36*
11.45 ± 3.04 #
12
3.885 ± 1.25
4.48 ± 1.23
6.09 ± 1.63*
3.70 ± 1.27
*p < 0.05 versus N control,
# p < 0.05 versus C control
[0000]
TABLE 3
Malondialdehyde level in organs of Normal and hypercholesterol
diet in Male Sprague Dawley rats with PLE supplements.
High Fat + 1%
Diets
Normal (N)
N + PLE
cholesterol (C)
C + PLE
MDA level (nmol/ml)
Brain
6.44 ± 0.91
11.91 ± 2.62*
15.78 ± 2.94*
13.09 ± 0.59*
Heart
3.64 ± 1.46
4.04 ± 0.92
13.98 ± 1.98*
6.23 ± 0.91 #
Kidney
4.73 ± 1.40
5.54 ± 0.51
7.92 ± 1.21*
4.20 ± 0.76 #
Liver
5.95 ± 0.25
5.72 ± 1.29
10.6 ± 0.96*
7.10 ± 0.75* #
Lung
2.94 ± 1.36
4.76 ± 0.40
3.86 ± 1.12
4.65 ± 1.67
*p < 0.05 versus N control,
# p < 0.05 versus C control
[0000]
TABLE 4
Plasma lipid level of Normal and hypercholesterol diet in
Male Sprague Dawley rats with PLE supplements
High Fat + 1%
Diets
Normal (N)
N + PLE
cholesterol (C)
C + PLE
Total cholesterol (mmol/L)
Week 0
1.38 ± 0.15
1.38 ± 0.29
1.38 ± 0.11
1.35 ± 0.27
2
1.37 ± 0.28
1.28 ± 0.18
1.67 ± 0.26*
1.41 ± 0.22
4
1.18 ± 0.09
1.13 ± 0.12
1.77 ± 0.43*
1.65 ± 0.39*
6
1.37 ± 0.11
1.22 ± 0.12
2.25 ± 0.48*
1.89 ± 0.28*
8
1.38 ± 0.33
1.15 ± 0.11*
2.55 + 0.37*
1.49 ± 0.26 #
10
1.39 ± 0.18
0.87 ± 0.11*
2.52 ± 0.33*
1.47 ± 0.39 #
12
1.45 ± 0.2
1.12 ± 0.17
2.88 ± 0.53*
1.12 ± 0.36 #
HDL-Cholesterol (mmol/L)
Week 0
0.57 ± 0.09
0.57 ± 0.17
0.58 ± 0.07
0.55 ± 0.08
2
0.54 ± 0.09
0.62 ± 0.09*
0.70 ± 0.10
0.69 ± 0.07
4
0.72 ± 0.20
0.75 ± 0.06
0.83 ± 0.07
0.85 ± 0.05
6
0.53 ± 0.04
0.77 ± 0.06*
0.56 ± 0.10
0.96 ± 0.08* #
8
0.64 ± 0.1
0.77 ± 0.03*
0.60 ± 0.09
0.79 ± 0.14* #
10
0.64 ± 0.11
0.68 ± 0.02
0.65 ± 0.12
0.76 ± 0.21 #
12
0.64 ± 0.19
0.70 ± 0.12*
0.55 ± 0.04*
0.88 ± 0.19* #
LDL-Cholesterol (mmol/L)
Week 0
0.31 ± 0.09
0.36 ± 0.17
0.27 ± 0.03
0.26 ± 0.06
2
0.25 ± 0.09
0.27 ± 0.04
0.32 ± 0.09
0.29 ± 0.08
4
0.24 ± 0.04
0.26 ± 0.06
0.41 ± 0.06*
0.41 ± 0.10*
6
0.29 ± 0.03
0.26 ± 0.02
0.52 ± 0.08*
0.42 ± 0.14
8
0.26 ± 0.006
0.26 ± 0.03
0.56 ± 0.006*
0.35 ± 0.08 #
10
0.25 ± 0.02
0.23 ± 0.05
0.55 ± 0.02*
0.29 ± 0.04 #
12
0.27 ± 0.06
0.23 ± 0.03
0.57 ± 0.06*
0.22 ± 0.06 #
Triglycerides (mmol/L)
Week 0
0.9 ± 0.09
0.86 ± 0.08
0.90 ± 0.10
0.91 ± 0.14
2
0.87 ± 0.11
0.81 ± 0.22
0.79 ± 0.08
0.64 ± 0.10
4
0.75 ± 0.19
0.63 ± 0.07
0.71 ± 0.18
0.60 ± 0.13
6
0.58 ± 0.09
0.58 ± 0.10
0.71 ± 0.10
0.64 ± 0.14
8
0.55 ± 0.08
0.55 ± 0.05
0.81 ± 0.10*
0.62 ± 0.03
10
0.43 ± 0.16
0.45 ± 0.06
0.85 ± 0.09*
0.47 ± 0.09 #
12
0.49 ± 0.05
0.42 ± 0.05*
0.86 ± 0.07*
0.39 ± 0.06* #
*p < 0.05 versus N control,
# p < 0.05 versus C control
|
A comestible composition with phytoestrogenic property against oxidative stress, retarding hormone related cancer, affecting fertility and effective to hinder or prevent ailments or conditions resulting from, or exacerbated by, a decrease in endogenous estrogen including: reproductive organ ailments, cardiovascular disease, osteoporosis, loss of cognitive function, urinary incontinence, body fat increase, post menopausal syndromes and vasomotor symptoms, and contains extract from palm leaf.
| 0 |
BACKGROUND AND SUMMARY OF INVENTION
This invention relates to a fish bait device and, more particularly, a device which not only provides the bait but installs the same on the fishhook. Two principle problems have faced fishermen over the years -- providing the right amount of bait and installing it on a hook. The latter problem is probably more poignant in most fishermen's minds inasmuch as almost every beginner has been stuck by a fishhook. However, the other problem is not far behind because a variety of baits are available, i.e., worms, insects, food in general and the whole gamut of artificial lures. No single approach in the past has made it possible for the novice fisherman, or, for that matter, the expert, to have the right amount of bait and to have it installed on a hook simultaneously. These twin goals have been achieved according to the invention.
In the invention, a tubular device is employed which has a plunger reciprocable therein so as to extract a predetermined amount of fish food, i.e., bait from a container holding bait of a dough-like consistency. Thereafter, the hook it introduced into the ensleeved plug and with the single step of expelling the plug, the hook is likewise expelled and in condition for immediate fishing.
Other objects and advantages of the invention may be seen in the details of the invention as set forth in the ensuing specification.
DETAILED DESCRIPTION
The invention is described in conjunction with the accompanying drawing, in which --
FIG. 1 is a perspective view of the inventive device shown being inserted into a container of dough-like fish food;
FIG. 2 is a fragmentary perspective view showing the device positioned to receive a fishhook;
FIG. 3 is a view similar to FIG. 2 but showing a subsequent step in the inventive procedure, i.e., the step of simultaneously expelling the plug of fish food with the hook embedded therein;
FIG. 4 illustrates the plug having the hook embedded therein being held in the hand of a fisherman;
FIG. 5 is a longitudinal sectional view of the inventive fishhook baiting device;
FIG. 6 is an end view of the thumb manipulatable plunger piece also seen at the extreme top center of FIG. 5;
FIG. 7 is a top plan view of the aforementioned thumb manipulatable plunger piece;
FIG. 8 is a top plan view of the plunger portion of the tubular device, being seen in the central portion of FIG. 5 as well; and
FIG. 9 is a top plan view of the tubular housing of the inventive device.In the illustration given and with reference first to FIG. 1, the numeral 10 designates generally the inventive fishhook baiting device which is seen in the process of being inserted -- see the arrow designated 11 -- into a container housing fish bait. Advantageously, the fish bait is of a dough-like consistency and can be housed in any suitable container such as that designated 12. At this point in time, the thumb piece 13 is suitably retracted, i.e., positioned as far toward the uninserted end as possible. This provides a space in the inserted end for the receipt of the bait.
After bait has been received within the end previously inserted -- the end being designated 14 in FIG. 2, a hook 15 suitably attached to a line 16 is inserted into the plug of dough housed within the device 10 -- the plug being designated 17 in FIG. 3. To proceed from the showing in FIG. 2 to that of FIG. 3, the thumb piece 13 is moved longitudinally toward the end 14 so as to simultaneously expel the plug of bait with the hook embedded therein. This results in the assembly of elements designated 17' and further illustrated in FIG. 4.
The device 10 (now referring to FIG. 5) includes a tubular element 18 in which is reciprocably positioned the plunger 19. In turn, the plunger 19 is connected to the thumb piece 13. In the illustration given, the tubular member 18 is open at both ends but has a tapered bore 20. The bore 20 adjacent the end 14 has a diameter of approximately 1/2 inch while at the other end, designated 21, the bore 20 has a diameter of about 3/4 inch. The plunger 19 has a reduced diameter end 22 to coincide generally within the bore 20 at the end 14 while, at its other end as at 23, the diameter is somewhat larger -- so as to substantially fill the bore 20 at the end 21. As can be appreciated from FIG. 8, the plunger 19 has a generally circular cross-section but of varying diameter throughout its length which saves on material by having neck down areas as at 24 and 25. Intermediate the ends of the plunger 19 an enlarged portion is provided as at 26 which contains a transverse bore 27. The bore 27, as can be appreciated from FIG. 5, receives an integral post portion 28 (see also FIG. 6) provided on the thumb piece 13. The post 28 is adapted to be received as by a press fit within the transverse bore 27.
Referring to FIGS. 5-7, it will be seen that the thumb piece 13, in the illustration given, is shaped to conform to the user's thumb for use in whichever direction the plunger 19 is desired to be moved. In other words, the upper surface as at 29 is curved upwardly adjacent the central portion 30 so as to develop convenient thumb pressing areas. The upper surface 29 is also arcuately curved (as in transverse section) as can be seen particularly from FIG. 6 in the area designated 31 so as to conform generally to the outer surface 32 of the tubular member 18. The tubular member 18 -- as best seen in FIG. 9 -- is equipped in its top surface with a longitudinally elongated slot 33 (see also FIG. 5) through which the post 28 of the thumb piece 13 extends.
In the operation of the invention, the thumb piece (for the sequence of steps depicted in FIGS. 1-4) -- is positioned so that the post 28 is essentially in the position designated 28a in FIG. 9. This means that the plunger 19 is retracted relative to the end 14, i.e., the plunger end 22 is sufficiently removed from the end 14 so as to permit a suitable plug to be developed in that end of the tubular member. After the material constituting the bait has been received within the bore and the hook 15 inserted into that plug (in the fashion illustrated in FIG. 2), the thumb piece 13 is moved to the dotted line position designated 28b in FIG. 9 so as to expel the plug 17 in the fashion illustrated in FIG. 3.
It will be appreciated that in some instances only a single open ended member may be provided if only a single size of bait plug is desired. Also, it is within the purview of the invention to provide assemblies for different sizes. For example, in addition to the illustrated embodiment which has bores of 1/2 and 3/4 inches at the two ends -- this being over a 5 foot length, another preferred embodiment also utilizes a 5 foot length but with the smaller bore measuring about 3/16 inch in diameter while the larger bore is approximately 3/8 inch in diameter. In either case, the plunger 19 has a length of about 4 inches so as to develop an approximately 4 inch long plug. In like fashion, the length of the slot 33 is approximately 1 inch.
While in the foregoing specification, an illustrative embodiment of the invention has been set down in detail for the purpose of explaining the same, many variations of the details hereingiven may be made by those skilled in the art without departing from the spirit and scope of the invention.
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A device and method for baiting fishhooks wherein a tubular member receives a quantity of fish bait having a dough-like consistency to provide a plug, a fishhook being inserted into said plug and thereafter a plunger on said tubular member being actuated to simultaneously expel said plug and hook.
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FIELD OF THE INVENTION
The invention relates to a motor-driven epilation head for an epilation device, in particular for plucking hairs of the human skin. The invention furthermore relates to an epilation device.
BACKGROUND OF THE INVENTION
Epilation devices serve for removing hairs, if possible including the roots thereof. Known epilation devices are designed in such a way, for example, that the hairs are clamped between adjacent clamping elements and plucked by means of a movement of the clamping elements relative to the skin. This typically requires that the clamping elements are closed in a predetermined position in each case in order to capture the hairs, moved into another predetermined position in a closed state together with the clamped hairs, and then reopened in order to release the plucked hairs. In order to implement this pattern of movement, the clamping elements may be arranged, for example, on a rotation cylinder that is set in rotation by means of an electric motor. The opening and closing of the clamping elements is controlled by means of a control mechanism that can be designed in various ways. Generally, the control mechanism has actuation elements that act on the clamping elements, such that the clamping elements are closed or opened.
A rotation cylinder of this type is known, for example, from EP 547 386 A. The rotation cylinder that is disclosed there for an epilation device is designed in such a way that movable clamping elements are coupled to actuation elements. The clamping elements can be moved toward one another in order to carry out a plucking movement. In the process, one clamping element in each case moves toward a central clamping element from the left and from the right.
Furthermore, an epilation device is known from EP 1 203 544 A1 in which the actuation elements are designed in the form of rods and arranged around the shaft of the rotation cylinder. All of the rods are coupled to a single return spring in such a way that the clamping elements are pretensioned via the rods in the direction toward the opened state. In order to close the clamping elements, the rods are actuated in such a way that the clamping elements are displaced in an axial direction by overcoming the spring force of the return spring. These are displaced by the action of the return spring while in the non-actuated state of the rods and the clamping elements are opened as a result.
An embodiment of the current invention equips an epilation device with a large number of clamping elements while keeping the expenditure of time and effort involved reasonable in order to attain as thorough and painless an epilation process as possible. In doing so, the epilation should be effective both on skin with thick hair growth and with sparse hair growth.
SUMMARY OF THE INVENTION
The invention relates to an epilation head for an epilation device, in particular for plucking hair from human skin having a rotating cylinder rotating around a rotational axis having a number of plucking units for grasping and plucking out hair, wherein each plucking unit comprises a movable clamping unit, a stationary clamping unit, wherein the movable clamping unit and the stationary clamping unit form a closable plucking gap, characterized in that the movable clamping unit has a hair guiding device which is associated with the movable clamping unit.
The epilation head according to the invention for an epilation device, particularly for plucking hairs of the human skin, has a rotation cylinder capable of rotating about a rotation axis. A multiplicity of plucking gaps is provided on the rotation cylinder for the purpose of plucking hairs. According to the present invention, a second closable plucking gap is found adjacent to a first closeable plucking gap. The first closeable plucking gap is determined by a first clamping element and by a second clamping element. These clamping elements are capable of moving towards one another, in order to thus close the plucking gap and optionally pluck at least one hair in the process. The second clamping element can form a, second closeable plucking gap together with the third clamping element in a similar manner.
The first clamping element and, if present, the second clamping element can be movably mounted. The first clamping element and the second clamping element should be capable of being jointly actuated by an actuation element. This serves for closing the first and the second plucking gap. For this purpose, the actuation element can, for example, exert pressure on the first clamping element, thereby moving it toward the second clamping element. This causes the first plucking gap to close. The actuation element can continue to move in such a way that also the second clamping element is moved toward the third clamping element, and also the second plucking gap is closed in this manner after the first plucking gap or simultaneously with the first plucking gap by means of the same actuation element in an essentially continuous movement.
According to the present invention, the moveable clamping unit (or generally at least one moveable clamping unit) has a hair guiding device is associated with the moveable clamping unit. Such a hair guiding device can have any form suitable to guide hair. Generally, the hair guiding device will guide hair in such way, that it is directed into a plucking gap.
Such a hair guiding device can generally comprise an elevation or recess. It can comprise an elevation for example in form of a tongue, that is an elevation with a major extension in the circumferential direction. Alternatively the elevation can have the form of a cylinder or mushroom. Such an elevation would have a small size in the circumferential direction. The hair guiding device could also take the form of a pike or nib.
Likewise, recessed hair guiding devices are considered. Again they can have different cross sections, either oblong or pike-like. One useful type of a recessed hair guiding device comprises a groove. As bodyhair will typically have a considerable height above skin level, it will reach into such a recess or groove, and hence can also be efficiently guided by a recessed hair guiding device.
It is possible and useful to attach the hair guiding device to the top of the moveable clamping unit. Many attempts have been made to efficiently use the limited surface space of an epilation head or epilation roll. So far, all attempts consider certain arrangements of plucking gaps and where they are present, certain arrangements of hair guiding devices. However, the two devices are arranged side by side and hence take up considerable surface space. It is a key insight of the present invention, that the two devices can be combined, if both devices are suitably formed to allow such a combination, while still maintaining an efficient hair removal.
It is also useful to have hairguided devices associated with several moveable clamping units, if several moveable clamping units are present.
The first and the second clamping element can move into the same direction during the process of closing the first plucking gap and the second plucking gap. The movement of the first and second clamping element in the same direction has a multitude of advantages. For one thing, this sequence of movements makes it possible to design the rotation cylinder to be very compact. As a result, the rotation cylinder can have small overall dimensions, such that a compact epilation device can be provided. Moreover, several clamping elements and consequently several plucking gaps can be situated on a rotation cylinder of a given size.
It is advantageous when the first clamping elements and the second clamping elements are designed as single components. For one thing, the clamping elements are rendered lightweight in this manner and are capable of moving toward one another rapidly with little inert mass.
It is also advantageous when the third clamping element is stationary. In this manner the third clamping element is capable of withstanding a high pressure that is exerted by the first clamping element and/or by the second clamping element. Furthermore, a desirable self-amplification effect of the clamping force then becomes dependent predominantly on the number of hairs in the first and the second plucking gap. Moreover, a device in which few parts are movable is mechanically simpler and therefore also more cost effective to produce.
Furthermore, it is advantageous when first spring elements for opening the first plucking gap are provided that act on the first clamping element and on the second clamping element independently from the actuation elements. Alternatively or additionally, second spring elements that act on the second clamping element and on the third element independently from the actuation elements are provided also for opening the second plucking gap. The spring elements in this context can advantageously be designed in the form of helical springs. Helical springs have a long serviceable life and provide an adequate spring force even in dynamic rapid cycles of motion.
In the epilation head the rotation axis of the rotation cylinder can extend and in the context of the present invention preferably extends outside the first clamping elements. One advantage of this is that the first clamping elements that extend maximally to the rotation axis of the rotation cylinder are thus relatively small and therefore have a low mass. This has a positive effect on the dynamics of the movements thereof and makes possible an operation of the epilation head according to the invention with comparatively low noise generation.
The first and the second clamping elements can be made of metal, such that they can absorb high mechanical loads in spite of small dimensions and, due to the hardness thereof, can clamp the hairs reliably. However, the first and the second clamping elements are preferably made of plastic. In this manner a very cost-effective production is possible. Additionally, the weight of the epilation head according to the invention can be kept relatively low. An additional advantage lies in a noise and vibration damping during the striking of the first clamping elements.
The third clamping elements can be arranged rigidly in the rotation cylinder. As a result, the mechanics are simplified and only small overall dimensions are required. In particular, several second clamping elements are arranged on a common support in each case. It is particularly advantageous in this case when the second clamping elements are distributed axially offset from one another over the circumference of the supports. A continuous plucking region can be implemented in this manner, wherein the plucking process occurs in rapid succession. The actuation elements are preferably designed in the form of rods that strike the first clamping elements in an axial direction. Such rods can be produced very cost-effectively and allow very simple and robust mechanics for the actuation of the first clamping elements. The third clamping elements can be provided from the same material as the other clamping elements.
An another important aspect, the present invention enables the provision of relatively smooth epilation heads. An epilation head will always have some form of elevation above surface level. Such elevations are at least the upper ends of the clamping units. Additionally, raised hair guiding elements can form elevations. The surface will hence have a certain base level and the elevations will have a certain height above these base level. The average height of all the elevations defines an elevation level. In one aspect the present invention achieves a low elevation level above the base level as compared with the diameter of the epilation cylinder. This diameter is to be taken between peripherally/diametrically opposed points of the elevation level. The present invention can achieve, that the elevation level has a distance from the base level which is less than 20%, or less than 10%, or less than 5%, or less than 2.5% of the diameter. The elevation level cart normally more than 0.5% or 1% of the respective diameter.
The invention additionally relates to an epilation device, in particular for plucking hairs of the human skin, comprising a handheld housing and the epilation head according to the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will be explained in further detail by means of the exemplary embodiments shown in the drawings below, in which:
FIG. 1 shows a side view of an exemplary embodiment of a typical epilation device which, however, is not designed in detail according to the invention,
FIG. 2 shows a sectional view through a rotation cylinder according to the invention,
FIG. 3 shows an exploded view of the same rotation cylinder according to the invention,
FIG. 4 shows a perspective view of the same rotation cylinder according to the invention,
FIG. 5 shows an enlarged sectional view of clamping elements for a rotation cylinder,
FIG. 6 shows a schematic diagram of the mode of operation of the clamping elements, which are shown with open plucking gaps,
FIG. 7 shows a schematic diagram of the mode of operation of the clamping elements, which are shown with closed plucking gaps.
DETAILED DESCRIPTION OF THE INVENTION
FIG. 1 shows a side view of an exemplary embodiment of an epilation device 1 typical of the generic type but not designed in detail according to the invention. The epilation device 1 has a housing 2 . This housing will typically have a motor and a power adapter. Additionally it can also have gear units. Placed upon the housing 2 is the epilation head 3 . A further main component of the device is the switch 4 , which is placed centrally on the front of the housing. With this switch the rotation cylinder 5 can then be set in motion in order to perform an epilation process. The rotation cylinder 5 can have, for example on its outer side walls, gear wheels that can be connected via appropriate drive elements (possibly also via a gear unit) to the motor. The depicted rotation cylinder has a multiplicity of plucking units, each of which, however, only has one closeable plucking gap and only two clamping elements and which, therefore, are not designed according to the invention. The depicted rotation cylinder 5 , however, could easily be replaced with a rotation cylinder according to the invention, since this rotation cylinder is compatible with a large number of conventional epilation devices and epilation heads.
FIG. 2 shows a sectional view through a rotation cylinder 5 according to the invention. This rotation cylinder first of all has a peripheral surface 10 . The first clamping element 11 , the adjacent second clamping element 12 and the adjacent third clamping element 13 and specifically their outer surfaces are essentially flush with this peripheral surface 10 . A first plucking gap 14 is provided between the first clamping element 11 and the second clamping element 12 . A second plucking gap 16 is provided between the second clamping element 12 and the third clamping element 13 . The three clamping elements together with the enclosed two plucking gaps form a plucking unit for capturing and plucking hairs. The rotation cylinder 5 has a multiplicity of such plucking units arranged thereon. All of them are essentially flush with the peripheral surface 10 . They preferably can be and are arranged axially and/or radially offset.
The rotation cylinder 5 is bordered laterally by two lateral side faces 18 . The rotation cylinder 5 surrounds a central axis 20 . Push rods 22 laterally protrude through the side faces into the rotation cylinder 5 . The push rods 22 have pusher heads 24 , with which they can be actuated, i.e. pushed deeper into the rotation cylinder 5 .
On pushing in the actuation elements in the form of the push rods 22 , the clamping elements are moved toward one another, such that the plucking gap closes. Springs carry out the opening of the plucking gaps and also the return movement of the push rods 22 . The first plucking gap 14 can be reopened by means of a first spring element 26 . The second plucking gap 16 can be reopened by means of a second spring element 28 . The spring elements can be designed, for example, in the form of a first and a second helical spring.
In an advantageous embodiment the rotation cylinder 5 is composed of a plurality of discs being placed one upon the other. The rotation cylinder depicted in FIG. 2 can be assembled using an outer jaw 30 . The outer jaw 30 functions like a stop disk. It provides an end stop for the movable clamping elements. In the context of the present invention, such an end stop can (optionally) be designed to further act as a third clamping element 13 .
Supports in the form of guiding disks 34 are provided between the outer jaws and the stop disks. The geometry of the guiding disks permits the guiding and anchoring of clamping elements.
As also visible in FIG. 2 all clamping element 11 , 12 and 13 comprise hair guiding devices 60 . The respective hair guiding devices 60 each comprise a recess 62 which is surrounded by a raised structures. The recess 62 hence is essentially provided in the form of a groove.
The design of a rotation cylinder 5 according to the invention can be seen particularly well also in the exploded view of FIG. 3 . Visible on the left is an outer jaw 30 that carries a multiplicity of push rods 22 . Adjoining the outer jaw 30 is a first layer of clamping elements, a clamping element 40 of which is emphasized by way of example. The clamping elements also have pusher feed-throughs 38 . The push rods 22 are led through these feed-throughs 38 and can exert force onto further inwardly situated clamping elements, without the clamping element that offers only one feed-through 38 being actuated by the push rods 22 as an actuation element. The ring of clamping elements 40 additionally is arranged in such a way that there is a rotation axis feed-through 36 . Such a rotation axis feed-through is provided for all of the layers of the rotation cylinder. Adjoining the layer of clamping elements 40 is a guiding disk 34 . Provided in this guiding disk 34 , also in the center, is a rotation axis feed-through 36 (in the description of this exploded view, components that are identical or similar to one another are denoted with the same reference symbols). In contrast to the layer of clamping elements 40 , the disk is a unitary piece. Adjacent to the disc are damping elements. These clamping elements again form a layer, but are not connected. Further adjacent elements are: an additional stop disk 32 , an additional layer of clamping elements 40 , an additional guiding disk 34 , etc., to the right outer jaw 30 , which likewise has posh rods 22 .
FIG. 4 provides a perspective illustration of the same rotation cylinder 5 according to the invention. The view is of an essential portion of the peripheral surface of the rotation cylinder 5 . Due to the advantageous construction of the rotation cylinder 5 , this peripheral surface 10 is capable of accommodating a particularly large number of plucking units. The first clamping element 11 , the second clamping element 12 and the third clamping element 13 of different clamping units are shown in each case by way of example. Components that are identical or similar to one another are denoted with the corresponding reference symbols in each case.
FIG. 5 provides enlarged sectional view of clamping elements. As can be nicely seen again, a first plucking gap 14 is provided between the first clamping element 11 and the second clamping element 12 . A second plucking gap 16 is provided between the second clamping element 12 and the third clamping element 13 . The three clamping elements together with the enclosed two plucking gaps form a plucking unit for capturing and plucking hairs. Clamping elements 12 and 13 are combined with a hair guiding devices 60 . Provided, that the clamping element has a sufficient area on its top, it is possible to have the hair guiding device 60 attached to the top of the moveable clamping elements. As shown for movable clamping element 12 , a raised structure 64 A is provided the left of the recess 62 and a raised structure 64 B is provided to the right of the recess 62 .
The bottom portions of the recess define a base level 70 , which for example spans from the bottom portion 70 A of recess 62 in clamping element 12 to the bottom portion 70 B in clamping element 13 . Elements above these base level from an elevation level. Generally, the average height of the elevations above the base level 70 defines an elevation level 72 . In the situation depicted in FIG. 5 all elevations have essentially the same height over the base level, such that elevation level corresponds to the level of the outer surfaces of the raised structures of the clamping elements, and hence connects portions 72 A, 72 B, and 72 C.
FIG. 6 shows a prior art epilation cylinder. The cylinder comprises a base surface defining a base level denoted as 70 . Above this base level a multitude of elements is arranged, which all represent relatively high elevations above the base level. The elevation level is roughly indicated as 72 . The epilation cylinder according to the present invention makes better use of the area of the epilation cylinder and provides an overall smoother and hence less aggressive appearance of the epilation cylinder.
The elements of the prior art epilation cylinder, which roughly correspond to elements of the epilation cylinder of the present invention are denoted by corresponding reference signs (but using primes). The epilation cylinder 5 ′ rotates about an axis 20 ′. It comprises moveable plucking elements 12 ′ and fixed plucking elements 13 ′. The fixed plucking elements 13 ′ are associated with hair guiding elements 60 ′. Most of the outer surface of the epilation cylinder 5 ′ is provided by a flat surface free of element, denoted as 70 ′. The elevation level defined by these elements is marked as elevation level 72 ′.
FIGS. 7 and 8 schematically illustrate the mode of operation of the rotation cylinder 5 . Portions of the rotation cylinder 5 are depicted in a simplified manner as a guide 52 . Such a guide can be provided, for example, by means of the stop disks 32 in combination with adjacent guiding disks 34 . However, other types of guides are also possible. The guide advantageously permits a displacement of the clamping elements 40 at least at the outer end thereof, that is, in the region of the clamping jaws 46 having the clamping surfaces 48 . This movement can be in part a rotational movement (as shown) or also a lateral displacement. During the epilation process hairs can be fed into the first plucking gap 14 and into the second plucking gap 16 . The movable first clamping element and the movable second clamping element 12 can be moved toward the stationary third clamping element by means of a force acting from one side. In the process, the first plucking gap 14 and the second plucking gap 16 close. In this manner, clamping forces are built up, by means of which hairs can then be plucked. To the extent that clamping forces are actuated by a predetermined motion amplitude of actuation elements, the force acting on the second plucking gap 16 increases with the number of hairs that are already located in the first plucking gap 14 . This leads to an amplifying effect that makes the epilation particularly efficient.
FIGS. 7 and 8 also show that the movement of the moveable clamping units leads to a movement of the hair guiding devices. This movement will generally move hairs towards the plucking gaps. Hence, the provision of hair guiding devices associated with the moveable clamping unit does not only give the benefit of using the surface area of the epilation cylinder very efficiently, but it also ensures that the hair guiding devices work more efficiently. The movement required for the operation of the plucking gaps is also beneficially used to impart a guiding movement to hair to be plucked.
The dimensions and values disclosed herein are not to be understood as being strictly limited to the exact numerical values recited. Instead, unless otherwise specified, each such dimension is intended to mean both the recited value and a functionally equivalent range surrounding that value. For example, a dimension disclosed as “40 mm” is intended to mean “about 40 mm.”
Every document cited herein, including any cross referenced or related patent or application, is hereby incorporated herein by reference in its entirety unless expressly excluded or otherwise limited. The citation of any document is not an admission that it is prior art with respect to any invention disclosed or claimed herein or that it alone, or in any combination with any other reference or references, teaches, suggests or discloses any such invention. Further, to the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall govern.
While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
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The invention relates to an epilation head for an epilation device, in particular for plucking hair from human skin. The epilation head having a rotating cylinder rotating around a rotational axis and having a number of plucking units for grasping and plucking out hair. Each plucking unit includes a movable clamping unit, and a stationary clamping unit. The movable clamping unit and the stationary clamping unit form a closable plucking gap. The movable clamping unit has a hair guiding device which is associated with the movable clamping unit.
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TECHNICAL FIELD
The present invention is related generally to barium magnesium aluminate (BAM) phosphors and methods for enhancing their performance in lighting and display applications. More particularly, the present invention is related to increasing the thermal stability and radiance maintenance of europium-activated BAM phosphors in highly loaded fluorescent lamps and plasma display panels.
BACKGROUND OF THE INVENTION
Europium-activated barium magnesium aluminate (BAM) phosphors are widely used as the blue-emitting component of the phosphor blends in most fluorescent lamps intended for white light generation. BAM phosphors also serve as the blue-emitting pixels in plasma display panels (PDPs). Despite its wide use, BAM is notorious for its shortcomings in brightness and maintenance, particularly in those applications involving exposure to high ultraviolet (UV) and vacuum ultraviolet (VUV) fluxes. Because of these shortcomings, the blue BAM emission is reduced at a significantly faster rate over time than the emissions of the other color components in the blends or pixels. This results in a loss of lumens and a color shift in the overall light output.
Theoretical and experimental investigations of various BAM compositions over the past few years have yielded clues about the degradation mechanisms involved in the phosphor's maintenance. A prolonged exposure to radiation with photons having energies above 5 eV (wavelengths less than 254 nm) causes a reduction in the phosphor's brightness and changes in the spectral power distribution of the phosphor's emission. These effects can be observed by spectroscopic methods after hundreds of hours of lamp operation or by a short period of high-intensity laser irradiation (e.g., a 193 nm excimer laser). In addition to an approximate 25% decrease in brightness after 500 hours of operation, there is an increase in the long wavelength side of the emission band of the phosphor. Very likely, these effects are linked to electron and hole centers formed during the phosphor synthesis and/or later generated as a result of ion bombardment and UV/VUV irradiation during lamp operation. In particular, electron centers (oxygen vacancies that have captured zero, one or two electrons) are believed to compete with the europium activator ions for UV/VUV photons and may also absorb a portion of the visible light emissions from the phosphor. It is also possible that oxygen vacancies with zero or one electron may capture electrons produced, for example, from the photoionization of Eu 2+ to Eu 3+ upon 185 nm UV irradiation. If the number of defects capable of capturing electrons from the ionization of the europium activator ions is comparable to the number of europium ions in the lattice, or becomes so during the operating life of the phosphor, a serious reduction of the emission intensity will follow over time.
SUMMARY OF THE INVENTION
We have discovered that by replacing some of the cations (Ba 2+ , Eu 2+ , Mg 2+ and Al 3+ ) in europium-activated barium magnesium aluminate phosphors with tetravalent cations of silicon, hafnium, and zirconium (Si 4+ , Hf 4+ and Zr 4+ ) the performance of the BAM phosphors in certain UV/VUV applications is improved. It is believed that the introduction of the tetravalent cations into the BAM lattice reduces the probability of forming the oxygen vacancies which lead to the degradation of the phosphor. Silicon, hafnium and zirconium were chosen because of their stable 4+-valence state in varying conditions. The tetravalent dopants may be used individually or in combination.
The BAM phosphor of this invention preferably contains from about 1 to about 5 weight percent of the europium activator, and more preferably about 2 weight percent europium. The dopant amounts preferably range from greater than 0 to about 2000 parts-per-million (ppm) silicon by weight, from greater than 0 to about 12500 ppm hafnium by weight, and from greater than 0 to about 6500 ppm zirconium by weight. More preferably, the dopant amounts range from about 100 to about 400 ppm silicon by weight, from about 600 to about 2500 ppm hafnium by weight, and from about 300 to about 1300 ppm by weight zirconium. Even more preferred, the dopant amounts range from about 100 to about 200 ppm silicon by weight, from about 600 to about 1300 ppm hafnium by weight, and from about 300 to about 650 ppm zirconium by weight.
In an alternative embodiment, the phosphors of this invention may be represented by (Ba 1−x Eu x )MgAl 10 O 17 : (Hf, Zr, Si) y where 0.05≦x≦0.25 and 0<y≦0.05; preferably, 0.0025≦y≦0.01; and, more preferably, 0.0025≦y≦0.005.
DETAILED DESCRIPTION OF THE INVENTION
For a better understanding of the present invention, together with other and further objects, advantages and capabilities thereof, reference is made to the following disclosure and appended claims.
A series of europium-activated barium magnesium aluminate phosphors were prepared with Hf, Zr and Si dopants. The phosphors had a composition which may be represented by the formula (Ba 0.90 Eu 0.10 )MgAl 10−y O 17 : (Hf, Zr, Si) y . The performance of these phosphors was compared with a control phosphor, (Ba 0.90 Eu 0.10 )MgAl 10 O 17 , made under the same conditions. Three different dopant levels were used: 0.02, 0.1, and 0.5 mole %. In each case, the molar amount of the tetravalent dopant ion was substituted for an equal molar portion of aluminum.
In a preferred method, the phosphors were made by combining stoichiometric amounts of the phosphor precursor compounds: BaCO 3 (0.800 moles), BaF 2 (0.100 moles) Eu 2 O 3 (0.050 moles), MgO (1.000 mole), Al(OH) 3 (10.0000−x moles), HfOCl 2 .8H 2 O (x=0.0002, 0.0010, and 0.0050 moles), ZrO(NO 3 ) 2 (x=0.0002, 0.0010, and 0.0050 moles) and SiO 2 (x=0.002, 0.0010, and 0.0050 moles). Barium fluoride, BaF 2 , was added as a flux substituting for 10 mole percent of the BaCO 3 . The precursor compounds were mixed together and wet milled for 4 hours using YTZ beads. The pH of the milled slurry was adjusted with ammonia to have a pH of above 8.0 in order to cause the soluble additives, primarily Hf or Zr precursors, to precipitate. The milled mixture was then filtered, oven dried at 120° C., crushed and fired at 1625° C. for about 1 to about 4 hours in a 75% H 2 /25% N 2 atmosphere. The presence of barium magnesium aluminate was confirmed by x-ray diffraction; no minor phases were detected. The phosphors exhibited the characteristic blue emission peak at about 450 nm under UV and VUV excitation.
The initial brightness of each phosphor sample was measured to be within a few percent of the brightness of a standard BAM phosphor. The samples containing 0.5 mole % Hf, Zr and Si were hard pressed into a recess in a copper holder in order to dissipate excess heat during testing. The samples were then irradiated in a vacuum with 193 nm VUV radiation from a Lambda-Physik Compex 110 excimer laser. Incident power density was maintained at about 1.75 W/cm 2 . A ten-minute irradiation time was selected to avoid the nearly complete saturation in degradation of the top surface of the plaque observed with prolonged exposures (e.g., an hour or more). Compared to the control phosphor, the samples doped with Si, Hf and Zr exhibited about 10% greater brightness under the same conditions. These results are summarized in Table 1. Brightness was measured as the integrated visible radiance in the range 350–600 nm under 250 nm excitation and is reported in relative units.
TABLE 1
Initial
Brightness after
Brightness vs.
Sample
Brightness
193 nm irradiation
control after 193
(mole %)
(Rel. Units)
(Rel. Units)
nm irradiation
Control
1.0
0.648
100.0%
0.5 Hf
1.0
0.707
109.1%
0.5 Zr
1.0
0.717
110.7%
0.5 Si
1.0
0.698
107.8%
The 0.5 mole % samples were also examined for their performance following exposure to a high-VUV-flux Xe discharge and an oxidizing heat treatment. In the first instance, the samples were exposed to 147/172 nm radiation from a Xe discharge for a 2-hour period in a vacuum. The power density of the incident VUV radiation was about 90 mW/cm 2 . As can be seen from the data in Table 2, the samples which were doped with Zr 4+ and Si 4+ cations exhibited a higher stability under the 2-hour exposure than the control sample. The sample doped with 0.5 mole % Hf exhibited a slightly inferior behavior under these conditions relative to the control. In the second test, the phosphor samples were heated in air for 1 hour at 450° C. to simulate conditions used in the manufacture of plasma display panels. The phosphors which were doped with Zr and Si exhibited better brightness than the control after the 1-hour heat treatment at 450° C. The sample doped with 0.5 mole % Hf did not enhance the stability of the phosphor under these conditions.
TABLE 2
Brightness under 147/172 nm Xe discharge
VUV-
Change
Heat-
Change
untreated
treated
relative
treated
relative
Sample
(Rel.
(Rel.
to
(Rel.
to
(mole %)
Units)
Units))
control
Units)
control
control
99.5
71.9
100.0%
90.5
100.0%
0.5 Hf
100.7
69.7
96.9%
91.5
99.9%
0.5 Zr
99.7
74.2
103.2%
93.2
107.1%
0.5 Si
101.5
78.6
109.3%
97.6
105.7%
Fluorescent lamps were constructed in order to determine the performance of the phosphors under high wall loadings. The lamps were an electrodeless compact fluorescent type having a wall loading of about 0.1 to 0.2 W/cm 2 . The phosphors were applied to the interior surface of the lamp envelope using a conventional organic-based coating technique. Two test lamps were made for each phosphor. Radiance values (integrated from 350–700 nm) were measured for each lamp before and after ˜500 hours of operation. The average radiance values are given in Table 3 in arbitrary units (a.u.). The average radiance maintenance of the lamps (500 h radiance/0 h radiance) is given relative to the average radiance maintenance of control lamps.
TABLE 3
Sample
Ave. 0 h
Ave. 500 h
Ave. Rel.
(mole %)
radiance (a.u.)
radiance (a.u.)
Maintenance
control
8.977
5.815
100.0%
0.02 Hf
8.487
5.216
94.9%
0.5 Hf
9.105
5.545
94.1%
0.02 Si
10.08
6.398
98.1%
0.5 Si
9.512
6.079
98.6%
0.02 Zr
9.352
6.252
103.2
0.5 Zr
9.884
6.987
109.2
In almost all cases, the average 0 h radiance for the lamps containing the phosphors doped with the tetravalent ions was greater than the average for the lamps containing the control phosphor. Under these tests conditions, the lamps containing the Zr and Si-doped phosphors continued to exhibit a higher radiance than the control lamps after ˜500 hours of operation. In terms of relative radiance maintenance, the lamps coated with the Zr-doped phosphor outperformed the control lamps.
The data from the various test environments demonstrate that the tetravalent dopants can improve the stability of BAM phosphors under harsh conditions. The performance of the Hf, Si and Zr dopants varied depending on the test environment with the Zr-doped phosphors exhibiting an improved stability under all test conditions.
While there has been shown and described what are at the present considered the preferred embodiments of the invention, it will be obvious to those skilled in the art that various changes and modifications may be made therein without departing from the scope of the invention as defined by the appended claims.
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A europium-activated barium aluminate phosphor is described wherein the phosphor is doped with tetravalent ions of Hf, Zr, or Si. Preferably, the phosphor is represented by (Ba 1−x Eu x )MgAl 10 O 17 :(Hf,Zr,Si) y where 0.05≦x≦0.25 and 0<y≦0.05. The tetravalent dopant ions are shown to enhance the stability of the phosphor in UV/VUV applications.
| 2 |
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates generally to interproximal reduction (IPR) in dentistry, and more particularly to an interproximal dental stripper providing both a single-sided abrasive as well as a double-sided abrasive portion.
[0003] 2. Description of the Prior Art
[0004] In the discipline of orthodontics, it is often necessary to reduce tooth structure interproximally to correct for inadequate space caused by dental crowding and in restorative dentistry to trim or contour various types of restorative materials such as amalgam or composite resin. Single-sided and double-sided abrasive strips are widely used in modern dentistry. The strips currently available do not have one- and two-sided regions on a single strip. The efficiency and effectiveness of the metal strip increases when abrasive is added to the other (reverse) side of the metal strip. When a double-sided strip is used, adequate space must exist between the teeth in question in order to allow for the added thickness of the strip to comfortably fit. If the teeth are in tight contact, minimal space must be initially created, using a single-sided strip, so that the thicker double-sided strip may be used. Initial use of a double-sided strip between tightly crowded teeth may lead to unacceptable patient discomfort and trauma of teeth already subject to orthodontic treatment. Thus a double-sided strip may not be substituted exclusively for a single-sided strip.
SUMMARY OF THE INVENTION
[0005] A combination strip would provide several advantages over prior products. The two regions on the strip allow the clinician to avoid having to first remove a single-sided strip and insert a second double-sided strip. The use of one strip to properly create adequate space reduces time spent stripping individual teeth by approximately 50%. Furthermore, single-sided and double-sided strips are currently advertised as being sterilizable for repeat use. However, due to the nature of microscopic entrapment of debris within the grit, the practice of using sterilized, recycled strips among different patients is objectionable. A combination strip would provide a more cost effective, hygienic alternative to conventional strips.
[0006] It is therefore an object of the present invention to provide an interproximal stripper that provides a single-sided strip distally joined and integral to a double-sided strip.
[0007] It is a further object to provide a combination interproximal stripper strip that provides a more hygienic and cost effective method of interproximal reduction.
[0008] According to a first broad aspect of the present invention, there is provided a interproximal strip comprising at least three zones arranged in longitudinal succession wherein a middle zone is a central smooth zone flanked by a first integral abrasive specialty zone and a second integral abrasive specialty zone.
[0009] According to a second broad aspect of the invention, there is provided a method of interproximal reduction whereby an interproximal strip is inserted between two adjacent teeth at a central smooth zone wherein said central smooth zone of said interproximal strip is flanked by a first integral abrasive specialty zone and a second integral abrasive specialty zone to create space between said adjacent teeth by abrading said teeth with said first integral abrasive specialty zone with a first degree of abrasiveness and to increase said space by abrading said teeth with said second integral abrasive specialty zone with a second degree of abrasiveness on a front side and a third degree of abrasiveness on a rear side of said second integral specialty zone.
[0010] Other objects and features of the present invention will be apparent from the following detailed description of the preferred embodiment.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] The invention will be described in conjunction with the accompanying drawings, in which:
[0012] FIG. 1A is a front view of an interproximal stripper constructed in accordance with an embodiment of the present invention; and
[0013] FIG. 1B is a rear view of the interproximal stripper of FIG. 1A .
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0014] It is advantageous to define several terms before describing the invention. It should be appreciated that the following definitions are used throughout this application. Definitions
[0015] Where the definition of terms departs from the commonly used meaning of the term, applicant intends to utilize the definitions provided below, unless specifically indicated.
[0016] For the purposes of the present invention, the term “abrasive” refers to a substance used for grinding, sanding or polishing enamel, dentin, amalgam, or any composite hybrid restorative material.
[0017] For the purposes of the present invention, the term “distally attached” refers to portions of a strip aligned without abutment.
[0018] For the purposes of the present invention, the term “double-sided” refers to a quality existing on two sides of a strip portion.
[0019] For the purposes of the present invention, the term “integral” refers to the characteristic of two portions being attached to each other in a manner to inhibit separation, such as by adhesive, molding, etc.
[0020] For the purposes of the present invention, the term “single-sided” refers to a quality existing on one side of a strip portion.
[0021] For the purposes of the present invention, the term “specialty zone” refers to a portion of a strip having distinct qualities, such as length, abrasiveness, etc.
DESCRIPTION
[0022] Interproximal reduction (IPR) is a dental procedure by which tooth structure or tooth restorative material is mechanically removed from the lateral surfaces of a tooth or teeth. In orthodontics, it is often necessary to reduce tooth structure interproximally in order to correct for inadequate space caused by dental crowding. This type of procedure, IPR, is routinely carried out when teeth are significantly crowded due to a lack of sufficient space for the teeth in their respective arches. It is also employed in restorative dentistry to trim or contour various types of restorative materials such as amalgam or composite resin. Additionally, this procedure allows for proper positioning of significantly malposed teeth before, during and after comprehensive orthodontic treatment. Most often, the reduction is carried out manually using abrasive strips that fit in between the teeth (interproximally) and enable conservative reduction of tooth structure and subsequent creation of space.
[0023] The majority of orthodontic cases involve dental crowding, and IPR is routinely used in combination with acceptable orthodontic treatment to resolve these crowding problems. A strip is initially wedged between crowded adjacent teeth along a portion of the strip that is smooth. Tooth reduction is achieved by moving the strip in a forward/backward or facial/lingual direction until adequate space is created. Single-sided strips allow for interproximal reduction of only one tooth at a time. This type of reduction requires an operator to adequately reduce tooth structure on a single tooth, and then remove the strip and reverse sides so that an adjacent tooth may be reduced.
[0024] A combination interproximal strip in accordance with the present invention allows fine tooth reduction of a single tooth and then a smoother transition to bilateral reduction. FIGS. 1A and 1B illustrate a combination interproximal strip according to the present invention. Combination strip 102 has two distinct distal ends. Strip 102 has a smooth central zone 108 flanked on either side by specialty zones 104 and 106 . Specialty zone 104 is a single-sided abrasive portion. Specialty zone 106 is a double-sided abrasive portion wherein the abrasives on either side of specialty zone 106 may be identical degrees of abrasiveness or two different degrees of abrasiveness. Specialty zones 104 and 106 may be substantially equal in length or may be different in length. For example, in a 145 mm combination strip, the smooth central zone 108 may be approximately 15 mm in length to allow for interproximal placement between crowded teeth. However, it should be understood that the combination strip may be 140 to 160 mm in length with specialty zones of 60 to 70 mm in length on the strip and the strip may be 7 to 10 mm wide. The combination strip of the present invention may be manufactured from a suitable material for a sterile environment while maintaining flexibility for maneuverability within a patient's mouth. Suitable materials for manufacture of a strip of the present invention include polyester, aluminum, aluminum alloy, etc. Any suitable coating, such as diamond coating having industrial coating or diamond particles, with an average grain diameter in the range of approximately 8 to 150 μm, may provide the abrasiveness of the specialty zones.
[0025] Successful IPR results from use of smooth zone 108 to interproximally introduce the strip between crowded teeth, primary creation of space using the single-sided specialty zone 104 , and secondary bilateral reduction with double-sided specialty zone 106 . A combination strip of the present invention allows use of a single strip to create adequate interproximal space and may reduce time spent stripping teeth by approximately 50%. Additionally, since a single strip is used for both primary and secondary tooth reduction, cost is also reduced.
[0026] The combination strips of the present invention may be a one-piece construction or formed of parts. Furthermore, the combination strips may be sterilizable through conventional methods. The strips of the present invention may be sold individually or sold as kits offering multiple strips of various abrasive degrees.
[0027] All documents, patents, journal articles and other materials cited in the present application are hereby incorporated by reference.
[0028] Although the present invention has been fully described in conjunction with the preferred embodiment thereof with reference to the accompanying drawings, it is to be understood that various changes and modifications may be apparent to those skilled in the art. Such changes and modifications are to be understood as included within the scope of the present invention as defined by the appended claims, unless they depart therefrom.
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Interproximal reduction (IPR) is accomplished with use of a combination stripper having two distinct ends. The first end has a single abrasive side and the second distinct end is abrasive on both sides.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of and priority to co-pending PCT application PCT/US11/30536 filed Mar. 30, 2011 and to U.S. Provisional Application No. 61/319,666, filed Mar. 31, 2010.
TECHNICAL FIELD OF THE INVENTION
This invention relates to light emitting diodes (LED) and more particularly to phosphors for use in LED applications such as phosphor-conversion LEDs.
BACKGROUND OF THE INVENTION
Current white-light-emitting phosphor-conversion LEDs (pc-LEDs) utilize one or more phosphors to partially absorb blue light emissions from InGaN LEDs in order to convert some of the blue light into a yellow light. The combination of the remaining unabsorbed blue light and converted yellow light yields light which is perceived as white. Other phosphors may be used in addition to the yellow-emitting phosphor, for example a red-emitting phosphor, in order to increase color rendering index (CRI) or achieve a different color temperature (CCT). However, the yellow-emitting phosphor remains the core component in white pc-LEDs.
The normal yellow-emitting phosphor used in a pc-LED is a cerium-activated yttrium aluminum garnet, Y 3 Al 5 O 12 :Ce, phosphor (YAG:Ce). However, other phosphors include a cerium-activated terbium aluminum garnet (TAG:Ce) phosphor as described in U.S. Pat. No. 6,669,866 and silicate-based phosphors such as those described in U.S. Pat. Nos. 6,943,380, 6,809,347, 7,267,787, and 7,045,826.
An example of a YAG:Ce phosphor and its application in an LED are described in U.S. Pat. No. 5,998,925. Some composition modifications of YAG phosphors are also described in this patent, such as using Ga to replace Al or Gd to replace Y in the garnet. Generally, Ga substitution of Al shifts the emission peak to shorter wavelength and Gd substitution of Y shifts emission peak to longer wavelength.
SUMMARY OF THE INVENTION
A new phosphor for light emitting diode (LED) applications has been developed with a composition represented by (Y 1-x Ce x ) 3 (Al 1-y Sc y ) 5 O 12 wherein 0<x≦0.04 and 0<y≦0.6. The color of the light emitted by the phosphor can be changed by adjusting the composition. For example, in one aspect, the phosphor can be used as a yellow-emitting phosphor in white pc-LEDs. In another aspect, the composition of the phosphor may be adjusted such that it may used as a green-emitting phosphor to fully convert the blue emission from a blue-emitting LED to a green emission. This is important since direct green-emitting InGaN LEDs have a very low efficiency. A green-emitting, full conversion pc-LED that uses the higher efficiency blue-emitting InGaN LEDs has the potential to offer more efficient green LEDs.
In accordance with an aspect of the invention, there is provided a phosphor having a composition represented by (Y 1-x Ce x ) 3 (Al 1-y Sc y ) 5 O 12 wherein 0<x≦0.04 and 0<y≦0.6.
In accordance with another aspect of the invention, there is provided a phosphor-conversion LED comprising: an LED that emits a blue light and a phosphor for converting at least a portion of the blue light into light of a different wavelength, the phosphor having a composition represented by (Y 1-x Ce x ) 3 (Al 1-y Sc y ) 5 O 12 wherein 0<x≦0.04 and 0<y≦0.6.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an illustration of an embodiment of a phosphor-conversion LED (pc-LED) according to this invention.
FIG. 2 is an illustration of an alternate embodiment of a pc-LED according to this invention.
FIG. 3 is an emission spectrum of a phosphor having a composition (Y 0.995 Ce 0.005 ) 3 (Al 0.8 Sc 0.2 ) 5 O 12 in accordance with this invention (Example Y1).
FIGS. 4 and 5 are emission spectra of the phosphors of Examples Y1, and Y3-Y9.
FIG. 6 is a graph of efficiency (lm/W o-B ) vs. the C x color coordinate for various phosphor compositions according to this invention compared with conventional (Y 1-x Ce x ) 3 (Al 1-y Ga y ) 5 O 12 phosphor.
DETAILED DESCRIPTION OF THE INVENTION
For a better understanding of the present invention, together with other and further objects, advantages and capabilities thereof, reference is made to the following disclosure and appended claims taken in conjunction with the above-described drawings.
FIG. 1 is an illustration of an embodiment of the phosphor-conversion LED 1 of this invention. The phosphor converter 3 in this case is a solid ceramic piece formed by pressing and sintering the powdered phosphor or its oxide precursors. The phosphor converter 3 is placed on top of the blue-emitting LED 5 , which preferably emits light having a wavelength from about 420 nm to about 490 nm. The LED 5 is shown here mounted in a module 9 having a well 7 with reflective sides, but the invention is not limited to this particular arrangement.
FIG. 2 is an illustration of an alternate embodiment of the invention. In this case, the phosphor-conversion LED 10 is encapsulated in a resin 15 in which particles of phosphor 13 are dispersed.
EXAMPLES
Several phosphors of varying composition were made using commercially available oxide powders of Y 2 O 3 , Al 2 O 3 , Sc 2 O 3 and CeO 2 which were mixed in amounts to produce the desired composition (see Table 1). The mixed powders were then pressed into discs and sintered under varying conditions to form the phosphors. Although these samples were formed as sintered ceramic discs, the phosphor may also be formed as a powder.
TABLE 1
Batch
Y 2 O 3
Al 2 O 3
sintering
(gram)
(gram)
(gram)
Sc 2 O 3 (gram)
CeO 2 (gram)
atmosphere
Y1
2.7513
1.6447
0.5029
0.0211
wet H 2
Y2
2.4623
0
2.5189
0.0189
wet H 2
Y3
2.5988
0.786
1.5951
0.0199
wet H 2
Y4
2.6592
1.4294
0.8286
0.0827
wet H 2
Y5
2.7115
1.4356
0.8322
0.0208
wet H 2
Y6
10.8864
5.7468
3.3306
0.0333
wet H 2
Y7
11.2138
7.6108
1.1443
0.0347
wet H 2
Y8
10.9668
6.203
2.7967
0.0343
wet H 2
Y9
10.7322
4.8557
4.3781
0.0328
wet H 2
Example Y1
Example Y1 was made with a nominal composition (Y 0.995 Ce 0.005 ) 3 (Al 0.8 Sc 0.2 ) 5 O 12 . The powder mix was dry pressed into discs under 300 MPa pressure. The pressed discs were sintered at 1800, 1850, 1880 and 1890° C. under wet H 2 . The resulting sintered ceramic was a green-yellow color. The ceramic became more translucent as sintering temperature increased. The emission intensity also increased as temperature increased.
An example of Y1 emission under blue-light excitation is shown in the FIG. 3 . The emission spectrum exhibits a broad yellow emission with a peak wavelength at 533 nm. The emission spectrum is very similar to YAG:Ce and indicates that the ceramic has a garnet structure.
Example Y2
Example Y2 was made with a nominal composition (Y 0.995 Ce 0.005 ) 3 SC 5 O 12 . The oxide powders were mixed and dry pressed into discs. The discs were sintered at 1850° C. and 1900° C. The resulting sintered ceramic was orange-red in color. However, no emission was observed under the blue excitation.
Example Y3
Example Y3 was made with a nominal composition (Y 0.995 Ce 0.005 ) 3 (Al 0.4 Sc 0.6 ) 5 O 12 . Discs were made by dry pressing the oxide powder mixture and then sintering at 1850° C. and 1900° C. Melting occurred when the sintering was done at 1900° C. yielding a near white body color whereas the disc sintered at 1850° C. had a green-yellow color. The emission of Y3 had a peak wavelength at 527 nm which is shifted to a shorter wavelength compared to example Y1.
Examples Y4 and Y5
Examples Y4 and Y5 were made with nominal compositions (Y 0.98 Ce 0.02 ) 3 (Al 0.7 Sc 0.3 ) 5 O 12 and (Y 0.995 Ce 0.005 ) 3 (Al 0.7 Sc 0.3 ) 5 O 12 respectively. Discs were made again by dry pressing mixed oxide powders and sintering at 1850° C., 1860° C. and 1880° C. The resulting sintered ceramics were translucent with Y4 having a yellow color and Y5 a green-yellow color.
Example Y6
Example Y6 was made with a nominal composition (Y 0.998 Ce 0.002 ) 3 (Al 0.7 Sc 0.3 ) 5 O 12 . Oxide powders were mixed with DI water, polymer binders, and ball milled for an extended time. The ball-milled slurry was then dried and ground into a powder. Discs were made by isopressing under 30 k Psi. Using ball milling allows for the oxides to be mixed more homogenously and reduces agglomerates. The isopressed discs were sintered at 1850, 1860 and 1880° C. under wet H 2 . Near fully transparent samples were obtained.
Example Y7
Example Y7 was made with a nominal composition (Y 0.998 Ce 0.002 ) 3 (Al 0.9 Sc 0.1 ) 5 O 12 . The oxide powders were mixed by ball milling as with Example Y6. The pressed discs were sintered at 1850 and 1880° C. The resulting sintered discs were opaque.
Examples Y8 and Y9
Examples Y8 and Y9 were made to have nominal compositions (Y 0.998 Ce 0.002 ) 3 (Al 0.75 Sc 0.25 ) 5 O 12 and (Y 0.998 Ce 0.002 ) 3 (Al 0.6 Sc 0.4 ) 5 O 12 respectively. The oxide powders were mixed by ball milling as in Example Y6. The isopressed discs were sintered at 1860 and 1880° C. Both compositions were found to capable of being sintered to near transparency.
Table 2 lists the CIE 1931 color coordinates (Cx,Cy), dominate wavelength (Ldom), peak wavelength (Lpeak), centroid wavelength (Lcentroid) and full width at half maximum (FWHM) of the blue-light-excited emissions for the above examples, except for Y2 which did not exhibit an emission. The C x color coordinates ranged from about 0.35 to about 0.44 and the C y color coordinates ranged from about 0.55 to about 0.58.
For the first group, examples Y7, Y1, Y8, Y6, Y9 and Y3, the emission peak shifts towards the green region of the visible spectrum (shorter wavelengths) as the percentage of Sc concentration increases. This behavior is very similar to increasing the level of Ga substitution for Al in (Y 1-x Ce x ) 3 (Al 1-y Ga y ) 5 O 12 suggesting that Sc may have a similar structural role as Ga in the ceramics.
TABLE 2
Cx
Cy
Ldom/nm
Lpeak/nm
Lcentroid/nm
FWHM/nm
Y7
(Y 0.998 Ce 0.002 ) 3 (Al 0.9 Sc 0.1 ) 5 O 12
0.4168
0.5599
567.0
551
572.5
113.0
Y1
(Y 0.995 Ce 0.005 ) 3 (Al 0.8 Sc 0.2 ) 5 O 12
0.3983
0.5671
564.5
533
567.5
108.3
Y8
(Y 0.998 Ce 0.002 ) 3 (Al 0.75 Sc 0.25 ) 5 O 12
0.3792
0.5673
562.0
530
562.5
108.2
Y6
(Y 0.998 Ce 0.002 ) 3 (Al 0.7 Sc 0.3 ) 5 O 12
0.3762
0.5673
561.6
528
561.6
108.9
Y9
(Y 0.998 Ce 0.002 ) 3 (Al 0.6 Sc 0.4 ) 5 O 12
0.3755
0.5746
561.3
537
560.7
107.9
Y3
(Y 0.995 Ce 0.005 ) 3 (Al 0.4 Sc 0.6 ) 5 O 12
0.3579
0.5601
559.0
527
555.0
112.2
Cx
Cy
Ldom
Lpeak
Lcentroid
FWHM
Y6
(Y 0.998 Ce 0.002 ) 3 (Al 0.7 Sc 0.3 ) 5 O 12
0.3762
0.5673
561.6
528
561.6
108.9
Y5
(Y 0.995 Ce 0.005 ) 3 (Al 0.7 Sc 0.3 ) 5 O 12
0.383
0.567
562.6
535
563.7
112
Y4
(Y 0.98 Ce 0.02 ) 3 (Al 0.7 Sc 0.3 ) 5 O 12
0.4323
0.5504
569.0
556
580.9
107
FIGS. 4 and 5 show emission spectra of examples Y1, and Y3-Y9. With regard to FIG. 5 (examples Y6, Y5 and Y4), it can be seen that as the Ce concentration increases (x=0.002, 0.005 and 0.02 for Y6, Y5 and Y4 respectively) the emission peak shifts towards the yellow region of the visible spectrum (longer wavelengths). This is also very similar to the YAG:Ce phosphor, in which the emission peak also shifts to yellow as Ce concentration increases.
FIG. 6 compares the efficiency (Lm/W o-B ) as a function of the C x color coordinate of the (Y 1-x Ce x ) 3 (Al 1-y Sc y ) 5 O 12 phosphors according to this invention with conventional (Y 1-x Ce x ) 3 (Al 1-y Ga y ) 5 O 12 phosphors. The efficiency measure, Lm/W o-B , is the ratio of lumens from a white pc-LED (blue-emitting LED die plus yellow-emitting phosphor) to the optical power from the same blue-emitting LED die without the yellow phosphor. This normalizes the performance of blue-emitting LED die and takes into account the human eye's visual sensitivity for different wavelengths. Consequently this measure yields a better indication of the real performance of the phosphor. However, it should also be noted that the efficiency is also related to the scattering in the phosphor. Nonetheless it may still be used to show in general that the (Y 1-x Ce x ) 3 (Al 1-y Sc y ) 5 O 12 phosphor has a similar or better efficiency as compared to the Y(AGa)G:Ce. The measured quantum efficiencies for Y3, Y6, Y7 and Y9 were 90%, 98%, 92% and 97%, respectively.
A new phosphor has been demonstrated that can convert blue light emitted by an InGaN LED into to green or yellow light that can be used for white pc-LEDs or full-conversion green pc-LEDs. The phosphor of this invention can be used in a powder or bulk ceramic form. Preferably the phosphor has been sintered to form a translucent ceramic piece that is mounted to the blue-emitting LED die to generate a white light. For full-conversion, green pc-LEDs, the phosphor is preferably sintered to a near transparent ceramic. The phosphor may also be used in a converter element that is remote from the blue-emitting LED. For example, embedded in a polymer film which is placed at a distance from the LED or an array of LEDs or formed as a dome which is placed over individual or multiple LEDs.
While there have been shown and described what are at present considered to be the preferred embodiments of the invention, it will be apparent to those skilled in the art that various changes and modifications can be made herein without departing from the scope of the invention as defined by the appended claims.
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There is herein described a phosphor for use in LED applications and particularly in phosphor-conversion LEDs (pc-LEDs). The phosphor has a composition represented by (Y 1-x Ce x ) 3 (Al 1-y Sc y ) 5 O 12 wherein 0<x≦0.04 and 0<y≦0.6 and can be as applied to an LED as a transparent sintered ceramic or used in a powder form. By adjusting the composition of the phosphor, the phosphor can be made to emit light in the green to yellow regions of the visible spectrum upon excitation by a blue-emitting InGaN LED.
| 2 |
FIELD OF THE INVENTION
[0001] This invention relates to an efficient process for synthesizing a CETP inhibitor and key chemical intermediates in the process. The product of the process is the CETP inhibitor anacetrapib, which raises HDL-cholesterol and lowers LDL-cholesterol in human patients, and may have utility in treating, preventing, or delaying the onset of atherosclerosis or slowing its progression.
BACKGROUND OF THE INVENTION
[0002] Atherosclerosis and its clinical consequences, coronary heart disease (CHD), stroke and peripheral vascular disease, represent an enormous burden on the health care systems of the industrialized world. In the United States alone, greater than one half million deaths are attributed to CHD each year. This toll is expected to grow as the average age of the population increases and as an epidemic in obesity and diabetes continues to grow.
[0003] Inhibition of CETP is a promising but unproven approach to reducing the incidence of atherosclerosis. Statins have reduced the incidence of CHD by reducing LDL-cholesterol (the “bad cholesterol”), but are relatively ineffective at raising HDL-cholesterol (“the good cholesterol”). CETP inhibitors raise HDL-cholesterol, and may provide a potent new tool for reducing CHD and atherosclerosis in the general population. Torcetrapib was the first CETP inhibitor to be tested in human patients. The pivotal clinical trial of torcetrapib, an outcomes study, was terminated early because of higher mortality in the test group of patients who were taking the drug concomitantly with a statin compared with a group of patients who were taking a placebo and a statin. Subsequent research has suggested that the higher mortality in the test group was caused by off-target activity and was not related to CETP inhibition. Two newer drugs, anacetrapib and dalcetrapib, have also been in Phase III outcomes trials. The dalcetrapib trial was terminated early because an interim review found that there was no clinical benefit to the patients who were taking dalcetrapib, but that there were also no safety issues with the drug. Anacetrapib is currently being studied in an outcomes trial which will not be completed until about 2017. Data from an earlier non-outcomes trial of anacetrapib indicated that anacetrapib is unlikely to have the same kinds of safety issues that were observed with torcetrapib.
[0004] A process for making anacetrapib was previously disclosed in a published patent application (WO 2007/005572).
SUMMARY OF THE INVENTION
[0005] An improved process is provided herein for manufacturing anacetrapib and key intermediates in its manufacture. Anacetrapib is shown below as the compound having Formula I:
[0000]
[0006] The final step in both processes is the alkylation reaction of an oxazolidinone compound of formula III wherein Ar is 3,5-bis(trifluoromethyl)phenyl with the biaryl chloride of Formula II yielding anacetrapib. The final step described herein uses a milder base than was used in WO 2007/005572.
[0000]
[0007] The process disclosed herein provides a more streamlined and economical process for making anacetrapib and the intermediate biaryl compound of formula II than was disclosed in WO 2007/005572. The process is more environmentally friendly (“greener”) than the process that was disclosed in WO 2007/005572 for making anacetrapib. The process described herein is more efficient in terms of energy use, reduction of solid waste products, control of impurities, higher chemical yields, and the reduced use of corrosive reagents. This process also eliminates a difficult step that requires cryogenic conditions. Finally, the mild alkylation conditions disclosed for the last step minimize or eliminate epimerization at the stereogenic centers which are present in the oxazolidinone compound (III), thereby leading to improved yields and purer products.
DETAILED DESCRIPTION OF THE INVENTION
[0008] A schematic description of the process is shown in the Scheme below:
[0000]
*Catalysts for Coupling Reaction
[0009]
[0010] The final step in the process for making compound I is the alkylation of oxazolidinone III with biaryl chloride II in the presence of a phase transfer catalyst, a base, and a solvent suitable for phase transfer catalysis.
[0011] The phase-transfer catalyst used in the alkylation reaction may be a tetraalkylammonium halide, a crown ether, or a quaternary phosphonium halide, where the halides are chloride, bromide, or iodide, wherein the 4 groups attached to the P in the quaternary phosphonium halides can be alkyl, aryl, or mixtures thereof, and wherein the alkyl groups in the ammonium and phosphonium halides can be C 1 -C 20 , but preferably are C 1 -C 4 . Examples of phase transfer catalysts as described above include, but are not limited to, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetramethylammonium chloride, tetramethylammonium iodide, tetraethylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide, Aliquat 336, alkyltrimethyl ammonium bromide, 18-crown-6, 15-crown-5, dibenzo-18-crown-6, tetraphenylphosphonium bromide, tri-tert-butylphosphonium tetrafluoroborate, (ethyl)triphenylphosphonium bromide, and tetrabutylphosponium bromide. Other phase-transfer catalysts that do not fall within the description above, such as bis(triphenylphophoranylidene)ammonium chloride, may also be suitable for this reaction. Preferred catalysts are lower tetraalkylammonium halides (C 1 -C 4 alkyl), such as tetrabutylammonium halides, tetraalkyl ammonium iodides such as tetramethyl ammonium iodide, and preferably tetrabutyl ammonium iodide.
[0012] The base used in the alkylation step is generally a carbonate, phosphate, or hydroxide of an alkali metal, including alkali metal hydrogen carbonates, hydrogen phosphates, and dihydrogen phosphates. These include, but are not limited to, K 2 CO 3 , Na 2 CO 3 , Cs 2 CO 3 , K 3 PO 4 , K 2 HPO 4 , KOH, and NaOH. Typically, excess base is used. A large excess of base is not generally required in the process disclosed herein. About 1-4 equivalents of base relative to the biaryl chloride reactant is generally sufficient. In many embodiments, the amount of base is about 1-3 equivalents, and in preferred embodiments about 2 equivalents. In the process disclosed in WO 2007/005572, the bases that were used are very strong bases, such as sodium hexamethydisilazide (NaHMDS), resulting in some epimerization at the stereogenic centers. The amount of epimerization with NaHMDS is less than 2% using the procedure of WO2007/005572, but the amount of epimerization is very sensitive to small variations in the amount of base. The bases described above for use with the phase transfer catalysts are mild compared with NaHMDS. The amount of epimerization is less than 1% or is non-detectable for the reactions carried out with the phase transfer catalysts and the bases described above.
[0013] Typical solvents that may be used in the alkylation reaction include, but are not limited to, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), acetonitrile, N,N-dimethylacetamide (DMAC), 1,3-dimethyl-2-imidazolidinone (DMI), N-methyl-2-pyrrolidone (NMP), sulfolane, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, and combinations thereof. Preferred solvents include DMF, acetonitrile, and DMSO. DMF is a highly preferred solvent. Acetonitrile is a highly preferred solvent. DMSO is a highly preferred solvent.
[0014] The temperature of the alkylation reaction is between about 50 and 100° C., preferably between about 50 and 80° C., and is about 60° C. in preferred embodiments.
[0015] The first three steps of the process were designed to eliminate or greatly reduce the amount of the impurity shown below (the “ethyl impurity”), which is difficult to remove and generates additional impurities by reacting in subsequent steps of the process:
[0000]
[0000] While not being bound by a particular reaction mechanism, it is believed that the “ethyl impurity” could be produced by hydrogenation of a byproduct that occurs during the first step of the process (the Grignard reaction) under the hydrogenation conditions of the previously published process. Based on NMR data, the impurity is believed to be the hemiketal shown below:
[0000]
[0000] In the process described herein, the Pd catalyst, which is “poisoned” with diphenylsulfide, is believed to be less active and more selective in its activity so that it produces little or no ethyl impurity during the hydrogenation step. The acetophenone that is the starting material in the process is produced as a byproduct during the hydrogenation step using the poisoned Pd catalyst. Since the acetophenone impurity is not brominated under the conditions of the bromination step of this process, it is removed unchanged during subsequent steps of the process using the purification procedures that are already in place. The process steps described above reduce the amount of “ethyl impurity” so that there is little or no ethyl impurity in the product after step (2), which means that the ethyl impurity is at a level comparable to or less than what is attained with the corresponding process steps in WO 2007/005572 but without having to use the cerium salt that is used in WO 2007/005572.
[0016] The possible explanation above of why the amount of the ethyl impurity is diminished by the sequence of the two process steps and the structure of the proposed intermediate are believed to be correct and are provided for informational purposes only. The applicants do not wish to be bound to the accuracy of the explanation or the identity of the proposed intermediate.
[0017] In summary, the first two steps of the overall process are (1) the reaction of MeMgCl with the acetophenone starting material in the absence of a transition metal or lanthanide metal salt, such as CeCl 3 , to yield a benzyl alcohol; and (2) the subsequent hydrogenation of the benzyl alcohol product using a palladium catalyst together with an organic sulfide to yield 2-fluoro-1-isopropyl-4-methoxybenzene which contains little or no ethyl impurity. In preferred embodiments, the organic sulfide is diphenyl sulfide. In preferred embodiments, the solvent for the first step is THF. In preferred embodiments, THF is the only solvent for the first step.
[0000] Definitions The technical terms and abbreviations used throughout this application, in the Scheme, and in the examples, are generally well known to chemists who work in the area of organic chemistry in general and particularly process chemistry. Many of the terms and abbreviations are defined below, but other terms and abbreviations that may not have been defined herein are readily found and defined on internet search engines, such as Google.
[0018] “DIPEA” is diisopropylethylamine.
[0019] “DMF” is N,N-dimethyformamide.
[0020] “DMAC” is N,N-dimethylacetamide.
[0021] “DMI” is 1,3-Dimethyl-2-imidazolidinone
[0022] “DMSO” is dimethylsulfoxide.
[0023] “Halogen” includes fluorine, chlorine, bromine and iodine.
[0024] “IPAC” is isopropyl acetate.
[0025] “IPA” is isopropyl alcohol.
[0026] “iPr” is isopropyl.
[0027] “Me” represents methyl.
[0028] “MeCN” is acetonitrile.
[0029] “(4-MeOC 6 H 4 ) 3 P” is tris(4-methoxyphenyl) phosphine.
[0030] “NaHMDS” is sodium hexamethydisilazide.
[0031] “NMP” is N-methylpyrrolidone.
[0032] “PCy 3 is tricyclohexyl phosphine.
[0033] Solka-Floc® is a commercial powdered cellulose which can be a filter aid.
[0034] “TBAI” is tetrabutylammonium iodide.
[0035] “THF” is tetrahydrofuran.
[0036] “TFA” is trifluoroacetic acid.
[0037] “TMEDA” is tetramethylethylenediamine.
[0000] Step 1. 2-(2-Fluoro-4-methoxyphenyl)propan-2-ol
[0000]
[0038] A solution of 2-fluoro-4-methoxyacetophenone (78.1 g, 460 mmol) in tetrahydrofuran (58.6 ml) was added to 3M methylmagnesium chloride solution in THF (199 ml, 598 mmol) at 20 to 35° C. under a nitrogen atmosphere over 30 min without cooling. Additional THF (19.53 ml) was used to rinse all starting material into the vessel. After complete addition, the mixture was stirred at 30° C. for 10 min., then was quenched into acetic acid (52.6 ml, 920 mmol) and water (273 ml) at 5-25° C. THF (20 ml) was used to rinse the vessel. Heptane (156 ml) was then added. The biphasic mixture was stirred at 20-25° C. for 30 min, and then the organic layer was separated. The organic layer was assayed and was found to contain 83.0 g of the desired product, which corresponds to 98% yield. The organic layer was concentrated under vacuum to remove THF, then was flushed with IPAC (200 ml), and the volume was increased to 500 ml by addition of more IPAC. This was used directly in the next step.
[0000] Step 2. 2-Fluoro-1-isopropyl-4-methoxybenzene
[0000]
[0039] The solution of 2-(2-fluoro-4-methoxyphenyl)propan-2-ol in IPAC (500 ml, 451 mmol) and diphenyl sulfide (0.151 ml, 0.901 mmol) were combined in a hydrogenation shaker. The reaction mixture was purged with nitrogen/vacuum cycles, and 5% palladium on carbon (7.67 g, 1.802 mmol) was added, followed by TFA (17.36 ml, 225 mmol). Hydrogenation was conducted at 60° C. under 50 psig pressures for 12 h. The catalyst was removed by filtration through a 1 inch plug of Solka-Floc® powdered cellulose and rinsed with IPAC (49.8 ml). The filtrate was assayed and was found to contain 76 g of the desired product, which corresponds to a quantitative yield.
[0000] Step 3. 2-Bromo-4-isopropyl-5-fluoroanisole
[0000]
[0040] The crude 3-fluoro-4-isopropylanisole solution from the previous step (100 ml, 0.82 M, 82 mmol) was stirred at 20° C. in the dark. Aqueous 48 wt % HBr (16.6 g, 98.5 mmol) and aqueous 35 wt % hydrogen peroxide (14.0 g, 144 mmol) were added concomitantly over 40 min. The reaction mixture was maintained at 25-30° C. during the addition. The mixture was stirred at 30° C. for 3 h and then was cooled to 5° C. Sodium sulfite (4.2 g) was added in portions over 30 min while maintaining the quench temperature at <20° C. The aqueous layer was removed, and the organic layer was washed with 2 M KHCO 3 (20 ml), concentrated, and flushed with heptane (50 ml) at 30-40° C. under reduced pressure to afford 2-bromo-4-isopropyl-5-fluoroanisole as a pale yellow liquid in 98% yield.
[0000] Step 4a. 4-Fluoro-5-isopropyl-2-methoxyphenylboronic acid
[0000]
[0041] A mixture of 2-bromo-4-isopropyl-5-fluoroanisole (85.4 wt %, 8.71 g, 30.1 mmol) and TMEDA (6.1 ml, 40.6 mmol) was placed in an oven-dried 100 ml 3 necked flask equipped with a magnetic stirrer and reflux condenser. The mixture was placed under an inert atmosphere by applying a vacuum/nitrogen cycle three times, and then i-PrMgCl.LiCl in THF (1.07 M, 38.0 ml, 40.6 mmol) was added slowly. The resulting brownish grey solution was warmed to 40° C. and was aged at that temperature for 3 hours, after which it was cooled to room temperature.
[0042] In a separate oven-dried 250 ml, 3 necked flask equipped with a mechanical stirrer was placed isopropyl borate (11.2 ml, 48.2 mmol) solution in heptane (22 ml), and the mixture was cooled to −20° C. To this was added the Grignard solution, while maintaining the internal temperature at or below −20° C. over 30 min. After the addition was complete, the mixture was aged 30 min at −20° C., then 3 M H 2 SO 4 (45 ml) was added, allowing the internal temperature to rise to ca. 20° C.
[0043] The resulting biphasic mixture was transferred to a separatory funnel with the aid of THF/heptane (1/1, 7 ml), and the aqueous layer was removed. The organic layer was extracted with 2 M KOH (30 ml) followed by 2 M KOH (15 ml). The combined KOH extracts were transferred to a 250 ml 3-necked flask equipped with a mechanical stirrer with the aid of IPA (8ml). The clear, pale yellow solution was cooled to 10° C., and 3 M H 2 SO 4 (15 ml) was added slowly over 30 min. The resulting thick slurry was aged for an hour at 10° C., then was filtered to collect the solid. The solid was washed with water (45 ml), 5% NaHCO 3 (45 ml), and finally with water (90 ml). The white crystalline solid thus obtained was dried under vacuum with a nitrogen sweep overnight to afford 5.57 g, 98.26 wt % (Yield=86%, corrected for purity).
[0000] Step 4b. 4-Fluoro-5-isopropyl-2-methoxyphenylboronic acid
[0044] A solution of 2-bromo-4-isopropyl-5-fluoroanisole (88 wt % in toluene, 10.44 g, 37.2 mmol) in anhydrous toluene was cooled to −10° C. under N 2 atmosphere, and 2.5 M, n-butyllithium solution in hexanes (16.36 ml, 40.69 mmol) was added slowly. After stirring at the same temperature for 10 minutes, the resulting solution was transferred to a cooled solution of triisopropyl borate (14.53 ml, 61.3 mmol) and TMEDA (2.80 ml, 18.59 mmol) in toluene slowly at −20° C. After stirring for 30 minutes, the reaction mixture was quenched with 3M H 2 SO 4 (45 ml), and the resulting mixture was worked up as described in Step 4a to provide the title compound in 83% yield (6.62 g, 98.5 wt %).
[0000] Step 5a. Palladium Catalyzed Suzuki Coupling—AllylPdCl Dimer Catalyst
[0000]
[0045] In a 250 ml flask equipped with a reflux condenser was placed 2-chloro-5-(trifluoromethyl)benzyl alcohol (10 g; 47.5 mmol), 4-fluoro-5-isopropyl-2-methoxyphenylboronic acid (10.81 g; 95 wt % purity, 48.4 mmol), acetonitrile (80 ml) and 3 M K 2 CO 3 (42.7 ml, 128 mmol). The resulting biphasic solution was sparged with nitrogen for several minutes. [AllylPdCl] 2 (0.043 g, 0.119 mmol) and PCy 3 .HBF 4 (0.087 g, 0.237 mmol) were added under nitrogen flow, and the reaction mixture was warmed to 70° C. until HPLC showed the reaction was complete.
[0046] The reaction mixture was then cooled to room temperature and the phases were separated. The organic layer was washed with 10% NaCl solution (50 ml). After phase separation, Darco® KB-G activated carbon (2.0 g) was added to the organic layer, and the mixture was stirred for 1 hr at room temperature. The mixture was then filtered through a pad of Solka-Floc®. The filtrate was assayed and was found to contain 15.5 g of product (95% yield). The filtrate was azeotropically dried with acetonitrile and concentrated to an oil under vacuum. The crude product was used in the next step without further treatment.
[0000] Step 5b. Palladium Catalyzed Suzuki Coupling—Aminobiphenyl-PCy 3 Precatalyst
[0047] In a 50 ml flask equipped with a reflux condenser was placed 3 M K 2 CO 3 (12.82 ml, 38.5 mmol), 4-fluoro-5-isopropyl-2-methoxyphenylboronic acid (3.24 g, 95 wt %, 14.53 mmol), 2-chloro-5-(trifluoromethyl)benzyl alcohol (3 g, 14.25 mmol), isopropyl alcohol (9 ml) and IPAC (9 ml). The resulting biphasic solution was sparged with nitrogen for approximately 45 min after which the (2′-aminobiphenyl-2-yl)palladium(II) chloride-tricyclohexyl phosphine precatalyst (0.042 g, 0.071 mmol) was charged under positive nitrogen flow. The reaction was then aged at 75° C. for approximately 3 hours or until the reaction was complete. The reaction mixture was then cooled to room temperature, diluted with isopropyl acetate, and the layers were separated. The organic layer was assayed and found to contain 4.78 g of the desired coupling product, which corresponds to 98% yield. The resulting organic layer was washed with water. To the organic layer was added Darco® KB-BG (0.75 g), and the mixture was stirred at room temperature for 1 hour, after which it was filtered through Solka-Floc®. The filtrate was concentrated and used without further purification in the next (chlorination) step.
[0000] Step 5c. Nickel Catalyzed Suzuki Coupling
[0000]
[0048] A mixture of nickel bromide (10.3 mg, 0.047 mmol) and tris(4-methoxyphenyl) phosphine (33 mg, 0.094 mmol) was placed in an 8 ml vial, and toluene was added (1 ml). The resulting slurry was stirred under nitrogen in a glovebox for 2.5 hours. The resulting dark green mixture was transferred to a mixture of 2-chloro-5-(trifluoromethyl)benzaldehyde (1.0 g, 4.7 mmol), 4-fluoro-5-isopropyl-2-methoxyphenylboronic acid (1.07 g, 4.8 mmol), potassium phosphate (1.6 g, 7.5 mmol), and toluene (9 ml). The resulting mixture was stirred at 80° C. for 15 hours, and was then cooled to room temperature. To this was added sodium borohydride (0.18 g, 4.7 mmol) and methanol (2 ml). After the reaction was complete as judged by HPLC analysis, the reaction mixture was acidified by adding hydrochloric acid. The organic layer was assayed and was found to contain 1.33 g of the desired product, which corresponded to an 83% yield.
[0000] Step 6. 2′-(Chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl
[0000]
[0049] A mixture of biaryl alcohol (5.23 g, 15.28 mmol) and DMF (26.2 ml) was cooled to <10° C., and thionyl chloride (1.45 ml, 19.86 mmol) was added slowly over 1 hour. The resulting reaction mixture was aged at 10-15° C. until the reaction was completed. To the mixture was added water (5.23 ml), and the resulting slurry was stirred for an hour at 10° C. Additional water (5.23 ml) was added slowly over 1 hour at 10° C., and the slurry was allowed to warm to room temperature. The solid was collected by filtration, washed with 1:1 DMF:water solution (26 ml) followed by water (52 ml), and dried under vacuum to afford 5.36 g of solids; 99.6 wt % (5.33 g corrected for purity; 96.8%).
[0000] Step 7. (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)methyl)-4-methyloxazolidin-2-one (anacetrapib)
[0000]
[0050] Oxazolidinone III (9.58 g, 30.6 mmol), biaryl chloride II (10.83 g, 30.0 mmol), tetrabutylammonium iodide (0.02 molar equivalents, based on the amount of biaryl chloride), K 2 CO 3 (2 equivalents), and DMF (12 mL) were charged to a 100 mL flask, and the resulting slurry was stirred at 60° C. for 17 hours. Then n-heptane and water were added at the same temperature. The aqueous layer was removed, and the organic layer was washed with water. The product was crystallized by cooling the organic mixture. Isolated crystals were washed with heptane and dried to afford 17.60 g of the titled compound (27.6 mmol, 92%).
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An efficient process is disclosed for producing the compound of formula I, which is the CETP inhibitor anacetrapib, which raises HDL-cholesterol and reduces LDL-cholesterol in human patients and may be effective for treating or reducing the risk of developing atherosclerosis:
| 2 |
This application is a continuation of application Ser. No. 702,732, filed Feb. 19, 1985, now abandoned.
CROSS-REFERENCE TO RELATED APPLICATION
Our copending application, Ser. No. 702,733, U.S. Pat. No. 4,588,532,filed concurrently herewith and assigned to the assignee hereof.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the preparation of para-acyloxybenzene sulfonates, and, more especially, to the preparation of para-acyloxybenzene sulfonates by basic catalysis, and wherein the acyloxy moiety of such sulfonates contains from 7 to 12 carbon atoms.
2. Description of the Prior Art
It is known to this art, from French Pat. No. 2,164,619, Example 1, to prepare the title compounds from an aliphatic acid chloride and potassium phenol sulfonate by direct condensation in an anhydrous reaction medium. The speed of condensation between the acid chloride and the phenol sulfonate is extremely slow (20 hours at 150° C.) and the product formed is very difficult to isolate. A large amount of HCl also forms in the process and is not always easy to eliminate.
It is also known [see Pueschel, Tenside, 7 (5), pp. 249-54 (1970)] to prepare these compounds by a method which differs slightly from that of French Pat. No. 2,164,619, but in the presence of an acid acceptor to avoid the elimination of gaseous hydrochloric acid. The product formed is neutralized by sodium carbonate, but as a result it is very difficult to separate the product obtained from the sodium chloride formed during neutralization.
The slowness of the reaction in which the acid chloride is condensed with the phenol sulfonate has prompted those skilled in this art to raise the reaction temperature considerably, but strongly colored products are then formed. Since such products are in fact principally used in detergency, however, it is necessary to produce perfectly white materials in order to meet commercial requirements.
It too is known, from French Pat. No. 2,299,321, to prepare para-acyloxybenzene sulfonates by condensing a powdered phenol sulfonate with acetic anhydride in vapor state; the reaction can be carried out dry, for acetic anhydride has a boiling point of 140° C., but it is not possible to proceed in this fashion as a means for condensing, e.g., nonanoic anhydride, with phenol sulfonate, since nonanoic anhydride has a boiling point of 260° C.
Nonetheless, it was hitherto unknown to condense an acid anhydride with a phenol sulfonate in a liquid reaction medium.
SUMMARY OF THE INVENTION
Accordingly, a major object of the present invention is the provision of an improved process for the preparation of para-acyloxybenzene sulfonates which is both quick and easy, is carried out in a liquid reaction medium, gives rise to the production of an easily separated reaction product in completely colorless state, and which otherwise avoids those disadvantages and drawbacks to date characterizing the state of this art.
Briefly, the present invention features the preparation of para-acyloxybenzene sulfonates having the general formula (I): ##STR1## wherein R 1 is a straight or branched chain aliphatic radical containing from 6 to 11 carbon atoms, R 2 is hydrogen, halogen, an alkyl radical having from 1 to 4 carbon atoms or the radical --SO 3 M, and M is an alkali or alkaline earth metal or an ammonium group, by acylating an alkali or alkaline earth metal or ammonium phenol sulfonate with an anhydride of a straight or branched chain carboxylic acid containing from 7 to 12 carbon atoms, in a polar aprotic solvent and in the presence of a catalytically effective amount of an alkali or alkaline earth metal salt of a straight or branched chain aliphatic carboxylic acid having from 7 to 12 carbon atoms.
DETAILED DESCRIPTION OF THE INVENTION
More particularly according to the present invention, exemplary reactant aliphatic anhydrides include heptanoic, octanoic, caprylic, nonanoic, pelargonic, decanoic, capric, dodecanoic, and lauric anhydrides. Preferably employed are the anhydrides of those carboxylic acids containing 9 carbon atoms. More preferred are pelargonic anhydride and 3,5,5-trimethylhexanoic anhydride, since these materials are readily commercially available.
The reactant acid anhydrides may be prepared in known manner by any one of a number of processes. In a first embodiment, described in Collective Organic Syntheses, 3, p. 28, John Wiley (1955), the acid chloride is contacted with the acid and a tertiary base, which will neutralize the acid formed. This gives the required anhydride and a hydrochloride with a tertiary base. In a second embodiment, described in Journal of Chemical Society, p. 755 (1964), the acid chloride and the sodium salt of the acid are contacted in water. This gives the required anhydride and sodium chloride. Since the reaction is carried out in water, the anhydride formed need not be easily hydrolyzable.
In a third embodiment, acetic anhydride is reacted with the acid according to the following mechanism: ##STR2##
It is preferred to carry out this particular reaction in the presence of an excess of acetic anhydride, which is distilled upon completion of the reaction.
Consistent herewith, it is preferred to use an acid anhydride which has been obtained in accordance with the aforesaid third embodiment.
As regards the various phenol sulfonates, it is preferred to use those in which R 2 is hydrogen, and more preferably the phenol sulfonate of sodium or potassium, since these compounds are the most readily commercially available.
Representative of the polar aprotic solvents intended, the following are exemplary:
(i) dimethylformamide;
(ii) N-methylpyrrolidone;
(iii) dimethylacetamide;
(iv) dimethylsulfoxide; and
(v) sulfolane
The solvent should nevertheless be odorless, for it is commercially impossible to incorporate a malodorous substance in a detergent. The boiling point of the solvent must not be too high, and its manufacturing cost must be low enough not to impose an unnecessary increase in the cost of the product to be obtained. From among all of the solvents intended, dimethylformamide is the preferred as it best conforms to the aforesaid conditions.
The alkali or alkaline earth metal salt of a carboxylic acid having from 7 to 12 carbon atoms, and which is used as the catalyst for the condensation reaction, has the following general formula (II):
R.sub.3 COOM (II)
wherein M is an alkali or alkaline earth metal, and R 3 is a straight or branched chain alkyl radical having from 6 to 11 carbon atoms. It is preferred to use the sodium salt of the same acid as that used to form the anhydride, since this avoids incorporating any chemical reagent foreign to those of the reaction.
To obtain a proper reaction speed it is preferable to use a molar excess of the anhydride relative to the phenol sulfonate. For a proper economic yield it is still more preferable to add an excess of anhydride of at least 0.2 mole and preferably from 0.2 to 0.3 mole relative to the stoichiometry of the reaction.
The molar ratio of solvent to phenol sulfonate preferably ranges from 5 to 50. A larger amount is not outside of the scope of the invention, but such amounts will have to be adapted to the economics of the process. The molar ratio more preferably ranges from 5 to 10 and still more preferably from 7 to 10.
The molar ratio of the compound (II) to the phenol sulfonate preferably is in excess of about 0.005 and more preferably ranges from 0.01 to 0.02.
The reaction temperature influences the speed of reaction; accordingly, a temperature in excess of 80° C. is advantageous. However, higher temperatures are not deleterious to the process of the invention. All that is necessary is to adapt the temperature to the economics of the process. The preferred reaction temperature thus ranges from 90° to 100° C.
The reaction is typically carried out at atmospheric pressure, although a higher pressure is also not deleterious to the process of the invention.
The final products according to the invention may facilely be extracted from the reaction medium by salting them out with acetone, at a temperature of 90° C. or above, and preferably from 90° to 100° C., by adding approximately the same weight of acetone as that of solvent introduced.
The title para-acyloxybenzene sulfonates are used in detergency applications, notably as surfactants. Especially representative formula (I) compounds are: sodium p-3,5,5-trimethylhexanoyloxybenzene sulfonate, sodium p-octanoylbenzene sulfonate and sodium p-dodecanoyloxybenzene sulfonate.
In order to further illustrate the present invention and the advantages thereof, the following specific examples are given, it being understood that same are intended only as illustrative and in nowise limitative.
EXAMPLE 1
Preparation of the sodium p-3,5,5-trimethylhexanoyloxybenzene sulfonate:
[1] Preparation of 3,5,5-trimethylhexanoic anhydride (TMH anhydride):
A 1000 liter reactor was used, having a distillation column at the top thereof. It was charged with 583 kg of trimethylhexanoic acid (3.69 Kmoles), 282 kg of acetic anhydride (2.76 Kmoles) and 0.1 kg of sodium acetate. The catalyst was selected because it only slightly discolored the TMH anhydride. The reaction medium was brought to 90° C. at a vacuum of 12,000 Pa to allow for distillation of the acetic acid formed; the vacuum was then adjusted as the temperature of the distillation vessel rose. The reaction was complete after 3 hours, at:
T°=110° C.;
Pressure=6,660 Pa
The reaction mixture was adjusted to 160° C. (at 1,300 Pa) to eliminate the excess acetic anhydride.
The very slightly colored 3,5,5-trimethylhexanoic anhydride was not distilled but was used as such:
Weight=550 kg;
Yield=100%
[2]Condensation of TMH anhydride with sodium p-phenol sulfonate:
A 3 m 3 reactor was used, with a small column ascending thereabove. 794 kg (10.9 Kmoles) of dimethylformamide, 301 kg (1.53 Kmoles) of sodium p-phenol sulfonate dried at 160° C. and 2,600 Pa (H 2 O<0.5%) and 3 kg (0.016 Kmole) of sodium isononanoate were charged into the reactor.
The reaction medium was brought to 90° C. and 550 kg (1.84 Kmoles) of TMH anhydride (20% excess) were introduced over one half to three quarters of an hour.
The temperature was maintained for three hours.
794 kg of acetone were added at 90° to 100° C. to salt out the ester which was in solution in the DMF.
The material was cooled to room temperature.
The ester was filtered, under pressure, through a filter having a surface area of 6 m 2 .
The filtered product was washed in acetone and dried at 150° C. and 2,600 Pa.
Weight=500 kg;
Yield=96%
The solutions were distilled and recycled.
EXAMPLE 2
Preparation of sodium p-2-ethylhexanoyloxybenzene sulfonate:
[1]Preparation of 2-ethylhexanoic anhydride:
The 2-ethyl hexanoic anhydride was prepared under the same conditions as in the previous example.
[2] Condensation of 2-ethylhexanoic anhydride with sodium p-phenol sulfonate:
66 g (0.9 mole) of DMF, 25 g (0.127 mole) of dehydrated sodium para-phenol sulfonate and 0.35 g (0.002 mole) of sodium 2-ethylhexanoate were charged into a 250 cm 3 reactor.
The reaction medium was brought to 100° C. and 45 g (0.160 mole), i.e., 25% excess of 2-ethylhexanoic anhydride, were added over 45 minutes.
The reaction was continued for 2 hours, 30 min, at that temperature.
80 g of acetone were then added at a temperature of 100° C.
The reaction product was cooled to room temperature and then filtered.
The ester was washed with acetone and dried at 150° C. and 2600 Pa, to give:
Weight =39 g sodium p-2-ethylhexanoylbenzene sulfonate
Yield=95%
While the invention has been described in terms of various preferred embodiments, the skilled artisan will appreciate that various modifications, substitutions, omissions, and changes may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the present invention be limited solely by the scope of the following claims.
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p-Acyloxybenzene sulfonates, well suited for detergency applications, are facilely and rapidly prepared by acylating an alkali or alkaline earth metal, or ammonium p-phenol sulfonate, with an anhydride of a straight or branched chain carboxylic acid having from 7 to 12 carbon atoms, in a polar aprotic solvent and in the presence of a catalytically effective amount of an alkali or alkaline earth metal salt of a straight or branched chain aliphatic carboxylic acid having from 7 to 12 carbon atoms.
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BACKGROUND OF THE INVENTION
This invention relates to a large lightweight gypsum article which has hitherto been difficult to obtain. The gypsum article, not only is large and lightweight but also has low expansion coefficient and further has improved fire- and water-resistance. More particularly, it relates to a large lightweight gypsum article comprising anhydrous or hemihydrous gypsum, ettringite, reinforcing members, and, if necessary, fibers and/or lightweight aggregate.
DESCRIPTION OF THE PRIOR ART
Heretofore, many problems were encountered in using gypsum (CaSO 4 2 H 2 O) as building material. The gypsum generates heat and expands upon hardening. Thus, if large construction members such as an all-white, thick member (e.g.) 10 cm- or 15 cm- thick), a member having locally irregular and greatly different thicknesses or a member moulded in a rigid moulding box is made of gypsum, problems such as occurrence of fissures and difficulty of release occur. Even if steel members are inserted for reinforcement, problems such as occurrence of rust and insufficiency of adhesion arise, and thus it has been deemed to be very difficult to use reinforcement members for gypsum in the same manner as in the case of reinforced concrete.
SUMMARY OF THE INVENTION
It is therefore a primary object of the present invention to provide a novel gypsum article which is large and lightweight and is free of the faults of prior art gypsum materials.
It has been found through much research that the addition of ettringite (3CaO.Al.sub. 2 O.sub. 3.3CaSO 4 .32 H 2 O) can solve the above problems and enable obtention of a large and lightweight gypsum article which has low expansion coefficient and improved fire- and water-resistance. Thus the present invention relates to a large lightweight gypsum article comprising anhydrous or hemihydrous gypsum, ettringite, reinforcing members, and, if necessary, fibers and/or lightweight aggregate.
The ettringite has a large affinity for gypsum and also has a large amount of water of crystallization, and so expansion coefficient of the article is low and occurrence of fissures in the article at the time of hardening can be prevented.
Furthermore, the presence of ettringite serves to make the blend alkaline, and for this reason the rust prevention treatment of the reinforcement members to be inserted is simplified, and also at the same time serves to secure adhesion of the members. Thus, the reinforcement members act effectively, and that arrangement of reinforcement members in the material has been made possible in turn makes it possible to mould large articles.
It is an additional merit of the present invention that since ettringite is lighter than gypsum, articles can be made lightweight also by the inclusion of ettringite per se.
The ettringite also serves to improve fire resistance of the construction material because it has a large amount of water of crystallization, and it contributes to the waterproofness of the construction material because, unlike gypsum, it does not dissolve in water. Thus, the present invention has many advantages over the prior art.
The present invention also relates to the process for the production of a large lightweight gypsum article, which comprises hardening a material prepared by blending anhydrous or hemihydrous gypsum, ettringite, water and, as occasion demands, fibers and/or lightweight aggregates and arranging reinforcing members in the blend, in a mould.
A large and lightweight gypsum article can thus be produced as simply as in the case of producing mortar or concrete to obtain a hardened article which can be very complicated in shape.
DETAILED DESCRIPTION
As the preferred reinforcing members, may be mentioned such members as steel members treated with a rust preventive or aluminous members. The steel members are particularly steel round bars of 3.2 to 22 mm in diameter treated with a rust preventive.
The fibers may be either inorganic or organic ones. The inorganic fibers are, for example, carbon fibres, aluminous fibres or glass fibers, and the organic fibres, for example, polyamides, polyester, acrylic or polyalkylene or rayon fibers. These inorganic or organic fibers are preferably of 2-25 microns in diameter and 3-25 mm in length.
The lightweight aggregate may be a natural lightweight aggregate, a modified or coated natural lightweight aggregate or an artificial lightweight aggregate. It is, for example, lapilli, volcanic ash and modification thereof or those coated with cement slurry; and expanded shale, clay, perlite or coal ash, preferably of 0.3 - 20 mm in diameter, as available in the market under the name of LECA or MESALITE.
The ettringite to be used in the present invention has a large specific heat value and includes a large amount of water in its crystal, and may be produced by a method in itself known. It can be produced, for example, by admixing water with the blended component materials such as (i) aluminous cement plus gypsum, (ii) lime plus gypsum plus bauxite, (iii) lime plus gypsum plus aluminous red mud, (iv) lime plus gypsum plus aluminous sludge or (v) any other combinations of component materials necessary for the formation of the ettringite illustrated by the following equation:
6CaO + Al.sub.2 O.sub.3 + 3SO.sub.3 + 32H.sub.2 O → 3CaO.Al.sub. 2 O.sub.3.3 CaSO.sub.4.32 H.sub.2 O
the obtained paste-like product may be used directly or after drying it at an elevated temperature such as 400°-600° C for a sufficient period of time, e.g., 30 minutes, into dry powder.
The ettringite ordinarily is used in an amount of about 10-100, preferably 30-70 weight percent of the amount of gypsum.
Additives usually used for gypsum articles, such as a hardening retarder, for example, potassium citrate, citric acid and calcium 2-keto- gluconate; or a dispersant may also be used without impairing the effects of the present invention.
The following are specific embodiments of the present invention, which embodiments are designed to illustrate, but not to limit the scope of the present invention.
EXAMPLE
Hemihydrous gypsum (class B of JIS R-9111; for the mould of ceramic material), ettringite, chopped glass fibres CS06 HB710 (product of Asahi Fibre Glass Co., Ltd. of Japan; about 9 microns in diameter and about 6 mm in length), potassium citrate as hardening retarder, MERMENT L10 (product of Showa Denko K.K., Japan; a liquid additive containing no chlorine and having the effect of dispersing gypsum particles at the hydration thereof) as dispersing agent and water are blended together in such proportions as shown in the following Table 1, and then moulded to obtain samples of the present invention. Their physical properties are as shown in the Table.
Ettringite used in producing the above samples is a paste-like product prepared by blending an aluminous sludge (discharged from the surface treatment of aluminium), gypsum and lime in a proportion of 1:3:3 (when calculated as Al 2 O 3 , CaSO 4 and CaO) in the presence of water.
The sample materials shown in Table 1 in which said ettringite has been incorporated are alkaline and show a pH of 10 - 12, so rust prevention treatment for the steel bars to be inserted is simplified, and at the same time, adhesion of the bars is secured. Table 2 compares the bonding strength between ordinary concrete and steel with that between sample No. 3 of Table 1 and steel.
Table 1______________________________________Sample No. 1 2 3______________________________________Hemi-hydrous 565 675 806 (Kg)gypsumEttringite 351 284 256 (Kg)Fibers 5.7 6.8 8.1 (Kg)Retarder 34 20.3 48.4 (1)Dispersant 28.3 33.8 40.3 (1)Water 487 508 430 (1)Specific 1.07 1.13 1.26gravityBending 48 50 53 (Kg/cm.sup.2)strengthCompression 80 112 174 (Kg/cm.sup.2)strengthExpansion -- -- *0.009 (%)Coefficient(after 24 hrs.)______________________________________ *0.1 - 0.2 % in an ordinary gypsum article
Table 2______________________________________ Ordinary concrete Sample No. 3______________________________________Round steel bar φ 9 mm *19 34.6(with anticorrosive (Kg/cm.sup.2) (Kg/cm.sup.2)paint on)Deformed steel bar **54 48.3D-10 (Kg/cm.sup.2) (Kg/cm.sup.2)(zinc-plated)______________________________________ *in case the compressive strength is 130 Kg/cm.sup.2 **in case the compressive strength is 167 Kg/cm.sup.2?
A large (3.6 m × 2.4 m), sashed wall plate and a large (4.0 m × 1.6 m), beamed roof plate are produced according to the process of the present invention in the manner per se the same as in the case of producing reinforced concrete construction members, but neither fissures nor separation of embedded components occur.
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A large lightweight gypsum article comprising anhydrous or hemihydrous gypsum, ettringite, reinforcing members, and, if necessary, fibers and/or light-weight aggregate.
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This application is a division of application Ser. No. 10/941,404, filed Sep. 15, 2004 now U.S. Pat. No. 7,271,105, now allowed, which is a continuation-in-part of application Ser. No. 10/803,009, filed on Mar. 17, 2004, now U.S. Pat. No. 6,881,677.
FIELD OF THE DISCLOSURE
The disclosure relates to micro-fluid ejection devices. More particularly, the disclosure relates an improved method for making micro-fluid ejection devices in order to increase the yield of usable product.
BACKGROUND
Micro-fluid ejection head such as used in ink jet printers are a key component of ink jet printer devices. The processes used to construct such micro-fluid ejection heads require precise and accurate techniques and measurements on a minute scale. Some steps in the ejection head construction process are necessary but can be damaging to the ejection head. Such damage to the ejection head affects the quality of fluid output, and, therefore, has an affect on the value of the ejection device containing the ejection head.
One example of a technique that can result in such damage to an ejection head is the removal of an etch mask layer from photoresist planarization and protection layer on a semiconductor chip in a given ejection head. Ejection heads include a silicon substrate and a plurality of layers including passivation layers, conductive metal layers, resistive layers, insulative layers, and protective layers on the substrate. Fluid feed holes or fluid supply slots are formed in the substrate and various layers in order for fluid to be transferred through the holes or slots to ejection devices on a substrate surface. Such holes of slots are often formed through the semiconductor chip using deep reactive ion etching (DRIE) or mechanical techniques such as grit blasting. A planarization and protection layer is preferably used to smooth the surface of the semiconductor chip so that a nozzle plate may be attached to the substrate more readily. The planarization layer also functions to protect the components between the planarization layer and the surface of the substrate from corrosion.
Before holes or slots are formed in the semiconductor chip containing a planarization layer, the planarization layer is desirably masked by an etch mask layer. Like the planarization layer, the etch mask layer is typically a photoresist material. In order to complete the hole formation process, the etch mask layer must be removed. However, techniques sufficient to remove the etch mask layer may also strip away portions of the planarization layer that are needed for protection of underlying layers. This undesirable effect results in less protection for the semiconductor chip. If, on the other hand, less aggressive stripping of the etch mask layer is conducted, portions of the semiconductor chip are left with an insoluble residue from the etch mask layer which makes the chips unsuitable for use. There is, therefore, a continuing need for a process that will remove substantially all of the etch mask layer without damaging the underlying planarization and protection layer.
SUMMARY
With regard to the above and other objects the disclosure describes a method of etching a semiconductor substrate. The method includes the steps of applying a photoresist etch mask layer to a device surface of the substrate. A select first area of the photoresist etch mask is masked, imaged and developed. A select second area of the photoresist etch mask layer is irradiated to assist in post etch stripping of the etch mask layer from the select second area. The substrate is etched to form fluid supply slots through a thickness of the substrate. At least the select second area of the etch mask layer is removed from the substrate, whereby mask layer residue formed from the select second area of the etch mask layer is significantly reduced.
In another embodiment there is provided a process of forming one or more fluid feed slots in a semiconductor substrate chip for use in a micro-fluid ejection head. The process includes applying a photoresist planarization layer to a first surface of the chip. The planarization layer has a thickness ranging from about 1 to about 10 microns. The photoresist planarization layer is patterned and developed to define at least one ink feed via location therein and to define contact pad areas for electrical connection to a control device. A photoresist etch mask layer is applied to the photoresist planarization layer on the chip. The photoresist etch mask layer has a thickness ranging from about 10 to about 100 microns. The photoresist etch mask layer patterned and developed with a first photomask to define the at least one fluid supply slot location in the photoresist etch mask layer. Deprotection of the photoresist etch mask layer in a select second area of etch mask layer is induced by exposing the select second area to radiation through a second photomask. The exposure through the second photomask is sufficient to deprotect the photoresist etch mask layer in the select second area so that the photoresist etch mask layer in the select second area can be substantially removed with a solvent without substantially affecting the photoresist planarization layer. The chip is dry etched to form at least one fluid supply slot in the defined at least one fluid supply slot location. Subsequently, the photoresist etch mask layer is removed from the planarization layer.
An advantage of certain embodiments described herein may be that select areas of the photoresist etch mask may be essentially completely removed from the substrate with less aggressive techniques. Also, the planarization layer is left relatively smooth and substantially unaltered after the dry etching process and removal of the photoresist etch mask layer. Unlike conventional techniques used to remove etch mask layers, the exemplary embodiments described herein provide removal of substantially all of the photoresist etch mask layer, leaving essentially no residue on critical components such as electrical bond pads thereby improving product yield.
BRIEF DESCRIPTION OF THE DRAWINGS
Further features and advantages of the embodiments described herein will become apparent by reference to the detailed description when considered in conjunction with the figures, which are not to scale, wherein like reference numbers indicate like elements through the several views, and wherein:
FIG. 1 is a cross-sectional view, not to scale, of a micro-fluid ejection head;
FIGS. 2-8 illustrate steps in a process for forming a micro-fluid ejection head according to one embodiment of the invention;
FIG. 9A is a cross-sectional view, not to scale, of an imaging process for activating select areas of a photoresist etch mask layer using radiation according to an embodiment of the disclosure;
FIG. 9B is a plan view, not to scale, of an etch mask for imaging a photoresist etch mask layer according to the disclosure;
FIG. 10 is a photomicrograph of a contact pad of a substrate containing residue from removal of a photoresist etch mask layer by a prior art method;
FIG. 11 is a photomicrograph of a contact pad of a substrate after removal of a photoresist etch mask layer treated with radiation according to the disclosure;
FIG. 12 is a plan view, not to scale, of a etch mask for imaging a photoresist etch mask layer according to another embodiment of the disclosure;
FIG. 13 is a cross-sectional view, not to scale, of a reactive ion etch process according to the disclosure; and
FIG. 14 is a cross-sectional view, not to scale, of a substrate according to the disclosure after removal of an etch mask layer.
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
In one embodiment, there are provided methods for substantially removing an etch mask layer from a surface of a silicon substrate during a manufacturing process for making a semiconductor silicon chip used in micro-fluid ejection devices, such as ink jet printers. With reference to FIG. 1 , a micro-fluid ejection head 10 for a micro-fluid ejection device such as an ink jet printer includes a semiconductor substrate 12 , preferably made of silicon, having a thickness T. The substrate includes a plurality of fluid ejection devices such as heater resistors 14 on a device surface 16 thereof. The device surface 16 of the substrate 12 also includes various conductive, insulative and protective layers for electrically connecting the heater resistors 14 to a control device for ejecting fluid from the ejection head 10 and for protecting the resistors 14 from corrosion by contact with the fluid.
In order to provide a relatively planar surface for attaching a nozzle plate 18 to the substrate 12 , a planarization layer 20 may be applied to the device surface 16 of the substrate 12 . An exemplary planarization layer 20 is provided by a radiation curable resin composition that may be spin-coated onto the surface 16 of the substrate 12 . A particularly advantageous radiation curable resin composition includes a difunctional epoxy component, a multifunctional epoxy component, a photoinitiator, a silane coupling agent, and a nonphotoreactive solvent, generally as described in U.S. Publication No. 2003/0207209 to Patil et al., the disclosure of which is incorporated by references as if fully set forth herein.
The nozzle plate 18 includes nozzle holes 22 and may include fluid chambers 24 laser ablated therein. In the alternative a thick film layer may be attached directly to the planarization layer 20 and a nozzle plate attached to the thick film layer. In the case of a separate thick film layer, the ink chambers are typically formed in the thick film layer and the nozzle holes are formed in the nozzle plate.
A fluid supply slot 26 is formed through the thickness T of the semiconductor substrate 12 to provide a fluid supply path for flow of fluid to the fluid chambers 24 and heater resistors 14 . The fluid supply slot 26 may be provided by an elongate slot or individual holes through the thickness T of the substrate 12 . Methods for making fluid supply slots 26 are known and include mechanical abrasion, chemical etching, and dry etching techniques. A particularly advantageous method for forming a fluid supply slot 26 is a deep reactive ion etching (DRIE) process, generally as described in U.S. Pat. No. 6,402,301 to Powers et al., the disclosure of which is incorporated by reference as if fully set forth herein. While the fluid supply slot 26 is shown as having substantially vertical walls, the walls of the fluid supply slot 26 are typically slightly tapered so that the fluid supply slot 26 is wider on one end than on the other end.
With reference to FIGS. 2-11 , an exemplary method for making micro-fluid ejection devices according to one embodiment of the disclosure is illustrated. The method includes providing a substrate 12 having a thickness ranging from about 200 to about 800 microns or more. A plurality of layers including insulative, conductive, and resistive materials are deposited on the device surface 16 of the substrate to provide a plurality of heater resistors 14 thereon and electrical tracing to the heater resistors 14 . The substrate 12 may also include driver transistors and control logic for the resistors 14 and contact pads 27 for connecting the heater resistors 14 to a control device as by use of a tape automated bonding (TAB) circuit or flexible circuit connected to the contact pads 27 .
In the next step of the process, shown in FIG. 3 , a planarization layer 20 , as described above, is applied to the surface 16 of the substrate. The planarization layer may have a thickness ranging from about 1 to about 10 microns or more. Since the planarization layer 20 may be spin-coated onto the substrate surface 16 , the layer 20 may be made to completely cover the exposed surface 16 of the substrate 12 including the heater resistors 14 and contact pads 27 as shown. The result after the deposition of the planarization layer 20 is a planarized surface 28 .
Next, with reference to FIG. 4 , the planarization layer 20 is photoimaged to cure selected portions of the layer 20 . The selected portions of the planarization layer 20 may be cured using a radiation source 30 such as ultraviolet (UV) radiation. A mask 32 having radiation blocking areas 31 and 33 is used to shield one or more portions and of the planarization layer 20 from the radiation 30 as illustrated so that the shielded portions of the planarization layer 20 remain uncured. The uncured portions are located in areas that are to be developed and removed from the device surface 16 of the substrate 12 . Accordingly, the planarization layer 20 atop the resistors 14 and contact pads 27 is removed and the device surface 16 of the substrate is exposed in location 34 for the fluid supply slot 26 . The fully cured and developed planarization layer 20 is illustrated in FIG. 5 .
With reference to FIG. 6 , an etch mask layer 36 is then applied to the planarization layer 20 , the exposed location 34 of the substrate 12 and the exposed contact pads 27 . The layer 36 acts as an etch mask layer for a DRIE process for forming one or more fluid supply slots 26 or holes through the thickness T of the substrate 12 . The etch mask layer 36 desirably has a thickness ranging from about 10 to about 100 microns, and more particularly, from about 30 to about 70 microns. The thickness of the etch mask layer 36 is not critical provided the thickness is sufficient to protect the planarization layer 20 , heater resistors 14 , and contact pads 27 during the etching process and not so thick that it inhibits a photoimaging process.
The etch mask layer 36 may be provided by a photoresist material comprised of a polymer containing acid labile protecting groups thereon. An exemplary polymer for use as the etch mask layer 36 includes a protected polyhydroxystyrene material available from Shin-Etsu MicroSi, Inc. of Phoenix, Ariz. under the trade name SIPR 7121M-16, and generally described in U.S. Pat. No. 6,635,400 to Kato et al., the disclosure of which is incorporated herein by reference thereto.
A second irradiation process as illustrated in FIG. 7 is used to provide a select first area 37 in the etch mask layer 36 for forming one or more fluid supply slots 26 through the thickness T of the substrate 12 . A second mask 38 is used to photoimage the etch mask layer 36 using a radiation source 40 such as UV radiation. Unlike the process described with respect to FIG. 4 , portions of the etch mask layer 36 in the first area 37 subject to radiation are transformed into materials that are readily removed with a suitable solvent rather than cured to prevent removal with a solvent. In the case of use of the photoresist etch mask layer 36 having acid labile protecting groups thereon, irradiation of the etch mask layer 36 causes deprotection of the acid labile protecting groups. Conventional developing solutions may then be used to remove portions of the etch mask layer 36 in area 37 wherein the substrate surface 16 is exposed as shown in FIG. 8 .
Prior to etching the substrate 12 , a third radiation process is used in conjunction with an etch mask 42 ( FIGS. 9A and 9B ) to irradiate select second areas 44 of the etch mask layer 36 for subsequent removal after the dry etch process is complete. Accordingly, the etch mask 42 contains substantially transparent areas 46 ( FIG. 9B ) corresponding to select second areas 44 on the substrate. The mask 42 is configured to expose the select second areas 44 which correspond to the contact pads on the substrate to enable easy removal of the photoresist etch mask layer 36 from the contact pads 27 .
Without desiring to be bound by theory, it is well known that exposure of a positive photoresist to UV radiation causes the photoresist to react in such away that solubility of the photoresist is increased in alkaline solvents as well as organic solvents such as acetone. The same is true for both chemically amplified positive photoresist materials as well as standard positive photoresist materials. However, in the embodiments described herein, a chemically amplified positive tone photoresist as described above is used as the etch mask layer 36 . Chemically amplified resists (CAR's) contain a phototacid generator (PAG) which upon exposure to the appropriate UV wavelengths will generate an acid and deprotect the photoresist thereby altering the solubility of the photoresist material. In the case of the use of a polyhydroxystyrene material as described above as the etch mask layer 36 , exposure to UV radiation induces deprotection of the acid labile groups in the mask layer 36 so that the layer 36 can then be cleanly removed with a solvent in which the mask layer 36 is substantially soluble while the cured planarization layer 20 remains substantially unaffected by the solvent. Suitable solvents include, but are not limited to, compounds in which polyhydroxystyrene is substantially soluble. Examples of such solvents include propyleneglycol monomethyletheracetate (PGMEA), cyclopentanone, N-methylpyrrolidone, aqueous tetramethyl ammonium hydroxide, acetone, isopropyl alcohol, and butyl cellosolve acetate. Aqueous tetramethyl ammonium hydroxide is particularly suitable for removing a chemically amplified resist.
It will be appreciated that during a DRIE process, the substrate 12 and the photoresist etch mask layer 36 are exposed to a variety of environmental conditions including UV radiation and heat. The extent of the exposure of the etch mask layer 36 to these conditions affects the stripability of the photoresist etch mask layer 36 upon completion of the etch process. Heat and UV radiation cause the photoresist etch mask layer 36 to interact with contact pads 27 , particularly contact pads 27 made of aluminum-copper. A photomicrograph of a contact pad 27 A using a prior art etch process having a residue 48 thereon after photoresist stripping is illustrated in FIG. 10 . In the prior art process, the step illustrated and described with respect to FIG. 9A is omitted.
It has been observed that if the substrate 12 has the residue 48 on the contact pads 27 , electrical leads connected to the contact pads 27 will not adequately bond to the pads 27 causing the ejection head to be discarded. However, if the photoresist etch mask layer 36 is deprotected in select areas 44 by exposing the select areas 44 to UV radiation prior to the DRIE step used to form the fluid supply slots 26 , then stripping of the etch mask layer 36 from the substrate 12 and planarization layer 20 is substantially improved as illustrated by the photomicrograph of a contact pad 27 B illustrated in FIG. 11 .
Exposure of select areas 44 of the photoresist etch mask layer 36 to UV radiation is conducted at an unconventional time. The exposure step, illustrated in FIG. 9A is conducted after the initial imaging and photoresist development steps illustrated in FIGS. 7 and 8 and before a DRIE step illustrated in FIG. 14 . Accordingly, the exposed areas 44 of the photoresist etch mask layer 36 are not washed away during the initial development cycle illustrated in FIG. 8 .
Blanket exposure of the photoresist etch mask layer 36 without the use of etch mask 42 to provide selective exposure is detrimental to the DRIE etch process as lateral etching of walls for the fluid supply slot 26 in the first area 37 may occur. Accordingly, the etch mask 42 is beneficial in selectively exposing areas of the photoresist etch mask layer 36 prior to DRIE etching.
In the case of chemically amplified resists, there is a short delay time between exposure of the select areas 44 of the photoresist etch mask layer 36 and the DRIE etching step. The delay time should be sufficient to enable the etch mask layer 36 in the select areas 44 to react to the exposure before the DRIE etch process is conducted. Typically, at least a five minute delay time may be required for reaction, depending on the thickness of the etch mask layer 36
In another embodiment, a mask 50 as illustrated in FIG. 12 may be used to expose the select second areas 44 to UV radiation through transparent areas 52 . Rounding the corners of the transparent areas 52 as shown may reduce internal stresses in the photoresist etch mask layer that may cause photoresist cracking.
In yet another embodiment, all areas of the photoresist etch mask layer 36 are exposed to UV radiation, except areas immediately adjacent the select first area 37 for etching the fluid supply slots 26 . Accordingly, exposure of the photoresist etch mask layer 36 may include all areas greater than about 0 to about 30 microns from the first area 37 . Such an overall exposure has the advantage of increasing etch mask layer 36 stripability over the largest substrate area without substantially contributing to lateral etching of the fluid supply slots 26 .
The UV radiation dose and spectrum for exposing the select second areas 44 are chosen such that the UV radiation induces a chemical transformation of the photo active compound in the photoresist etch mask layer 36 (.i.e., deprotection and or rearrangement) thereby reducing interaction between the etch mask layer 36 and the Al—Cu surface of the contact pads 27 . Further, since this exposure is done selectively, the lateral etch problem associated with etching the fluid supply slots 26 may be avoided.
After exposing the photoresist etch mask 36 to UV radiation as set forth above, formation of the ink vias 26 is provided by DRIE 54 as described above. FIG. 13 illustrates an exemplary dry etching process used for forming the one or more fluid supply slots 26 through the thickness T of the substrate 12 . Once the fluid supply slot 26 is formed through the thickness of the substrate 12 , the etch mask layer 36 may be removed as shown in FIG. 14 . Finally, with reference to FIG. 1 , the nozzle plate 18 is then attached to the planarization layer 20 to provide the micro-fluid ejection head 10 described above.
Having described various aspects and exemplary embodiments of the disclosure and several advantages thereof, it will be recognized by those of ordinary skills that the disclosed embodiments are susceptible to various modifications, substitutions and revisions within the spirit and scope of the appended claims.
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A method of etching a semiconductor substrate. The method includes the steps of applying a photoresist etch mask layer to a device surface of the substrate. A select first area of the photoresist etch mask is masked, imaged and developed. A select second area of the photoresist etch mask layer is irradiated to assist in post etch stripping of the etch mask layer from the select second area. The substrate is etched to form fluid supply slots through a thickness of the substrate. At least the select second area of the etch mask layer is removed from the substrate, whereby mask layer residue formed from the select second area of the etch mask layer is significantly reduced.
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FIELD OF THE INVENTION
[0001] The invention is drawn to plant genetic transformation, particularly to methods for the transformation of Setaria species.
BACKGROUND OF THE INVENTION
[0002] Current protocols for S. viridis transformation use callus derived from mature embryos as the target tissue for Agrobacterium -mediated transformation. Agrobacterium -mediated transformation is performed by co-cultivation of Agrobacterium cells harboring the transformation vector with the plant tissue to be transformed. After the Agrobacterium cells are substantially removed from the plant tissue, the plant tissue is then transferred to selection medium. This selection medium contains appropriate chemicals (e.g., antibiotics and/or herbicides) to select for transformed cells. Following selection, plant tissue is transferred to regeneration medium, where shoots are produced. These growing shoots are then transferred to rooting medium. Following root development, plantlets are then transferred to soil for cultivation.
[0003] Optimizing transformation protocols for a plant species requires optimization of the tissue culture response of the species to improve the condition of the plant tissue to be transformed. Typically, a suitable tissue culture response has been obtained by optimizing medium components, explant material and source, and/or growing conditions. This has led to some success, but it still takes a significant amount of effort to efficiently obtain a sufficient number of independent transgenic events quickly. It would save considerable time and money if genes could be more efficiently introduced. Accordingly, methods are needed in the art to increase transformation efficiencies in a wide variety of plant species including those of the Setaria genus including S. viridis.
SUMMARY OF THE INVENTION
[0004] The present invention provides an improved method for stably transforming S. viridis, which is a widely recognized model C4 grass. This model plant species can serve as a gene discovery/validation platform for maize, sugarcane, and other economically important crops. Improving the transformation efficiency of S. viridis is important because large numbers of transgenic plants are needed to enable studies on the effect of a large number of candidate genes or gene combinations within a given period of time. The method of the present invention is less labor-intensive than currently available protocols and provides improved transformation efficiency relative to previously developed transformation protocols for Setaria species. The method involves inducing callus growth from mature embryos at a light intensity of 5-30 μE m −2 sec −1 , pre-treating quality callus on CSM medium for 3 to 5 days, growing Agrobacterium cells harboring a functional plant transformation vector for three days at a temperature of 19-22° C., re-suspending the Agrobacterium cells in infection medium to an optical density of less than 1.0 at 600 nm, co-cultivating the resuspended Agrobacterium cells with callus tissue in infection medium containing greater than 30 g/L sucrose, culturing the infected cells on selection medium at a temperature of 25-35° C. for 32-49 days to produce transformed tissue expressing the nucleic acid, and regenerating the transformed tissue on at least one regeneration medium to produce a transformed plant. Using the methods of the invention, transformation efficiencies of greater than about 10% up to greater than about 20% can be achieved.
[0000] Embodiments of the invention include:
[0005] 1. A method of transforming callus derived from mature embryos of Setaria species comprising:
(a) inducing callus growth from mature embryos at a light intensity of 5-30 μE m −2 sec −1 , (b) pre-treating quality callus on CSM medium for 3 to 5 days, (c) growing Agrobacterium cells harboring a functional plant transformation vector for three days at a temperature of 19-22° C., (d) re-suspending the Agrobacterium cells in infection medium to an optical density of less than 1.0 at 600 nm, (e) co-cultivating the resuspended Agrobacterium cells with callus tissue in infection medium containing greater than 30 g/L sucrose, (f) culturing the infected cells on selection medium at a temperature of 25-35° C. for 32-49 days to produce transformed tissue expressing the nucleic acid, and (g) regenerating the transformed tissue on at least one regeneration medium to produce a transformed plant,
[0013] wherein the resulting transformation efficiency is at least 20%.
[0014] 2. The method of embodiment 1 wherein said callus is derived from Setaria viridis.
[0015] 3. The method of embodiment 1 wherein said callus is derived from Setaria italica.
[0016] 4. The method of embodiment 1 wherein said inducing callus growth occurs at a light intensity of 15-25 μE m −2 sec −1 .
[0017] 5. The method of embodiment 1 wherein said inducing callus growth occurs at a light intensity of 10-20 μE m −2 sec −1 .
[0018] 6. The method of embodiment 1 wherein said Agrobacterium cells are resuspended in infection medium at an optical density of 0.10-0.24.
[0019] 7. The method of embodiment 1 wherein said Agrobacterium cells are resuspended in infection medium at an optical density of 0.10-0.20.
[0020] 8. The method of embodiment 1 wherein said Agrobacterium cells are resuspended in infection medium at an optical density of 0.12-0.18.
[0021] 9. The method of embodiment 1 wherein said Agrobacterium cells are resuspended in infection medium at an optical density of 0.14-0.16.
[0022] 10. The method of embodiment 1 wherein said Agrobacterium cells are resuspended in infection medium at an optical density of 0.15.
[0023] 11. The method of embodiment 1 wherein said infected cells are cultured on selection medium at a temperature of 26-30° C.
[0024] 12. The method of embodiment 1 wherein said infected cells are cultured on selection medium at a temperature of 28° C.
[0025] 13. The method of embodiment 1 wherein said growing Agrobacterium cells occurs on solid YEP medium containing the appropriate antibiotics for plasmid maintenance.
[0026] 14. The method of embodiment 2 wherein said callus derived from Setaria viridis is derived from the accession A10.1.
[0027] 15. The method of embodiment 2 wherein said callus derived from Setaria viridis is derived from the accession ME034V.
[0028] 16. The method of embodiment 1 wherein said CSM medium does not contain a cytokinin.
[0029] 17. The method of embodiment 1 wherein said selection medium is CSM supplemented with appropriate chemicals to affect selection.
[0030] 18. The method of embodiment 1 wherein said selection medium is CIM supplemented with appropriate chemicals to affect selection.
[0031] 19. The method of embodiment 17 or embodiment 18 wherein said appropriate chemicals to affect selection are selected from the group of hygromycin, bialaphos, and kanamycin.
[0032] 20. The method of embodiment 1 wherein said co-cultivating the resuspended Agrobacterium cells occurs in the dark for three days.
[0033] 21. The method of embodiment 1 wherein said culturing the infected cells on selection medium occurs in the dark.
DETAILED DESCRIPTION OF THE INVENTION
[0034] Improved methods for transformation and regeneration of Setaria species are provided herein. The examples below detail the application of these methods. These improved methods result in significantly increased plant transformation frequency as compared to previously established transformation protocols.
[0035] An “increased transformation efficiency,” as used herein, refers to any improvement, such as an increase in transformation frequency and quality of events that impact the overall efficiency of the transformation process by reducing the amount of resources required. “Transformation efficiency” as used herein is calculated by dividing the number of regenerated plants containing resulting from a given transformation experiment and containing the DNA of interest by the number of callus pieces used for said transformation experiment. The methods of the invention are able to increase transformation efficiency greater than about 10%, greater than about 15%, and greater than about 20% as compared to art recognized methods for transformation of Setaria.
[0036] Selectable marker genes for selection of transformed cells or tissues can include genes that confer antibiotic resistance or resistance to herbicides. Examples of suitable selectable marker genes include, but are not limited to, genes encoding resistance to chloramphenicol (Herrera Estrella et al. (1983) EMBO J. 2:987-992); methotrexate (Herrera Estrella et al. (1983) Nature 303:209-213; Meijer et al. (1991) Plant Mol. Biol. 16:807-820); hygromycin (Waldron et al. (1985) Plant Mol. Biol. 5:103-108; Zhijian et al. (1995) Plant Science 108:219-227); streptomycin (Jones et al. (1987) Mol. Gen. Genet. 210:86-91); spectinomycin (Bretagne-Sagnard et al. (1996) Transgenic Res. 5:131-137); bleomycin (Hille et al. (1990) Plant Mol. Biol. 7:171-176); sulfonamide (Guerineau et al. (1990) Plant Mol. Bio. 15:127-136); bromoxynil (Stalker et al. (1988) Science 242:419-423); glyphosate (Shaw et al. (1986) Science 233:478-481); phosphinothricin (DeBlock et al. (1987) EMBO J. 6:2513-2518).
[0037] Although Setaria viridis has been proposed as an excellent model plant species for studying traits of potential agronomic performance, genetic transformation of Setaria species has historically been difficult to perform with a high efficiency. Few reports of Setaria transformation exist in the scientific literature. The first S. viridis transformation protocol that we are aware of was made public in 2010 (Brutnell et al (2010) Plant Cell 22:2537-2544); a transformation efficiency was not reported in this publication. The laboratory of Joyce Van Eck has also worked to optimize the Setaria transformation protocol (van Eck and Swartwood (2014) The First Annual Setaria Genetics Conference Abstracts. Beijing; Swartwood and van Eck (2014) The First Annual Setaria Genetics Conference Abstracts. Beijing; van Eck and Swartwood (2015) Methods Mol Biol 1223:57-67); 5-10% transformation efficiencies are reported for S. viridis transformation using these protocols. A recent publication reported efficiencies of up to 29% for transformation of S. viridis , but this efficiency was obtained only in one experiment; the overall efficiency obtained by this group was 13.8% (Martins et al 2015 Biotechnology Reports 6:41-44).
[0038] An increased “transformation efficiency,” as used herein, refers to any improvement, such as an increase in transformation frequency and quality of events that impact the overall efficiency of the transformation process by reducing the amount of resources required. Transformation efficiency can be calculated by dividing the number of transgenic plants recovered from a given transformation experiment by the number of callus pieces used for said transformation experiment. In order to provide reliable and reproducible transformation efficiencies, such efficiencies should be calculated from at least one hundred (100) callus pieces. The use of too few callus pieces may result in an overestimate or underestimate of the transformation efficiency that may be achieved by a given transformation protocol.
[0039] The transformation protocols and methods of the present invention provide a transformation efficiency of at least 20%. This is an increased efficiency over the previously published methods of Setaria transformation.
[0040] The following examples are offered by way of illustration and not by way of limitation.
EXPERIMENTAL
Example 1
Media Compositions
YEP Medium:
[0041] 5 g/L yeast extract, 10 g/L peptone, 5 g/L NaCl, 15 g/L Bacto-agar. Adjust pH to 6.8 with NaOH. Appropriate antibiotics (Kanamycin stock at 50 mg/L) should be added to the medium when cooled to 50° C. after autoclaving.
S. viridis Callus Induction Medium (CIM):
4.33 g/L MS salt and MS vitamins, 40 g/L maltose, 35 mg/L ZnSO 4 .7H 2 O, 0.6 mg/L CuSO 4 .5H2O, 2.0 mg/L 2,4-D (1 mg/mL), 8.0 g/L agar. Adjust with KOH to pH 5.8, autoclave. Filter-sterilized 0.5 mg/L Kinetin is added prior to use.
S. viridis Callus Subculture Medium (CSM):
4.33 g/L MS salt and MS vitamins, 40 g/L maltose, 35 mg/L ZnSO 4 .7H 2 O, 0.6 mg/L CuSO 4 .5H 2 O, 2.0 mg/L 2, 4-D (1 mg/mL), 8.0 g/L agar. Adjust with KOH to pH 5.8, autoclave.
Co-Cultivation Medium:
[0042] 4.33 g/L MS salt and MS vitamins, 30 g/L sucrose, 2.5 mL/L 2,4-D (1 mg/mL), 8.0 g/L agar. Adjust with KOH to pH 5.8, autoclave. Add 1 mL/L acetosyringone (100 mM) before use.
Infection Medium:
[0043] 2.16 g/L MS salt, 1 mL/L MS vitamins (1000X), 68.5 g/L sucrose, 36 g/L glucose, 0.115 g/L L-proline, 1.5mL/L 2,4-D (1 mg/mL). Adjust with KOH to pH 5.2, autoclave. Add 1 mL/L acetosyringone (100 mM) before use.
Selection Medium:
[0044] 4.33 g/L MS salt and MS vitamins, 40 g/L maltose, 35 mg/L ZnSO4.7H2O, 0.6 mg/L CuSO 4 .5H 2 O, 2 mg/mL 2,4-D, 8.0 g/L Agar. Adjust with KOH to pH 5.8, autoclave. Filter-sterilized 40 mg/L hygromycin, 100 mg/L Timentin, 150 mg/L cefotaxime cocktail with or without kinetin is added prior to use.
Regeneration Medium I
[0045] 4.33 g/L MS salt and vitamins, 30 g/L sucrose, adjusted with KOH to pH 5.8, autoclave. Filter-sterilized 0.2 mg/L Kinetin, 20 mg/L hygromycin, 100 mg/L Timentin, 150 mg/L cefotaxime cocktail is added prior to use.
Regeneration Medium II:
[0046] 2.16 g/L MS Salts and vitamins, 30 g/L sucrose, 2.6 g/L Phytogel (pH 5.8).
Example 2
[0047] S. viridis A10.1 transformation
Materials:
[0048] Plant materials: Compact light-yellow colored S. viridis calli derived from S. viridis cultivar A10.1
[0049] Agrobacterium strain: AGL-1 or LBA4404 harboring binary vector pMDC99 or super binary vector pSB1 with a strong constitutive promoter driving an appropriate selectable marker gene (such as Hpt or Bar/PAT).
Transformation:
[0050] 1. Transfer compact calli derived from mature embryos and grown in dim light (10-20 μE m −2 s −1 ) to CSM medium at 28° C. for three to five days.
[0051] 2. Agrobacterium cultures (AGL-1 hosting regular binary vector) are grown for three days at 19 to 22° C. on solid YEP medium amended with 50 mg/L kanamycin.
[0052] 3. A small amount of bacterial culture is scraped from the plate and suspended in approximately 15 mL of liquid Infection Medium in a 50 mL conical tube. Adjust the optical density to OD 600=0.15 before use.
[0053] 4. For each construct, transfer a small amount of actively growing calli to a tube. Using sterile forceps, subculture compact calli from their original plates and transfer them to their corresponding petri dish. Callus pieces should be approximately 2-4 mm in diameter, as if they are too small, they will not survive the transformation.
[0054] 5. Add 4 mL Agrobacterium suspension, vortex at full speed for 15 seconds, then allow calli to incubate in culture at room temperature for 5-7 minutes in the dark.
[0055] 6. Place infected calli onto dry filter paper in a 100×15 mm plate and leave in hood until no major trace of liquid is visible.
[0056] 7. Transfer calli with filter paper to co-cultivation plate, re-arrange the calli to ensure no aggregation.
[0057] 8. Co-cultivation plates are incubated in the dark at 25° C. for three days.
[0058] 9. Transfer infected calli off the filter paper and place on top of Selection Medium.
[0059] 10. Selection plates are wrapped and placed in the dark at 28° C.
[0060] 11. Every two weeks, the tissue is sub-cultured onto fresh Selection Medium. There will be a five to six week selection period with three separate sub-cultures to fresh Selection Medium.
[0061] 12. Transfer active growing calli/emerging shoots to regeneration/selection plates containing Regeneration Medium I for shoot induction at 28° C. in light growth chamber until shoots become excisable (in about 2 weeks).
[0062] 13. Transfer all regenerated shoots with forceps and Regeneration Medium II for rooting/selection at 28° C. and 16/8 photoperiods.
[0063] Transformations were performed according to the protocols described above. Following the transfer of regenerated shoots to Regeneration Medium II and allowing sufficient time for the plants to grow in this medium, tissue samples were collected and DNA was extracted from these tissue samples. A PCR-based assay was performed to detect the presence of the selectable marker gene (i.e., the gene encoding a protein that provides antibiotic or herbicide resistance for selection). Transformation efficiencies were calculated by dividing the number of PCR-positive rooted plantlets by the number of callus pieces that were used for the transformation experiment. Twenty-one transformation experiments were performed with vectors containing a selectable marker gene as well as different genes of interest, with the resulting transformation efficiencies shown in Table 1.
[0000]
TABLE 1
S. viridis accession A10.1 transformation efficiencies
Callus Pieces
Used
PCR+
Efficiency
40
12
30.0%
40
2
5.0%
40
3
7.5%
40
1
2.5%
40
7
17.5%
40
7
17.5%
40
11
27.5%
40
10
25.0%
40
8
20.0%
40
7
17.5%
40
12
30.0%
40
13
32.5%
40
6
15.0%
20
3
15.0%
20
14
70.0%
20
10
50.0%
20
12
60.0%
20
14
70.0%
20
10
50.0%
20
21
105.0%
20
19
95.0%
Totals:
680
202
29.7%
Example 3
[0064] S. viridis ME034V transformation
Materials:
[0065] Plant materials: Compact light-yellow colored S. viridis calli derived from S. viridis cultivar ME034V
[0066] Agrobacterium strain: AGL-1 or LBA4404 harboring binary vector pMDC99 or super binary vector pSB1 with a strong constitutive promoter driving an appropriate selectable marker gene (such as Hpt or Bar/PAT).
Transformation:
[0067] 1. Transfer compact calli derived from mature embryos and grown in dim light (10-20 μE m −2 s −1 ) to CIM medium at 28° C. for three to five days.
[0068] 2. Agrobacterium cultures (AGL-1 hosting regular binary vector) are grown for three days at 19 to 22° C. on solid YEP medium amended with 50 mg/L kanamycin.
[0069] 3. A small amount of bacterial culture is scraped from the plate and suspended in approximately 15 mL of liquid Infection Medium in a 50 mL conical tube. Adjust the optical density to OD 600=0.15 before use.
[0070] 4. For each construct, transfer a small amount of actively growing calli to a tube. Using sterile forceps, subculture compact calli from their original plates and transfer them to their corresponding petri dish. Callus pieces should be approximately 2-4 mm in diameter, as if they are too small, they will not survive the transformation.
[0071] 5. Add 4 mL Agrobacterium suspension, vortex at full speed for 15 seconds, then allow calli to incubate in culture at room temperature for 5-7 minutes in the dark.
[0072] 6. Place infected calli onto dry filter paper in a 100×15 mm plate and leave in hood until no major trace of liquid is visible.
[0073] 7. Transfer calli with filter paper to co-cultivation plate, re-arrange the calli to ensure no aggregation.
[0074] 8. Co-cultivation plates are incubated in the dark at 25° C. for three days.
[0075] 9. Transfer infected calli off the filter paper and place on top of Selection Medium.
[0076] 10. Selection plates are wrapped and placed in the dark at 28° C.
[0077] 11. Two weeks after the initial transfer to Selection Medium, the tissue is sub-cultured onto fresh Selection Medium. Two weeks after this sub-culture, the tissue is transferred to a fresh plate containing CIM medium supplemented with 40-60 mg/L hygromycin.
[0078] 12. Transfer active growing calli/emerging shoots to regeneration /selection plates containing Regeneration Medium I for shoot induction at 28° C. in light growth chamber until shoots become excisable (in about 2 weeks).
[0079] 13. Transfer all regenerated shoots with forceps and Regeneration Medium II for rooting/selection at 28° C. and 16/8 photoperiods.
[0080] Transformations were performed according to the protocols described above. Following the transfer of regenerated shoots to Regeneration Medium II and allowing sufficient time for the plants to grow in this medium, tissue samples were collected and DNA was extracted from these tissue samples. A PCR-based assay was performed to detect the presence of the selectable marker gene (i.e., the gene encoding a protein that provides antibiotic or herbicide resistance for selection). Transformation efficiencies were calculated by dividing the number of PCR-positive rooted plantlets by the number of callus pieces that were used for the transformation experiment. Eight transformation experiments were performed with the resulting transformation efficiencies shown in Table 2.
[0000]
TABLE 2
S. viridis accession ME034V transformation efficiencies
Callus Pieces
Used
PCR+
Efficiency
27
21
77.8%
45
60
133.3%
20
9
45.0%
20
17
85.0%
20
2
10.0%
20
29
145.5%
20
15
75.0%
20
31
155.0%
20
18
90.0%
Totals:
212
202
95.3%
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This invention relates to methods for the transformation of Setaria species such as Setaria viridis and transformed plants produced according to the method. Specifically, this invention relates to direct transformation of callus derived from mature embryos using Agrobacterium -mediated transformation, and plants regenerated from the transformed callus tissue. The methods comprise utilizing Setaria mature embryos as the source of plant material for callus induction; induced calli can be infected by Agrobacterium hosting an appropriate vector. Transgenic plants are regenerated from transgenic calli grown under conditions favoring growth of transformed cells while substantially inhibiting growth of non-transformed cells. These methods provide for significantly increased plant transformation efficiency with minimal ratio of escapes.
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GOVERNMENTAL INTEREST
The invention described herein may be manufactured, used and licensed by or for the Government.
BACKGROUND OF THE INVENTION
Today, RDX is probably the most important high brisance explosive; its brisant power is high owing to its high density and high detonation velocity. It is relatively insensitive (as compared to say PETN, which is an explosive of a similar strength); it is very stable; its performance properties are only slightly inferior to those of the homologous Octogen (HMX).
In the prior art, RDX vis. hexamethylene tetramine is nitrated to hexogen by concentrated nitric acid. After the nitration mixture has reacted it is poured into cold water and the product is thereby caused to precipitate. In the conventional industrial practice hexamethylene tetraamine dinitrate is reacted with ammonium nitrate and the necessary excesses of nitric acid and acetic anhydride in acetic acid solvent medium, the hexogen is precipitated by addition of water, and the excess acetic anhydride is lost by hydrolysis to acetic acid. Waste acetic acid formed during the reaction is re-concentrated, and subjected to an energy intensive ketene process being thereby, converted back to useful acetic anhydride. The regenerated acetic anhydride is recycled back to the process. The yield of RDX is good, about 80% based upon two molecules of RDX per molecule of hexamine. The production of the prior process always contains some HMX contamination. The amount of HMX may vary greatly when enhanced by variation of the reaction conditions.
SUMMARY OF THE INVENTION
DAPT is an intermediate in the synthesis of HMX. Our method for the conversion of DAPT to RDX provides the "GARDEC PROCESS" a greatly expanded nitramine capability and does not require extensive duplication or modification of facilities when pure HMX is desired. In fact our yield of either RDX or HMX is quantitative. We have achieved at least 97% efficiency.
An object of the present invention is to provide a practical and cost effective process for preparing high yields of RDX from 3,7-DIACETYL 1,3,5,7-TETRAAZA[3.3.1]BICYCLONONANE (DAPT). Other objects will become apparent from the following description of the invention.
Outstanding features which are unique to this invention are the quantitative yield, reduced reactant requirements, and added flexibility; all due to the fact that we are starting with a preacetylated reactant.
The process of the present invention is considered to be unobvious in view of the fact that RDX formation does not follow logically as being readily derivable from the structure of DAPT. The structure of DAPT is such that those skilled in the field would generally conclude that it would naturally react instead to provide HMX. It is not apparent or easily explainable why the DAPT structure is so completely broken down and reassembled to provide very high yields of RDX.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following examples illustrate specific embodiments of the method of carrying out the process of the present invention. It is to be understood that they are illustrative only and do not in any way limit the invention.
EXAMPLE 1--BACKGROUND
Note should be taken, our preparations of RDX have been accomplished on a 5-100 gram scale. On this scale no adverse reactions have been noticed which would indicate any safety hazard on scale-up. A 100 gram procedure based upon this work is as follows.
A 100 ml beaker is charged with 11.3 grams of DAPT dissolved in 6.8 grams of acetic acid. To this is added two reactant liquids. These liquids are added alternately and intermittently. Liquid one is comprised of 10.5 grams of ammonium nitrate and 13.1 grams of nitric acid. The second liquid is composed of 30 grams of acetic anhydride. The addition of these two liquids to the initial mixture produces an exotherm.
The temperature of the reaction is kept closely to 68 degrees Centigrade. Cooling is minimal and said cooling is only required from time to time. The addition sequence is started with the nitric acid/ammonium nitrate solution and is followed by the acetic anhydride. The nitric acid solution is added in small portions, as dictated by the exotherm, a gram or so at a time. After a couple of seconds the acetic anhydride is added stoichiometrically in a ratio of 1.8 moles acetic anhydride to 1.0 mole of ammonium nitrate and the cycle of addition of reactants continued. An initial unknown precipitate forms almost from the first addition of ammonium nitrate/nitric acid to the system. The precipitate redissolves and the solution clears. The solution remains clear until about 2/3 of the additional reactants are added. A second precipitate now forms which we discovered to be RDX. As the additions are continued the RDX precipitate will become noticeably heavier. After complete addition a small sample may be assayed. The moist filtered cake will be found to contain about 0.035 grams of RDX/gram of reaction mixture.
EXAMPLE 2
We found, using the method, reactants, and quantities as set forth in example 1, that by modifying and continuing the addition of the DAPT to the system, that the yield could be greatly improved. These results are set forth in Table 1.
TABLE 1______________________________________APPROXIMATE YIELD DATASAMP. RDX % DAPT TOTAL# G CAKE/G MIX YIELD ADDITION G DAPT______________________________________1 0.026 G 7.6% 11.3 G 11.3 G2 0.136 G 39% 2.8 G 14.1 G3 0.166 G 48% 2.8 G 16.9 G4 0.196 G 56% 2.8 G 19.7 G5 0.211 G 60% 2.8 G 22.5 G6 0.339 G 98% 12.5 G 35.0 G______________________________________
It is obvious from Table 1 that after the first addition of DAPT, very little RDX is formed. However, even small incremental increases of DAPT dramatically increases the RDX yield, as shown. As can be seen for a less that 10% increase in DAPT, we have achieved a 500% increase in yield. As dramatically shown in Table 1, the yield of RDX is dramatically increased by our method. Using the same method, reactants and quantities [except for incremental addition of DAPT]. It is readily observed that the concentration of RDX increases dramatically as soon as the first small portion of additional DAPT is made. By the time the last addition is made, the reacting mixture has about reached equilibrium. Further additions of reactants may now be continued indefinitely without a decrease in efficiency. Alternatively a portion of the reaction mixture may be taken out and identical processing being made to it. In other words, we may have a continuous process of a batch system if desired. This all depends upon requirements such as the quantity of product needed. The high level of efficiency will be maintained indefinitely so long as nothing is done to disrupt the equilibrium.
EXAMPLE 3
We found using, the method, and reactants as set forth in example 2, that the quantities of reactant liquids may be varied. The relative molar ratio of the two liquid reactant acetic anhydride and ammonium nitrate (dissolved in nitric acid) should not be varied and should be maintained within tight tolerance of 1.8 moles of acetic anhydride to 1.0 mole of ammonium nitrate. However, the tightly maintained ratio of these two reactants may be varied somewhat relative to the quantity of DAPT, such variation having little or no effect upon yield. The degree of variation may be within the range of about 4.2 to 5.8 moles of acetic anhydride per mole of DAPT and 1.88 to 2.59 moles of ammonium nitrate. with the latter corresponding and dependant upon the quantity of acetic anhydride used. On the other hand, the quantity of acetic acid and nitric acid used are of less critical importance and may be varied plus or minus about 25% without effecting the yield.
SUMMARY
In conclusion, the process of the present invention is an improvement on the prior art. Note should be taken that the use of hexamine instead of DAPT may result in violent eruptions from the solution. On the other hand, use of DAPT allows for invention to be simple, effective, efficient, and facile in use. It is very safe to carry out because of the much reduced exothermicity relative to the art. In fact, if a total nitramine facility were constructed, our RDX process would offer substantial savings. We get quantitative yields and in several cases the yields are greater than those achieved by other processes of the art.
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1,3,5-TRINITROHEXAHYDRO-1,3,5-TRIAZINE (RDX) is prepared in a new simplif and efficient manner which provides near quantitative yield. Our process is based upon the nitration of 3,7-DIACETYL 1,3,5,7 TETRAAZA[3.3.1.]BICYCLONONANE (DAPT).
| 2 |
This continuing application is the national phase of international application PCT/US94/09648, filed Sep. 6, 1994, which was a continuation-in-part of U.S. Ser. No. 08/143,695 filed 27 Oct., 1993, now abandoned.
BACKGROUND OF THE INVENTION
Prostaglandin E 1 (PGE-1) is an inherently unstable compound. PGE-1 is chemically (11α, 13E, 15S )-11,15-dihydroxy-9-oxoprost-13-en-1-oic acid; or 3-hydroxy-2-(3-hydroxy-1l-octenyl)-5-oxo-cyclopentaneheptanoic acid; and is commonly referred to as alprostadil or PGE 1 . PGE-1 is a primary prostaglandin which is easily crystallized from purified biological extracts. A goal of this invention was the development of a room temperature stable formulation of PGE-1. More preferred would be a method to stabilize a low dose (5-20 μg) formulation of PGE-1 suitable for use in the treatment of erectile dysfunction.
Various attempts to freeze-dry PGE-1 have been described in U.S. Pat. Nos. 3,952,004 and 3,927,197. The first patent "004 describes the stabilization of PGE-1 in tertiary butyl alcohol and sodium chloride and that lactose or other "simple sugars" destabilize PGE-1. The second patent '197 describes PGE-1 stabilized with tertiary butyl alcohol.
Despite various attempts to stabilize PGE-1, better and more effective methods are in demand to increase shelf life and maintain efficacy. PGE-1 formulations in lactose appears to degrade through an apparent second order mechanism with respect to PGE 1 concentration in the solid state. Maximum stability can be achieved by either minimizing the PGE-1 concentration in a suitable lactose diluent or by optimizing other parameters which may impact the second order rate constant. The second order rate constant is affected by the solid state pH, the buffer content, the moisture content, the use of tertiary butyl alcohol during processing, the freezing rate, and the drying rate. All of these parameters have been optimized to minimize the value of the second order rate constant.
SUMMARY OF THE INVENTION
In one aspect the subject invention is a lyophilized formulation of PGE-1 made by the process comprising:
a) dissolving PGE-1 in a solution of lactose and tertiary butyl alcohol wherein the tertiary butyl alcohol is present in an amount of from about 15% to 33% volume/volume and the ratio of lactose to PGE-1 is from about 40,000 to 1 to about 10,000 to 1 weight/weight (25 to 100 ppm in lactose) whereby a formulation of PGE-1dispersed in lactose is formed;
b) adjusting and maintaining the pH of the formulation from about 3.5 to about 6 with an organic acid buffer (preferably sodium citrate);
c) freezing the formulation to about -50° C.; and
d) drying the formulation to obtain a moisture content of less than 1% by dry weight and a tertiary butyl alcohol content of less than 3% by dry weight.
Preferably, the PGE-1 in the formulation is in an amount of about 25 to 100 ppm lactose and the pH is adjusted and maintained at 4 to 5 by the presence of a buffer. Preferably, the freezing step (c) includes an annealing process by freezing the formulation to about -50° C., warming to about -25° C. for about 2 hours then refreezing to about -50° C.
In another aspect, the subject invention is a method for preparing a stabilized, lyophilized formulation of PGE-1 comprising the steps set forth above.
In yet another aspect, the present invention is a freeze-dried formulation of PGE-1 for use in the treatment of erectile dysfunction. Typical dosages of the formulation are (5-20 μg) formulations of PGE-1. These formulations correspond to a ratio of lactose to PGE-1 of from about 40,000 to 1 to about 10,000 to 1 weight/weight (25 to 100 ppm in lactose). That is, 5 μg corresponds to 40,000 to 1; 10 μg corresponds to 20,000 to 1 and 20 μg corresponds to 10,000 to 1.
DETAILED DESCRIPTION OF THE INVENTION
The subject invention is a lyophilized PGE-1 composition made from a bulk sterile filtered solution which contains 20% v/v tertiary butyl alcohol (TBA) and has an apparent pH of approximately 4. Both the water and TBA are removed during the freeze-drying process. Residual water and TBA remaining after lyophilization are <0.5% and 0.5-2% respectively of the dried cake mass. In one formulation, a vial dosage contains after completion of lyophilization: 23 μg of PGE-1 (alprostadil), 193.8 mg of anhydrous lactose, and 53 μg of sodium citrate. After reconstitution of this freeze-dried powder with 1.0 ml of either water for injection or bacteriostatic water for injection, a solution containing 20 μg/ml of PGE-1 is obtained. The freeze-dried powder is packaged in a 5 ml vial and sealed with a lyophilization style closure within the freeze-dry chamber, and capped with an aluminum overseal. The chemical stability of the PGE-1 can be predicted by use of the Arrhenius equation and accelerated stability data. Initial rate kinetic analyses (i.e., monitoring the rate of formation of the major degradation product, PGA 1 ) can be used to assess the chemical stability. The projected stability analysis indicates that when the product is properly manufactured with the optimized formulation and process, the shelf-life should be greater than 24 months when the product is stored at 25° C. or less.
Initial work centered on the use of a lactose diluent and lyophilization from a tertiary butyl alcohol (TBA)/water co-solvent system. The freeze-dried formulation produced appeared to possess the properties of a solid solution. The degradation of the PGE-1 in this type of formulation could be best described by a second order mechanism. Stability could be increased by maximizing the amount of lactose diluent or minimizing the amount of PGE-1 present. The solid state second order kinetics fit well to an Arrhenius type temperature relationship. Residual moisture was shown to have a deleterious effect on the stability. The pH of the cake also affected the stability. Optimum stability was achieved at about pH 4-5. A minimum amount of citrate buffer was added to the formula to control pH. Lyophilization from a TBA/water co-solvent mixture improved stability of the formulations compared to water only. Typically, standard freeze drying techniques can be used to prepare the stabilized PGE-1. More preferably, an annealing technique can be performed to decrease and more uniformly control the residual tertiary butyl alcohol in the freeze dried product. Optimum stability was achieved when freeze-drying from a 17-25% TBA/water mixture.
The method for preparing a stabilized, freeze-dried formulation of PGE-1 controls key parameters which affect product stability including the following: the level of lactose diluent present, the apparent pH of the lyophilized cake, the moisture content, the use of the co-solvent tertiary butyl alcohol during processing, the freezing rate and methodology prior to lyophilization, the freeze-drying rate, and the size of the vial used to manufacture the product.
Lyophilization of a buffered lactose formulation of PGE-1 from a tertiary butyl alcohol (TBA)/water mixture provides superior product stability than when freeze-drying from only an aqueous system. The level of TBA which afforded the product maximum stability appeared to be when the TBA amount ranged from 17-25% (v/v). The 20% TBA level was selected as the amount of co-solvent for the PGE-1 formulation since it fell within the optimum co-solvent range. The lower the level of TBA used also reduced the flammability potential, reduced the amount of TBA waste which would be generated after lyophilization, reduced the level of isopropyl alcohol (a process impurity in the TBA) in the product, and lowered the precipitation potential during manufacturing for the lactose from the co-solvent system. Stability data clearly indicated that lyophilization of the buffered lactose formulation of PGE-1 from a TBA/water co-solvent system would be significantly more stable than freeze-drying from an aqueous system. The mechanism for the improvement in stability when using the TBA is unknown but it is likely enabling the PGE-1 molecules to be kept further apart during the freezing and lyophilization phases of manufacture. Therefore, it is recommended that the final formulation be lyophilized from a co-solvent system containing 20% v/v TBA. It is important that this level of TBA be used because lower levels of TBA (≦17%) in the final formulation will produce a product which is much less stable than when using at least 20% TBA.
The resulting residual TBA in the final product is expected to be approximately 0.5 to 2% of the cake weight. A safety assessment of TBA and its impurities (isopropyl alcohol, 2-butyl alcohol, and isobutyl alcohol) concluded that TBA levels of not more than 3% of a 200 mg freeze-dried cake was acceptable and that other residual organic solvents should be not more than 0.5% of a 200 mg freeze-dried cake.
The application of heat to the lactose may adversely affect product stability. The stability data clearly dictates that close control of the freeze-dry cycle (both primary and secondary drying) is critical to reproducible manufacture lots with equivalent stability. Stability can therefore be a function of processing parameters.
Since the PGE-1 degradation kinetics fit (at least empirically) a second order mechanism, stability can be improved by simple dilution of the PGE-1 with lactose. This would suggest that maximizing the amount of lactose for a given amount of PGE-1 should provide the optimum stability. For a 20 μg/ml formulation of PGE-1 the amount of lactose chosen for formulating the optimum formulation is 204 mg of lactose monohydrate. After lyophilization, the 5% water is removed and the resulting lactose present in the vial is 193.8 mg. The cake volume for 193.8 mg of anhydrous lactose is approximately 0.13 ml. Therefore, the theoretical solution concentration of lactose after reconstitution with 1.0 ml is (193.8 mg/1.13 ml) or 172 mg/ml. The amount of PGE-1 needed to produce a 20 μg/ml solution after reconstitution with 1.0 ml is (1.13 ml×20 μg/ml) or 22.6 μg.
It has been determined that the cake pH also affected product stability. Maximum stability is achieved when the cake pH is held near pH 4 to 5. Both citrate and acetate buffers can be used; however, citrate buffer was selected as the buffer of choice for the PGE-1 formula since it is a common buffer for parenteral products. Since PGE-1 is susceptible to both acid and base hydrolysis, it is probable that some buffer catalysis of the PGE-1 molecule may occur. The amount of citrate buffer selected for the final formulation was chosen based on a compromise between sufficient buffer to adequately control pH and yet not itself significantly provide an alternate catalytic route. The level of citrate chosen for the final formulation was 53 μg of sodium citrate/23 μg PGE-1 (3.17 moles citrate/mole PGE-1). This level of citrate will theoretically cause only a relatively minor increase (<7%) in the degradation rate constant. In order to determine if sufficient buffer was present to control pH for the shelf life of the product, samples with this amount of buffer present were degraded to less than 90% of initial potency under accelerated conditions. The pH was measured initially and after the >10% drop in potency had taken place. No significant change in pH occurred. This demonstrates that sufficient buffer was present to maintain pH during the normal shelf life of the product where less than 10% degradation will take place.
The presence of moisture in the product will have a negative impact on product stability. It is therefore preferred that the formulation have the level of moisture as low as possible during the processing and to maintain that level throughout the shelf life of the product.
The rate of freezing also has an effect on product stability. The unique kinetics of the degradation pathway indicates that it is imperative that the PGE-1 molecules be kept as far apart as possible in order to minimize the interaction of two PGE-1 molecules. Typically, the lyophilization cycle is designed to proceed as fast as possible without exceeding the melting temperature of the frozen solution during primary drying. Therefore, as long as no meltback occurs during the primary drying phase and the water content is reduced to a sufficiently low level during the secondary drying phase, then the product would normally be acceptable. However, the PGE-1 formulation can be quite different from the normal situation because the major component in the formulation is lactose. The literature reports that lactose possesses a very low glass transition temperature (T g ) which is on the order of -31° C. It is possible to lyophilize above the glass transition temperature for an excipient such as lactose without exceeding the melting temperature of the bulk solution. If the product temperature exceeds T g , the frozen solution viscosity decreases significantly resulting in a rubbery system where the mobility of the PGE-1 molecules will increase substantially. This type of event could lead to a situation where the PGE-1 molecules could either aggregate, micellize, or come into closer proximity than if the frozen solution is kept below the T g . It is important, therefore, that the drying cycle be optimized to prevent such an occurrence from happening.
Typically, the PGE-1 in lactose formulation is freeze dried using standard techniques, More preferred, an annealing process is used to enable the residual tertiary butyl alcohol to be reduced and controlled. In an annealing process the initial stage of the freeze drying process is carried out by freezing the PGE-1 formulation to about -50° C., warming it to about -25° C. for about 2 hours then refreezing it to about -50° C. Next, the freeze drying is continued to obtain a moisture content of less than 1% by dry weight and a tertiary butyl alcohol content of less than 3% by dry weight.
The conclusion is that in order to achieve the proper product stability, not only must the formulation be carefully chosen, but also the manufacturing process must be appropriately optimized. The mechanisms may not be fully understood on a theoretical basis at this time, however, the effects described are reproducible. It is therefore, mandated that a conservative cycle be used to consistently achieve maximum product stability.
Prototype lactose base formulations of PGE-1 indicated that the stability correlated well with an Arrhenius type temperature relationship. This fit to an Arrhenius relationship was apparent whether the rate constants were plotted for the degradation rate of PGE-1 or for the rate of formation of the major degradation product PGA 1 . Therefore, the stability of the lactose formulation for PGE-1 can be accurately assessed by initial rate type kinetic analysis (i.e., by monitoring the rate of PGA 1 formation).
Optimization of a freeze-dried formulation PGE-1 (Alprostadil S.Po.) and preferably as designed for use in an injectable such as in the treatment of erectile dysfunction has been determined as explained above. The formulation appears to degrade through an apparent second order mechanism with respect to PGE-1 concentration in the solid state. Maximum stability can be achieved by either minimizing the PGE-1 concentration in the lactose diluent or by optimizing those parameters which impact the second order rate constant. The amount of lactose diluent chosen for the optimized formulation was based on solubility limitations and the irritation potential of the lactose. In one embodiment the amount of PGE-1 present was based on the proposed clinical dose for an injection volume of 1 ml or less. The second order rate constant is affected by the solid state pH, the buffer content, the moisture content, the use of tertiary butyl alcohol during processing, the freezing rate, and the drying rate. All of these have been optimized to minimize the value of the second order rate constant. The product is lyophilized from a bulk sterile filtered solution which contains 20% v/v tertiary butyl alcohol (TBA) and has an apparent pH of approximately 4. Both the water and TBA are removed during the freeze-drying process. Residual water and TBA remaining after lyophilization are <0.5% and 0.5 to 2% respectively of the dried cake mass. The final formulation, for example, per vial contains after completion of lyophilization: 23 μg of PGE-1 (alprostadil), 193.8 mg of anhydrous lactose, and 53 μg of sodium citrate. After reconstitution of this freeze-dried powder with 1.0 ml of either water for injection or bacteriostatic water for injection, a solution containing 20 μg/ml of PGE-1 will be obtained. Or, the final formulation, for example, per vial contains after completion of lyophilization: 11.9 μg of PGE-1 (alprostadil), 193.8 mg of anhydrous lactose, and 53 μg of sodium citrate. After reconstitution of this freeze-dried powder with 1.0 ml of either water for injection or bacteriostatic water for injection, a solution containing 10 μg/ml of PGE-1 will be obtained. Or, the final formulation, for example, per vial contains after completion of lyophilization: 6.1 μg of PGE-1 (alprostadil), 193.8 mg of anhydrous lactose, and 53 μg of sodium citrate. After reconstitution of this freeze-dried powder with 1.0 ml of either water for injection or bacteriostatic water for injection, a solution containing 5 μg/ml of PGE-1 will be obtained. The freeze-dried powder, as per these examples, is packaged in a 5 ml vial, sealed with a lyophilization style closure within the freeze-dry chamber, and capped with an aluminum overseal. The chemical stability of the PGE-1 can be predicted by use of the Arrhenius equation and accelerated stability data. Initial rate kinetic analyses (i.e., monitoring the rate of formation of the major degradation product, PGA 1 ) can also be used to assess the chemical stability. The projected stability analysis indicates that when the product is properly manufactured with the optimized formulation and process, the shelf-life should be greater than 24 months when the product is stored at 25° C. or less.
A lot for the various strengths of PGE-1 stabilized product freeze dried under the conditions described above was prepared and stability measured. The results are shown in the Tables that follow:
TABLE I______________________________________20 μg StrengthTime Potency at 5° C. Potency at 25° C.(months) (% of Initial) (% of Initial)______________________________________0 100.5% 100.5%0 100.0% 100.0%0 100.5% 100.5%0 99.5% 99.5%0 100.0% 100.0%3 99.5% 100.5%3 100.5% 101.5%6 100.0% 98.5%6 -- 100.5%9 99.5% 96.6%9 99.0% 98.5%11.44 100.0% 96.6%11.44 99.5% 96.6%11.44 99.5% 96.1%12 99.5% 97.6%12 100.5% 97.6%12 101.0% 97.6%12 101.0% 97.6%15 101.0% 96.1%15 102.0% 95.6%18 100.0% 95.6%18 99.5% 94.6%21 99.0% 96.1%21 99.5% 95.1%______________________________________
TABLE II______________________________________10 μg StrengthTime Potency at 5° C. Potency at 25° C.(months) (% of Initial) (% of Initial)______________________________________0 99.1% 99.1%0 100.9% 100.9%0 100.0% 100.0%0 100.0% 100.0%0 99.1% 99.1%0 101.9% 101.9%0 100.9% 100.9%0 100.9% 100.9%0 100.0% 100.0%0 100.0% 100.0%1 99.1% 102.8%1 100.0% 102.8%1 100.0% 102.8%2 100.9% 102.8%2 102.8% 102.8%2 102.8% 102.8%3 99.1% 100.0%3 100.9% 99.1%3 99.1% 98.1%4 100.9% 100.9%4 100.9% 100.9%4 100.9% 100.0%5 100.0% 97.2%5 100.0% 99.1%5 100.0% 99.1%6 98.1% 97.2%6 97.2% 98.1%6 96.3% 98.1%7.95 97.2% --7.95 98.1% --7.99 98.1% --7.99 98.1% --8 98.1% --8 97.2% --9 101.9% 99.1%9 100.9% 99.1%9 102.8% 100.0%12 98.1% 97.2%12 98.1% 96.3%12 99.1% 96.3%15 99.1% 96.3%15 99.1% 94.3%15 99.1% 95.3%______________________________________
TABLE III______________________________________5 μg StrengthTime Potency at 5° C. Potency at 25° C.(months) (% of Initial) (% of Initial)______________________________________0 101.5% 101.5%0 99.3% 99.3%0 100.4% 100.4%0 98.9% 98.9%0 99.6% 99.6%0 99.8% 99.8%0 99.6% 99.6%0 100.9% 100.9%0 100.2% 100.2%0 100.4% 100.4%1 101.1% 100.7%1 100.7% 99.4%1 100.2% 99.8%2 100.0% 99.3%2 100.6% 100.7%2 100.6% 99.4%3 100.4% 99.8%3 100.4% 100.2%3 100.6% 99.8%4 103.5% 100.0%4 99.6% 99.4%4 100.6% 100.6%5 98.9% 99.4%5 100.0% 99.4%5 100.9% 100.2%6 100.7% 99.4%6 100.9% 99.6%6 100.9% 100.2%6 100.0% 99.1%6 99.3% 98.5%______________________________________
The Tables show that excellent stability was maintained for the life of lyophilized product.
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A stable and lyophilized formulation of prostaglandin E-1 made by the process comprising a) dissolving PGE-1 in a solution of lactose and tertiary butyl alcohol wherein said tertiary butyl alcohol is present in an amount of from about 15% to about 33% volume/volume and the ratio of said lactose to PGE-1 is from about 40,000 to 1 to about 10,000 to 1 weight/weight whereby a formulation of PGE-1dispersed in lactose is formed; b) adjusting and maintaining the pH of said formulation from about 3.5 to about 6 with an organic acid buffer; c) freezing said formulation to about -50° C.; and d) drying said formulation to obtain a moisture content of less than 1% by dry weight and a tertiary butyl alcohol content of less than 3% by dry weight. Preferably, step c) includes after freezing said formulation to about -50° C., warming to about -25° C. for about 2 hours then refreezing to about 50° C. Preferably, the prostaglandin is in an amount of about 25 to 100 ppm in lactose and the pH is maintained at about 4 to 5.
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RELATED APPLICATIONS
This application claims priority to U.S. Provisional Application Ser. No. 61/263,112 filed with the United States Patent and Trademark Office on Nov. 20, 2009 and is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
The invention generally relates to a pest entrapment device and method for controlling and entrapping flying pests. More particularly, the present invention relates to an apparatus affixed to the underside of a person's head covering, such as a bill, brim, visor, or the like that attracts and captures flying insects.
BACKGROUND
Typically, persons spending time outside will apply chemical repellants to their skin and clothing in an attempt to keep flying insects away. Flying insects that come near the face can bite the skin and be annoying. Many of the repellants available today are prohibited from use in certain outdoor activities, like golfing, for example, because of their chemical destructiveness to grass. Most insect repellants contain chemicals such as DEET, which has secondary harmful effects to humans and the environment. A majority of these repellents come in the form of sprays that are difficult to control and localize to prevent harming the environment. In addition, some people do not want to spray chemicals onto their bodies and clothing. Thus, these people will often end up making use of appendages such as hands to ward off the flying insects. However, this constant warding-off of pests makes enjoying the outdoors very difficult.
Therefore, there is a need for a pest entrapment device that is easy to use, consists of a non-toxic pest attractant, does not need to be sprayed onto a person's body or clothing, can be reapplied, and entraps flying pests that would otherwise be in a person's face.
SUMMARY OF THE INVENTION
In one aspect of the invention, a pest entrapment device may include an artificial pest attractant in combination with heat, sweat, and carbon dioxide, which are natural pest attractants, that are emitted from a person's face. The pest entrapment device can capture flying insects near the source of these natural pest attractants by attaching to the underside of an individual's head covering, for instance the bill, brim, visor, or the like of a baseball cap, hunting/fishing cap, helmet, visor, etc. Another aspect of the pest entrapment device is the removability and transferability of the device from one head covering to another head covering.
In one embodiment of the present invention, a pest entrapment device may include at least one clip consisting of at least three members: a top member, a middle member and a bottom member. The clip can be made out of metal, for example, iron, steel, or the like or any combination thereof, or plastic or composite. The top, middle and bottom members may all be fastened together by soldering, adhesive, fusion, or the like, or the members can be one piece, or any combination thereof. The middle member can be a flexible U-shaped piece that is releasable and engageable for expansion and retention over the various sizes of head covering bills, brims, visors, or the like in which the pest entrapment device may be attached to. The bottom member can have at least one cavity wherein a person can apply the pest attractant for pest capture. The top member of the pest entrapment device can be a solid metal piece in various sizes and shapes. The top member can contain a logo or similar type of advertisement, or it can be engraved or otherwise marked. The top member can be made out of a ferrous metal on which other objects can be magnetically attached to the top member, for example a ball marker.
Another embodiment of the invention can consist of one continuous piece of U-shaped flexible material such as metal or plastic or composite having a top base member and a bottom retaining member. The embodiment can be releasable and engagable with a head covering's bill, brim, visor, or the like. The top base member can be a solid piece in different shapes or sizes. The top base member can contain a logo, advertisement or other design, or can otherwise be engraved or marked. The top base member can also be made out of a ferrous metal in which other objects can be magnetized thereto, for example a ball marker. The bottom retaining member can contain at least one cavity on the outer surface wherein a person can apply the pest attractant for pest capture.
Another embodiment of the invention can include at least one member containing an upper surface and a lower surface. The lower surface can contain at least one cavity to support an insect attractant. The member can be releasably engaged with the underside of a bill, brim, visor or the like of a head covering, for example a baseball cap. The upper surface can include a type of attaching device, for example, adhesive, Velcro™, clip, alligator clip, double-sided tape, snaps, or other fastening device and the like.
Another embodiment of the invention can include at least one attachable attractant visor that can be attached to the underside of a head covering's bill, brim, visor, or the like of a head covering. The attractant visor can be made of plastic or other durable material that is lightweight and flexible to the contours of the underside of head covering's bill, brim, visor or the like. The attractant visor material can be clear or come in different colors. The attractant visor can be one size or it can have at least one perforation in which a person can cut or otherwise resize the attractant visor to size to fit a specific purpose head covering's brim, bill, visor, or the like. The attractant visor can have an upper surface and a lower surface. The upper surface can contain a substance or other adhesive means whereby the attractant visor can be attached to the underside of a head covering's bill, brim, visor, or the like. The upper surface can be attached by using an adhesive, double-sided tape, clips, alligator clips, snaps, Velcro™, and the like. The lower surface can provide a surface for a pest attractant to be applied to and entrap pests. One embodiment of the attractant visor can be that it is reusable wherein the attractant visor can be disengaged from the underside of a head covering's bill, brim, visor or the like, cleaned of entrapped pests, re-applied with pest attractant, and reengaged with the underside of the head covering's bill, brim, visor, or the like.
In another embodiment of the attractant visor, the attractant visor can be disposable, providing for a one-time use application wherein the attractant visor can be temporarily attached to the underside of a head covering's bill, brim, visor, or the like for a period of time and the user would like to remove the attractant visor and throw it away. For example, a disposable attractant visor can be used on a daily basis wherein the disposable attractant visor can be discarded after being used for the day. A new disposable attractant visor can then be attached to the underside of the head covering's bill, brim, visor, or the like. A further embodiment of the attractant visor can consist of layers of material, for example plastic sheets or the like. The attractant visor can have an upper surface and a lower surface. The upper surface can attach to the underside of a head covering's bill, brim, visor or the like by an adhesive, double-sided tape, snaps, Velcro™, clips, alligator clips, and the like. The lower surface can be a thin, hard plastic base wherein sheets of plastic can be attached thereto. The insect attractant can be applied to the outer surface of the top most plastic sheet wherein pests can be entrapped. After entrapment, the top sheet of plastic may be torn from the rest and disposed of, and the pest attractant can be applied to the outer surface of the next plastic sheet. Another embodiment can have the pest attractant already applied to the sheets of plastic so that after one is pulled off and disposed of, pest attractant will already be on the outer surface of the next plastic sheet. This type of disposable plastic sheet can be made out of other suitable material.
A further embodiment of the invention can include a pest entrapment kit. One embodiment of the pest entrapment kit can include at least one pest entrapment device, a pest entrapment device cleaning cloth, and a pest attractant. In one embodiment of the kit, the pest entrapment device is an attractant clip. In another embodiment of the kit, the pest entrapment device can be an attractant visor that can be reusable, disposable, or any combination thereof. The pest attractant can be in a solid or liquid state wherein the pest attractant is dispensed from a pest application device.
The above summary of the various aspects of the invention is not intended to describe each embodiment or every implementation of the invention. Rather, the embodiments are chosen and described so that others skilled in the art may appreciate and understand the principles and practices of the invention. The figures in the detailed description that follows more particularly exemplify these embodiments.
BRIEF DESCRIPTION OF THE DRAWINGS
These as well as other objects and advantages of this invention will be more completely understood and appreciated by referring to the following more detailed description of the exemplary embodiments of the invention in conjunction with the accompanying drawings of which:
FIG. 1 is a perspective view of a person outside encountering a pest problem;
FIG. 2 is a perspective view of a person outside using a pest entrapment device;
FIG. 3 is a perspective view of a pest entrapment kit;
FIG. 4 is a perspective view of one embodiment of an attractant clip;
FIG. 5 is side view of one embodiment of an attractant clip;
FIG. 6 is an illustration of a method of applying an attractant 26 to one embodiment of an attractant clip 24 ;
FIG. 7 is a perspective view of a pest attractant applicator;
FIG. 8 is an illustration of a method of cleaning an attractant clip;
FIG. 9 is a perspective view an attractant visor;
FIG. 10 is an illustration of a method of applying pest attractant to an attractant visor; and,
FIG. 11 is an illustration of a method of cleaning an attractant visor.
While the invention is amenable to various modifications and alternative forms, specifics thereof have been shown by way of example in the drawings and will be described in detail. It should be understood, however, that the intention is not to limit the invention to the particular embodiments described. On the contrary, the invention is to cover all modifications, equivalents, and alternatives.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The several embodiments as shown in the figures may allow the user of the pest entrapment device to have multiple choices to certain features and subcombinations of each embodiment, as there are several choices relating to the several embodiments available. Advantages and embodiments of this invention are further illustrated by the following examples, but the particular materials and amounts thereof recited in these examples, as well as other conditions and details, should not be construed to unduly limit this invention.
FIG. 1 is a perspective view of a person 12 outside 18 , for example, playing golf and experiencing the environmental problem of pests 14 , including biting and flying insects, mites, and ticks. These pests 14 are attracted to the face of a person by a number of chemical and physical factors, including carbon dioxide and water vapor from the person's breath 22 , body heat, and chemicals from a person's sweat that sits on the surface of the skin. Additionally, pests 14 are also attracted to certain colors and textures of clothing, as well as to the odor from soaps, perfumes, lotions and hair-care products. While that person may spray or otherwise put on pest repellent to ward off these pests, sometimes these repellents contain toxic chemicals that keep people from applying these repellents to their face. Additionally, sometimes these repellents, because they contain certain chemicals, are not allowed in certain outdoor activities as they may harm the environment, like grass on a golf course. Therefore, a person is left with swatting at these pests 14 as they fly around a person's face with their own hand and putting up with the pests 14 .
FIG. 2 is a perspective view of a person 12 outside 18 , for example, playing golf and using the pest entrapment device 24 . Once a person decides to go outside, that person may be subjected to pests 14 , such as flying and biting flies, etc. These pests 14 are attracted to the person's face because this is where a person's natural attractants for pests are released, such as carbon dioxide and water vapor from the breath 22 , body heat, and chemicals in the sweat found on the surface of the skin of the face. A person may use these natural attractants to their benefit by the addition of the pest entrapment device. The entrapment device can consist of an attractant clip 24 , which contains an artificial pest attractant 26 , that can be releasable and engageable to a person's head covering 16 , such as the bill, brim, visor, and the like. The entrapment device's location puts it in the vicinity of where pests 14 are already drawn because of a person's natural attractants, such as their breath 22 and sweat. The entrapment device redirects the pests 14 from the face toward the artificial pest attractant 26 , wherein the pests 14 are then trapped and no longer in the person's face. The pest entrapment device can come in a kit 20 that can be easily taken with a person and used, as described more fully in FIG. 3 below.
FIG. 3 is a perspective view of a pest entrapment kit 20 . The entrapment kit 20 can easily be carried on or with a person, for example in a purse, golf bag, or the like. The pest entrapment kit 20 can contain an attractant clip 24 , an attractant 26 , an attractant visor 42 and a cleaning cloth 44 . Another embodiment of the pest entrapment kit 20 may include at least one or more of an attractant clip 24 , a pest attractant 26 , an attractant visor 42 , and a cleaning cloth, or any combination thereof.
FIG. 4 is a perspective view of one embodiment of the attractant clip 24 . The attractant clip 24 can be constructed of metal or any other suitable material. The attractant clip can have a top surface 28 and a bottom surface 30 . The top surface 28 and bottom surface 30 can be joined by connecting member 32 , as further described in FIG. 5 . The top surface 28 can be imprinted with an image or logo or otherwise engraved or marked, which such marking can encourage the use of the attractant clip 24 . The bottom surface 30 can have at least one cavity 38 wherein the pest attractant 26 can be applied to entrap pests 14 . The top surface 28 , bottom surface 30 , and the connecting member 32 can all be one piece, separate pieces, or any combination thereof.
FIG. 5 is side view of one embodiment of the attractant clip 24 . The attractant clip 24 can have a tension spring 34 used to secure the attractant clip 24 to a head covering 16 . The tension spring 34 can be part of the connecting member 32 or it can be fastened by solder, adhesive, fusion or the like, to the connecting member 32 . The attractant clip 24 can also have a stop 60 . The stop 60 can be used in conjunction with an accessory marker 40 . The accessory marker 40 can be made of metal, as well, can be imprinted with an image or logo or otherwise marked. One or more accessory markers 40 can be stacked on the top surface 28 adjacent to the stop 60 and can be held in place by a magnet 36 . Accessory markers 40 can be used by a person 12 , for example, a golfer to mark a ball location, a hiker to mark a trail location, or the like to leave a mark in an environment 18 .
FIG. 6 is an illustration of a method of applying an attractant 26 to one embodiment of an attractant clip 24 . A person can after engaging an attractant clip 24 with a head covering's 16 bill, brim, visor and the like, invert the head covering 16 , wherein the bottom surface 30 will be upright exposing a cavity 38 . A person can then open a pest attractant applicator 48 by removing a lid 52 and holding the body 50 of the applicator 48 with one hand 46 , then using the other hand 46 to advance the pest attractant 26 from within the body 50 of the applicator 48 by turning a knob 54 that is located at the bottom of the applicator 48 . After an amount of pest attractant 26 is advanced beyond the opening of the body 50 of the applicator 48 , a person can then apply the pest attractant 26 to the cavity 38 on the bottom surface 30 of an attractant clip 24 .
FIG. 7 is a perspective view of a pest attractant applicator 48 . The attractant applicator 48 can come in different sizes and shapes, such as an applicator, a cartridge, a tube and the like. The attractant applicator 48 can have a lid 52 that comes off completely through the use of a detent or the like, or the lid 52 and the top of the body 50 are threaded and the lid 52 can be twisted off and on. The applicator 48 can have a lid that is fastened to the body 50 of the applicator 48 by means of a hinge, detent, or the like. Extraction of the attractant 26 from the applicator 48 can be a linear actuator application when the knob 54 is rotated. There can be a base piece or carriage 58 that is housed within the body 50 of the applicator 48 and engaged by a linear actuator, which can also be housed within the body 50 of the applicator 48 . The pest attractant 26 can be situated within the body 50 of the applicator 48 and on top of the base piece. As the knob 54 is rotated, the base piece is moved up the threaded rod and the pest attractant is expelled from the body 50 of the applicator 48 . Other applicators that can apply a viscid material are contemplated, for example, a squeeze tube.
The pest attractant 26 can be comprised of a grease makeup base, impregnated with carbon dioxide, sweetener and a sticky, viscid matter. The formulation for pest attractant 26 can allow it to be of a moldable solid form, in which it can be applied by pressure and rubbing on the cavity 38 of the bottom surface 30 of an attractant clip 24 . The pest attractant can stay moist for at least five hours after dispensing and applying to the cavity 38 of the attractant clip 24 .
FIG. 8 is an illustration of a method of cleaning an attractant clip 24 . A person can hold an attractant clip 24 in one hand 46 wherein the bottom surface 30 is upright and the cavity 38 is exposed. A person can use a cleaning cloth 44 with the other hand 46 to wipe out the pest attractant 26 and entrapped pests 14 that are in the cavity 38 of the attractant clip 24 . The cleaning cloth 44 can be made of microfiber cloth, paper, or any other type of cloth or paper or the like. The cleaning cloth 44 can be washed and reused or it can be a disposable cloth that is thrown out after each use, or any combination thereof. The attractant clip 24 is then ready to be used again, as described above in FIG. 6 .
FIG. 9 is a perspective view of an attractant visor 42 . The attractant visor 42 can have an upper surface and a lower surface. The upper surface can be releasable and engageable with the underside of a head covering's bill, brim, visor, or the like. The upper surface can be engaged with the use of an adhesive, double-sided tape, Velcro™, clips, alligator clips, snaps, or the like. The attractant visor 42 can be made out of a sturdy and flexible plastic with at least a 0.06 to 0.12 inch thickness. The lower surface of the attractant visor 42 would be used to apply the pest attractant 26 to, as described more fully in FIG. 10 . The attractant visor 42 can come in one size, or it may come in different sizes, or it can be of a larger size with the ability to be cut to a specific size depending on the head covering's 16 specific bill, brim, visor, or the like, size constraints, or any combination thereof.
FIG. 10 is an illustration of a method of applying pest attractant 26 to an attractant visor 42 . A person can attach the upper surface of an attractant visor 42 to the underside of a head covering's 16 bill, brim, visor, and the like and invert the head covering such that the lower surface of the attractant visor 42 is exposed. A person can then open a pest attractant applicator 48 by removing a lid and holding the body 50 of the applicator 48 with one hand 46 , then use the other hand 46 to advance the pest attractant 26 from within the body 50 of the applicator 48 by turning a knob 54 that is located at the bottom of the applicator 48 . After an amount of pest attractant 26 is advanced beyond the opening of the body 50 of the applicator 48 , a person can apply the pest attractant 26 to the bottom surface of an attractant visor 42 . The use of an attractant visor 42 provides for a greater area in which to apply attractant 26 and entrap pests 14 .
FIG. 11 is an illustration of a method of cleaning an attractant visor 42 . A person can hold a head covering 16 inverted in one hand 46 wherein the bottom surface of an attractant visor 42 is exposed. A person can use a cleaning cloth 44 with the other hand 46 to wipe the bottom surface of the attractant visor 42 removing the pest attractant 26 and entrapped pests 14 that are entrapped in the attractant 26 on the attractant visor 42 . The cleaning cloth 44 can be made of microfiber cloth, or any other type of cloth or paper or the like. The cleaning cloth 44 can be washed and reused or it can be a disposable cloth that is thrown out after each use, or any combination thereof. The attractant visor 42 is then ready to be used again, as described above in FIG. 10 . The attractant visor 42 can be reusable or it can be disposable or any combination thereof.
The preceding description has been presented only to illustrate and describe exemplary embodiments of invention. It is not intended to be exhaustive or to limit the invention to any precise form disclosed. Many modifications and variations are possible in light of the above teaching. Although specific examples have been illustrated and described herein, it will be appreciated by those of ordinary skill in the art that any arrangement calculated to achieve the same purpose could be substituted for the specific examples shown. This application is intended to cover adaptations or variations of the present subject matter. Therefore, it is intended that the invention be defined by the attached claims and their legal equivalents.
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The invention is directed at to a pest entrapment device for attracting and trapping flying pests around the head of a person. The apparatus includes an attachable device having at least one member, which member contains at least one cavity to hold a pest attractant. The attachable device is affixed to a head covering on the underside of a bill, brim, visor or the like. The pest attractant can be of a combination of grease, carbon dioxide, sweetener, and a sticky, viscid matter. The pest attractant also acts as a trapping substance to capture the flying insects. The pest entrapment device can be removed for cleaning and reapplication of the pest attractant.
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BACKGROUND
[0001] 1. Technical Field
[0002] This invention relates to formable surgical fasteners and, more particularly, to directionally biased formable staples for use in surgical staplers having anvil pockets for forming the staples.
[0003] 2. Background of Related Art
[0004] Surgical stapling instruments have become critical to many life saving surgical procedures. Surgical staples are usually mechanically inserted into tissue with surgical stapling instruments such as those known as anastomosis devices, including gastrointestinal anastomosis devices and transverse anastomosis devices. In such devices, the staples are loaded in one or more elongated rows into a cartridge. A mechanism for pushing, or driving the stapler is actuated to drive the staples through two or more sections of tissue toward a deforming anvil. At the conclusion of the driving operation, the legs of each staple are conventionally clamped or bent, by the anvil, to a closed configuration to complete the suture and join the tissue sections together. Gastrointestinal anastomosis-type devices drive and bend the staples aligned in a row sequentially in rapid sequence, while transverse anastomosis-type devices drive and bend all staples simultaneously. See, e.g. U.S. Pat. Nos. 4,520,817 and 4,383,634. Circular anastomosis-type devices simultaneously apply annular rows of staples to tissue. See, e.g. U.S. Pat. No. 4,304,236.
[0005] One type of conventional staple 20 , shown in FIGS. 1 - 3 , used with both gastrointestinal anastomosis and transverse anastomosis-type surgical stapling devices is made of stainless steel or titanium. The undeformed staple 20 (FIG. 1) is generally U-shaped and includes a back span 22 and two legs 24 depending substantially perpendicularly from the back span. Each leg 24 has a sharp chiseled end point 26 for piercing body organs or tissue. The chisel point also creates torque in the staple, allowing it to form. The staple penetrates the tissue from one side to engage an anvil spaced apart and located at an opposing side of the tissue. The staple is bent by having the legs engage and follow an anvil 25 to form a B-shaped closed staple 28 as shown in FIG. 2. In this closed configuration tissue is compressed between the legs and backspan of the staple.
[0006] Because of their substantially circular cross-section (FIG. 3), these conventional staples require approximately the same amount of force to form the staple into its final shape as is required to twist or malform it.
[0007] For example, referring back to FIG. 3, a conventional round cross section staple has a moment of inertia in the x forming dimension (I x ) given by the equation:
I x =¼πr 4
[0008] Its moment of inertia in the y twisting dimension (I y ) is given by the same equation
I y =¼πr 4
[0009] Using a round wire stock of uniform 0.009 in diameter (r=0.0045),
[0010] [0010] I x = I y = 1 4 π ( .0045 ) 4
= 3.22 × 10 - 10 in 4
[0011] The Moment of Inertia Ratio, given by the equation:
is I y /I x
[0012] [0012] 3.22 × 10 - 10 in 4 3.22 × 10 - 10 in 4 = 1
[0013] In order to insure accurate and consistent formation of these conventional staples, considerable research and development has been conducted in the areas of forming and driving structures. For example, anvils have been developed with specific coatings and/or structure, see, e.g. U.S. Pat. Nos. 5,173,133 and 5,480,089. Also, staple cartridges have been configured with driver structure to balance forces encountered during staple formation. See, commonly assigned U.S. Pat. No. 4,978,049 to Green. Thus, to control and insure consistent staple formation without twisting or deformation, extremely strict manufacturing tolerances have been implemented.
[0014] Other types of staples for different types of instruments are also found in the prior art. Some have non-circular cross-section. FIGS. 4, 4A and 4 B illustrate by way of example a staple of this type marketed by United States Surgical of Norwalk, Conn. for use with its MULTIFIRE ENDO HERNIA and ENDO UNIVERSAL 65 staplers. The anvil in these staplers, as shown in FIGS. 4C and 4D, is adjacent the backspan of the staple as tissue is approached from only one side. Unlike the staples described above which are formed by contact of the staple legs with anvil pockets, these staple legs are bent around an anvil abutting the backspan. This staple has a side portion H with a height dimension greater than the dimension of the base portion B (i.e. 0.020 in vs. 0.015 in.).
[0015] The Moment of Inertia Ratio is given by the equation:
Moment of Inertia Ratio = I y Ix = Moment of Inertia About Twisting Axis Moment of Inertia About Forming Axis
[0016] where I x =({fraction (1/12)})bh 3 and I y =({fraction (1/12)})hb 3 , with h=0.020 in. and b=0.015 in.
[0017] Thus, I x =({fraction (1/12)})(0.015)(0.020) 3 =1.0×10 −8 in 4 , and I y =({fraction (1/12)})(0.020)(0.015) 3 =6.0×10 −9 in 4 .
[0018] Accordingly,
Moment of Inertia Ratio = 6.01 × 10 - 9 in 4 1.10 × 10 - 8 in 4 = .60 / 1 = .60
[0019] This staple is specifically configured to accommodate twisting during staple formation to permit the legs of the staple to cross as shown in FIG. 4E. Thus, it is engineered so the force to form the staple is slightly greater than the force to malform or twist the staple. The forming is accomplished by bending the staple legs around an anvil positioned adjacent the inner surface 32 of the backspan 34 .
[0020] U.S. Pat. No. 5,366,479 describes a hernia staple with adjacent anvil having a height of 0.38 mm and a thickness of 0.51 mm. This staple is formed the same way as in FIGS. 4C and 4D. The moment of inertia ratio of this staple in accordance with the foregoing formula is as follows:
I x =({fraction (1/12)}) (0.51) (0.38) 3 =2.33×10 −3
I y =({fraction (1/12)}) (0.38) (0.51) 3 =4.2×10 −3
[0021] [0021] Moment of Inertia Ratio = 4.2 × 10 - 3 2.33 × 10 - 3 = 1.8
[0022] This staple for use as described would actually result in greater force to produce the desired shape. In fact, the staple legs would likely contact each other before crossing over into their crossed configuration.
[0023] Thus, it is apparent that this type of hernia staple, i.e. where the anvil is adjacent the backspan as the tissue is approached from only one side, is quite different than the staple of the present invention, e.g. the B-shaped staple, wherein the legs penetrate through the tissue to contact anvil pockets. These anvil pockets direct the staple legs to form the staple into a closed configuration. Thus staple configuration and considerations of twisting, bending and staple formation of these hernia staples are inapplicable to these considerations for anvil pocket directed staples, such as the B-shaped staples.
[0024] It would therefore be desirable to provide a staple configuration for a staple designed to penetrate tissue and contact an anvil pocket on the opposing side of tissue, which, in complement with conventional cartridge and anvil technology, enhances correct staple formation while reducing twisting/malformation caused by misalignment or unusual tissue while minimizing reliance on strict manufacturing tolerances.
SUMMARY
[0025] In accordance with the present disclosure a directionally biased staple is provided for use in surgical staplers having anvil structure spaced from the cartridge and having anvil pockets against which the staple is formed as the legs are forced into contact with the anvil. The directionally biased staple may be constructed in a wide variety of cross-sectional configurations including rectangular, elliptical, trapezoidal, etc. All of the configurations are distinguished by having a bending region requiring more force to twist or malform the staple than is required to properly form the staple. Preferably, these staples have Moment of Inertia Ratios on the order of between about 1.1 to about 3.0. The staple preferably corresponds in other respects to conventionally formed staples, i.e. having at least a pair of leg members interconnected by a crown portion wherein the leg members come into contact with and are formed by the anvil.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] Various preferred embodiments are described herein with reference to the drawings, wherein:
[0027] [0027]FIG. 1 is a side view of a conventional staple as known in the art;
[0028] [0028]FIG. 2A is a side view of the staple of FIG. 1 formed into a “B” configuration;
[0029] [0029]FIGS. 2B, 2C and 2 D illustrate the staple of FIG. 2 being formed as the legs, after penetrating tissue, come into contact with the anvil pockets;
[0030] [0030]FIG. 3 is a cross-sectional view of the staple of FIG. 1 taken along line 3 - 3 ;
[0031] [0031]FIG. 4 is a perspective view of a conventional rectangular cross-section staple as known in the art which is formed around an anvil contacted by the backspan;
[0032] [0032]FIG. 4A is a side view of the staple of FIG. 4.
[0033] [0033]FIG. 4B is a cross-sectional view of the staple of FIG. 4 taken along line 4 B- 4 B;
[0034] [0034]FIG. 4C, 4D and 4 E illustrate the staple of FIG. 4 being formed as the legs are bent by the pusher and the backspan is held against the anvil;
[0035] [0035]FIG. 5 is a side view of a directionally biased staple in accordance with the present disclosure;
[0036] [0036]FIG. 6 is a perspective view of the staple of FIG. 5;
[0037] [0037]FIG. 7 is a top view of the staple of FIG. 5;
[0038] [0038]FIG. 8 is a cross-sectional view of the staple of FIG. 5 taken along line 8 - 8 ;
[0039] [0039]FIG. 9A is a side view of the staple of FIG. 5 after it has been deformed to a “B” configuration;
[0040] [0040]FIG. 9B is an end view showing the coplanarity of the “B” sections of the staple of FIG. 9A;
[0041] FIGS. 10 A- 10 F are side views showing staple formation of the staple of FIG. 5 as the staple penetrates tissue and the legs come into contact with the anvil pockets;
[0042] [0042]FIG. 11A graphically illustrates the comparison of the mean twist (in inches) vs the offset of the conventional staple of FIG. 1 and the novel staple of FIG. 5.
[0043] [0043]FIG. 11B graphically illustrates the comparison of the mean twist (in %) vs the offset of the conventional staple of FIG. 1 and the novel staple of FIG. 5;
[0044] [0044]FIG. 12A is a cross-sectional view of another embodiment of a directionally biased staple in accordance with the present disclosure;
[0045] [0045]FIG. 12B is a cross-sectional view of another embodiment of a directionally biased staple in accordance with the present disclosure;
[0046] [0046]FIG. 12C is a cross-sectional view of another embodiment of a directionally biased staple in accordance with the present disclosure;
[0047] [0047]FIG. 13 is a cross-sectional view of another embodiment of a directionally biased staple in accordance with the present disclosure;
[0048] [0048]FIG. 14 is a cross-sectional view of another embodiment of a directionally biased staple in accordance with the present disclosure;
[0049] [0049]FIG. 15 is a perspective view of an endoscopic gastrointestinal anastomosis-type device for firing the staple of FIG. 5;
[0050] FIGS. 16 - 16 C are enlarged views showing the staple formation by the anvil pockets of the instrument of FIG. 15;
[0051] [0051]FIG. 17 is a perspective view of a gastrointestinal anastomosis-type device for firing the staple of FIG. 5;
[0052] [0052]FIG. 18 is a perspective view of a transverse anastomosis-type device for firing the staple of FIG. 5;
[0053] [0053]FIG. 18A is an enlarged view of the staple forming anvil and a portion of the disposable loading unit of the device of FIG. 18;
[0054] [0054]FIGS. 18B and 18C are enlarged views showing the staple formation by the anvil pockets of the instrument of FIG. 18A;
[0055] [0055]FIG. 19 is a perspective view of a circular anastomosis-type device for firing the staple of FIG. 5;
[0056] [0056]FIG. 19A is an enlarged view of the staple forming anvil and a portion of the disposable loading unit of the device of FIG. 19;
[0057] [0057]FIGS. 19B and 19C are enlarged views showing the staple formation by the anvil pockets of the instrument of FIG. 19A;
[0058] [0058]FIG. 20 is a perspective view of another embodiment of a directionally biased staple in accordance with the present disclosure;
[0059] [0059]FIG. 21 is a cross-sectional view taken along section lines 21 - 21 of FIG. 20;
[0060] [0060]FIG. 22 is a front elevational view of the directionally biased staple shown in FIG. 20 after the staple has been deformed to the B-shaped configuration;
[0061] [0061]FIG. 23 is a side elevational view from the direction of lines 23 - 23 of FIG. 22;
[0062] [0062]FIG. 24 is a perspective view of an anvil adapted for attachment to an endoscopic gastrointestinal anastomosis-type device;
[0063] [0063]FIG. 25 is an enlarged view of the indicated area of detail shown in FIG. 24;
[0064] [0064]FIG. 26 is a top partial cutaway view of the anvil shown in FIG. 24;
[0065] [0065]FIG. 27 is a cross-sectional view taken along section lines 27 - 27 of FIG. 26; and
[0066] [0066]FIG. 28 is a cross-sectional view taken along section lines 28 - 28 of FIG. 26.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0067] Preferred embodiments of the presently disclosed directionally biased staple will now be described in detail with reference to the drawings, in which like reference numerals designate identical or corresponding elements in each of the several views.
[0068] A directionally biased staple 50 in accordance with one embodiment of the present disclosure is illustrated in FIGS. 5 - 9 . Referring specifically to FIGS. 5 - 7 , staple 50 has a U-shaped configuration and includes a pair of substantially parallel legs 52 connected by a crown portion 54 with a bending region 55 therebetween. The legs are shown perpendicular to the backspan and are substantially straight along their length. Tissue penetrating portions 56 are preferably formed adjacent a distal end of legs 52 . These penetrating portions 56 may be of any known configuration which facilitates entry of the legs 52 into tissue to be stapled. As shown in FIG. 5, the tissue penetrating portions 56 are preferably formed in a chisel shape with points 58 adjacent inner facing sides of legs 52 .
[0069] In this embodiment, the cross section is preferably formed in a substantially rectangular configuration as shown in FIG. 8 with x designating the major base dimension (b) and y designating the minor height dimension (h) of the crown portion of the staple when positioned in an inverted-U configuration as shown in FIG. 5. As used herein, the staple is intended to be formed about the x dimension (x axis). Thus, as illustrated in FIGS. 10 A- 10 F staple 50 is formed downward relative to the page.
[0070] This cross-sectional configuration may be achieved by any known method including extrusion, rolling, coining, etc. Preferably, this configuration is accomplished by flat rolling round wire stock on opposing sides. In the fabrication process, the stock can be pre-rolled by the wire manufacturer or may be round wire stock which is rolled into the desired cross-sectional configuration by the staple manufacturer.
[0071] I y of the cross-sectional configuration of the novel staple illustrated in FIG. 5 is given by the equation:
I y =({fraction (1/12)})(b) 3 (h)
[0072] For a base dimension b=0.010 in and a height dimension h=0.008 in,
I y =({fraction (1/12)})(0.010) 3 (0.008)
I y =6.67×10 −10 in 4
[0073] I x is given by the equation:
I x =({fraction (1/12)}) (b)(h) 3
I x =({fraction (1/12)}) (0.010) (0.008) 3
I x =4.26×10 −10 in 4
[0074] The Moment of Inertia ratio (I y /I x ) is thus
6.67 × 10 - 10 in 4 4.26 × 10 - 10 in 4 = 1.57
[0075] Similarly, for a base dimension b=0.012 in and a height dimension h=0.008 in, I x =1.0×10 −9 in 4 and I y =5.12×10 −10 in 4 , yielding a Moment of Inertia ratio of 1.95.
[0076] Given that I y defines the dimension corresponding to proper formation of the staple when fired and I x defines the dimension corresponding to twisting and/or malformation, it is readily apparent that the directionally biased configurations provide a “functionally similar” forming force as a conventional round staple while requiring up to twice as much force to twist or malform when compared to conventional staples. This novel staple provides a substantial improvement over conventional staples.
[0077] Table 1 below sets forth by way of example Moment of Inertia Ratios for a variety of sizes and types of novel directionally biased staples for use in surgical staplers. Clearly staples of other dimensions are contemplated so long as they have the novel moment of inertia ratio described herein.
I y /I x Moment of Staple Height Base Inertia Size (in.) (in.) I y I x Ratio 3.5 mm. .007 .010 5.83 × 2.86 × ≈2.04/1 Titanim 10 −10 10 −10 3.5 mm. .007 .0115 8.87 × 3.29 × ≈2.70/1 Stainless 10 −10 10 −10 Steel 3.8 mm. .007 .010 5.83 × 2.86 × ≈2.04/1 Stainless 10 −10 10 −10 Steel 4.8 mm. .009 .014 2.00 × 8.51 × ≈2.35/1 Titanim 10 −9 10 −10 4.8 mm. .007 .0115 8.87 × 3.29 × ≈2.70/1 Titanim 10 −10 10 −10
[0078] Further, as illustrated below, for comparable size staples, the novel staple configuration provides increased resistance to twist without changing firing forces.
[0079] For example, twisting stress σ b is defined by the equation:
σ b = Mc I y
[0080] with moment M kept constant at M=1 lb•in.
[0081] For a conventional round 0.009 in. diameter staple: M=1 lb•in; c=0.0045 in; and I x =I y =3.22×10 −10 in 4 , so
σ b = ( 1.0 lb in ) ( .0045 in ) 3.22 × 10 - 10 in 4 σ b = 13 , 975 ksi
[0082] For the directionally biased staple of FIG. 8 having b=0.010 in and h=0.008 in: M=1.0 lb•in; c=0.005 in; and I y =6.67×10 −10 in 4 .
σ b = ( 1.0 lb in ) ( .005 in ) 6.67 × 10 - 10 in 4 σ b = 7 , 496 ksi
[0083] Thus, not only is this embodiment of the novel staple more resistant to twisting and/or malformation, e.g.≈14,000 ksi for the conventional staple vs.≈7,500 ksi for the novel staple, it also maintains minimal firing forces. The directionally biased staple is effectively desensitized against the effects of misalignment during staple formation while, at the same time maintaining a minimal firing force. This directionally intelligent design can reduce malformations caused by misalignment or twisting as well as reduce the need for very sensitive manufacturing tolerances for anvils and anvil forming cups, cartridges, etc.
[0084] The benefits of the novel staple can also be appreciated by reference to the graphs of FIGS. 11A and 11B. Since staples are forced through thick tissue and the staple cartridge and anvil can flex as tissue is compressed and can move slightly relative to another, this affects the point of contact between the staple leg points and the anvil. For example, if the anvil moves slightly out of alignment, the staple legs will contact a different point of the anvil which can affect uniform formation of the staple. Additionally, due to manufacturing tolerances, the staple points may not contact the anvil in the exact optimal location. Although such staple formation is clinically satisfactory and effective, the novel staple of the present application provides for more uniform formation of the row of staples and accommodates for manufacturing tolerances as it is more resistant to twisting. That is, the staple will have the tendency to bend in the direction of the thinner dimension which is desired since in this case the thinner dimension defines the desired bending direction. By relaxing manufacturing tolerances, the cost of manufacturing is reduced as well.
[0085] As shown in FIG. 11A, the prior art round staple, since the height and width are the same, can twist in different directions if there is misalignment between the staple and anvil. Thus the direction of twisting cannot be controlled. In contrast, the Moment of Inertia ratio of the novel staple of the present invention results in reduced twisting. Note that not only is there more twisting initially with the prior art staple, but as the offset increases, the amount of twisting in the current staple is greater at any degree of offset. The percentage of twist is defined as x/d×100% wherein x is the distance between the centerline of the staple and d is the diameter (or width) of the staple.
[0086] FIGS. 12 - 14 illustrate alternate directionally biased cross-sectional configurations in accordance with the disclosure. These cross-sectional configurations all have aspect ratios in the range of about 1.1 to about 3.0 wherein the x axis designates the major base dimension (b) and the y-axis designates the minor height dimension (h) in each of these cross-sections.
[0087] FIGS. 15 - 19 disclose by way of example several types of surgical staplers which can utilize the novel directionally biased staples. Other types of surgical staplers are also contemplated.
[0088] [0088]FIG. 15 illustrates a known endoscopic sequential stapler 100 including an anvil 110 and a staple cartridge 102 having novel directionally biased staples 50 loaded into the staple cartridge 102 thereof Referring to FIGS. 16 - 16 C, with anvil 110 and staple cartridge 102 in an open position (FIG. 16), tissue 120 is positioned between anvil 110 and cartridge 102 (FIG. 16A). Anvil 110 is now pivoted in the direction indicated by arrow “A” towards cartridge 102 (FIG. 16B) in a known manner to compress tissue 120 between anvil 110 and staple cartridge 102 . Thereafter, staples 50 are ejected from staple cartridge 102 into pockets 122 formed on anvil 110 . Pockets 122 deform staples 50 into a substantially B-shaped configuration (FIG. 16C). Anvil 110 can now be pivoted to the open position to permit tissue 120 to be removed from stapler 100 .
[0089] [0089]FIG. 17 illustrates a known open type sequential stapler 150 including an anvil 152 and a staple cartridge 154 having novel directionally biased staples loaded therein. Ejection of staples from stapler occurs in a manner similar to that disclosed in FIGS. 16 - 16 C and will not be discussed in further detail herein.
[0090] [0090]FIG. 18 illustrates a known transverse type surgical stapler 200 including an anvil 210 and a staple cartridge 202 having novel directionally biased staples 50 loaded into the staple cartridge 202 . Referring to FIGS. 18 A- 18 C, with anvil 210 and staple cartridge 202 in an open position, tissue 220 is positioned therebetween (FIG. 18A). Anvil 210 is now moved in the direction indicated by arrow “B” to an approximated position towards cartridge 202 (FIG. 18B) in a known manner to compress tissue 220 between anvil 210 and staple cartridge 202 . Thereafter, staples 50 are ejected from staple cartridge 202 into pockets 222 formed on anvil 210 . Pockets 222 deform staples 50 into a substantially B-shaped configuration (FIG. 18C). Anvil 210 can now be moved to the open position to permit tissue 220 to be removed from stapler 200 .
[0091] [0091]FIG. 19 illustrates a circular stapler 300 including an anvil 310 and a staple cartridge 302 having the novel directionally biased staples 50 loaded in the staple cartridge 302 . Referring to FIGS. 19 A- 19 C, with anvil 310 and staple cartridge 302 in an open position, tissue 320 is positioned therebetween (FIG. 19A). Anvil 310 is now moved towards cartridge 302 in a known manner to compress tissue 320 between anvil 310 and-staple cartridge 302 (FIG. 19B). Thereafter, staples 50 are ejected from staple cartridge 302 into pockets 322 formed on anvil 310 . Pockets 322 deform staples 50 into a substantially B-shaped configuration (FIG. 19C). Anvil 110 can now be moved to the open position to permit tissue 320 to be removed from stapler 300 .
[0092] FIGS. 20 - 23 illustrate another preferred embodiment of the presently disclosed directionally biased staple shown generally as 400 . Directionally biased staple 400 includes a crown portion 410 and a pair of outwardly angled legs 412 with a bending region 414 . Legs 412 define an angle about 5° to about 15° with crown portion 410 . Preferably, legs 412 define an angle of about 9° with respect to crown portion 410 . Alternately, other angle orientations are envisioned. The angle of legs 412 function to retain the staple within staple receiving slots of a staple cartridge prior to use, i.e., legs 412 frictionally engage the slot walls of a staple cartridge to retain the staple within a cartridge slot. Tissue penetrating portions 416 are formed at the distal end of legs 412 and preferably have a chisel shape with points 418 adjacent inner facing sides of legs 412 . Referring to FIG. 21, staple 400 has a cross-section having flat top and bottom surfaces 420 and 422 and semi-circular side surfaces 424 and 426 . Preferably, this cross-section is achieved by rolling top and bottom surfaces of wire stock. Alternately, other methods including extrusion and coining may be used to form staple 400 . Using the appropriate formulas, the Moment of Inertia ratio of staple 400 is approximately 2. Alternately, the dimensions of staple 400 may be varied in a manner to achieve a Moment of Inertia ratio within the preferred range of about 1.1 to about 3.
[0093] [0093]FIGS. 22 and 23 illustrate staple 400 in the formed state wherein staple 400 assumes a B-shaped configuration. FIGS. 24 - 28 illustrate an anvil 500 which is configured for attachment to a transverse-type surgical stapler such as shown in FIG. 18. Anvil 500 includes a plurality of staple pockets 510 formed in the surface of the anvil. Each staple pocket 510 includes first and second staple forming cups 512 and 514 and a channeling surface 516 disposed around each of the staple forming cups. An anvil including such a staple forming pocket has been disclosed in U.S. Pat. No. 5,480,089 filed Aug. 19, 1994, the entirety of which is incorporated herein by reference. Anvil 500 , including staple forming cups 512 and 514 and channeling surface 516 can be adapted for use with any of the surgical stapling devices described in the specification above including endoscopic gastrointestinal anastomosis-type devices (FIG. 15), gastrointestinal anastomosis-type devices (FIG. 17), transverse anastomosis-type devices (FIG. 18) and circular anastomosis-type devices (FIG. 19).
[0094] There are various methods of manufacture of the surgical staple. For example, the method could include the steps of flat rolling the wire stock to form at least one flat surface thereon and cutting a length of round wire stock to a predetermined length corresponding to a desired length of a finished staple or extruding the stock with a flat surface. The stock is bent into a form having a backspan and a pair of legs wherein the staple has an aspect ratio of between about 1.1 to about 3.0.
[0095] Although a specific embodiment of the present disclosure has been described above in detail, it will be understood that this description is merely for purposes of illustration. Various modifications of and equivalent structures corresponding to the disclosed aspects of the preferred embodiment in addition to those described above may be made by those skilled in the art without departing from the spirit of the present disclosure which is defined in the following claims, the scope of which is to be accorded the broadest interpretation so as to encompass such modifications and equivalent structures. For example the anvil shown and described in U.S. Pat. No. 5,480,089, the contents of which are incorporated herein by reference, can also be utilized.
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In accordance with the present disclosure a directionally biased staple is provided for use in all types of surgical staplers having anvil structure against which the staple is formed. The directionally biased staple may be constructed in a wide variety of cross-sectional configurations including rectangular, elliptical, trapezoidal, etc. All of the configurations are distinguished by having a bending region requiring more force to twist or malform the staple than is required to properly form the staple. Preferably, these staples have Moment of Inertia Ratios on the order of between about 1.1 to about 3.0. The staple preferably corresponds in other respects to conventional formed staples, i.e. having at least a pair of leg members interconnected by a crown portion wherein the leg members are formed by direct contact with the anvil.
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FIELD OF THE INVENTION
The present invention relates to implantable devices made from expanded polytetrafluoroethylene (e-PTFE) having improved ability to bind with body tissues, higher resistance to suture leakage and enhanced blood tightness. More specifically, the present invention relates to a sheet or a tubular implantable prosthesis, e.g., vascular prostheses or surgical patches or mesh, having a porous e-PTFE structure, whereby said porous structure has a solid insoluble, biocompatible and biodegradable material of natural origin present in the pores.
BACKGROUND OF THE INVENTION
e-PTFE porous tubes made by stretching and sintering have been used as tubular prostheses for artificial blood vessels for a number of years. These polymeric tubes have certain advantages over conventional textile prostheses, but also have disadvantages of their own. The e-PTFE tube has a microporous structure consisting of small nodes interconnected with many thin fibrila. The diameter of the fibrils, which depend on the processing conditions, can be controlled to a large degree and the resulting flexible structure has greater versatility in many aspects than conventional textile grafts. For example, e-PTFE grafts can be used in both large diameter, i.e. 6 mm or greater artificial blood vessels, as well as in diameters of 5 mm or less.
One particular problem, however, with expanded PTFE tubes, is their tendency to leak blood at suture holes and often propagate a tear line at the point of entry of the suture. As a result, numerous methods of orienting the node and fibril structure have been developed to prevent tear propagation. These processes are often complicated and require special machinery and/or materials to achieve this end.
Additionally, expanded PTFE arterial prostheses have been reported as suffering from poor, cellular infiltration and collagen deposition of the microporous structure by surrounding tissue. Numerous attempts to achieve improved blood compatibility and tissue binding properties have thus far fallen short. For example, in a study reported by Guidoin, et al., "Histopathology of Expanded PTFE", Biomaterials 1993, Volume 14, No. 9, cellular infiltration of the e-PTFE microporous structure was observed as being minimal. In an attempt to produce instant endothelial cell monolayers on graft surfaces, cryopreserved cultivated human saphenous vein endothelial cells were cultivated on reinforced PTFE prostheses. Prior to seeding of the endothelial cells on the prosthesis, the graft surface was precoated with human fibronectin. This study, reported by Kadletz, et al. in "Invitro Lining of Fibronectin Coated PTFE Grafts With Cryopreserved Saphenous Vein Endothelial Cells", Thorac. Cardiovasc. Surgeon 35 (1987) 143-147, reported discouraging results. More recently a study using laminin, collagen type I/III as well as fibronectin as precoating materials prior to seeding of endothelial cells on e-PTFE grafts was performed by Kaehler, et al., reported in "Precoating Substrate and Surface Configuration Determine Adherence and Spreading of Seeded Endothelial Cells on Polytetrafluoroethylene Grafts", Journal of Vascular Surgery, Volume 9, No. 4 April (1989). This study reported that cell adherence and cell spreading were distinctly superior on the surfaces which were precoated with fibronectin/type I/III collagen.
Thus far, e-PTFE substrates still suffer from endothelial cell adherence problems. The present invention is an attempt to address this problem, along with the problem of suture hole bleeding, by introducing into the porous walls of the e-PTFE prosthesis a solid natural material such as collagen, gelatin or derivatives of these materials. In addition to the above advantages, material such as collagen also serves to denucleate e-PTFE. Denuclearization removes air pockets and therefore reduces the thrombogenicity of the e-PTFE surface. Thus, the present invention seeks to improve prosthesis assimilation into the surrounding tissue, enhance the healing process as well as provide a more blood-tight prosthetic implant.
More recently, materials such as collagen and gelatin have been applied as coatings or as impregnations to textile grafts to avoid the need for preclotting the textile substrate prior to implantation. For example, U.S. Pat. Nos. 3,272,204, 4,842,575 and 5,197,977 disclose synthetic vascular grafts of this nature. Additionally, the '977 patent includes the use of active agents to enhance healing and graft acceptance once implanted in the body. The collagen source used in these patents is preferably from bovine skin or tendon dispersed in an aqueous solution that is applied to the synthetic textile graft by massaging or other pressure to cover the entire surface area and/or penetrate the porous structure.
U.S. Pat. No. 4,193,138 to Okita discloses a composite structure comprising a porous PTFE tube in which the pores of the tube are filled with a water-soluble polymer. The water-soluble polymer is used to form a hydrophilic layer which imparts an anti-thrombogenic characteristic to the e-PTFE tube. Examples of such polymers are polyvinylalcohol, polyethylene oxides, nitrogen-containing polymers and avionic polymers such as polyacrylic acid and polymethacrylic acid. Additionally, hydroxy esters or carboxy esters of cellulose and polysaccarides are also disclosed. This patent describes the diffusion of the water-soluble polymer into the pores of the tube and subsequent drying. The water-soluble polymer is then subjected to a cross-linking treatment to render it insoluble in water. Cross-linking treatment such as heat treatment, acetalization, esterification or ionizing radiation-induced cross-linking reactions are disclosed. The water-soluble materials disclosed in this patent are synthetic in nature.
SUMMARY OF THE INVENTION
The prostheses of the present invention include expanded PTFE substrates having pores present in the substrate wall structure wherein said pores contain a solid biocompatible material of natural origin. These biocompatible, biodegradable materials are selected from generally extracellular matrix proteins as will be further described hereinbelow. Extracellular matrix proteins are known to be involved in cell-to-cell and cell-to-matrix adhesion mechanisms. The pores of the present invention are present in the expanded PTFE structure as the interstices of the node/fibril configuration. As previously mentioned, the pore size is dependent on the processing and stretching parameters used in preparation of the tubular substrate. For purposes of this invention, the term "pores" will be used interchangeably with other terms such as interstices, voids and channels.
The present invention also concerns a method of making the biomaterial-containing PTFE prostheses. The method involves contacting and/or filling the voids of the e-PTFE substrate with a fluid containing a soluble biocompatible material which is capable of solidifying and preferably cross-linking to form an insoluble material, and preferably cross-linking of the biocompatible material is accomplished once it has sufficiently contacted and/or filled the voids.
Once the biocompatible material is solidified and/or cross-linked in the voids of the e-PTFE substrate, it serves as a solid natural binding surface which tends to promote further endothelial cell attachment and tissue ingrowth which is so critical to proper prosthesis acceptance and healing. As previously noted, prior to the present invention, no existing method has resulted in good endothelial cell attachment, due to the inert chemical nature of the PTFE surface which allows the layers of endothelial cells to easily peel off. The present invention is an attempt to overcome such deficiencies. As importantly, the structure of the present invention assists in the denuclearization of the e-PTFE structure. Also, a reduction in suture hole bleeding is obtained.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a portion of an implantable expanded PTFE member 1, having walls 10 and 11 nodes 14, fibrils 15, voids 12 and insolubilized biocompatible, biodegradable material 13.
FIG. 2 shows member 1 of FIG. 1 formed into an implantable tubular prosthesis 20.
FIG. 3 shows member 1 of FIG. 1 formed into an implantable surgical mesh or patch 30.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
For purposes of this invention, the term PTFE shall include fluorinated ethylene propylene polymers and perfluoroalkoxytetrafluoroethylene, as well as polytetrafluoroethylene, all of which are capable of being extruded, stretched and sintered to form porous walled tubular structures e-PTFE). Also for purposes of the present invention, the term tubular protheses shall include vascular prostheses such as grafts, endovascular prostheses and other tubular prostheses useful as implantable devices for the repair, maintenance or replacement of conduit vessels in the body. The preferred prosthetic devices of the present invention are those used in the vascular system. While tubes for vascular use are described as a preferred embodiment of the present invention, it is not limited thereto. Sheets and other structure which may be used or other purposes such as for hernia repair or repair of the myocardium are also within the contemplation of the present invention.
Those biocompatible, biodegradable materials of the present invention are generally extracellular matrix proteins which are known to be involved in cell-to-cell and cell-to-matrix adhesion mechanisms. These materials are selected from the group of extracellular matrix proteins consisting of collagen, including collagen I-V, gelatin, vitronectin, fibronectin, laminin, reconstituted basement membrane matrices such as those marketed under the trademark MATRIGEL® by Collaborative Biomedical Products, Inc. of Bedford, Mass. and derivatives and mixtures thereof. All of these extracellular matrix proteins are capable of being introduced into the voids, preferably via aqueous dispersion or solution and precipitated out to form a solid and optionally undergoing cross-linking to form body fluid insoluble materials. Alternately, the biocompatible, biodegradable material may be introduced in solid form using fluid-pressure or other techniques such as precrosslinking. As used herewith the term biodegradable means it will break down and/or be absorbed in the body. These biocompatible, biodegradable materials preferably substantially fill the voids of the e-PTFE wall and provide a binding substrate of natural origin on which surrounding tissue can easily attach. Rather than merely coat a portion of the e-PTFE, these materials are intended to serve as fillers for the voids.
One of the advantages to using e-PTFE as the material from which tubular prostheses are made is its natural antithrombogenic properties. While the inherent surface chemistry of e-PTFE promotes antithrombogenicity, permanent attachment of the neotima is generally compromised. For example, an outer capsule of perigraft material forms easily around the outer surface of a PTFE prosthesis, but may be easily stripped away. Typically, only a very thin inner capsule is formed on the intraluminal surface of a e-PTFE graft as compared with a conventional textile graft. When this happens, embolization may occur if some or all of the neotima detaches and becomes trapped in small blood vessels. Additionally, suture holes in PTFE prostheses walls generally require compression or topical pressure to accomplish hemostasis.
It is apparent, therefore, that the prostheses of the present invention must reach a balance between the natural antithrombogenic properties of e-PTFE and the properties of collagen which may tend to contribute somewhat to thrombosis formation, while providing a better blood-tight binding surface for tissue ingrowth.
In preparing the prostheses of the present invention, a solution or dispersion of the biocompatible, biodegradable material are separately formed. The extracellular matrix proteins which are used in the dispersions/solutions may be in the soluble form. These materials may be difficult to dissolve in water. Collagen is considered insoluble in water, as is gelatin at ambient temperature. To overcome this difficulty, collagen or gelatin may be preferably formed at acidic pH, i.e. less than 7 and preferably at a pH of about 2 to about 4. The temperature range at which these dispersions/solutions are formed is between about 4° C. to about 40° C., and preferably about 30° C.-35° C.
Type I collagen is the preferred collagen used in the present invention, although other types are contemplated. This molecule is a rod-like structure having an approximate average length of 300 nm and an approximate diameter of about 1.4 nm. These rods, referred to as tropocollagen, are composed of three alpha chains. Each chain is a left-handed helix comprising approximately 1,000 amino acids. The left-handed helix chains are wrapped around one another to form a super right-handed helix.
It is theorized that under physiclogic conditions, collagen molecules spontaneously aggregate into units of five molecules which then combine with other 5 unit aggregates in a lateral mode. The larger aggregates then combine with similar aggregates in a linear mode, eventually forming a collagen fiber. Collagen fibers are insoluble in physiclogic fluids because of the covalent cross-links that convert collagen into a network of its monomeric elements. Collagen fibers are responsible for the functional integrity of bone, cartilage and skin, as well as reinforcement of the structural framework of the blood vessels and most organs. Collagen is a hydroxy propylene, glycine-type protein which can be denatured by a variety of methods to form gelatin.
Another important property of collagen is that it initiates the clotting response when exposed to whole blood. Thus, collagen present in the voids of the prosthesis contributes to inhibition of prosthesis leakage during and immediately after implantation.
Once the biocompatible, biodegradable material is introduced into the e-PTFE voids and precipitated out into solid form, it is optionally cross-linked. Cross-linking of the material can be accomplished by any conventional method so long as it is not disruptive or have a negative effect on the e-PTFE substrate. For example, in the case of collagen, cross-linking can be accomplished by exposure to analdehyde vapor then dried to remove excess moisture and analdehyde or the collagen may be precrosslinked prior to introduction into the voids via a dispersion. In the case of gelatin, cross-linking is effectuated by similar methods.
In one embodiment, the process of preparing the e-PTFE prostheses of the present invention includes using a force to cause the dispersion of biocompatible material to penetrate the tubular walls of the prostheses, thereby contacting the internodal voids. This can be accomplished in a number of ways, such as by clamping one end of the tubular prosthesis, filling the inner lumen with a dispersion of the biocompatible, biodegradable material and using pressure to cause migration of the dispersion into the interstices of the e-PTFE walls. The transluminal flow of the dispersion is believed to permit sufficient contact between the biocompatible, biodegradable materials and the voids. While impregnation time depends on the e-PTFE pore size, graft length, impregnation pressure, collagen concentration and other factors, generally it can be accomplished in a short period of time, for example from less than 1 minute to 10 minutes at a preferred temperature range of 30° C. to 35° C. These parameters are not critical however, provided the voids are substantially filled with the biocompatible, biodegradable material. The soluble biocompatible, biodegradable material may be optionally subjected to cross-linking treatment such that it is solidified in place. For example, cross-linking by exposure to various cross-linking agents and methods such as formaldehyde vapor is then preferably carried out. Subsequent to formation of the cross-linked collagen, the prosthesis can then be rinsed and prepared for sterilization by known methods. Vacuum drying or heat treatment to remove excess moisture and/or cross-linking agents can then be used. The entire process of contacting the e-PTFE with the dispersion/solution can be repeated several times, if necessary, to achieve the desired impregnation.
In a preferred embodiment, the e-PTFE surface of the prosthesis is chemically modified to impart greater hydrophilicity thereto. For example, this can be accomplished by glow discharge plasma treatment or other means whereby hydrophilic moieties are attached to or otherwise associated with the e-PTFE surface. Such treatment enhances the ability of the e-PTFE to imbibe the biocompatible dispersion/solution.
Various pharmacological actives such as antimicrobials, antivirals, antibiotics, growth factors, blood clotting modulators such as heparin and the like, as well as mixtures and composite layers thereof can be added to the biocompatible dispersion prior to impregnation into the prosthesis.
In another embodiment of the present invention, the collagen or gelatin dispersion can be insolubilized prior to exposure to the prosthesis. This of course makes impregnation of the prosthesis and filling of the interstitial voids somewhat more difficult.
A preferred method of preparing the prostheses of the present invention includes preparing a mixture, i.e. a solution or dispersion of a known concentration of a biocompatible, biodegradable material selected from the group consisting of collagen, gelatin, derivatives of collagen, derivatives of gelatin and mixtures thereof, having a pH within a range of from about 2 to about 4 and preferably at a pH of about 3.5-3.9. The dispersion should have a low ionic strength, and prepared at temperatures of about 4° C. to about 40° C., and preferably about 30° C. to about 35° C. The e-PTFE surface is preferably modified by enhancing hydrophilicity with glow discharge plasma deposition prior to contacting the prosthesis with the biocompatible dispersion. The tubular prosthesis is then contacted under force with the dispersion to allow for impregnation and transluminary flow of the dispersion through the walls of the prosthesis, thereby substantially filling the interstitial voids. The prostheses are then treated with a chemical solution, such as buffered phosphate at a pH of about 7.4, to insolubilize the biocompatible material in place. Optionally, subsequent formaldehyde vapor exposure can be used to cross-link the material once deposited in the voids.
Although illustrative embodiments of the present invention have been described herein, it should be understood that the invention is not limited to those described, and that various other changes or modifications may be made by one skilled in the art without departing from the scope or spirit of the invention.
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An implantable prosthesis comprising an expanded polytetraethylene member having pores present in its wall structure wherein said pores contain a solid insoluble biocompatible, biodegradable material of natural origin. A process of preparing said prostheses is also disclosed.
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FIELD OF THE INVENTION
The present invention relates to a joint prosthesis and more particularly to an improved bipolar acetabular cup assembly for use in hip-joint replacements.
BACKGROUND OF THE INVENTION
Replacement of the hip joint due to deterioration from aging, illness or traumatic injury has become a relatively common procedure. Unfortunately, due to the complex articulation of the hip joint and the stresses present therein, it is relatively difficult to produce an adequate prosthetic device. More particularly, the natural hip joint can pivot in two directions as well as swivel to a limited extent. This flexibility is due to the ball and socket structure of the joint and has been mimicked by most prosthetics. Moreover, the stress applied in the hip joint and the limited choice of materials which can be used in human implants make it difficult to create a hip prosthesis with adequate durability and resistance to dislocation.
Perhaps because of the many challenges in designing a well-functioning hip replacement, numerous prosthetic devices have been developed for use in hip-joint replacement procedures. A common type of hip prosthetic utilizes a two-part structure including a femoral implant and an acetabular cup. The femoral implant has a head and neck which replace the head and neck of the femur and the acetabular cup fits into the acetabulum in the pelvis and receives the head of the femoral implant. The head on the femoral implant is typically spherically-shaped and is received in a correspondingly-shaped cavity in the cup. This ball and socket configuration replicates the natural flexibility in the hip joint.
As described generally above, significant difficulties arise in the design of a hip joint prosthetic and in some cases an improvement in one area results in a disadvantage in another area. For instance, the head of the femoral implant is typically captured in the acetabular cup by an inwardly projecting lower lip in the cup. Increasing the diameter of this lower lip generally increases the range of motion of the prosthesis, but also makes the joint less resistant to dislocation. Decreasing the size of the opening, on the other hand, can make the device more resistant to dislocation, but also may increase the difficulty of assembly during the operation.
Ease of assembly during operation is an important consideration in the design of a hip joint prosthetic. During the operation, the surgeon first separately installs the femoral implant and the acetabular cup. The head of the implant is then inserted into the cup. Because assembly occurs in the patient, the pieces are relatively hard to grasp. Furthermore, since the cup is normally spherical and polished, it can be particularly difficult to manipulate. Thus, any impediments to assembly are magnified during the installation and great care must be taken to insure that the implant can be easily assembled.
Because hip joint prosthetics occasionally require replacement, it is also important that the surgeon be able to disassemble the device. Moreover, because the surgeon may not know what type of prosthetic has been installed, it is important that the surgeon be able to disassemble the prosthetic without the need for implant-specific tools.
Most acetabular cups utilize a hollow stainless steel or titanium shell into which an ultra-high molecular weight polyethylene liner fits. Some type of deformable structure is formed at the opening of the cup to allow the head of the femoral implant to be inserted and captured. There are two common types of deformable structures that are used. In the first, such as illustrated in U.S. Pat. No. 4,770,658 to Gerimakis, plural fingers are formed in the lower end of the insert. A tapered locking ring fits around the fingers and may be moved between an assembly position where the fingers are free to flex outward to receive the head and a retention position where the fingers are constrained by the locking ring.
In a second type of deformable structure, such as shown in U.S. Pat. No. 4,241,463 to Khovaylo, the liner is formed with an upwardly and outwardly tapering recess to receive a retaining ring. The head, as it is installed, presses the retaining ring upwardly in the recess where it is able to let the head pass through. After the head passes through, the ring contracts down around the bottom of the head. Downward forces on the head simply pull the ring tighter because of the taper. The ring must be lifted back up into the top of the recess to allow the head to be removed. This often requires a special tool because of the confined space.
U.S. Pat. No. 5,062,853 to Forte illustrates, in one embodiment, an implant that combines the locking ring of Gerimakis with the retaining ring of Khovaylo. In Forte, when the locking ring is in a lower position, a recess is left for the retaining ring to expand into. When the locking ring is shifted into an upper position, the recess is eliminated, thereby preventing the locking ring from expanding to receive the femoral implant head. The locking ring includes an exterior rib that fits into a channel in the shell to retain the locking ring in place. Both the locking ring and retaining ring are split in Forte to allow the locking ring to contract sufficiently to disengage the rib from the channel to allow the ring to be moved between the upper and lower positions.
As mentioned above, because of the external rib in Forte, the locking ring must be contracted to be shifted between the upper and lower positions. While the splits in the locking and retaining rings allow this contraction to occur, the retaining ring must not fit too closely against the head or it would not be possible to contract the locking ring or the retaining ring. Therefore, in order to allow the retaining ring to contract, significant play must be left between the retaining ring and the head, which increases wear. Maintaining good conformity to the head is important to reducing wear. Furthermore, any play makes it more likely that the femoral implant head can be accidentally dislocated. Unfortunately, if the play were eliminated in Forte, it would be nearly impossible to retract the locking ring once the head was in the cup.
In addition to requiring some play for operation, the split locking ring in Forte also increases the chance that the ring will jam while being pressed in or removed. The split can also catch and tear the surgeon's glove, with the accompanying increased risk of infection.
It is therefore an object of the present invention to provide an acetabular cup that provides high conformity between the head of the femoral implant and the cup.
It is another object to provide such a cup that has a high lever-out force for the femoral implant head.
One more object of the present invention is to provide an acetabular cup that has a play-free fit with the femoral implant head.
It is also an object of the present invention to provide an acetabular cup in which the flexibility of the joint can be selected as desired.
Another object is to provide an acetabular cup that can be assembled and disassembled easily without special tools.
SUMMARY OF THE INVENTION
The present invention is an acetabular cup assembly for use with a femoral implant having a generally spherical head. The cup includes an outer shell with a generally spherical outer surface, an open end and a cavity extending into the shell from the open end. The cavity has a generally cylindrical section adjacent the open end and a top disposed opposite said open end with the cylindrical section including a first circumferential groove. The cup assembly also includes a bearing liner with an upper surface and a lower surface, with the lower surface including a generally hemispherical pocket configured to receive the spherical head. The bearing liner is configured to be disposed in the cavity in the shell with the upper surface disposed adjacent the top of the cavity and the lower surface facing the open end of the shell. A generally annular retaining ring is provided to be disposed adjacent the lower surface of the bearing liner. The retaining ring includes an inner surface that tapers inwardly and downwardly from the lower surface of the bearing liner toward a pocket opening to form a generally spherical continuation of the hemispherical inner pocket of the bearing liner. The pocket opening has an adjustable perimeter size and the retaining ring also includes an outer surface that tapers inwardly and downwardly from the lower surface of the bearing liner. The cup assembly further includes a generally annular locking ring with an upper end, a lower end, a cylindrical outer surface disposed between the upper end and the lower end and an inner surface that tapers inwardly and downwardly from the upper surface. The cylindrical outer surface includes at least one small circumferential rib and is configured to fit slidably into the cylindrical section of the cavity. The locking ring has a locked configuration in the cavity in which the rib is engaged in the first circumferential groove and the inner surface is disposed closely around the retaining ring to prevent expansion of the perimeter of the pocket opening and thereby prevent passage of the femoral implant head through the pocket opening. The locking ring further has a free configuration in which the locking ring is spaced apart from the bearing liner and the perimeter of the pocket opening is thereby free to expand to pass the femoral implant head. The locking ring is slidable between the locked and free configurations and at least part of the locking ring between the upper and lower ends is formed as a closed loop to prevent radial contraction of the locking ring inner surface as the locking ring is slid between the free and locked configurations.
Many other features, advantages and additional objects of the present invention will become apparent to those versed in the art upon making reference to the detailed description which follows and the accompanying sheets of drawings in which the preferred embodiments incorporating the principles of this invention are disclosed as illustrative examples only.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a cross-sectional view of an acetabular cup constructed according to the present invention.
FIG. 2 is an exploded view of the acetabular cup of FIG. 1 with an outer shell and bearing liner partially broken away.
FIGS. 3A-3C are cross-sectional views of the acetabular cup of the present invention showing insertion of a femoral implant head.
FIGS. 4A-4B are expansion views of a slot in a retaining ring as the formal implant head is inserted into the acetabular cup.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
An acetabular cup constructed according to the present invention is shown generally at 10 in FIG. 1. Cup 10 includes an outer shell 12, a bearing liner 14, a retaining ring 16 and a locking ring 18. Cup 10 is configured to fit into the acetabulum of a patient's pelvis and receive and selectively retain a spherical head 20 of a femoral implant 22. Femoral implant 22 is constructed generally according to the prior art.
As shown in FIG. 2, outer shell 12 includes a generally spherical outer surface 24, an open lower end 26 and a cavity 28 extending inwardly from the open lower end. The cavity has a cylindrical section 30 adjacent the lower end and extending up to a hemispherical top 32. An upper circumferential groove 34 and a lower circumferential groove 36 are formed in cylindrical section 30. Outer shell 12 is preferably formed of stainless steel or titanium, with the outer surface being highly polished to allow smooth rotation in the acetabulum.
Bearing liner 14 includes a hemispherical upper surface 38 configured to fit tightly into cavity 28 adjacent the hemispherical top. In the preferred embodiment, the liner is pressed into the shell and held in place by a small rib (not shown), although there are numerous other possibilities for holding the liner in place as will be understood by those of skill in the art.
A lower surface 40 is disposed opposite upper surface 38 and includes a central lower pocket 41 adapted to receive and form a bearing surface for the upper half of femoral implant head 20. Because head 20 and pocket 41 are both spherical in shape, the head is able to rotate and pivot freely within the pocket. Note that the spherical center of the pocket, or its center of curvature, is offset vertically upward from the center of curvature of the outer surface of the shell. As is understood in the art, this tends to urge the shell back to an orientation with the open lower end centered opposite the applied load.
Annular retaining ring 16 floats freely in cavity 28 between bearing liner 14 and locking ring 18. The retaining ring includes an upper surface 42 configured to fit against the lower surface of the bearing liner, a lower surface 43, and an outer surface 44 that tapers inwardly and downwardly from the upper surface. The outer surface includes a cylindrical section 45 adjacent upper surface 42. The cylindrical section allows the retaining ring to expand outward farther than would be the case if the taper were continuous over the entire ring. As will be described below, this expansion is necessary for the femoral implant head to pass into the cup.
An inner surface 46 includes an upper portion 48 that extends inwardly and downwardly from upper surface 42 toward a pocket opening 50. A lower portion 52 extends downwardly and outwardly from the pocket opening to the lower surface.
Upper portion 48 is shaped to form a spherical continuation of pocket 41 to thereby fit around and capture head 20. It should be noted that the extent to which upper portion 48 curves under head 20 controls both the range of pivotal motion of the femoral implant in the cup as well as the security with which the head is captured. For instance, if upper portion 48 curves under head 20 substantially, the head will be more securely captured, but the femoral implant will have less range of motion as well because it will impact lower portion 52 sooner. Thus, the size and angle of the lower portion controls the security and range of motion of the femoral implant. By providing multiple retaining rings with lower portions of different extents, it is possible to provide the surgeon with the option of selecting a desired balance of range of motion and resistance to dislocation.
Retaining ring 16 further includes a radial slot 54 which extends from the outer surface entirely through the retaining ring to the inner surface. The slot permits the ring to flex outward to thereby expand the perimeter of the pocket opening to allow the head to pass therethrough, as shown in FIGS. 3A-3C and 4A-4B.
Locking ring 18 is selectively positionable in cavity 28 to either prevent or allow the retaining ring to expand to pass the head. More particularly, locking ring 18 includes an upper end 60, a lower end 62, a cylindrical outer surface 64 disposed between the upper and lower ends and an inner surface 66 that tapers inwardly and downwardly from the upper surface. Outer surface 64 is sized to closely and slidably fit within cylindrical section 30 of shell 12. When the locking ring is fully engaged in the cavity with upper end 60 disposed against lower surface 40 of bearing liner 14, as shown in FIG. 3C, inner surface 66 fits closely against outer surface 44 of retaining ring 16. This locked position of the locking ring prevents the pocket opening from expanding to pass the head into or out of the cup.
When the locking ring is withdrawn partially from the cavity in a free configuration, as shown in FIG. 3A, the retaining ring, and therefore the pocket opening, is able to expand outwardly to allow the head to pass. Once the head is in place in the cup, the locking ring is shifted up into the locked configuration to secure the head. See FIG. 3C. Note that the locking ring includes a taper 67 which forms a continuation of lower portion 52 to allow maximum range of motion of the femoral implant.
Locking ring 18 is stabilized in cavity 28 by an upper circumferential rib 68 and a lower circumferential rib 70 formed on outer surface 64. When the locking ring is in the free configuration, upper rib 68 engages lower groove 36 to stabilize the locking ring in the free configuration. When the locking ring is located in the locked configuration, upper and lower ribs 68, 70 are engaged in upper and lower grooves 34, 36, respectively. The ribs thus resist movement of the locking ring out of the locked configuration. Note that when the head is installed and locked in the cup and then pulled downwardly, the downward pressure on the retaining ring is converted into outward pressure on the locking ring and inward pressure on the retaining ring by the taper of the interface therebetween. This tightens the locking ring in the cavity and the retaining ring around the femoral implant head and thereby prevents the locking ring from pulling out of the cavity and the head from pulling out past the retaining ring.
Ribs 68 and 70 must be relatively small to allow the locking ring to slide into the cavity without the need for a constriction in diameter of the locking ring. In the preferred embodiment, the ribs have a radial height of about 0.025-inches. Because the locking ring must undergo a localized deformation to allow the ribs to enter the cavity, the ribs are preferably formed with a sloping upper surface 72 to ease entry. A flat lower surface 74 is utilized to increase the force required to pull the ribs out of the grooves to withdraw the locking ring after pushing it into the locked configuration.
Although the ribs are sized to allow the surgeon to push the locking ring into the locked position with finger pressure, a circumferential ledge 76 is provided adjacent the lower end to facilitate removal. Importantly, no special tools are required to remove the locking ring. In particular, a surgeon can use a bone chisel between the ledge and the shell to lever the ring out of the locked position. The ledge is necessary because more force is required to remove the ring than to insert it and there is no area for the surgeon to grip the ring once it is fully installed.
During insertion of the locking ring into the cavity, considerable forces are created on the ribs. As described above, the locking ring is formed as a closed loop to eliminate contraction of the inner surface during installation and removal. However, because the locking ring cannot contract, the ribs must deform during installation. Although the sloping upper surface permits the ribs to enter the cavity without substantial permanent deformation, once installed, the flat lower surface causes the ribs to be significantly disfigured upon removal. This is not a problem because the only time the locking ring is removed is with revision of the hip joint, in which case the entire cup is removed and replaced.
The invented structure provides numerous advantages. In particular, the described structure allows for nearly perfect conformity to the spherical head of the implant over the entire surface area, with no substantial gaps. This is important because accurate conformity is critical to reducing wear on the surface of the plastic bearing.
Use of small ribs on the locking ring also helps to maximize conformity. Because the ribs are small and the locking ring is not split, the ring does not contract in diameter when moved between the locked and free configurations or positions. This means that the retaining ring, which directly abuts the locking ring, also does not need to contract to allow the locking ring to be engaged or disengaged. Thus, because it does not need room to contract, the retaining ring can be fit tightly against the lower portion of the implant head, thereby eliminating the need for any gap or play between the head and the retaining ring to allow for contraction. The use of a solid locking ring also reduces the chance of jamming the ring during installation due to uneven insertion.
The good conformity and play-free fit of the present invention also results in an acetabular cup with a high lever out force. In addition, as described above, a selection of various retaining rings with different diameter openings can be used to provide more or less freedom of movement of the head within the cup.
It will now be clear that an improvement in this art has been provided which accomplishes the objectives set forth above. While the invention has been disclosed in its preferred form, it is to be understood that the specific embodiments which have been depicted and described are not to be considered in a limited sense because there may be other forms which should also be construed to come within the scope of the appended claims.
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An acetabular cup assembly for use with a femoral implant. The cup assembly includes an outer shell, a bearing liner configured to fit into a cavity in the shell, a generally annular retaining ring and a locking ring configured to hold the retaining ring in the shell adjacent the bearing liner. The locking ring is slidable between locked and free configurations, with at least part of the locking ring being formed as a closed loop to prevent radial contraction of the locking ring inner surface as the locking ring is slid between the free and locked configurations. At least one small circumferential rib is formed on the outer surface of the locking ring to engage a corresponding circumferential groove in the shell when the locking ring is installed therein in the locked configuration.
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[0001] This application claims priority of European Patent Application No. 99204466.9, filed on Dec. 22, 1999.
[0002] The invention pertains to cross-linkable resin compositions which are obtainable from the reaction of glyoxylic acid and a hydroxy and/or epoxide group-containing polymer.
BACKGROUND OF THE INVENTION
[0003] Polymers that are used as binders in the preparation of compositions such as coatings, printing inks, adhesives, paper additives, and the like usually require that a cross-linking reaction occurs after the application of the composition.
[0004] This cross-linking reaction is necessary to obtain desired properties such as mechanical strength, resistance against chemical agents, durability, et cetera.
[0005] The cross-linking is often the result of the reaction between functional groups on the polymer and co-reactive functional groups on a cross-linker added to the composition. Examples are the reaction between the hydroxy groups of a polymer and melamine-formaldehyde resins or between hydroxy groups and polyisocyanate resins.
[0006] When the composition needs to remain stable as a one-component system, it is necessary to select cross-linkers with very low reactivity at ambient temperature. If the reactivity is too high, the composition will start to cross-link even before it is applied onto the substrate. Therefore, compositions are made the cross-linking reaction of which usually occurs at elevated temperatures. These elevated temperatures are required to increase the reactivity of the cross-linker or else to remove the blocking groups used to diminish said reactivity.
[0007] However, it would be beneficial, and in fact for certain applications it is mandatory, to have stable cross-linkable compositions that nevertheless are able to cross-link at room temperature. Such stable one-component systems have been described as having the ability to cross-link at room temperature after evaporation of the liquid carrier. In these systems the liquid carrier effectively blocks the cross-linking reaction. Examples of such reactive systems are aldehyde or ketone groups that react with hydrazides or hydroxylamines. In other systems the reactive groups are blocked by a volatile base. Acetoacetoxy groups that are converted to the corresponding enamine with ammonia will react with polyamines when the composition is applied and the ammonia is allowed to evaporate. Another possibility is to physically separate the functional groups, for example by means of steric hindrance, rendering the cross-linking reaction impossible before the composition is dried. An example of this is the reaction of a polymer dispersion with ethylene urea groups that react with a second polymer dispersion modified with aldehyde or acetal groups. However, all these reactive systems suffer from a major disadvantage, i.e. that the functional groups in the polymer and/or in the cross-linker must contain nitrogen atoms.
[0008] The presence of nitrogen atoms in the cross-link bonds makes the cross-linked composition susceptible to yellowing on exposure to certain chemicals and on aging. This yellowing is highly undesirable.
[0009] Another disadvantage of nitrogen atom-containing cross-linkers is the toxic nature of most of these compounds. The possibility of residual nitrogen-containing cross-linker migrating can render a composition unsuitable for use in applications where direct or indirect food contact is possible.
[0010] On the other hand, nitrogen-free cross-linkers are known, but they require hardening temperatures well above room temperature. Such a cross-linker has been disclosed in German patent DE 2,944,025, where glyoxylic acid is used as cross-linker for hydroxy group-containing polymers. It is described that 70 to 120% of glyoxylic acid is required with respect to the hydroxy value of the polymer. Under these conditions lower hardening temperatures at short hardening times are possible. Nevertheless, the hardening temperature still is 100° C. at 60 sec. There is a need for further improvement, one where non-toxic cross-linkers can be used at room temperature, giving a product that is resistant to yellowing.
SUMMARY OF THE INVENTION
[0011] The present invention has for its object to provide a stable one-component composition that is able to cross-link at ambient temperature without the use of nitrogen-containing cross-linkers. The present invention therefore pertains to a cross-linkable resin composition which is obtainable from the reaction of glyoxylic acid and a hydroxy and/or epoxy group-containing polymer in the absence of amino-containing cross-linkers, characterized in that 0.05-0.6 mole equivalent of glyoxylic acid is used per mole hydroxy group, with the epoxy groups being calculated as two hydroxy groups.
DETAILED DESCRIPTION OF THE INVENTION
[0012] Preferably 0.15-0.45 mole equivalent, more preferably 0.20-0.35 mole equivalent, of glyoxylic acid is used per mole hydroxy group.
[0013] The main polymer comprises oxirane (epoxy) and/or hydroxy-functional groups. These groups can be introduced into the polymer by several techniques. If the polymer is prepared by means of radical polymerization, the following functional monomers can be used:
[0014] Hydroxy-Functional Monomers:
[0015] Hydroxyethyl(meth)acrylate, hydroxypropyl(methacrylate), hydroxybutyl(meth)acrylate, esters of di- or trialkylene glycols, adducts of acrylic or methacrylic acid with epoxy-functional compounds, such as glycidyl versatate (Cardura™ E-10), or other glycidyl-functional materials.
[0016] Oxirane-Functional Monomers:
[0017] Glycidyl(meth)acrylate, allyl glycidyl ether, or monomers wherein the oxirane group is separated from the ethylenically unsaturated bond by a spacer. Such monomers can be prepared by the reaction of suitable hydroxy-functional monomers with epichlorohydrin, followed by removal of hydrochloric acid and subsequent ring-closure to the oxirane.
[0018] Furthermore, monomers having a cycloaliphatic oxirane group can be used. These monomers have the following structure:
[0019] R 1 =CH 3 or H
[0020] R 2 =—(CH 2 CH 2 ) n —, —(CH 2 CH 2 O) n —, or —[CH(CH 3 )CH 2 O] n —, wherein n=1-30 and which group is attached to the ethylenically unsaturated carboxylate moiety through a carbon atom.
[0021] Besides these functional monomers, the polymer can contain monomers selected from the esters of acrylic or methacrylic acid, such as methylmethacrylate, butyl(meth)acrylate, 2-ethylhexyl(meth)acrylate, ethylacrylate, vinylic monomers such as styrene, vinyl toluene, and vinyl acetate.
[0022] The copolymer can also contain minor amounts of monomers with a second functionality other than hydroxy or oxirane.
[0023] Preferably, the hydroxy and/or epoxy group-containing polymer is a (meth)acrylate polymer.
[0024] The radical polymerization can be carried out by means of different techniques, which are known in the art. Solution polymerization in an organic solvent or in a mixture of organic solvents using peroxides, hydroperoxides, or azo-initiators is one way to prepare the binders of this invention.
[0025] If the composition is water borne, emulsion polymerization of the monomers in the presence of a surface-active material and an initiator that generates free radicals in water is a convenient preparation method. Alternatively, the copolymer can be prepared in an organic solution and subsequently emulsified in water.
[0026] The glyoxylic acid in the prescribed amounts can be added to the polymer immediately after its preparation or simultaneously with the composition's preparation. The glyoxylic acid may be added neat or in combination with an organic solvent to better dissolve it in the liquid medium. Glyoxylic acid is usually used as a commercially available aqueous solution, for instance as a 50% solution.
[0027] The curable compositions of the present invention may optionally further comprise a curing catalyst. For the reaction of the hydroxy groups of the binder with the hydroxy and carboxyl groups of the glyoxylic acid monohydrate use is made of catalysts, including sulfonic acids, such as para-toluene sulfonic acid, aryl, alkyl, and aralkyl acid phosphates, mineral acids, such as sulfuric acid, and fluorinated acids such as trifluoroacetic acid and trifluoromethane sulfonic acid. Metal chelate complexes such as aluminum tris(acetylacetonate) or titanium bis(acetylacetonate) are useful catalysts to promote the reaction of the carboxyl group of glyoxylic acids with the epoxy groups of the binder. The weight % of the curing catalyst, if present, is in the range from about 0.01 to about 3 weight %, based on the total solids of the binder and cross-linker.
[0028] The following examples illustrate the invention.
EXAMPLE 1
[0029] Solvent Borne Acrylic Resin with Oxirane and Hydroxyl Groups
[0030] A round-bottomed flask was charged with 2,060 g of xylene. Cumene hydroperoxide (100 g) dissolved in 35 g of xylene was added by means of a membrane pump. 43.5 g of xylene were used to rinse the pump and the feed lines. In a separate container a monomer mixture was prepared consisting of:
styrene 1,318 g hydroxyethyl methacrylate 329 g butyl acrylate 1,407 g glycidyl methacrylate 1,000 g
[0031] The mixture of xylene and cumene hydroperoxide was heated to reflux (±140° C.) and the monomer mixture was dosed to the flask with a membrane pump over a period of 90 min. Xylene (52.2 g) was used to rinse the pump and the feed lines. After the addition was completed, the batch was held at reflux temperature for an additional 3 h.
[0032] The batch was then cooled down to 110° C. and 385 g of xylene and 194 g of n-butanol were added. The resin solution was filtered and stored in a container for use in Example 4.
EXAMPLE 2
[0033] Water Borne Polymer Dispersion with Oxirane and Hydroxyl Groups
[0034] A reactor was charged with the following ingredients: 323.1 g of demineralized water, 8.21 g of Igepal™ CO-897 (nonylphenol polyethylene oxide with 40 moles of ethylene oxide, ex Rhodia) and 12.52 grams of Trigonox™ AW-70 (70% aqueous solution of tert-butyl hydroperoxide, ex Akzo Nobel). The reactor was heated to 65° C. under a nitrogen blanket. At 65° C. a mixture of 8.5 g of styrene and 10.6 g of butyl acrylate was added to the reactor. Subsequently, a solution of 0.3 g of sodium formaldehyde sulfoxylate in 8.3 g of water was added to the reactor. In the meantime a monomer pre-emulsion was prepared in a separate container using the following ingredients in grams.
Demineralized water 400.6 Igepal - CO-897 ™ 41.8 Poly(vinylpyrrolidon) (molecular weight 30000) 4.4 Styrene 312.4 hydroxyethyl methacrylate 70.3 butyl acrylate 243.8 glycidyl methacrylate 215.2 2-mercaptoethanol 18.4
[0035] This pre-emulsion was added to the reactor over a period of 3 h. Simultaneously, the addition of a solution of 4.3 g of sodium formaldehyde sulfoxylate in 131.1 g of water was started. The addition of this mixture was completed in 4 h. After the additions were completed, the batch was kept at 65° C. for an additional 15 min. The batch was then cooled to room temperature (R.T.) and filtered. The polymer dispersion was stored in a container for use in Examples 3 and 5.
[0036] The polymer dispersion thus obtained had the following properties: solids content 50.0%, particle size 165 nm, pH 8.6. Size exclusion analysis on the polymer gave the following results: Mn 2,661; Mw 6730 (relative to polystyrene standards).
EXAMPLE 3
[0037] In a reaction flask 40 g of the water borne dispersion of Example 2, containing 1.61 meq epoxy groups/g solids and 0.58 meq hydroxy groups/g solids, to a total of 3.80 meq hydroxy groups per gram, were mixed with 3.60 g of a 50% aqueous solution of glyoxylic acid. The molar % of glyoxylic acid applied relative to the total of hydroxy groups was 32%. The dispersion was stirred gently for 5 h at 50° C. and then stirred at 70° C. for 3 h more after the addition of 200 mg of aluminum trisacetylacetonate. After cooling down to room temperature, the dispersion as such was subjected to coating experiments.
[0038] Using a 120 micron doctor's blade, the dispersion was applied onto glass plates and subsequently cured to clear films under the conditions mentioned in Table 1.
[0039] Spot tests on the films were carried out by contacting the film with a small wad of cotton wool completely soaked in solvent for 1 to 5 minutes. After the removal of the cotton wool, the spot was swept dry with a tissue and the damage to the film was visually observed.
[0040] In Table 1 the reference sample 1 was the dispersion prepared as described in Example 2. Reference sample 2 was a mixture of 40 g of the dispersion of Example 2 to which 200 mg of the aluminum (trisacetylacetonate) were added.
TABLE 1 Persoz Solvent spot tests Curing hardness methylethyl Example conditions (s) ketone xylene 3 30 min at 140° C. 320 Resistant Resistant Reference 1 30 min at 140° C. 135 Blister Blister 3 1 h at 80° C. 300 Slight stain Resistant formation Reference 1 1 h at 80° C. 111 Blister Blister Reference 2 1 h at 80° C. 130 Blister Blister 3 1 day at R.T. 107 2 days 172 5 days 258 7 days 268 21 days 277 Resistant
EXAMPLE 4
[0041] The solvent borne solution of Example 1 having a solid content of 60% was used. The solution contained 1.75 meq of epoxy/g of solids and 0.62 meq of hydroxy groups/g of solids, to a total amount 4.12 meq hydroxy groups per g solids.
[0042] Table 2 shows the Persoz hardness values and the appearance of the films after 7 days at R.T. obtained for different ratios of glyoxylic acid (=GA) applied versus the total of hydroxy groups of the binder. The films were prepared as mentioned in Example 3.
TABLE 2 Molar % glyoxylic Persoz hardness (s) acid versus at r.t. hydroxy Appear- after after Added to 20 g solution groups of ance after 7 14 of Example 1 binder of the film 1 day days days 3.42 g of solid glyoxylic 75 Strongly tacky — — acid monohydrate opaque 6 g of n-butanol 0.4 g of demi-water (Reference) 2.05 g of solid glyoxylic 45 Slightly tacky 165 213 acid monohydrate opaque 6 g of n-butanol 0.4 g of demi-water 1.45 g of solid glyoxylic 32 Clear not 168 220 acid monohydrate tacky 6 g of n-butanol 0.4 g of demi-water 1.75 g of 50% aqueous 24 Clear 85 203 249 glyoxylic acid 6 g of n-butanol 1.17 g of 50% aqueous 16 Clear 104 209 233 glyoxylic acid 6 g of n-butanol
EXAMPLE 5
[0043] The experiments performed in Example 4 were repeated with the water borne dispersion from Example 2. Formulations and results are given in Tables 3 and 4.
TABLE 3 Molar % glyoxylic Persoz hardness (s) acid versus at r.t. hydroxy Appear- after after Added to 20 g dispersion groups of ance after 7 14 of Example 1 binder of the film 1 day days days 5.62 g of 50% aqueous 100 Clear 61 87 120 glyoxylic acid 3.37 g of 50% aqueous 60 Clear 75 143 205 glyoxylic acid 2.40 g of 50% aqueous 43 Clear 98 169 249 glyoxylic acid 1.80 g of 50% aqueous 32 Clear 101 166 246 glyoxylic acid 1.20 g of 50% aqueous 21 Clear 105 187 241 glyoxylic acid 0.3 g of proglyde DMM
[0044] [0044] TABLE 4 Persoz hardness (s) after x days at room Curing Appearance temperature xylene conditions of the film 1 day 7 days spot test Added to 20 g dispersion of Example 2, 1.80 g of 50% aqueous glyoxylic acid fresh formulation 1 h at 80° C. clear 268 — resistant 30 min at 60° C. clear 170 230 3 months old 1 h at 80° C. clear 275 — resistant Added to 20 g dispersion of Example 2, 1.20 g of 50% aqueous glyoxylic acid 0.3 g of Proglyde DMM fresh formulation 1 h at 80° C. clear 195 — 3 months old 1 h at 80° C. clear 190 —
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The invention pertains to a cross-linkable resin composition which is obtainable from the reaction of glyoxylic acid and a hydroxy and/or epoxy group-containing polymer in the absence of amino-containing cross-linkers, characterized in that 0.05-0.6 mole equivalent of glyoxylic acid is used per mole hydroxy group, with the epoxy groups being calculated as two hydroxy groups. The composition can be cross-linked at room temperature, is non-toxic, and is not susceptible to yellowing.
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This application is a continuation-in-part application of a previous application by the same inventor bearing U.S. Ser. No. 29/019,951 filed Mar. 14, 1994.
This application is not, however, a continuation-in-part application of a previous application by the same inventor bearing U.S. Ser. No. 08/213,220 filed Mar. 14, 1994; however, the entire previous application Ser. No. 08/213,220 is incorporated herein by reference as if set forth in full below.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The apparatus of the present invention relates to sterilization containers for use in operating rooms of hospitals and other medical uses where sterilization is required.
2. General Background
Conventional hospital procedure places medical instruments for use in operating rooms in containers which are then placed in an "autoclave" which is a chamber in which critical temperature and humidity are obtained for a critical period of time to sterilize the instruments. The chamber is evacuated under a vacuum and the sterilized instruments, which are normally in a wrapping, are removed to storage until needed for use in the operating room or other section of the hospital.
The apparatus of the present invention provides a sterilization container with an improved fastening means, improved sealing means and improved visual sterilization indicator.
SUMMARY OF THE INVENTION
A sterilization container for medical instruments providing a closure having upper and lower members sealingly fastened together. Apertures are provided in the upper member of the closure and a removable plate having apertures therein snaps onto an annular collar provided integrally on the underside of the upper member and surrounding the apertures in the upper member to securely position a layer of material between the apertures of the upper member of the closure and the plate. The layer of material between the apertures of the upper member and the plate under temperature and humidity conditions achieved only during sterilization, allows vapors to pass through the sets of apertures and the material, but, under ambient temperature and humidity conditions the material is dry and prevents the passage of vapors therethrough.
BRIEF DESCRIPTION OF THE DRAWING
For a further understanding of the nature and objects of the present invention, reference should be had to the following description taken in conjunction with the accompanying drawing in which like parts are given like reference numerals and, wherein:
FIG. 1 is a top, front and left side perspective view of the preferred embodiment of the apparatus of the present invention;
FIG. 2 is a top plan view of the embodiment of FIG. 1;
FIG. 3 is a bottom plan view of the embodiment of FIG. 1;
FIG. 4 is a front elevational view of the embodiment of FIG. 1, the rear elevational view being a mirror of that shown;
FIG. 5 is a right side elevational view of the embodiment of FIG. 1, the side opposite being a mirror of that shown;
FIG. 6 is an exploded view of the cover or lid of the preferred embodiment of FIG. 1;
FIG. 7 is a partial cross-sectional view taken along LINES 7--7 of FIG. 5; and,
FIG. 8 is a partial cross-sectional view taken along LINES 8--8 of FIG. 1.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to the drawing, and in particular FIGS. 1-5, sterilization container 10 comprises a closure 12 having bottom member or base 14 and a top or cover or lid 16. These members are preferably spring stainless steel. The lid 16 sealingly mates with bottom 14 at sealing means 20, best seen in FIG. 8 and described further herein. Sterilization container 10 has a plurality of fastening means 40 mounted on the front and rear near sealing means 20 and these fastening means 40 are best seen in FIGS. 1, 4 and 5 and are described further herein. Fastening means 40 has mounted thereon a means 50 for indicating the integrity of sealed container 10 and a means 52 for indicating that container 10 has reached terminal sterilization, as best seen in FIGS. 1 and 4. Sterilization container 10 further comprises a means 70 for allowing the steam or sterilizing vapors into container 10 for sterilizing the instruments therein, best seen in FIGS. 1, 2, 6 and 7 and described further herein.
Referring now to FIGS. 1, 4, 5 and 8, the bottom 14 and top 16 of chamber 12 which forms sterilization container 10 is sealed by means 20. Means 20 comprises mating portions 22, 26 which form the edges of the side members of lid 16 and base 14, respectively. As best seen in FIG. 8, side portion 22 of lid 16 has at its marginal edge slots or notches 21, 23 which define protrusion or tooth 24. The marginal edge of side 26 of bottom 14 has a plurality of slots or notches 25, 29, 27 which define protrusions or teeth 28, 30. When lid or top 16 is closed onto bottom 14, the marginal edges of sides 22, 26 mate by having tooth 24 snugly fit into recess 29 and teeth 28, 30 snugly fitting into recesses 21, 23, respectively. Further, there is provided an extrudable gasket 33, best seen in FIG. 6, between the edges of side portions 22, 26 so that the sealing upon closure is air-tight. The gasket is preferably a silicone gasket which is removable and replaceable.
As best seen in FIGS. 1, 4 and 5, sterilization container 10 has its top or lid 16 removably fastened to bottom 14 by a plurality of fastener means 40. Fastener means 40 are connected to the bottom 14 and lid 16 as will be described herein and can be placed at selected locations on any side or front or rear of sterilization container 10. In the preferred embodiment, as shown in FIGS. 1-5, two such fastener means 40 are provided and they are provided at the front and rear of chamber 12, although such fasteners may be provided on either or both sides of chamber 12 or in a plurality of positions on the front, rear or sides of chamber 12. Fastener means 40 comprise plates 47 fixedly connected to bottom 14 and top 16, respectively. The connection can be by integral molding, welding or other conventional means. To upper plate 47 on lid 16 is mounted member 46 which has curled edge 44. This edge 44 accepts a plurality of conventional spring-loaded fasteners 42 which have claws 45 which engage the curled portion 44 of plate 46 and thereby fastens bottom 14 and lid 16. In the preferred embodiment, there are three (3) such fasteners 42 although more or less can be employed.
Also, provided at each fastener means 40 is a handle 62. Handle 62 has U-shaped end portions which fit at end 63 into a slot in fastener means 40 for connection thereto. A pad 60 in the form of a hollow cylindrical member can be placed over handle 62 for the comfort of the user. Also, padding 60 can be color coordinated to be an indicator of the type of instruments contained in sterilization container 10 (color indication of the instruments in sterilization container 10 can also be provided in alternate ways such as putting the color indication on the face 43 of fasteners 42). In this way, the user has a ready indication of the types of instruments that have been sterilized and are in sterilization container 10.
As best seen in FIGS. 1 and 4, the sterilization container 10 has mounted on fastener means 40 means 50 for indicating whether fastener means 40 has been unfastened after sterilization. Means 50 comprises a plastic piece in the shape of an arrow. Which upon unfastening of fastener 42 will splinter or break indicating a possible contamination of the instruments in sterilization container 10. This plastic arrow then when it is intact is an indication that sterilization container 10 has not been opened since it left an autoclave wherein the instruments were sterilized (this process will be described further herein).
Also, mounted on fastener means 40 is a means 52 for indicating the terminal sterilization of sterilization container 10. Means 52 comprises a plate 54 connected by some conventional means (such as welding, riveting or screw to fastener means 40). The plate has a small hole within which is placed chemically treated paper 56. This chemically treated paper 56 contains an ink which changes color when the proper parameters of temperature, time and humidity accomplish the terminal sterilization desired. (This chemically treated paper functions in much the same manner at litmus paper.)
As best seen in FIGS. 1, 2, 6 and 7, sterilization container 10 has provided in its lid 16 a means 70 for allowing sterilization of the instruments contained therein during sterilization conditions in an autoclave (one means 70 is shown, but several may be provided depending on the size of sterilization container 10). As best seen in FIGS. 1 and 2, means 70 comprises a plurality of lances or apertures 72, 74 placed in a pattern through lid 16 (while the rectangular 72 and circular-shaped 74 apertures are shown in the preferred embodiment, other shapes can be used). As best seen in FIG. 6, the underside 17 of lid 16 has upwardly (in FIG. 6, thus downwardly in normal use) projecting collar 75 of means 70. Further, as best seen in FIG. 7, collar 75 takes a slight "S" shape bending in and then bowing out and bending in again before it reaches its terminus at point 77. Collar or projection 75 is integrally formed with surface 17 of lid 16 (such as by integral molding or welding). Further, as best seen in FIGS. 6 and 7, a disposable paper filter 80 is placed over collar 75. Such a paper is disposable and has pores which open as heat and humidity are increased from ambient conditions in an autoclave. Suitable paper may be SPUNGUARD™ (phonetic) such as made by Kimberly-Clark. This paper has characteristics that when it is treated with heat and humidity, it allows the vapors to pass into chamber 12 through and when it dries it seals itself. With paper 80 mounted on collar 75 so that it overlaps in the manner shown in FIG. 7, a mounting plate 90 snaps onto collar 75 and secures the paper in the taught position shown in FIG. 7. Mounting plate 90 has a plurality of lances or apertures 92 therein and has an annular collar 94 sized to snap over collar 75. The apertures 92 should not align with apertures 72, 74 when means 70 is assembled.
With sterilization container 10 having paper 80 and plate 90 properly mounted as illustrated in FIG. 7 and with indicating paper 56 proper mounted in means 52 and with a second piece of such paper 56 placed within fastened and sealed chamber 12 with the instruments to be sterilized therein, the entire sterilization container 10 is placed in an autoclave (not shown). As described above, the autoclave is a conventional device used in a hospital for sterilization and provides proper parameters of temperature and humidity for a selected time to reach a desired sterilization condition (also known as "terminal sterilization"). After the necessary time period for terminal sterilization, the vapor that provides the temperature and humidity is evacuated under a vacuum and the sterilization container 10 is then removed and stored for selected use in the operating room or other location. In the autoclave, the disposable paper 80 becomes wet due to the heat and humidity of the autoclave and also porous. This allows the vapors to enter (ARROWS A and B of FIG. 7) sterilization container 10 and sterilize the instruments placed therein. When the autoclave is under a vacuum, the vapors are drawn out, the paper 80 then eventually dries and creates a seal at means 70. This in conjunction with sealing means 20 and fasteners 40 provides an effective, air-tight sterilization container 10 containing the now sterilized instruments. During the sterilization process in the autoclave, paper 56 has changed colors to indicate "terminal sterilization." The paper 56 in means 52 indicates that sterilization container 10 has been sterilized and the second portion of sterilization paper (not shown) that was placed in the sterilization container 10 also changed color due to the heat and humidity conditions in the autoclave indicating sterilization of instruments in sterilization container 10. Additionally, portions of such paper 56 can be used in the apertures 72 or 74 of means 70 for an indication to the user. Thus, when sterilization container 10 is removed from the autoclave, the color on padding 62 of handle 60 on fastener 42 of fastener means 40 indicates the type of instruments stored therein; the paper 56 indicates the existence of terminal sterilization of the sterilization container 10 and a means 50 indicates the integrity of the fastening of sterilization container 10. Upon opening of fastener means 40 means 50 will break and within sterilization container 10 should be sterilized instruments so indicated by chemical paper 56 therein.
Because many varying and differing embodiments may be made within the scope of the inventive concept herein taught and because many modifications may be made in the embodiment herein detailed in accordance with the descriptive requirement of the law, it is to be understood that the details herein are to be interpreted as illustrative and not in a limiting sense.
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A sterilization container for medical instruments comprising a closure having upper and lower members sealingly fastened together. Apertures are provided in the upper portion of the closure and a layer of material overlaps the apertures on the inside of the upper member so that under selected heat and humidity conditions vapors are allowed to pass through the apertures and the paper but under lower heat and humidity conditions the paper is dry and prevents the passage of vapor therethrough.
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The present invention relates to novel complexes in which amorphous calcium phosphates are stabilised by phosphopeptides. These complexes have anti-cariogenic effects, and may also be used as dietary supplements to increase calcium bioavailability and to heal or prevent diseases associated with calcium deficiencies. Methods of making the complexes of the invention and of treatment or prevention of dental caries, calcium malabsorption, and bone diseases are also provided.
BACKGROUND
Dental Caries
Dental caries is initiated by the demineralisation of hard tissue on the teeth by organic acids produced from fermentation of dietary sugar by dental plaque odontopathogenic bacteria.
Even though the prevalence of dental caries has decreased through the ‘use of fluoride in most developed countries, the disease remains a major public health problem. The estimated economic burden of treating dental caries in Australia in 1991 was $471 million, being higher than that for other diet-related diseases including coronary heart disease, hypertension or stroke.
In developing countries where the availability of industrialised food products is increasing, prevalence of dental caries is also increasing. Recent studies have highlighted a number of socio-demographic variables associated with the risk of developing caries; high risk is associated with ethnicity and low socio-economic status. The level of high-risk individuals has remained constant even though the overall severity and prevalence of disease in the community has decreased. Dental caries is therefore, still a major public health problem, particularly in ethnic and lower socioeconomic groups. This highlights the need for a non-toxic, anticariogenic agent that could supplement the effects of fluoride to further lower the incidence of dental caries. An agent which would reduce the dose of fluoride required to reduce the incidence of caries would be particularly desirable in view of community anxiety about fluoride, and in view of the fact that fluorosis can develop even at currently used doses.
The food group most recognised as exhibiting anticaries activity is dairy products (milk, milk concentrates, powders and cheeses). U.S. Pat. No. 5,130,123 discloses the component responsible for this anticariogenic activity as casein. However, the use of casein as an anticariogenic agent is precluded by adverse organoleptic properties and the very high levels required for activity.
Preliminary investigations determined that tryptic casein phosphopeptides contributed to the anticariogenic activity and this was made subject of U.S. Pat. No. 5,015,628. In particular, peptides Bos α s1 -casein X-5P (f59-79) (SEQ ID NO: 1), Bos β-casein X-4P (f1-25) (SEQ ID NO: 2), Bos α s2 -casein X-4P (f46-70) (SEQ ID NO: 3) and Bos α s2 -casein X-4P (f1-21) (SEQ ID NO: 4) were disclosed in U.S. Pat. No. 5,015,628 as follows:
(SEQ ID NO: 1)
Gln 59 -Met-Glu-Ala-Glu-Ser(P)-Ile-
Ser(P)-Ser(P)-Ser(P)-Glu-Ile-Val-
Pro-Asn-Ser(P)-Val-Glu-Gln-Lys 79 .
α s1 (59-79)
(SEQ ID NO: 2)
Arg 1 -Glu-Leu-Glu-Glu-Leu-Asn-Val-
Pro-Gly-Glu-Ile-Val-Glu-Ser(P)-Leu-
Ser(P)-Ser(P)-Ser(P)-Glu-Glu-Ser-
Ile-Thr-Arg 25 . β(1-25)
(SEQ ID NO: 3)
Asn 46 -Ala-Asn-Glu-Glu-Glu-Tyr-Ser-
Ile-Gly-Ser(P)-Ser(P)-Ser(P)-Glu-
Glu-Ser(P)-Ala-Glu-Val-Ala-Thr-Glu-
Glu-Val-Lys 70 . α s2 (46-70)
(SEQ ID NO: 4)
Lys 1 -Asn-Thr-Met-Glu-His-Val-Ser(P)-
Ser(P)-Ser(P)-Glu-Glu-Ser-Ile-Ile-
Ser(P)-Gln-Glu-Thr-Tyr-Lys 21 .
α s2 (1-21)
The preliminary determination of the above phosphopeptides for use in combination with CaHPO 4 and hydroxyapatite provided novel peptides having anticariogenic properties. However, subsequent investigations have determined that the Ser(P) cluster sequence motif within the previous disclosed phosphopeptides have the unexpected ability to stabilize their own weight in amorphous calcium phosphate. The ability of the above phosphopeptides and in particular the Ser(P) motif to stabilize amorphous calcium phosphate was quite unexpected and neither disclosed or taught in any publications known to the Applicants. We have now found that the amorphous form of calcium phosphate Ca 3 (PO 4 ) 1.87 (HPO 4 ) 0.2 xH 2 O where x≧1 stabilised by the casein phosphopeptides is the most soluble, basic form of non-crystalline calcium phosphate and a superior form of calcium phosphate which prevents caries and increases calcium bioavailability. Amorphous calcium phosphate (ACP) must be formed by careful titration of Ca ions (eg CaCl 2 ) and phosphate ions (eg Na HPO 4 ) while maintaining the pH above 7 (preferably 9.0) in the presence of the phosphopeptide. As the ACP is formed, the phosphopeptide binds to the nascent nuclei and stabilises the ACP as a phosphopeptide-ACP complex. Without the phosphopeptide, the ACP will precipitate out of solution and transform within minutes into the most stable calcium phosphate phase, crystalline hydroxyapatite (HA). HA, by being insoluble has limited anticariogenic activity and presents calcium in a poorly bioavailable form. The acidic phase of calcium phosphate CaHPO 4 , while certainly being more soluble than hydroxyapatite, is poorly bound by the phosphopeptide and poorly localised at the tooth surface and therefore also has limited anticariogenic activity. The unexpected ability of the aforementioned phosphopeptides and in particular Ser(P) cluster motif to stabilize amorphous calcium phosphate was not disclosed or taught in U.S. Pat. No. 5,015,628 and provides for the first time a reliable and effective method of producing a stabilized amorphous calcium phosphate complex having distinct and novel advantages in calcium treatments and delivery. U.S. Pat. No. 5,015,628 does not disclose the unique amorphous calcium fluoride phosphate phase Ca 8 (PO 4 ) 5 FxH 2 O where x≧1 which we have now found to be stabilised by the above phosphopeptides and can be localised at the tooth surface to provide superior anticaries efficacy. This unexpected ability to stabilize amorphous calcium phosphate forms the basis of the instant invention.
SUMMARY OF THE INVENTION
In one aspect, the invention provides a stable calcium phosphate complex, comprising amorphous calcium phosphate or a derivative thereof stabilized by a phosphopeptide, wherein said phosphopeptide comprises the sequence Ser(P)-Ser(P)-Ser(P)-Glu-Glu-(SEQ ID NO: 5).
In one embodiment, the complex may include phosphopeptide stabilized amorphous calcium fluoride phosphate.
The phosphopeptide (PP) may be from any source; it may be obtained by tryptic digestion of casein or other phospho-acid rich proteins such as phosphitin, or by chemical or recombinant synthesis, provided that it comprises the core sequence—Ser(P)-Ser(P)-Ser(P)-Glu-Glu-(SEQ ID NO: 5). The sequence flanking this core sequence may be any sequence. However, those flanking sequences in α s1 (59-79) (SEQ ID NO: 1), β(1-25) (SEQ ID NO: 2), α s2 (46-70) (SEQ ID NO: 3) and α s2 (1-21) (SEQ ID NO: 4) are preferred. The flanking sequences may optionally be modified by deletion, addition or conservative substitution of one or more residues. The amino acid composition and sequence of the flanking region are not critical as long as the conformation of the peptide is maintained and that all phosphoryl and carboxyl groups interacting with calcium ions are maintained as the preferred flanking regions appear to contribute to the structural action of the motif.
When the complex takes the form of phosphopeptide stabilized amorphous calcium fluoride phosphate, the calcium fluoride phosphate may be of the approximate formula [Ca 8 (PO 4 ) 5 F x H 2 O] where x≧1.
The complex may further include HPO 4 as a minor optional component to the complex. The HPO 4 is believed to act as a coating for the ACP cluster. When the complex takes the alternative form of a stable soluble alkaline calcium phosphate complex including stabilized amorphous calcium phosphate, the amorphous calcium phosphate may be of the approximate formula [Ca3(PO 4 ) 2 x H 2 O] where x≧1.
The complex may further include HPO 4 as a minor optional componet. The complex most preferably has a pH of about 9.0.
The complex formed preferably has the formula [(PP)(CP) 8 ] n where n is equal to or greater than 1, for example, 6. The complex formed may be a colloidal complex.
The phosphopeptide binds to the ACP cluster to produce a metastable solution in which growth of ACP to a size that initiates nucleation and precipitation is prevented. In this way, calcium and other ions such as fluoride ions can be localised, for instance at a surface on a tooth to prevent demineralisation and prevent formation of dental caries.
Thus, in a second aspect, the invention provides a stable calcium phosphate complex as described above, which complex acts as a delivery vehicle that co-localises ions including, but not limited to calcium, fluoride and phosphate ions at a target site. In a preferred embodiment, the complex is in a slow-release amorphous form that produces superior anti-caries efficacy.
In a particularly preferred embodiment of the invention, the stable calcium complex is incorporated into dentifrices such as toothpaste, mouth washes or formulations for the mouth to aid in the prevention and/or treatment of dental caries or tooth decay. The calcium complex may comprise 0.05-50% by weight of the composition, preferably 1.0-50%. For oral compositions, it is preferred that the amount of the CPP-ACP and/or CPP-ACFP administered is 0.05-50% by weight, preferably 1.0%-50% by weight of the composition. The oral composition of this invention which contains the above-mentioned agents may be prepared and used in various forms applicable to the mouth such as dentifrice including toothpastes, toothpowders and liquid dentifrices, mouthwashes, troches, chewing gums, dental pastes, gingival massage creams, gargle tablets, dairy products and other foodstuffs. The oral composition according to this invention may further include additional well known ingredients depending on the type and form of a particular oral composition.
In certain highly preferred forms of the invention the oral composition may be substantially liquid in character, such as a mouthwash or rinse. In such a preparation the vehicle is typically a water-alcohol mixture desirably including a humectant as described below. Generally, the weight ratio of water to alcohol is in the range of from about 1:1 to about 20:1. The total amount of water-alcohol mixture in this type of preparation is typically in the range of from about 70 to about 99.9% by weight of the preparation. The alcohol is typically ethanol or isopropanol. Ethanol is preferred.
The pH of such liquid and other preparations of the invention is generally in the range of from about 5 to about 9 and typically from about 7.0-9.0. The pH can be controlled with acid (e.g. citric acid or benzoic acid) or base (e.g. sodium hydroxide) or buffered (as with sodium citrate, benzoate, carbonate, or bicarbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, etc).
In other desirable forms of this invention, the oral composition may be substantially solid or pasty in character, such as toothpowder, a dental tablet or a toothpaste (dental cream) or gel dentifrice. The vehicle of such solid or pasty oral preparations generally contains dentally acceptable polishing material. Examples of polishing materials are water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, dihydrated calcium phosphate, anhydrous dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calcium carbonate, hydrated alumina, calcined alumina, aluminum silicate, zirconium silicate, silica, bentonite, and mixtures thereof. Other suitable polishing material include the particulate thermosetting resins such as melamine-, phenolic, and urea-formaldehydes, and cross-linked polyepoxides and polyesters. Preferred polishing materials include crystalline silica having particle sized of up to about 5 microns, a mean particle size of up to about 1.1 microns, and a surface area of up to about 50,000 cm 2 /gm., silica gel or colloidal silica, and complex amorphous alkali metal aluminosilicate.
When visually clear gels are employed, a polishing agent of colloidal silica, such as those sold under the trademark SYLOID as Syloid 72 and Syloid 74 or under the trademark SANTOCEL as Santocel 100, alkali metal alumino-silicate complexes are particularly useful since they have refractive indices close to the refractive indices of gelling agent-liquid (including water and/or humectant) systems commonly used in dentifrices.
Many of the so-called “water insoluble” polishing materials are anionic in character and also include small amounts of soluble material. Thus, insoluble sodium metaphosphate may be formed in any suitable manner as illustrated by Thorpe's Dictionary of Applied Chemistry, Volume 9, 4th Edition, pp. 510-511. The forms of insoluble sodium metaphosphate known as Madrell's salt and Kurrol's salt are further examples of suitable materials. These metaphosphate salts exhibit only a minute solubility in water, and therefore are commonly referred to as insoluble metaphosphates (IMP). There is present therein a minor amount of soluble phosphate material as impurities, usually a few percent such as up to 4% by weight. The amount of soluble phosphate material, which is believed to include a soluble sodium trimetaphosphate in the case of insoluble metaphosphate, may be reduced or eliminated by washing with water if desired. The insoluble alkali metal metaphosphate is typically employed in powder form of a particle size such that no more than 1% of the material is larger than 37 microns.
The polishing material is generally present in the solid or pasty compositions in weight concentrations of about 10% to about 99%. Preferably, it is present in amounts from about 10% to about 75% in toothpaste, and from about 70% to about 99% in toothpowder. In toothpastes, when the polishing material is silicious in nature, it is generally present in amount of about 10-30% by weight. Other polishing materials are typically present in amount of about 30-75% by weight.
In a toothpaste, the liquid vehicle may comprise water and humectant typically in an amount ranging from about 10% to about 80% by weight of the preparation. Glycerine, propylene glycol, sorbitol and polypropylene glycol exemplify suitable humectants/carriers. Also advantageous are liquid mixtures of water, glycerine and sorbitol. In clear gels where the refractive index is an important consideration, about 2.5-30% w/w of water, 0 to about 70% w/w of glycerine and about 20-80% w/w of sorbitol are preferably employed.
Toothpaste, creams and gels typically contain a natural or synthetic thickener or gelling agent in proportions of about 0.1 to about 10, preferably about 0.5 to about 5% w/w. A suitable thickener is synthetic hectorite, a synthetic colloidal magnesium alkali metal silicate complex clay available for example as Laponite (e.g. CP, SP 2002, D) marketed by Laporte Industries Limited. Laponite D is, approximately by weight 58.00% SiO 2 , 25.40% MgO, 3.05% Na 2 O, 0.98% Li 2 O, and some water and trace metals. Its true specific gravity is 2.53 and it has an apparent bulk density of 1.0 g/ml at 8% moisture.
Other suitable thickeners include Irish moss, iota carrageenan, gum tragacanth, starch, polyvinylpyrrolidone, hydroxyethylpropylcellulose, hydroxybutyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose (e.g. available as Natrosol), sodium carboxymethyl cellulose, and colloidal silica such as finely ground Syloid (e.g. 244). Solubilizing agents may also be included such as humectant polyols such propylene glycol, dipropylene glycol and hexylene glycol, cellosolves such as methyl cellosolve and ethyl cellosolve, vegetable oils and waxes containing at least about 12 carbons in a straight chain such as olive oil, castor oil and petrolatum and esters such as amyl acetate, ethyl acetate and benzyl benzoate.
It will be understood that, as is conventional, the oral preparations are to be sold or otherwise distributed in suitable labelled packages. Thus, a jar of mouthrinse will have a label describing it, in substance, as a mouthrinse or mouthwash and having directions for its use; and a toothpaste, cream or gel will usually be in a collapsible tube, typically aluminium, lined lead or plastic, or other squeeze, pump or pressurized dispenser for metering out the contents, having a label describing it, in substance, as a toothpaste, gel or dental cream.
Organic surface-active agents are used in the compositions of the present invention to achieve increased prophylactic action, assist in achieving thorough and complete dispersion of the active agent throughout the oral cavity, and render the instant compositions more cosmetically acceptable. The organic surface-active material is preferably anionic, nonionic or ampholytic in nature and preferably does not interact with the active agent. It is preferred to employ as the surface-active agent a detersive material which imparts to the composition detersive and foaming properties. Suitable examples of anionic surfactants are water-soluble salts of higher fatty acid monoglyceride monosulfates, such as the sodium salt of the monosulfated monoglyceride of hydrogenated coconut oil fatty acids, higher alkyl sulfates such as sodium lauryl sulfate, alkyl aryl sulfonates such as sodium dodecyl benzene sulfonate, higher alkylsulfo-acetates, higher fatty acid esters of 1,2-dihydroxy propane sulfonate, and the substantially saturated higher aliphatic acyl amides of lower aliphatic amino carboxylic acid compounds, such as those having 12 to 16 carbons in the fatty acid, alkyl or acyl radicals, and the like. Examples of the last mentioned amides are N-lauroyl sarcosine, and the sodium, potassium, and ethanolamine salts of N-lauroyl, N-myristoyl, or N-palmitoyl sarcosine which should be substantially free from soap or similar higher fatty acid material. The use of these sarconite compounds in the oral compositions of the present invention is particularly advantageous since these materials exhibit a prolonged marked effect in the inhibition of acid formation in the oral cavity due to carbohydrates breakdown in addition to exerting some reduction in the solubility of tooth enamel in acid solutions. Examples of water-soluble nonionic surfactants suitable for use are condensation products of ethylene oxide with various reactive hydrogen-containing compounds reactive therewith having long hydrophobic chains (e.g. aliphatic chains of about 12 to 20 carbon atoms), which condensation products (“ethoxamers”) contain hydrophilic polyoxyethylene moieties, such as condensation products of poly (ethylene oxide) with fatty acids, fatty alcohols, fatty amides, polyhydric alcohols (e.g. sorbitan monostearate) and polypropyleneoxide (e.g. Pluronic materials).
The surface active agent is typically present in amount of about 0.1-5% by weight. It is noteworthy, that the surface active agent may assist in the dissolving of the active agent of the invention and thereby diminish the amount of solubilizing humectant needed.
Various other materials may be incorporated in the oral preparations of this invention such as whitening agents, preservatives, silicones, chlorophyll compounds and/or ammoniated material such as urea, diammonium phosphate, and mixtures thereof. These adjuvants, where present, are incorporated in the preparations in amounts which do not substantially adversely affect the properties and characteristics desired.
Any suitable flavouring or sweetening material may also be employed. Examples of suitable flavouring constituents are flavouring oils, e.g. oil of spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, marjoram, cinnamon, lemon, and orange, and methyl salicylate. Suitable sweetening agents include sucrose, lactose, maltose, sorbitol, xylitol, sodium cyclamate, perillartine, AMP (aspartyl phenyl alanine, methyl ester), saccharine, and the like. Suitably, flavour and sweetening agents may each or together comprise from about 0.1% to 5% more of the preparation.
In the preferred practice of this invention an oral composition according to this invention such as mouthwash or dentifrice containing the composition of the present invention is preferably applied regularly to the gums and teeth, such as every day or every second or third day or preferably from 1 to 3 times daily, at a pH of about 4.5 to about 9, generally about 7.0 to about 9, for at least 2 weeks up to 8 weeks or more up to a lifetime.
The compositions of this invention can also be incorporated in lozenges, or in chewing gum or other products, e.g. by stiring into a warm gum base or coating the outer surface of a gum base, illustrative of which may be mentioned jelutong, rubber latex, vinylite resins, etc., desirably with conventional plasticizers or softeners, sugar or other sweeteners or such as glucose, sorbitol and the like.
In another embodiment, the complex of the invention is formulated to form a dietary supplement preferably comprising 0.1-100% w/w, more preferably 1-50% w/w, most preferably 1-10% and particularly 2% w/w. The complex may also be incorporated into food products.
Accordingly, in a third aspect, the invention provides compositions including pharmaceutical compositions comprising the calcium complex as described together with a pharmaceutically-acceptable carrier. Such compositions may be selected from the group consisting of dental, anti-cariogenic compositions, therapeutic compositions and dietary supplements. Dental compositions or therapeutic compositions may be in the form of a gel, liquid, solid, powder, cream or lozenge. Therapeutic compositions may also be in the form of tablets or capsules.
In a fourth aspect, there is provided a method of treating or preventing dental caries or tooth decay comprising the step of administering a complex or composition of the invention to the teeth or gums of a subject in need of such treatments. Topical administration of the complex is preferred.
In a fifth aspect, the invention relates to methods of treating one or more conditions related to calcium loss from the body, especially from the bones, calcium deficiency, calcium malabsorption, or the like. Examples of such conditions include, but are not limited to, osteoporosis and osteomalacia. In general any condition which can be improved by calcium bioavailability is contemplated.
In a sixth aspect, the invention also provides a method of producing a stable complex of calcium phosphate as described above, comprising the step of:
(i) obtaining a solution of phosphopeptide having a pH of about 9.0; (ii) admixing (i) with solutions comprising calcium, and inorganic phosphate and optionally fluoride at a pH of about 9.0; (iii) filtering the mixture resulting from step (ii), and (iv) drying to obtain the said complex.
The complexes of the invention are useful as calcium supplements in subjects in need of stimulation of bone growth, for example subjects undergoing fracture repair, joint replacement, bone grafts, or craniofacial surgery.
These complexes are also useful as dietary supplements in subjects who for any reason, such as dietary intolerance, allergy, or religious or cultural factors, are unable or unwilling to consume dairy products in an amount sufficient to supply their dietary calcium requirements.
It will be clearly understood that, although this specification refers specifically to applications in humans, the invention is also useful for veterinary purposes. Thus in all aspects the invention is useful for domestic animals such as cattle, sheep, horses and poultry; for companion animals such as cats and dogs; and for zoo animals.
DETAILED DESCRIPTION OF THE INVENTION
The invention will now be described in detail by way of reference only to the following non-limiting Examples.
EXAMPLE 1
Preparation of CPP-ACP and CPP-ACFP
A. Preparation of CPP-ACP
A 10% w/v casein (Murray Goulburn, Victoria, Australia) or caseinate solution was prepared at pH 8.0 and then digested with trypsin at 0.2% w/w of the casein for 2 h at 50° C. with the pH controlled to 8.0±0.1 by NaOH addition. After digestion the solution was adjusted to pH 4.6 by the addition of HCl and the precipitate removed by centrifugation or microfiltration. However, the solution can also be clarified by microfiltration at pH 8.0 without acidification. The supernatant or microfiltrate was then adjusted to pH 9.0 with NaOH, then CaCb (1.6 M) and Na 2 HPO 4 (1 M) at pH 9.0 were added slowly (≦1% vol per mm) with constant agitation with the pH held constant at 9.0±0.1 by NaOH addition. CaCl 2 and sodium phosphate were added to the final concentrations of 100 mM and 60 mM respectively. Following the addition of the calcium and phosphate solutions, the solution was microfiltered through a 0.1 or 0.2 μm microfilter (ceramic or organic) to concentrate the solution five fold. The retentate was then diafiltered with one to five volumes of distilled water. The retentate after diafiltration was spray-dried to produce a white powder that was 50% CPP and 40% ACP and residue water. Analysis of the CPP of the CPP-ACP complex by reversed-phase HPLC, sequence analysis and mass spectrometry revealed that the only peptides that are capable of stabilizing the amorphous calcium phosphate and retained during the microfiltration and diafiltration are Bos α s1 -casein X-5P (f59-79) (SEQ ID NO: 1), Bos β-casein X-4P (f1-25) (SEQ ID NO: 2), Box α s2 -casein X-4P (f46-70) (SEQ ID NO: 3) and Bos α s2 -casein X-4P (f1-21) (SEQ ID NO: 4) and truncated and heat modified forms of these peptides.
B. Preparation of CPP-ACFP
A 10% w/v casein or caseinate solution was prepared at pH 8.0±0.1 and then digested with trypsin at 0.2% w/w of the casein for 2 h at 50° C. After digestion the solution was adjusted to pH 4.6 by the addition of HCl and the precipitate removed by centrifugation or microfiltration. However the solution can also be clarified by microfiltration at pH 8.0 without acidification. The supernatant or microfiltrate was then adjusted to pH 9.0 with NaOH, then CaCl 2 (1.6 M), Na 2 HPO 4 (1 M) at pH 9.0 and 200 mM NaF were added slowly (≦1% vol per min) with constant agitation with the pH held constant at 9.0±0.1 by NaOH addition. CaCl 2 , sodium phosphate and NaF were added to the final concentrations of 100 mM, 60 mM and 12 mM respectively. Following the addition of the calcium, phosphate and fluoride solutions the solution was microfiltered through a 0.1 or 0.2 μm microfilter (ceramic or organic) to concentrate the solution five fold. The retentate was then diafiltered with one to five volumes of distilled water. The retentate after diafiltration was spraydried to produce a white powder that was 50% CPP and 40% ACFP and residue water.
The powdered CPP-ACFP was then reconstituted in distilled water to produce highly concentrated solutions. For example, a 10% w/v CPP-ACFP solution containing 640 mM Ca, 400 mM phosphate and 80 mM F (1,520 ppm F − ) at pH 9.0 has been prepared as well as a 20% CPP gel containing 1.28 M Ca, 800 mM phosphate and 160 mM F (3,040 ppm F − ) at pH 9.0. This solution and gel exhibit a significantly greater anticariogenicity relative to the fluoride alone and therefore are superior additives to toothpaste and mouthwash and for professional application to improve the efficacy of the current fluoride-containing dentifrices and professionally-applied products.
EXAMPLE 2
Structural Studies of CCP-ACP
A. Structure and Interaction of CCP-ACP
Casein phosphopeptides containing the Ser(P) cluster, i.e. the core sequence motif Ser(P)-Ser(P)-Ser(P)-Glu-Glu-(SEQ ID NO: 5), have a marked ability to stabilize calcium phosphate in solution. Solutions containing 0.1% w/v α s1 (59-79) (SEQ ID NO: 1) at various pH, calcium and phosphate concentrations, but constant ionic strengths were used to characterize the peptide's interaction with calcium phosphate. The peptide was found to maximally bind 24 Ca and 16 Pi per molecule as shown in Table 1.
The ion activity products for the various calcium phosphate phases [hydroxyapatite (HA); octacalcium phosphate (OCP); tricalcium phosphate (TCP); amorphous calcium phosphate (ACP); and dicalcium phosphate dihydrate (DCPD) were determined from the free calcium and phosphate concentrations at each pH using a computer program that calculates the ion activity coefficients through the use of the expanded Debye-Hückel equation and takes into account the ion pairs CaHPO 4 o , CaH 2 PO 4 + , CaPO 4 − and CaOH + the dissociation of H 3 PO 4 and H 2 O and the ionic strength. The only ion activity product that significantly correlated with calcium phosphate bound to the peptide independently of pH was that corresponding to ACP [Ca 3 (PO 4 ) 1.87 (HPO 4 ) 0.02χ H 2 O] indicating that this is the phase stabilized by a α s1 (59-79) SEQ ID NO: 1. The peptide α s1 (59-79) (SEQ ID NO: 1) binds to forming ACP clusters producing a metastable solution preventing ACP growth to the critical size required for nucleation and precipitation. The binding of α s1 (59-79) (SEQ ID NO: 1) to ACP results in the formation of colloidal complexes with the unit formula [α s1 (59-79) (SEQ ID NO: 1)(ACP) 8 ] n where n is equal to or greater than one. It is likely that the predominant form is n=6 as α s1 (59-79) (SEQ ID NO: 1) cross-linked with glutaraldehyde in the presence of ACP runs as a hexamer on polyacrylamide gel electrophoresis. Interestingly, the synthetic octapeptide α s1 (63-70) AcGlu-Ser(P)-Ile-Ser(P)-Ser(P)-Ser(P)-Glu-GluNHMe (SEQ ID NO: 6) only binds 12 Ca and 8 Pi per molecule i.e. (ACP) 4 and the synthetic peptides corresponding to the N-terminus α s1 (59-63), Gln-Met-Glu-Ala-Glu (SEQ ID NO: 7) and the C-terminus α s1 (71-78), Ile-Val-Pro-Asn-Ser(P)-Val-Glu-Gln (SEQ ID NO: 8) of α s1 (59-79) did not bind calcium phosphate as shown in Table 1. These results indicate that conformational specificity is essential for full ACP binding.
B. NMR Studies
Protein flexibility in solution is the outstanding characteristic to emerge from spectroscopy studies on proteins containing the Ser(P) cluster sequence (-Ser(P)-Ser(P)-Ser(P)-) such as phosvitin from egg yolk and phosphophoryn from tooth dentine. Phosphorylation appears to destabilise secondary and tertiary structure rather than promote higher levels of ordering. However, flexible phosphorylated sequences adapt more regular conformations when bound to calcium phosphate. Optical rotatory dispersion (ORD), circular dichroism (CD), hydrodynamic and 31 P nuclear magnetic resonance (NMR) measurements of the caseins all indicate that α s1 -casein and β-casein have a rather open structure in solution with many amino acid side chains exposed to solvent and relatively flexible. 31 P-NMR relaxation measurements indicate that Ser(P) residues are relatively mobile in β-casein.
We have demonstrated medium- and long-range nuclear Overhauser enhancements (nOes) in 2D 1 H NMR spectra of α s1 (59-79) (SEQ ID NO: 1) in the presence of Ca 2+ indicating a conformational preference. Two structured regions were identified. Residues Val72 to Val76 are implicated in a β-turn conformation. Residues Glu61 to Ser(P)67, which extend over part of the Ser(P) cluster motif—Ser(P)-Ser(P)-Ser(P)-Glu-Glu- (SEQ ID NO: 5) are involved in a loop-type structure. 2D NMR studies on β-casein(1-25) (SEQ ID NO: 2) in the presence of calcium have shown a medium range nOe in the—Ser(P) 17 -Ser(P)-Ser(P)-Glu-Glu 21 - (SEQ ID NO: 5) motif region between the CαH of Ser(P) 18 and NH of Blu 20 . Further medium range nOes include one between the CαH of Ser 22 and NH of Thr 24. Evidence from the 1 H NMR spectra of α s2 -casein(1-21) [4] have shown that several residues including those around the—Ser(P)-Ser(P)-Ser(P)-Glu-Glu- (SEQ ID NO: 5) are perturbed. Furthermore, there are medium range nOes between NH of Ser(P) 8 and NH of GLU 10 . This is yet another example of a medium range nOe in the—Ser(P)-Ser(P)-Ser(P)-Glu-Glu- (SEQ ID NO: 5) motif. Other examples of medium range nOes include that between the NH of Ile 14 and NH of Ser(P) 16 .
In summary the NMR data indicates that preferred conformations exist for these peptides in the presence of calcium ions. Molecular modeling of both α s1 (59-79) (SEQ ID NO: 1) and β(1-25) (SEQ ID NO: 2) using the constraints derived from the NMR spectroscopy have indicated that the peptides adopt conformations that allow both glutarnyl and phosphoseryl side chains of the cluster motif—Ser(P)-Ser(P)-Ser(P)-Glu-Glu (SEQ ID NO: 5) to interact collectively with calcium ions of the ACP.
The relationship between CPP structure and interaction with amorphous calcium phosphate was investigated using a series of synthetic peptide homologues and analogues indicated in Table 1. These studies showed that the cluster sequence—Ser(P)-Ser(P)-Ser(P)-Glu-Glu- (SEQ ID NO: 5) was mainly responsible for the interaction with ACP and that all three contiguous Ser(P) residues are required for maximal interaction with ACP.
TABLE 1
Calcium Phosphate Binding by CPP and Synthetic Homologues
and Analogues
V ca
V Pi
mol/mol
mol/mol
Ca/P
(SEQ ID NO: 5) ΣΣΣEE
9
6
1.5
(SEQ ID NO: 9) SΣΣEE
2
1
2.0
(SEQ ID NO: 10) EΣΣEE
2
1
2.0
(SEQ ID NO: 11) DΣΣEE
2
1
2.0
(SEQ ID NO: 12) θθθEE
9
6
1.5
(SEQ ID NO: 13) SθθEE
2
1
2.0
(SEQ ID NO: 14) AΣAE
0
0
(SEQ ID NO: 15) IAΣAEA
0
0
(SEQ ID NO: 16) EAIAΣAEA
0
0
(SEQ ID NO: 17) AΣAΣAE
0
0
(SEQ ID NO: 18) AΣAΣAΣAE
2
1
1.5
(SEQ ID NO: 19) AΣAΣAΣAΣAE
6
4
1.5
(SEQ ID NO: 1) α s1 (59-79)
24
16
1.5
QMEAEΣIΣΣΣEEIVPNΣVEQK
(SEQ ID NO: 6) α s1 (63-70) EΣIΣΣΣEE
12
8
1.5
(SEQ ID NO: 5) α s1 (66-70) ΣΣΣEE
9
6
1.5
(SEQ ID NO: 8) α s1 (71-78) IVPNΣVEQ
0
0
(SEQ ID NO: 7) α s1 (59-63) QMEAE
0
0
(SEQ ID NO: 2) β(1-25)
24
16
1.5
RELEELNVPGEIVEΣLΣΣΣEESITR
(SEQ ID NO: 20) β(14-21)EΣLΣΣΣEE
12
8
1.5
Σ = Ser(P), θ = Thr(P), E = Glu, D = Asp, S = Ser, A = Ala, I = Ile, Q = Gln, M = Met, V = Val, P = Pro, K = Lys, L = Leu, T = Thr, G = Gly and R = Arg.
EXAMPLE 3
Structural Studies Using Hydroxyapatite (HA)
Similarly, we investigated the adsorption of the CPP and synthetic homologues and analogues onto HA (Table 2). These data also confirm that the Ser(P) cluster sequence is the major determinant for high affinity binding and that all three contiguous Ser(P) residues are essential as loss of any one, even when substituted with a Glu or Asp, resulted in a considerably lower affinity constant K as shown in Table 2.
TABLE 2
CPP and Synthetic Peptide binding to HA at 37° C.
K
N
ml/
μmol/
Molecular
μmol
m 2
Area nm 2
(SEQ ID NO: 1) α s1 (59-79)
415
0.35
4.75
QMEAEΣIΣΣΣEEIVPNΣVEQK
(SEQ ID NO: 6) α s1 (63-70) EΣIΣΣΣEE
10,370
0.47
3.56
(SEQ ID NO: 5) α s1 (66-70) ΣΣΣEE
12,845
0.52
3.27
(SEQ ID NO: 8) α s1 (71-78) IVPNΣVEQ
—
—
—
(SEQ ID NO: 7) α s1 (59-63) QMEAE
—
—
—
(SEQ ID NO: 5) ΣΣΣEE
12,845
0.52
3.27
(SEQ ID NO: 10) EΣΣEE
1,513
0.96
1.74
(SEQ ID NO: 11) DΣΣEE
6,579
0.81
2.04
(SEQ ID NO: 12) θθθEE
12,234
0.51
3.27
(SEQ ID NO: 21) TθθEE
1,013
0.55
3.03
(SEQ ID NO: 22) θTθEE
837
0.44
3.77
(SEQ ID NO: 23) θθTEE
1,799
0.46
3.61
Σ = Ser(P), θ = Thr(P)
Interestingly, repeating these HA adsorption experiments with salivary coated HA (sHA) revealed that the Ser(P) cluster motif was still the major determinant for adsorption although the affinities of the peptides for the sHA was slightly reduced by the presence of the salivary proteins. These results suggest that the predominant interaction of the CPP with pellicle and plaque is likely to be electrostatic and mediated by the Ser(P) cluster motif of the CPP.
We have also studied the docking of the peptide Ser(P)-Ser(P)-Ser(P)-Glu-Glu- (SEQ ID NO: 5) onto three crystallographic planes of HA, {100}, {010} and {001} using computer simulation techniques and the unit cell coordinates of synthetic HA. These simulation studies revealed that the peptide—Ser(P)-Ser(P)-Ser(P)-Glu-Glu- (SEQ ID NO: 5) is more likely to the {100} surface, followed by the {010} surface. The Ser(P)- cluster motif can therefore bind to both {100} and {010} surfaces thus allowing deposition of calcium, phosphate and hydroxyl ions on the {100} surface enabling growth of the HA crystal along the c-axis only. These results therefore can know explain the c-axis growth of HA crystals in enamel and dentine. Detailed examination of the computer simulation data shows that the—Ser(P)-Ser(P)-Ser(P)-Glu-Glu- (SEQ ID NO: 5) conformer with the greatest relative binding energy is positioned on the HA surface such that the carboxyl groups of the glutamyl residues and the phosphoryl groups of the phosphoseryl residues are in proximity to the HA surface with maximal contact between these groups and surface calcium atoms.
EXAMPLE 4
Anticariogenic Activity of CPP-ACP in Human In Situ Studies
The ability of the 1.0% w/v CPP-ACP pH 7.0 solution to prevent enamel demineralisation was studied in a human in situ caries model. The model consists of a removable appliance containing a left and right pair of enamel slabs placed to produce a plaque retention site. The inter-enamel plaque that developed (3-5 mg) was bacteriologically similar to normal supragingival plaque. On frequent exposure to sucrose solutions over a three week period, the increase in levels of mutans streptococci and lactobacilli and in sub-surface enamel demineralisation resulted in the formation of incipient “caries-like” lesions.
Two exposures of the CPP-ACP solution per day to the right pair of enamel slabs for 12 subjects produced a 51% ±19% reduction in enamel mineral loss relative to the left-side, control enamel. The plaque exposed to the CPP-ACP solution contained 78±22 μmol/g calcium, 52±25 μmol/g P 1 and 2.4±0.7 mg/g CPP compared with 32±12 μmol/g calcium and 20±11 μmol/g P 1 in the control plaque. The level of the CPP was determined by competitive ELISA using an antibody that recognizes both α s1 (59-79) (SEQ ID NO: 1) and β(1-25) (SEQ ID NO: 2). Electron micrographs of immunocytochemically stained sections of the plaque revealed localization of the peptide predominantly on the surface of microorganisms but also in the extracellular matrix.
Although these results indicate that CPP are incorporated into developing dental plaque, the actual level determined by ELISA would not be a true representation of that incorporated due to the breakdown of the CPP in plaque through the action of phosphatase and peptidase activities. The incorporation of the CPP-ACP in the plaque resulted in a 2.4 fold increase in the plaque calcium and a 2.6 fold increase in plaque P i with a Ca/P i ratio consistent with ACP.
EXAMPLE 5
Anticariogenic Potential of the CPP-ACP in a Mouthwash Study
A clinical trial of a mouthwash used thrice daily containing 3.0% CPP-ACP pH 9.0 showed that the calcium content of supragingival plaque (lower anterior teeth excluded) increased from 169±103 μmol/g dry weight to 610±234 μmol/g after use of the mouthwash for a three day period, and inorganic phosphate increased from 242±60 μmol/g dry weight to 551±164 μmol/g. These post-mouthwash levels of calcium and inorganic phosphate are the highest ever reported for non-mineralised supragingival plaque.
Without wishing to be bound by any proposed mechanism for the observed advantages, it is believed that the mechanism of anticariogenicity for the CPP-ACP is the incorporation of amorphous calcium phosphate in plaque, thereby depressing enamel demineralisation and enhancing remineralisation. In plaque, CPP-ACP would act as a reservoir of calcium and phosphate, buffering the free calcium and phosphate ion activities thereby helping to maintain a state of supersaturation with respect to tooth enamel. The binding of ACP to CPP is pH dependent with very little bound below pH 7.0.
EXAMPLE 6
Remineralisation of Enamel Lesions by CPP-ACP
A. In Vitro Studies
An in vitro enamel remineralisation system was used to study remineralisation of artificial lesions in human third molars by CPP-ACP solutions. Using this system, a 1.0% CPP-ACP solution replaced 56±21% of mineral lost. A 0.1% CPP-ACP solution replaced 34±18% of mineral lost. A further number of solutions containing various amounts of CPP (0.1-1.0%), calcium (6-60 mM) and phosphate (3.6-36 mM) at different pH values (7.0-9.0) were prepared. The associations between the activities of the various calcium phosphate species in solution and the rate of enamel lesion remineralisation for this series of solutions were then determined.
The activity of the neutral ion species CaHPO 4 O in the various remineralising solutions was found to be highly correlated with the rate of lesion remineralisation. The diffusion coefficient for the remineralisation process was estimated at 3×10 −10 m 2 s −1 which is consistent with the coefficients of diffusion for neutral molecules through a charged matrix. The rate of enamel remineralisation obtained with the 1.0% CPP-ACP solution was 3.3×10 −2 mol HA/m 2 /10 days which is the highest remineralisation rate ever obtained. Calcium phosphate ions, in particular the neutral ion pair CaHPO 4 O , after diffusion into the enamel lesion, will dissociate and thereby increase the degree of saturation with respect to HA. The formation of HA in the lesion will lead to the generation of H 3 PO 4 , which being neutral itself, will diffuse out of the lesion down a concentration gradient.
The results indicate that the CPP-bound ACP, CPP[Ca 3 (PO 4 ) 1.87 (HPO 4 ) 0.2 xH 2 O] 8 acts as a reservoir of the neutral ion species, CaHPO 4 O that is formed in the presence of acid. The acid can be generated by dental plaque bacteria; under these conditions, the CPP-bound ACP would buffer plaque pH and produce calcium and phosphate ions, in particular CaHPO 4 O . The increase in plaque CaHPO 4 O would offset any fall in pH thereby preventing enamel demineralisation. Acid is also generated in plaque as H 3 PO 4 by the formation of HA in the enamel lesion during remineralisation. This therefore explains why the CPP-ACP solutions are such efficient remineralising solutions as they would consume the H 3 PO 4 produced during enamel lesion remineralisation generating more CaHPO 4 O thus maintaining its concentration gradient into the lesion. These results are therefore consistent with the proposed anticariogenic mechanism of the CPP being the inhibition of enamel demineralisation and enhancement of remineralisation through the localisation of ACP at the tooth surface.
B. Human In Situ Remineralisation Studies
The ability of CPP-ACP added to sugar-free (sorbitol) chewing gum to remineralise enamel sub-surface lesions was investigated in a randomized, cross-over, double-blind study. Ten subjects wore removable palatal appliances with six, human-enamel, half-slabs inset containing sub-surface demineralised lesions. The other half of each enamel slab was stored in a humidified container and was used as the control demineralised lesion. There were four treatment groups in the study, sugar-free gum containing 3.0% w/w CPP-ACP, sugar-free gum containing 1.0% w/w CPP-ACP, sugar-free gum with no CPP-ACP and a no-gum-chewing control. The gums were chewed for 20 min periods, four times a day. The appliances were worn for this 20 min period and a further 20 min period after gum chewing. Each treatment was for 14 days duration and each of the ten subjects carried out each treatment with a one week rest between the treatments. At the completion of each treatment the enamel slabs were removed, paired with their respective demineralised control, embedded, sectioned and subjected to microradiography and computer-assisted densitometric image analysis to determine the level of remineralisation. The sugar-free gum treatment resulted in 9.82±1.81% remineralisation relative to the no-gum-chewing control whereas the gum containing 1.0% CPP-ACP produced 17.06±2.48% remineralisation and the 3.0% CPP-ACP gum produced 22.70±3.40% remineralisation with all values being significantly different. These results showed that addition of 1.0% and 3.0% CPP-ACP to sugar-free gum produced a 74% and 131% increase respectively in sub-surface enamel remineralisation.
EXAMPLE 7
CPP-ACFP Mouthwash Study
A mouthwash study was conducted to determine the ability of a 3.0% CPP-ACFP mouthwash used thrice daily to increase supragingival plaque calcium, inorganic phosphate and fluoride ions. The 3.0% CPP-ACFP solution used as a mouthwash for four days contained 192 mM-bound calcium ions, 120 mM bound phosphate ions and 24 mM (456 ppm) bound F ions stabilised by CPP. The use of the mouthwash resulted in a 1.9 fold increase in plaque calcium, a 1.5 fold increase in plaque phosphate and a dramatic 18 fold increase in plaque fluoride ion as shown in Table 3.
TABLE 3
Effect of CPP-ACFP on Plaque, Ca, P i and F Levels
Ca
Pi
F
μmol/g
μmol/g
μmol/g
Control
177 ± 53
306 ± 82
1.1 ± 0.9
3% CPP - ACFP
336 ± 107
471 ± 113
19.9 ± 14.1
1000 ppm F
158 ± 54
287 ± 29
1.9 ± 1.0
3% CaCPP
193 ± 56
343 ± 102
1.5 ± 0.8
Although these marked increases in plaque calcium, phosphate and fluoride were found, dental calculus was not observed in any of the subjects, suggesting that the plaque calcium fluoride phosphate remained stabilised as the amorphous phase by the CPP and did not transform into a crystalline phase. These increases in the supragingival plaque levels of Ca, phosphate and fluoride ions produced by CPP-ACP are markedly greater than those obtained in a similar study using CaCPP and 1000 ppm F (MFP and NaF) toothpastes twice daily for a similar time period as indicated in Table 3. These results show a marked synergistic effect between fluoride ions and the CPP-ACP. This is particularly advantageous in view of the fact that the level of fluoride in oral compositions such as toothpaste can then be reduced, resulting in cost savings and lowered risk of fluorosis for individuals living in high-fluoride areas.
EXAMPLE 8
Interaction of CPP-ACP with Fluoride
An synergistic anticariogenic effect of the 1.0% CPP-ACP together with 500 ppm F − was observed in a rat caries model. Analysis of the solution containing 1.0% CPP, 60 mM CaCl 2 , 36 mM sodium phosphate and 500 ppm F (26.3 mM NaF) pH 7.0 after ultrafiltration revealed that nearly half of the fluoride ion had incorporated into the ACP phase stabilised by the CPP to produce an amorphous calcium fluoride -phosphate phase of composition Ca 8 (PO 4 ) 5 F.xH 2 O, with 24 Ca, 15 PO 4 and 3F molecules per CPP molecule.
Without wishing to be limited by any proposed mechanism for the observed beneficial effect, we consider that the anticariogenic mechanism of the CPP-ACP is the localisation of ACP at the tooth surface such that in the presence of acid, the ACP dissociates to release Ca and phosphate ions increasing the degree of saturation with respect to HA preventing enamel demineralisation and promoting remineralisation. The anticariogenic mechanism of fluoride is the localisation of the fluoride ion at the tooth surface, particularly in plaque in the presence of Ca and phosphate ions. This localisation increases the degree of saturation with respect to fluorapatite (FA) thus promoting remineralisation of enamel with FA. It is clear that for the formation of FA [Ca 10 (PO 4 ) 6 F 2 ], calcium and phosphate ions must be co-localised in plaque at the tooth surface with the fluoride ion. The synergistic anticariogenic effect of CPP-ACP and F is therefore attributable to the localisation of ACFP at the tooth surface by the CPP which in effect would co-localise Ca, Pi and F.
This was demonstrated in the mouthwash study described in Example 7.
Metastable solutions of the CPP at pH 7.0 have been prepared containing amorphous calcium fluoride phosphate at remarkably high concentrations. For example, a 10% w/v CPP -ACFP solution containing 640 mM Ca, 400 mM phosphate and 80 mM F (1,520 ppm F − ) at pH 7.0 has been prepared as well as a 20% CPP gel containing 1.28 M Ca, 800 mM phosphate and 160 mM F (3,040 ppm F − ) at pH 7.0. This solution and gel exhibit a significantly greater anticariogenicity relative to the fluoride alone, and therefore are superior additives to toothpastes and mouthwash and for professional application to improve the efficacy of the current fluoride-containing dentifrices and professionally-applied products.
Specific examples of formulations containing the complexes of the invention are provided below.
EXAMPLE 9
Toothpaste Formulations Containing CPP-ACFP
Ingredient
% w/w
Formulation 1
Dicalcium phosphate dihydrate
50.0
Glycerol
20.0
Sodium carboxymethyl cellulose
1.0
Sodium lauryl sulphate
1.5
Sodium lauroyl sarconisate
0.5
Flavour
1.0
Sodium saccharin
0.1
Chlorhexidine gluconate
0.01
Dextranase
0.01
CPP-ACFP
1.00
Water
balance
Formulation 2
Dicalcium phosphate dihydrate
50.0
Sorbitol
10.0
Glycerol
10.0
Sodium carboxymethyl cellulose
1.0
Sodium lauryl sulphate
1.5
Sodium lauroyl sarconisate
0.5
Flavour
1.0
Sodium saccharin
0.1
Sodium monofluorophosphate
0.3
Chlorhexidine gluconate
0.01
Dextranase
0.01
CPP-ACFP
2.0
Water
balance
Formulation 3
Dicalcium phosphate dihydrate
50.0
Sorbitol
10.0
Glycerol
10.0
Sodium carboxymethyl cellulose
1.0
Lauroyl diethanolamide
1.0
Sucrose monolaurate
2.0
Flavour
1.0
Sodium saccharin
0.1
Sodium monofluorophosphate
0.3
Chlorhexidine gluconate
0.01
Dextranase
0.01
CPP-ACFP
5.0
Water
balance
Formulation 4
Sorbitol
22.0
Irish moss
1.0
Sodium Hydroxide (50%)
1.0
Gantrez
19.0
Water (deionised)
2.69
Sodium Monofluorophosphate
0.76
Sodium saccharine
0.3
Pyrophosphate
2.0
Hydrated alumina
48.0
Flavour oil
0.95
CPP-ACFP
1.0
sodium lauryl sulphate
2.00
Formulation 5
Sodium polyacrylate
50.0
Sorbitol
10.0
Glycerol
20.0
Flavour
1.0
Sodium saccharin
0.1
Sodium monofluorophosphate
0.3
Chlorhexidine gluconate
0.01
Ethanol
3.0
CPP-ACFP
2.0
Linolic acid
0.05
Water
balance
EXAMPLE 10
Mouthwash Formulations
Ingredient
% w/w
Formulation 1
Ethanol
20.0
Flavour
1.0
Sodium saccharin
0.1
Sodium monofluorophosphate
0.3
Chlorhexidine gluconate
0.01
Lauroyl diethanolamide
0.3
CPP-ACFP
2.0
Water
balance
Formulation 2
Gantrez S-97
2.5
Glycerine
10.0
Flavour oil
0.4
Sodium monofluorophosphate
0.05
Chlorhexidine gluconate
0.01
Lauroyl diethanolamide
0.2
CPP-ACFP
2.0
Water
Balance
EXAMPLE 11
Lozenge Formulation
Ingredient
% w/w
Sugar
75–80
Corn syrup
1–20
Flavour oil
1–2
NaF
0.01–0.05
CPP-ACFP
3.0
Mg stearate
1–5
Water
balance
EXAMPLE 12
Gingival Massage Cream Formulation
Ingredient
% w/w
White petrolatum
8.0
Propylene glycol
4.0
Stearyl alcohol
8.0
Polyethylene Glycol 4000
25.0
Polyethylene Glycol 400
37.0
Sucrose monostearate
0.5
Chlorohexidine gluconate
0.1
CPP-ACFP
3.0
Water
balance
EXAMPLE 13
Chewing Gum Formulation
Ingredient
% w/w
Gum base
30.0
Calcium carbonate
2.0
Crystalline sorbitol
53.0
Glycerine
0.5
Flavour oil
0.1
CPP-ACFP
2.0
Water
balance
EXAMPLE 14
Dietary Supplement
CPP-ACP was added at 1.0% w/w of the diet of rachitic chickens to determine the ability of the CPP-ACP to provide bioavailable calcium for bone accretion. CPP-ACP at 1.0% w/w in the diet produced a 34% reduction in the incidence of growth plate abnormalities, a 17% increase in tibial ash and a 22% reduction in the cartilaginous growth plate in the animals which was significantly greater than the CPP alone (Table 4) indicating that the CPP-ACP is superior to the CPP in providing bioavailable dietary calcium and in facilitating bone accretion.
TABLE 4
Effect of 1.0% CPP-ACP addition to the diet of rachitic
chickens on incidence of growth plate abnormalities, tibial
ash and cartilaginous growth plate width
% Growth
Growth Plate
Abnormalities
% Tibial Ash
Width
%
%
(mm)
Control
53 ± 5
30 ± 2
5.4 ± 0.2
1.0% CPP
47 ± 9
30 ± 2
5.3 ± 0.2
1.0% CPP-ACP
35 ± 3
35 ± 1
4.2 ± 0.2
It should be understood that while the invention has been described in detail for the purposes of clarity and understanding, the examples were for illustrative purposes only. Other modifications of the embodiments of the present invention will be apparent to those skilled in the art of molecular biology, dental diagnostics, and related disciplines and are within the scope of the invention as described.
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Phosphopeptides containing the Ser(P) cluster sequence motif Ser(P)-Ser(P)-Ser(P)-Glu-Glu- can stabilize their own weight in amorphous calcium phosphate (ACP) [Ca 3 (PO 4 ) 1.87 (HPO 4 ) 0.2 xH 2 O] and amorphous calcium fluoride phosphate (ACFP) [Ca 8 (PO 4 ) 5 F x H 2 O]. The amorphous phases stabilised by the phosphopeptides are an excellent delivery vehicle to co-localise Ca, F, and phosphate at the tooth surface in a slow-release amorphous form producing superior anticaries efficacy. These amorphous phases stabilised by the phosphopeptides also have utility as dietary supplements to increase calcium bioavailability and to help prevent diseases associated with calcium deficiencies.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority of German Patent Application DE 102012210703.7 filed Jun. 25, 2012, the contents of which are incorporated herein by reference.
FIELD OF THE INVENTION
The invention relates to a method and to an apparatus for handling portions respectively comprising at least one slice, wherein the slices are produced by slicing food products. In this process, incomplete portions, in particular portions low in weight, are automatically recognized.
BACKGROUND OF THE INVENTION
Such apparatus are used, for example, in the food industry to supply product slices cut off by a cutting apparatus, such as a high-performance slicer, portion-wise to a downstream processing apparatus, for example to a packaging machine. In particular a belt conveyor or a strap conveyor can be considered as product conveyors. To ensure that only those portions are further processed which satisfy a predefined specification, for example a specific weight or a specific number of slices, incomplete and/or deficient portions are automatically recognized, e.g. with the aid of a sensor, and manually corrected, for example, i.e. are in particular brought up to a demanded desired weight. For this purpose, a corresponding operator, however, requires a certain amount of time so that ultimately the economy of the production plant is restricted by such a correction. Furthermore, on a manual correction, as a consequence of an absence or lack of attention of the operator, it may occur that deficient portions are conveyed on and are finally packaged. Such a further processing of portions of deficient portions is, however, absolutely to be avoided in food production.
SUMMARY OF THE INVENTION
It is therefore an object of the invention to provide a possibility by which incomplete portions can be corrected reliably and automatically.
In accordance with the invention, the portions are conveyed, in particular line-wise, after one another in a main conveying stream along a conveying direction. The conveying of the portions preferably takes place in a plurality of tracks arranged next to one another, for example. In this process, the portions in particular first arise by a simultaneous slicing of food products in different tracks. It is conceivable in this respect that the food products are sliced in multiple tracks by a common slicing machine. Alternatively, a plurality of slicing machines each associated with one track are conceivable.
Incomplete portions, in particular portions low in weight, are recognized and/or classified automatically, e.g. via a sensor, preferably scales. With a multitrack product conveying, multitrack scales can also be used. Specific properties such as the weight, the shape, the slice thickness and/or the fat content of all portions can be recognized, for example. Alternatively or additionally, the portions can, for example, be classified with respect to specific limit values which e.g. relate to the weight, the shape, the slice thickness and/or the fat content.
The determined data can in particular be forwarded to a control. Incomplete portions are expelled from the main conveying stream and supplied to a correction station in a correction stream. The expulsion takes place, for example, by a controllable switch element or rocker element such as known in the technical area.
The correction station can in this respect be configured as a separate component which is e.g. positioned between a slicing machine and a packaging machine. It is, however, also conceivable to integrate the correction station into a slicing machine, into a conveyor unit, into a format set former or into a packaging machine.
Incomplete portions are respectively completed with the aid of an automatic transfer unit by at least one single slice which is taken from a slice store. A plurality of transfer units which are arranged after one another and/or next to one another are also conceivable. The slice store is preferably integrated into the correction station, but can also be provided as a separate station which the transfer unit can access.
The single slice is preferably removed automatically from the slice store, in particular with the aid of the transfer unit. Finally, the completed portions are again automatically channeled back into the main conveying stream. The channeling takes place e.g. by a controllable switch element or rocker element.
Incomplete portions are thus automatically recognized and/or classified in accordance with the invention and are expelled from the main conveying stream. The performance capability or capacity of the slicing apparatus for the food products in this manner does not have to be adapted to the performance capability or capacity of the transfer unit(s). Modern high-speed slicers have such high cutting performances that a transfer unit provided for completing the products would have to be equipped with kinematics which allow very fast movement routines. Even if such kinematics can be technically realized, a corresponding transfer unit frequently does not have the carrying capability required by practice, i.e. from a specific portion weight onward the portions can no longer be moved at the actually desired sped.
Since mostly only comparatively few portions leave the slicing machine in an incomplete manner in practice, the transfer unit has sufficient time to complete the incomplete portions in the correction stream. Portions complete from the start can be moved onward and processed in the main conveying stream in an uninfluenced manner, in particular past the correction station or beneath the correction station or above the correction station. The main conveying stream can in this respect also be conducted through the correction station.
No errors by an operator occur either due to the automatic completion. In addition, costs can be saved.
The automatic completion takes place precisely since single slices—optionally a plurality of single slices after one another—are used for completing respective incomplete portions for the completion.
Since the incomplete portions are first completed by the automatic transfer unit before they are again channeled into the main conveying stream, the correction stream is interrupted. Due to the interruption of the correction stream, the incomplete portions are not transported away from the correction station again unless they have previously been completed and actively brought back into the main conveying stream.
The invention also relates to an apparatus, in particular for carrying out a method in accordance with the invention. The apparatus comprises a main conveyor which conveys the portions after one another, in particular line-wise, in a main conveying stream along a conveying direction. The conveying can, for example, take place in multitracks in tracks arranged next to one another and/or above one another. The food products are sliced, simultaneously, for example, for this purpose, in particular with the aid of a common slicing machine. The apparatus additionally comprises a correction station to which incomplete portions expelled from the main conveying stream can be supplied in a correction stream. In addition, the apparatus comprises a slice store which is configured to store single slices such that the single slices can be removed individually, in particular automatically. A transfer unit in particular works in a correction plane. The transfer unit is configured to complete incomplete portions in each case by means of at least one single slice from the slice store. The transfer unit can in particular be configured to remove the single slices from the slice store individually.
Further developments of the invention are set forth in the dependent claims, in the description and in the enclosed drawings.
In accordance with an embodiment, the completion of the portions and the removal of single slices take place in tracks disposed next to one another with respect to the conveying direction. The movement paths of the transfer unit are thereby minimized. Alternatively, however, it is also conceivable to arrange at least two of the tracks above one another.
In accordance with a further embodiment, single slices are branched off from the main conveying stream to fill the slice store and are supplied to the slice store with the aid of the transfer unit. The filling in particular takes place in that one single slice after the other is picked up by the transfer unit and supplied to the slice store. In this manner, the single slices can in particular also again be removed individually from the slice store. It is alternatively also conceivable that, for example, two or more single slices disposed above one another are always branched off from the main conveying stream and are supplied together to the slice store with the aid of the transfer unit.
In accordance with a further embodiment, at least one conveying device of the slice store is moved against the conveying direction. The slice store, which is in particular configured as a belt conveyor, can thus gradually be filled with single slices. If required, the belt conveyor can again be moved in the conveying direction to make single slices available to the transfer unit for completing incomplete portions.
In accordance with a further embodiment, single slices can be requested on the reaching of a specific minimum filling level of the slice store. If too few single slices are located in the slice store, single slices can be produced directly e.g. with the aid of a control by the slicing apparatus or single slices can be directly expelled from the main conveying stream. The filling level of the slice store can in this respect be determined with the aid of a sensor, for example. This sensor can e.g. be integrated into a belt conveyor of the slice store. It can be ensured in this manner that sufficient single slices to complete incomplete portions are always available.
In accordance with a further embodiment, the slice store is filled by means of the transfer unit. The single slices are in particular in this respect removed from the correction stream individually and supplied to the slice store by the transfer unit. Alternatively or additionally, the single slices are removed from the slice store by means of the transfer unit for completing incomplete portions. In this manner, both the filling and the emptying of the slice store can take place fully automatically. It is, however, alternatively also conceivable that the slice store is filled manually, for example, that is in particular only the removal of the single slices takes place automatically.
In accordance with a further embodiment, the single slices are classified by means of a sensor, in particular by means of an optical sensor. The classification in particular takes place by the size, the shape and/or the weight of the single slices.
In accordance with a further embodiment, the single slices are supplied to the slice store in accordance with their classification.
In this respect, the single slices are preferably supplied to different zones of the slice store in accordance with their classification. The single slices are thus present in the slice store sorted, for example, by size, shape and/or weight. Depending on the property and/or classification of the incomplete portion, a suitable single slice for completing the portion can thus be directly removed from the slice store.
The slice store can, for example, be one or more belt conveyors disposed next to one another. It is alternatively or additionally also conceivable to form the slice store as at least one vertical store. The single slices are accordingly supplied to zones of a vertical store disposed above one another. The individual zones can each be configured as belt conveyors. The vertical store is moved in the vertical direction for supplying and removing single slices until a respectively required single slice can be supplied and/or removed, in particular by means of the transfer unit. A plurality of vertical stores are preferably arranged next to one another and/or behind one another. Single slices which correspond to a specific classification can thereby in particular be directly stored or removed.
In accordance with a further embodiment, single slices are supplied to the slice store which at least on average have a smaller surface and/or a smaller weight than the slices of the incomplete portions. The fact is thereby taken into account that incomplete portions usually only differ slightly from the norm. Unwanted “give-aways” are thereby minimized. The surface and/or the weight of the single slices can be selected in accordance with the deficient weight history of the portions.
In accordance with a further embodiment, the transfer unit is moved in three dimensions. The transfer unit can thus both access all tracks of the correction stream and can raise and lower single slices or portions. The transfer unit can furthermore be moved in and against the conveying direction. Possible interruptions of the tracks in the correction stream can thus be bridged by the transfer unit. It is also conceivable that the transfer unit channels complete portions directly back into the main conveying stream.
In accordance with a further embodiment, the transfer unit first picks up an incomplete portion at a correction track. Subsequently, the transfer unit is moved to the slice store and there picks up at least one single slice in addition to the incomplete portion. An incomplete portion is thus completed by a single slice. If a single slice is not yet sufficient for the completion, any desired further single slices can be brought onto or beneath the incomplete portion one after the other. In this respect, the transfer unit can comprise a sensor, for example scales, to determine how many single slices are required for the completion or whether the portion on the transfer unit is already complete or is still incomplete.
Alternatively, the transfer unit first picks up a single slice from the slice store. So many single slices as are required for completing a specific incomplete portion are picked up after one another on the basis of the classification of the incomplete portions. Subsequently, the transfer unit is moved to a correction track. An incomplete portion is therefore picked up in addition to the at least one single slice. A complete portion also arises overall in this manner.
In accordance with a further embodiment, the transfer unit is moved synchronously with a conveying device of the slice store and/or of the correction station, in particular in the conveying direction, for picking up a single slice from the slice store and/or of an incomplete portion. In this manner, a single slice or an incomplete portion is transferred from the conveying device onto the transfer unit without disturbance.
In accordance with a further embodiment, incomplete portions are branched off from the main conveying stream by means of at least one conveying section and completed portions are supplied with the aid of the transfer unit to at least one second conveying section by means of which the completed portions are again supplied to the main conveying stream. The branching off from or the channeling into the main conveying stream takes place with the help of a rocker belt, for example. The correction track is thus interrupted. The transfer unit is consequently used to bridge a gap in the correction track. It is thus prevented that incomplete portions unintentionally arrive back on the main conveying stream. It is alternatively also conceivable that after the completion of the portions the transfer unit supplies the completed portions directly to the main conveying stream. A second conveying section does not need to be provided in this case.
In accordance with a further embodiment, the single slices are produced by means of a slicing apparatus, in particular a high-performance slicer, which also produces the portions, with in particular the portions being produced in a normal mode of operation and the single slices being produced with an idle normal mode of operation in a single slice operation or the slicing apparatus working in multitracks and at least one track being provided for the production of the single slices. It is thus conceivable that, for example, at the start of the slicing procedure, first only single slices are produced which are expelled from the main conveying stream into the correction stream and are supplied to the slice store. Subsequently, the slicing apparatus changes into a normal mode of operation, for example. It is in particular maintained for so long unit a minimum filling level of the slice store is fallen below. Once a minimum filling level has been reached, single slices are again produced.
In accordance with a further embodiment, the portions are supplied to the correction station line-wise in a multitrack operation, with each portion line containing at least one incomplete portion. It is conceivable in this respect first to expel a complete line, i.e. all portions which are located on different tracks of the main conveying stream, but which are located on the same position with respect to the conveying direction. It is alternatively also conceivable only to expel portions of individual tracks of the main conveying stream, i.e. only to carry out the expulsion for a partial quantity of all tracks.
If a line of the first conveying section contains a complete portion, it is conveyed—without being corrected—by the transfer unit from the first conveying section to the second conveying section or directly onto a track of the main conveying stream. The incomplete portions of the individual lines can, in contrast, be completed, for example by the transfer unit, one after the other. It is conceivable in this respect to complete the incomplete portions e.g. line by line or track by track. It is also conceivable to complete incomplete portions from tracks on which more incomplete portions are located than on the other tracks.
In accordance with a further embodiment, the number of tracks in the correction stream differs from the nominal number of tracks in the main conveying stream. In this respect, the transfer unit orders the incoming portions in outgoing portion lines according to the nominal number of tracks.
The transfer unit can therefore also work as a format set former. A desired format set, i.e. a specific arrangement of complete portions, which are e.g. intended to be supplied to a packaging machine, can thus be achieved by a specific positioning of the completed portions. Portions which are supplied to the transfer unit in e.g. K tracks can be transferred such that they leave the correction station in H tracks. The number of tracks is preferably matched to the number H of tracks in the main conveying stream with the aid of the transfer unit. Completed portions, which are arranged, for example, next to one another in H tracks, can thus be channeled together into a gap of the main conveying track.
In accordance with an embodiment of the apparatus in accordance with the invention, it comprises at least one sensor for the automatic recognition and/or classification of incomplete portions. The sensor can, for example, be an optical sensor such as a product scanner. Scales are also alternatively or additionally conceivable. Multitrack scales can also be used, for example, in multitrack operation. The data determined by the sensor are in particular forwarded to a control. Incomplete portions, in particular portions low in weight, are reliably recognized and/or classified in this manner.
In accordance with a further embodiment, the slice store is arranged next to at least one correction track of the correction station viewed in the conveying direction. In this manner, the transfer unit can access a correction track or the slice store with a travel path which is as small as possible. It is alternatively also conceivable to arrange at least a part of the slice store, e.g. a belt conveyor, above or beneath the correction track.
In accordance with a further embodiment, the slice store comprises at least one conveying device which is movable both in and against the conveying direction, with the slice store preferably having exactly one track. On the movement against the conveying direction, the slice store can be filled, for example. If it is necessary to make use of the single slices from the slice store, it is moved in the conveying direction. The single slices are in this respect, for example, transported onto the transfer unit or are transported into a zone which is accessible to the transfer unit. Alternatively, the slice store can also have a plurality of tracks which are arranged next to one another and/or above one another, for example. The individual tracks can be configured as belt conveyors, for example.
In accordance with a further embodiment, the slice store comprises a vertical store having a plurality of zones which are disposed above one another, with the vertical store being movable perpendicular to a correction plane for supplying and removing single slices. In such a vertical store, which is formed, for example, from a plurality of belt conveyors and/or compartments arranged above one another and/or next to one another, singe slices can, for example, be placed down in a specific zone in accordance with their classification. The slice store can in this respect have an upstream belt conveyor in addition to the vertical store. The vertical store is moved vertically for supplying and removing single slices until a desired zone lies in the plane of the belt conveyor of the slice store so that single slices which are located in the specific zone can be moved into or out of the vertical store with the aid of the belt conveyor of the slice store.
A plurality of vertical stores are preferably arranged next to one another and/or behind one another. Space can be saved by the use of vertical stores. In addition, it is possible to place down or remove single slices directly in accordance with a specific classification.
In accordance with a further embodiment, at least one first conveying section is arranged upstream of the correction station viewed in the conveying direction and at least one second conveying section is arranged downstream. Incomplete portions can be branched off from the main conveyor by means of the first conveying section and completed portions can be supplied to the second conveying section with the aid of the transfer unit. The completed portions can again be supplied to the main conveyor by means of the second conveying section, with the first conveying section and the second conveying section preferably each being configured as a rocker or as an inserter, preferably in the form of a continuous belt. Alternatively, a second conveying section can also be fully dispensed with. In this respect, the completed portions are directly supplied to the main conveyor with the aid of the transfer unit. In this manner, an automatic expulsion and completion of incomplete portions is ensured. The completed portions are also again automatically supplied to the main conveyor.
In accordance with a further embodiment, the transfer unit comprises a picker robot. It can be operated electrically and/or pneumatically, for example.
In accordance with a further embodiment, the picker robot can be moved along two axes extending perpendicular to one another in a correction plane as well as along an axis extending perpendicular to the correction plane. The picker robot can thus be moved, for example, such that it can pick up single slices, incomplete portions and/or complete portions, can move between individual tracks and can additionally, for example, be moved between a first conveying section and a second conveying section. The picker robot has at least one servo axle, for example, for movements in the conveying plane and/or at least one pneumatic or hydraulic axle for the movement in the vertical direction.
In accordance with a further embodiment, the picker robot comprises at least one pick-up fork which can pass through grid structures of the correction station for picking and/or placing single slices and/or portions. In particular the end section so the tracks of the first conveying section, an end section of a belt conveyor of the slice store, the individual zones of the vertical store and/or the tracks of the second conveying section can have grid structures through which the pick-up fork can engage. The pick-up fork can thus, for example, coming from below, pick up a single slice, an incomplete portion or a complete portion or, coming from above, can put on a single slice, an incomplete portion or a complete portion.
In accordance with a further embodiment, the grid structures are each formed by a strap conveyor or by a stationary placing grid, with in particular the strap conveyor comprising a plurality of continuous straps extending in the conveying direction and spaced apart from one another transverse to the conveying direction. The grid structures can thus in particular be passed through by the picker robot and can moreover be moved in or against the conveying direction.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will be described in the following by way of example with reference to the drawings.
FIG. 1 shows a plan view of an embodiment of an apparatus in accordance with the invention;
FIG. 2 shows a side view of a vertical store of an apparatus in accordance with the invention; and
FIG. 3 shows a side view of a pick-up fork of an apparatus in accordance with the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
FIG. 1 shows a correction station 10 of an apparatus in accordance with the invention for handling portions 12 which have been produced by slicing food products, for example with the aid of a high-performance slicer, not shown.
The correction station 10 comprises a first conveying section 14 having two correction tracks 15 which are in particular individually controllable and on which incomplete portions 16 are located. The first conveying section 14 can be moved along a conveying direction F. The first conveying section 14 is in particular configured as a continuous conveyor belt 14 . The continuous conveyor belt 14 has a grid structure 18 at an end region. The grid structure 18 is formed by a strap conveyor (not shown), wherein the strap conveyor comprises a plurality of continuous straps which extend in the conveying direction, which are spaced apart transverse to the conveying direction and which are conducted by rollers.
The correction station 10 additionally comprises a slice store 20 on which single slices 22 are located. It is configured as a continuous belt conveyor 20 which can be moved in the conveying direction B, i.e. in and against the conveying direction F. The slice store 20 has a grid structure 18 at an end zone.
The correction station 10 furthermore comprises a transfer unit 24 which is configured as a picker robot 24 . This transfer unit 24 is movable into the movement directions X, Y and Z (into the plane of the drawing). The movement takes place by electrical or pneumatic drives (not shown). The picker robot 24 has a pick-up fork 26 which is configured such that it can engage through the grid structure 18 .
The correction station 10 additionally has a second conveying section 28 which is configured as a continuous conveyor belt 28 having a grid structure 18 . Complete portions 30 are shown on the second conveying section 28 .
Portions 12 of a food product are first cut off by a slicing machine, not shown. These portions 12 move over a main conveyor, in particular over a plurality of continuous conveyor belts disposed next to one another, to a sensor, not shown. This sensor is configured, for example, as multitrack scales and is suitable to classify the portions 12 and in particular to recognize incomplete portions, i.e. portions 16 low in weight. Incomplete portions 16 are expelled, for example via a rocker, not shown, from the main conveyor and supplied to the correction station 10 . In this respect, either only the incomplete portion 16 is directly expelled on an individual track basis or a total line, i.e. simultaneously prepared portions 12 which are disposed next to one another on a common conveyor belt or on mutually separate conveyor belts of the main conveyor and which contain an incomplete portion 16 . Lines which do not contain any incomplete portions 17 are, in contrast, not expelled and move onward along the conveying direction F on the main conveyor. The main conveyor is located beneath the correction station 10 , for example, or is conducted through the correction station 10 beneath a correction plane (not shown).
The expelled portions 12 are, in contrast, brought line-wise up to an end region of the first conveying section 14 . In this case, no individually controllable correction tracks 15 are provided. A common continuous belt conveyor 14 is sufficient in this respect. If, however, a plurality of individually controllable correction tracks 15 are used, the incomplete portions can also be individually brought to an end region of the first conveying section 14 .
Once the expelled portions 12 reach an end region of the first conveying section 14 , the continuous conveyor belt 14 is stopped. The picker robot 24 is now controlled such that it transfers any complete portions 30 present from the first conveying section 14 to the second conveying section 28 . Incomplete portions are, in contrast, first corrected. In this respect, an incomplete portion 16 which is located on the grid structure 18 of a correction track 15 is first picked up from below by the transfer unit 24 . The incomplete portion 16 is now located on the pick-up fork 26 of the picker robot 24 . The latter is subsequently moved to the slice store 20 . Since an incomplete portion 16 is already lying on the pick-up fork 26 , it is not possible to pass through the grid structure 18 of the slice store 20 from below and to pick up a single slice 22 in this manner. The picker robot 24 is therefore in particular positioned beneath the slice store 20 . The slicer store 20 now moves synchronously with the picker robot 24 along the conveying direction F so that a single slice 22 is applied from above onto the incomplete portion 16 . In this manner, any desired further single slices can be picked up until the incomplete portion 16 forms a completed portion 30 .
Alternatively, it is also conceivable that the picker robot 24 first picks up a certain number of single slices 22 and subsequently picks up an incomplete portion 16 from a correction track 15 . In this case, the first conveying section 14 is also moved synchronously with the picker robot 24 along the conveying direction F.
Once an incomplete portion 16 has been completed, the picker robot 24 is moved in the X direction until it is located above the second conveying section 28 . It is now lowered in the Z direction. In this process, the pick-up fork 26 engages through the grid structure 18 of the second conveying section 28 , while the completed portion 30 is placed on the second conveying section 20 .
Subsequently, the picker robot 24 is again moved to the first conveying section 14 to complete further incomplete portions 16 .
In this embodiment, the transfer unit 24 is additionally configured as a format set former. The portions 12 which are supplied to the transfer unit 24 in two correction tracks 15 of the first conveying section 14 are finally placed in four rows in the second conveying section 28 .
The complete portions 30 are finally again channeled into the main conveyor, in particular line-wise, for example with the aid of a rocker and/or of an inserter.
To fill the slice store 20 with single slices 22 , only single slices 22 are cut off with the aid of the slicing machine at the start of the slicing procedure. They move via the main conveyor into the correction station 10 . The picker robot 24 now picks up a single slice 22 from the first conveying section 14 and conveys it up to the slice store 20 . The slice store 20 is moved against the conveying direction F, in particular by at least one slice length. This is repeated for so long until a desired minimum filling level of single slices 22 is reached in the slice store 20 .
If the filling level in the slice store 20 becomes too low during the completion of the portions, which can be determined with the aid of a sensor, for example, single slices 22 can be directly requested from the slicing machine. The slice store 20 can be filled again with these single slices 22 .
An alternative embodiment of a slice store 20 is shown in FIG. 2 which can be used in a correction station 10 in accordance with FIG. 1 instead of the slice store 20 shown there. The slice store 20 in this respect comprises a vertical store 36 as well as a grid structure 18 which is formed by endless straps 32 which are arranged at rollers 34 . The continuous straps 32 can be moved along the conveying direction B.
The vertical store 36 comprises compartments 38 which are arranged in different zones 38 of the vertical store 36 . These compartments 38 are formed from tines 40 which can be moved through gaps in the grid structure 18 . For this purpose, the vertical store 36 can be moved along the adjustment direction V. It is possible in this manner to store single slices 22 above one another. The single slices 22 can in particular be associated by their weight, for example, with a specific compartment 38 .
A plurality of vertical stores 36 are preferably arranged behind one another and are filled in each case with single slices 22 of a specific property, e.g. of a specific weight. If now a single slice 22 having a specific weight is required for completing an incomplete portion 16 , the corresponding vertical store 36 is moved along the adjustment direction V until the corresponding single slice 22 is placed on the grid structure 18 .
A side view of a picker robot 24 is shown in FIG. 3 . The pick-up fork 26 in this respect comprises a plurality of L-shaped tines 42 which can engage through the grid structure 18 of the first conveying section 14 , of the slice store 20 and/or of the second conveying section 28 . This is realized in that the individual tines 42 , here L-shaped tines, are only connected to one another sufficiently far above by a transverse connection 44 . The L-shaped tines 42 can thus engage through the grid structure 18 and can pick up a portion 12 from below, for example and can place a portion 12 from above on the grid structure 18 .
Incomplete portions are reliably and automatically completed by the apparatus in accordance with the invention.
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The invention relates to a method of handling portions comprising a respective at least one slice, wherein the slices have been produced by slicing food products, wherein the portions are conveyed, in particular line-wise, one after the other in a main conveying stream along a conveying direction, wherein incomplete portions, in particular portions low in weight, are automatically recognized and/or classified, wherein incomplete portions are expelled from the main conveying stream and are supplied to a correction station in a correction stream, wherein incomplete portions are respectively completed by at least one single slice which is removed from a slice store with the aid of an automatic transfer unit and wherein completed portions are automatically channeled back into the main conveying stream.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser. No. 10/909,033 entitled “Endovascular Tumescent Infusion Apparatus and Method”, and claims priority to U.S. provisional application No. 60/491,573, filed Jul. 31, 2003, which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a medical device and method for treatment of blood vessels. More particularly. the present invention relates to an endovascular tumescent infusion apparatus and method for minimally invasive treatment of venous reflux disease.
BACKGROUND OF THE INVENTION
[0003] Veins can be broadly divided into three categories: the deep veins. which are the primary conduit for blood return to the heart; the superficial veins, which parallel the deep veins and function as a channel for blood passing from superficial structures to the deep system; and topical or cutaneous veins, which carry blood from the end organs (e.g., skin) to the superficial system. Veins are thin-walled and contain one-way valves that control blood flow. Normally, the valves open to allow blood to flow into the deep veins and close to prevent back-flow into the superficial veins. When the valves are malfunctioning or only partially functioning. however, they no longer prevent the back-flow of blood into the superficial veins. This condition is called reflux. As a result of reflux, venous pressure builds within the superficial system. This pressure is transmitted to topical veins, which, because the veins are thin walled and not able to withstand the increased pressure, become dilated, tortuous or engorged.
[0004] In particular, venous reflux in the lower extremities is one of the most common medical conditions of the adult population. It is estimated that venous reflux disease affects approximately 25% of adult females and 10% of males. Symptoms of reflux include varicose veins and other cosmetic deformities, as well as aching, itching, and swelling of the legs. If left untreated, venous reflux may cause severe medical complications such as bleeding, phlebitis, ulcerations, thrombi and lipodermatosclerosis.
[0005] Endovascular thermal therapy is a relatively new treatment technique for venous reflux diseases. With this technique, thermal energy generated by laser, radio or microwave frequencies is delivered to the inner vein wall causing vessel ablation or occlusion. Typically a catheter, fiber or other delivery system is percutaneously inserted into the lumen of the diseased vein. Thermal energy is delivered from the distal end of the delivery system as the device is slowly withdrawn through the vein.
[0006] The procedure begins with an introducer catheter or sheath being placed into the main superficial vein, called the saphenous vein, at a distal location and advanced to within a few centimeters of point at which the saphenous vein enters the deep vein system, (the sapheno-femoral junction). Once the sheath is properly positioned and after the instillation of tumescent anesthesia as described below, the thermal delivery system is inserted into the lumen of the sheath and advanced until positioned near the saphenous-femoral junction area. It is to be noted, however, that in many vascular treatment procedures, the sheath is optional. To treat the vein, the energy source is activated causing energy to be emitted from the distal end of the thermal delivery system into the vessel. The energy reacts with the vessel wall causing cell necrosis and eventual vein collapse. With the energy source turned on, the delivery device is slowly withdrawn until the entire diseased segment of the vessel has been treated.
[0007] Prior to the application of thermal energy, tumescent anesthesia is injected along the entire length of the vein into space between the vein and the surrounding perivenous tissue. A mixture of saline and 0.1-0.5% lidocaine or other similar anesthetic agent is typically used. Tumescent anesthesia or tumescent fluid as used herein is a fluid that anatomically isolates the saphenous vein that creates a barrier to protect the tissue and nerves from the thermal energy, and/or reduces patient pain during the procedure.
[0008] The tumescent injections are typically administered every few centimeters along the entire length of the vein under ultrasonic guidance. A 10 or 20 cc syringe is filled with the solution and then attached to a micropuncture needle or flexible tube set. Relatively small syringes are used in order to generate sufficient pressure during the injection to cause the fluid to travel longitudinally along the perivenous space. Small syringes are also preferred because they can be more easily handled by a treating physician than larger, bulky syringes. The length of the vein being treated varies but is typically between 30 and 50 cm long. A total of approximately 60-120 cc of fluid is generally injected along the length of the vein during a normal treatment procedure.
[0009] Tumescent injections are delivered under ultrasound guidance. Ultrasound is used to visualize the vein, confirm proper location of the needle tip in the perivenous space, and to determine correct injection volumes. Ultrasound images are obtained by use of a handheld transducer that must be held in a precise position relative to the anatomy being visualized. After the user has confirmed that the needle tip is correctly positioned between the vein and fascia tissue through ultrasonic imaging, the tumescent fluid is slowly injected. Under ultrasound, the physician can see the fluid being injected and filling the perivenous space. The fluid eventually begins to dissipate radially into the surrounding tissue based on distance, resistance and venous anatomy. At this point, the physician removes the needle and repositions it to another location for the next injection.
[0010] One problem with the current method of tumescent injections is the difficulty in controlling the needle, syringe and ultrasonic transducer or probe all at the same time. As illustrated in FIG. 1 , the physician utilizes the syringe as a handle to control the needle position and injection volumes. The physician must maintain the needle device 5 position while holding the syringe 30 and depressing the plunger to inject the tumescent agent. In addition, the ultrasound probe 19 must be held in position over the injection area in order to visualize the needle tip placement and the fluid flow path. Maintaining the position of the needle device 5 while depressing the syringe 30 plunger or otherwise adjusting the syringe is difficult since the two components are directly connected. Optimal control over the needle position occurs when the operator's hand is holding the needle hub. The further away the operator's hand is from the needle the more difficult it is to control needle placement. When injecting fluid using the method depicted in FIG. 1 , the operator's hand holds the proximal section of syringe so as to control the plunger. This hand position negatively impacts the accuracy and control over the needle position. The bulkiness of the syringe and the decreased control over the needle makes it difficult for the physician to operate the syringe 30 without impacting the position of the needle device 5 .
[0011] The problem of inadvertent needle movement after initial positioning has been addressed by using a needle with a flexible tubing set as shown in FIG. 2 . With this technique, flexible tubing 31 placed between the needle device 5 and the syringe 30 allows for independent movement and adjustments of the syringe 30 without causing a corresponding movement of the needle device 5 . Control and accuracy during injection is increased because the syringe can be operated independently of the needle. As shown in FIG. 2 , however, this technique requires two operators to perform the procedure. One operator guides the ultrasound probe and controls the needle position while the other one controls syringe and injection volumes. Although this method increases control, it is expensive, inefficient and requires coordination between the two operators. Both operators are performing within the sterile field, and accordingly must be scrubbed and prepped for sterile conditions.
[0012] Another problem with the current procedure involves the risk of introducing air into the body during syringe changes. As previously discussed, 10 or 20 cc syringes are used to ensure that sufficient pressure can be generated during the injection. Use of the relatively small syringe means that the operator needs to change syringes numerous times during the procedure. When the fluid level in the syringe becomes low, the operator must disconnect the syringe from the needle and replace it with another, pre-filled syringe. During the syringe exchange, a small amount of air often enters the needle through the hub opening. Subsequent injection of the tumescent agent then cause the air pocket to advance through the needle into the surrounding tissue.
[0013] Although a small amount of air introduced into the tissue will not harm the patient, the air creates an ultrasonic shadow that impairs the operator's imaging. visibility. Specifically, the air bubble creates a void on the ultrasound display. Any anatomical structure behind the air bubble may be obscured from view, including the vein and needle tip.
[0014] Multiple syringe change outs are also very time consuming, increasing overall procedure time and costs. Typically, the multiple syringes are filled with the lidocaine/saline solution prior to the procedure. The procedure preparation time is lengthened by the need for multiple syringes. The actual procedure time is also lengthened by the requirement for syringe exchanges during injections. In addition, multiple syringes increase the overall cost of the procedure.
[0015] Therefore, it is desirable to provide a tumescent fluid infusion device that is efficient and easy to deliver fluid to the perivenous space. It is also desirable to eliminate the need for multiple operators and multiple syringe change outs. It is also desirable to provide for user-controlled infusion volumes at consistent pressure levels and provide an infusion mechanism that is easy to handle and control. In addition, it is desirable to provide such a device that is inexpensive to manufacture, and is easy and inexpensive to use.
SUMMARY OF THE DISCLOSURE
[0016] According to the principles of the present invention, a tumescent fluid infusion apparatus for use in treatment of a vascular disease is provided. The apparatus includes a needle having a channel and operable to penetrate a skin. A valve device is attached to the needle and is adapted to receive tumescent fluid from a fluid source. When the valve device is in an open position, it administers the tumescent fluid from the fluid source through the needle channel.
[0017] In another aspect of the invention, the valve device of the tumescent fluid infusion apparatus is in a normally closed position to block the administration of the tumescent fluid.
[0018] In another aspect of the invention, the valve device includes a manually depressible member that switches the closed position to an open position upon depression of the manually depressible member.
[0019] In another aspect of the invention, the fluid source is a pressurized source and the open position of the valve device allows the tumescent fluid to flow from the pressurized source through the needle channel.
[0020] In another aspect of the invention, release of the manually depressible member automatically closes the valve device to block the fluid flow.
[0021] In another aspect of the invention, the apparatus includes a flexible tube having one end coupled to the valve device and the other end adapted to be coupled to the fluid source.
[0022] In another aspect of the invention, the manually depressible member adjusts the flow rate of the fluid through the needle channel based on the amount of depression of the manually depressible member.
[0023] Advantageously, the present invention allows a single hand of a user to control the needle insertion and the infusion of the tumescent fluid to free the other hand for operating a probe such as an ultrasound probe to eliminate the requirement of a second operator. The infusion apparatus also allows a user to control the amount of infused fluid without requiring syringe changes.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] FIG. 1 is a plan view of the endovascular tumescent injection technique of prior art.
[0025] FIG. 2 is a plan view of an alternative endovascular tumescent injection technique of prior art.
[0026] FIG. 3 is a plan view of an endovascular tumescent infusion apparatus according to the present invention.
[0027] FIG. 4 is a plan view of the endovascular tumescent infusion apparatus connected to a pressurized fluid reservoir.
[0028] FIG. 5A is a cross-sectional view of the endovascular tumescent infusion apparatus with the button valve in the closed position.
[0029] FIG. 5B is a cross-sectional view of the endovascular tumescent infusion apparatus with the button valve in the open position.
[0030] FIG. 6A and FIG. 6B are schematics of the endovascular tumescent infusion method of the present invention using the apparatus of FIG. 3 .
DETAILED DESCRIPTION OF THE INVENTION
[0031] One embodiment of the present invention is shown in FIG. 3 . The endovascular tumescent infusion apparatus 1 includes a non-vented spike 2 for connection to a fluid source such as a reservoir 27 (see FIG. 4 ), a flexible PVC tube or other similar type tubing 3 , a button valve device 4 and a small gauge needle device 5 . The needle device 5 is comprised of a needle 7 and a needle hub 6 having a needle hub port 32 (see FIGS. 5A and 5B ). The needle 7 has a beveled needle tip 8 . A fluid channel 9 extends from the spike 2 through the tubing 3 , the lumen of the button valve 5 , and the needle device 5 .
[0032] The non-vented spike 2 is connected to a pressurized fluid reservoir 27 containing the tumescent fluid such as a lidocaine/saline mixture, as shown in FIG. 4 . Pressurizing the reservoir 27 is accomplished by wrapping a standard pressure cuff 23 around the reservoir 27 . Other alternative methods well known in the art may also be used to create a pressurized reservoir. Typically a 100 to 250 cc saline bag, commonly available, is used for the fluid reservoir. Lidocaine is injected into the saline bag through a port and then the solution is mixed. The spike 2 is inserted into the bag port to create a pressurized fluid connection/line between the reservoir 27 and the tumescent infusion apparatus 1 . The reservoir 27 is pressurized by squeezing the bulb 24 which causes the cuff 23 to inflate, generating pressure against the fluid reservoir 27 . Pressure levels of up to 300 mm/Hg may be used to ensure sufficient fluid flow into the perivenous space. The pressure dial 25 provides an indication as to pressure levels.
[0033] When the spike 2 is connected to the pressurized reservoir 27 , a fluid channel 9 is created through the spike, the tubing 3 and the button valve device 4 , at which point the fluid channel 9 is blocked by the normally closed position of the button valve device 4 . Button valves by themselves, also known as trumpet valves, are well known in the prior art. The valve component illustrated within this application is disclosed, for example, in U.S. Pat. No. 5,228,646, which is incorporated herein by reference. Any valve device, especially one having a normally closed position, can be used in conjunction with this device.
[0034] Referring to 5 A and 5 B, the button valve device 4 includes an inlet port 10 connectable to the flexible tube 3 , and an outlet port 11 connectable to the hub 6 . Inlet port 10 is sealably connected to the tubing 3 . Outlet port 11 allows for removable connection to the needle hub 6 . The valve device 4 also includes a manually actuatable member such as a cap 12 , return spring 13 that biases the valve device into a closed position, a plunger shaft 14 with a distal plunger seal 16 and a proximal plunger seal 17 . In the embodiment shown, the manually actuatable member 12 is a manually depressible member that opens the valve device 4 by manual depression by the user. While the valve device 4 is shown with a manually depressible member 12 , other types of valve actuating members can be used. For example, the present invention can be used with a roller switch that closes or opens in response to rotational movement of a rolling member or a sliding valve switch that uses a sliding member.
[0035] When in the normally closed position, the position of the plunger shaft 14 and the distal plunger seal 16 effectively blocks the passage of fluid through channel 9 . Depressing the cap 12 compresses the return spring 13 causing the plunger shaft 14 to move deeper within the plunger cavity 15 , as shown in FIG. 5B . When the plunger shaft 14 is repositioned as such, the distal plunger seal 16 no longer seals the channel 9 between the inlet port 10 and the outlet port 11 . In the embodiment shown, the valve device 4 opens by manual pressure applied to the cap 12 along an axis which is substantially perpendicular to the longitudinal axis of the needle 9 . The perpendicular axis of the cap movement allows a physician to more consistently maintain the depth of the inserted needle 7 . Pressurized fluid then flows around the plunger shaft 14 as indicated by the arrows in FIG. 5B through channel 9 into the needle hub port 32 . When the cap 12 is released, the return spring 13 expands to cause the plunger shaft 14 to return to the originally closed position as illustrated in FIG. 5A .
[0036] Alternatively, the valve opening of the valve device 4 can be made to vary according to the amount of depression of the manually depressible member 12 such that the flow rate of the fluid through the needle channel increases as the amount of depression of the depressible member 12 increases.
[0037] A preferred method of using the endovascular tumescent infusion apparatus 1 for treating a vascular disease will now be described with reference to FIG. 6A and FIG. 6B . The treatment procedure begins with the standard pre-operative preparation of the patient as is well known in the art. Prior to the procedure, the patient's diseased venous segments are marked on the skin surface. Typically, ultrasound guidance is used to map the greater saphenous vein 20 from the sapheno-femoral junction to the popliteal area.
[0038] The greater saphenous vein 20 is accessed using a standard Seldinger technique. A small gauge needle is used to puncture the skin and access the vein. A guide wire is advanced into the vein through the lumen of the needle. The needle is then removed leaving the guidewire in place. A hemostasis introducer sheath may be introduced into the vein over the guidewire and advanced to 1 to 2 centimeters below the sapheno-femoral junction. The distal end of a thermal treatment device such as a laser treatment device 21 is then inserted into and is advanced through the sheath. Alternatively, the thermal treatment device 21 may be inserted and advanced through the vein 20 without the use of a sheath.
[0039] Once the device is positioned correctly within the vein 20 , the tissue immediately surrounding the diseased vessel segment is treated with percutaneous infusions of a tumescent anesthetic agent. In some cases, however, injection of tumescent anesthesia is done after the sheath placement but before the fiber. introduction. As shown in FIG. 6A , the user inserts the needle 7 through the skin at puncture site 22 and into the perivenous space 18 . The ultrasonic probe 19 is placed on the skin in the proximity of puncture 22 to provide an image of the needle 7 position in the perivenous space 18 . One hand is used to position the needle device 5 while the other hand positions the ultrasonic probe 19 .
[0040] To infuse the tumescent fluid, the user simply holds the needle device 5 with one hand and uses a finger to depress the cap 12 of the button valve device 4 in order to initiate fluid flow. As can be appreciated, this arrangement advantageously allows the user to maintain control of the needle device 5 and the infusion with one hand, freeing the other hand to position the ultrasound transducer 19 . The user can easily control the infusion volume by holding the cap 12 down until the desired volume has been administered and then simply releasing the cap 12 . Once the cap 12 is released, the valve device 4 automatically returns to a closed position as shown in FIG. 5A , preventing any further infusion of fluid.
[0041] When the tumescent fluid begins to dissipate radially into the surrounding tissue and is no longer flowing longitudinally within the perivenous space 18 , as shown under the ultrasonic image, the user removes the needle 7 from puncture site 22 . The needle is repositioned in another location, typically a few centimeters away from the original puncture site 22 . The ultrasound transducer is also repositioned near the new needle location. FIG. 6B depicts the location of the repositioned needle 7 and transducer 19 at the second puncture site 28 . Once correctly positioned and sufficiently imaged, the user infuses through the second puncture site by pressing down on the cap 12 . The infused fluid anatomically isolates the vein from the surrounding structures by compressing the vein and creating a fluid barrier between the vein and surrounding tissue as shown in FIG. 6B .
[0042] Alternatively, other veins such as lesser saphenous veins may be targeted using alternative access techniques such as cut-down.
[0043] The entire length of the diseased vein segment is treated in this manner. Typically between 5 and 15 separate infusions are administered to sufficiently anesthetize the area and create a sufficient fluid barrier for treatment. A total of between 60 and 120 cc of fluid will be infused along the vein during treatment preparation. Once the vein has been sufficiently anesthetized, thermal energy is applied to the interior of the diseased vein. The thermal delivery system is slowly withdrawn through the vein until the entire vein segment has been treated.
[0044] The invention disclosed herein has numerous advantages over prior art treatment devices and methods. The current invention provides user control over the infused volume by allowing the user to monitor the infusion in real-time using the ultrasonic probe, providing improved visualization of the fluid flow.
[0045] Providing an infusion device which can be operated using a single hand, allows a single user to be able to simultaneously control the infusion and monitor the process real-time using an ultrasound probe. Thus, the present invention eliminates the need for two operators within the sterile field during the preparation of the vein.
[0046] Eliminating the need for multiple, small syringes results in a preparation procedure that is faster, easier and more precise. Preparing for infusion fluid with the current invention requires only a single connection to the reservoir and a step of pressurizing the reservoir. In addition, the risk of introducing air into the body through the exposed needle hub during syringe exchanges is eliminated with the apparatus and method of the current invention.
[0047] Accordingly, the advantages of the present endovascular tumescent infusion device include decreased procedural preparation time, convenience to the user and increased control over the infusion process. In addition, because common medical device components are used to assemble the device, it can be manufactured easily and at a low cost. Thus the device provides an inexpensive option for users in injecting tumescent fluid into the body.
[0048] The above description and the figures disclose particular embodiments of an endovascular tumescent infusion devices and method of treatment. It should be noted that various modifications to the device and method might be made without departing from the scope of the invention. The tumescent infusion needle and valve components can be of various designs as long as they provide ease of entry and controlled infusion volumes. For example, the valve can be of a configuration that allows for user control over flow rate. The needle configuration can be longer to provide fluid delivery further along the perivenous pathway. It may also be of a curved configuration to allow angled entry with longitudinal positioning adjacent to the vein. Coaxial needle configurations are also possible.
[0049] The technique for pressurizing the fluid reservoir can also be accomplished using other methods well known in prior art. The method of treatment can also be altered without departing from the scope of the invention. For example, the user may infuse longer perivenous space segments by increasing pressure levels. Veins other than the greater saphenous vein can be treated using the method described herein. Tumescent fluid injection for even non-venous structures is also possible using the present invention.
[0050] The foregoing specific embodiments represent just some of the ways of practicing the present invention. Many other embodiments are possible within the spirit of the invention. Accordingly, the scope of the invention is not limited to the foregoing specification, but instead is given by the appended claims along with their full range of equivalents.
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A tumescent fluid infusion apparatus for use in treatment of a vascular disease includes a needle attached to a valve device. The valve device is designed to receive tumescent fluid from a fluid source. When the valve device is in an open position, it administers the tumescent fluid from the fluid source through the needle channel to allow a single hand of a user to control the needle insertion and the infusion of the tumescent fluid to free the other hand for operating a probe such as an ultrasound probe to eliminate the requirement of a second operator. The infusion apparatus also allows a user to control the amount of infused fluid without requiring syringe changes.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of U.S. patent application Ser. No. 10/608,656, filed Jun. 27, 2003, now U.S. Pat. No. 6,860,571, which claims the benefit of U.S. Provisional Application No. 60/392,155, filed on Jun. 27, 2002.
TECHNICAL FIELD OF THE INVENTION
The present invention relates generally to a wheel and belt or track driven device, and more particularly to a suspension system, positive hydraulical four wheel disc braking system, positive drive belt system, and belt tensioning device for wheel and belt devices.
DESCRIPTION OF THE RELATED ART
The popularity and nearly universal acceptance of wheel propulsion systems rather than track systems in agricultural use has stemmed primarily from the past track system's “rough ride,” relatively higher noise levels, higher initial cost, lower maximum travel speed and inability to transport itself on improved road surfaces without inflicting damage thereto.
Present day track systems have overcome the majority of these objections by utilizing a propulsion system in which a continuous rubber belt encompasses a pair of wheels. Problems encountered in actually reducing such belt systems to practice include how to drive such belt with the entrained wheels, how to maintain structural integrity of the belt and wheels, how to encompass the belt in lateral alignment with the wheels when the wheels are subjected to large lateral loads, how to provide long life for the belt and wheels, how to accommodate debris ingested between the wheels and belt while maintaining the driving relationship therebetween without damaging either, how to preclude the belt from coming off the wheels, how to brake the belt and wheel systems, how to preclude the belt from coming off of the wheels during braking, and how to maintain proper belt tension during braking and turning.
Elastomeric belt systems have been used but they operate such that the elastomeric belt needs to be highly tensioned about a pair of wheels to provide frictional engagement with the wheels. Interposed between the wheels is a roller support system for distributing a portion of the weight and load imposed on the machine frame to the belt. The roller support system includes a mounting structure, which is pivotally connected to the machine frame and, therefore, free to rotate relative to the machine frame to accommodate undulations in the terrain surface while maintaining uniform ground pressure.
The frictional elastomeric drive belt system requires a higher belt tension than is required for a positive drive belt system. This higher belt tension causes premature failure of the belt. Further, the elastomeric suspension system only provides for a limited amount of suspension travel. This allows for an exorbitant amount of force being transferred to the frame and operator cabin when crossing rough terrain. Friction drive technology has many disadvantages. For example, track failure is common in wet and rocky conditions, and the track tends to fall off during braking and turning.
Current positive drive belt systems usually have only one wheel positively engaged with the belt causing premature wear when braking occurs. Further, known positive drive belt systems provide insufficient recoil to allow foreign material to escape from the belt system.
In addition, track driven systems are “hard” riding. Specifically, track driven systems lack suspension systems entirely or have primitive suspension systems resulting in a rough ride.
The present invention is directed to overcome one or more of the problems as set forth above.
SUMMARY OF THE INVENTION
The present invention includes a novel independent suspension for use in conjunction with a positive drive belt system, belt tensioner adapted for use with a positive drive belt system, drive wheel for use in conjunction with a positive drive belt system, and positive braking system for use with a positive drive belt system.
There present invention also includes a plurality of middle rollers for use with a positive drive belt system, wherein the group of middle rollers aid in the support of the wheel and belt device and provides a low ground pressure distribution.
The present invention further includes an independent suspension system, a positive drive system, and a belt tensioner system for use on a track system.
BRIEF DESCRIPTION OF THE DRAWINGS
These and other features and advantages of the present invention will be better understood by reading the following detailed description, taken together with the drawings wherein:
FIG. 1 is a side view of a lower section of a track driven device having a suspension system, belt tensioner system, positive braking system and positive drive system thereon according to the present invention;
FIG. 2 is a side view according to FIG. 1 but with phantom lines illustrating hidden components of the track driven device;
FIG. 3 is a front view of a wheel for the track driven device shown in FIGS. 1 and 2 ;
FIG. 4 is a side view of the wheel shown in FIG. 3 for the track driven device;
FIG. 5 is an exploded, side view of one side of the track driven device having the suspension system, belt tensioner system, positive braking system and positive drive system thereon according to FIG. 1 ;
FIG. 6 is an exploded, top view of one side of the track driven device having the suspension system, belt tensioner system, positive braking system and positive drive system thereon according to FIG. 1 ;
FIG. 7 is a front view of one side of the track driven device having the suspension system, belt tensioner system, positive braking system and positive drive system thereon according to FIG. 1 ;
FIG. 8 is a front view of one side of the track driven device having the suspension system, belt tensioner system, positive braking system and positive drive system thereon according to FIG. 5 but with phantom lines illustrating hidden components of the track driven device;
FIG. 9 is a top view of one side of the track driven device having the suspension system, belt tensioner system, positive braking system and positive drive system thereon according to FIG. 1 ;
FIG. 10 is a top view of one side of the track driven device having the suspension system, belt tensioner system, positive braking system and positive drive system thereon according to FIG. 9 but with phantom lines illustrating hidden components of the track driven device;
FIG. 11 is a side view of the lower section of the track driven device with cutouts showing a hydraulically operated four-wheel disc braking system thereon;
FIG. 12 is a side view according to FIG. 11 but with phantom lines illustrating hidden components of the track driven device;
FIG. 13 is a top view of one side of the braking system according to FIG. 9 with cross-sections through the wheels;
FIG. 14 is a top view according to FIG. 13 but with phantom lines illustrating hidden components of the track driven device; and
FIG. 15 is a top view according to FIG. 12 isolating one of the disc brakes.
DETAILED DESCRIPTION OF THE INVENTION
In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. Additionally, the present invention contemplates that one or more of the various features of the present invention may be utilized alone or in combination with one or more of the other features of the present invention.
Referring now to the drawings, wherein like reference numerals designate identical or corresponding parts throughout the several views, FIGS. 1 & 2 show a lower section 11 of a track driven device 10 . The track driven device 10 has two belts 13 each encompassing an idler wheel 14 and a drive wheel 15 . The drive wheels 15 drive the belts 13 . The drive wheels 15 are powered by an engine, a transmission system, and other components substantially similar to a CATERPILLAR® brand Challenger® system.
Referring now to FIGS. 3 & 4 , the idler wheels 14 and the drive wheels 15 are shown. In the preferred embodiment, the idler wheels 14 are 26 inches in width by 41.05 inches in diameter, and the drive wheels 15 are 29 inches in width by 41.05 inches in diameter, although such dimensions are not a limtation of the present invention. The idler wheels 14 and the drive wheels 15 have front windows or openings 16 in the circumference. In an alternative embodiment, side windows (not shown) are provided in the side of the wheels 14 , 15 . The windows 16 allow snow, ice, soil, rocks and other foreign matter to pass freely during operation. In addition, the front windows 16 are used to receive lugs 18 on belts 13 , best shown in FIGS. 1 & 2 . The lugs 18 enter the front windows 16 in much the same way that meshing gears interact with one another. As the drive wheels 15 rotate, the lugs 18 mate with the front windows 16 , and the belts 13 are positively driven by the drive wheels 15 . In an alternative embodiment, there are no windows 16 in the wheels 14 , 15 ; rather, the wheels 14 , 15 and the lugs 18 mate in much the same way as two gears mesh.
A suspension system 12 is operatively mounted to each side of the lower sections 11 of the track driven device 10 . The suspension systems 12 provide independent suspension for the belts 13 . The suspension systems 12 absorb load stresses and allows the idler wheel 14 to move vertically when an object is encountered providing a more comfortable, controlled and safe ride while prolonging the life of the track driven device 10 .
Although it is understood that the track driven device 10 has two belts 13 and two suspension systems 12 , the description that follows describes one side of the track driven device 10 . Referring in combination to FIGS. 1 & 2 , the suspension system 12 has a lower suspension bracket 19 . The lower suspension bracket 19 has front ends 23 that are operatively connected to a frame 20 of the track driven device 10 via a suspension cylinder 21 and upper suspension bracket 22 . The suspension cylinder 21 has a first end 50 operatively attached to the lower suspension bracket 19 and a second end 51 operatively attached to the upper suspension bracket 22 . The upper suspension bracket 22 is operatively attached to the frame 20 .
FIGS. 5 and 6 show the idler wheel 14 rotatably mounted between a first side 28 and a second side 29 of the lower suspension bracket 19 via an axle 30 . The lower suspension bracket 19 has distal ends 24 operatively attached to a main frame 25 . The main frame 25 is pivotally mounted to a track frame pivot 26 . The track frame pivot 26 is operatively attached to the main frame 25 . The track frame pivot 26 extends from one side of the main frame 25 to the other side for each suspension system 12 . The track frame pivot 26 is operatively connected to the main frame 25 via a bearing cup 38 and a bearing cap 39 . Ends of the track frame pivot 26 ride in the bearing cup 38 and the bearing cap 39 . To hold the track frame pivot 26 in place, the bearing cap 39 is bolted over the track frame pivot 26 to the bearing cup 38 . In the preferred embodiment, the bearing cap 39 and the bearing cup 38 are lined with neoprene rubber. The track frame pivot 26 is preferably a steel bar but other materials could be substituted.
The suspension cylinder 21 is generally readily available and one such cylinder is made by Caterpillar Industrial Products, Inc. in Peoria, Ill. under Part No. 151-1179. The suspension cylinder 21 is hydraulically connected to an accumulator 27 via a suspension pressure line 49 to provide suspension travel and load support. Preferably, the accumulator 27 is a high capacity nitrogen accumulator. The accumulator 27 is available over-the-counter and one such accumulator is made by Caterpillar Industrial Products, Inc. in Peoria, Ill. under Part No. 7U5050. It is obvious to those with ordinary skill in the art that other cylinders and accumulators could be substituted for these specific cylinders and accumulators.
When the idler wheel 14 encounters an object, the idler wheel 14 moves upwardly and the suspension cylinder 21 absorbs the initial shock of the object. During this upward movement, the suspension system 12 pivots about the track frame pivot 26 . On the downward movement, the suspension cylinder 21 precludes a rapid descent for a smooth ride. FIGS. 9 and 10 show a roller bearing or side thrust bearing 52 operatively attached between the lower suspension bracket 19 and an inside support 53 to prevent side bearing thrust movement. The side thrust bearing 52 allows the lower suspension bracket 19 to move up and down pivoting about the track frame pivot 26 . The side thrust bearing 52 moves up and down and keeps the track frame from moving.
Referring now to FIGS. 1 , 2 , 9 and 10 , a track belt tensioner 31 is used to maintain tension on the belt 13 between the idler wheel 14 and the drive wheel 15 . The amount of tension in the belt 13 is determined by the horizontal distance between the idler wheel 14 and the drive wheel 15 . The drive wheel 15 is rotatably mounted about a powered axle 54 , and the idler wheel 14 is rotatably mounted to a yoke 80 via the axle 30 .
Referring now to FIGS. 5 & 6 , the yoke 80 includes a first axle bracket 81 and a second axle bracket 82 for supporting the rotating axle 30 . A yoke housing 83 is operatively attached to the first and second axle brackets 81 , 82 . The yoke 80 has guide member 84 moveably mounted to a top surface of the main frame 25 , and the yoke 80 moves horizontally along the main frame 25 when urged by a track tension cylinder 32 . The yoke 80 has a first track guide 85 and a second track guide 86 that surrounds the main frame 25 . The first and second track guides 85 , 86 are attached to the first and second axle brackets 81 , 82 and the yoke housing 83 , and the first and second track guides 85 , 86 keep the yoke 80 on the main frame 25 during the back and forth horizontal movement. The idler wheel 14 and the yoke 80 move along a horizontal axis via the track tension cylinder 32 .
A piston rod 90 from the track tension cylinder 32 extends moving the idler wheel 14 and the yoke 80 backward and forward, thereby adding tension on the belt 13 . When the piston rod 90 is retracted, the idler wheel 14 and the yoke 80 are moved closer to the drive wheel 15 , thereby reducing the tension on the belt 13 . The idler wheel 14 is encapsulated in the lower suspension bracket 19 , and the lower suspension bracket 19 keeps the belt 13 from falling off of the wheels 15 , 15 . During the extension and retraction of the piston rod 90 from the track tension cylinder 32 , the yoke 80 slides on the track frame 20 . Once again, the position of the yoke 80 along with the idler wheel 14 is adjusted horizontally via the track tension cylinder 32 to adjust the belt 13 tension. In addition to adjusting the horizontal position of the yoke 80 to adjust the belt 13 tension, the lower suspension bracket 19 pivots in the vertical direction as previously described. The lower suspension bracket 19 pivots about the track frame pivot 26 but does not move horizontally with the yoke 80 .
The combination of the suspension cylinder 21 and the track tension cylinder 32 absorbs the shock placed on the idler wheel 14 . This shock absorption prevents the belt 13 from tearing and falling off the idler wheel 14 and the drive wheel 15 and also provides a smooth ride.
The track belt tensioner 31 has the track tension cylinder 32 . The track belt tensioner 31 is operatively mounted to the frame 20 via a cylinder bracket 33 . The cylinder bracket 33 is welded to the lower suspension bracket 19 . A first end of the track tension cylinder 32 is pinned to the cylinder bracket 33 . A second end of the track tension cylinder 32 has the piston rod 90 for adjusting the yoke 80 and the idler wheel 14 in the horizontal direction. The piston rod 90 is operatively mounted to a piston cylinder bracket 34 . In the preferred embodiment, the piston cylinder bracket 34 is triangular as viewed from the side and welded to the frame 20 . The track tension cylinder 32 is hydraulically connected to a tension accumulator 35 to provide belt 13 tensioning and a smooth ride. The tension accumulator 35 is preferably mounted above the track tension cylinder 32 . It is important to note that in the preferred embodiment, there is one tension accumulator 35 and one track tension cylinder 32 per belt 13 ; however, the track tension cylinders 32 could be connected to one accumulator. In yet another embodiment, the track tension cylinders 32 and the suspension cylinder 21 are connected to one accumulator.
The tension accumulator 35 is hydraulically connected to the track tension cylinder 32 via a hose 36 . The track tension cylinder 32 is, preferably, a tow large-bore, long-stroke cylinder to provide excellent cushioning and dampening. J.R. Schneider Company, is located at 849 Jackson Street, Benicia, Calif., 94510 and provides a suitable cylinder under the name BAILEY330™ Part No. 216-141. Preferably, the tension accumulator 35 is a high capacity nitrogen accumulator. The tension accumulator 35 can be purchased from DYNA TECH, A Neff Company, located at 1275 Brume Elk Grove Village, Ill., 60007, and provides a suitable accumulator under Part No. A2-30-E-OSG-BTY-MIO. It is obvious to those with ordinary skill in the art that other cylinders and accumulators could be substituted for these specific cylinders and accumulators.
The tension on the belt 13 needs to be set after the belt 13 is assembled on the idler wheel 14 and the drive wheel 15 . To set the tension, hydraulic fluid is added to the track belt tensioner 31 until the gauge on the track tension cylinder 32 reads 10,000 pound per square inch. The tension accumulator 35 is pre-charged at 600 pounds per square inch with nitrogen.
The combination of the suspension system 12 and the track belt tensioner 31 provides independent track suspension. When an object is encountered by the idler wheel 14 , the idler wheel 14 is allowed to move vertically and horizontally because of the suspension system 12 and the track bolt tensioner 31 , respectively.
Referring now to FIGS. 1 , 2 and 5 , middle rollers 40 are shown. The middle rollers 40 are rotatably mounted to the frame 20 and fixed; the middle rollers 40 are not capable of moving up and down or back and forth. In the preferred embodiment, there are eight middle rollers 40 per belt 13 . There are four middle rollers 40 along the outside of the belt 13 , and there are four middle rollers 40 along the inside of the belt 13 . The eight middle rollers 40 are weight bearing and, thus, provide a low ground pressure design and are load bearing rollers. The middle rollers 40 , preferably, are 21 inches in diameter by 2-5 inches in width fork truck wheels press on wheels. Suitable middle rollers 40 are available through Caterpillar Industrial Products, Inc. under Part No. 120-5746. In arctic use, the ground contacting surfaces of the middle rollers 40 are coated with rubber. Normally, the middle rollers 40 are made with solid rubber. The middle rollers 40 are beveled on one side to match the bevel of the cog of the rubber track.
Referring now to FIGS. 11-15 , a braking system 41 for positive braking is shown. The braking system 41 has calipers 42 , preferably four. The calipers 42 are used on each of the four wheels 14 , 15 .
There are two calipers 42 for each belt 13 system (i.e., one caliper 42 for the idler wheel 14 and one caliper 42 for the drive wheel 15 ). The two calipers 42 operatively controlling the two idler wheels 14 are operatively mounted to the yoke 80 . The two calipers 42 operatively controlling the two drive wheels 15 are mounted to the main frame 25 . Large diameter discs 43 are operatively mounted to the idler wheels 14 and the drive wheels 15 . The calipers 42 act on or contact the discs 43 causing the track driven device 10 to slow or stop. Dust covers 44 enclose the calipers 42 . The braking system 41 results in positive braking due to the combination of lugs 18 on the belts 13 mating with the idler wheels 14 and the drive wheels 15 . The lugs 18 enter the front windows 16 of the idler wheels 14 and the drive wheels 15 in much the same way that meshing gears interact with one another. As the calipers 42 work on the discs 43 , the idler wheels 14 and the drive wheels 15 are slowed as a result of the front windows 16 acting on the lugs 18 thereby positively slowing or stopping the belts 13 from rotating about the idler wheels 14 and the drive wheels 15 .
In the braking system 41 , hydraulic pumps 47 supply hydraulic fluid to a master cylinder 46 via brake lines 45 . The hydraulic pump 47 is a mechanically driven hydraulic pump. Supply lines 48 provide pressurized hydraulic fluid from the master cylinder 46 to the calipers 42 . The operation of the braking system 41 is readily apparent by the elements previously described.
Modifications and substitutions by one of ordinary skill in the art are considered to be within the scope of the present invention, which is not limited except by the following claims.
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A track driven device having a suspension system, positive hydraulic braking system, positive drive belt system and belt tensioning system for an improved ride, reducing belt wear and belt failure.
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RELATED APPLICATION
[0001] The present application claims priority from prior U.S. Provisional Patent Application No. 60/329,260, filed Oct. 12, 2001, which is fully incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention relates to a floor cleaning machine for scrubbing floors and, in particular, to controlling the containment of a liquid cleaning solution and/or other materials, such as debris, during the scrubbing process in order to continue or enhance use of cleaning solution over a greater floor surface.
BACKGROUND OF THE INVENTION
[0003] Of the various types of floor cleaning machines that have been developed, the expeditious use and reuse of a cleaning solution remains important to efficient cleaning or scrubbing of floors. In particular, many floor cleaning machines have rotary scrubbing brushes that rotate about a substantially vertical axis when scrubbing a floor. Accordingly, such rotary motion tends to eject the cleaning solution away from where the scrubbing brushes contact the floor. Thus, the cleaning solution must be constantly applied to the floor surface at a rate at least sufficient to replenish the cleaning solution at the scrub brush(es) that has been ejected by the centrifugal forces induced by the rotary motion of the brush(es). Accordingly, it would be advantageous to have a cleaning machine that retains the cleaning solution a longer time period within proximity of the scrubbing brush(es) so that the cleaning solution does not have to be applied to the floor surface at as high a rate, and/or there is a greater amount of cleaning solution available under or about the scrubbing brush(es), thus providing for better floor cleaning. Additionally, it would be advantageous to be able to recirculate the cleaning solution on the floor surface such that when it is ejected from the scrubbing brush(es), a substantial amount of ejected solution is channeled along a flow path that leads this ejected solution back under the scrubbing brush(es). More particularly, it would be advantageous for the ejected cleaning solution to be channeled or pooled just behind the scrubbing brush cleaning assembly in a manner such that the same rotary action of scrubbing brush(es) causes this channeled or pooled cleaning solution to move toward the front of the scrubbing brush cleaning assembly, and thus once again come in operational contact with the scrubbing brush(es).
SUMMARY OF THE INVENTION
[0004] The floor cleaning machine can be any number of differently configured scrubbing apparatuses including a rider machine or a walk behind machine with the scrubbing assembly located beneath or forward of the cleaning machine body, or any other scrubbing machine with a body or handle for engagement by the operator. Regardless of the machine's configuration, each of them has at least a first barrier for use in containing materials within the area serviced by the scrubbing assembly for a relatively longer period of time by preventing or substantially preventing the escape of liquid from the rear of the scrubbing assembly. In addition to the rear, the scrubbing assembly has a front. The front of the scrubbing assembly leads the scrubbing assembly over the floor during the floor scrubbing operation when the machine is moved in a forward direction, in contrast to movement of the machine in a reverse direction.
[0005] In one embodiment, the scrubbing assembly has at least a first scrubbing brush with a circumference that has a circumferential portion that is less than the circumference. For example, the circumferential portion may be between about 90° and about 270°. The first barrier has portions that are disposed radially outwardly of this circumferential portion.
[0006] One or more embodiments can also include a skirt or splash guard. The skirt is located outwardly of both the scrubbing assembly and the first barrier. The skirt has utility in substantially preventing or at least reducing unwanted splash that may occur during the operation of the floor cleaning machine.
[0007] Each of the embodiments also preferably has a squeegee assembly that is located behind the scrubbing assembly in the context of movement of the floor cleaning machine when it is scrubbing a floor. Whenever the floor cleaning machine includes such a squeegee assembly, the first barrier is located closer to the first scrubbing brush than it is to the squeegee assembly.
[0008] Based on the foregoing summary, a number of salient aspects of the present invention are readily noted. One or more barriers is provided that maintain solution for use by a scrubbing assembly for a longer period of time. Preferably, each barrier does not completely surround the associated brush of the scrubbing assembly, but is open at its front and closed at its rear. In one or more embodiments, the floor cleaning machine can include a skirt, in addition to the one or more barriers, for use in controlling any splash. The floor cleaning machine of the present invention can also include a squeegee assembly that is useful in picking up solution after the scrubbing assembly is finished with it scrubbing function. The squeegee assembly has preferred positioning relative to the one or more scrubbing brushes of the scrubbing assembly.
[0009] Other advantages and benefits of the present invention will become evident from the accompanying drawings and the descriptions of the inventive features set out hereinbelow.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] [0010]FIG. 1 is a perspective exterior view of a cleaning machine 20 according to the present invention. Note that FIG. 1 shows a cavity 28 that provides storage for carrying various items used in cleaning a floor surface.
[0011] [0011]FIG. 2 is a perspective view of an alternative embodiment of a cleaning machine 20 , wherein the cavity 28 does not have holding mechanisms 36 (FIG. 1) for retaining items in the cavity.
[0012] [0012]FIG. 3 is another perspective view of the cleaning machine 20 shown in FIG. 2, wherein a different assortment of items are shown residing in the cavity 28 .
[0013] [0013]FIG. 4 is a top perspective view of an embodiment of a scrubbing assembly 30 according to the present invention.
[0014] [0014]FIG. 5 is a plan view of an alternative embodiment of a scrubbing assembly 30 according to the present invention.
[0015] [0015]FIG. 6 shows a partial cross section of the scrubbing assembly 30 of FIG. 5, wherein the cross section is taken through the cutting plane identified by “A” in FIG. 5.
[0016] [0016]FIG. 7 shows a magnified view of a portion of FIG. 6 thereby providing greater detail of some of the scrubbing assembly 30 components.
[0017] [0017]FIG. 8 is a top perspective view of another embodiment of the scrubbing assembly 30 according to the present invention.
[0018] [0018]FIG. 9 is a bottom perspective view of the scrubbing assembly 30 of FIG. 8.
[0019] [0019]FIG. 10 is a top perspective view of an embodiment of the scrubbing assembly 30 with a hood 120 providing a splash guard between the scrubbing brushes 64 and 68 (e.g., FIG. 9) and the motors 84 and 88 .
[0020] [0020]FIG. 11 is a bottom perspective view of the scrubbing assembly 30 and hood 120 of FIG. 10.
DETAILED DESCRIPTION
[0021] With reference to FIG. 1, one embodiment of a floor cleaning machine 20 includes a body or housing 24 that is part of a walk behind floor cleaning machine which is moved under power activated by the operator who controls machine operation. The body 24 includes a main assembly 26 of the floor cleaning machine, wherein the main assembly includes at least the exterior side panels 27 a, and front panel(s) 27 b as well as a supporting frame (not shown). and to which a scrubbing assembly 30 is joined at one or more lower portions of the body 24 . The scrubbing assembly 30 has a front 30 f which extends generally forwardly from the front panel(s) 27 b, and thus this front 30 f leads the main assembly 26 during forward motion of the machine 20 . The front 30 f of the scrubbing assembly 30 has a lower portion 33 that serves as splash guard about the front of the machine 20 , thereby reducing and preferably preventing the cleaning solution (more generally, floor application substance) from an airborne exit from the scrubbing assembly 30 along the extent of the splash guard 33 . Note that the splash guard 33 is substantially adjacent to floor surface 31 about the front of the machine 20 , and further extends at least partially about the sides of the machine 20 . The scrubbing assembly rear 30 r (FIGS. 4 and 5) is generally underneath the main assembly 26 . The scrubbing assembly 30 includes:
[0022] (a) at least one scrubbing brush (not shown in FIG. 1, but one of which is labeled 64 in FIG. 4) positioned within the scrubbing assembly 30 for rotationally contacting the floor surface 31 ,
[0023] (b) at least one brush motor (not shown in FIG. 1, but one of which is labeled 88 in FIG. 4) for rotating the at least one scrubbing brush, and
[0024] (c) a frame assembly (also not shown in FIG. 1, but an embodiment of which is labeled 69 in FIG. 4) upon which the at least one brush motor is operably attached.
[0025] Note that such a scrubbing brush may usually be comprised of a number plurality of bristles connected to a disk shaped head or base member (not shown in FIG. 1, but one of which is labeled 72 in FIG. 7). The ends of the scrubbing brush bristles scrub the floor surface 31 during the cleaning process.
[0026] Positioned at the rear of the machine 20 is a squeegee assembly 29 for extracting excess and/or spent cleaning solution (more generally, a surface application substance or solution) from the floor surface 31 . Note that the squeegee assembly 29 may extend outwardly beyond the side panels 27 a so as to capture the surface application substance or solution that escapes from underneath the machine 20 .
[0027] In one embodiment, the machine body 24 includes a cavity or recess 28 of a desired size to accommodate and hold any one or a number of items that may be useful related to cleaning operations. The cavity 28 illustrated in FIG. 1 is generally centered along the top or upper portions of the body 24 between its front and rear ends and its two side walls. These upper portions can be defined as having a total outer surface area. The outer surface area of the cavity or cavities 28 is at least about 10 percent of the total outer surface area of the upper portions. In another embodiment, the outer surface area of the cavity or cavities 28 can be at least about 15 percent and, in yet another embodiment, the outer surface area of the cavity or cavities 28 can be at least about 20 percent. In the embodiment of FIG. 1, although it may not be necessary, a containment structure may be utilized to secure the one or more items in the cavity 28 . The containment structure might include one or more straps or cords 32 , which can have elastic or resilient properties, that extend laterally (and/or could extend longitudinally) relative to the machine body 24 . The straps 32 are held to the body 24 adjacent to the edges of the cavity 28 using holding mechanisms 36 , such as hooks, eyelets or fasteners, such as rivets, screws, bolts or the like, which may be fixed or removable. The number of straps 32 can vary and may depend on the size of the items that are to be held within the cavity 28 . As can be understood, other containment structures can be utilized including a single cover piece or a mesh, which could be made of a flexible material or relatively rigid material. Regardless of the physical characteristics of the containment structure, the portions thereof are positionable to permit access to the cavity 28 in order to place the one or more items within the cavity. After doing so, the containment structure is positioned to hold such items within the cavity 28 , such as during transport or movement of the machine 20 .
[0028] Referring to FIGS. 2 and 3, representative examples of items that can be positioned and held in the cavity 28 are illustrated. As seen in FIG. 2, a sign or other indicator 34 useful in notifying or warning others that a particular section of floor is being cleaned can be transported using the cavity 28 . The sign 34 can be subsequently set up by the operator at a desired location. The cavity 28 can also hold a container or bucket 38 . The container 38 can itself contain a number of separate cleaning utensils or articles, such as a liquid cleaning container 42 and a hand brush 44 . In addition to the cavity 28 , located adjacent the back of the body 24 of the machine 20 , wells or recesses can be formed therein for holding items, such as a spray bottle 50 and/or a drinking cup 54 . Referring to FIG. 3, the cavity 28 has a size sufficient to hold spare cleaning components, such as brushes 58 . The dimensions of the cavity 28 are even of a size to hold a relatively large battery charging unit 62 . The battery charging unit 62 can be used to charge the batteries that power the cleaning machine 20 . As can be appreciated, the cavity 28 can be part of cleaning machines other than a walk behind scrubbing machine. The structure and associated feature of the cavity 28 can be implemented or otherwise included with a variety of relatively larger cleaning machines including cleaning machines that have one or more of a sweeper, a burnisher and/or a scrubber, as one skilled in the art will appreciate.
[0029] With reference to FIGS. 4 - 7 , one embodiment of a scrubbing assembly 30 that can be joined to the cleaning machine body 24 is next described. In this embodiment, the scrubbing assembly 30 includes a pair of scrubber subassemblies 61 having a first scrubbing brush 64 and a second scrubbing brush 68 , respectively, and having a combined frame assembly 69 . Each of the two scrubbing brushes 64 , 68 is essentially disk-shaped with an outer perimeter or circumference. When activated or energized, each of the two brushes 64 , 68 rotates about its own central, vertical axis 70 (one of which is shown in FIG. 6).
[0030] Referring to FIGS. 5, 6 and 7 , FIG. 5 shows a plan view of the scrubber subassemblies 61 and the sectioning plane, identified by “A” in FIG. 5, shows where the cross section illustrated in FIGS. 6 and 7 is located.
[0031] Accordingly, FIGS. 6 and 7 show a depiction in more detail directed to the cross section of the second scrubbing brush 68 . The second scrubbing brush 68 includes a number of scrubbing bristles 72 (FIG. 7) attached to a head or base member 76 . As seen in FIG. 6, the base member 76 is formed with a recessed area at about its mid-portion to receive a driver element 80 that can be caused to rotate using a second scrubbing brush motor 84 . Note that a first scrubbing brush motor 88 is illustrated in FIGS. 4 and 5 for similarly causing the first scrubbing brush 64 to rotate when the motor 88 is powered on.
[0032] A key component of the present invention is one or more barrier or blocking units, each of which has a shape that generally follows the outer circumference of a corresponding scrubbing brush, and wherein each barrier tends to confine the cleaning solution so that it stays under or near the corresponding scrubbing brush for the barrier. In one preferred embodiment, each such barrier is attached to the frame assembly 69 (FIG. 4) by attachment components such as rivets, bolts, welds, clamps, etc. However, other barrier attachment sites and mechanisms are within the scope of the invention. Moreover, in the embodiment having two scrubbing brushes 64 , 68 (e.g., FIG. 4), there are two such barriers 90 a, 90 b. That is, a barrier for each of the two scrubber subassemblies 61 .
[0033] Each such barrier 90 a and/or 90 b (and/or additional barriers) may be substantially identical in terms of structure and operation. Accordingly, even though some of the following descriptions may describe only one of a plurality of barriers (e.g., one of the two barriers 90 a, 90 b of FIG. 4), in terms of structure and operation, it is to be understood that such a description applies to each such barrier if there is more than one barrier. Referring to each of the two barriers 90 a, 90 b of FIG. 4, each barrier is joined to the scrubbing assembly 30 , and in particular, to a respective one of the scrubber subassemblies 61 (and more particularly to the frame assembly 69 ) using, e.g., fasteners, rivets, slots, openings and the like. In a preferred embodiment, each of the two barriers 90 a, 90 b is comprised of a bracket 100 and a relatively rigid extender member 104 made of rubber (more generally an elastomeric) or the like. The extender member 104 of each of the barriers 90 a, 90 b can be defined as including a bottom edge 106 that continuously contacts the floor surface being cleaned during the cleaning process or operation of the machine 20 . Each barrier 90 a, 90 b is located generally, at least, at the rear of the scrubbing assembly 30 (i.e., generally, the portion of the scrubbing assembly that trails the scrubbing brush(es) 64 and 68 ) during forward motion of the machine 20 ). Moreover, it is preferred that each such barrier follow a contour or profile of the corresponding scrubbing brush about which the barrier at least partially surrounds. In particular, such a barrier may be shaped so that at least the bottom edge 106 of the barrier is coincident with an offset profile of the perimeter of the corresponding scrubbing brush, wherein this offset is from this scrubbing brush's floor contacting perimeter, and is approximately in the range of about one to about four inches from this perimeter. However, smaller offsets are also within the scope of the invention, such as, offsets within the range of ½ to one inch. Additionally, note that each such barrier follows its corresponding scrubbing brush's perimeter for at least most (if not the entire) rearward portion of the corresponding scrubbing brush. More specifically, each such barrier follows an offset contour of its corresponding scrubbing brush for at least approximately 120° of angular extent about the rotational center of the corresponding scrubbing brush. Based on this rearward location of the barrier(s), together with its design or construction, the cleaning solution or other liquid used in scrubbing the floor surface is captured or trapped in the retention area 108 , at least for a relatively longer period of time in comparison with scrubbing assemblies that do not have one or more barriers 90 a, 90 b, in order that the cleaning material can be used for a longer time by the scrubbing brush(es) having the barrier associated therewith. More generally, each such barrier can be described as not exceeding a predetermined offset from a corresponding one of the scrubbing brushes for at least most of the width (e.g., diameter) of this corresponding scrubbing brush when the machine 20 is operatively moving in a forward direction and cleaning the floor surface 31 .
[0034] Additionally, note that one embodiment may include a single unified barrier that follows an offset from each of a plurality of scrubbing brushes. Thus, e.g., in such an embodiment, the barriers 90 a and 90 b of FIG. 4 may be combined into a single unified barrier, wherein the adjacent ends of the barriers 90 a and 90 b that are generally between the scrubbing brushes 64 and 68 are attached to one another.
[0035] It is an aspect of the machine 20 that the cleaning solution or other floor surface application materials or substances can be characterized as being held, at least for some time interval, in a the retention area 108 (FIGS. 4, 9 and 11 ) at those portions of the scrubbing brushes 64 , 68 which are then adjacent to the rear 30 r of the scrubbing assembly 30 . In particular, the retention area 108 may be within two inches of each scrubbing brush, and preferably within 1.5 inches of each scrubbing brush, and more preferably within one inch of each scrubbing brush. Moreover, during rotation of, e.g., the first scrubbing brush 64 , the materials or solutions, including, e.g., the cleaning solution in the retention area 108 , are caused to move in a direction from the rear 30 r to the front 30 f of the scrubbing assembly 30 . In the embodiment in which there are two scrubbing brushes 64 , 68 , rotation of the scrubbing brushes 64 , 68 causes at least some of such materials, including liquids, to move forwardly past and between the peripheral circumferential portions of the scrubbing brushes 64 , 68 that are adjacent to each other. In any case, such a liquid surface application substance or solution, that is retained in the retention area 108 for a relatively short period of time adjacent the scrubbing brushes, is caused to move towards the front 30 f of the scrubbing assembly 30 and escape from the peripheral or circumferential portions of the scrubbing brushes 64 , 68 that are not bounded by the barriers 90 a, 90 b since these barriers do not extend about the entire perimeter or all circumferential portions of either the first and second scrubbing brushes 64 , 68 . Moreover, note that the lower portion 33 substantially prevents the surface application substance or solution from spraying out the front of the machine 20 in the embodiments of the invention wherein the barrier(s) (e.g., 90 a and 90 b ) do not completely surround the front of the scrubbing brushes. Moreover, the lower portion 33 is generally further from the scrubbing brush(es) than the barrier(s). In particular, where the lower portion 33 and a barrier overlap radially from the center of a scrubbing brush, the barrier overlap is closer to the scrubbing brush than the splash guard 33 .
[0036] Since each of the two barriers 90 a, 90 b may be configured to correspond or match the disk circular shape of each of the scrubbing brushes 64 , 68 , each barrier 90 a, 90 b may be arcuate-shaped and is located a desired radial distance outwardly from the circumferential or peripheral portions of its respective scrubbing brush 64 , 68 (e.g., such radial distance being less than two inches, and preferably less than one inch). The arcuate length or perimeter of each arcuate-shaped barrier 90 a, 90 b is less than that of the perimeter or circumference of its respective scrubbing brush 64 , 68 . In one embodiment, the perimeter of such a barrier, particularly the extender member 104 , can be characterized in terms of its arcuate extent. Specifically, the actuate extent defines an arc of at least about 90° about the corresponding scrubbing brush, and generally no greater than about 270°. Hence, each barrier extends radially outwardly about the circumference or perimeter of its associated scrubbing brush generally no greater than about 270°.
[0037] With respect to the positioning of the barrier relative to a scrubbing brush, it is preferred that the radial distance between the inner surface of the extender member 104 and the closest bristle 72 portion of the scrubbing brush being be less than 2 inches, more preferably less than about 1.5 inches and most preferably less than about 1 inch. This desired radial distance ensures or facilitates the desired retention of cleaning solution or other liquid surface application substance relative to the scrubbing brush bristles 72 . It is also preferred that each barrier be fixedly held to the scrubbing assembly 30 so that there is no relative movement therebetween, particularly that there be no pivotal movement between each of the barriers and the scrubbing assembly 30 , e.g., about an axis of rotation of a scrubbing brush.
[0038] With reference to FIGS. 8 and 9, an embodiment of the barriers 90 a and 90 b is illustrated in which each of these barriers 90 has a perimeter or arcuate shape that extends for about 270° and has, or is at least close to, the desired maximum arc for controlling the liquid substance or solution within the scrubbing assembly 30 , while allowing a sufficient open area for materials including the liquid solution to escape from the scrubbing assembly 30 at its front 30 f.
[0039] In yet another embodiment, at least the extender member 104 could extend a complete 360° radially outwardly of and surrounding a scrubbing brush. According to this embodiment, a slot, notch or other open area would be formed in the extender member 104 to allow for the escape of the surface application substance or solution (and, e.g., surface materials suspended and/or dissolved therein) at the front 30 f of the scrubbing assembly 30 . This open area could be formed by providing the extender member 104 with at least two different heights. The first height of the extender member 104 that includes portions adjacent to the rear 30 r of the scrubbing assembly 30 could be greater than the height of the extender member 104 at the front 30 f of the scrubbing assembly 2430. The reduced height defines a space or gap at the bottom of the extender member 104 so that it does not contact the floor surface and thereby allows the surface application substance or solution to escape.
[0040] In still another embodiment, the height of the extender member 104 could be the same throughout but still a space or gap is defined at its front 30 f to enable liquid and other materials to exit the scrubbing assembly 30 . In one embodiment, the open area defined by the space between the floor surface 31 and the bottom edge 106 of the extender member 104 has an area comparable to the area in the embodiment in which the extender member terminates after a desired number of degrees, such as 270°.
[0041] With reference to FIGS. 10 and 11, a further preferred embodiment of the scrubbing assembly 30 is illustrated that has essentially the same features and construction of FIGS. 1 - 7 , for example. Additionally, this embodiment includes a skirt hood or splash guard 120 which serves as an internal splash guard for preventing airborne particles and/or cleaning application substances or solutions from interfering with the operation of the scrubbing brush motor(s), e.g., 84 and 88 . The skirt hood 120 may include an downwardly directed skirt 124 that is located outwardly of each barrier 90 a and 90 b. In one embodiment, the shortest distance between any portion of a barrier 90 a or 90 b and the skirt 124 is greater than any radial distance between each such barrier 90 and its associated scrubbing brush. Like splash guards or skirts used in conventional designs, the skirt 120 is useful in preventing or otherwise controlling liquid spattering or splashing of the surface application substance or solution that typically occurs during the a scrubbing process.
[0042] The foregoing discussion of the invention has been presented for purposes of illustration and description. Further, the description is not intended to limit the invention to the form disclosed herein. Consequently, variation and modification commensurate with the above teachings, within the skill and knowledge of the relevant art, are within the scope of the present invention. The embodiments described hereinabove are further intended to explain the best mode presently known of practicing the invention and to enable others skilled in the art to utilize the invention as such, or in other embodiments, and with the various modifications required by their particular application or uses of the invention.
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A floor cleaning machine has one or more barriers immediately behind one or more scrubbing brushes, wherein the barriers capture and control flow of a cleaning solution (and/or other substances) that exits from beneath the scrubbing brush(es) so that such a solution is retained adjacent the scrub brush(es) and recycled underneath the scrub brush(es) for enhancing the floor cleaning effectiveness of the floor cleaning machine. The captured solution is urged back into contact with the scrubbing brush(es) by the same rotating action that urged the solution to be ejected from the scrubbing brush(es). The machine also includes at least one splash guard and a squeegee mounted at the rear of the machine, with each of these latter components serving distinctly different functions from that of the barriers. The machine may also include an exterior top storage area for retaining various items that are useful in cleaning the floor.
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BACKGROUND OF THE INVENTION
The invention relates to a device for the delivery of folded products with fan arrangements which are positioned opposite to one another.
With the processing of folded products very high demands are made on folding apparatuses which generally are arranged behind high-speed rotary printing presses. The continuous product stream being created has to be directed securely into receiving pockets of fan arrangements, in order to slow-down the folded products and to enable delivery thereof in a shingled stream on a transport tape.
From U.S. Pat. No. 5,112,033 a device is known, wherein the individual folded produces of a product stream are received by respective pockets of alternating fan wheels. For this purpose the circumferential circles defined by the fan blade tips of the fan arrangements situated opposite to one another overlap. In order to avoid collision of the fan blade tips with one another, the individual fan blades of each fan arrangement are provided with recesses, and the tip of the respective opposite fan blade can dip into a corresponding recess.
It has become apparent that centrifugal forces created by high rotary speeds and the dimensional tolerances allowed in the manufacture of large parts have a negative influence, which makes it difficult for the fan blade tips to keep their exact predetermined positions. The deviation of the fan blade tips in axial as well as in radial direction from their predetermined end position should, however, fall within a narrow tolerance range with respect to both sides of the predetermined end position, in order to ensure optimal running smoothness as well as absolute operating safety.
SUMMARY OF THE INVENTION
In view of the above-mentioned state of the art, it is the object of the present invention to ensure that fan blade tips maintain their predetermined position, particularly at high rotary speeds.
The solution according to the present invention, furthermore, serves the purpose of compensating for manufacturing tolerances, so that even those parts with a dimension at the tolerance limit still can be used.
It is an additional object of the invention to reinforce one fan wheel arrangement.
According to the invention, these objects can be achieved by way of a device for truing fan blades of an apparatus for receiving and delivering folded products. The fan blades each have a first side or face and a second side, as well as a tip. The fan blades moreover are organized in at least one fan arrangement that is disposed so as to rotate about an axis. The circumference of the fan arrangement overlaps with the circumference of another such fan arrangement which rotates about an axis that is parallel to the axis about which the first mentioned fan arrangement rotates. The device for truing fan blades includes a biasing member having a first end and a second end. The first end is coupled to the fan blade at a first position on the first face of the fan blade. A coupling is fixed or coupled to the first face of the fan blade at a second position. This coupling secures the second end of the biasing member. The device also includes an adjustment mechanism which is disposed adjacent to the coupling and which is coupled to the biasing member to permit modification of the tension of the biasing member. With this configuration, a change in the tension of the biasing member effects a change in the position of the tip of the corresponding blade.
The solution according to the present invention permits the fan arrangements situated opposite to one another to be biased in an advantageous way. The degree of bias can be selected through the biasing means such that the positions of the fan blade tips, when stationary or at operating speed, can be precisely controlled. The process for precisely positioning the fan blade tips can either be made dependent on the elasticity of the material of which the fans are made or on the operating speed of the fan arrangements, allowing for exact compensation of tolerances on each fan blade. According to an aspect of the present invention an axial movement of the fan blade ends parallel to the axis of rotation can be achieved by way of a loosening or tightening of the corresponding biasing means.
According to another aspect of the present invention means are provided for biasing the fan blade tips on both sides of fan blade segments. This allows for an axial adjustment of the fan blade ends from either side, using an embodiment of the invention as a tensioning device.
Also, the biasing means could be provided on one side of the fan blade segment. In this case a tensioning of the device will move the fan blade ends towards the side on which the device is installed. A loosening of the device will move the fan blade end away from the side on which the device is installed, due to the inherent tension of the fan blade material.
Furthermore, the biasing means can be spoke-shaped and be provided with adjustment means. The fan blades of each fan segment or fan can have multiple openings for receiving the spoke-shaped biasing means. This allows a wide-range variation in biasing characteristics of the individual fan blades.
The openings in the fan blades may serve to receive the angular ends of the biasing means. Moreover, bearing elements may be disposed in the openings in which the biasing means can be received. In order to simplify the biasing of the fan blades, the biasing means are received in abutments in the region of the adjustment means. On a fixture which may be provided with a slot-shaped alignment device, the individual fan blades and/or the blade tips thereof are aligned in the axial as well as in the circumferential direction through the loosening or tightening of the biasing means in such a manner that the distance between each blade tip and the edge of the alignment device is equal. Thus, the positions of the individual fan blade tips can be accurately adjusted, depending on the fan blade material, manufacturing tolerance and operating speed, so that great improvement in smooth and safe operation is achieved.
BRIEF DESCRIPTION OF THE DRAWINGS
Further characteristic features of the invention will be explained in the following description, which will be best understood when read in connection with the accompanying drawings, in which:
FIG. 1 is a perspective view of a fan segment,
FIG. 2 is a cross-section of a biased fan blade with an angled tensioning biasing means,
FIG. 3 is a cross-section of a biased fan blade with bi-directional biasing means supported in support pieces,
FIG. 4 is a cross-section of a biased fan blade with adjustment means on both sides of a fan segment,
FIG. 5 is a side view of a fan segment having adjustment means arranged in a series and
FIG. 6 shows a configuration of fan blade ends being alternately positioned on opposite sides of the fan segment.
DETAILED DESCRIPTION
FIG. 1 illustrates a perspective view of a fan segment 6 consisting of five fan blades 6.1, 6.2, 6.3, 6.4 and 6.5.
The fan segment 6 is rotatable around an axis of rotation 4 which is mounted in a frame part 1. On the frame part 1 there is provided an alignment device 2 having a slot-shaped opening 3 through which all fan blades 6.1, 6.2, 6.3, 6.4 and 6.5 can be rotated. In the embodiment illustrated herein the fan segment 6 is supported on a symmetrical carrier 5. A complete fan thus consists of three fan segments 6. This is easier to manufacture. However, it would also be feasible for a fan to consist of one part arranged on a carrier 5 so as to rotate around the axis of rotation 4.
Between the individual fan blades 6.1, 6.2, 6.3, 6.4 and 6.5 there are formed pockets 7 into which the folded products from the transport tapes enter. The respective pockets 7 have a curved contour and are defined by two adjacent fan blades 6.1, 6.2, 6.3, 6.4 and 6.5. Each of the individual fan blades 6.1-6.5 of the shown fan segment 6 has a recess 8. During the rotation of two fans that are situated opposite to one another, the fan blade tip of a respective opposite fan blade dips into the recess 8. In this manner, a collision of fans that are situated opposite to one another and having overlapping circumferences can be avoided. Each of the fan blades 6.1-6.5 has a fan blade end 9 (see lower part of FIG. 1), a blade tip 9.1 and an adjacent free space 9.2. It is the blade tip 9.1 which dips into the recesses 8 of the fan (not shown) that is situated opposite to the fan segment 6 shown in FIG. 1. Each one of the fan blades 6.1-6.5 has the same configuration of the blade ends 9, a blade tip 9.1 and an adjacent free space 9.2. Each of the shown fan blades 6.1-6.5 is provided with a spoke-shaped, slim tensionable biasing means 10. With these biasing means 10 a bias which exceeds the inherent tension of the material can be created between each of the fan blade ends 9 and the fan segment 6, and this bias can be maintained and adjusted, if required.
FIG. 2 illustrates a cross-section of a biased fan blade 6.2 with the angled biasing means. This fan blade 6.2 is provided with recesses 15 and 16 for receiving the biasing means 10, which may comprise a spoke-shaped biasing or tension member. In this exemplary embodiment only one biasing means 10 is shown. The angled, broad end of the biasing means 10, serving as its base, is disposed in an opening 20 in the body of the fan blade 6.2. The other end of the spoke-shaped biasing means 10 is held in an abutment 12 secured to the fan blade 6.2 by means of a nut 14. Adjacent to the abutment 12 there is shown an adjustment means 13, which may for example be a nipple, by means of which the tension of the spoke-shaped biasing means 10 can be changed. In this embodiment an adjustment means 13 is installed only on one side of the fan segment 6. A tightening of the adjustment means 13, causes movement of the fan blade end 9 parallel to the axis of rotation and towards the blade side to which the biasing means 10 is mounted. A loosening of the adjustment means 13 causes movement away from the blade side to which the biasing means 10 is mounted by utilizing the inherent tension of the fan blade material. By way of such loosening or tightening, the tip of each fan blade may be trued with precision to its appropriate position.
In coordination with the alignment device on frame 1, as shown in FIG. 1, the distance of each fan blade end 9 from the opening 3 of the alignment device can be set accurately by means of the respective biasing means 10. This does not only apply to radial adjustment of the fan blade ends 9. If, for example, biasing means 10 are provided on both sides of the fan blade 6.2, even possible manufacture-related imbalances in the parts can be compensated. The lateral distance of the fan blade end 9 of each fan blade 6.1-6.5 with respect to the slot-shaped opening 3 can be set accurately through the spoke-shaped biasing means 10, so that overlapping fan blades being situated opposite to one another cannot collide during operation. The tension to be applied to the material can be rated such that centrifugal forces occurring during operation of the fan blades at machine speed are already taken into account. The fan blade ends 9 are held in a position corresponding to the predetermined position, so that an exact dipping-in of the blade tips 9.1 into the respective recesses 8 of the opposite fan is ensured.
If complete fans or, as illustrated herein, individual fan segments with inherent manufacturing tolerances are used, these tolerances can be compensated by biasing the fan blade ends 9 to effect a positional adaptation of the blade tips 9.1.
FIG. 2 shows an exemplary opening 20 in the fan blade 6.2. Actually, there may be provided several openings 20 in each of the individual fan blades 6.1-6.5, into which the angled ends of the spoke-shaped biasing means 10 can be hooked. This would enable the biasing characteristics to be adapted when biasing means 10 of different lengths are used.
FIG. 3 shows a cross-section of a biased fan blade with adjustable biasing means supported in bearing elements. In this alternative embodiment a slim, adjustable biasing means 17 with a slotted head on one end and threaded on the other end is screwed into a bearing part 18. The biasing means 17 has a groove to receive a snap ring 19. The abutment 12 is captured between the snap ring 19 and the head of the biasing means 17. The bearing part 18 receiving the one end of the biasing means 17 as well as the abutment 12 receiving the opposite end of the biasing means 17 are secured to the fan blade 6.2 by means of nuts 14. In this configuration the biasing means 17 is required on only one side of the fan blade 6.2. When tightened, the head of the biasing means 17 is forced against the abutment 12 to create tension in the biasing means 17. The tension causes the fan end 9 to move laterally towards the blade side on which the biasing means 17 is installed. When the biasing means 17 is loosened, the snap ring 19 is forced against the abutment 12. A jacking force is created which causes the fan blade end 9 to move laterally away from the blade side on which the biasing means 17 is installed. The fan blade 6.2 also is provided with several openings 21, in order to effect a change in the biasing characteristics according to different lengths and elasticity of the biasing means 17.
It is understood that any possible readjustment of the bias, which may become necessary after long operation, can be carried out with ease and in short time.
FIG. 4 shows an embodiment of the present invention comprising spoke-shaped biasing means 10 in recesses 15, 16 provided on both sides of the fan blade 6.2. The openings 20 are arranged so as to be offset from one another. Using such a configuration the fan blade end 9 can be positioned in an axial direction to the axis of rotation, allowing an adjustment to either side of the fan blade. Furthermore, an alternate positioning of the fan blade ends 9 according to FIG. 6 can easily be accomplished. Using two biasing means to on both sides of the respective fan blade 6.1-6.5 allows the force acting upon one biasing means to be cut in half. An adjustment of fan blade ends 9 in radial direction can easily be achieved using biasing means 10 on both sides of the fan segment 6.
FIG. 5 shows a fan segment 6 with multiple biasing means 10 arranged in a series. The use of multiple biasing means 10 would provide for a greater degree of fan blade ends 9 repositioning. This applies for axial as well as for radial adjustments.
Finally, FIG. 6 shows a fan segment 6 having the fan blades 6.1-6.5 intentionally distorted into alternately arranged positions.
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The invention relates to a device for the delivery of folded products with fan arrangements that are positioned opposite to one another. Multiple fans are disposed in spaced relation on a common axis of rotation. The circumferences of the fans overlap in the region of the fan blade ends. Furthermore, the fan blades include a mechanism for preventing the collision of fan blade tips situated opposite to one another. The fan blades also include an adjustable biasing mechanism for biasing the fan blade ends.
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DESCRIPTION
The invention relates to a control apparatus for a material flow emitted by a vacuum heated evaporation source and intended to equip a thin film deposition or coating machine using vacuum evaporation and in particular a machine having several sources for depositing a mixture of materials.
It is frequently necessary to control the speed of deposition or, in the case of a simultaneous deposition of several materials to regulate their proportion when it is wished to e.g. regulate the refractive index of a filter. Several methods exist. In one of them, for each source use is made of a quartz balance, which is connected to a servocontrol device, which deduces the evaporation speed from the readings of the balance and controls the variations of the source supply in order to obtain the desired flow rate. This servocontrol is not always adequate, because the response delay of the sources to the supply variations is not accurately known. According to another method, one of the materials is extracted from a source and then projected towards the object to be coated, whereas the other is introduced into the enclosure containing said object by another means, such as a flow of gas or ion bombardment. The first of these methods is not very accurate due to the inertia of the gas flow and their inadequate uniformity in the enclosure and the second requires a special apparatus.
A novel method is proposed with the apparatus according to the invention. It consists of using screens, masks or covers provided with openings and which constantly move in front of the source, so as to present in front of it the openings alternating with the solid parts. The cover is mobile relative to the source in such a way that it makes it possible to vary the degree of source hiding, i.e. the proportion of the time during which the source is covered by the solid parts compared with the total passage time. The flow rate of the source in the direction of the part to be covered is, under these conditions, perfectly defined. The support in which the cover is fitted is preferably mobile relative to that of the source, so that it is possible to continuously vary the hiding level on displacing the source. It is also possible to make the variations of the degree of hiding proportional to the support displacement.
A preferred embodiment of said apparatus comprises several sources and the same number of covers moved by motors. All the covers and motors are mounted on a single plate and the covers are designed in such a way that the displacements of the support relative to that of the sources bring about different variations of the degree of hiding of each source. It is then possible to freely modify the compositions of the deposits made.
The invention is described in greater detail hereinafter relative to non-limitative embodiments and the attached drawings,
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a view of a vacuum evaporation coating machine using the apparatus according to the invention, the cover being a disk seen by its edge.
FIG. 2 is a view of an embodiment with two fixed sources, the complementary covers seen from the front being mounted on a support performing a translatory movement.
FIG. 3 is a view of a vacuum evaporation coating machine using the apparatus of FIG. 2.
FIG. 4 is a view of an embodiment with two sources, the identical covers seen from the front being in each case rotated about a fixed axis and the two sources perform an oscillatory movement on a circular path.
With reference to FIG. 1, the vacuum evaporation machine comprises an enclosure 1 in which is placed the sample 2 to be covered with a deposit in front of a source 3 subject to an evaporation, supplied by an electric cable 4 and a current generator 5.
A cover 6 is placed between the sample 2 and the source 3 and much closer to the latter. It is a disk of limited thickness and a shape which will be described hereinafter. In its centre it has a shaft 7, which spins it and which extends at some distance from the source 3. The shaft 7 is placed in a case 8, which contains an electric motor 9. The latter has a drive shaft 10 in the extension of the shaft 7 and which is separated from the latter by a tight partition 11 passing across the interior of the case 8. Thus, there is no mechanical connection between the drive shaft 10 and the shaft 7, but the drive is ensured by permanent magnets 12 located on their facing ends and which are constituted by groups of magnets arranged in ring-like manner and alternating poles positioned so as to produce an attraction force whilst opposing relative rotations.
Ducts 13 traverse the enclosure 1, the case 8 and lead to the electric motor 9. They contain electric supply wires and are traversed by a cooling air current. The electric motor 9 is consequently protected from the high temperature of approximately 300° C. created on the mask or cover 6 by the source 3. The shaft 7 rotates in an open part of the case 8 by means of ballbearings 14, which must not be lubricated with grease and which are covered with a thin molybdenum disulphide film. The balls are made from a ceramic material. The drive shaft 10 can be guided by ordinary ballbearings.
The case 8 is mounted on a table 15 serving as a support and which moves in the enclosure 1 towards the source 3 and away from the latter. It can e.g. be provided with a rack 16, which can be advanced by a pinion 17 controlled by a crank 18, which extends externally of the enclosure 1. It can be seen that the cover 18 is moved in front of the source 3, whilst remaining in the same plane, so as to pass in front of it a circumference with a selected diameter when the motor 9 is started up and the shaft 7 rotates.
The means for sealing the enclosure 1 and for creating the vacuum necessary for deposition under satisfactory conditions are of a conventional, not shown nature. The devices permitting the sliding of the table 15 and which can be constituted by slides or rails fixed to the wall of the enclosure 1 are also not shown.
FIG. 2 illustrates a machine having two fixed sources 3a,3b supplied by respective electric cables 4a,4b and cooperating with a respective cover 6a or 6b located on a support 15 performing a translatory movement on the rails 29 and rotating under the effect of a shaft 7a or 7b. Two main shapes for the covers 6 are shown. The first cover 6a is a disk having a circular outer contour 20 and which is provided with three lobe-shaped openings 21, whereof the arc extension ceaselessly decreases towards the periphery. The openings meet almost to form a circumference with a relatively small radius, but are then interrupted towards the inside in such a way that the first cover 6a has central surface 22a for connection to the shaft 7a. Three solid portions 23 extend between the openings 21 and meet at the periphery of the first cover 6a in order to form the circular outer contour 20, whilst being in one piece with the central surface 22.
The second cover 6b has a different shape, because it has three solid, lobed portions 24, whose shape is like the openings 21. The solid portions 24 are joined together and extend on the shaft 7b. Cavities 25 between the solid portions 24 form openings on the periphery of the second cover 6b, but which is solid within its contour 26. In the same way as the solid portions 24, the openings 21 are equidistant of the shaft 7 and regularly distributed over the circumference of the covers 6. The openings 21 and the solid portions 24 have identical shapes and sizes.
The covers 6a and 6b having complementary shapes rotate independently in the same plane. They can be moved by different motors or by a single motor having two transmission systems joining it to the two shafts 7a and 7b. In this embodiment of the invention shown in FIGS. 2 and 3, both the motors 9a and 9b are fixed to the table 15. The latter slides on rails 29 whilst the sources 3a,3b are stationary. A movement of the table in the direction S1, by a purely radial movement, moves the sources 3a,3b towards the rotation axis of their associated mask. Thus, the source 3a moves away from the circular outer contour 25 of the mask 6a, which increases the passage time of the openings 21 in front of the source 3a and decreases the passage time of the solid portions 23, i.e. the degree of hiding of the source 3a. The source 3b approaches in the same time and by the same quantity the shaft 7b, so that the passage time of the solid portions 24 and its degree of hiding increase. Therefore this apparatus makes it possible to bring about an opposite variation of the degrees of hiding of the sources 3a and 3b, whose sum remains equal to 1 if the lobes of the solid portions 24 are shaped for this purpose. The mixture deposited on the object to be covered has a variable composition and the deposition rate remains constant.
In another embodiment of the invention shown in FIG. 4, the covers 6c,6d are identical, have the same shape as the cover 6a and are at fixed locations in the enclosure 1, on which they are supported, but the sources 3 are attached to the ends of two arms of a balance or pendulum 27, which extends beneath the covers 6c,6d and which is mobile in its centre about a pivot 28, parallel to the shafts 7, which can be moved from the exterior of the enclosure 1 by a crank or a similar means.
Thus, unlike in the preceding case, instead of being fixed the sources 3a,3b perform an oscillatory movement on a circular path about the axis 28 of the balance 27.
The displacements of the balance 27 move one of the sources 3 away from the shaft 7 of the associated cover and does the opposite with the other source 3, whilst maintaining the sources 3 at a constant distance from the covers 6. A clockwise movement of the balance 27 consequently moves the source 3a radially towards the outer circular contour 20 of the first cover 6c, which reduces the passage time of the openings 21 in front of the source 3a and increases the passage time of the solid portions 23, i.e. the degree of hiding of the source 3a. The source 3b radially approaches in the same time and by the same quantity the shaft 7b, if the axis 28 is equidistant of the two sources 3, so that the passage time of the solid portions 23 and its degree of hiding decrease. Therefore this apparatus permits an opposite variation of the degrees of hiding of the sources 3a,3b, whose sum can remain the same if the lobes of the solid portions 23 are formed or shaped for this purpose. Thus, when the material flows from the sources 6c,6d are identical, the deposition rate remains constant and the mixture deposited on the object to be covered has a composition, whose variation is controlled by the conditions imposed by the shape of the covers and the movement of the balance.
It is clear that covers having different shapes or positioned at different locations would make it possible to vary the degrees of hiding in accordance with other principles, i.e. with different variations, as a function of the sought result and in particular the fineness of the regulation of the composition or the deposition rate of the mixture which is evaporated and then deposited. These results can be achieved by placing the sources 3 at the end of different arm lengths of the balance, by using the covers with lobes or openings of different widths, or by placing the covers on two sides of the balance. It is also possible to use covers 6 and shafts 7 which are detachable and which can be replaced for each machine use. Conversely, it would be possible to fix the sources 3 to the enclosure 1 as in the preceding embodiment and place the covers 6 and their motor 9 on the balance.
A vacuum evaporation deposition machine of the same type can be equipped in the same way with identical covers having the same shape as the cover 6b.
The shapes of the lobes are advantageously chosen in such a way that the variations of the degree of hiding are proportional to the displacements. In the case of translatory movements between the source 3 and the cover 6, this result is achieved if the limits of the openings or lobes are spiral portions (of equation R=aθ+b, in which a and b are constant coefficients, with the conventions of FIG. 2 and in which R and θ are polar coordinates centered on the shaft 7).
Covers other than rotary disks are possible and endless belts or belts subject to an alternating movement and having a sawtooth contour are possible examples. The fundamental advantages of the invention, namely the ease, precision and fineness of the evaporation flow from the sources towards the object to be covered would be retained.
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Source evaporation machine for covering samples optionally by a mixture produced by several sources (3).
Mobile covers (6) are placed between the sources (3) and the sample. The covers (6) are designed so as to ensure that the solid parts (23,24) and the openings (21,25) alternate and the sources (3) move relative to the covers in such a way that different circumferences of the covers pass in front of them. As the angular sectors surrounded by the openings differ for each circumference, the degree of hiding of the sources (3) can be regulated in a very accurate and reliable manner. It is possible to modify the flow of the source on the sample or, in the case of several sources, vary the composition of the deposited mixture.
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BACKGROUND
This invention relates to a sighting device for an examination of the eye. It also relates to a sighting method implemented in this device, as well as a system for examining the eye by in vivo tomography equipped with this device.
While examining the eye in general and the retina in particular, unconscious movements of the eye, even during a fixation, can considerably limit the performance of the examination.
Residual movements during a fixation are of three types:
Physiological nystagmus (or tremor): very rapid oscillations (from 40 to 100 Hz), of low amplitude (movement of images of the order of a micron on the retina); Drift: slow movements (1 μm in a few ms), decorrelated from one eye to the other; Micro-saccades: very rapid movements (a few hundreds per second), correlated between the eyes, for approximate recentring of the field.
Experience shows that fixation performances for a given subject are very variable, depending on the subject's state of fatigue, the ambient lighting or the fixation period. It is also known that fixation with both eyes is better than with a single eye.
The addition of a system for compensating movements of the eye may be shown to be very complex, costly, and sometimes incompatible with the existing instrumentation.
SUMMARY
The purpose of this invention is to remedy these drawbacks, by proposing a sighting device which optimises the subject's fixation performance, this sighting device being intended to equip an examination system by procuring for it a very good spatial resolution. This therefore improves the overall performance of the examination by improving that of the subject.
According to the invention, the sighting device comprises at least one moving target having a programmable shape and trajectory, this or these target(s) being displayed on viewing means such as a screen and visible by both eyes during the examination period.
In a first operating mode, the target(s) is/are moved so as to alternate fixation intervals on a given position with intervals termed rest on one or more other positions. The duration of the fixation intervals may be adjusted in order to optimise the quality. The diversity, position and duration of the rest positions may also be adjusted.
In a second operating mode, a continuous movement is ordered, which forces the subject to concentrate on a moving target. If the tracking performances are better than those of fixation, a priori knowledge of the trajectory enables readjustment of the images of the eye obtained with more accuracy than if the subject is observing a stationary target.
According to another aspect of the invention, a system for examining the eye by in vivo tomography is proposed, comprising:
a Michelson interferometer, producing a full field OCT setup, an adaptive optical device, arranged between the interferometer and an eye to be examined, producing correction of the wavefronts originating from the eye as well as those reaching the eye, and a detection device, arranged downstream of the interferometer, capable without synchronous modulation or detection, of carrying out the interferometric measurement according to the OCT principle,
characterized in that it also comprises a sighting device according to the invention, comprising at least one moving target, having a programmable shape and trajectory, said target being displayed on viewing means and visible from at least one of the two eyes of said patient throughout the examination.
This sighting device enables to guide the sight of the patient while at the same time ensuring his visual comfort and optimizing his fixation performances.
Other advantages and characteristics of the invention will become apparent on examination of the detailed description of an embodiment which is in no way limitative, and the attached diagrams, in which:
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 illustrates the structure of an in vivo tomography system incorporating a sighting device according to the invention, and
FIGS. 2A and 2B represent respectively a first and a second embodiment of active targets implemented in a sighting device according to the invention, on a computer screen.
FIG. 3 is a diagram of another example of an embodiment of an in vivo tomography system according to the invention.
DETAILED DESCRIPTION
We will now describe, with reference to FIG. 1 , a practical embodiment of an in vivo tomography system according to the invention. This system comprises an interferometer of the Michelson type, comprising a measurement arm designed to illuminate the eye and collect the returned light and a reference arm designed to illuminate a moving mirror enabling in depth exploration of the retinal tissue.
The interferometer is used with light polarized rectilinearly and perpendicularly in the two arms. The light source S is a diode with a short temporal coherence length (for example, 12 μm), the spectrum of which is centred on 780 nm. In theory, it confers on the in vivo tomography an axial resolution equal to half the coherence length divided by the refractive index of the medium.
This light source S may be pulsed. In this case, it is then synchronised with the shot of the image and the adaptive correction. The beam is limited by a field diaphragm corresponding to 1 degree in the field of view of the eye (300 μm on the retina) and a pupil diaphragm corresponding to an opening of 7 mm on a dilated eye.
An input polarizer P enables optimal balancing of the flux injected into the two arms of the interferometer.
The two arms have a configuration termed Gauss, afocal, which enables the conjugation of the pupils on the one hand, and the materialisation of an intermediate image of the field where a diaphragm blocks a large part of the corneal reflection, on the other hand. Quarter-wave plates ensure by the rotation of polarization of the sole light returned by the eye, and the moving mirror, an effective filtering of parasitic reflections in the in vivo tomography system according to the invention.
In order to maintain the equality of the optical paths in the two arms, with the same conjugation of the pupils and the field, the reference arm is similar to the measurement arm but with a static optic.
The detection path of the in vivo tomography system according to the invention will now be described. The two beams on the output arm are still polarized perpendicularly, and they interfere only if they are projected on a common direction. A Wollaston W prism has the function of simultaneously projecting the two radiations on two perpendicular analysis directions. A simultaneous measurement of the intensity may then be made after interference in two interference states in opposition, without synchronous modulation or detection, on a single two-dimensional detector. The addition of a quarter-wave plate, after division of the beam, makes it possible to access two additional measurements, thus removing any ambiguity between the amplitude and phase of the fringes. A half-wave plate at the input to the detection path enables suitable orientation of the incident polarizations.
The Wollaston prism is placed in a pupil plane, hence conjugated with the separator cube of the Michelson interferometer. The separation angle of the Wollaston prism is chosen as a function of the field to be observed. The focal length of the final objective determines the sampling interval of the four images.
The detector is of the CCD type, with an image rate of more than 30 images per second. This detector is associated with a dedicated computer (not shown) in which the digital processing of the images is carried out: extraction of the four measurements, calibration, calculation of the amplitude of the fringes.
The adaptive correction of the wavefronts is carried out upstream of the interferometer and thus in the measurement arm. Each point of the source S thus sees its image on the retina corrected of aberrations, and the return image is also corrected. The amplitude of the fringes is thus maximum.
The adaptive optics sub-assembly comprises a deformable mirror MD. Measurement of the wavefront is carried out by an analyser SH of the Shack-Hartmann type on the return beam of a luminous spot itself imaged on the retina via the deformable mirror MD. The analysis wavelength is 820 nm. Illumination is continuous and provided by a temporally incoherent superluminescent diode SLD. The dimensioning of the analyser corresponds to an optimisation between photometric sensitivity and wavefront sampling. The control refreshment frequency of the deformable mirror MD may reach 150 Hz. A dedicated computer (not shown) manages the adaptive optical loop. The control is, however, synchronised in order to freeze the shape of the mirror during the interferometer measurement.
An appropriate control on the focussing of the analysis path, using a lens LA 2 , enables to adapt the focussing distance to the layer selected by the interferometer. This arrangement is essential for maintaining an optimum contrast at any depth.
The deformable mirror MD is conjugated with the pupil of the system and of the eye. The field of the system is defined by the system input field diaphragm DCM. It should preferably be chosen to be a value less than that of the isoplanetism field of the eye, which guarantees the validity of the adaptive correction in the field of the only wave front measurement made from the spot, at the centre of the field. For example, the system field may be chosen equal to 1 degree, but the value of this field could be increased.
Moreover, the rotation of the deformable mirror MD makes it possible to choose the angle of arrival of the beam in the eye and thus the portion of the retina studied.
The addition of corrective lenses to the subject's view, thus low orders of geometric aberrations such as focus or astigmatism, just in front of the eye, makes it possible to loosen the requirements on the travel of the deformable mirror MD, and also guarantee an improved sighting. An adaptive corrective system by transmission may be used in preference to fixed lenses for an optimum correction.
As illustrated in FIG. 3 , the system may also comprise conventional imaging means, such as a camera IMG, capable of combining interferometric measurements with a simple imaging of the zones examined, for example to facilitate the exploration and selection of the zones to be examined.
Arranged directly at the output (the return) of the measurement arm, and therefore just before of the polarizing cube CPR of the interferometer, a second polarizing cube CNPI may deflect the return beam towards an imaging camera IMG having its own means LI of focussing the image. On this path, a direct image of the sighted retinal zone will be observable. In particular the measurement arm and this additional path may be arranged such that they provide a wider field of observation than the interferometric mode, the field of which is limited, in particular by the interferometric contrast measurement technique in itself.
A sighting device according to the invention, collaborative or active, is installed upstream of the assembly. This sighting system, which comprises an active target pattern MAM, presents to the subject the image of a luminous point, deviating periodically from the sought sighting axis. The patient is then invited to follow all the movements of this image. Each time that the image returns to the axis, and after an adjustable latency time, a series of interferometric measurements is carried out. The periodic movement of the viewing direction makes it possible to obtain from the patient an improved fixation capacity when he aims at the desired axis. The amplitude and the frequency are adaptable to the subject and to the measurements undertaken. For reasons of convenience, the target pattern may be produced with a simple office computer on which a light point is displayed and moved. The active target pattern MAM, the adaptive optics, the source S and the image shot are synchronized.
The active target pattern may be produced on the screen of a computer or a monitor connected to a control system (not shown) of the sighting device, as illustrated by FIGS. 2A and 2B . In this embodiment, a graphic user interface IA or IB comprises for example a first window F 1 for managing a spot, a second window F 2 for shooting an image in bursts, and a moving target CA or CB on a part of the screen. This moving target may be produced, for example, as a conventional representation target consisting of concentric circles and a sighting cross in the centre of these circles ( FIG. 2A ), or even as a graduated cursor and a superimposed sighting cross ( FIG. 2B ).
In the example illustrated in FIG. 3 , the system is arranged so that the target of the active target pattern MAM is visible by both eyes OD 1 and OG 1 of the subject to be examined. A sighting with both eyes may actually improve the fixation or stability performances and facilitate the examination. In this example, the image of the target pattern is introduced into the optical path between the reference source SLD and the eye examined by a separator BST 3 .
This separator may be chosen dichroic for reflecting 50% of all the light coming from the target pattern MAM towards the examined eye OEX, and transmitting the remaining 50% towards the other eye OV 1 or OV 2 to enable a sighting by both eyes. The dichroic separator BST 3 then transmits all the light from the reference source SLD towards the examined eye OEX, at the same time taking advantage of a spectral difference between the reference source SLD (830 nm) and the target pattern MAM (800 nm). A 50/50 separator plate, which is spectrally totally neutral is also suitable, but 50% of the light from the SLD is then sent towards the eye which is not studied. A filter makes it possible to eliminate this image if it is judged uncomfortable by the subject.
In order to be able to examine either eye, while simultaneously ensuring a sighting by both eyes, the system has a central examination location OEX, as well as two sighting locations OV 1 and OV 2 , arranged on either side of this examination location OEX.
When the left eye is at the central location in order to be examined, the right eye receives the image of the target pattern MAM in its sighting location OV 1 by the retractable return means, for example two mirrors MT 1 and MT 2 . When it is the right eye which is at the location OEX, the return means may be retracted or cancelled and the image of the target pattern MAM reaches the left eye in its sighting location OV 2 .
As illustrated in FIG. 3 , the system may also comprise, or collaborate with, means IRIS of tracking movements of the eye to be examined, collaborating with the tomography device. This may be, for example, a camera with image recognition carrying out a monitoring or “tracking”, for example of the retina or of the pupil or edges of the iris, in order to detect and evaluate the movements of the eye.
Knowledge of the movements of the eye may then be used by the system to adapt to displacements of the zone to be examined, for example by coordinating the adjustments and exposures with the different positions detected or envisaged for this zone to be examined, or by enabling a spatial and/or temporal optimisation of the adaptive optics. It is possible, for example, to take advantage of natural periods of stabilisation of the pupil or the retina in order to carry out all or some of the desired adjustments or measurements.
The image of the eye examined reaches the means IRIS of tracking the eye by a separator BST 2 inserted into the optical path, for example between the eye and the reference source SLD. Advantageously, for example in order not to discomfort the subject, this separator BST 2 is dichroic and the tracking of the movements of the eye is carried out in non-visible light, for example, infrared.
The means of tracking IRIS may comprise, for example, a device for measuring ocular movements, such as those developed by the Metrovision company.
The invention may in particular be used to produce or complement a device for retinal imaging, or for corneal topography, or for measuring a film of tears.
Of course, the invention is not limited to the examples which have just been described and numerous adjustments can be made to these examples without exceeding the framework of the invention.
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A sighting device is provided for an examination of the eye, including at least one moving target with a programmable form and trajectory, the target being displayed on a visualisation unit, such as an appropriate screen and visible from both eyes during the examination. An in-vivo tomographical eye examination system is also provided, including: a Michelson interferometer, generating a full-field OCT image, adaptable optical apparatus, arranged between the interferometer and an eye for examination, achieving the correction of the wavefronts coming from the eye and also the wavefronts going to the eye, detection apparatus, arranged after the interferometer, permitting the interferometric measurement by the OCT principle without modulation nor synchronized detection and a sighting device, with at least one mobile target with a programmable form and trajectory, the target being displayed on an appropriate screen and visible from at least one of the eyes during the examination.
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This invention relates generally to cored panels, of the kind having a core sandwiched between skins. The invention is in two aspects: firstly, in a manner of making the core for such a panel; and secondly, in a manner of filling the cored panel with plastic resin foam.
PRIOR ART
It is well known in the art for panels to be made in the conventional honeycomb manner. When a honeycomb core is secured to the skins, the cells of the core are not normally connected to each other, and it is of course very difficult to fill such cells evenly with foam. A number of proposals have been made for filling the cells with plastic resin foam, as taught in U.S. Pat. No. 3,644,158, STRUMBOS, Feb. 22, 1972, for example, or in U.S. Pat. No. 1,744,042, PACE, May 01, 1956. These proposals have involved the pre-positioning of the ingredients of the foam, in liquid form, into the cells, and of then activating the foam in some manner.
Other examples of using foam and honeycomb cores between skins for various structural panels are shown in U.S. Pat. No. 3,970,324, HOWAT, July 20, 1976, and U.S. Pat. No. 3,816,573, HASHIMOTO, June 11, 1974, where the core material has holes in to permit the foam to pass from cell to cell.
Even when there is no core, the manner of applying the liquid ingredients of the foam into the space between the skins is subject to some restrictions. A problem arises if the skins are simply placed vertically parallel to each other with a space between them; if one tries to fill space with foam as if one were casting concrete. The liquid ingredients sink to the bottom of the space, and some parts of the body of foam start to cure, and become rigid, before the rest of the foam has finished expanding. This leads to the generation of very high pressures locally in the body of foam, which can cause the foam cells to become crushed, and which can cause the skins to bulge. It also leads to an uneconomical use of the foam.
U.S. Pat. No. 3,242,240, TANTLINGER, Mar. 22, 1966, shows how the liquid ingredients can be conveyed into the space between skins on a carrier member, by the expedient of using a carrier member which remains embedded in the foam after curing. U.S. Pat. No. 3,846,525, KINNE, Nov. 05, 1974, shows how the liquid ingredients can be applied layer by layer. In these two cases, the manner shown of conveying or applying the liquid ingredients could not be used if the panels were provided with cores of the honeycomb variety.
It is known from, for example, U.S. Pat. No. 3,869,778, YANCEY, Mar. 11, 1975, for a core to be not of the usual honeycomb variety, but to comprise a piece of sheet metal pierced and bent so as to form alternating crests and troughs. The skins are secured to the crests and troughs.
BRIEF DESCRIPTION OF THE INVENTION
One aspect of the present invention lies in the recognition that cores of the kind shown in YANCEY are especially suitable for use in foam-filled panels. This is because such cores present, when viewed from one edge, the appearance of openended, straight-through tubes. The liquid ingredients of the foam may be injected through nozzles into and along the tubes. The so-called tubes do not however have continuous closed walls: the walls are quite open, and allow for the easy transference of foam from tube to tube.
One of the benefits of such a foamed, cored panel is that the core does not need to be glued or welded, or otherwise secured, to the skins. The foam itself adheres both to the core and to the skins, and is quite adequate, it is recognized, in itself to secure the core and skins together. FIG. 23 of YANCEY, for example, particularly illustrates the difficulties of trying to secure the core to the skins directly, if foam is not used. On the other hand, the fixing of the core to the skins by means of foam could be strengthened and enhanced by an additional securing means, either before or after the foam is applied.
When injecting the liquid ingredients of foam into a sandwich of core and skins that is placed vertically, the method shown in KINNE might be used to avoid the difficulty referred to above of the liquid tending to settle in one place.
Preferably, however, in the invention, the sandwich is placed horizontally, and the foam is injected along the tubes from the edges.
The invention also lies in the manner of making the core itself. A pair of dies is provided, one die to go above and one to go below the sheet material from which the core is to be made. The dies each have complementary teeth; the teeth of one die exactly fit the spaces in the other die.
When the dies are brought together, material at the very edge of a tooth is cut by the shearing action between the complementary dies. Material caught on a tooth, either of the upper die or the lower die, is not cut but is moved by the tooth either downwards or upwards, respectively, away from the plane of the material, to form troughs and crests in the material.
When the dies are opened, the strip of material is indexed through the dies a sufficient distance that, after the dies have closed again, a substantial land is left between the adjacent rows of cut and bent ribbons of material.
The dies described are suited for use in a reciprocating press of conventional construction and operation. However, if desired, the same effect of sheared cuts and bent ribbons as described could be provided using rollers with the teeth formed on them, and by passing the sheet material through the nip of the rollers.
The invention lies also in the use of the particular core described above in combination with the as described injection of the liquid ingredients into the core, for it will be noted that the core as described presents a series of open tubes when viewed from one edge.
Further aspects of the invention will become apparent from the following.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
FIG. 1 is a view of a pair of dies;
FIG. 2 and FIG. 3 are side views of the dies at different stages of closure;
FIG. 4 is an end view of the dies, also showing a core;
FIG. 5 is a view of a core;
FIG. 6 is a view of a panel, looking transversely from a longitudinal edge of the panel;
FIG. 7 is a view of apparatus for injecting foam into sandwiches;
FIG. 8 is a view, partially cut away, of a panel;
FIG. 9 is an end view of another panel.
MAKING A CORE
FIG. 1 shows an upper die 20 and a lower die 22. Each die has respective teeth 23,24 which are fitted to respective die blocks 25.
The teeth 23 in the upper die 20 are arranged to fit into the spaces 27 between the teeth 24 of the lower die 22. The edges 29,30 of all the teeth, as seen in the section of FIG. 2, are sharp.
FIGS. 3 and 4 show what happens when the dies 20,22 are closed. Metal 32 that is located between the edges 29,30 is cut or sheared. The metal 33 that is caught under a tooth 23 of the upper die 20 is bent downwards, and the metal 34 that is caught over a tooth 24 of the lower die 22 is bent upwards, with respect to the plane 35 of the strip 36 of sheet metal.
The metal 33,34 is not removed from the strip 36. The cuts that are made at 32 extend only in the longitudinal direction 37, not in the transverse direction 39. It should be noted that actual shearing only takes place over the longitudinal width 40 of the teeth: over the rest of the length of the cut, i.e., over that part of the length of the cut that is between the sloping portions 42,43,44,45 (see FIG. 6), the metal is torn rather than sheared. The shape of the teeth can be adjusted if the tears become unpredictable as to their extent and direction; but almost straight-sided teeth with slightly radiused corners, as shown in FIG. 4, give rise to quite adequately controlled tears in sheet steel when it is of the proportions shown.
Sloping portions 42 and 43, together with a flat portion 46, make up a ribbon 47 between a pair of cuts. The teeth 23,24 extend transversely across the strip 36, so that all the cuts are the same length and the ribbon 47 is of a rectangular shape; other shapes of ribbon may be provided if required in particular cases, by, for example, placing the dies at an angle to the transverse direction 39.
Ribbons 49, complementary to ribbons 47, are formed from the sloping portions 44,45 and the flat portion 50. The ribbons 47 form crests 52 and the ribbons 49 form troughts 53.
It will be appreciated that the cuts might alternatively be formed as a separate operation, which would be completed prior to bending the ribbons. This could be done by a punching operation which removed a thin piece of metal along the line of the cut. In the method described above however, only one closure of the dies is required to effect both the shearing and the bending of the metal. The cuts are nominally of zero width in that no metal is removed. No scrap is produced. The operation is very efficient as to time taken, and as to the load capacity needed of the press in which the dies are mounted.
After closure, the dies are opened, and the strip 36 is stripped off the teeth 23,24. The strip 36 is indexed longitudinally forwards between the dies. Tables 54,55 support the strip 36 in its passage through the press, and the bar 56 serves to hold the strip in its plane 35.
As shown, the strip 36 is held in the plane 35 and the upper and lower dies 20,22 are set to push the metal up or down by equal amounts, for symmetry. It might be arranged that the plane 35 were not symmetrically disposed, in that the crests 52 and the roots 53 might be different distances away from the plane 35, to the extent, indeed, that the plane 35 might coincide with the level either of the crests 52 or the roots 53.
Between closures, the strip is indexed sufficiently far that the originally formed row 57 of ribbons, and the succeeding row 59, are spaced apart the distance D as shown. This spacing ensures the presence of a flat land 60, between the rows, which has a width 61 measured in the longitudinal direction; the land 60 extends transversely right across the strip 36.
As shown, the rows 57,59 are not staggered in the transverse sense, i.e., the crests 52 in one row 57 are directly in line with the crests in the next row 59. However, if the press were of the kind that permitted transverse movement of the dies between closures, the crests 52 in one row 57 could for example, be aligned with the troughs 53 in the next row 59.
The shearing/bending operation described above is suitable for use with a press of the conventional reciprocating type. Alternatively, the operation could be carried out using rollers. A roller would be as long as the desired transverse width of the strip, and would have several rows of teeth around its circumference. A complementary roller would have spaces meshing with the teeth of the first roller. A strip passed through the nip of the rollers would be sheared and bent in the same manner as desribed. Even less force would be needed to shear the cuts than with the reciprocating press, because the shearing would be progressive. However, the reciprocating operation can be carried out at sufficient speed and efficiency for most requirements.
The strip 36 becomes the core 62 shown in FIG. 5 after the shearing and bending operations desribed have been carried out. The shapes of the crests 52 and the roots 54 are mutually the same, but different shapes could be provided if required. The core might be curved in the transverse or longitudinal sense; or in both senses, since compound curves are easy to produce in the core shown. Even if the core is made straight as shown in FIG. 5, it is easy to bend it later to a compoundedly-curved shape of some intricacy.
MAKING A PANEL
To form a panel 63, the core 62 is sandwiched between two skins 64,65.
The core 62 may be secured to the skins by applying respective layers of glue to the upper surface of the bottom skin 64, and to the lower surface of the top skin 65, and by squeezing the skins onto the core 62 while the glue sets. The flat portions 46,50 of the ribbons should be long, if this glueing method is being used, to ensure a good area of contact of the glue. Alternatively, the core could be welded to the skins, or riveted. The skins 64,65 may be flat or may have a simple or compound curved shape as previously described. The skins should preferably be the same distance apart over the whole panel, although some variation in panel thickness can be provided simply by pressing the skins together harder in local areas. Alternatively, the core could be manufactured (though not so simply) with the crests or the troughs of varying heights, to provide a panel of varying thickness.
As may be seen in FIG. 6, when the core 63 is viewed in the transverse direction 39 (i.e., from one of its edges that are parallel to the longitudinal direction 37) the core 62 presents the appearance of a series of tubes 66. The roof of such a tube comprises crests 52, and the floor of the tube 66 comprises the troughs 53. The tube 66 extends into the body of the panel 63 from the longitudinal edge, and indeed extends right through the panel from edge to edge.
The tube 66 is not closed, in that the walls of the tube are open to the respective channels 67,69 above and below a land 60, and to the skins 64,65. In fact, in combination with the skins, the channels 67,69 themselves also form tubes that are open at the longitudinal edges of the sandwich.
INJECTING FOAM
In the other aspect of the invention, foam is injected into the tubes 66, and into the channels 67,69 which also constitute tubes. The injection is carried out using the apparatus shown in FIG. 7.
The apparatus 70 includes a flat support plate 72. Onto this, a bottom skin 64 is placed. A core 62 is placed on the bottom skin 64 and a top skin 65 onto the core 62, to form a first sandwich 73. Several more sandwiches are similarly assembled, the whole being built up to form a stack 74 of sandwiches.
A fence 76 is assembled around the stack 74. The fence includes front and back boards 77,79 and sideboards 90. The front and back boards each have holes 92. The holes 92 are for receiving nozzles 93 through which the liquid foam is to be injected into the sandwiches. The nozzles 93 are coupled to storage vessels and suitable conduits which, in accordance with normal foam injection practice, are set up so as to minimise the effects of the foam starting to cure in the conduits.
A flat clamp plate (not shown) is placed on top of the stack 74, and its surrounding fence 76 and the clamp plate and the support plate 72 are clamped together onto the fence 76. The fence is slightly less high than the nominal height of the stack 74, so that the crests 52 and troughs 53 of the cores are clamped into firm contact with the respective skins.
The nozzles 93 are placed in the holes 92, and the liquid ingredients of polyurethane foam are injected into the stack. The nozzles are then withdrawn, so that the holes 92 can act as vents. Since the skins are horizontal the liquid tends to spread out, and not to settle at any particular place. Once the liquid starts to foam, the foam can spread evenly in all directions through the open tubes 66 of the core 62. There is little tendency to the formation of local pockets of foam at different cure-stages, which, as mentioned, could lead to damage to the foam.
The described manner of filling the sandwiches with foam can result in homogeneously foamed panels, and economical use of the foam materials. These characteristics depend on the size and spacing of the nozzles, the distance apart of the skins, the overall size of the panel, and the height of the stack; and upon the ambient temperature and the mix of the ingredients. The ingredients of foam can be prepared so as to give a fast or slow foam-rise-time; to give a very sticky or a not so sticky foam; and other parameters can be varied. All these matters are within the competence of a person skilled in the art of foam injection, who will know that some experimentaton is necessary with a given panel configuration before the best combination can be found which will provide the most homogeneous foaming of the panel.
An aspect of foam technology that is particularly important is that of temperature. The panel described has a good deal of metal exposed to the foam, being metal not only of the skins but of the core too. It has been found that the core, the skins, and indeed the metal parts of the press in contact with the skins, should all be brought to about the same temperature as that of the foam. Otherwise, the foam does not flow or expand properly. It has been found that the most reliable foaming occurs when the foam, and the metal components, are in the 35 to 40 degrees C. region. The density of the foam can be varied, by, for example, altering the injection pressure of the foam, or the quantity injected. Dense foam is stronger and more rigid: less dense foam is lighter.
When the foam has cured and set, the fence 76 is removed. A space 94 was left between the stack 74 and the front board 77, to ensure that there was no pressure build up in the foam at the edge of the panel, and the space 94 is filled with foam. Such excess foam is trimmed from the stack 74, simply by cutting it off. There is a corresponding layer of excess foam between the other longitudinal edge of the stack and the backboard 79 (foam was injected by nozzles also through holes in the backboard 79). At a transverse edge 96 of the stack, the side-board 90 was much closer, and of course no foam was injected into that edge because the cores are closed when viewed from that edge. The edge 96 allows substantially no access whereby injected foam could enter the core. Whatever foam remains at an edge 96 again is removed by simply cutting it off.
Since the transverse edges are closed in this manner, the skins may be shaped to provide, for example, a channel or a lip 97 as is illustrated in FIG. 8. The longitudinal edges cannot hae such formations but must, in the invention, be open to receive the injected foam.
It will be noted that when making the cores, the metal must be shaped into crests and troughs right up to its edges, so that the core does not restrict the flow of the incoming injected liquid.
Separation of the foamed panels is made easier if the skins are lightly greased on their outside surfaces. Similarly, the components of the fence should be greased, since polyurethane foam will not stick in the presence of grease. Naturally, the cores and the inside surfaces of the skins should be scrupulously free of grease and other contaminants.
CHARACTERISTICS AND USES OF FOAMED PANELS
Panels that have the core and the homogeneous foam filling as described above offer a combination of strength, rigidity, lightness, durability, versatility and economy that has not been possible with panels known hitherto. As an example, the rear doors of box-bodies on trucks conventionally have been made of metal-faced plywood. Such doors made in the cured and foamed manner described above are better in substantially every aspect of performance and life, yet can be initially less expensive than plywood doors.
With regard to the ease with which foam may be injected into the sandwich, it is important that the core present as little obstruction as possible to the free entry of the liquid ingredients, and to the free spreading of the ingredients, once they are in; and of the foam, once it starts to rise. When the core is of sheet material, only the thickness of the material should be presented in the direction from which the liquid is injected. If, instead of just the thickness, a surface of the material is presented, then that surface will deflect the incoming liquid. The liquid would tend to settle more at the edges of the panel, to the detriment of the centre of the panel.
The core could alternatively be of wire lattice, or it could be moulded in plastic. In any case the interior should be accessible from the edges, and the injected foam should be able to permeate throughout the core.
With regard to the strength of the panel, it should be noted that foam has little strength in itself. The foam contributes only to the rigidity of the panel, which it enhances because of its bulk. On the other hand the foam is rendered somewhat more able to contribute to the resistance to crushing of the panel than might be expected, for this reason. The bubbles or cells in foams tend to be egg-shaped, with the long axes of the bubbles predominantly aligned vertically, providing the foam was allowed to rise in a reasonably unrestricted and well-vented manner. A cell of that shape can resist crushing along its long axis to a much greater extent than along one of its shorter axes. The long axes of the foam cells, which tend to be vertical, are in the above described panel, aligned in the direction where the cells will most favourably contribute to the crush strength, i.e. across the thickness of the panel.
Most of the strength, as opposed to the rigidity, of the panel, though, comes from the core. The sloping portions 42,43,44,45 should be nearly at right angles to the skins for good crush-strength, but should be inclined at a substantial angle for good shear strength. The kind of angle obtained from the shearing and tearing manner of producing the cuts, as described, is a very good compromise angle.
Not only is the foam material not very strong, but it is also brittle. It is important therefore that the core should be such as to promote a good shape to the foam. The foam should preferably be of a chunky shape throughout the panel. It should not take the form of lumps held together by relatively thin connections. In this regard, it will be noted that the asdescribed core provides a foam-shape that is nowhere thin, but is uniformly chunky, whether in the tube 66, in the channel above 67 or below 69 the land 60, or in the transition between the two, or indeed anywhere. This aspect might be contrasted with the core shape that would be produced for example if the core shown in the YANCY reference mentioned above were used. Here, there is nothing corresponding to the land 60. Hence there will be a narrow gap for the foam to pass through, between tubes. If the panel flexes, or is subject to vibration, such a thin narrow section of foam will soon crack and the foam will, in time, break up into a series of plugs, one in each tube, that are substantially not connected with each other. This will be especially the case if the walls of the tube are brought nearly at right angles to the skins for good crush-strength. Once the foam has started to crack, rigidity is lost and then more flexure is permitted, so that the effect tends to snow-ball. With the core described herein, however, the connections between all portions of the foam are thick and chunky,, not thin and subject to cracking. Such chunkiness arises from the wide access space between the tubes and the channels. The wide access space also provides little restriction to the free passage of liquids, and of the foam itself as it rises. Thus, the provision of the lands 60, of substantial width, contributes greatly to the ease of manufacture and to the durability of the foamed panel.
As mentioned above, the core might be moulded in plastic, or be formed of plastic sheet. The skins too could be of plastic, such as the familiar glass fibre reinforced resin kind of plastic material. Polyurethane foam breaks up if exposed to ultra-violet light and the skin material should be opaque if there is a danger of such exposure. When the skins are of plastic the panel has good heat insulative properties, though not of course as much strength as it had when the skins and core were made of metal. On the other hand, metal skins and cores can be used on panels that are to have insulative properties if the core is spaced from the skins, and does not touch the skins. This can be achieved by resting the cores and skins on appropriately located spacers, of plastic, during foaming.
The panels may be provided with pipes or wires embedded into the panel, and running along the tubes of the core. This can be done whether the panel is foamed or not. Furthermore, a sandwich could be made which comprises three skins and two cores, as shown in FIG. 9. One of the cores 100 is not injected with foam (by being masked during injection, or by being aligned at right angles to the direction of injection, for example).
The resulting composite panel could be used for example to convey hot (or cold) air along the unfoamed core 100 to heat or cool the skin 102, while the foamed core 103 acts to provide structural strength and rigidity. The foamed portion might alternatively be insulative if made of the appropriate materials.
The core 62 should preferably occupy the whole area of the panel 63. The core 62 need not be in one piece however, so that the dies 20,22 need not be as wide as the panel. The core can be in several strips with virtually no loss of strength or rigidity.
The foamed, cored panel may be through-drilled to provide a bolt-hole, for fixing door hinges for example. Such a hole may allow water to come in contact with the core, even if the bolt is well-tightened. Water would cause a rapid deterioration of the core if the core were made of wood, but wate has no effect on polyurethane foam.
The core and panel of the invention can be used in many different ways. The shape of a foamed panel is limited by the requirement that the foam has to be injected from an edge along unobstructed tubes. Within that limitation, though, the cross-section of the panel can be of any shape: it could be an annulus for example, so that the finished product is itself a hollow tube. The panel could follow a compound curve, such as that, for example, of a boat hull.
As to the core itself, normally it will be used between skins in the manner described. However, the core could be used without skins, for instance as reinforcement for cast concrete. In some applications, concrete is formed over a wire-mesh reinforcing base, and the concrete has a very thin wall-thickness. The core of the invention could be used to define that thickness, by casting the concrete over the core, and later removing the concrete down to the core. Thus the use of the core as a structural framework is not confined to its use between skins.
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Disclosed is a manner of making a core by shearing and bending a strip (36) of sheet metal into ribbons. The ribbons thereby constitute a series of troughs (53) and crests (52). The core is sandwiched between two skins (64,65). The crest and troughs are presented as tubes (66) extending into the interior of the core from an edge of the panel. Polyurethane foam is injected into these tubes. The foam rises and sticks the cores to the skins. The resulting panel is strong, rigid, durable, inexpensive, and extremely versatile.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method of testing and a testing apparatus for a magnetoresistive effect head, and in more detail to a method and testing apparatus that apply an external magnetic field to (hereinafter, simply “magnetize”) a magnetoresistive effect head as external stress and then measure the output voltage of the magnetoresistive effect head and repeat such magnetizing and measuring a plurality of times to test the quality of the shield film of the magnetoresistive effect head.
2. Related Art
In recent years, magnetoresistive effect heads that use a magnetoresistive effect, as represented by so-called “MR heads”, have been commercialized as thin-film magnetic heads for use with magnetic media such as magnetic disks.
However, although MR heads use the magnetoresistive effect of a magnetic thin film and can obtain a large reproduction output without being dependent on the relative velocity of the head to the magnetic medium, there is a problem that defective MR heads are produced where the magnetic domain of a shield film, i.e., a magnetic layer disposed on both sides of the MR element, can be changed by an external magnetic field, resulting in variation in the output of the MR head.
Since MR heads where the output may vary cannot be expected to carry out reproduction operations properly, such heads need to be rejected during the tests carried out as part of the manufacturing process.
However, since it has not been possible to quantitatively ascertain which MR heads have unstable characteristics where the magnetic domain of the shield film (hereinafter, simply “shield magnetic domain”) changes, the method of testing MR heads has been problematic.
The following method has been used as a conventional method of testing a MR head. An operation that applies a magnetic field in a direction that is parallel to the shield film of the MR head and makes an angle of 0° to a float surface of a magnetoresistive effect head (hereinafter this is referred to as “normal magnetization”) and measures the output voltage of the MR head is repeatedly carried out and the difference between the highest and lowest output voltages is calculated as the variation and used to evaluate how the output varies.
However, the above method has had a problem in that it is not possible to completely detect MR heads where the shield magnetic domain is susceptible to changing.
The inventors of the present invention found that by implementing a method of testing the quality of the shield film of the magnetoresistive effect head composed of a procedure of repeatedly carrying out an operation where an external magnetic field that is parallel to the shield film of the magnetoresistive effect head but makes an extremely small angle to the float surface is applied (hereinafter such operation is referred to as “minute angle magnetization”) and the output voltage of the magnetoresistive effect head is then measured, it becomes possible to detect magnetoresistive effect heads where the shield magnetic domain is susceptible to changing that could not be detected by the conventional method of testing via normal magnetization (see FIGS. 4A to 4D ).
The present invention uses this principle and by setting the minute angle and the intensity of the applied magnetic field in appropriate ranges provides a favorable testing apparatus and method of testing a magnetoresistive effect head.
One example of a method of testing a magnetoresistive effect head is disclosed by Japanese Laid-Open Patent Publication No. H10-124828 and is shown in FIG. 6 .
This reference proposes a method where a magnetic field is applied as stress in an inclined direction to MR stripes and the characteristics of the MR heads are measured.
Due to the MR heads being formed on a wafer with a large diameter (for example, 5 to 6 inches), the direction of magnetization of the MR stripes is susceptible to becoming non-uniform between central peripheries and outer peripheries of the heads and the magnetic domain control film described above is also susceptible to becoming non-uniform. For this reason, the problem to be solved by Japanese Laid-Open Patent Publication No. H10-124828 is to test such non-uniformities.
In this way, such object differs to the object of the present invention which is “to detect magnetoresistive effect heads where the shield magnetic domain is susceptible to changing that could not be detected by testing methods that use normal magnetization”.
Patent Document 1
Japanese Laid-Open Patent Publication No. H10-124828
SUMMARY OF THE INVENTION
The present invention was conceived in view of the situation described above and it is an object of the present invention to provide a method of testing and a testing apparatus that test the quality of a shield film of a magnetoresistive effect head and can detect MR heads where the shield magnetic domain is susceptible to changing that could not be completely detected by a conventional method of testing that uses normal magnetization.
To achieve the stated object, a method of testing according to the present invention applies an external magnetic field to a magnetoresistive effect head as external stress, measures the output voltage of the magnetoresistive effect head, and repeats the applying of the external magnetic field and the measuring a plurality of times to test the quality of a shield film of the magnetoresistive effect head, wherein the magnetic field is applied in a direction parallel to the shield film of the magnetoresistive effect head and at an angle to a floating surface of the magnetoresistive effect head, and the intensity of the applied magnetic field is lower than the coercive force of a hard bias film and higher than the coercive force of the shield film.
By doing so, even when testing a magnetoresistive effect head that could be mistakenly determined to be non-defective by a conventional method of testing that uses normal magnification but where the shield magnetic domain is actually susceptible to changing, by repeatedly applying a magnetic field at a minute angle and measuring the output voltage of the head, the variation in the output voltage will increase, making it possible to detect the magnetoresistive effect head as a defective product.
The angle may be in a range of 5 to 10°, inclusive.
When the angle θ is in a range of 5 to 10°, inclusive, the variation in the output voltage of the tested heads critically increases, and therefore by carrying out magnetization with the stated angle range, the method of testing according to the present invention can favorably detect MR heads where the shield magnetic domain is susceptible to changing as defective products.
The intensity of the external magnetic field may be in a range of 1500 to 5000, inclusive.
When the intensity of the external magnetic field is in a range of 1500 to 5000 gauss, inclusive, the variation in the output voltage of the tested heads critically increases, and therefore by carrying out magnetization with the stated range for the intensity of the magnetic field, the method of testing according to the present invention can favorably detect MR heads where the shield magnetic domain is susceptible to changing as defective products.
A testing apparatus according to the present invention is capable of implementing the method of testing according to the present invention and includes: a power supply unit for supplying the magnetoresistive effect head with the testing current; a magnetic field generating unit for applying an external magnetic field to the magnetoresistive effect head; a measuring unit for measuring the output voltage when the external magnetic field is applied to the magnetoresistive effect head, and an angle measuring unit for disposing the magnetoresistive effect head at an angle to a direction in which the external magnetic field is applied.
By using this testing apparatus, it is possible to implement the method of testing according to the present invention and therefore possible to detect even magnetoresistive effect heads that could be mistakenly determined to be non-defective but where the shield magnetic domain is actually susceptible to changing as defective products.
BRIEF DESCRIPTION OF THE DRAWINGS
The aforementioned and other objects and advantages of the present invention will become apparent to those skilled in the art upon reading and understanding the following detailed description with reference to the accompanying drawings.
In the drawings:
FIGS. 1A and 1B are schematic diagrams useful in explaining the method of testing according to an embodiment of the present invention;
FIG. 2 is a characteristics graph showing the relationship between a minute angle θ and variation in the output voltages of tested heads;
FIG. 3 is a characteristics graph showing the relationship between the intensity M of an external magnetic field and the variation in the output voltages of the tested heads;
FIG. 4A to FIG. 4D are measurement graphs showing variations in output voltage where the magnetization angles of two types of tested heads are respectively changed;
FIG. 5 is a view showing one example of tested heads where the shield magnetic domain has changed due to magnetization; and
FIG. 6 is a schematic diagram showing one example of a conventional testing method.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
A preferred embodiment of the present invention will now be described in detail with reference to the attached drawings for an example where samples on a row bar that has been cut out from a wafer are tested.
FIGS. 1A and 1B are schematic diagrams useful in explaining the method of testing according to the present embodiment of the invention. FIG. 2 is a characteristics graph showing the relationship between the minute angle θ and the variation in the output voltages of tested heads 1 . FIG. 3 is a characteristics graph showing the relationship between the intensity M of the external magnetic field and the variation in the output voltages of the tested heads 1 . FIG. 4A to FIG. 4D are measurement graphs showing output voltage variations where the magnetization angles of two types of tested heads are respectively changed. FIG. 5 is a view showing one example of the tested heads 1 where the shield magnetic domain has changed due to magnetization. FIG. 6 is a schematic diagram showing one example of a conventional testing method.
The construction of a testing apparatus for implementing the testing method according to the present invention will now be described.
In FIG. 1A , reference numeral 1 designates tested heads that are formed on a row bar with a plurality of magnetoresistive effect heads 3 disposed with their lengthwise directions. Reference numeral 2 designates an external magnetic field applying coil unit for applying an external magnetic field as external stress to the tested heads 1 . The testing apparatus is also equipped with a power supply unit (not shown) for generating a current (hereinafter referred to as the “sensing current”) for testing the tested heads 1 , a measuring unit (not shown) for measuring the output voltages of the tested heads 1 , and an angle measuring unit for disposing the floating surfaces 4 of the tested heads 1 at an angle to the direction in which the external magnetic field is applied.
FIG. 1B is an enlargement of a magnetoresistive effect head part (the part H) in FIG. 1A . The rear surface shown in FIG. 1B is the floating surface 4 of a magnetoresistive effect head.
Next, the procedure of the method of testing according to the present invention will be described.
First, the tested heads 1 are set within the external magnetic field applying coil unit 2 . When doing so, as shown in FIG. 1A , the tested heads 1 are set so that the direction in which the external magnetic field is applied is parallel to shield films 5 of the tested heads 1 and makes a minute angle θ with respect to the floating surfaces 4 of the tested heads 1 .
Next, after the tested heads 1 have been magnetized by the external magnetic field applying coil unit 2 , the output voltages outputted from the tested heads 1 are measured using the sensing current. The method of testing according to the present invention is carried out by repeatedly magnetizing and measuring the voltages.
As one example, the magnetization operation and measurement of output voltage are carried out three times for the tested heads 1 , and then the direction of the sensing current is reversed and the output voltages from the tested heads 1 are measured again.
When doing so, the difference between the highest value and lowest value in the output voltage data from the measured tested heads 1 is calculated as the “variation”.
In both the conventional method of testing and the method of testing according to the present invention, by investigating the characteristics of this variation, it is possible to distinguish whether the tested heads 1 are defective or non-defective.
FIGS. 4A to 4D show a comparison between the conventional method of testing that carries out normal magnetization and the method of testing according to the present invention that carries out minute-angle magnetization.
FIG. 4A shows output voltage measurements for one sample (referred to as “sample a”) using normal magnetization (where the magnetization angle θ=0°), while FIG. 4C shows output voltage measurements for sample a using minute-angle magnetization (where the magnetization angle θ=7.6°).
On the other hand, FIG. 4B shows output voltage measurements for another sample (referred to as “sample b”) using normal magnetization (where the magnetization angle θ=0°), while FIG. 4D shows output voltage measurements for sample b using minute-angle magnetization (where the magnetization angle θ=7.6°).
In all of these graphs, the horizontal axis represents the output voltage (expressed in μV) from the tested heads 1 after magnetization has been carried out once, while the vertical axis represents the output voltages (expressed in μV) from the tested heads 1 after magnetization has been carried out twice and after magnetization has been carried out three times.
As the standard for judging whether the tested heads 1 are defective or non-defective, as one example, the tested heads 1 are judged to be non-defective when there is no variation in the output voltage outputted from the tested heads 1 between the plurality of measurements, as in the case shown in FIG. 4B .
On the other hand, as shown in FIGS. 4A , 4 C, and 4 D, when the variations are plotted in the ranges that have been circled by ovals, that is, when there are large variations in the output voltages from the tested heads 1 among the plurality of measurements, the tested heads 1 are identified as defective products where the shield magnetic domain is susceptible to changing.
Here, for the sample a shown in FIGS. 4A and 4C , the tested heads 1 whose variations are plotted in the circled ranges by the conventional method of testing that uses normal magnetization (see FIG. 4A ) can be distinguished as defective products even if the method of testing according to the present invention is not implemented, and therefore the testing of such heads is not problematic.
However, the sample b shown in FIGS. 4B and 4D includes defective heads where the variations are not plotted in the circled ranges by the conventional method of testing that uses normal magnetization (see FIG. 4B ). This means such products may be mistakenly determined to be non-defective. If such tested heads 1 are tested using the method of testing according to the present invention that carries out magnetization at a minute angle, the variations will be plotted in the regions circled by the ovals (see FIG. 4D ). This means that the tested heads 1 can be determined to be defective products where the shield magnetic domain is susceptible to changing, and can be rejected.
Next, the minute angle used when carrying out magnetization will be described in detail.
FIG. 2 shows one example of the variation in the output voltage of the tested heads 1 (number of samples=2) when the external magnetic field described above is applied with the minute angle θ described above being changed in a range of 0 to 90°.
In FIG. 2 , the horizontal axis shows the angle θ (expressed in degrees) and the vertical axis shows the variation (the difference between the highest output voltage and the lowest output voltage) in the output voltage (expressed in μV) of the tested heads 1 when the magnetization operation and measurement of output voltage are repeated three times on the tested heads 1 and then the sensing current is reversed and the output voltage from the tested heads 1 is measured again.
As shown in FIG. 2 , when the angle θ is in a range of 5 to 10°, inclusive, the variation in the output voltage of the tested heads 1 critically increases.
By using these characteristics, even with tested heads 1 which have been determined to be non-defective since no variation in output voltage was detected when testing using normal magnetization, by setting the tested heads 1 in a testing apparatus at a minute angle where θ=5 to 10°, measuring the output voltage of the tested heads 1 using the sensing current after the external magnetic field has been applied to the tested heads 1 , and repeating the applying and measuring operations a plurality of times, the characteristic whereby the shield magnetic domain is susceptible to changing can be made more apparent and the variation in the output voltage can be increased, thereby making it possible to detect tested heads that are defective.
FIG. 3 shows one example of how the output voltage of the tested heads 1 (number of samples=2) vary when the intensity of the applied external magnetic field is changed from 0 gauss to 5000 gauss. Note that this data is for the case where the minute angle θ described above is 7.6°.
In FIG. 3 , the horizontal axis shows the intensity M (in gauss) of the applied external magnetic field and the vertical axis shows the variation (the difference between the highest output voltage and the lowest output voltage) in the output voltage (expressed in μV) of the tested heads 1 when the magnetization operation and measurement of output voltage are repeated three times on the tested heads 1 and then the sensing current is reversed and the output voltage from the tested heads 1 is measured again.
As shown in FIG. 3 , when the intensity M of the magnetic field is in a range of 1500 gauss (≈119 kA/m) to 5000 gauss (≈398 kA/m), inclusive, the variation in the output voltage of the tested heads 1 critically increases.
By using these characteristics, even with tested heads 1 which have been determined to be non-defective since no variation in output voltage was detected when testing using normal magnetization, by setting the intensity M of the external magnetic field applied to the tested heads 1 at 5000 gauss, for example, measuring the output voltage of the tested heads 1 using the sensing current after the external magnetic field has been applied to the tested heads 1 , and repeating the applying and measuring operations a plurality of times, the characteristic whereby the shield magnetic domain is susceptible to changing can be made more apparent and the variation in the output voltage can be increased, thereby making it possible to detect the tested heads that are defective.
Note that although the method of testing disclosed in Japanese Laid-Open Patent Publication No. H10-124828 indicated as prior art proposes applying an external magnetic field of 50 to 200 gauss, as shown in FIG. 3 , magnetic fields of such intensity are not in the region where the variation in output voltage becomes more apparent as disclosed in this specification.
Although an example of MR heads on a row bar has been described, it is also possible to apply the method of testing and testing apparatus according to the present invention to the testing of individual MR heads that have been completed.
The method of testing and testing apparatus according to the present invention are also not limited to testing MR heads.
It was also confirmed that changes in the structure of the shield magnetic domain occur for MR heads with variations in output voltage that can be detected using the method of testing according to the present invention (see FIG. 5 ).
This means that the method of testing according to the present invention can also be used as a method for determining the magnetic domain structure by evaluating the output voltage of tested heads 1 .
Note that the upper part of FIG. 5 shows the state of the magnetic domain of a tested head 1 when looking from the floating surface, while the lower part of FIG. 5 shows the state of the magnetic domain of a tested head 1 when looking from a direction perpendicular to the floating surface.
In this example, a magnetic field is applied as external stress to a tested head 1 with the initial magnetic domain structure shown on the left, the stress is then removed, and the magnetic domain structure changes as shown on the right.
Also, by inverting the principle of the present invention, the present invention can be used as a method of detecting that the magnetization angle θ of a testing apparatus is not correctly set at 0° if variation in output voltage occurs when a master head (an MR head for which variations in output voltage occur only when minute angle magnetization is carried out) is set in the testing apparatus and the head output voltage is measured using the method of testing that uses normal magnetization.
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When testing the quality of shield films of magnetoresistive effect heads, a method of testing and a testing apparatus can detect heads where the shield magnetic domain is susceptible to changing that could not be completely detected by conventional methods of testing that use normal magnetization. The method of testing applies an external magnetic field to a magnetoresistive effect head as external stress, measures the output voltage of the head, and repeats the applying of the external magnetic field and the measuring a plurality of times to test the quality of the shield film. The magnetic field is applied in a direction parallel to the shield film and at an angle to a floating surface of the magnetoresistive effect head. The intensity of the applied magnetic field is smaller than the coercive force of a hard bias film and larger than the coercive force of the shield film.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention relates to the facilitation of hip reduction following hip dislocation. More particularly, the present invention describes a device and provides a method that allows a physician to effect reduction of a patient's dislocated hip joint without exerting significant manual effort or being in an awkward, unstable position.
[0003] 2. Description of the Related Art
[0004] The dislocated hip is a common joint dislocation encountered by emergency physicians and orthopedic surgeons. Hip dislocations are especially prevalent among elderly patients fitted with artificial hip joints. To reduce a dislocated hip, the practice among treating physicians is to do so manually. The procedure to reduce a dislocated hip is called an Allis maneuver. The Allis maneuver is at present a preferred method of care and a defined standard of treatment for orthopedic and emergency physicians.
[0005] The Allis maneuver is basically a manual procedure in that the treating physician uses his or her personal force to effect the relocation. In this procedure, the physician must exert a significant amount of energy to produce the large force that is required to perform the maneuver. The application of this large force places a substantial strain on the physician's back. In addition, in performing this maneuver the physician is frequently required to stand atop the patient's bed to gain mechanical advantage. This practice of the physician positioning himself atop the patient places the doctor and patient in an awkward and potentially unstable position. As such, a need has been identified in the art for a device to assist physicians in applying the force necessary to effect the reduction of a dislocated hip.
[0006] In anatomic terms, the hip is a ball-and-socket joint stabilized by strong ligamentous and muscular attachments. Dislocation of a native hip joint occurs when the femoral head is displaced from the acetabulum. Similarly, dislocation of a prosthetic, bipolar hip joint occurs when the prosthetic femoral component is displaced from the acetabular cup. Strong muscular and ligamentous attachments surround the hip joint and combine to make the hip an extremely stable joint. This environment of strong muscles and ligaments also work against the treating physician when he or she attempts to overcome their resistance in manually reducing a hip dislocation. Thus it is that a considerable force is often needed to effect the hip reduction. This required level of force can be a challenge for some physicians and can also lead to the patient and physician entwined in tense positions that are awkward and dangerous.
[0007] As previously stated, the Allis maneuver is currently the standard of care for hip reduction. During the Allis maneuver, the patient typically lies supine on the examining bed with the hip and knee joints flexed to 90 degrees. An assistant then stabilizes the patient's pelvis by applying downward pressure. Standing over the patient, the treating physician typically directs upward traction indirectly on the femur by pulling the knee upward in a direction nearly perpendicular to the patient. The physician is thereby able to draw the femoral head, or prosthetic ball, anteriorly into the hip joint. Occasionally, slight internal or external rotation of the femur may also be required. A palpable jolt, with or without an audible click, indicates that the ball has re-entered the socket and that the hip joint has been successfully reduced.
[0008] Standing over the patient in a bent-over position allows the physician to drape the patient's flexed knee over the physician's flexed elbow. This enables the physician to exert the necessary upward tractional force, but it is an awkward and unstable practice. In addition, this action places a tremendous amount of force on the physician's back, leaving the physician himself susceptible to injury.
[0009] Accordingly, it has been recognized that there is a need for a mechanical device that is capable of exerting the necessary upward tractional force on a patient during reduction of a hip dislocation. The mechanical device would permit treatment of the dislocated hip in a way that the treating physician is not required to stand in an unstable position over the patient and exert a large force manually. The hip reduction device should be able to exert the proper force, but be manually operable and give flexibility to the physician. The device should be adjustable to accommodate a wide range of patient physiognomies. In addition, the device should be compatible with the types of beds on which hip reduction procedures are performed, as well as typical hospital equipment and architecture.
SUMMARY OF THE INVENTION
[0010] The present invention is directed to a device that satisfies one or more of the above identified needs to facilitate hip reduction following hip dislocation. In one embodiment, a hip reduction device having features of the present invention comprises a base, a powered vertical lifter that is attached to the base, a transverse support arm that is attached to the powered vertical lifter, a leg sleeve that is attached to the transverse support arm, and a pelvic belt.
[0011] The pelvic belt, attached to the patient's bed, is fastened around the patient's pelvis to hold the pelvis down. The padded, contoured leg sleeve is attached around the patient's lower extremity both above and below the patient's knee. The sleeve hangs from the transverse support arm above the patient, and it is detachable from the arm.
[0012] The transverse arm rotates freely about the vertical lifter. The vertical lifter is powered, and power application is controlled by the physician. As power is applied, the vertical lifter slowly lifts the transverse support arm and the leg sleeve attached to the patient's leg, applying the necessary upward tractional force on the patient's femur. While the device applies the force, the physician directs the leg movement until the patient's femoral head or prosthetic ball pops back into the hip joint. The power to the lifter is then stopped.
[0013] The present invention describes a truly novel device that safely and effectively reduces a dislocated hip, while avoiding the risk of back strain to the physician, since the physician need not apply the significant upward tractional force with his or her own physical strength. Furthermore, danger to both the physician and patient resulting from the physician's awkward and unstable position over the patient is avoided. This represents a vast enhancement over the current practice, which relies on the physician's strength and position relative to the patient. The device mechanically reproduces the standard Allis maneuver as it exerts the necessary upward force that indirectly applies traction to the flexed femur and thereby reduces the dislocated hip.
[0014] A first advantage of the hip reduction device is that it can exert an upward tractional force on a human patient so as to effect hip reduction on the patient.
[0015] A further advantage of the hip reduction device is that it allows the treating physician to reduce a dislocated hip on a patient without the need for the physician to stand over the patient. Further the device allows patient treatment without the need for the physician to stand, rest, or be supported on the patient's bed.
[0016] An additional advantage of the hip reduction device is that it allows a treating physician to reduce a patient's dislocated hip without the need for the physician himself or herself to exert personally a large manual force. Thus the hip reduction device further extends hip reduction treatment procedures to those physicians who may have previously lacked the size, dexterity or robustness to capably carry out the Allis maneuver.
[0017] Additionally the hip reduction device may be a moveable device that is adaptable to conventional hospital and emergency room fixtures such as patient beds, operating tables, and other equipment found in hospital rooms.
[0018] The hip reduction device is further adaptable to accommodate different patient physiognomies.
[0019] Other independent features and advantages of the hip reduction device will become apparent from the following detailed description, taken in conjunction with the accompanying drawings which illustrate, by way of example, the principles of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] Characteristics and advantages of a novel hip reduction device according to the present invention will emerge more clearly from the ensuing detailed description, which is provided to give an explanatory and non-limiting example with reference to the accompanying drawings and which illustrate the principles of the invention:
[0021] FIG. 1 is a perspective view of a hip reduction device according to the present invention;
[0022] FIG. 2 is a detailed view of the pelvic belt assembly of the present invention;
[0023] FIG. 3 is a detailed view of the base assembly of the present invention;
[0024] FIG. 4 is a detailed view of the powered vertical lifter assembly of the present invention;
[0025] FIG. 5 is a detailed view of the transverse support arm assembly according to one embodiment of the present invention;
[0026] FIG. 6 is a detailed view of the leg sleeve assembly according to one embodiment of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0027] Reference will now be made in detail to exemplary embodiments of the invention, examples of which are illustrated in the accompanying drawings. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts.
[0028] With reference to FIG. 1 , one embodiment of the hip reduction device of the present invention is shown in assembled form and is generally indicated with the reference numeral 10 . The hip reduction device 10 comprises a base assembly 20 , a powered vertical lifter assembly 40 , a transverse support arm assembly 70 , a leg sleeve assembly 80 , and a pelvic belt assembly 60 (not shown in FIG. 1 ).
[0029] The pelvic belt assembly of the present invention is generally indicated as 60 in FIG. 2 . With reference to FIG. 2 , the pelvic belt assembly 60 is mounted to the bed or bed rails 67 that are already a part of the hospital bed. In one embodiment, the pelvic belt assembly 60 includes two straps made of, for example, woven thread webbing, a buckle strap 61 and a connector strap 62 . On each strap 61 and 62 , there is a metal belt loop 63 for attaching the straps to the bed rails 67 . The buckle strap 61 has an adjustable buckle 64 attached to the end of the strap, to enable connection with the connector 65 attached to the end of the connector strap 62 , thus securing the pelvis of the patient 68 . Securing the pelvis of the patient includes securely holding the pelvic/torso area of the human anatomy in order to sufficiently resist the opposing force needed to effect a hip reduction. As an alternative means of connection, the buckle strap 61 could have velcro 66 attached to it in lieu of a buckle, and the connector strap 62 could have a metal belt loop 63 in lieu of the connector. In this alternative, the buckle strap 61 is threaded through the metal belt loop 63 attached to the end of the connector strap 62 , and then the buckle strap is secured against itself with the velcro 66 . The applicant intends to encompass within the language any means of connecting the straps presently existing or developed in future that would perform the same function.
[0030] The base assembly of the present invention in its assembled form is generally indicated as 20 in FIGS. 1 and 3 . In one embodiment, with reference to FIG. 3 , the base assembly 20 includes a metal base plate 21 , to which is attached the shaft 22 that contains the lifting components of the powered vertical lifter 40 . The shaft 22 is preferably attached to the base plate 21 using a flange 23 and a bushing 24 . The flange 23 is attached to the base 20 plate 21 by fasteners 25 . Optionally, to make the hip reduction device mobile, rollers or casters 26 are attached to the base plate 21 with fasteners 30 . To enable the operator of the hip reduction device to stabilize it, a rear caster bracket may be attached by hinges to the base plate 21 using fasteners. The rear casters 26 are attached to the rear caster bracket by fasteners. Spring-loaded locking latches 28 may be attached to the base plate 21 by fasteners, such that, when the rear caster bracket is pushed downward, the locking latches 28 lock the bracket in place. In this position, the casters 26 touch the ground and allow the hip reduction device to be rolled on the floor. When the locking latches 28 are released, the rear caster bracket is raised, and the hip reduction device is moved onto pads 34 on the bottom surface of the base plate 21 and is thereby stabilized.
[0031] The powered vertical lifter of the present invention in its assembled form is generally indicated as 40 in FIGS. 1, 3 and 4 . The vertical lifter can take a variety of different structural configurations. In one embodiment, with reference to FIG. 4 , the vertical lifter assembly 40 includes a hydraulic jack with a foot pump 41 attached to the base plate 21 by fasteners 42 . Alternatively, a hydraulic hand pump or other means of applying lifting power may be used. Examples of other means to apply lifting force include a mechanic ratcheting assembly and a threaded screw jack. A torsion spring 43 is attached to the pump, as is the lifting cylinder 45 , which fits inside the lower shaft 22 . The lifting cylinder 45 is attached to the base of the lower shaft 22 by a flange 44 . In one embodiment, an extension 46 is attached to the top of the lifting cylinder 45 inside the shaft 22 . On the top of the extension 46 , a bearing cup 50 is fitted, in which a ball bearing 49 sits. An upper shaft 47 is placed on top of the ball bearing 49 . Brass bearings 48 are press fitted inside the lower shaft 22 and attached with fasteners 51 to provide rotational stability to the upper shaft 47 . As pressure is applied to the pump 41 , the extension 46 and upper shaft 47 are lifted in small, accurate increments. In one embodiment, graduated rule markings, or any similar visual or electronic measuring device, are included along the upper shaft 47 to enable the physician to observe the incremental movement of the vertical lifter. Thus the vertical lifter may also comprise a scale that indicates the lateral position of said lifter assembly in its range of movement.
[0032] The transverse support arm of the present invention in its assembled form is generally indicated as 70 in FIGS. 1 and 5 . The transverse support arm can take a variety of different structural configurations. In a preferred embodiment, the transverse support arm is moveably attached to the vertical lifter assembly 40 . In this manner the transverse support arm may be moved in a radial direction with respect to vertical lifter assembly 40 so as to further position the transverse support arm properly over the patient. Preferably, a lock or stop allows the transverse support arm to be secured in a preferred location. Leg sleeve assembly 80 may be affixed to transverse support arm 70 and preferably is affixed in a manner that allows lateral movement of leg sleeve assembly 80 along the length of transverse support arm 70 .
[0033] In an alternative preferred embodiment, with reference to FIG. 5 , a linear rail system 71 is attached to a transverse beam 72 by fasteners 73 . The rail system allows the leg sleeve assembly 80 to slide laterally on the linear guide 77 . The transverse beam 72 is fixed to a collar 74 as by a weld. The collar is placed over a hollow shaft 75 , and the collar 74 and shaft 75 are affixed by a locking collar 76 to the upper shaft 47 of the vertical lifter. A preferred linear rail system is a Thompson linear rail system.
[0034] The leg sleeve of the present invention in its assembled form is generally indicated as 80 in FIGS. 1 and 6 . In one embodiment, a mounting bracket 81 is attached by fasteners 82 to the linear guide 77 of the transverse support arm assembly. The leg securing device 88 is made of fiberglass, plastic, neoprene, velcro, aluminum, and/or vinyl and is shaped to accommodate a range of sizes of patients' lower extremities. The leg securing device 88 is attached to an adapter 84 , which is affixed to a quick release mechanism 83 . The quick release mechanism 83 can be easily attached and removed from the mounting bracket 81 . In another embodiment, a strain gauge (not shown) is incorporated into the mounting bracket 81 to measure the force exerted on the patient's leg. In yet another embodiment, a ratcheting cable (not shown) is used to attach the leg securing device 88 to the mounting bracket 81 .
[0035] It is within the scope of the invention herein to modify the hip reduction device from the embodiments described above. For example, a hip reduction device may be constructed that does not include a base. Thus, for example, a vertical lifter assembly could be permanently affixed to a bed or other operating table. Alternatively, a vertical lifter assembly could be affixed to a location in the floor.
[0036] In a further alternative embodiment, a transverse support arm assembly may be configured so that the patient's leg rests on top of the transverse support arm assembly. In such an embodiment a saddle or harness affixed to the transverse support arm assembly may secure the patient's leg to this arm. In this configuration, raising the transverse support arm will also raise the patient's leg. In this embodiment a leg sleeve assembly may also be positioned on top of the transverse support arm assembly.
[0037] To use the present invention, with reference to FIGS. 1 through 6 , first the patient's pelvis is secured to the bed using the pelvic belt assembly 60 . By having adjustability, the pelvic belt assembly 60 can accommodate a wide range of patient physiognomies. Then the patient's lower extremity is raised and secured to the leg sleeve 80 . By having velcro attachments, the patient's leg can easily be fitted in the leg securing device 88 . Through the lateral movement of the linear rail system 71 , the leg securing device 88 can be positioned correctly for inserting the patient's leg. A version of the present invention that includes a ratcheting cable (not shown) on the leg sleeve assembly 80 may make securing the patient's lower extremity easier. A version of the present invention that includes a force meter or strain gauge (not shown) on the mounting bracket 81 allows the physician to monitor the amount of force being exerted on the patient's lower extremity. By having rotational freedom, the transverse support arm assembly 70 assists in positioning the leg securing device 88 correctly for coupling with the lower extremity of the patient. This also allows the physician the freedom of movement to manipulate the lower extremity during the application of force, for proper reduction of the patient's femoral head or prosthetic ball into the hip joint.
[0038] The base assembly 20 of the present invention provides stability and strength in the device, thus preventing tipping. By having casters 26 , the device can be rolled on the floor. However, by having a means to lift the casters, the device can be secured and stabilized at the patient's bed side.
[0039] Using the present invention, the physician can remain at the side of the patient's bed, instead of having to stand over the patient and bend over to apply the necessary force. In one embodiment of the present invention, the application of force takes place through the use of a hydraulic foot pump 41 . By using a foot pump, the physician has his or her hands free to manipulate the patient's lower extremity during application of the force. The physician can also control the amount of force being applied. The pump calibration provides the proper force and lift increments. The pump allows for the application of a large total upward force in small and accurate increments. Once enough force is applied and the patient's femur has been moved an adequate distance, the physician may gently manipulate the patient's femoral head or prosthetic ball into the hip joint and thus complete the hip reduction.
[0040] It is within the scope of this invention that treatment of a patient with a dislocated hip includes both mechanical force applied by the hip reduction device as well as force applied by the treating physician. In addition, the invention includes use of the device where the physician guides or directs the application of the force. Thus in using the device, the device may replace all or part of the force that the physician would otherwise apply manually through the Allis maneuver. One use of the device by the treating physician may be as a supplemental force added to that of the physician. In this manner, when the hip reduction device assists the physician, the physician is relieved of the burden of applying strenuous force directly and manually to the patient's body, and thus the physician will be freed to better direct or guide the force in order to reduce the displaced hip joint with more efficiency. Likewise it is the case that different patients call for a greater or lesser degree of force in effecting a hip reduction. Thus, the hip reduction device may be of particular benefit with respect to those patients for whom a relatively larger degree of force is required to treat the dislocated hip.
[0041] While the invention has been described with reference to a preferred embodiment or embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt to a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.
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A device to assist a physician in treating a dislocated hip is disclosed. A hip reduction device comprises a base, a powered vertical lifter attached to the base, a transverse support arm attached to the vertical lifter, and a leg sleeve attached to the transverse support arm. In addition the hip reduction device includes a pelvic belt attached to a patient's hospital bed with which to secure the patient to the hospital bed. The operation of the hip reduction device mechanically mimics the Allis maneuver that a physician may use to manually reduce a dislocated hip. A patient suffering from a dislocated hip is secured to a hospital bed with a pelvic belt. The patient's leg is then placed in the leg sleeve. Raising the vertical lifter raises the transverse support arm, and thus raises the patient leg. In this way sufficient mechanical force is generated on the patient's leg so that a dislocated hip is reduced to its normal position.
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CROSS-REFERENCE TO RELATED APPLICATION
This is a continuation of application Ser. No. 024,748, filed Mar. 11,1987, U.S. Pat. No. 4,755,542.
FIELD OF THE INVENTION
The present invention pertains to thermoplastic epoxy resins and coatings prepared therefrom.
BACKGROUNG OF THE INVENTION
Thermoplastic (non-thermoset) epoxy resins have been employed in the formulation of highway pavement marking paints as disclosed by J. M. Dale in "Development of Lane Delineation With Improved Durability", Report No. FHWA-RD-75-70, July 1975, available from U.S. Dept. of Trans. Off. of Dev., Federal Hwy. Adms., Wash. D.C., 20590. The paint formulations are maintained at elevated temperatures, usually 450° F. to 500° F., during application. While they provide an excellent highway marking paint in terms of abrasive resistance, they are deficient in terms of applicability since they exhibit a substantial increase in viscosity while being maintained at the application temperature. Even if the thermoplastic epoxy resins could maintain it's viscosity, the resulting thermoplastic epoxy resins do not have the necessary flexibility to allow wide-spread use.
It would be desirable to have a thermoplastic (non-thermoset) epoxy resin which exhibits a much reduced viscosity increase at elevated temperatures, i.e. it is more thermally stable and exhibits improved flexibility over those thermoplastic epoxy resins disclosed by J. M. Dale. It is desirable that the flexibility of the formulated thermoplastic resin for use in highway marking paints be at least about 15 percent.
SUMMARY OF THE INVENTION
The present invention pertains to a thermally stable, flexible thermoplastic epoxy resin resulting from
(A) reacting , in the presence of an effective quantity of a catalyst for effecting the reaction between a vicinal epoxide group and an aromatic hydroxyl group, a mixture comprising
(1) at least one aromatic based epoxy resin having an average of more than 1 but not more than about 2.1 vicinal epoxy groups per molecule;
(2) at least one aliphatic based epoxy resin having an average of more than 1 but not more than about 2.1 vicinal epoxy groups per molecule;
(3) at least one material having an average of more than 1 but not more than about 2 phenolic hydroxyl groups per molecule;
wherein components (1) and (2) are employed in quantities such that from about 90 to about 99.6, suitably form about 94 to about 99.6, more suitably from about 96 to about 99.6, percent of the vicinal epoxy groups are contributed by the aromatic based epoxy resin and from about 10 to about 0.4, suitably from about 6 to about 0.4, more suitably from about 4 to about 0.4, percent of the vicinal epoxy groups are contributed by the aliphatic based epoxy resin; and wherein component (3) is employed in quantities such that the resultant product has an epoxide equivalent weight (EEW) of from about 1600 to about 2500, suitably from about 1650 to about 2100, more suitably from about 1700 to about 1900, calculated on the basis that the aromatic groups contained therein are free of substituent groups even if they do in fact contain substituent groups;
(B) reacting, in the presence of an effective quantity of a catalyst for effecting the reaction between a vicinal epoxide group and a carboxyl group, the product resulting from (A) with
(4) at least one aromatic or aliphatic monocarboxylic acid in a quantity which provides a ratio of moles of component (4) per epoxide group contained in component (1) of from about 0.033:1 to about 0.2:1, suitably from about 0.033:1 to about 0.1:1, more suitably from about 0.038:1 to about 0.07:1;
(C) optionally, reacting, in the presence of an effective quantity of a catalyst for effecting the reaction between a vicinal epoxide group and a group selected from --OH, --SH, --COOH and --CO--O--CO-- groups, the product resulting from (B) with a mixture comprising
(5) an aromatic based epoxy resin having an average of more than 1 but not more than about 2.1 vicinal epoxy groups per molecule and an EEW of not greater than about 225, suitably not greater then about 200, more suitably not greater than about 195, calculated on the basis of the aromatic groups being free of substituent groups whether or not they do in fact contain substituent groups; and
(6) a reactant material having only one group per molecule which is reactive with a vicinal epoxy group selected from --OH, --SH, --COOH and --CO--O--CO-- groups;
wherein component (5) is employed in an amount which provides a ratio of vicinal epoxy groups from component (5) to the combined amount epoxy groups contained in components (1) and (2) of from about 0.42:1 to about 0.48:1, suitably from about 0.43:1 to about 0.47:1, more suitably from about 0.44:1 to about 0.46:1; and component (6) is employed in an amount which provides from about 0.87 to about 1, suitably from about 0.96 to about 1, more suitably from about 0.98 to about 1, group reactive with a vicinal epoxy group per combined vicinal epoxy group contained in the product from (B) and component (5); and
(D) reacting, in the presence of an effective quantity of a catalyst for effecting the reaction between a vicinal epoxide group and a carboxyl group, the product resulting from (C) with
(7) a carbocyl terminated elastomer in an amount which provides a ratio of carboxyl groups to combined vicinal epoxy groups contained in components (1) and (2) of from about 0.0028:1 to about 0.03:1, suitably from about 0.003:1 to about 0.009:1, more suitably from about 0.0035:1 to about 0.008:1;
with the proviso that (a) the combined quantity of groups reactive with an epoxide group from components (3), (4), (6) and (7) cannot exceed the combined quantity of epoxide groups contained in components (1), (2) and (5) and (b) if step (C) is not performed, then step (D) is conducted employing the product from step (B) instead of that from step (C).
Another aspect of the present invention pertains to a mixture comprising
(I) from about 70 to about 95, suitably from about 80 to about 95, more suitably from about 84 to about 94 percent by weight based upon the combined weight of components (I) and (II) of a thermally stable, flexible thermoplastic epoxy resin resulting from
(A) reacting, in the presence of an effective quantity of a catalyst for effecting the reaction between a vicinal epoxide group and an aromatic hydroxyl group, a mixture comprising
(1) at least one aromatic based epoxy resin having an average of more than 1 but not more than about 2.1 vicinal epoxy groups per molecule;
(2) at least one aliphatic based epoxy resin having an average of more than 1 but not more than about 2.1 vicinal epoxy groups per molecule;
(3) at least one material having an average of more than 1 but not more than about 2 phenolic hydroxyl groups per molecule;
wherein components (1) and (2) are employed in quantities such that from about 90 to about 99.6, suitably from about 94 to about 99.6, more suitably from about 96 to about 99.6, percent of the vicinal epoxy groups are contributed by the aromatic based epoxy resin and from about 10 to about 0.4, suitably from about 6 to about 0.4, more suitably from about 4 to about 0.4, percent of the vicinal epoxy groups are contributed by the aliphatic based epoxy resin; and wherein component (3) is employed in quantities such that the resultant product has an EEW of from about 1600 to about 2500, suitably from about 1650 to about 2100, more suitably from about 1700 to about 1900, calculated on the basis that the aromatic groups contained therein are free of substituent groups even if they do in fact contain substituent groups;
(B) reacting, in the presence of an effective quantity of a catalyst for effecting the reaction between a vicinal epoxide group and a carboxyl group, the product resulting from (A) with
(4) at least one aromatic or aliphatic monocarboxylic acid in a quantity which provides a ratio of moles of component (4) per epoxide group contained in component (1) of from about 0.033:1 to about 0.2:1, suitably from about 0.037:1 to about 0.1:1, more suitably from about 0.038:1 to about 0.07:1;
(C) optionally, reacting, in the presence of an effective quantity of a catalyst for effecting the reaction between a vicinal epoxide group and a group selected from --OH, --SH, --COOH and --CO--O--CO-- groups, the product resulting from (B) with a mixture comprising
(5) an aromatic based epoxy resin having an average of more than 1 but not more than about 2.1 vicinal epoxy groups per molecule and an EEW of not greater than about 225, suitably not greater than about 200, more suitably not greater than about 195, calculated on the basis of the aromatic groups being free of substituent groups whether or not they do in fact contain substituent groups; and
(6) at least one reactive material having only one group per molecule which is reactive with a vicinal epoxy group selected from --OH, --SH, --COOH and --CO--O--CO-- groups;
wherein component (5) is employed in an amount which provides a ratio of vicinal epoxy groups from component (5) to vicinal epoxy groups from components (1) and (2) of from about 0.42:1 to about 0.48:1, suitably from about 0.43:1 about 0.47:1, more suitably from about 0.44:1 to about 0.46:1; and component (6) is employed in an amount which provides from about 0.87 to about 1, suitably from about 0.96 to about 1, more suitably from about 0.98 to about 1, group reactive with a vicinal epoxy group per combined vicinal epoxy group contained in the product from (B) and component (5); and
(D) reacting, in the presence of an effective quantity of a catalyst for effecting the reaction between a vicinal epoxide group and a carboxyl group, the product resulting from (C) with
(7) at least one carboxyl terminated elastomer in an amount which provides a ration of carboxyl groups to vicinal epoxy groups contained in components (1) and (2) of from about 0.0028:1 to about 0.03:1, suitably from about 0.003:1 to about 0.009:1, more suitably from about 0.0035:1 to about 0.008:1;
with the proviso that (a) the combined quantity of groups reactive with an epoxide group from components (3), (4), (6) and (7) cannot exceed the quantity of epoxide groups contained in components (1), (2) and (5) and (b) if step (C) is not preformed, them step (D) is conducted employing the product from step (B) instead of that from step (C); and
(II) from about 5 to about 30, suitably from about 5 to about 20, more suitably from about 6 to about 16 percent by weight based upon the combined weight of components (I) and (II) of the product resulting from reacting, in the presence of an effective quantity of a catalyst for effecting the reaction between a vicinal epoxide group and a group selected from --OH, --SH, --COOH and --CO--O--CO-- groups,
(8) at least one aromatic based epoxy resin having an average of more than 1 but not more than about 2.1 vicinal epoxy groups per molecule and an EEW of not greater than about 225, suitably not greater than about 200, more suitably not greater than about 195 calculated on the basis of the aromatic groups being free of substituent groups whether or not they do in fact contain substituent groups; and
(9) at least one reactant material having only one group per molecule which is reactive with a vicinal epoxy group selected from --OH, --SH, --COOH and --CO--O--CO--groups; and
wherein components (8) and (9) are employed in an amount which provides a ration of groups reactive with a vicinal epoxy group to vicinal epoxy group of from about 0.9:1 to about 1.1:1, suitably from about 0.94:1 to about 1:1, more suitably from about 0.96:1 to about 1:1.
A further aspect of the present invention pertains to an essentially solvent-free paint formulation comprising the aforementioned mixture of components (I) and (II) and at least one of (A) at least one pigment or dye or combination thereof; or (B) (1) at least one filler material; (2) at least one light reflective material; or (3) a combination of (1) and (2). In these essentially solvent-free paint formulations, the aforementioned compositions require that step (C) be conducted.
Still another aspect of the present invention pertains to a solvent based paint comprising the aforementioned paint formulation and one or more inert solvent materials. In these solvent containing paint formulations, steps (I-C) and step (II) are optional in the preparation of the aforementioned compositions employed in the paint formulation.
The present invention provides thermplastic epoxy resin formulations suitable for use in highway marking paints which are thermally stable and which have good flexibility.
DETAILED DESCRIPTION OF THE INVENTION
The reaction enumerated in step (A) involving the mixture of the aromatic epoxy resin and aliphatic epoxy resin and the aromatic hydroxyl-containing material can be conducted at any temperature between about 150° C. and 225° C., usually between about 175° C. and 200 ° C. for a time sufficient to complete the reaction, usually between about 0.5 and about 3 hours, more usually between about 1 and about 2 hours. Higher temperature require shorter reaction times to reach the same level of reaction, while lower temperatures require longer reaction times to reach the same level of reaction. In this reaction, in order to prepare a product having the desired equivalent weight, components (1), (2) and (3), are usually employed in amounts which provide a ration of phenolic hydroxyl groups from component (3) to vicinal epoxide groups contained in components (1) and (2) of from about 0.8:1 to about 0.9:1, suitably from about 0.81:1 to about 0.87:1, more suitably from about 0.82:1 to about 0.85:1.
When the amount of epoxide groups contributed by the aromatic based epoxy resin is less than about 90 percent, the resultant formulated paint may become tacky when applied to highway surfaces in warm climates thereby resulting in the loss of paint visibility.
When the amount of epoxide groups contributed by the aromatic based epoxy resin is greater than about 99.6 percent, the resulting formulated paint will decrease in flexibility and have a shorter service life for highway lane delineation.
When the EEW of the product produced in step (A) (the product resulting from the reaction of an aromatic epoxy resin and aliphatic epoxy resin and an aromatic hydroxyl-containing material), is less than about 1600, the resulting formulated paint will become tacky and tend to dicolor due to highway traffic. this tendency is more predominant when the formulated paint is applied in warmer climates or in the summer time in colder climates.
When the EEW of the product produced in step (I-A) (the product resulting from the reaction of an aromatic epoxy resin and aliphatic epoxy resin and an aromatic hydroxyl-containing material) is greater than about 2500, the resulting formulated paint will become difficult to apply with conventional spray equipment which is currently employed.
The reation enumerated in step (B) (the reaction between the product produced in step (A) and the aromatic or aliphatic monocarboxylic acid) can be conducted at any temperature between about 120° C. and 190° C., usually between about 150° C. and 190° C. for a time sufficient to complete the reaction, more usually between about 0.25 and about 0.6 hours, usually between about 0.3 and about 0.5 hours. Higher temperatures require shorter reaction times to reach the same level of rection. At temperatures below about 120° C., undesirably long reaction times are required to complete the reaction and mechanical problems result with the reaction equipment due to high viscosity of the reaction mixture.
At temperatures above about 190° C., undesired side reactions may take place which could lead to undesirable high viscosity in the formulated paint.
In this reaction, in order to prepare a product having the desired equivalent weight, component (4) is usually employed in an amount which provides a ratio of aromatic or aliphatic carboxyl groups from component (4) to vicinal epoxide groups contained in component (1) of from about 0.033:1 to about 0.2:1, suitably from about 0.037:1 to about 0.1:1, more suitably from about 0.038:1 to about 0..07:1.
The reaction enumerated in step (C), (the reaction between the product produced in step (B) and the aromatic based epoxy resin and the material having a group reactive with an epoxy group), can be conducted at any temperature between about 150° C. and 210° C., usually between about 175° C. and 200° C. for a time sufficient to complete the reaction, usually between about 1 and about 4 hours, more usually between about 1.5 and about 2 hours. Higher temperatures require shorter reaction times to reach the same level of reaction, while lower temperatures require longer reaction times to reach the same level of reaction. At temperatures below about 150° C., the viscosity becomes too high for effective agitation in conventional equipment.
At temperatures above about 210° C., undesired side reactions may take place which could lead to high viscosity in the formulated paint.
The reaction enumerated in step (D) involving the reaction between the product produced in step (C) and the carboxyl terminated elastomer can be conducted at any temperature between about 150° C. and 210° C., usually between about 175° C. and 190° C. for a time sufficient to complete the reaction, usually between about 1 and about 3 hours, more usually between about 1 and about 2 hours. Higher temperatures require shorter reaction times to reach the same level of reaction, while lower temperatures require longer reaction times to reach the same level of reaction. At temperatures below about 150° C., the viscosity becomes too high for effective agitation in conventional reaction equipment.
At temperatures above about 210° C., undesirable side reactions may take place which could lead to high viscosity in the formulated paint.
The reaction between components (8) and (9) in component (II) of the paint formulation involving the reaction between an aromatic based epoxy resin and material containing groups reactive with an epoxy resin can be conducted at any temperature between about 150 ° C. and 210° C., usually between about 175° C. and 200° C. for a time sufficient to complete the reaction, usually between about 1 and about 4 hours, more usually between about 1 and about 3 hours. Higher temperatures require shorter reaction times to reach the same level of reaction, while lower temperatures require longer reaction times to reach the same level of reaction. At temperature below about 150° C., the viscosity becomes too high for effective agitation in conventional reaction equipment.
At temperature above about 210° C., undesireable side reactions may take place which could lead to high viscosity in the formulated paint.
The amount of catalyst employed depends upon the particular components which are being reacted together. However, usually, the catalyst is employed in amounts which correspond to from about 0.0004 to about 0.002, more usually from about 0.0005 to about 0.001, most usually from about 0.0006 to about 0.0009, mole of catalyst per epoxy group contianed in the reaction mixture. At catalyst amounts below about 0.0004 mole per epoxy group, the reaction rate becomes very slow and if the catalyst amount is very low, the reaction may be incomplete.
At catalyst amounts above about 0.002 mole per epoxy group, the reaction rate can become so great that the energy of the reaction cannot be removed fast enough to stop side reactions that could lead to gellation.
Suitable aromatic based epoxy resins which can be employed herein include, for example, but are not limited to those represented by the following Formula I ##STR1## wherein each A is a divalent hydrocarbyl group having from 1 to about 12, preferably from 1 to about 6 carbon atoms, --SO--, --SO 2 ----O--, or --CO--; each R is independently hydrogen or a hydrocarbyl group having from 1 to about 4, preferably from 1 to about 2 carbon atoms; each X is independently hydrogen, a hydrocarbyl or hydrocarbyloxy group having from 1 to about 8, preferably from 1 to about 4, carbon atoms, or a halogen, preferably chlorine or bromine; m has an average value from about zero to about 0.5, and n has a value of zero or 1.
Particularly suitable aromatic based epoxy resins include, for example, the diglycidyl ethers of bisphenols such as, for example, the diglycidyl ether of biphenol, the diglycidyl ether of bisphenol A, the diglycidyl ether of bisphenol F, combinations thereof and the like.
The term hydrocarbyl as employed herein means any aliphatic, cycloaliphatic, aromatic, aryl substituted aliphatic or cycloaliphatic group, or aliphatic or cycloaliphatic substituted aromatic group. Likewise, the term hydrocarbyloxy means a hydrocarbyl group having an oxygen linkage between it and the object to which it is attached.
Suitable aliphatic based epoxy resins which can be employed herein include, for example, glycidyl ethers of polyhydroxyl-containing aliphatic compounds. Suitable such aliphatic based epoxy resins include, for example, but not limited to those represented by the following formulas II and III. ##STR2## wherein A' is a divalent aliphatic hydrocarbyl group having from 2 to about 12 carbon atoms; R is as defined above; R' is an alkyl group having from 1 to about 6 carbon atoms and n' has an average value from 1 to about 15 suitably from about 1 to about 10. Particularly suitable aliphatic based epoxy resins include, for example, the diglycidyl ethers of polyoxyalklene compounds such as, for example, the diglycidyl ether of dipropylene glycol, the diglycidyl ether of polyoxypropylene glycol having from about 2 to about 15 oxypropylene groups, the diglycidyl ether of polyoxybutylene glycol having from about 2 to about 10 oxybutylene groups, combinations thereof and the like.
Suitable materials containing an average of more than one aromatic hydroxyl groups which can be employed herein include, for example, but not limited to those represented by the following Formula IV ##STR3## wherein A, X and n are as defined above.
Suitable aliphatic or aromatic monocarboxylic acids which can be employed herein include, for example, those having from about 2 to about 24, suitably from about 8 to about 20, more suitable from about 12 to about 18, carbon atoms. The aliphatic or aromatic carboxylic acids may also contain in addition to the carboxyl group, other groups which are not reactive with either an aliphatic hydroxy group or an epoxy group such as, for example, halogen atoms, alkyl or alkyoxy groups, and the like. Particularly suitable monocarboxylic acids include, for example, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, phenylacetic acid, toluic acid, combinations thereof and the like.
Suitable anhydrides of monocarboxylic acids, those materials containing a --CO--O--CO-- group which can be employed herein include, the anhydrides of the aforementioned monocarboxylic acids.
Suitable materials having only one --OH group per molecule which can be employed herein include, for example, monohydric aliphatic and aromatic alcohols which may be substituted with any group which does not react with an aliphatic or aromatic hydroxyl group or with an epoxide group, such as, for example, halogen atoms, alkyl or alkyoxy groups, and the like. Particularly suitable monohydric alcohols include, for example, methanol, ethanol, propanol, isopropanol, butanol, pentanol, hexanol, ethylene glycol monomethyl ether, propylene glycol monomethyl ether, ethylene glycol monoethyl ether, propylene glycol monoethyl ether, combinations thereof and the like. Particularly suitable monohydric aromatic alcohols include, for example, phenol, alkylphenols, such as, for example, nonylphenol, t-butylphenol, cresol, combinations thereof and the like.
Suitable thiols, materials containing an --SH group, which can be employed herein include, for example, hydrogen sulfide, thiopropane, thiopentane, combinations thereof and the like.
Suitable elastomer materials which can be employed herein include, for example, any elastomeric material which is terminated in carboxyl groups. Particularly suitable elastomer materials include, for example butadiene-acrylonitrile copolymers which are terminated in carboxyl groups. Particularly suitable are the carboxyl terminated butadiene-acrylonitrile copolymers containing from about 20 to about 25 percent by weight acrylonitrile and from about 75 to about 80 percent by weight butadiene based on the weight of acrylonitrile and butadiene. The carboxyl terminated butadiene-acrylonitrile copolymers have carboxyl contents of from about 1.7 to about 3 percent by weight based upon total weight of the carboxyl-containing polymer.
Suitable catalysts for effecting the reaction between the epoxy resin, the phenolic hydroxyl-containing materials and monocarboxylic acids or monohdyric alcohols or anhydrides of monocarboxylic acids include, for example, those disclosed in U.S. Pat. Nos. 3,306,872; 3,341,580; 3,379,648; 3,477,990; 3,547,881; 3,948,855; 4,048,141; 4,093,650; 4,131,633; 4,132,706; 4,171,420; 4,177,216; 4,302,574; 4,320,222; 4,366,295; and 4,389,520 all of which are incorporated herein by reference.
Particularly suitable catalysts are those quaternary phosphonium and ammonium compounds such as, for example, ethyltriphenylphosphonium chloride, ethyltriphenylphosphonium bromide, ethyltriphenylphosphonium iodide, ethyltriphenylphosphonium acetate, ethyltriphenylphosphonium diacetate (ethyltriphenylphosphonium acetate.acetic acid complex), tetrabutylphosphonium chloride, tetrabutylphosphonium bromide, tetrabutylphosphonium iodide, tetrabutylphosphonium acetate, tetrabutylphosphonium diacetate (tetrabutylphosphonium acetate.acetic acid complex), butyltriphenylphosphonium tetrabromobisphenate, butyltriphenylphosphonium bicarbonate, benzyltrimethylammonium chloride and tetramethylammonium hydroxide, combinations thereof and the like.
Suitable pigments, dyes or other colorants which can be employed herein include, any of those which will provide the coating or paint with the desired color, such as for example, titanium dioxide, lead chromate, zinc chromate, chrome green, pthalocyamine green and blue, iron oxide, combinations thereof and the like. These pigments or colorants are employed in quantities which provide the composition with the desired color which will depend upon the particular paint formulation as well as the particular pigment or colorant being employed. Suitable amounts of pigments or colorants or combinations thereof include, for example from about 5 to about 25, suitably from about 10 to about 23, more sutitably from about 12 to about 20 parts by weight based upon the amount of non-volitile components employed in the paint or coating formulation.
Suitable fillers which can be employed herein include, for example, calcium carbonate, talc, powdered or flaked zinc or alumina, powdered or flaked glass, titanium dioxide, colloidal silica, combinations thereof and the like. The fillers are usually employed in quantities of from about 5 to about 30, suitably from about 5 to about 27, more suitably from about 5 to about 25, percent by weight based upon the weight of the total formulation.
Suitably light reflective materials which can be employed herein include, for example, glass beads, glass flakes, glass fibers, glass bubbles, combinations thereof and the like. The light reflective materials are usually employed in quantities of from about 10 to about 40, suitably from about 13 to about 40, more suitably from about 15 to about 37, percent by weight based upon the weight of the total formulation.
Suitable solvents which can be employed herein to prepare solvent borne coatings or paints include, for example, ketones, aromatic hydrocarbons, combinations thereof and the like. Particularly suitable solvents include, for example, acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexane, methylene chloride, combinations thereof and the like. These solvents, when employed, are employed in quantities which provide the compositions with the desired application viscosity, usually in amounts from about 10 to about 50, suitably from about 15 to about 40, more suitably from about 20 to about 35 based upon total paint or coating formulation including the solvent.
The following examples are illustrative of the invention but are not to be construed as to limiting the scope thereof.
MATERIALS EMPLOYED IN THE EXAMPLES AND COMPARATIVE EXPERIMENTS
EPOXY RESIN A is the diglycidyl ether of bisphenol A having an epoxide equivalent weight (EEW) of 188.
EPOXY RESIN B is the diglycidyl ether of bisphenol A having an EEW of 189.
EPOXY RESIN C is the diglycidyl ether of bisphenol A having an EEW of 188.6.
EPOXY RESIN D is the diglycidyl ether of polypropylene glycol having a weight average molecular weight of 425. The resultant epoxy resin had an EEW of 300.
CATALYST A is a 70 weight percent solution of ethyltriphenylphosphonium acetate.acetic acid complex in methanol.
CATALYST B is a 70 weight percent solution of tetra-n-butylphosphonium acetate.acetic acid complex in methanol.
ELASTOMER A is a carboxyl terminated acrylonitrile-butadiene rubber containing 18 weight percent acrylonitrile and 80 weight percent butadiene and having a carboxyl equivalent weight of 2000. This material is commerically available from B. F. Goodrich as HYCAR™ CTBN 1300X8.
FILLER A is a mixture containing 29.4 parts by weight (pbw) titanium dioxide, 29.4 pbw calcium carbonate and 41.2 pbw 200 mesh (U.S. Standard Sieve Series) glass beads.
THICKNER A is THIXATROL™ ST commerically available from NL Chemicals.
DESCRIPTION OF TESTS
FLEXIBILITY
The flexibility is determined by pressing out a thin film, 15-25 mils (0.381-0.635 mm) thick, between plastic sheets at a temperature of about 200° C. After cooling overnight 0.8-1 cm×6-8 cm specimens were cut from the film. The coupons were then placed between the jaws of a caliper. The jaws were then moved toward each other by constant hand pressure until the specimen broke or is stopped. The initial length is the length of the specimen between the two jaws.
The final length is the length between the two jaws when the specimen broke or the test is terminated. The percent elongation is calculated by the formula
[(initial length-final length)÷initial length]×100.
ABRASION
The Abrasion test is conducted on a Teledyne Taber Abraser Model No. 503 using CS-10 grind stones with a 1 kg mass added to each grind stone arm. The rotation speed is 1.2 cycles per second. The grind stones are cleaned by letting the stones roll over sand paper for 10 cycles then the sand paper is replaced with the specimen to be evaluated. The test sample mass is determined before and after abrasion to determine the mass loss. The test material is placed onto a 4 in.×4 in.×20 gauge (101.6 mm×101.6 mm×0.95 mm) cold rolled steel panel.
REACTION PRODUCT OF EPOXY RESIN AND STEARIC ACID
To a reaction vessel equipped with a means for stirring, heating control and nitrogen purge is added 615 g (3.275 epoxy equiv.) of Epoxy Resin A and 884.3 g (3.275 equiv.) of stearic acid. After heating to 90° C., 1.2 g (0.002 mole) of Catalyst A is added. The temperature is increased to 170° C. and maintained thereat for 2 hours. The resultant solid product is hereafter designated as Reaction Product A.
EXAMPLE 1
To a reaction vessel equipped with a means for stirring, heating control and nitrogen purge is added 172 g (0.91 epoxy equiv.) of Epoxy Resin B, 2.85 g (0.0095 epoxy equiv.) of Epoxy Resin D, 87.5 g (0.767 equiv.) of bisphenol A. After heating to 90° C., 0.3 g (0.0006 mole) of Catalyst B is added. The temperature is increased to 180° C. and maintained thereat for 1.33 hours. The resultant product had an EEW of 1791. To this advanced epoxy resin is added 11 g (0.041 carboxyl equiv.) of stearic acid and the reaction temperature of 180° C. is maintained for 0.33 hours. This product had an EEW of 2018. Then, 78.1 g (0.413 epoxy equiv.) of Epoxy Resin B and 113.2 g (0.515 equiv.) of nonyl phenol is added and the temperature is increased to 180° C. and maintained thereat for 1.5 hours after which, 7.2 g (0.0036 carboxyl equiv.) of Elastomer A is added and the reaction continued for an additional 2 hours.
A portion, 21 g, of the material prepared above is mixed with 4 g of Reaction Product A at 200° C., after which 16.7 g or Filler A is added and the mixture blended. The flexibility of the resultant product is 45%.
EXAMPLE 2
To a reaction vessel equipped with a means for stirring, heating control and nitrogen purge is added (0.0095 epoxy equiv.) of Epoxy Resin D, 87.5 g (0.767 equiv.) of bisphenol A. After heating to 90° C., 0.3 g (0.0006 mole) of Catalyst B is added. The temperature is increased to 180° C. and maintained thereat for 1.33 hours. The resultant product had an EEW of 1791. To this advanced epoxy resin is added 11 g (0.041 carboxyl equiv.) of stearic acid and the reaction temperature of 180° C. is maintained for 0.33 hours. The resultant PG,30 product had an EEW of 2018. Then, 78.1 g (0.413 epoxy equiv.) of Epoxy Resin B and 113.2 g (0.515 equiv.) of nonyl phenol is added and the temperature is increased to 180° C. and maintained thereat for 1.5 hours after which, 7.2 g (0.0036 carboxyl equiv.) of Elastomer A is added and the reaction continued for an additional 2 hours.
A portion, 23 g, of the material prepared above is mixed with 2 g of Reaction Product A at 200° C., after which 16.7 g of Filler A is added and the mixture blended. The flexibility of the resultant product is 20%.
EXAMPLE 3
To a reaction vessel equipped with a means for stirring, heating control and nitrogen purge is added 172 g (0.91 epoxy equiv.) of Epoxy Resin B, 2.89 g (0.0096 epoxy equiv.) of Epoxy Resin D, 87.5 g (0.767 equiv.) of bisphenol A. After heating to 90° C., 0.31 g (0.0006 mole) of Catalyst B is added. The temperature is increased to 180° C. and maintained thereat for 1.12 hours. The resultant product had an EEW of 1845. To this advanced epoxy resin is added 17 g (0.063 carboxyl equiv.) of stearic acid and the reaction temperature of 180° C. is maintained for 0.37 hours. The resultant product had an EEW of 2063. Then, 78 g (0.413 epoxy equiv.) of Epoxy Resin B and 107.2 g (0.487 equiv.) of nonyl phenol is added and the temperature is increased to 180° C. maintained thereat for 1.45 hours after which, 7.2 g (0.0036 carboxyl equiv.) of Elastomer A is added and the reaction continued for an addition 2 hours.
A portion, 23 g, of the material prepared above is mixed with 2 g of Reaction Product A at 200° C., after which 16.7 g of Filler A is added and the mixture blended. The flexibility of the resultant product is 22%.
EXAMPLE 4
To a reaction vessel equipped with a means for stirring, heating control and nitrogen purge is added 172 g (0.91 epoxy equiv.) of Epoxy Resin B, 2.89 g (0.0096 epoxy equiv.) of Epoxy Resin D, 87.5 g (0.767 equiv.) of bisphenol A. After heating to 90° C., 0.31 g (0.0006 mole) of Catalyst B is added. The temperature is increased to 180° C. and maintained thereat for 1.12 hours. The resultant product had an EEW of 1845. To this advanced epoxy resin is added 17 g (0.063 carboxyl equiv.) of stearic acid and the reaction temperature of 180° C. is maintained for 0.37 hours. The resultant product had an EEW of 2063. Then, 78 g (0.413 epoxy equiv.) of Epoxy Resin B and 107.2 g (0.487 equiv.) of nonyl phenol is added and the temperature is increased to 180° C. and maintained thereat for 1.45 hours after which, 7.2 g (0.0036 carboxyl equiv.) of Elastomer A is added and the reaction continued for an additional 2 hours.
A portion, 21 g, of the material prepared above is mixed with 4 g of Reaction Product A at 200° C., after which 16.7 g of Filler A is added and the mixture blended. The flexibility of the resultant product is 70%.
EXAMPLE 5
To a reaction vessel equipped with a means for stirring, heating control and nitrogen purge is added 430.15 g (2.281 epoxy equiv.) of Epoxy Resin C, 3.45 g (0.012 epoxy equiv.) of Epoxy Resin D, 214.4 g (1.881 equiv.) of bisphenol A. After heating to 90° C., 1.5 g (0.0028 mole) of Catalyst B is added. The temperature is increased to 185° C. and maintained thereat for 1.17 hours. The resultant product had an EEW of 1792. To this advanced epoxy resin is added 24 g (0.089 carboxyl equiv.) of stearic acid and the reaction temperature of 185° C. is maintained for 0.33 hours. The resultant product had an EEW of 2113. Then, 195.9 g (1.039 epoxy equiv.) of Epoxy Resin C and 248.2 g (1.292 equiv.) of nonyl phenol is added and the temperature is increased to 180° C. and maintained thereat for 1.53 hours after which, 16 g (0.008 carboxyl equiv.) of Elastomer A is added and the reaction continued for an additional 2.17 hours.
A portion, 20 g, of the material prepared above is mixed with 3.5 g of Reaction Product A at 200° C., after which 15.7 g of Filler A is added and the mixture blended. The flexibility of the resultant product is 50%.
EXAMPLE 6 (SOLUTION)
To a reaction vessel equipped with a means for stirring, heating control and nitrogen purge is added 490 g (2.593 epoxy equiv.) of Epoxy Resin B, 26.8 g (0.089 epoxy equiv) of Epoxy Resin D, 236.9 g (2.078 equiv.) of bisphenol A. After heating to 90° C., 1.3 g (0.0024 mole) of Catalyst B is added. The temperature is increased to 190° C. and maintained thereat for 1.28 hours. The resultant product had an EEW of 1307. To this advanced epoxy resin is added 138.1 g (0.511 carboxyl equiv.) of stearic acid and the reaction temperature of 190° C. is maintained for 1.03 hours. The resultant product had an EEW of 8113. Then, 120.1 g (0.06 carboxyl equiv.) of Elastomer A is added and the reaction continued for an additional 2.5 hours. After cooling to 130° C., 338 g of methyl ethyl ketone is added. The result product contained 75% non-volatiles.
A portion, 47.3 g, of the material prepared above is mixed with 22.5 g of acetone, 32.7 g of Filler A and 0.1 g of Thickner A.
The above coating composition is compared to a commercially available solution paint, "Fast Set" available from Sherwin-Williams, by an abrasion test. This paint from Sherwin-Williams is being employed as a highway marking paint. The results are given in the following Table I.
TABLE I______________________________________ EXAMPLE 6 FAST SET*CYCLES mass loss, mg mass loss, mg______________________________________ 0 0 0 20 9.1 N.T.** 40 13.5 20.0 60 21.7 30.8 80 24.7 40.9100 32.4 51.5120 41.4 61.9140 44.9 71.3160 51.6 80.6180 58.0 90.9200 64.6 N.T.220 72.5 N.T.240 80.1 N.T.______________________________________ *Not an examp1e of the present invention. **Not tested
COMPARATIVE EXPERIMENT A
To a reaction vessel equipped with a means for stirring, heating control and nitrogen purge is added 1720.6 g (9.104 epoxy equiv.) of Epoxy Resin B, 13.8 g (0.046 exposy equiv.) of Epoxy Resin D, 871 g (7.64 equiv.) of bisphenol A. After heating to 90° C., 3 g (0.006 mole) of Catalyst B is added. The temperature is increased to 150° C., the contents allowed to exotherm to 203° C. and then cooled to 185° C. and maintained thereat for 1.07 hour. The resultant product had an EEW of 1807. To this advanced epoxy resin is added 48.2 g (0.178 carboxyl equiv.) of stearic acid and the reaction temperature of 185° C. is maintained for 1.95 hours. The resultant product had an EEW of 2216. A portion, 289.9 g, of this material (containing 0.131 epoxy equiv.) is placed into another reaction vessel containing 84.7 g (0.448 epoxy equiv.) of Epoxy Resin B and 125.5 g (0.57 equiv.) of nonyl phenol. The temperature is increased to 180° C. and maintained thereat for 1.5 hours, after which 7.6 g (0.004 carboxyl equiv.) of Elastomer A is added and the reaction continued for an additional 2.33 hours.
A portion, 23. g, of the material prepared above is mixed with 2 g of Reaction Product A at 200° C., after which 16.7 g of Filler A is added and the mixture blended. The flexibility of the resultant product is <1%.
COMPARATIVE EXPERIMENT B
To a reaction vessel equipped with a means for stirring, heating control and nitrogen purge is added 1720.6 g (9.104 epoxy equiv.) of Epoxy Resin B, 13.8 g (0.046 epoxy equiv.) of Epoxy Resin D, 871 g (7.64 equiv.) of bisphenol A. After heating to 90° C., 3 g (0.006 mole) of Catalyst B is added. The temperature is increased to 150° C., the contents allowed to exotherm to 205° C. and then cooled to 185° C. and maintained thereat for 1 hour. The resultant product had an EEW of 1770. To this advanced epoxy resin is added 24.2 g (0.089 carboxyl equiv.) of stearic acid and the reaction temperature of 185° C. is maintained for 1.5 hours. The resultant product had an EEW of 2018. A portion, 280 g, of this material (containing 0.139 epoxy equiv.) is placed into another reaction vessel containing 81.9 g (0.433 epoxy equiv.) of Epoxy Resin B and 124.3 g (0.565 equiv.) of nonyl phenol. When the temperature reached 120° C., 0.5 g (0.0009 mole) of Catalyst B is added. The temperature is increased to 180° C. and maintained thereat for 1.83 hours, after which 7.5 g (0.004 carboxyl equiv.) of Elastomer A is added and the reaction continued for an additional 1.5 hours.
A portion, 21 g, of the material prepared above is mixed with 4 g of Reaction Product A at 200° C., after which 16.7 g of Filler A is added and the mixture blended. The flexibility of the resultant product is 2%.
COMPARATIVE EXPERIMENT C
To a reaction vessel equipped with a means for stirring, heating control and nitrogen purge is added 172 g (0.91 epoxy equiv.) of Epoxy Resin B, 2.9 g (0.0097 epoxy equiv.) of Epoxy Resin D, 87.5 g (0.767 equiv.) of bisphenol A. After heating to 90° C., 0.31 g (0.0006 mole) of Catalyst B is added. The temperature is increased to 180° C. and maintained thereat for 1.02 hours. The resultant product had an EEW of 1777. To this advanced epoxy resin is added 78.1 g (0.413 epoxy equiv.) of Epoxy Resin B and 7.2 g (0.0036 carboxyl equiv.) of Elastomer A is added and the reaction continued for an additional 2 hours.
COMPARATIVE EXPERIMENT D
To a reaction vessel equipped with a means for stirring, heating control and nitrogen purge is added 1720.6 g (9.104 epoxy equiv.) of Epoxy Resin B, 13.8 g (0.046 epoxy equiv.) of Epoxy Resin D, 871 g (7.64 equiv.) of bisphenol A. After heating to 90° C., 3 g (0.006 mole) of Catalyst B is added. The temperature is increased to 150° C., the contents allowed to exotherm to 203° C. and then cooled to 185° C. and maintained thereat for 1.07 hours. The resultant product had an EEW of 1807. To this advanced epoxy resin is added 48.2 g (0.178 carboxyl equiv.) of stearic acid and the reaction temperature of 185° C. is maintained for 1.95 hours. This product had an EEW of 2216. A portion, 289.9 g, of this material (containing 0.131 epoxy equiv.) is placed into another reaction vessel containing 84.7 g (0.448 epoxy equiv.) of Epoxy Resin B and 125.5 g (0.57 equiv.) of nonyl phenol. After mixing, at a temperature of 98° C., 0.5 g (0.0009 mole) of catalyst B is added. The temperature is increased to 180° C. and maintained thereat for 1.5 hours, after which 7.6 g (0.004 carboxyl equiv.) of Elastomer A is added and the reaction continued for an additional 2.33 hours.
A portion, 21 g, of the material prepared above is mixed with 4 g of Reaction Product A at 200° C., after which 16.7 g of Filler A is added and the mixture blended. The flexibility of the resultant product is 7%.
COMPARATIVE EXPERIMENT E
To a reaction vessel equipped with a means for stirring, heating control and nitrogen purge is added 1720.6 g (9.104 epoxy equiv.) of Epoxy Resin B, 13.8 g (0.046 epoxy equiv.) of Epoxy Resin D, 871 g (7.64 equiv.) of bisphenol A. After heating to 90° C., 3 g (0.006 mole) of Catalyst B is added. The temperature is increased to 150° C., the contents allowed to exotherm to 205° C. and then cooled to 185° C. and maintained thereat for 1 hour. The resultant product had an EEW of 1770. To this advanced epoxy resin is added 24.2 g (0.089 carboxyl equiv.) of stearic acid and the reaction temperature of 185° C. is maintained for 1.5 hours. The resultant product had an EEW of 2018. A portion, 280 g, of this material (containing 0.139 epoxy equiv.) is placed into another reaction vessel containing 82.2 g (0.435 epoxy equiv.) of Epoxy Resin B and 123.6 g (0.562 equiv.) of nonyl phenol. After mixing, and increasing the temperature to 145° C., 0.5 g (0.0009 mole) of catalyst B is added. The temperature is increased to 180° C. and maintained thereat for 1.58 hours, after which 15.3 g (0.0077 carboxyl equiv.) of Elastomer A is added and the reaction continued for an additional 2 hours.
A portion, 21.5 g, of the material prepared above is mixed with 3.5 g of Reaction Product A at 200° C., after which 16.7 g of Filler A is added and the mixture blended. The flexibility of the resultant product is 5%.
COMPARATIVE EXPERIMENT F
To a reaction vessel equipped with a means for stirring, heating control and nitrogen purge is added 172 g (0.91 epoxy equiv.) of Epoxy Resin B, 2.84 g (0.0095 epoxy equiv.) of Epoxy Resin D, 87.5 g (0.767 equiv.) of bisphenol A. After heating to 90° C., 0.3 g (0.0006 mole) of Catalyst B is added. The temperature is increased to 180° C. and maintained thereat for 1.33 hours. The resultant product had an EEW of 1720. To this advanced epoxy resin is added 7.2 g (0.027 carboxyl equiv.) of stearic acid and the reaction temperature of 180° C. is maintained for 0.33 hours. The resultant product had an EEW of 2131. Then, 78.4 g (0.415 epoxy equiv.) of Epoxy Resin B and 117.6 g (0.535 equiv.) of nonyl phenol is added and the temperature is increased to 180° C. and maintained thereat for 1.5 hours after which, 7.2 g (0.0036 carboxyl equiv.) of Elastomer A is added and the reaction continued for an additional 2.17 hours.
A portion, 23.5 g, of the material prepared above is mixed with 1.5 g of Reaction Product A at 200° C., after which 16.7 g of Filler A is added and the mixture blended. The flexibility of the resultant product is 4%.
EXAMPLE 7
The thermal stability is determined for Example 1 and Comparative Experiment C. The stability is determined by mixing the resins to be compared with a second resin and determining the thermal stability on the resin blend.
THERMAL STABILITY TEST
The thermal stability test is run using a Brookfield Thermosel set at 232° C. The resin mixture (9 g) ws placed into the Thermosel cup which is then placed into the viscometer oven. When the resin mixture is fluid, the spindle (No. 21) is lowered into the resin and the viscometer motor started. The viscosity is determined and recorded as the initial viscosity. The resin mixture is left in the viscosity oven for 4 hours and the viscosity measured again and recorded as the final viscosity. The results are given in Table II.
TABLE II______________________________________SAM- INITIALPLE VIS- FINALNUM- RESIN 1 RESIN 2 COSITY VISCOSITYBER Type/grams Type grams cps/Pa.s cps/Pa.s______________________________________A* Comp. Exp. Epoxy Resin 940.094 1625/1.625 C/23.5 B/1.5B Example 1/21 Reaction 196/0.196 201/0.201 Product A/4______________________________________ *Not an exampIe of the present invention.
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Flexible thermoplastic epoxy resins are prepared by reacting (1) an advanced epoxy resin prepared by reacting a mixture of an aromatic based epoxy resin and an aliphatic based epoxy resin with a polyhydric phenol in the presence of an advancement catalyst with (2) a monocarboxylic acid or anhydride thereof; reacting the resultant product with a mixture of an aromatic based epoxy resin and a monofunctional material reactive with vicinal epoxy groups; and reacting the resultant product with a carboxyl terminated elastomer. These resins are particularly useful in formulating pavement marking paints.
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FIELD OF THE INVENTION
[0001] The present invention relates to repair and maintenance equipment for railway vehicles and locomotives, in particular to an Under-Floor Lifting Jack (UFLJ) applicable to various types of Electric Multiple Unit (EMU) trainsets and the repair & maintenance of the whole EMU trainset.
BACKGROUND OF THE INVENTION
[0002] To guarantee the safety of an EMU trainset during its practical travelling, bogies (i.e. travel units) of the EMU trainset are required to be replaced and maintained at certain intervals. Thus, it is necessary to lift the whole trainset to a proper height to take off the bogies. For this purpose, a lifting jack is necessary.
[0003] An Under-Floor Lifting Jack consists of Bogie Lifting Means with Lifting Rails arranged in several spaced pits and Body Hoists arranged at both sides of the Bogie Lifting Means. Fixed Rails arranged on the ground between adjacent pits and the Lifting Rails of the Bogie Lifting Means form a continuous track on which the EMU trainset and the bogies may travel. The EMU trainset usually consists of a basic unit of 8 cars, and each of the cars has two bogies. The Bogie Lifting Means can lift the whole trainset and the bogies together to a proper height. After the lifting, the Body Hoists lift and maintain the car bodies at the height, and then the bogies are disconnected from the car bodies and lowered along with the Bogie Lifting Means, and separated from the car bodies.
[0004] The UFLJ is indispensable equipment for the repair and maintenance of the EMU trainset, and can be used to change all bogies of a whole EMU trainset without uncoupling the trainset or to repair and maintain any single bogie of a car after the trainset is uncoupled. The prevalent EMU trainset in China usually consists of a basic unit of 8 cars including two locomotives and 6 intermediate cars. In practice, two basic 8-cars units can be linked to form a 16-cars EMU trainset, which, however, is always uncoupled into two basic units for repair and maintenance. In China, the four types of EMU trainsets, i.e. CRH1, CRH2, CRH3 and CRH5, production of which began in 2007, have become the main high-speed railway passenger trains. Since such four types of EMU trainsets are different from each other in dimensions such as the total length, locomotive length, intermediate-car length, the tread (i.e. the distance between two wheels of a wheel-set), the fixed distance (i.e. a distance between centers of two bogies of a car) and the car width (as shown in Table 1 below). For any existing UFLJ in the world, both the distances between adjacent pits and lengths of the bogie lifting means are the same and correspond to the lengths of the respective type of trainset. As a result, each of the UFLJs only matches one type of EMU trainset. Therefore, the existing UFLJs all over the world are not compatible with all the four types of EMU trainsets.
[0000]
TABLE 1
Geometry Parameter
Length (mm)
Fixed
Car
Wheel
Intermediate
Tread
Distance
Width
Diameter
Type
Trainset
Locomotive
Car
(mm)
(mm)
(mm)
(mm)
CRH1
214000
26950
26600
2700
19000
3331
915
CRH2
201400
25700
25000
2500
17500
3380
860
CRH3
200685
25675
24775
2500
17375
3265
920
CRH5
215000
27600
27500
2700
19000
3200
890
[0005] Due to the tight-lock type coupler between cars of the EMU trainset, the permitted height tolerance between cars during the lifting process in repair & maintenance is strictly confined to ±4 mm, which requires the UFLJ to be equipped with an accurate positioning function and a synchronous lifting & lowering function. A concentrated repair and maintenance mode is adopted for the EMU trainsets in maintenance bases (e.g. an EMU depot) in China. Each of the maintenance bases is built for several or all types of EMU trainsets. If one type of UFLJ is designed for a single type of EMU trainset, a great waste would occur for the construction of the EMU trainset maintenance bases. Thus, the compatibility of the UFLJ is essential.
SUMMARY OF THE INVENTION
[0006] The invention aims to provide an Under-Floor Lifting Jack compatible with various types of EMU trainsets, so that the repair and maintenance of different types of EMU trainsets can be implemented with one UFLJ.
[0007] The technology solution of the invention is described as follows.
[0008] There is provided an Under-Floor Lifting Jack for High-Speed Electric Multiple Unit Trainset, comprising: a Main Electric Control Part for controlling the Under-Floor Lifting Jack, multiple Bogie Lifting Means arranged in pits, Fixed Rails on the ground between adjacent pits, and Body Hoists movable along dedicated rails on both sides of the Bogie Lifting Means, wherein Lifting Rails of the Bogie Lifting Means and the Fixed Rails form continuous rails, and one or more of the Bogie Lifting Means are set in each of the pits and adapted for lifting individually or synchronously in combination according to the wheel positions of different types of Electric Multiple Unit Trainsets under the control of the Main Electric Control Part.
[0009] Preferably, the pits and the Bogie Lifting Means are arranged longitudinally with respect to a midpoint of the Electric Multiple Unit Trainset symmetrically. At one side of the midpoint, a first Bogie Lifting Means is mounted in a first pit; a second Bogie Lifting Means is mounted in a second pit which is separated from the first pit by first Fixed Rails; a third Bogie Lifting Means is mounted in a third pit which is separated from the second pit by second Fixed Rails; fourth, fifth and sixth Bogie Lifting Means are mounted in a fourth pit which is separated from the third pit by third Fixed Rails; seventh, eighth and ninth Bogie Lifting Means are mounted in a fifth pit which is separated from the fourth pit by fourth Fixed Rails; tenth and eleventh Bogie Lifting Means are mounted in a sixth pit which is separated from the fifth pit by fifth Fixed Rails, and short Fixed Rails are arranged between the two first pits at both sides of the midpoint.
[0010] Preferably, a length of the first Bogie Lifting Means is 3700 mm; lengths of the second and the third Bogie Lifting Means are both 4750 mm; lengths of the fourth and the fifth Bogie Lifting Means are both 4600 mm; a length of the sixth Bogie Lifting Means is 3700 mm; lengths of the seventh, eighth and ninth Bogie Lifting Means are each 4600 mm; lengths of the tenth and eleventh Bogie Lifting Means are both 4000 mm; a length of the first Fixed Rails is 13815 mm; a length of the second Fixed Rails is 2070 mm; a length of the third Fixed Rails is 11930 mm; a length of the fourth Fixed Rails is 10555 mm; a length of the fifth Fixed Rails is 8785 mm; a length of the short Fixed Rails is 3430 mm.
[0011] Preferably, a Laser Distance-Measuring Device composed of a Laser Range Finder and a Data Display Screen is installed on a telescopic device on one side of an end of the continuous rails and adapted to measure a position error in stopping the Electric Multiple Unit trainset, the output of the Laser Range Finder is connected to the Main Electric Control Part.
[0012] Preferably, a driving wheel driven by a motor is equipped under the Body Hoist.
[0013] Preferably, a Supporting Head of the Body Hoist is equipped with a transverse displacement device.
[0014] Preferably, the motor which drives the Supporting Head up and down is an asynchronous AC motor driven by a transducer, and an encoder is arranged on the shaft of the AC motor.
[0015] Preferably, a Location-Sensing Slice is installed at the initial longitudinal position of the Body Hoist and a sensor corresponding to the Location-Sensing Slice is installed on the Body Hoist.
[0016] In view of the fact that the existing UFLJ is applicable to only one type of EMU trainset, the present invention is proposed to achieve that one type of UFLJ may be applicable to various types of EMU trainsets, e.g. the existing four types of CRHs in China, and the invention is advantageous in that: (1) the UFLJ is symmetrically aligned with respect to the midpoint of the EMU trainset longitudinally, thus reducing the position errors of respective bogies of various EMU trainsets by one half; (2) four lengths for the Bogie Lifting Means enable the bogies different from each other slightly in position to be lifted by the same Bogie Lifting Means; (3) the quantity of the Bogie Lifting Means is increased for lifting bogies different from each other significantly in position. Theoretically, an 8-car-unit EMU trainset is equipped with 16 bogies, and thus 16 Bogie Lifting Means should be enough for lifting the EMU trainset. However, 22 Bogie Lifting Means are provided in the present invention, that is, the quantity of the Bogie Lifting Means is more than that of the bogies. Owning to the above three optimum technologies, the inventive UFLJ is the most reasonable, feasible and simplest equipment to realize the compatibility for repair & maintenance of various types of EMU trainsets.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] The detailed explanation of the present invention is provided below according to the accompanying drawings and embodiments.
[0018] FIG. 1 is a schematic structural diagram showing the Bogie Lifting Means according to an embodiment of the invention, with an EMU trainset being on the Bogie Lifting Means;
[0019] FIG. 2 is a schematic structural diagram showing the arrangement of the left half of the EMU trainset of the CRH1 type on the Bogie Lifting Means;
[0020] FIG. 3 is a schematic structural diagram showing the arrangement of the left half of the EMU trainset of the CRH2 type on the Bogie Lifting Means;
[0021] FIG. 4 is a schematic structural diagram showing the arrangement of the left half of the EMU trainset of the CRH3 type on the Bogie Lifting Means;
[0022] FIG. 5 is a schematic structural diagram showing the arrangement of the left half of the EMU trainset of the CRH5 type on the Bogie Lifting Means;
[0023] FIG. 6 is a schematic diagram showing the transverse layout of the Bogie Lifting Means and the Body Hoist in a pit; and
[0024] FIG. 7 is a schematic diagram of the Laser Distance-Measuring Device.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0025] As shown in FIGS. 1-6 , according to an embodiment of the invention, a main electrical control part controlling a lifting jack is included. The Main Electric Control Part mainly controls the up and down movements of the Bogie Lifting Means, as well as travelling, up and down movements and transverse movements of Body Hoists. Multiple pits separate from each other are arranged longitudinally. Fixed Rails are set on the ground between adjacent pits. Lifting Rails 1 - 11 of the Bogie Lifting Means in the pits and the Fixed Rails 12 - 17 set on the ground between pits may form standard continuous rails on which the EMU trainsets can travel. One or more Bogie Lifting Means are set in each pit. Under the control of the Main Electric Control Part, the bogie lifting means can lift individually or synchronously in group according to wheel positions of different EMU trainsets. Multiple body hoists 18 which are movable along dedicated rails 20 are arranged at both sides of the bogie lifting means in the pits.
[0026] When an EMU trainset is driven onto the Bogie Lifting Means along the standard continuous rails and stops at the appointed position, the Bogie Lifting Means in several pits may lift the whole EMU trainset synchronously to a specified height. The lifting jack can also lift any single car after the EMU trainset is uncoupled. Under the instruction of the Main Electric Control Part, the Body Hoists 18 move lengthwise along with the rails to precisely align with the lifting points of the EMU trainset and lift the cars to a specified height, so that the bogies may be separated from the cars for repair and maintenance. Preferably, the Bogie Lifting Means are arranged symmetrically with respect to the longitudinal midpoint of the EMU trainset, thus, the position error of the respective bogies of different types of EMU trainsets on the lifting jack is reduced by half.
[0027] As shown in FIGS. 2-3 , on the left side of the midpoint of the EMU trainset, a first Bogie Lifting Means 1 is mounted in a first pit; a second Bogie Lifting Means 2 is mounted in a second pit which is separated from the first pit by first Fixed Rails 12 ; a third Bogie Lifting Means 3 is mounted in a third pit which is separated from the second pit by second Fixed Rails 13 ; fourth, fifth and sixth Bogie Lifting Means 4 , 5 and 6 are mounted in a fourth pit which is separated from the third pit by third Fixed Rails; seventh, eighth and ninth Bogie Lifting Means 7 , 8 and 9 are mounted in a fifth pit which is separated from the fourth pit by fourth Fixed Rails 15 ; tenth and eleventh Bogie Lifting Means 10 and 11 are mounted in a sixth pit which is separated from the fifth pit by fifth Fixed Rails 16 . The other 11 Bogie Lifting Means are set symmetrically on the right side of the midpoint. Short Fixed Rails 17 are set between the two first pits at two sides of the midpoint, and the midpoint of the short Fixed Rails 17 is at the same position as the midpoint of the arrangement of the Under-Floor Lifting Jack. That is, there are 6 pits and 11 Bogie Lifting Means on each side of the midpoint. Each car is lifted by 4 Body Hoists, and thus there are 32 Body Hoists in total, with 16 Body Hoists being arranged on each side of the midpoint.
[0028] Preferably, the length of the first Bogie Lifting Means 1 is 3,700 mm; the lengths of the second and third Bogie Lifting Means 2 and 3 are both 4,750 mm; the lengths of the fourth and fifth Bogie Lifting Means 4 and 5 are both 4,600 mm; the length of the sixth Bogie Lifting Means 6 is 3,700 mm; the lengths of the seventh, eighth and ninth Bogie Lifting Means 7 , 8 and 9 are each 4,600 mm; and the lengths of the tenth and eleventh Bogie Lifting Means 10 and 11 are both 4,000 mm. The above Bogie Lifting Means with various lengths increase the compatibility. The length of the first Fixed Rails 12 is 13,815 mm; the length of the second Fixed Rails 13 is 2,070 mm; the length of the third Fixed Rails 14 is 11,930 mm; the length of the fourth Fixed Rails 15 is 10,555 mm; the length of the fifth Fixed Rails 16 is 8,785 mm; and the length of the short Fixed Rails 17 is 3,430 mm. The longitudinal midpoint of the short Fixed Rails 17 is the same as the midpoint of the Under-Floor Lifting Jack. In actual operations, bogies of different types of EMU trainsets are set in different positions on the Bogie Lifting Means. FIGS. 2 , 3 , 4 and 5 are the schematic structural diagrams showing the arrangement of the left halves of the EMU trainsets of the CRH1, CRH2, CRH3, and CRH5 on the Bogie Lifting Means. As shown in these Figures, a bogie may be lifted by one single Bogie Lifting Means or by two adjacent Bogie Lifting Means synchronously. Hereinafter, EMU trainsets of CRH1 and CRH2 are taken as examples to explain the mode of combining the Bogie Lifting Means for lifting. When all Bogie Lifting Means are in the initial non-lift state, the Lifting Rails 1 - 11 are aligned and joined with the Fixed Rails 12 - 17 to form continuous standard rails, along which the trainsets can travel onto the Under-Floor Lifting Jack. After alignment of the longitudinal midpoint of the EMU trainset with the midpoint of the short Fixed Rails 17 by the Laser Distance-Measuring Device 23 , the Bogie Lifting Means may be operated for lifting. In the case of the EMU trainset of the type CRH1 (refer to FIG. 2 ), the Bogie Lifting Means other than the tenth Bogie Lifting Means 10 are all involved in lifting. For example, the front bogie of the locomotive 31 is lifted by the eleventh Bogie Lifting Means 11 and the rear bogie of the locomotive 31 is lifted by the ninth Bogie Lifting Means 9 ; the front bogie of the first middle-car 32 is lifted by the eighth Bogie Lifting Means 8 and the seventh Bogie Lifting Means 7 together, and the rear bogie of the first middle-car 32 is lifted by the sixth Bogie Lifting Means 6 ; the front bogie of the second middle-car 33 is lifted by the fifth Bogie Lifting Means 5 and the Fourth Bogie Lifting Means 4 together, and the rear bogie of the second middle-car 33 is lifted by the third Bogie Lifting Means 3 ; and the front bogie of third middle-car 34 is lifted by the second Bogie Lifting Means 2 and the rear bogie of the third middle-car 34 is lifted by the first Bogie Lifting Means 1 .
[0029] As shown in FIGS. 2-5 , because of the symmetrical alignment of the Bogie Lifting Means with respect to the midpoint of the EMU trainset, errors of bogies positions are small for the bogies close to the midpoint and getting larger for the bogies far from the midpoint. For the three bogies closest to the midpoint, altering the lengths of Bogie Lifting Means 1 - 3 can satisfy the compatibility requirements for the different types of EMU trainsets, so that the EMU trainsets can be lifted although they are in different lengths. As for the bogies far from the midpoint, in additional to extending the length of the Bogie Lifting Means, additional Bogie Lifting Means may be added in the respective pit. For example, the Bogie Lifting Means 10 and 11 are mounted in the sixth pit, the Bogie Lifting Means 7 , 8 and 9 are mounted in the fifth pit, and the Bogie Lifting Means 6 , 5 and 4 are mounted in the fourth pit.
[0030] Different types of EMU trainsets are different in length and hence different in positions of car supporting points, thus, the Body Hoist 18 may be moved longitudinally along the dedicated rails 20 longitudinally through wheels driven by a motor 21 (which is described in another patent application), so that the Supporting Heads 22 of the Body Hoists 18 can be aligned with supporting points of the car. Each car of the EMU trainset may be lifted by 4 Body Hoists, and thus totally 32 Body Hoists are needed for lifting the whole trainset. Due to different car widths of various types of EMU trainsets, the Supporting Heads 22 are equipped with transverse displacement device (which is described in another patent application) to adapt to different cars. In the non-lift state, the Supporting Head 22 returns to its initial position. During the lifting process, the transverse extending distances of the Supporting Heads 22 are set by the Main Control System according to the different car widths, to align the Supporting Heads 22 with the supporting points of the car vertically. The Supporting Head 22 is moved up and down by the control of a transducer-driven asynchronous motor 24 and reducer, as shown in FIG. 6 .
[0031] When the EMU trainset travels onto the UFLJ, accurate positioning of the EMU trainset is important, so that the EMU trainset is placed evenly at both sides of the UFLJ. The existing 4 types of EMU trainsets in China are longer than 200 m and different in lengths, therefore it is very difficult for the driver to stop the EMU trainset precisely at the appointed position on the UFLJ. Thus, a Laser Distance-Measuring Device 23 including a Laser Range Finder and a Display Screen is installed at one side of the end of the continuous standard rails, as shown in FIG. 7 , and a “Stop Position” sign is set as a reference for driver to stop the trainset. The Laser Distance-Measuring Device is installed on a telescopic device so that the laser distance-measuring device can be set above the continuous standard rails before the EMU trainset travels onto the UFLJ. The distance between the “stop position” sign and the Laser Distance-Measuring Device denoted by Li is a given value which varies with the type of EMU trainsets and is known value. The Laser Distance-Measuring Device 23 measures the distance denoted by Lx between itself and the locomotive of the EMU trainset when the EMU trainset travels along the rails. The distance Lx is returned in real time to the Main Electric Control Part and the Display Screen. When the difference between the distances Lx and Li is within the range of ±150 mm, i.e. −150<Lx−Li<150, the driver can stop the EMU trainset. Subsequently, the Laser Distance-Measuring Device 23 sends the result of the detected position of the stopped EMU trainset to the Main Electric Control Part, so that the body hoists 18 can move along the dedicated rails 20 and align with the car supporting points accordingly. The functions of information feedback and position error compensation of the Laser Distance-Measuring Device 23 realize the precise, effective and automatic alignment between the EMU trainset and the UFLJ.
[0032] As described above, the EMU trainset stops accurately at the appointed position and all bogies of the EMU trainset are positioned on the Bogie Lifting Means. Then the Bogie Lifting Means lift the whole EMU trainset to a specified height. As per instructions from the Main Control Part, the Body Hoists move lengthwise and the Supporting Heads move crosswise to align with the supporting points of the EMU trainset. The Support Heads of the Body Hoists can then lift the car bodies after the alignment and separate the car bodies from the bogies. Because of the high requirement of synchronization precision of lifting the whole EMU trainset, the lifting of the Supporting Head 22 is driven by a transducer-driven asynchronous AC motor 24 . An encoder is equipped on the shaft of the asynchronous AC motor 24 to provide a feedback signal of motor speed. Also, the Main Electric Control Part sends a predefined speed signal which is passed to the control drivers through a communication bus. A digital PID regulator compares the predefined speed signal and the feedback signal of motor speed to adjust the working frequency of the transducer accordingly, so as to adjust the rotating speed of the AC motor and guarantee the synchronization of the lifting. The control driver may consist essentially of a Digital Signal Processor (DSP), an amplifying circuit, a transducer, a protection circuit and an interface circuit. A sensor is installed on the Body Hoist 18 and a Location-Sensing Slice is set at the initial position of the Body Hoist 18 . After each completion of lifting of the car body, the Body Hoists can return to their initial positions through the interaction of the sensing slices and the sensors, thereby ensuring that the body hoist can arrive at an accurate position ready for lifting under the control of the main electrical control part. The lifting synchronization precision which is ≦±1 mm and the lifting speed difference which is ≦±10% during the lifting of the UFLJ both exceed the existing standards.
[0033] The above is detailed description of the illustrative embodiments of the present invention. However, these embodiments are not intended to limit the scope of this invention. All equivalent implementations or modifications which do not depart from the technology spirit of the invention, such as different dimensions, a different quantity of bogie lifting means and different embodiments of the control circuits, should be contained in scope of the invention.
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The invention discloses an Under-Floor Lifting Jack for High-Speed EMU trainset, comprising: a Main Electric Control Part for controlling the Jack, multiple Bogie Lifting Means arranged in pits, Fixed Rails on the ground between adjacent pits, and Body Hoists movable along dedicated rails on both sides of the Bogie Lifting Means, wherein Lifting Rails of the Bogie Lifting Means and the Fixed Rails form continuous rails, and one or more of the Bogie Lifting Means are set in each pit and adapted for lifting individually or synchronously in combination according to the wheel positions of different types of Electric Multiple Unit Trainsets under the control of the Main Electric Control Part. The invention is compatible with the maintenance of various EMU trainsets, thus the same lifting jack can satisfy maintenance requirements of various EMU trainsets, resulting in high compatibility and construction cost-reduction of the maintenance base for the EMU trainset.
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This is a division of application Ser. No. 306,137, filed Feb. 2, 1989 now U.S. Pat. No. 4,967,760.
BACKGROUND OF THE INVENTION
The present invention relates to phonocardiograms and in particular to an improved technique for taking spectral phonocardiograms.
The prior art has noted the potential utility of computer-based Fourier analysis of heart sounds for diagnostic purposes. However, the meager amount of previous experimental work that has been done in this area has largely been limited to average studies of first (S1) and second (S2) heart sound spectra for normal individuals. Typically, such studies have been restricted to frequencies below about 150 Hz and the utility of the approach has been severely limited by the long computing time required for Fourier analysis. In addition, the previous work has largely been limited by the noise level, inadequate dynamic range and frequency response of then-available sound detection and recording apparatus.
SUMMARY OF THE INVENTION
The present system is directed to a system for obtaining projections of spectral surfaces of the Fourier transform of heart sounds in real time on a video monitor while the physician is listening to the same sounds. This technique would result in a dynamic Spectral Phonocardiogram (SPG) which in turn would provide a sensitive method of picking out irregular sound patterns at different portions of the heart cycle as a function of frequency. Because such displays would extend the sensitivity of the human ear and supplement that sensitivity with the ability of the human eye to perform pattern recognition, it would also provide a useful supplementary auscultation tool for cardiologists, for those assessing a patient's general health, and for those learning the art of physical diagnosis. With the current availability of the echocardiogram, the most immediate applications of this method would be to provide a permanent record of the heart sound spectra which could be used comparatively to monitor the progression of heart disease in a given patient and to provide rapid screening for valvular malfunctions of large groups of people (for example, school children, factory workers, military personnel, government employees, etc.) in locations remote from a major hospital by a nurse or general physician. Indication of valvular dysfunctions would then be refered to a specialist in cardiology. Variations of the invention include methods of grade level identification and computer-automated diagnosis.
These and other features and advantages of the present invention will be seen from the following detailed description of the invention, taken with the attached drawings, wherein:
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic drawing of the human heart showing the basic geometry, direction of blood flow, and valve locations;
FIG. 2 is a frontal drawing of the human chest indicating orientation of the heart, the valve locations, and principal auscultation points.
FIG. 3 is a schematic representation of the system according to the present invention;
FIG. 4 is a detailed view of the apparatus for placing a microphone on a patient's body in accordance with the method of the present invention;
FIG. 5 is a schematic of the apparatus for carrying out the method according to the present invention;
FIG. 6 is a detailed graph showing frequency response curves for A-, B-, and C-weighting and an anti-aliasing filter attenuation curve in accordance with the method of the present invention;
FIG. 7 illustrates a variable resolution time window function in accordance with the present invention;
FIG. 8 is a spectral phonocardiogram at the apex of the heart with an A-weighting spectral function of a normal heart with split first sound;
FIG. 9 is a spectral phonocardiogram of heart sounds at the apex of the heart with A-weighting and showing a grade 2 out of 6 murmur from mitral prolapse;
FIG. 10 is a spectral phonocardiogram of heart sounds at the base of the heart near the aortic region showing grade 3-4 out of 6 systolic murmurs from aortic stenosis and aortic regurgitation;
FIG. 11 is a spectral phonocardiogram of heart sounds at the aortic region with A-weighting showing a grade 5 out of 6 aortic murmur, aortic stenosis and regurgitation, chronic heart failure, and atrial fibrillation.
FIG. 12 is a log plot of a spectral phonocardiogram of heart sounds at the apex with B-weighting showing a grade 2 out of 6 mitral murmur which illustrates a quantitative method for grade level determination.
DETAILED DESCRIPTION OF THE INVENTION
ANATOMY AND HEART SOUND SOURCE MECHANISM
FIG. 1 shows a cross-sectional drawing of the human heart. The path of blood flow through the normal heart is shown by the heavy arrows and the four valves are indicated in large bold type. Blood flows in through the vena cava to the right atrium, through the tricuspid valve to the right ventricle, and through the pulmonary valve to the lungs. Blood returning from the lungs enters the left atrium, flows through the mitral valve to the left ventricle, and through the aortic valve to the aorta. The "First Sound" (S1) in the heart cycle is normally strongest in the apex region, occurs when the heart contracts, and is primarily due to the near simultaneous closing of the tricuspid and mitral valves. During this contraction, blood flows from the right ventricle through the pulmonary valve to the lungs and from the left ventricle through the aortic valve to the aorta. The width of the pulse varies with spectral response function, but typically ranges from about 70 to 100 msecs with A-weighting.
The "Second Sound" (S2) is strongest in the base region, occurs when the heart expands, and is primarily due to the aortic and pulmonary valves closing. During this expansion, blood flows from the right atrium through the tricuspid valve to the right ventricle and from the left atrium through the mitral valve to the left ventricle. The width of this pulse again varies with spectral response function, but is typically about 25 to 60 msecs with A-weighting.
The separation between S1 and S2 is typically about 300 msecs. Because the unfiltered spectral components for both S1 and S2 peak below about 5 Hz, observation times in excess of 200 msecs would be required to observe the full spectra for each sound. Conversely, to observe variations in the spectral components well within the S1-S2 time interval requires filtering (such as the A- or B-weighting curves shown in FIG. 6) to remove the extreme low frequency components.
The ideal heart sound observed with A-weighting would thus consist of two smooth pulses with durations of about 80 and 40 msecs, separated by about 300 msecs over a typical 1 sec heartbeat cycle. These sounds would give rise to smoothly-shaped pulses in the frequency domain which could be well-resolved as a function of time. However, this result for the "normal" heart sound requires laminar flow of blood through the valves, heart chambers and blood vessels, as well as simultaneous closure of the two pairs of valves generating the first and second sound.
Marked departures from the "normal" heart sound spectra can arise in a variety of ways. There are characteristic recognizable patterns in the frequency domain which are analogous to those which have been previously studied in the time-domain through auscultation:
(1) Non-simultaneous closure of either pair of valves. This results in a pair of pulses within S1 or S2 which shows up in a strong interference pattern in the frequency domain. This effect may arise from benign causes (e.g., the split S1 in FIG. 8) or from pathological ones which result in more complex patterns in different regions of the SPG. Because the timing between opening and closure of valves is part of the recorded data, the spectra can be used to diagnose or confirm electrocardiagram findings.
(2) Valvular prolapse can result in regurgitation of blood through the valve during that portion of the cycle in which the valve is supposed to be closed. This in turn results in strong turbulence in the blood flow which results in random high frequency noise components (e.g., 300 to 1000 Hz; see FIG. 9.)
(3) Narrowing (stenosis) of a valve or blood vessel can result in strong low-frequency pulsations ("palpable thrill") at one extreme, as well as higher-frequency turbulence (see FIGS. 10 and 11).
(4) Miscellaneous: Any marked disruption in normal blood flow will produce some characteristic spectral fingerprint. For example, septal defects, systolic click, diastolic snap, pericardial knock, ejection murmurs, diastolic murmurs, and, in general, any form of valvular incompetence. It may not always be possible to diagnose the specific problem from the Spectral Phonocardiogram; however, abnormalities tend to stand out in the spectral surface plots.
FIG. 2 shows a diagram of the human (female) chest in which the heart location is indicated by a dashed line and the locations of the four valves are shown with heavy solid lines. Because of the geometry of the heart and the presence of the sternum and costal cartilage, the optimum microphone placement to detect individual valve sounds is seldom directly above the valve in question. Optimum locations for detecting the specific valve sounds are shown in the FIG. 2 by the large circles enclosing single capital letters ("A" for aortic, "P" for pulmonary, "T" for tricuspid, and "M" for mitral). The numbered short horizontal lines in the figure show the approximate locations of costal cartilages Nos. 2 through 6; the optimum locations tend to be within the corresponding intercostal spaces and on either the right (aortic) or left (pulmonary, tricuspid, and mitral) side of the sternum. Generally, mitral murmurs can be picked up selectively anywhere in the apex region.
Referring now to FIG. 3, the system according to the present invention for producing a spectral phonocardiogram includes microphones 11 and 12 placed at different regions of the chest over the heart and connected to circuitry 20 for obtaining projections of spectral surfaces of Fourier transforms of heart sounds in real time on a video monitor. Box 20 comprises elements 21-29 shown in FIG. 5. The audio signal may be heard by the attendant using stereophonic earphones 30 connected to box 20 of FIG. 3 and box 21 of FIG. 5 of the SPG (Spectral Phonocardiograph) apparatus. The earphones 30 serve as a highly sensitive electronic stethoscope for positioning the microphones 11 and 12 in FIG. 3.
The sensitive diaphragm of each microphone should be no larger than the diameter of a typical heart valve and each microphone may be positioned for optimum response from the individual valves at the positions A, P, T, and M, as indicated in FIG. 2. Listening to the heart sounds stereophonically while looking at waveform displays provides a helpful aid in identifying the physical location of unusual heart sounds and for positioning the microphones for optimum sensitivity. Under these conditions, the heart sounds appear to be spread out spatially with remarkable clarity. For example, positioning the microphones at the tricuspid (T) and mitral (M) valve regions in FIG. 2 permits identifying which of these valves closes first in the case of a split first sound, and, hence, provides a method of confirming the split-sound diagnosis.
Referring to FIG. 5, it is seen that this schematic diagram of the system depicts two parallel channels for microphone input to the final video display. These two channels function in identical manner and the flow of data through the system is indicated by the arrows. The digital circuit elements 23 through 28 utilize at least 16-bit digital signal processing (DSP) chips and are synchronized and controlled by one central processor unit (CPU) in box 29.
Analog signals from microphone 11 and 12 go through variable gain amplifier 21 and are monitored by stereophonic earphones 30 worn by the attendant. Amplifier 21 is equipped with separate gain controls and both instantaneous- and peak-reading level indicators for each amplifier so that the signals can be adjusted to optimum level without overloading the A/D converters in box 23. Optionally, these signals can be recorded with a 2-channel, 16 bit/sample digital audio tape (DAT) recorder 40 for later analysis, or re-analysis.
Referring to FIG. 5, the analog signals from amplifier 21 pass through anti-aliasing analog filter 22 which introduces a sharp attenuation characteristic amounting to about 100 dB in going from the maximum signal frequency (about 1 kHz) to be used in the spectral phonocardiograph (SPG) display to half the sample frequency (Fs) of the A/D converter 23 in accordance with the Nyquist criterion. The value of Fs can be varied somewhat but is typically about 2,550 Hz for the present application. Filter 22 eliminates spurious signals which might otherwise be produced in A/D Converter 23 by mixing signal frequency components with the sample frequency. The approximate attenuation introduced by the anti-aliasing filter is shown by the dashed curve in FIG. 6.
It will be realized that a filter which falls off by about 100 dB in going from 1,000 Hz to Fs/2=about 1275 Hz (or over a range of about 1275-1000=275 Hz=about a quarter of an octave) and is relatively constant in frequency response below 1 kHz is hard to achieve in practice without a large number of lumped circuit elements. Further, such a sharp attenuation characteristic must unavoidably introduce large frequency-dependent phase shifts throughout its pass band.
Alternatively, the need for such a sharp cut-off, anti-aliasing filter as that shown by the dashed curve in FIG. 6 can be avoided by using a technique of "over-sampling". Here, instead of sampling initially at frequency Fs (=about 2,550 Hz), one samples at a much higher frequency, LFs, where L is an integer much larger than one and preferably some power of 2. For example, L=16 would be a practical value for the present application, for which the actual sample frequency would be LFs=16Fs=about 40,800 Hz. Here, in order to avoid spurious signals produced in the A/D Converter 23 by mixing signal frequency components with the sample frequency, the attenuation characteristic of the anti-aliasing filter only has to fall off by about 100 dB in going from 1 kHz to a frequency LFs/2=about 20,400 Hz. Hence, the 100 dB attenuation only has to occur over a range of a little more than 4 octaves (about 20,400-1,000=19,400 Hz). An analog filter with this attenuation characteristic and flat response over the pass band is much easier to construct and has substantially less phase shift over its pass band than that for the dashed curve in FIG. 6. In implementing this over-sampling technique, one then takes only one digital signal out of L (e.g., one out of 16 for L=16) coming out of the A/D converter. In this way, one regains the initially desired sample rate, Fs=about 2,550 Hz, without the difficulties presented by the steep attenuation characteristic (dashed curve) in FIG. 6. By choosing L to be a power of two, a simple binary counter driven from the actual sample frequency clock can be used to select the desired output samples.
For optimum results, A/D converter 23 (together with the rest of the digital circuit elements in boxes 24-27) should have a resolution of at least 16 bits per sample on each channel; in that case no additional filtering is required in analog filter 22 for typical signals from heart sounds. However, if the resolution of the A/D converter is significantly less than 16 bits/sample, additional low frequency filtering is required to display spectra with A- or B-weighting satisfactorily; this means adding different lumped circuit filter elements in box 22 to obtain the low frequency attenuation characteristics for the A- and B-weighting curves shown in FIG. 6.
For example, the full dynamic range over frequencies varying from 5 to 1000 Hz of a first- or second- heart sound containing a Grade 1 out of 6 murmur in the range from 200 to 1000 Hz is about 70 dB. To see the murmur with a minimum signal-to-noise ratio of about 15 dB requires a total dynamic range of about 85 dB, hence more than 14 bits/sample resolution. Thus, if data were to be analyzed using a 12 bit/sample A/D converter, additional lumped-circuit filtering would be required in box 22 to provide adequate A- and B-weighted results. However, in a more ideal system with 16-bit/sample resolution, results with smoother frequency response would be obtained merely by using an anti-aliasing filter in box 22 and by introducing A-, B-, or C-weighting curves digitally in box 27 of FIG. 5.
After A/D converter 22 in FIG. 5, the serial digital data are stored in buffer memory 24 in blocks of 1,024 points which are successively shifted by N points in the serial stream of data. To provide a synchronized real-time video display of the SPG at 30 frames/sec and to provide a resolution of M slices/sec in the spectral surface with maximum resolution (say 400 points) over the frequency domain from 0 to about 1000 Hz from a 1,024 point FFT (Fast Fourier Transform), requires very special integer relationships between N, M and Fs. We consider two useful cases:
(i) Moderately high resolution plots such as those contained in FIGS. 8-11, are achieved with a sample frequency Fs=2550 Hz, M=30 slices/sec, and 1,024 point blocks in the time domain shifted by N=85 points in the serial stream of data.
(ii) Lower resolution plots (see FIG. 12) can be obtained at 30 frames/sec, with a sample frequency Fs=2560 Hz, M=10 slices/sec, and 1,024 point blocks in the time domain shifted by N=256 points in the serial stream of data.
It will be appreciated that other solutions with different resolution may be found.
The successive blocks of 1,024 points stored in buffer memory 24 are multiplied sequentially by a 1,024 point time-window function in box 25. Ideally, this window consists of a smoothly varying multiplicative function with zero amplitude and slope at both the start and end of the time window which forces the original signal amplitude to zero at the start and end of the window without appreciably distorting the spectral amplitudes of real signals that are periodic in the window interval. The purpose of this time-window function in the present invention is two-fold: It minimizes erroneous spectral components which would be generated in the following FFT by signals which are nonperiodic over the window. In addition it permits obtaining higher (and adjustable) time resolution (at the expense of frequency resolution) in the successive slices of the surface representing the final spectral phonocardiogram. As applied to the first and second heart sounds where strong low frequency components are present, absence of such a time window function results in a large quasi-exponential decaying pedestal of spurious frequency components on log plots of the sound pressure level vs frequency, which components extend far beyond the bandwidth of the actual signal.
FIG. 7 shows representative forms taken by an adjustable resolution time-window function in accordance with the present invention. This window function (F) has an adjustable value for its full width at half-maximum response (W) over the time interval between 0 and T and is described mathematically by:
F=0.5[1-cos(Pi(t-T/2+W)/W)] for T/2-W<t<T/2+W
and
F=0 otherwise, where Pi=3.14159. . .
The curves for this function in FIG. 7 are plotted for different values of W/T. The optimum values of the adjustable parameter range from about W=T/6 to T/2 for the present application. This time window function includes the widely-used "Hanning window" as one special case (W=T/2).
Because the FFT algorithm incorporates precisely 2 k points in the time domain (where k=10 provides near-optimum results for the present application), the frequency- and time-resolution determined by the number of points in the time-domain per FFT cycle can only be changed by discrete, factor-of-two jumps. These jumps are too large to provide optimum time resolution in the present application and the present adjustable time-window function provides a convenient practical means to accomplish that objective.
After multiplication by the time window in box 25, each successive block of 1,024 points in the time domain is processed by the FFT in box 26. The rate at which these FFT's are performed determines the number of slices/second generated in the real-time SPG video display. Thus, for example, considering cases (i) and (ii) enumerated above:
(i) a resolution of 30 slices/sec requires one FFT per 33 msecs in each channel;
(ii) a resolution of 10 slices/sec only requires one FFT per 100 msecs in each channel.
Real-time 16 bit 1,024 point FFT's can be performed at this speed by currently available DSP (digital signal processing) chips.
Signal in the frequency domain coming out of the FFT consists of 512 point blocks of data spread over (Fs/2) Hz, and typically the first 400 points will represent the spectrum up to about 1 kHz. These blocks of data, which now represent rms amplitudes of the spectral components, are fed sequentially to digital filter 27, where the low frequency attenuation characteristics of the A-, B- or C- weighting curves shown in FIG. 6 are stored digitally and where one pre-selected characteristic is used to multiply the frequency domain data.
The A-weighting curve is especially useful for making audio-visual comparisons of the data because the low frequency fall-off of the A-weighting curve corresponds to the attenuation of the human ear in the same frequency range. (The A-weighting curve corresponds roughly to the response of the normal ear at a loudness level of about 40 phons.) Other, less severe attenuation characteristics are desirable to study SPG patterns in the frequency range where the ear is insensitive. Although other attenuation characteristics could have been chosen arbitrarily for the present purposes, the A-, B-, and C-weighting curves shown in FIG. 6 have the virtue of being defined by the American National Standards Institute (ANSI) under standard ANSI S1.4-1983, adopted as weighting functions in sound noise-level meters. As discussed below, the low frequency attenuation of the B-weighting curve is a particularly useful compromise for quantitative determination of the grade of heart murmurs and for displaying lower frequency components in the SPG.
The blocks of frequency-domain data from digital filter 27 are presented sequentially to the video display module 28 at the slice rate desired for the final graphic display. These data are entered row-wise into a storage matrix which contains all of the frequency data to be displayed at one time. This storage matrix has a number of columns (e.g., 400) corresponding to the number of frequency components to be plotted and a number of rows (e.g., 120) corresponding to the number of slices with which the spectral surface is to be displayed. The way in which data in the storage matrix are mapped into the graphic display device determines the specific shape of the spectral surface forming the SPG.
Creating the illusion of three dimensions in this type of plot has been discussed in Chapter 3 of the book by W. R. Bennett, Jr. entitled "Scientific and Engineering Problem Solving with the Computer", (Prentice-Hall Englewood Cliffs, 1976). The illusion is produced by plotting the spectral amplitudes of each successive row of frequency-domain data from the storage matrix at positions on the display device which are shifted incrementally by amount dX in the horizontal direction and by amount dY in the vertical direction. The examples shown in FIGS. 8-11 correspond to incremental shifts of dX=2 pixels and dY=2 pixels for each successive row of 400 points, displayed using one pixel/frequency channel in the horizontal direction. Hence in this case, the time axis appears to recede at 45 degrees=arctan(dY/dX) in respect to the horizontal.
The data entered in the first row of the storage matrix are used to initialize a "horizon array" for a hidden-line algorithm. The horizon array has a number of elements equal to the total number of pixels in the horizontal direction and the values stored in the horizon array represent the running maximum value of the absolute vertical coordinate for a particular horizontal coordinate (the array index) which has been previously plotted (including the vertical displacement, MdY, which is given to the Mth slice in creating the illusion of perspective). The horizon array is up-dated as each successive row of the matrix is plotted. If the old value stored in the horizon array is larger than the new value for that same horizontal coordinate, the new point is suppressed in the plot. Otherwise, the new point is plotted and the value for the horizon array is set equal to the new maximum vertical coordinate for that horizontal coordinate. This process results in "hiding" data points which would fall behind taller foreground structures already entered in the plot of the surface.
We outline here two basically different methods for creating a dynamic real-time SPG display from data fed into the storage matrix. For the sake of specific example and numerical comparison, we will illustrate with a 640×480 pixel format which is commonly available in high-speed color displays. We will assume the complete picture is to be refreshed at 30 Hz so that the frame rate can be synchronized with conventional video displays and VCR's (video cassette recorders). We shall also assume that 4 seconds of data are to be displayed at 30 slices/sec for a total of 4×30=120 slices in the surface and that there are 400 frequency components to be displayed. Hence, there are 120 rows and 400 columns in the storage matrix. Increments of dX=dY=2 pixels per row would permit a maximum displayed amplitude of 240 pixels per scan; i.e., for these assumptions, 400+120×2=640 pixels are needed in the horizontal direction and 240 +120×2=480 pixels are needed in the vertical direction.
Method I) results in a continuous real-time display. Here, each block of 400 points is initially entered in the first row of a storage matrix in the display module. When a new row of 400 points is entered, the other rows are moved sequentially upward in the storage matrix, with the exception that the top row is deleted. The most recent events are then plotted in the left foreground, and the surface appears to move continuously in the diagonally upward direction. At any given instant, the entire surface displayed on the screen will portray earlier events in the background and the most recent events in the foreground. Thus, as shown in FIGS. 8-11, time advances diagonally from background to foreground in an instantaneous picture of the surface and S1 (the first sound) falls behind the second sound (S2) in any given heartbeat. At 30 frames per second, a continuous real-time display of this surface requires a total pixel plotting rate of 120×400×30=1.44-MHz per microphone channel, with 120×30=3600 full-screen erases per second.
Although the plotting rates required for Method I) can be achieved with some currently available plotting devices, an alternative method with less-demanding data-plotting rates is also included in the present invention.
Method II) results in a quasi-static mode of real-time display that is continuously up-dated. In this method, 400 point blocks of frequency domain data from digital filter 27 are again presented sequentially to the video display module 28 at the slice rate desired for the final graphic display. As before, the first 400 point block of frequency-domain data is entered on the first row of the storage matrix, but the successive 400 point blocks of data are directly entered in successively higher rows of this matrix. However, as each new line of data is about to be entered in the storage matrix and plotted on the display device, the display from the old row of data is erased. With some display devices, this erasure and replotting can be done on a point-by-point basis within the particular row of the storage matrix. For example, the "erasure" process might be accomplished by replotting the original data point on that row, using the same color as the background screen (e.g., by plotting white points on a white screen, or black points on a black screen) before adding the new point in a different color or grayscale level. In this method, one only has to erase and replot 400 points in each frame. Hence in this case, a realtime display up-dated 30 times per second only requires a maximum pixel plotting rate of 2×400×30=24 kHz per microphone channel, with no full screen erasures. In this mode, when the screen is completely filled, the plot "wraps" around vertically, starts over again at the bottom of the screen, and the horizon array is reinitialized. In this case, time appears to flow diagonally from the foreground to the background and S1 (the first sound) will fall in front of the second sound (S2). In general, there will be a moving discontinuity in the plot at the row of the display where new data are being entered. However, the remainder of the surface appears static.
Although the basic properties of the SPG can be displayed using a monochrome video monitor with only one microphone channel, a simple three-color display can be used to substantial advantage. The contrast in the surface plot can be enhanced by plotting non-zero signal components in different colors from that used to depict the zero-signal background plane and the fixed scale markings. By using different colors for non-zero signals from each of the two microphone channels, a three-color display results in which the two signals from different regions of the heart are simultaneously shown in different colors. Such 3 color 2 microphone channel displays make it easier to pin-point the source of heart sound irregularities, especially when viewed while listening to the heart sounds with stereo earphones. Alternatively, different color palettes can be used on more elaborate color monitors so that the color still changes with intensity, but with different hues for each of the two microphone channels, and is still distinct from the color of the zero-signal background plane.
One can enhance some characteristics of the heart-sound spectral display by plotting a surface of the difference between the two microphone signals at box 28. This approach has the advantage that common signals (including background noise levels) from two different regions of the heart cancel out, leaving a display which exaggerates differences between these two regions. Although the optimum way to achieve this cancellation is to take the difference signal after the two signals have passed the digital filter 27, many benefits of this approach could be obtained in a less complex system by taking the difference between the two analog signals emerging from amplifier 21 and sending this difference signal through a one-channel system containing elements equivalent to those in boxes 22-28 of FIG. 5.
It should be noted that the use of 30 Hz synchronization of the sample frequency and slice-rate in the present method makes the SPG suitable for display on conventional video monitors and TV sets. Thus, permanent copies of the SPG display can easily be obtained as a function of time through use of a conventional VCR in box 50. Similarly the original sound channels could easily be added to the VCR audio input from the output of amplifier 21. However, the audio quality in the video tape would be limited by properties of the VCR itself. Unless the VCR has the capability for digital sound recording with 16 bit resolution, the audio signal on the video tape would be severely limited. Alternatively, an inverse FFT could be performed on the output from digital filter 27, fed through a D/A converter and provided to the analog audio input of the VCR; this method would retain an audio signal roughly representative of the video SPG display, but this additional complexity has not been shown in FIG. 5. Providing the entire apparatus in FIG. 5 is available, the simplest way to retain a permanent record of an individual time-dependent SPG is to make a digital recording of the initial sound with (16 bit/sample) DAT recorder 40 and play that recording back with circuit elements 22-29.
Finally, one can always "freeze" time at some point in the display from the dynamic spectral phonocardiograph and run off the display of the SPG at that point in time with any commonly available high-resolution hard copy device (e.g., graphic display printer, pen plotter, photographic copier, etc) as indicated in box 50 of FIG. 5. The 4 second onscreen display for the system discussed above would then typically permit displaying an SPG for the last four heartbeats, as illustrated in the examples below.
It will be appreciated that the availability of higher-resolution video display devices would permit preserving data over a larger block of time in one screenful, by suitable adjustment of the parameters in the digital circuit elements in FIG. 5. Alternatively, the availability of higher-resolution display monitors would permit showing the time-development of the SPG with greater resolution. For example, the use of currently available monitors containing 1280×1024 pixels (with in excess of 4 thousand to 16 million color palettes) would permit doubling the time resolution of the display over the results presented here. (This doubling is accomplished by setting dX=4 pixels instead of 2 in the surface plotting algorithm, and by doubling the data processing rates.) The principal advantage of this improvement in time resolution would be in resolving low-frequency structure between S1 and S2, which, for example, can arise from aortic stenosis.
EXAMPLES
Measurements were made using two Sennheiser model MKH104 condensor microphones 11, 12 with frequency response curves which were flat within about 1 dB from about 5 Hz to well over 20-kHz and had absolute pressure sensitivity of about 2 mV/microbar. As shown in FIG. 4, each microphone was housed in a double rubber cup. The inner cup 113 has an inside diameter of about 2 cm and suspends the diaphragm 112 of the microphone about 5 mm above the chest wall, sealing the small enclosed volume (about 1.5 ml) from the outside and providing good acoustic coupling for the microphone to the chest wall. The outer rubber cup 114 is about 5.5 cm in diameter and provides a double acoustic shield from outside noises, as well as increasing the stability of positioning and holding the microphone. Each cup has a hole drilled in the center which fits snugly about the shaft 111 of the microphone.
These cups provide acoustic isolation so that the microphone can be positioned and held lightly in place with the fingers on top of the surface of the rubber cup 114. In this case, the double cup structure serves an additional important function of shielding the microphone from acoustic pick-up of the pulse in the attendant's fingers. Alternatively, the microphone housing can be held in place with a broad elastic belt attached to the outer cup 114 and fastened by a buckle (not shown) for extended monitoring of heart sounds.
In the measurements presented here, amplifier 21 and DAT recorder 40 in FIG. 5 consisted of a 16 bit/sample SONY PCM F1 2-channel digital recorder and associated video cassette recorder (VCR). A portable apparatus consisting of blocks 11, 12, 21, 30, and 40 in FIG. 5 was transported to Yale-New Haven Hospital where many recordings were made of patients. Some other representative cases were also studied in a quieter acoustic environment away from the hospital.
Data were taken simultaneously from the two microphones, typically, with one placed at the base of the heart (feeding the left stereo channel of the recorder and the other placed at the apex (feeding the right stereo channel). In practice, each recording was made for a period of about 5 minutes in order to provide representative data and to insure that sections of data would be recorded which were relatively free of digestive and breathing noises.
Room noise levels varied substantially in this work. Under the best conditions, even allowing 6 dB "headroom" in recording peak signals, the outside acoustic and electrical noise levels were about 85 dB to 90 dB below maximum signal at frequencies extending from 20 kHz down to about 5 Hz. However, there was substantial variation in the different hospital locations--especially in the form of low-frequency room noise generated by air conditioning systems and in some instances by radio frequency interference from fluorescent lighting.
These digital recordings were then fed into block 21 and the output of block 21 was fed into block 22 of a prototype version of the rest of the system in FIG. 5, and where it was demonstrated that the digital analysis required to produce an SPG could be done in real time. Hard copy results generated by a graphics display line printer of such SPG's (spectral phonocardiograms) are shown in FIGS. 8-11 described below.
The four examples shown were all taken with A-weighting and thus correspond to the impression that the same sounds would make on the human ear. In each case, the altitude of the spectral surface is proportional to the linear rms sound pressure amplitude of the Fourier components, frequency is displayed from about 0 to 1000 Hz along the horizontal axis, and time over a 4 sec interval is displayed by the major intervals going diagonally from the final horizon to the foreground for a continuous stream of data. The fine lines in the background plane are separated by 1/30 sec intervals and, typically, data are presented for four heartbeats for each patient. For the normal heart (FIG. 8), data of this type appear to be moderately coherent from one beat to the next and confined largely to the frequency range below about 200 to 400 Hz. The presence of a murmur often shows up as a more random fluctuation in the surface which can extend over the entire frequency domain, but is most easily noticeable for frequencies above about 400 Hz where there is relatively little amplitude in the normal heartbeat spectrum. For more severe problems, such as aortic stenosis, one sees a lot of additional structure in between S1 and S2 which frequently is strongly modulated in time.
FIG. 8 is a Spectral Phonocardiogram for a healthy 29 year old female taken at the apex with A-weighting. Note the extreme coherence of the spectra for the first (S1) and second (S2) sounds and the similarity of the structure from one heartbeat to the next. The absence of any significant random background to the surface and the clear isolation of the spectra for S1 and S2 indicate a complete absence of any significant heart murmurs. The strong interference pattern at frequencies around 100 Hz is somewhat unusual and arises from a marked splitting of S1. In this case, the mitral and triscupid valves closed at time intervals separated by about 35-msec and generated a strong interference pattern modulated at about 30 Hz.
FIG. 9 is a Spectral Phonocardiogram taken with A-weighting at the apex of a 54 year old male with prolapse of the posterior leaf of the mitral valve. This murmur was actually discovered with the present prototype apparatus and was later diagnosed as a grade 2 out of 6 murmur from mitral insufficiency. This holosystolic murmur exhibits random spectral components that peak in the range from about 300 to 900 Hz, which arise from turbulence created by regurgitation from the mitral valve. The scraping or rasping noise one hears through the earphones in this part of the heart cycle obviously corresponds to the randomness in this portion of the spectral distribution.
FIG. 10 is a Spectral Phonocardiogram taken at the base of the heart near the aortic region for a 66 year old female suffering from aortic stenosis. It was diagnosed as a grade 3 to 4 out of 6 systolic murmur with a palpable thrill, together with a grade 1 out of 6 aortic regurgitation murmur. The maximum in the intensity distribution with A-weighting is at about 90 Hz, occurs shortly after S1, and persists for roughly half the systolic interval. Here, the spectrum has numerous peaks in frequency with a nearly uniform spacing of about 30 Hz and corresponds to the Fourier series for a quasi-periodic waveform rich in harmonic content, whose principal frequency is about 30 Hz. This seems to be a characteristic spectral fingerprint of aortic stenosis (see FIG. 11.)
FIG. 11 is a Spectral Phonocardiograph taken in the aortic region with A-weighting for a 66 year old female suffering from a large number of problems: aortic and mitral insufficiency, aortic stenosis and regurgitation with a grade 5 out of 6 aortic murmur, mitral regurgitation, chronic heart failure, and atrial fibrillation. The patient had rheumatic fever at age 12 and had been a candidate for a triple-valve replacement which was never carried out. As with FIG. 10, the mid-systolic region is marked by a series of regularly-spaced peaks that go through a maximum about 1/3 of the time between S1 and S2; but here, the spectrum of S1 is completely hidden by the mid-systolic structure. In this case, the Fourier series points to a quasi-periodic waveform with a fundamental frequency of about 35 Hz, which evidently is excited when blood tries to flow through the narrowed aortic valve. The granular random patterns at various times throughout the heart cycle arise from the various other valve defects summarized above.
GRADE LEVEL MEASUREMENT
Although the spectral pattern generated by the linear display of rms pressure amplitude as shown in FIGS. 8-11 provides the most useful basis to recognize the patterns from different valvular dysfunctions, a logarithmic scale provides a better basis for quantitatively judging the grade of a murmur. The currently used grading scale is based on a psycho-acoustic judgement of relative loudness of the murmur when heard through a stethoscope in which the loudness range is divided into six categories. Because of the inherent logarithmic response of the ear to loudness, the use of a Log scale in the SPG would permit defining an equivalent grade level based on a simple linear measurement from the peak intensity of the heart sound to the murmur level from a vertical scale calibrated in dB. Log plots using B-weighting and 10 dB steps in the audible spectral intensity would provide a good way to define the loudness boundaries in grade levels for two reasons: first, psychoacoustic studies have shown that people generally associate a doubling in loudness with 10-dB increments in sound pressure level; second, we have found empirically from Log plots of the SPG using B-weighting that grade "0" murmur levels (i.e., a level where the cardiologist does not detect a murmur) are typically about 60 dB down from the low frequency peak in the spectral distribution.
FIG. 12 provides a Log plot of the rms spectral amplitudes of heart sounds obtained at the apex for a grade 2 out of 6 mitral murmur using B-weighting. The vertical scale has a full range of 60 dB in this plot and one can clearly see the strong components at very low frequencies which can be used as a reference in the grade level measurement. In this case, lower time resolution has been used to portray the spectral surface at the rate of 10 slices/sec (rather than 30/sec used in FIGS. 8-11) and values of the vertical pixel increment per slice have been increased substantially to enhance the contrast. The location of the cut-off base plane on the SPG can be adjusted at different heights to optimize the ease of pattern recognition and to accomplish the murmur grade measurement itself. One can move up the cut-off plane until the murmur in the 300 to 1000 Hz spectral region just disappears visually. At that point one can read the peak height of the low frequency maximum above the murmur directly from the vertical scale in dB. For the case illustrated, one needs to move the cut-off plane up to about 20 dB out of 60 dB, in rough agreement with the 2 out of 6 grade level determined by the cardiologist.
AUTOMATED DIAGNOSIS
After an extensive catalog of characteristic spectral "fingerprints" from linear SPG plots has been accumulated, it is possible to develop an automated computer-based diagnostic method which will at least determine a minimum list of heart defects that would be implied by a particular SPG. The mathematical basis of this identification process has been discussed in a more general context in Section 2.23 of the book by W. R. Bennett, Jr., "Scientific and Engineering Problem Solving with the Computer", op. cit., Chapter 2. The method consists of the following steps:
(i) expanding the unknown linear function, which consists of the pressure amplitude of the heart sound, over the time-domain of a full heart cycle, or in subdivisions of the cycle including the first sound (S1), the second sound (S2) the interval between the first and second sound (S2-S1), and the interval between the second and first sound of the next heartbeat. This expansion is done in terms of the complete set of orthonormal functions over the time interval, T, consisting of the sine and cosine functions used in the discrete Fourier transform;
(ii) identifying the particular sequence of expansion coefficients (which represent the spectral amplitudes obtained by the FFT) through use of a generalized scalar product with similar sets of expansion coefficients based on previously identified, normalized patterns (i.e, the different spectral distributions characteristic of accurately diagnosed heart dysfunctions.)
Specifically, let F n (t) be the complete set of base functions which are orthonormal over the time domain 0<t<T. Hence, ##EQU1## where δ nm =1 for n=m and δ nm =0 for n≠m.
A particular pattern, V(t), is characterized by the spectral expansion coefficients, C n , defined by ##EQU2## where these coefficients are given as a consequence of Eqs. (1) and (2) by ##EQU3## It is desirable to normalize all of the unknown and identified pattern functions studied so that ##EQU4## In this case, it follows from Eqs. (1)-(4) that ##EQU5## The exact value of the normalization in Eq (5) is not important, so long as the same normalization is used for all patterns analyzed. The important thing is that the generalized vectors corresponding to the different pattern functions all be of the same length. Identification of a particular unknown pattern distribution V(t)' amounts to finding a particular, known subset of expansion coefficients C m such that
C'.sub.m =C.sub.m (6)
within some arbitrarily chosen degree of accuracy for each member m of the subset, where C' m is determined by substituting V'(t) in Eq. (3). This process may be automated by defining a set of normalized expansion coefficients C m ,k for each identified pattern, V k (t), and by then computing the set of generalized scalar products ##EQU6## for the different values of k, where k labels a particular known pattern. That value of k which provides the maximum value for S in Eq (7) then represents the best possible identification of the unknown pattern distribution in terms of the previously identified set.
This entire identification process is implemented through the use of a FFT to determine the expansion coefficients. In this case, the number of points in the FFT and the adjustable width for the time window function may be optimized for the computer-diagnostic process. A look-up table of these expansion coefficients for the previously identified patterns would be stored in the computer memory in order to perform the identification. This computer-automated diagnostic process does not actually require the real-time graphic display apparatus and could be implemented by itself in a much smaller electronic package. Alternatively, the automated diagnostic method can supplement the graphic display of the SPG.
It will be appreciated that the instant specification, examples and claims are set forth by way of illustration and not limitation, and that various modifications and changes may be made without departing from the spirit and scope of the present invention.
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A system of generating a spectral phonocardiogram which summarizes time-dependent changes in the heart sounds throughout the heart cycle. The system is based on the projection of spectral surfaces of the Fourier transform of heart sounds as a function of time and is a useful diagnostic tool both for a cardiologist and a general practitioner. Permanent copies of the spectral phonocardiograms can provide useful records for monitoring the development of heart disease in a given individual. The system provides a useful means for rapid screening of large groups of people for heart disease by non-specialists in cardiology. A variant of the system provides automated computer diagnosis of the probable nature of the heart disease.
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The invention concerns a power shift transmission for motor vehicles and automotive construction machinery.
BACKGROUND OF THE INVENTION
Power shift transmissions in general have one hydrodynamic converter as starting device. Such converters require great space and involve power loss to hydraulic and churning losses. In order to reduce the length of the transmission and prevent such power losses, the converter has been eliminated in a special development of the invention described in European patent No. 0 214 989 B2, its function as starting component being assumed by a transmission brake. Such a brake is, however, severely stressed.
SUMMARY OF THE INVENTION
The problem on which the invention is based is to provide a compact, economical and wear resistant starting device of long service life and high efficiency.
According to the invention, this problem is solved by a front-mounted, regulated multiple disc clutch wherein a one-way clutch prevents the motor vehicle from rolling opposite to the travel direction intended by the gear selection.
To design the multiple disc clutch as compact as possible, the loading of the clutch must be kept low. At the same time, the clutch must be operated only as briefly as possible under drag in order to minimize its wear and thermal stress. In any case, the vehicle must not be held with the clutch on hills. To avoid such a load the power shift transmission has said one-way clutch which prevents the vehicle from rolling opposite to the travel direction intended by a gear selection.
Another solution of the problem, on which the invention is based and for which separate protection is claimed, is to design the regulated gear clutch as compact, economical and wear resistant starting device. This is advantageous insofar as there is already a gear clutch in power shift transmissions. Such a gear clutch serving as starting device must be dimensioned only somewhat larger. The regulation ensures that the gear clutch be thermally loaded and used up as little as possible. Length and weight of the power shift transmission are considerably reduced in this solution, since the hydrodynamic converter is eliminated and also no separate front mounted clutch is needed.
The gear clutch is preferably a regulated multiple disc clutch.
In such a gear clutch designed to act as integrated starting clutch and is a regulated multiple disc clutch, a one-way clutch advantageously prevents the rolling of the vehicle opposite to the travel direction intended by a gear selection.
In an advantageous development of the invention, the one-way clutch is designed as free wheel unit, especially as sprag unit or pawl unit.
The one-way clutch (free wheel unit) is preferably mounted on the input shaft of the power shift transmission, that is, on the side of the multiple disc clutch facing the transmission, especially in the area of the multiple disc clutch.
Alternatively to a free wheel unit, an unintended rolling opposite to the travel direction can be prevented by an electronic gearshift system which acts upon shifting components. One possibility here is to activate the service brake in case of an unintended rolling. The brake system must here, of course, be synchronized with the transmission system. Another possibility is to design the one-way clutch in the transmission combined with the starting clutch as closed system (transmission brake). The braking action is preferably obtained by adjusting in the transmission a combination of shifting components which blocks the output of the transmission. The electronic control of said transmission brake must be effected as an overlapping control, that is, when the starting clutch begins to grip, the braking action of a shifting component is released to the same extent the starting clutch absorbs the torque. How strong the retaining torque overlap must be depends on the drive force of the vehicle due to a downhill gradient. The retaining torque of the transmission brake, which is determined by the overlapping control, is advantageously adapted to this drive force. Thus, there are no frictional losses that are great enough to destroy the mechanical power and produce unneeded thermal load.
When the vehicle weight is known, this drive force can be determined by its effect upon the vehicle, that is, by the acceleration of the vehicle during a very brief testing time within which the vehicle hardly noticeably rolls away. This requires measuring of the angular velocity of the transmission output shaft and a power calculation from the change in angular velocity.
Alternatively, the drive force resulting from a slope can be determined by measuring the torque of the transmission output shaft resulting therefrom.
In another development of the invention, the slope output power is determined, when the vehicle weight is known, by means of a gradient sensor.
When the vehicle weight is known the drive power is advantageously found by a change of the transmission output speed.
The multiple disc clutch may be a wet clutch in order to obtain a good dissipation of heat.
Another solution of the problem on which the invention is based and for which separate protection is claimed is to design a regulated transmission brake as a compact, economical and wear resistant starting device wherein by activating the service brake an overlapping shift prevents the motor vehicle from rolling opposite to the travel direction intended by the gear selection. This is advantageous insofar as there is in any case a transmission brake in power shift transmissions. Said transmission brake serving as starting device must be dimensioned somewhat larger. The regulation ensures that the transmission brake be thermally loaded and used up as little as possible. Length and weight of the power shift transmission are considerably reduced in this solution, since the hydrodynamic converter is eliminated and also no separate front-mounted clutch is needed.
BRIEF DESCRIPTION OF THE DRAWING(S)
Two embodiments of the invention are illustrated in the drawings which show:
FIG. 1 diagrammatically shows a power transmission of a motor vehicle with power shift transmission; and
FIG. 2 shows said power transmission course with a free wheel unit on the input shaft against the transmission housing.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
An engine 1 drives a vehicle, via a starting clutch 2 , designed as a wet multiple disc clutch and a power shift transmission 3 , together with a rear-mounted differential gear 4 .
In the embodiment of the invention, shown in FIG. 2, a mechanical free wheel unit 3 . 1 between transmission input shaft 3 . 2 and transmission housing 3 . 3 prevents rotation of said shaft opposite to the engine direction of rotation. In forward gears engaged in the power shift transmission 3 this is a rear rolling stop and in engaged reverse gear a forward rolling stop, that is, in both cases unintended rolling of the motor vehicle opposite to the travel direction intended by the gear selection is prevented.
In the embodiment of the invention shown in FIG. 1, the free wheel, which prevents rolling of the vehicle opposite to the travel direction intended by the gear selection, is designed as an electronically regulated stop which acts by activation of the above mentioned combination of shifting components. In this case, the rolling of the motor vehicle opposite to the travel direction intended by the gear selection is prevented by a combination of shifting components in the transmission blocking the transmission output. This is done as follows:
1st Case: Forward start with the first gear:
The brakes D and E are applied and the clutch B is engaged. When the starting clutch 2 begins to grip, the brake D is released in the proportion in which the starting clutch absorbs the torque. The sun gear 3 . 4 of larger radius, which is driven by the clutch B, drives the planetary gear 3 . 5 which, in turn, drives the planetary gear 3 . 6 . If the retaining torque of the brake D is removed, the sun gear 3 . 7 of smaller radius begins to turn in opposite direction to the sun gear 3 . 4 of larger radius. Thus, the ring gear 3 . 8 can start turning in the direction of rotation of the sun gear 3 . 4 of larger radius. The power on the gearing of the ring gear 3 . 8 conditioned by the slope drive output of the vehicle and by the torque of the transmission output shaft 3 . 9 resulting therefrom, which via the planetary gears 3 . 5 and 3 . 6 is transmitted to both sun gears 3 . 4 and 3 . 7 , is redistributed by the sun gear 3 . 7 of smaller radius to the sun gear 3 . 4 of larger radius.
2 nd Case: Forward start with the second gear:
The brakes D and E are applied and the clutch B is engaged. When the starting clutch 2 begins to grip, the brake E is released in the proportion in which the starting clutch absorbs the torque. The sun gear 3 . 4 of larger radius, which is driven by the clutch B, drives the planetary gear 3 . 5 which, in turn, drives the planetary gear 3 . 6 . If the retaining torque of the brake E is removed, the planet carrier 3 . 10 starts turning, since the planetary gear 3 . 6 has rolled away to the stalled sun gear 3 . 7 of smaller radius. The planetary gear 3 . 6 drives the ring gear 3 . 8 . Thus the ring gear 3 . 8 can start turning in the direction of rotation of the sun gear 3 . 4 of larger radius. The power on the gearing of the ring gear 3 . 8 conditioned by the slope drive output of the vehicle and by the torque of the transmission output shaft 3 . 9 resulting therefrom, which via the planetary gears 3 . 5 and 3 . 6 is transmitted to the sun gear 3 . 7 of smaller radius and the planet carrier 3 . 10 , is redistributed by the planet carrier 3 . 10 to the sun gear 3 . 4 of larger radius.
3 rd Case: Start with the reverse gear:
The brakes D and E are applied and the clutch C is engaged. When the starting clutch 2 begins to grip, the brake D is released in proportion in which the starting clutch absorbs the torque. The sun gear 3 . 7 of smaller radius, which is driven by the clutch C, drives the planetary gear 3 . 6 . If the retaining torque of the brake D is removed, the sun gear 3 . 7 of smaller radius begins to turn. The planetary gear 3 . 6 begins to turn in opposite direction to the sun gear 3 . 7 of smaller radius. Thus, the ring gear 3 . 8 begins turning in opposite direction to the sun gear 3 . 7 of smaller radius. The power on the gearing of the ring gear 3 . 8 conditioned by the slope drive output of the vehicle and by the torque resulting therefrom of the transmission output shaft 3 . 9 , which is transmitted via the ring gear 3 . 8 and the planetary gear 3 . 6 to the sun gear 3 . 7 of smaller radius, is redistributed by the brake D to the gear clutch C.
In the independent solution of the problem on which the invention is based in the form of the regulated gear clutch as starting device for which separate protection is claimed, the start clutch 2 of FIG. 1 is eliminated. The clutch B is given larger dimensions for the purpose and serves as a starting clutch. To start, it is disengaged with regulation, the first gear is thus engaged. For starting in reverse, the clutch C is closed with regulation. Said clutch as a starting clutch is also dimensioned larger. The start in reverse is, of course, not as frequent as the forward start so that the requirement regarding wear on the clutch C is not as strict as in the clutch B.
The clutches B and C are advantageously further unloaded by overlapping gearshifts.
The forward start is formed as follows: The brakes D and E are applied and the clutch B engaged. When the clutch B starts to grip, the brake D is released in the proportion in which the clutch B absorbs torque.
The start in reverse is analogously formed as follows: The brakes D and E are applied and the clutch C is engaged. When the clutch C begins to grip, the brake D is released in the proportion in which the clutch C absorbs torque.
In the second independent solution of the problem on which the invention is based and for which separate protection is claimed, in which one regulated transmission brake serves as starting device and an overlapping gearshift prevents, by activating the service brake, the rolling of the vehicle opposite to the travel direction intended by the gear selection, the starting clutch 2 of FIG. 1 is eliminated. The brake E is made of larger dimensions for that and serves as starting clutch. To start in first gear, the clutch B is disengaged. The service brakes is applied so that the vehicle cannot roll away. As long as the brake E is disengaged, the planet carrier 3 . 10 can freely turn and thus transmits no torque to the ring gear 3 . 8 . The planetary gear 3 . 6 meshing with the ring gear 3 . 8 rolls here upon the latter. To start, the brake E is now disengaged with regulation and in the proportion in which the planet carrier absorbs torque, the service brake is released. To start in reverse gear, the clutch C is engaged. The starting process develops in the same way as above. The service brake is applied so that the vehicle cannot roll away. As long as the brake E is open, the planet carrier 3 . 10 can freely turn and thus transmits no torque to the ring gear 3 . 8 . The planetary gear 3 . 6 meshed with the ring gear 3 . 8 rolls here upon the latter. To start, the brake E is now engaged with regulation and in the proportion in which the planet carrier absorbs torque, the service brake is released.
Reference numerals
1
engine
3.5
planetary gear
2
starting clutch
3.6
planetary gear
3
power shift transmission
3.7
sun gear
3.1
free wheel unit
3.8
ring gear
3.2
transmission input shaft
3.9
transmission output shaft
3.3
transmission housing
3.10
planet carrier
3.4
sun gear
4
differential gear
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A power shift transmission ( 3 ) for motor vehicles in which instead of a hydrodynamic torque converter a controlled or regulated multiple disc clutch serves to assist starting. The loading of clutch is minimized by a fitted catch which prevents the motor vehicle from rolling in the opposite direction to the direction of travel intended by the gear selection. Catch can take the form of a mechanical catch, as sprag unit, or the form of an electronically adjusted catch which acts on one and/or more transmission brakes and/or clutches and/or into the service brake of the vehicle.
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FIELD AND BACKGROUND OF THE INVENTION
The present invention builds on a method for the production of a disk-form or disk-shaped workpiece based on a dielectric substrate, which production method comprises the treatment in a plasma process volume, formed between two opposing electrode faces in a vacuum receptacle.
DEFINITION
We are defining “electrode face” as a surface freely exposed to the plasma process volume.
In said method, on which the present invention builds, an electric high-frequency field is generated between the electrode faces and therewith in the process volume charged with a reactive gas, a high-frequency plasma discharge is generated. The one electrode face is herein comprised of a dielectric material and a high-frequency potential is applied to it with a specified distribution varying along the face. The distribution of the electric field in the plasma process volume is set through the potential distribution on the dielectric electrode face. In the method forming the basis, the substrate either forms the dielectric electrode face or the substrate is disposed at the second electrode face developed metallically. Furthermore, at the electrode face opposing the substrate the reactive gas is introduced into the process volume through an aperture pattern.
In recent years increased effort has been exerted to produce larger disk-form workpieces incorporating reactive high-frequency plasma-enhanced methods. One of the reasons was the wish to reduce the production costs. High-frequency plasma enhanced methods (P Hf ECVD) are employed for substrate coating or as reactive high-frequency plasma-enhanced etching methods. Said efforts can be seen in particular in the production of liquid crystal displays (LCD), of TFT or plasma displays, as well as in the field of photovoltaics, and therein especially in the field of solar cell production.
When carrying out such production methods by means of said high-frequency plasmas-enhanced reactive methods with the known use of areal metal electrodes opposing one another in parallel, each with a planar electrode face facing the process volume in a vacuum receptacle and applying the electric high-frequency field for the plasma excitation, it was observed that with substrates increasing in size and/or increasingly higher excitations frequency f Hf the dimension of the vacuum receptacle, in top view onto the substrate, is no longer of secondary importance. This is especially true in view of the wavelength of the applied high-frequency electromagnetic field in a vacuum. The distribution of the electric high-frequency field in the vacuum chamber, viewed parallel to the electrode faces, becomes inhomogeneous and to some extent differs decisively from a mean value, which leads to the inhomogeneous treatment of the workpiece positioned on one of the electrode faces: during etching an inhomogeneous distribution of the etching action results, with coating, for example of the layer thickness, the layer material stoichiometry, etc. Such significant inhomogeneities in the treatment are not acceptable for some applications, such as in particular in the production of said liquid crystals, TFT or plasma displays, as well as in photovoltaics, and here especially in the production of solar cells. Said inhomogeneities are more pronounced the more said dimension or extent of the receptacle approaches the wavelength of the electric field in the receptacle.
To solve this problem, in principle different approaches are known:
U.S. Pat. No. 6,631,692 as well as US A 2003/0089314 discloses forming the plasma process volume between two metallic electrode faces, which are opposite one another, and to shape one or both of the opposing metallic electrode faces.
The metallic electrode face, which is opposite the substrate disposed on the other electrode face or the metallic electrode face on which the substrate is supported, or both opposing metallic electrode faces are developed such that they are concave. This known approach is shown schematically in FIG. 1 , in which denote:
1 a and 2 b : the metallic electrode faces opposing one another above the process volume, between which faces the high-frequency field E is generated, E r , E c : the electric field, respectively generated peripherally and centrally.
A physically fundamentally different approach, on which also the present invention builds in order to solve the above problem, is known from U.S. Pat. No. 6,228,438 by the applicant of the present application. The principle of this approach according to U.S. Pat. No. 6,228,438 will be explained in conjunction with FIG. 2 , which, however, represents a realization not disclosed in said document. But this realization is intended to serve as the foundation for an understanding. One of the opposing electrode faces 2 a , for example, as depicted is metallic. The second electrode face 2 b , in contrast, is comprised of the dielectric material, for example a dielectric areal thin plate 4 . Along the dielectric electrode face 2 b a potential distribution φ 2b is generated, which, in spite of a constant distance between the two electrode faces 2 a and 2 b , in the process volume PR yields a desired local field distribution, as shown for example in the margin region a stronger field E r than in the center region E c . This can be realized, for example as shown in FIG. 2 , thereby that a high-frequency generator 6 is coupled to the dielectric plate 4 across capacitive elements C R , C c differently, according to the desired distribution. In the implementation depicted in
FIG. 2 , however not disclosed in said U.S. Pat. No. 6,228,438, of the principle realized in said patent, the coupling capacitors C R must be selected to have higher capacitance values than the center capacitors C c . The development of the capacitors C R or C c is solved according to U.S. Pat. No. 6,228,438 in the manner depicted in FIG. 3 . A dielectric 8 is provided which, on the one hand, forms the electrode face 2 b according to FIG. 2 , which simultaneously, due to its locally varying thickness d, with respect to a metallic coupling face 10 forms the locally varying capacitances C R, C provided according to FIG. 2 ,. The dielectric 8 can therein, as shown in FIG. 4 , be formed by a solid dielectric or by an evacuated or gas-filled hollow volume 8 a between metallic coupling face 10 and a dielectric plate 4 forming the electrode face 2 b . It is essential that in this hollow volume 8 a no plasma discharge is developed.
The present invention builds on the known method according to U.S. Pat. No. 6,228,438, which was explained in principle in conjunction with FIGS. 2 to 4 . In this approach the question arises of where to place a substrate to be treated in the process volume P R , wether at the dielectric electrode face 2 b or at the metallic electrode face 2 a . Said U.S. Pat. No. 6,228,438 teaches placing dielectric substrates on the electrode face 2 b or electrode face 2 a , but (column 5 , line 35 ff) substrates with electrically conducting surface on the metallic electrode face 2 a.
It is furthermore known from said document to introduce reactive gas into the process volume and specifically distributed from an aperture pattern at the electrode face opposite the substrate to be treated. Therefore, if a dielectric substrate according to FIG. 3 or 4 is disposed on the electrode face 2 b , the aperture pattern with the gas supply is to be provided on the side of the metallic electrode face 2 a . If the substrate is disposed on the metallic electrode faces 2 a , the aperture pattern for the reactive gas is to be provided on the side of the dielectric electrode face 2 b . In this case, as is clearly evident in FIG. 4 , the hollow volume 8 a can be employed as equalization chamber and the reactive gas is only introduced through the metallic coupling configuration with coupling face 10 into the equalization chamber 8 a and through the aperture pattern provided in dielectric plate 4 into the process volume Pr. However, it is entirely possible to fill the hollow volume 8 a with a dielectric solid, be that with the material forming the dielectric electrode surface 2 b or one or more to some extent different therefrom and to supply the aperture pattern through this solid via distributed lines with the reactive gas.
It can fundamentally be assumed that the combination of the aperture pattern for the inflow of the reactive gas into the process volume and the dielectric 8 or 8 a according to FIG. 3 or 4 on a single electrode configuration requires significantly more effort than providing the aperture pattern on the electrode face 2 a according to FIG. 3 and placing the substrate to be treated on the dielectric electrode face 2 b or even developing the dielectric electrode face 2 b by a dielectric substrate itself.
For it appears advantageous to separate functionally the gas inlet measures with the aperture pattern and the measures for affecting the electric field, i.e. if possible to deposit the substrate to be treated on the dielectric electrode face 2 b or to structure the dielectric electrode face 2 b at least partially by the substrate and to shape the gas inlet conditions through the aperture pattern on the metallic electrode face 2 a.
SUMMARY OF THE INVENTION
It is the task of the present invention to propose a method for the production of a disk-form workpiece based on a dielectric substrate, by means of which workpieces provided with a special layer can be produced utilizing the method fundamentally known from U.S. Pat. No. 6,228,438. The disk-form workpieces produced in this way are to be suitable in particular for use as solar cells. This is attained thereby that the dielectric substrate, first, thus before the treatment in said high-frequency plasma process volume, is coated at least regionally with a coating material to whose specific resistance applies:
10 −5 Ωcm≦ ≦10 −1 Ωcm
and on which for the surface resistance R S of the layer applies:
0 <R S ≦10 4 Ω □ ,
subsequently the coated substrate is positioned on the metallic electrode face is reactively and under plasma enhancement etched or coated in the plasma process volume.
Although, as has been stated, the aim in the known method was the separation of the function of gas inlet measures and field affecting measures and their assignment on particular electrode faces for reasons of structuring, it has now been found that the combination of precoating the dielectric substrate with said layer and the basically known P Hf ECVD method is only successful if, after the coating, the substrate is deposited in the plasma process volume on the metallic electrode face and the field affecting measures as well as the reactive gas inlet through said aperture pattern are combined and realized on or in the proximity of the dielectric electrode face.
It has been found that after the completed coating of the dielectric substrate with the specific layer only said substrate position leads to success and therewith the function combination, which initially was considered to be rather disadvantageous, must be realized on the dielectric electrode face.
With the proposed approach, in addition, high flexibility with respect to the type of Hf plasma treatment is advantageously attained. Independently of whether or not the dielectric substrate previously coated with the specified layer is being etched or coated, further also independently of whether or not it is being coated by a P Hf ECVD process to be dielectric up to electrically highly conducting: the particular treatment process is not affected by it as far as the effect of the field distribution measures in the plasma process volume or the gas inlet measures are concerned.
As previously stated, within the scope of the present invention the dielectric substrate is first coated with a material whose specific electric resistance is significantly higher than on materials conventionally referred to as “metallic” or “electrically conducting”. The specific resistances of conventional conductor materials, such as of gold, silver, copper or aluminum are in the range from 1.7×10 −6 Ωcm to 2.7×10 −6 Ωcm.
Definition
The surface resistance R S is obtained from the quotient of the specific resistance and the layer thickness. It has the dimension Ω indicated by the symbol □ .
The surface resistance R S of a considered layer is consequently a function of the material as well as also the layer thickness.
It was found according to the present invention that the choice of the method depends not only on whether or not the surface of a dielectric substrate is precoated with a more electroconducting or less electroconducting material but critically also on the surface resistance R S of the layer in the case of said materials.
In an embodiment of the method according to the invention the distribution of the high-frequency potential at the dielectric electrode face and the inlet of reactive gas into the process volume is realized thereby that the dielectric electrode face is formed by a surface of a dielectric plate configuration facing the process volume, whose backside forms with a metallic coupling face a chamber, and the distance of the backside from the coupling face varies along these faces and that, further, the reactive gas is introduced into the chamber, then through the aperture pattern provided in the plate configuration into the process volume. On the coupling face and the other electrode face, which is electrically conducting, a high-frequency signal is applied for the plasma excitation.
Due to the varying distance between metallic coupling face and backside of the dielectric plate configuration, the capacitance distribution according to FIG. 2 is realized and the chamber volume between this backside and the metallic coupling electrode face, is simultaneously utilized as a distribution chamber for the reactive gas, which flows through the aperture pattern in the dielectric plate configuration into the process volume.
When within the scope of the present application the term “reactive gas” is used, it should be understood that under this term is also included a gas mixture of one or several reactive gases.
In view of FIG. 2 , the stated dielectric plate configuration forms with its capacitance value also determined by its thickness, a portion of the coupling capacitors C R or C C depicted in FIG. 2 . Therewith, in one embodiment, the dielectric plate configuration with a specified varying thickness distribution can be utilized. However, in another embodiment the dielectric plate configuration with an at least approximately constant thickness is employed. In a further embodiment, the potential distribution on the dielectric electrode face approximates from the center toward its periphery increasingly the potential on the coupling face. In the realization of the above described chamber between metallic coupling face and backside of the dielectric plate configuration this is attained, for example, thereby that the respective distance is chosen to be smaller in the peripheral region than in the central region and/or thereby that the thickness of the dielectric plate configuration is laid out such that it is less in the peripheral region than in the center region.
The capacitance value is selected to be lower in the center region than in the peripheral region. When developing this capacitance across a chamber ( 8 a of FIG. 4 ), this is realized for example in that
a) the metallic coupling face is developed substantially planar, the dielectric plate configuration substantially of constant thickness, and convex, when viewed from the direction of the process volume, b) the dielectric plate configuration is developed such that it is planar with substantially constant thickness, the coupling face, when viewed from the direction of the process volume, concave, c) the coupling face is developed such that it is concave, the backside of the dielectric plate configuration also, and, when viewed from the direction of the process volume, the dielectric electrode face concave, d) the coupling face is developed such that it is substantially planar, the dielectric plate configuration with planar backside parallel to the coupling face and with convex electrode face when viewed from the direction of the process volume, e) the coupling face is developed such that it is planar, likewise the electrode face, the plate backside, in contract, convex when viewed from the direction of the process volume.
If no chamber is provided, the coupling face and the electrode face can, for example, be parallel, the dielectric constant of the solid dielectric disposed between them can increase toward the periphery.
It is evident that for the optimization, on the one hand, of the field distribution in the process volume, on the other hand, of the gas inlet direction distribution into the process volume, high flexibility is given. Although the field distribution measures and the gas distribution measures are realized on the same electrode configuration, each of the two values can be optimized. It is possible to mix or combine said approaches described for example, and employ them. For example, the coupling face can be developed to be substantially planar, the dielectric plate configuration with varying thickness with the backside concave when viewed from the process volume and a convex electrode face. Moreover, it is evident to a person skilled in the art that a further layout value for the capacitance distribution explained in FIG. 2 is also the dielectric constant of the dielectric plate configuration or its distribution can be applied. By selecting different materials along the dielectric plate configuration, said capacitance distribution, and therewith the potential distribution on the dielectric electrode face, can be affected additionally or alternatively to the distance or thickness variation.
In particular the dielectric electrode face can be planar and parallel to the other electrode defining the process volume in order to realize therewith a plasma process volume of constant depth perpendicularly to the electrode faces. This preferred embodiment results for example thereby that the metallic coupling face, viewed from the process volume, is developed such that it is concave, the backside of the plate configuration planar or thereby that the backside of the dielectric plate configuration, viewed from the process volume, is developed such that it is convex, the coupling face such that it is planar or thereby that along the dielectric plate configuration of electrode face materials having different dielectric constants are employed, with planar metallic coupling face and planar plate backside parallel to it, in the peripheral region, materials having dielectric constants higher than in the center region are applied.
If it is taken into consideration that with the method according to the invention in particular large substrates with an extent of their circumscribed circle of at least 0.5 m are first coated according to the invention and subsequently are subjected to the Hf plasma treatment, it is evident that providing the above dielectric plate configuration with aperture pattern and chamber formation is demanding.
In one embodiment, therefore, the dielectric plate configuration is formed by ceramic tiles. These tiles can be mounted at a spacing in a position central with respect to the metallic coupling face. Consequently, the dielectric electrode face, due to the thermal deformation of the tiles, does not become deformed, which might have a negative effect on the field distribution and possibly the reactive gas supply into the process volume. Furthermore, the tiles of different materials with different dielectric constants, with different thicknesses and thickness profiles can be flexibly employed for the selective formation of desired plate properties. They can be employed by mutual overlapping and multilayer arrangement for the shaping of concave or convex electrode faces or configuration backsides.
It should be emphasized again that—if a chamber is formed—it is essential to prevent that in this chamber formed between metallic coupling face and backside of the dielectric plate configuration parasitic plasma discharges occur, which would eliminate the effect of this chamber as an areally distributed coupling capacitance. As is known to the person skilled in the art, this is ensured by dimensioning the spacing ratio between metallic coupling face and backside of the dielectric plate configuration, in any case less than the dark space distance valid in the particular process.
In a further embodiment of the method according to the invention the distance of the plate configuration backside varies from the metallic coupling face in one, preferably in several steps and/or the thickness of the plate varies in one, preferably in several steps. This development is realized, for example, through the use of overlapping tiles for structuring the dielectric plate configuration or when using several tile layers with locally varying layer number.
In a further embodiment the distance of the plate configuration backside from the metallic coupling face is continuously varied and/or the thickness of the plate configuration is continuously varied. This development is utilized if a substantially planar dielectric plate configuration is employed with constant thickness and the metallic coupling face, viewed from the process volume, is formed in concavely.
In a further embodiment of the production method according to the invention, in particular for solar cells, the dielectric substrate before the treatment in the plasma process volume is coated with an electrically conducting oxide, preferably an electrically conducting and transparent oxide. This coating, which is carried out before the treatment, can take place for example through reactive magnetron sputtering. Further preferred the dielectric substrate is therein coated with at least one of the following materials: ZnO, InO 2 , SnO 2 , therein additionally doped or undoped, with a thickness D to which applies:
10 nm≦D≦5 μm.
The coating of said materials within the stated thickness range fulfills the specific layer properties stated above with respect to the specific resistance and surface resistance R S .
The substrate coated in this manner is subsequently reactive etched and/or coated through treatment in the plasma process volume. Preferably as the reactive gas at least one of the following gases is utilized: NH 3 , N 2 , SF 6 , CF 4 , Cl 2 , O 2 , F 2 , CH 4 , monosilane, disilane, H 2 , phosphine, diborane, trimethylborane, NF 3 .
For example, the following layers are deposited:
Layer Reactive Gas amorphous silicon (a-Si) SiH 4 , H 2 n-doped a-Si SiH 4 , H 2 , PH 3 p-doped a-Si SiH 4 , H 2 , TMB, CH 4 microcrystalline Si SiH 4 , H 2
For reactive etching for example SF 6 mixed with O 2 is employed as the reactive gas.
Furthermore, the electric high-frequency field is preferably excited with a frequency f Hf , to which applies:
10 MHz≦f Hf ≦500 MHz
or
13 MHz≦f Hf ≦70 MHz.
The produced workpieces preferably have further a radius of the circumscribed circle which is at least 0.5 m.
A vacuum treatment installation utilized within the scope of the method according to the invention has
a vacuum receptacle, therein a first planar, metallic electrode face, a second dielectric electrode face opposing the first, which forms the one surface of a dielectric plate configuration, a metallic coupling face facing the backside of the dielectric plate configuration, electric connections on each the coupling and the first electrode face, a gas line system, which opens through the coupling face and a distributed pattern of apertures through the plate configuration, and
is distinguished thereby that the plate configuration is formed by several ceramic tiles.
Embodiments of the vacuum treatment installation utilized according to the invention will readily present themselves to a person skilled in the art in the claims as well as the following description by example of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will be described further in the following in conjunction with embodiment examples and figures. Therein depict:
FIG. 1 is a side sectional and schematic view of a known metallic electrode face which is opposite a substrate disposed on another electrode face,
FIG. 2 is a schematic illustration of a known arrangement according to U.S. Pat. No. 6,228,438,
FIG. 3 is a view of the known capacitors C R or C c according to U.S. Pat. No. 6,228,438,
FIG. 4 is a view of a known arrangement where a dielectric is formed by a solid dielectric or by an evacuated or gas-filled hollow volume between a metallic coupling face and a dielectric plate forming the electrode face,
FIG. 5 schematically the sequence of the production method according to the invention in conjunction with a function block diagram,
FIG. 6 in cross section schematically and simplified, an embodiment of a vacuum treatment installation utilized within the scope of the method according to the invention,
FIG. 7 further simplified, the view onto a coupling face utilized in the installation according to FIG. 6 ,
FIG. 8 as a reference example, the resulting layer thickness distribution over the diagonals on a rectangular dielectric substrate with P Hf ECVD coating utilizing conventional opposing planar metallic electrodes,
FIG. 9 as a reference example and depicted analogously to FIG. 8 , the distribution result on a dielectric substrate, positioned directly above a concavely formed-in metallic electrode face,
FIG. 10 further as a reference example and depicted analogously to FIGS. 8 and 9 , the result when proceeding according to FIG. 9 , however on a substrate coated according to the invention with an InO 2 layer,
FIG. 11 the layer thickness distribution profile resulting when using the method according to the invention,
FIG. 12 simplified and schematically an installation according to the invention utilized for carrying out the method according to the invention in a further preferred embodiment,
FIG. 13 a detail from the region denoted by “A” in FIG. 12 to explain a further preferred embodiment,
FIG. 14 represented analogously to that of FIG. 12 a further embodiment of the installation used according to the invention,
FIG. 15( a ) to ( f ) schematically a selection of feasibilities for increasing the electric field peripherally in the process volume through the corresponding shaping of the dielectric plate configuration and the metallic coupling face,
FIG. 16 in detail a preferred mounting of a ceramic tile for forming the dielectric plate configuration on the metallic coupling face, and
FIG. 17 the realization of the feasibilities presented by example in FIG. 15 by structuring the dielectric plate by means of ceramic tiles.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In conjunction with a simplified block diagram the sequence of the method according to the invention is depicted in FIG. 5 . A dielectric substrate 100 is at least partially coated in a first vacuum coating station 102 , for example a station for reactive magnetron sputtering, with a layer whose material has a specific resistance , for which applies
10 −5 Ωcm≦ ≦10 −1 Ωcm
and specifically such, that the resulting surface resistance R S of the layer is in the following range:
0 <R S ≦10 4 Ω □ .
The lower limit can approximate 0, since the surface resistance R S is a function of the thickness of the deposited layer. This thickness D S of the layer is preferably selected as follows:
10 nm≦D S ≦5 μm
especially if the deposited layer material, as is far preferred, is an electrically conducting oxide (CO), optionally a transparent electrically conducting (TCO). For this purpose at least one of the following materials InO 2 , ZnO or SnO 2 is deposited on the dielectric substrate 100 in doped or undoped form. The coated dielectric substrate 104 is subsequently transported to a reactive Hf plasma treatment step in station 105 , namely to a P Hf ECVD treatment step, or to a reactive Hf plasma enhanced etching step. A workpiece 106 results, which is suitable in particular for use as solar cells.
The substrate 100 , and thus also the substrate 106 , resulting according to the invention has therein preferably a radius of the circumscribed circle R U of at least 0.25 m, corresponding to a diameter of the circumscribed circle of 0.5 m, as is depicted in FIG. 5 on a workpiece W formed in any desired shape.
In FIG. 6 , a first embodiment of an inventive station or installation 105 according to FIG. 5 and utilized according to the invention, is shown in cross section and simplified. A metallic vacuum receptacle 105 a has a planar base 3 , which, facing the interior volume, forms a first electrode face EF 1 . Thereon lies the substrate 104 of a dielectric material, coated— 7 —with said layer material.
Opposite the substrate 104 provided with layer 7 or the first electrode face EF 1 , is mounted an electrode configuration 9 . It forms the second electrode face EF 2 .
The second electrode face EF 2 , in the depicted example it is disposed planar opposite the electrode face EF 1 , is formed by the surface of a dielectric plate configuration 27 . The backside ER of the dielectric plate configuration 27 forms together with a metallic coupling face KF a chamber 10 . In the depicted example the coupling face KF is developed as a formation-in 10 , which, viewed from the process volume PR, is concavely worked into a metal plate 14 . As shown schematically in FIG. 7 , the formation-in 10 depicted in the example is rectangular and forms a distance distribution of distance d between coupling face KF and backside ER of the dielectric plate configuration 27 , which abruptly jumps from 0 to the constant distance in the formation-in 10 . The substrate 104 is entered in dashed lines in FIG. 7 . Via the metal plate 14 a high-frequency generator 13 is connected with the coupling face KF, which is further connected with the electrode face EF 1 which is conventionally at reference potential.
From a gas reservoir 15 reactive gas G R or a reactive gas mixture and optionally an working gas G A , such as for example argon, is introduced via a distribution line system 17 into an pre-chamber 19 to the rear of plate 14 . The pre-chamber 19 is, on the one hand, rimmed by a mounting 18 isolating the plate 14 with respect to the receptacle 105 a , on the other hand, formed by the backside of plate 14 and the front wall 21 of the receptacle 105 a facing the metallic electrode face EF 1 . Plate 14 has a pattern of gas line bores 25 led through it.
The gas line apertures 25 in plate 14 continue, preferably aligned, into openings 29 through the dielectric plate configuration 27 . The plate configuration 27 in this example is comprised of a ceramic, for example of Al 2 O 3 .
By means of generator 13 , via the coupling face KF a high-frequency plasma discharge is generated in the process volume PR.
From the metallic coupling face KF via the areally distributed capacitance C, entered in FIG. 6 in dashed lines, at the dielectric electrode face EF 2 a selectively specified potential distribution was realized as has already been explained.
The excitation frequency f Hf is selected as follows:
10 MHz≦f Hf ≦500 MHz
therein especially
13 MHz≦f Hf ≦70 MHz.
The diameter of the circumscribed circle of the substrate 104 is at least 0.5 m and can be entirely up to 5 m and more.
In the embodiment according to FIG. 6 the distance d changes abruptly from 0 to 1 mm.
As stated above, in the embodiment variants of the installation according to the invention yet to be discussed, the chamber 10 is not laid out with a distance d changing abruptly from 0 to a constant value, but rather said distance, which, after all, contributes decisively to the determination of the capacitance distribution which is critical for the field distribution, is optimized and laid out with a specific distribution. This distance d is selected, depending on the frequency, to be between 0.05 mm and 50 mm so that no plasma can form in chamber 10 .
By means of generator 13 a power of 10 to 5000 W/m 2 per substrate area is preferably supplied.
For P Hf ECVD coating of substrate 104 preferably at least one of the following is used as the reactive gas: NH 3 , N 2 , SF 6 , CF 4 , Cl 2 , O 2 , F 2 , CH 4 , monosilane, H 2 , phosphine, diborane or trimethylborane.
Lastly, the total gas flow through the system 15 , 17 from apertures 29 is for example between 0.05 and 10 sim/m 2 per m 2 of substrate area.
The above stated values apply in particular to reactive high-frequency plasma-enhanced coating.
For the subsequent experiments the following values were set:
Process:
P Hf ECVD coating
f Hf :
27 MHz
Substrate dimension:
1.1 × 1.25 m 2
Depth of formation-in d
1 mm
according to FIG. 6:
Total pressure:
0.22 mbar
Power per substrate area:
280 W/m 2
Substrate material:
float glass with specific conductivity:
10 −15 (Ωm) −1
Prior applied coating:
InO 2 doped with tin
Surface resistance R s
3 Ω ▭
of the coating:
Reactive gas:
monosilane with the addition of H 2
Dilution of monosilane in H 2 :
50%
Total gas flow per unit area:
0.75 slm/m 2
The experiments were carried out in the installation configurations according to FIG. 6 or 7 .
As a reference result is shown in FIG. 8 the resulting layer thickness distribution in nanometers with respect to the mean layer thickness value measured over both diagonals of the rectangle of the workpiece, if on the configuration according to FIG. 6 the plate 14 without formation-in 10 with a planar metallic face is employed directly as the electrode face opposite the electrode face EF 1 .
Analogously to the representation in FIG. 8 , in FIG. 9 , furthermore as reference, the result is shown which is obtained if, on the one hand, as the workpiece to be coated an uncoated dielectric substrate 100 according to FIG. 5 , namely a float glass substrate is placed in position.
Furthermore, as was already the case for the measurement according to FIG. 8 , the plate is developed without formation-in 10 and forms one of the electrodes in the process volume PR. However, an formation-in corresponding to the formation-in 10 is provided on the base 3 beneath the substrate.
Again in analogous representation and as a reference, FIG. 10 shows the result if in the installation configuration, such as was also used for the results according to FIG. 9 , i.e. with the formation-in 10 in the base 3 , covered by the substrate and with the development of the second electrode face by the planar surface, exposed to the process volume PR, of plate 14 , the precoated substrate 104 is treated, namely the float glass substrate precoated with InO 2 .
The following results:
From FIG. 8 : that due to the inhomogeneous field distribution in the process volume PR, the resulting coating thickness distribution is unacceptably in homogeneous.
From FIG. 9 : that if the substrate to be treated is purely dielectric, the formation-in on the workpiece-supporting electrode ( 3 ) leads to a significant improvement of the field distribution and therewith to layer thickness distribution homogeneity.
From FIG. 10 : that the configuration, which for a purely dielectric workpiece according to FIG. 9 leads to a significant improvement of the layer thickness distribution, in the case in which the workpiece is comprised of a substrate 104 precoated according to the invention, leads to an unacceptable layer thickness distribution.
But if, according to the invention, said precoated substrate is coated for example with the installation according to FIG. 6 , the good layer thickness distribution shown in FIG. 11 results.
It is evident that, in spite of the high specific resistance of the layer material (InO 2 ), exclusively the process proposed according to the present invention is surprisingly suitable for attaining the homogeneous action distribution on the workpiece.
Additionally simplified and schematically, in FIG. 12 is depicted a further preferred embodiment of the treatment step according to the invention or of the installation 105 according to FIG. 5 employed for this purpose.
The precoated substrate 104 is again placed onto the planar first electrode face EF 1 . The metallic coupling face KF connected with the high-frequency generator 13 is formed in as a continuous concavity.
The dielectric plate configuration 27 forms, on the one hand, the planar dielectric electrode face EF 2 and, of constant thickness, the backside ER which is also planar. In FIG. 12 the aperture pattern through the dielectric plate configuration 27 is not shown. The dielectric plate configuration 27 has a thickness D, to which preferably applies:
0.01 mm≦d≦5 mm.
Definition
By the term dielectric plate configuration is understood in the context of the present invention an areal dielectric formation extending in two dimensions and manifest in the form of films or foils up to plates.
Since the capacitance of the dielectric plate configuration 27 is manifest in series with the capacitance between coupling face KF and backside ER of the dielectric plate, the possibly large plate capacitance resulting in the case of a thin dielectric plate configuration 27 is not significantly capable of affecting the small capacitance across the chamber 10 a.
FIG. 13 shows a detail, encircled at A, of the configuration according to FIG. 12 . It is evident that at least a portion of the bores 25 through the metal plate 14 a in the embodiment according to FIG. 12 , as well as also in all other embodiments according to the invention, can be aligned with apertures 29 (not shown) through the dielectric plate configuration 27 further can at least approximately have identical aperture cross sections.
Although the coupling face KF in FIG. 12 has a continuous curvature, it is readily possibly to realize it formed in one step or in several steps. As the material of the plate configuration 27 , which is exposed to high temperature loading, an aggressive chemical atmosphere, high vacuum and the plasma, as stated, a ceramic, for example Al 2 O 3 can be utilized. Depending on the process, other dielectric materials can optionally also be employed up to high-temperature-resistant dielectric foils with the aperture pattern.
As shown in FIG. 14 , said dielectric plate configuration 27 can be replaced by several plate configurations 27 a , 27 b spaced apart and one disposed above the other, which are positioned relative to one another by dielectric spacers. All of these individual plates 27 a , 27 b have the aperture pattern in analogy to the pattern of the apertures 29 according to FIGS. 6 and 12 and 13 . Its thickness can again be between 0.01 and 5 mm.
In FIG. 15( a ) to ( f ) feasible mutual assignments of metallic coupling face KF and dielectric electrode face EF 2 are shown schematically. All of them lead to the fact that in the process volume PR, the electric field in the peripheral region is intensified with respect to the field in the center region.
In FIG. 15( a ) the metallic coupling face KF is planar. The dielectric plate configuration 27 is convex with respect to the process volume PR and of constant thickness D. Due to its metallic properties, the coupling face KF under the action of a high-frequency potential functions as an equipotential face with φ Hf . As a first approximation the configuration according to FIG. 15( a ) can be viewed as follows: at each volume element dV along chamber 10 the series connection results of a capacitor C 10 and C 27 as shown on the left in the Figure. While the capacitance C 10 is determined by the varying distance between coupling face KF and backside ER of the dielectric plate configuration 27 as well as the dielectric constant of the gas in chamber 10 , the capacitance C 27 is locally constant, due to the constant thickness D and the dielectric constant ∈ of the plate configuration 27 .
The dielectric constant of the plate material is conventionally significantly greater than that of the gas in chamber 10 , wherewith especially with a thin plate configuration 27 , the capacitance C 27 connected in series with C 10 , becomes negligible at least in a first approximation. In the peripheral region of the dielectric electrode face EF 2 , C 10 becomes increasingly greater due to the decreasing distance d, and consequently locally the potential distribution φ EF2 along the electrode face EF 2 as it approaches the peripheral region approximates the potential φ KF of the coupling face KF. Consequently, over the process volume PR lies in the peripheral region of the electrode face EF 2 the approximate entire potential difference between φ KF and the potential applied at the counterelectrode face EF 1 . In the center region of the electrode face EF 2 , due to the greater distanced, C 10 is smaller than in the peripheral region, and thus a greater high-frequency voltage drop occurs thereon and consequently here the potential φ EF2 has a greater decrease relative to potential φ KF . Consequently, over the process volume PR now an electric field is present in this center region which is decreased relative to the peripheral region.
Based on the examination of FIG. 15( a ) and taking into consideration the fact that chamber 10 is a pressure equalization chamber for the reactive gas supplied from the aperture pattern (not shown) through the dielectric plate configuration 27 to the process volume PR, it is evident that by using a foil-like high temperature-resistant plate configuration 27 , the convex shaping can advantageously be generated due to the pressure difference between process volume and chamber 10 .
In FIG. 15( b ) further the metallic coupling face KF is planar. The dielectric plate configuration 27 has a backside ER which with respect to the process volume PR, is formed convex, but a planar electrode face EF 2 parallel to the coupling face KF. Due to the conventionally higher dielectric constant ∈ of the material of the dielectric plate configuration 27 , the capacitance C 27 affects the capacitance C 10 (s. FIG. 15( a )) only insignificantly in the peripheral region, in spite of greater thickness of the configuration 27 , such that in the embodiment according to FIG. 15( b ) the locally varying capacitance C 10 in series connection dominates and, as has been explained, the major effect was exerted on the field distribution in process volume PR.
In the embodiment according to FIG. 15( c ) the coupling face KF is also planar. The dielectric plate configuration 27 has a constant thickness, but, in contrast, is formed by sectionally different materials of differing dielectric constants ∈a to ∈d. Here the chamber 10 can be omitted.
Toward the periphery the dielectric constant ∈ of the plate material increases, and thus, in view of the equivalent circuit diagram in FIG. 15( a ), C 27 increases. In this embodiment the capacitance C 10 formed by the chamber 10 is locally constant. If here the constant thickness of the dielectric plate configuration 27 is sufficiently large, the capacitance C 27 increasing toward the peripheral region in series with C 10 becomes dominant and the already described effect is attained: in the margin region of the electrode face EF 2 the electric field in process volume PR is attenuated less than in the central region, where C 27 with ∈ d is decreased relative to C 27 with ∈ a .
FIG. 15( d ) shows the already explained conditions according to FIG. 6 and FIG. 12 .
FIG. 15( e ) shows a planar coupling face KF. The dielectric plate 27 has a planar backside E parallel to coupling face KF, however, viewed from the process volume PR, a convex dielectric electrode face EF 2 . Based on the explanation up to this point, a person skilled in the art can readily infer that therewith the same field compensation effect can be achieved in the process volume PR as has been explained up to now, according to the selected plate thickness and the plate material dielectric constants.
In FIG. 15( f ) the coupling face KF as well as also the electrode face EF 2 is concave with respect to the process volume PR, however, the backside ER of plate configuration 27 is planar.
If the dielectric constant of the plate configuration 27 is substantially greater than that of the gas in chamber 10 , then C 10 also dominates here and yields the desired field distribution in process volume PR.
Based on FIGS. 15( a ) to ( f ) it is evident that there is a high degree of flexibility especially with respect to the form of the dielectric electrode face EF 2 . As a person skilled in the art recognizes readily, the variants depicted in FIG. 15 can be expanded and combined, as, for example, providing different materials on the plate configuration 27 combined with varying thickness, etc., which further increases the leeway with respect to layout. As was already stated, chamber 10 can be omitted and the capacitance distribution can exclusively be realized through the plate configuration 27 .
If it is considered that the reactive gas is introduced into the process volume through the aperture pattern provided on the plate configuration 27 and further that the desired field compensation measures can be largely realized independently of the form of the electrode face EF 2 , it becomes evident that it is possible to optimize simultaneously the direction of the gas injection into the process volume PR as well as affecting the field in the process volume PR.
In realizing the dielectric plate configuration 27 it must be taken into consideration that it is exposed during the treatment process especially to high temperatures. Therewith thermal differences of expansion between dielectric plate configuration 27 and, via its securement, the plate 14 forming the coupling face KF. It must further be considered that with the described installation large, even very large, substrates 104 are to be treated. The realization of a dielectric plate configuration of this size as well as its mounting in a manner that thermal expansions and contractions can in every case be absorbed without deformations, represents problems especially if the configuration 27 is not of foil type, but rather as a rigid dielectric plate is comprised for example of a ceramic, such as Al 2 3 .
In an embodiment preferred in this case the solid configuration 27 , as will be explained in conjunction with FIG. 16 , is composed of a large number of dielectric, preferably ceramic, tiles. In FIG. 16 a view of such a tile and its mounting is shown and depicted in cross section. The particular tile 50 , which, as shown, is preferably rectangular or square and fabricated of a ceramic material, such as for example Al 2 O 3 , is positioned substantially centrally relative to the coupling face KF on plate 104 by means of a dielectric spacer bolt 52 , such as for example a ceramic bolt, as well as by means of a dielectric washer 54 . Thereby the relevant distance between face KF and backside ER of the tiles 50 forming the plate configuration 27 is ensured. So that the tiles 50 are peripherally supported and yet can nevertheless freely expand without tension on all sides under thermal loading, they are guided on support pins 56 with respect to the coupling face KF. The tiles 50 are secured against twisting by means of a guide pin 58 in a slot guidance 59 . The tiles 50 are provided with the aperture pattern not shown in FIG. 16 , which, if necessary, is supplemented by gaps between the tiles 50 . The tiles 50 can optionally also overlap. One or several layers of such tiles can be provided, optionally locally varying, and different ceramic materials, especially with differing dielectric constants can be employed in different regions. Therewith flexibly different formations and material profiles can be realized on the dielectric plate configuration 27 .
In FIG. 17( a ) to ( f ) the configurations according to FIG. 15( a ) to ( f ) are shown schematically, which are structured by means of tiles preferably as explained in conjunction with FIG. 16 . Only the tiles disposed directly opposite the coupling face KF according to FIG. 17 must be supported, layers of tiles adjacent on the side of the process volume are mounted on the subjacent tiles. When examining FIGS. 17( a ) to ( f ) a person skilled in the art readily understands the manner of said preferred tile structuring of the configurations according to FIGS. 15( a ) to ( f ). In accordance with said aperture pattern, the gas injection into the process volume distributed to the desired extent, must be ensured, be that by utilizing the labyrinth channels remaining between the tiles and/or by providing additional bores or apertures through the tiles 50 (not shown).
The thickness of the ceramic tiles D K is preferably
0.1 mm≦D K ≦2 mm.
With the production method according to the invention or the installation utilized according to the invention, homogeneously large, even very large, dielectric substrates can be, first, coated with special conducting layers, subsequently be surface-treated, in particular coated, by reactive high-frequency plasma-enhanced methods, whereby in particular large, up to very large, solar cells can be produced on an industrial scale.
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A method for producing a disk shaped workpiece with a dielectric substrate includes treatment in a plasma process volume between two electrode faces bounding a high-frequency plasma discharge. One electrode face is of dielectric material and is at a high-frequency potential with a varying distribution along the face. The other electrode face is metallic. Reactive gas is introduced into the process volume through an aperture pattern. The dielectric substrate, before treatment, is at least regionally coated with a layer material to whose specific resistance applies: 10 −5 Ωcm≦ ≦10 −1 Ωcm, and to the resulting surface resistance R S of the layer applies: 0<R S ≦10 4 Ω. Subsequently, the coated substrate is positioned on the metallic electrode face and is etched or coated reactively under plasma enhancement in the plasma process volume.
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PRIORITY INFORMATION
[0001] This application claims priority to U.S. Patent Application No. 60/641,091, the contents of which are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention relates generally to the field of molecular imaging, and more specifically to the field of functional imaging, including glucose transporters, thymidine kinase activity, and peripheral benzodiazepine receptors as targeted agents that incorporate near-infrared fluorophores as signaling agents.
BACKGROUND OF THE INVENTION
[0003] Current state-of-the-art detection and surgical resection tools used in cancer treatment are insufficient. Early stage disease can be missed, resection can be incomplete and these two factors alone are major contributors to morbidity and mortality. Outcomes are intrinsically linked to disease detection and treatment efficacy. Therefore, improvement in the detection of early cellular changes, as well as enhanced visualization of diseased tissue, is of paramount importance.
[0004] Optical methods continue to provide a powerful means for studying cell and tissue function. Recent discoveries in Molecular Imaging (MI) are certain to play a vital role in the early detection, diagnosis, and treatment of disease. MI will also aid in the study of biological and biochemical mechanisms, immunology, and neuroscience. MI agents commonly consist of a signaling moiety (fluorophore, radioisotope or Gd 3+ ion) and a targeting functionality such as an antibody or peptide, sugar or a peripheral benzodiazepine receptor (PBR) ligand. NIR molecular imaging agents are particularly attractive due to the inherently low water and tissue absorption in the NIR spectral region. Additionally, the low scattering cross-section and lack of autofluorescence background in the near infrared (NIR) region facilitate deep penetration and high-resolution images from small interrogated volumes.
[0005] While glandular and secretory tissues are normally rich in PBR, other quiescent tissue ordinarily express PBR at relatively low levels. Primarily spanning the bi-layered mitochondrial membrane, the PBR is expressed almost ubiquitously and thought to be associated with many biological functions including the regulation of cellular proliferation, immunomodulation, porphyrin transport, heme biosynthesis, anion transport, regulation of steroidogenesis and apoptosis. Given the importance of PBR toward regulating mitochondrial function, it is not surprising that PBR density changes have been observed in acute and chronic neurodegenerative states in humans, as well as numerous forms of cancer. For example, temporal cortex obtained from Alzheimer's patients showed an increase in PBR, and correlations with Huntington's disease, multiple sclerosis and gliosis have been demonstrated. Breast cancer generally demonstrates increased PBR expression and represents another potentially attractive target, especially in the NIR. The development of high affinity ligands for PBR (such as, for example, PK-11195, Ro5-4864, DAA1106, and DAA1107) has made non-invasive imaging modalities more suitable.
[0006] Other functional imaging targets include the glucose transporter and thymidine kinase 1. By targeting the glucose transporter, [ 18 F]-fluoro-deoxyglucose (FDG) has been successfully employed as a positron emission tomography (PET) agent to determine the metabolic statues (cellular respiration) of suspect tissues. Modest functionalization of glucose at the C-2 position does not hinder sugar uptake but does prevent cellular metabolism, therefore glucose agents can accumulate intracellularly. Since tumor cells metabolize glucose a higher rate than normal cells, the accumulation of glucose mimics (i.e. FDG and similar agents) can facilitate discrimination of tissues based on their metabolic status. While FDG imaging certainly has demonstrated utility to the clinical oncologist, the requirement of a cyclotron and a PET scanner somewhat limit its use.
[0007] Recently, in effort to improve the specificity of functional imaging agents like FDG, new probes for cellular proliferation imaging have been developed. Targeting the enzyme thymidine kinase 1 (TK1), an enzyme responsible for DNA replication, [ 18 F]3′-deoxy-3′fluorothymidine (FLT) has been shown to be an attractive complement to FDG imaging. Similar to FDG, FLT is not fully metabolized by cells and accumulates in target tissues, making it a promising imaging agent for rapidly proliferating tissues. When used in combination with FDG, clinical imaging of diseased tissue has the ability to be highly sensitive and specific.
[0008] It has been shown that NIR emitting Ln-Chelates can be prepared opening the avenue to complexes with spectral properties more compatible with biological imaging such as visible absorption, NIR emission and microsecond-long emission lifetimes. These complexes have high molar absorptivity and have luminescent lifetimes in the microsecond regime allowing temporal rejection of noise.
[0009] The present inventors have demonstrated the synthesis and utility of Eu-PK11195 and Gd-PK11195. Others have prepared PK11195 as a PET agent for use in humans. A NIR Pyropheophorbide agent has been reported for imaging glucose transporters, however this agent was not spectroscopically optimized for deep tissue in-vivo imaging (ex. 679 nm, em. 720 nm). At present, the authors are unaware of any NIR imaging agents based on thymidine imaging.
SUMMARY OF THE INVENTION
[0010] The peripheral benzodiazepine receptor (PBR) has been shown an attractive target for contrast-enhanced imaging of disease. See Publication No. 2003/0129579, incorporated herein by reference. Embodiments of the present invention include PBR targeted agents which incorporate near-infrared (NIR) fluorophores as signaling agents. Aspects of the present invention include a previously unknown class of NIR absorbing/emitting PBR targeted contrast agents which utilize a conjugable form of PK11195 as a targeting moiety.
[0011] Additionally, aspects of the present invention include the synthesis of NIR-metabolic and proliferation probes. The authors report a sacharide agent suitable for metabolic imaging in similar fashion to 18 FDG and a NIR-thymidine probe suitable for imaging cellular proliferation (DNA synthesis). The NIR contrast agents disclosed herein are suitable for optical imaging using spectral and time-gated detection approaches to maximize the signal-to-background ratio. High molar extinction dyes that absorb and emit in the NIR, such as IRdye800CW™ (available from LiCOR) and CY7 (Amersham), as well as NIR Lanthanide chelates are demonstrated. Since thymidine, PK11195 and other PBR ligands have been suggested as therapeutic agents, the molecules demonstrated here could also be useful therapeutics which also offers direct monitoring of dose delivery and therapeutic efficacy.
[0012] With absorption and emission closer to the tissue transparency window (780 nm, 830 nm respectively), the dyes reported here are much more suited for in-vivo imaging. Additionally, no one has demonstrated NIR PBR ligands for imaging PBR expression and/or therapy.
[0013] Thus, one aspect of the present invention is a method of imaging a molecular event in a sample, the method steps comprising administering to the sample a probe having an affinity for a target. The probe has at least one of a ligand/signaling agent combination, or conjugable form of a ligand/signaling agent combination. After the probe is administered, a signal from the probe may be detected. In embodiments of the present invention, the sample can be at least one of cells, tissue, cellular tissue, serum, cell extract, bodily fluids. The bodily fluids may be, for example, breast milk, sputum, vaginal fluids, urine.
[0014] Another aspect of the present invention is a method of measuring glucose uptake. This embodiment comprises the steps of administering to a sample a conjugate, the conjugate comprising a conjugable glucosamine compound and a signaling agent; and then detecting a signal from said conjugate. In embodiments of the present invention, the sample is at least one of cells, tissue, cellular tissue, serum, cell extract, bodily fluids.
[0015] Another aspect of the present invention is a method of quantifying the progression of a disease state progression that includes the steps of (a) administering to a first sample a conjugate that comprises a conjugable deoxythymidine compound and a signaling agent; (b) detecting a signal from the conjugate; (c) after a period of time from step (b), administering to a second sample a conjugate, (d) detecting a second signal; and (e) comparing the first signal with the second signal to determine the progress of a disease state. Again examples of the sample are at least one of cells, tissue, cellular tissue, serum, cell extract, bodily fluids.
[0016] Another aspect of the present invention is the above method, where the conjugate includes a peripheral benzodiazepine affinity ligand or conjugable form thereof and a signaling agent.
[0017] Another aspect of the present invention is the above method, where the conjugate includes a glucosamine compound and a signaling agent.
[0018] In the above embodiments and other embodiments of the present invention, the administration step is in vivo or in vitro.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1 is a color photograph that shows white light and fluorescence pictures of dosed cells and un-dosed cells in accordance with the present invention, and is further discussed in Example 6, below. Picture A is a white light picture of dosed cells, Picture B is a fluorescence picture of dosed cells, Picture C is a white light picture of un-dosed cells, and Picture D is a fluorescence picture of un-dosed cells.
[0020] FIG. 2 is a color photograph that shows white light and fluorescence pictures of dosed cells and un-dosed cells in accordance with the present invention, and is further discussed in Example 7, below. Picture A is a white light picture of dosed cells, Picture B is a fluorescence picture of dosed cells, Picture C is a white light picture of un-dosed cells, and Picture D is a fluorescence picture of un-dosed cells.
[0021] FIG. 3 is a color photograph that shows in vivo cancer imaging of a small laboratory animal.
[0022] FIG. 4 is a color photograph that shows in vivo neurodegenerative imaging of a small laboratory animal.
DESCRIPTION OF THE INVENTION
[0023] Embodiments of the present invention include NIR agents for the PBR based on NIR dyes, including Lanthanide chelates. Additionally, complimentary imaging agents are disclosed using a novel NIR sacharide and NIR thymidine agent. Aspects of the present invention include both being used separately, as well as where the agents are used together as a cocktail whereby both PBR expression and metabolic and or cellular proliferation status could be simultaneously monitored in-vivo.
[0024] PBR ligands such as PK11195 have been suggested as therapeutic agents. Mitochondria localized anti-death proteins of the Bcl-2 family play a central role in inhibiting apoptosis and therefore present therapeutic targets. PBR shares a close physical association with the permeability transition pore complex (PTPC) and binding of PK11195 has been shown to cause Bcl-2 resistant generation of oxidative stress. The agents reported here are unique in that they facilitate in-vivo monitoring of therapeutic delivery and efficacy.
[0025] As stated above, aspects of the present invention include methods of imaging a molecular event. in a sample, the method steps comprising administering to the sample a probe having an affinity for a target. The probe has at least one of a ligand/signaling agent combination, or conjugable form of a ligand/signaling agent combination. One such ligand/signaling agent combination comprises PBR ligands, or conjugable forms thereof.
[0026] Examples of the PBR ligands of the present invention include conjugable forms, or conjugable analogs of the following compounds:
[0027] For the purposes of the present invention, the term analog encompases isomers, homologs, or other compounds sufficiently resembling the base compound in terms of structure and do not destroy activity. “Conjugable forms,” “conjugable compounds,” and similar terms describe a form of the compound that can readily form a covalent form a covalent bond with a signaling agent such as an IR dye.
[0028] For exemplary purposes, conjugable forms of PK11195, above, include at least the following compounds, and/or analogs or derivatives thereof:
wherein R is H or alkyl, n is 0-10, and “halo” is fluorine, chlorine, bromine, iodine. In other embodiments of the present invention, halo is chlorine.
[0029] The term “halo” or “halogen,” as used herein, includes radio isotopes of halogen compounds, such as I 121 and F 19 .
[0030] Additionally, for exemplary purposes, conjugable forms of Ro5-4864 include the following and/or analogs or derivatives thereof:
wherein the variables are defined above. In other embodiments of the present invention, halo is chlorine.
[0031] Additionally, for exemplary purposes, conjugable forms of DAA1106 include the following and/or analogs or derivatives thereof:
wherein the variables are defined above, and:
[0032] In other embodiments of the present invention, halo is chlorine or fluorine.
[0033] Additionally, for exemplary purposes, conjugable forms of SSR180575 include the following and/or analogs or derivatives thereof:
wherein the variables are defined above. In other embodiments of the present invention, halo is chlorine.
[0034] Non-limited examples of PBR ligands and signaling moieties include the following compounds:
or an analog thereof, wherein R 1 is a signaling moiety; “halo” is fluorine, chlorine, bromine, iodine; and n is 0-10.
[0035] Preferably, in the above examples, the signaling moiety is a dye.
[0036] Additionally, other aspects of the present invention include NIR-sacharide agents suitable for metabolic imaging in similar fashion to 18 FDG. Given the ubiquitous clinical use of 18 FDG, 2-deoxyglucose derivatives have been extensively biologically characterized. See Czernin, J.; Phelps, M. E. Annu Rev Med 2002, 53, 89-112. These derivatives are useful metabolic imaging agents given the overexpression of glucose transporters and increased hexokinase activity in tumors. See Medina, R. A.; Owen, G. I. Biol Res 2002, 35, 9-26. 2-deoxyglucose imaging agents are incorporated into cells via the glucose transporter and are subsequently phosphorylated by hexokinase. In phosphorylating the probe, the neutral molecule becomes anionic and membrane impermeable. Functionalization at the 2-position prevents further metabolism, and thus the probe is trapped in the cells, with further uptake leading to significant accumulation. See Zhang, M.; Zhang, Z. H.; Blessington, D.; Li, H.; Busch, T. M.; Madrak, V.; Miles, J.; Chance, B.; Glickson, J. D.; Zheng, G. Bioconjugate Chem 2003, 14, 709-714.
[0037] Additionally, other aspects of the present invention include a NIR-thymidine probe for monitoring cellular proliferation, similar in fashion to [ 18 F]3′-deoxy-3′fluorothymidine (FLT). FLT has been used clinically and extensively compared to FDG. See Halter et al. General Thoracic Surgery 2004, 127, 1093-1099 and Francis et al. Eur J Nucl Med Mol Imaging 2003, 30, 988-994. In proliferating cells, FLT metabolism takes place within the anabolic arm of the DNA salvage pathway. TK1 controls entry into the salvage pathway and converts FLT to the mono-phosphate species. The agent is further phosphorylated, but can not be incorporated into DNA due to its lack of a hydroxyl group at 3′.
[0038] With respect to the signaling agents used in connection with the present invention, embodiments include near infrared signaling agents. Also includes are dyes, such as, for example, near-infrared fluorophores/fluorescent dyes. Examples include cyanine dyes which have been used to label various biomolecules. See U.S. Pat. No. 5,268,486, which discloses fluorescent arylsulfonated cyanine dyes having large extinction coefficients and quantum yields for the purpose of detection and quantification of labeled components.
[0039] Additional examples include compounds of the following formulas:
and analogs thereof.
[0040] Additional examples include dyes available from Li-Cor, such as IR Dye 800CW™, available from Li-Cor.
[0041] Additional examples include dyes disclosed in U.S. Pat. No. 6,027,709.
[0042] U.S. Pat. No. '709 discloses dyes which have the following general formula:
wherein R is —OH, —CO 2 H, —NH 2 , or —NCS and each of x and y, independently, is an integer selected from 1 to about 10. In preferred embodiments, each of x and y, independently, is an integer between about 2 and 6.
[0043] In one embodiment, the dye is N-(6-hydroxyhexyl)N′-(4-sulfonatobutyl)-3,3,3′,3′-tetramnethylbenz(e)indodicarbocyanine, which has the formula:
[0044] In a second embodiment, the dye is N-(5-carboxypentyl)N′-(4-sulfonatobutyl)3,3,3′,3′-tetramethylbenz(e)indodicarbocyanine, which has the formula:
[0045] These two dyes are embodiments because they have commercially available precursors for the linking groups: 6-bromohexanol, 6-bromohexanoic acid and 1,4-butane sulton (all available from Aldrich Chemical Co., Milwaukee, Wis.). The linking groups provide adequate distance between the dye and the biomolecule for efficient attachment without imparting excessive hydrophobicity. The resulting labeled biomolecules retain their solubility in water and are well-accepted by enzymes.
[0046] These dyes, wherein R is —CO 2 H or —OH can be synthesized, as set forth in detail in the U.S. Pat. No. '709 patent, by reacting the appropriate N-(carboxyalkyl)- or N-(hydroxyalkyl)-1,1,2-trimethyl-1H-benz(e)indolinium halide, preferably bromide, with sulfonatobutyl-1,1,2-trimethyl-1H-benz(e)indole at a relative molar ratio of about 0.9:1 to about 1:0.9, preferably 1:1 in an organic solvent, such as pyridine, and heated to reflux, followed by the addition of 1,3,3-trimethoxypropene in a relative molar ratio of about 1:1 to about 3:1 to the reaction product and continued reflux. The mixture subsequently is cooled and poured into an organic solvent such as ether. The resulting solid or semi-solid can be purified by chromatography on a silica gel column using a series of methanol/chloroform solvents.
[0047] As an alternative, two-step, synthesis procedure, also detailed in U.S. Pat. No. '709, N-4-sulfonatobutyl-1,1,2-trimethyl-1H-benz(e)indole and malonaldehyde bis(phenylimine)-monohydrochloride in a 1:1 molar ratio can be dissolved in acetic anhydride and the mixture heated. The acetic anhydride is removed under high vacuum and the residue washed with an organic solvent such as ether. The residual solid obtained is dried and subsequently mixed with the appropriate N-(carboxyalkyl)- or N-(hydroxyalkyl)-1,1,2-trimethyl-1H-benz(e)indolinium halide in the presence of an organic solvent, such as pyridine. The reaction mixture is heated, then the solvent is removed under vacuum, leaving the crude desired dye compound. The procedure was adapted from the two step procedure set forth in Ernst, L. A., et al., Cytometry 10:3-10 (1989).
[0048] The dyes also can be prepared with an amine or isothiocyanate terminating group. For example, N-(omega.-amino-alkyl)-1,1,2-trimethyl-1H-benz(e)indolenium bromide hydrobromide (synthesized as in N. Narayanan and G. Patonay, J. Org. Chem. 60:2391-5 (1995)) can be reacted to form dyes of formula 1 wherein R is —NH 2 . Salts of these amino dyes can be converted to the corresponding isothiocyanates by treatment at room temperature with thiophosgene in an organic solvent such as chloroform and aqueous sodium carbonate.
[0049] These dyes have a maximum light absorption which occurs near 680 nm. They thus can be excited efficiently by commercially available laser diodes that are compact, reliable and inexpensive and emit light at this wavelength. Suitable commercially available lasers include, for example, Toshiba TOLD9225, TOLD9140 and TOLD9150, Phillips CQL806D, Blue Sky Research PS 015-00 and NEC NDL 3230SU. This near infrared/far red wavelength also is advantageous in that the background fluorescence in this region normally is low in biological systems and high sensitivity can be achieved.
[0050] The hydroxyl, carboxyl and isothiocyanate groups of the dyes provide linking groups for attachment to a wide variety of biologically important molecules, including proteins, peptides, enzyme substrates, hormones, antibodies, antigens, haptens, avidin, streptavidin, carbohydrates, oligosaccharides, polysaccharides, nucleic acids, deoxy nucleic acids, fragments of DNA or RNA, cells and synthetic combinations of biological fragments such as peptide nucleic acids (PNAs).
[0051] In another embodiment of the present invention, the ligands of the present invention may be conjugated to a lissamine dye, such as lissamine rhodamine B sulfonyl chloride. For example, a conjugable form of DAA1106 may be conjugated with lissamine rhodamine B sulfonyl chloride to form a compound of the present invention.
[0052] Lissamine dyes are typically inexpensive dyes with attractive spectral properties. For example, examples have a molar extinction coefficient of 88,000 cm −1 M −1 and good quantum efficient of about 95%. It absorbs at about 568 nm and emits at about 583 nm (in methanol) with a decent stokes shift and thus bright fluorescence.
[0053] Coupling procedures for the PBR ligands and Glucosamine proceed via standard methods and will be recognized by those skilled in the art. In general, the nucleophilic N terminus of the targeting moieties are reactive towards activated carbonyls, for example an NHS (N-hydroxysuccinimide ester), sulfonyl chlorides, or other electrophile bearing species. Solvent of choice for coupling reactions can be dye specific, but include dimethyl sulfoxide (DMSO), chloroform, and/or phosphate buffered saline (PBS buffer). The resulting conjugates, amides, sulfonamides, etc. resist hydrolysis under physiological conditions, and are thus useful for in-vivo and in-vitro application.
[0054] The following are examples of compounds of the present invention:
[0055] The following compound is an example of one of the coupled compounds described above:
and analogs thereof, wherein n and x are integers from 1 to 10.
[0056] As stated above, the compounds of the present invention can be employed as signaling agents in NIR imaging. The resulting signal may be used to image a molecular event. Non-limiting examples of specific molecular events associated with the present invention include at least one of peripheral benzodiazepine expression, cell proliferation, glucose uptake, epidermal growth factor receptor expression, coronary disease.
[0057] Thus, the resulting signal may be used to diagnose a disease state such as, for example, cancer, neurodegenerative disease, multiple sclerosis, epilepsy, coronary disease, etc. Specifically, brain cancer and breast cancer are two cancers that may be diagnosed with the compounds and methods of the present invention. Two additional examples are non-Hodgkin's lymphoma and colon cancer.
[0058] Another embodiment of the present invention is a method of measuring glucose uptake. This method comprises, comprises administering to a sample a conjugate, the conjugate comprising a conjugable glucosamine compound and a signaling agent; and detecting a signal from said conjugate. As in the other methods, the sample is at least one of cells, tissue, cellular tissue, serum or cell extract. An example of a conjugable glucosamine includes the following compound and conjugable analog thereof:
[0059] The administration step may be in vivo administration or in vitro administration. The in vivo administration step further comprises at least one time course imaging determination, and in other embodiments, the in vivo administration step further comprises at least one bio distribution determination.
[0060] Other embodiments of the present invention include conjugable compounds associated with this glucosamine method, specifically including the following:
where R 1 is a signaling moiety, and
and analogs thereof.
EXAMPLES
[0061] The following examples are presented purely for exemplary purposes, and as such the material in this section should be considered as embodiments of the present invention and not to be limiting thereof.
Example 1
[0062] This example demonstrates the conjugation of a NIR dye of the present invention and a conjugable analog or conjugable form of PK11195 for deep tissue imaging. In this example, IRDye800CW (LiCOR) is coupled to conjugable PK11195.
[0063] Dye800CW-PK111195 (Scheme 1)—To a 10 mL round bottom flask, about 196.5 μL of a 1 mg/ml conjugable PK11195 solution (DMSO) is mixed with about 300 μL of an about 1 mg/mL Dye800CW (DMSO). The reaction proceeds under nitrogen flow for about 1 hour at RT. Reaction progress is monitored via HPLC and ESI MS.
[0064] Yield is about 99% and requires no further purification.
Example 2
[0065] This example demonstrates an example of the formulation of a NIR-glucosamine conjugate of the present invention.
[0066] Dye800CW-glucosamine (Scheme 2)—To a 10 mL round bottom flask, about 9.3 mg sodium methoxide and about 37 mg D-glucosamine hydrochloride are reacted in about 2 mL DMSO. The solution is stirred under nitrogen for about 3 hours at RT. Next, about 3 μL of the resulting solution are mixed with about 150 μL of an about 1 mg/mL Dye800CW/DMSO solution in a separate 10 mL flask. The mixture is stirred under nitrogen for another 1.5 hours at RT.
[0067] Reaction progress was monitored via HPLC and ESI MS and the reaction yielded 98% pure conjugate.
Example 3
[0068] This example demonstrates the use of compounds of the present invention in ESI (Electrospray Ionization) mass spectra.
[0069] Initially, about 20 μL of the reaction solution of Example 1 is diluted to about 180 μL using 5 mM ammonium acetate aqueous solution containing about 0.05% acetic acid. The sample is injected the sample immediately into a Mariner ESI mass spectrometer. Some major instrument settings are: spray tip at about 3.4 kv, nozzle potential at about 200 v, quadrupole temperature at about 150° C. and nozzle temperature at about 150° C. Spectra is collected every 100 seconds. In spectrum for Dye800W-glucosamine complex, the expected molecular peak is observed at 1164 Da. In the spectrum for Dye800CW-PK11195 complex, the expected molecular peak is observed at 1365.9 Da.
Example 4
[0070] This example shows a synthetic pathway yielding a conjugable Ro5-4864 of the present invention, and conjugation to an imaging agent, such as Lanthanide chelate or NIR-dye.
[0071] A conjugable form of compounds similar to Ro5-4864 has been previously reported (see U.S. Pat. No. 5,901,381) and a synthetic procedure in Scheme 3 will be used to synthesize a conjugable form of Ro5-4864. A solution of KOH in methanol will be treated with a solution of 4-chlorophenyl-acetonitrile 1 and 4-chloronitro-benzene 2 in benzene. The mixture will be stirred for 3 hours and then poured to ammonium chloride solution. Compound 3 will then precipitate out. Compound 4 will be produced by stirring compound 3 and dimethyl sulfate for 5 hours, followed by being treated with ethanol, water, iron fillings and hydrochloric acid. See Vejdelek Z, Polivka Z, Protiva M. Synthesis of 7-Chloro-5-(4-Chlorophenyl)-1-Methyl-1,3-Dihydro-1,4-Benzodiazepin-2-One. Collection of Czechoslovak Chemical Communications 1985;50:1064-1069. Compound 4 and semicarbazide, after heated to 210° C., will produce compound 5. Compound 7 will be used as a linker to combine compound 5 and lanthanide chelate/dye800cw. Compound 7 can be synthesized by the reaction between compound 6 and thionyl chloride. Lanthanide chelate (with carboxylic acid group) or dye800cw (a N-hydroxysuccinimide ester) can then react with compound 7 in basic solution to produce a compound in the form of compound 8. The chlorine on the signaling part will react with N—H group in compound 5 to produce the final imaging agent (compound 9). The product can be further chelated by adding lanthanide chloride solution (LnCl 3 , EuCl 3 etc) into product solution with pH 6.5. The synthetic pathway for lanthanide chelate has been reported. See Griffin J M M, Skwierawska A M, Manning H C, Marx J N, Bornhop D J. Simple, high yielding synthesis of trifunctional fluorescent lanthanide chelates. Tetrahedron Letters 2001;42:3823-3825.
Example 5
[0072] This Example shows a scheme for the synthesis of a conjugable form of DAA1106 of the present invention, which cnathen be conjugated to an imaging agent.
[0073] The synthetic pathway for conjugable DAA1106 is shown in Scheme 4. Compound 2 will be obtained by reaction of compound 1 with phenol in DMF. Compound 2 will then be reduced by PtO2 under hydrogen flow in methanol. Compound 3 can react with acetyl chloride in pyridine to produce compound 4 after the reaction refluxes for 2 hours. The hydroxyl group in compound 5 will be substituted by bromide to produce compound 6. One hydroxyl group in compound 6 will be deprotected in DMF by Sodium ethanethiolate to produce compound 7. Compound 4 and 7 will then react in DMF with the presence of sodium hydride. After compound 8 is obtained, the hydroxyl group will be brominated to form compound 9. Conjugable DAA1106 (compound 10) is prepared by treatment of compound 9 with hexane-1,6-diamine. The conjugation position on DAA1106 is determined according to another conjugation that has been done on DAA1106 which did not affect the biological activity of DAA1106. See Zhang M R, Maeda J, Furutsuka K, Yoshida Y, Ogawa M, Suhara T, et al. [F-18]FMDAA1106 and [F-18]FEDAA1106: Two positron-emitter labeled ligands for peripheral benzodiazepine receptor (PBR). Bioorganic & Medicinal Chemistry Letters 2003;13:201-204. The product should be conjugable to lanthanide chelator in water/DMF/dioxane/TEA mixture. The conjugate will be further chelated by adding Lanthanide chloride solution (LnCl 3 , EuCl 3 etc) into pH 6.5 product solution.
Example 6
[0074] This example shows an example of the synthesis, characterization, and preliminary cell study for an embodiment of the present invention, a dye800cw-DAA1106 conjugation, as well as the conjugation of the PBR ligand DAA1106 to a NIR dye, followed by cell uptake.
[0075] In this example, dye800CW (5 mg, 4.3 μmol) and conjugable DAA1106 (5 mg, 10 μmol) is mixed in DMSO (1 mL) in a 10 mL round bottom flask. The solution is stirred under argon flow for 10 hours. The reaction scheme is shown in Scheme 5, below. Product is purified through neutral alumina column using 0.1 M triethyl ammonium acetate in 80/20 acetonitrile/water solution.
[0076] Upon preparing dye800CW-DAA1106, absorption and emission spectra (Table 1) are obtained at room temperature with a Shimadzu 1700 UV-vis spectrophotometer and ISS PCI spectrofluorometer respectively. The same sample (2 μM) is used for taking both UV and fluorescence spectrum. UV spectrum was scanned from 190 nm to 900 nm with sampling rate of 1 nm. Cuvette path length was 1 cm. Fluorescence sample was excited at 797 nm. Spectrum was collected from 700 nm to 900 nm with scan rate 1 nm/second. Slit width was set to 1.5. Photo multiplier tube (PMT) voltage was at 75 watts. Dye800CW-DAA1106 has maximum absorption at 779 nm and fluorescence at 801 nm in methanol.
[0077] Regarding cell uptake, C6 glioma cell lines are a widely used cell line in neurobiological research that has high PBR expression. C6 cells were incubated with 10 μM dye800CW-DAA1106 in culture media for half hour and then rinsed and re-incubated with saline before imaging. FIG. 1 shows white light and fluorescence pictures of dosed and un-dosed cells. Instrument used is Nikon epifluorescence microscope equipped with Ludl Qimaging camera, Nikon S fluor 20×/0.75 objective, mercury lamp and ICG filter set. Picture B shows cell take-up of dye800CW-DAA1106, while un-dosed cell (picture D) does not show any significant fluorescence.
Example 7
[0078] This example shows the synthesis, characterization and preliminary cell study of a lissamine-DAA1106 conjugation. An example of a lissamine dye has a molar extinction coefficient of 88,000 cm −1 M −1 and good quantum efficient of about 95%. It absorbs at 568 nm and emits at 583 nm (in methanol) with a decent stokes shift and thus bright fluorescence.
[0079] Lissamine rhodamine B sulfonyl chloride (4 mg, 6.9 μmol), conjugable DAA1106 (5 mg, 10 μmol) and tri-ethylamine (10 μL) was mixed in dichloromethane (0.8 mL) in a 10 mL round bottom flask. The solution was stirred under argon flow for 3 hours. The reaction scheme is shown in Scheme 6. Product was purified through column chromatography (silica gel) using 19/1 dichloromethane/methanol solution.
[0080] Upon preparing lissamine-DAA1106, absorption and emission spectra (Table 2) was obtained with a Shimadzu 1700 UV-vis spectrophotometer and ISS PTI spectrofluorometer at room temperature. The same sample (2 μM) was used for taking both UV and fluorescence spectrum. UV spectrum was scanned from 190 nm to 900 nm with sampling rate of 1 nm. Cuvette path length was 1 cm. Fluorescence sample was excited at 561 nm. Spectrum was collected from 700 to 900 nm with scan rate 1 nm/second. Slit width was set to 1.5. Photo multiplier tube (PMT) voltage was at 75 watts. Lissamine-DAA1106 has maximum absorption at 561 nm and fluorescence at 579 nm in methanol.
[0081] C6 cells were incubated with 10 μM lissamine-DAA1106 in culture media for half hour and then rinsed and re-incubated with saline before imaging. FIG. 2 shows white light and fluorescence pictures of dosed and un-dosed cells. Instrument used was Nikon epifluorescence microscope equipped with Ludl Qimaging camera, Nikon S fluor 20×/0.75 objective, mercury lamp and Texas red filter set. Picture B shows cell take-up of lissamine-DAA1106 at perinuclear location. This observation was expected since PBR is a mitochondrial protein. Un-dosed cells (picture D) exhibited no fluorescence.
Example 8
[0082] This example shows an example of a synthetic pathway yielding a conjugable form of a SSR180575 compound of the present invention.
[0083] Starting from m-chloroaniline, which was diazotised and coupled with ethyl α-methylacetoacetate, the azo-ester was converted into ethyl pyruvate m-chlorophenylhydrazone 1 (the Japp-Klingeman reaction). Polyphosphoric acid facilitated the conversion to molecule 2. Next, N-methylation with dimethylcarbonate in presence K 2 CO 3 yielded the ester 3 and was treated with hydrazine and converted into hydrazide 4. The ring was closed in the presence of POCl 3 and compound 5 was obtained. N-phenylation with using PhI and CuI (as catalyst) provide compound 6. Mild hydrolysis with dilute KOH in EtOH yield acid 7. To conjugated mono-N-BOC protected N-methyl-1,6-hexanediamine to 7 used BOP. Removal of protecting group with TFA in CH 2 Cl 2 is yields 8.
Example 9
[0084] Example 9 demonstrates specific, in vivo tumor labeling using a method of the present invention. A NIR-PK 11195 deep tissue imaging agent was made as shown in Example 1. Tumor bearing Smad3 gene knockout mice and control animals were injected with 10 nmoles of the imaging agent and imaged about 14 hours following injection. Specific labeling was observed in the abdominal region of tumor animals and clearance in the control animals. This selective uptake is shown in FIG. 3 . A post-imaging autopsy confirmed localization of the imaging agent in the SMAD3 animal.
Example 10
[0085] This Example shows NIR-PK 11195 imaging in connection with neurodegenerative processes in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. Additionally, this Example shows the use of the present invention to monitor the progression of a disease state. A conjugated imaging agent NIR-PK 11195 was made in accordance with Example 1. An EAE induced and control animals were injected with NIR-PK 11195 and imaged. EAE animals demonstrate strong fluorescence along the spinal column indicating activated T cell and macrophage response which signal the onset of the demylenation processes characteristic to EAE. The EAE/treated mouse was treated with a curcumin composition.
[0086] FIG. 3 shows images associated with this example that confirm insignificant uptake of the imaging agent in the control, but indicate full onset of a disease state in the EAE mice. Subsequent imaging shows the progression of the disease after a disease state treatment is administered.
REFERENCES
[0087] Throughout this application, various publications are referenced. All such publications, specifically including the publications listed below, are incorporated herein by reference in their entirety.
1. Manning H C, Goebel, T. S. Thompson, R. C., and Bornhop, D. J. A PBR Targeted Molecular Imaging Agent for Cellular-Scale Bi-modal Imaging. Bioconjugate Chemistry 2003; Bioconjugate Chem 2004, 15, 1488-1495. 2. Broaddus W C, Bennett J P, Jr., Department of Neurosurgery UoVHSCC. Peripheral-type benzodiazepine receptors in human glioblastomas: pharmacologic characterization and photoaffinity labeling of ligand recognition site. Brain research. 1990; 518(1-2):199-208. 3. Zhang M R, Maeda J, Furutsuka K, Yoshida Y, Ogawa M, Suhara T, et al. [F-18]FMDAA1106 and [F-18]FEDAA1106: Two positron-emitter labeled ligands for peripheral benzodiazepine receptor (PBR). Bioorganic & Medicinal Chemistry Letters 2003; 13:201-204. 4. Kozikowski A P, Kotoula M, Ma D, Boujrad N, Tueckmantel W, Papadopoulos V. Synthesis and Biology of a 7-Nitro-2,1,3-benzoxadiazol-4-yl Derivative of 2-Phenylindole-3-acetamide: A Fluorescent Probe for the Peripheral-Type Benzodiazepine Receptor. Journal of Medicinal Chemistry 1997; 40:2435-2439. 5. Starosta-Rubinstein S, Ciliax B, Penney J, McKeever P, Young A. Imaging of a glioma using peripheral benzodiazepine receptor ligands. proceedings of the national academy of sciences of the United States of America 1987; 84:891-5. 6. Black K L, Ikezaki K, Toga A W. Imaging of Brain-Tumors Using Peripheral Benzodiazepine Receptor Ligands. Journal of Neurosurgery 1989; 71 :113-118. 7. Sutter A P, Maaser K, Hèopfner M, Barthel B, Grabowski P, Faiss S, et al. Specific ligands of the peripheral benzodiazepine receptor induce apoptosis and cell cycle arrest in human esophageal cancer cells. International journal of cancer. Journal international du cancer. 2002; 102(4):318-27. 8. Jakubikova J, Duraj J, Hunakova L, Chorvath B, Sedlak J. PK11195, an isoquinoline carboxamide ligand of the mitochondrial benzodiazepine receptor, increased drug uptake and facilitated drug-induced apoptosis in human multidrug-resistant leukemia cells in vitro. Neoplasma 2002; 49:231-236. 9. Okaro A C, Fennell D A, Corbo M, Davidson B R, Cotter FE. Pk11195, a mitochondrial benzodiazepine receptor antagonist, reduces apoptosis threshold in Bcl-X-L and Mcl-1 expressing human cholangiocarcinoma cells. Gut 2002; 51:556-561. 10. Okaro M C, Fennel D A, Corbo M, Cotter F E, Davidson B R, Winslet M C. In vivo reversal of apoptosis resistance by the mitochondrial benzodiazepine receptor antagonist, PK11195 in cholangiocarcinoma cells. Gut 2000; 46:A47-A47. 11. Okaro M C, Fennell D A, Cotter F E, Davidson B R. Pk111195, a mitochondrial benzodiazepine receptor antagonist radiosensitizes bcl-x(L) and mcl-1 expressing cholangiocarcinoma to apoptosis. British Journal of Cancer 2000; 83:22-22. 12. Maaser K, Hèopfner M, Jansen A, Weisinger G, Gavish M, Kozikowski A P, et al. Specific ligands of the peripheral benzodiazepine receptor induce apoptosis and cell cycle arrest in human colorectal cancer cells. British journal of cancer. 2001; 85(11):1771-80. 13. Fennell D A, Corbo M, Pallaska A, Cotter F E. Bcl-2 resistant mitochondrial toxicity mediated by the isoquinoline carboxamide PK11195 involves de novo generation of reactive oxygen species. British Journal of Cancer 2001; 84:1397-1404. 14. Ntziachristos V, Chance B. Probing physiology and molecular function using optical imaging: applications to breast cancer. Breast Cancer Research 2001; 3:41-46. 15. Licha K, Riefke B, Ntziachristos V, Becker A, Chance B, Semmler W. Hydrophilic cyanine dyes as contrast agents for near-infrared tumor imaging: Synthesis, photophysical properties and spectroscopic in vivo characterization. Photochemistry and Photobiology 2000; 72:392-398. 16. Hawrysz D J, Sevick-Muraca E M. Developments toward diagnostic breast cancer imaging using near-infrared optical measurements and fluorescent contrast agents. Neoplasia 2000; 2:388-417. 17. Weissleder R, Mahmood U. Molecular imaging. Radiology 2001; 219:316-333. 18. Gaietta G, Deerinck T J, Adams S R, Bouwer J, Tour O, Laird D W, et al. Multicolor and electron microscopic imaging of connexin trafficking. Science 2002; 296:503-507. 19. Louie A Y, Huber M M, Ahrens E T, Rothbacher U, Moats R, Jacobs R E, et al. In vivo visualization of gene expression using magnetic resonance imaging. Nature Biotechnology 2000; 18:321-325. 20. Wolfe H R, Mendizabal M, Lleong E, Cuthbertson A, Desai V, Pullan S, et al. In vivo imaging of human colon cancer xenografts in immunodeficient mice using a guanylyl cyclase C-specific ligand. Journal of Nuclear Medicine 2002; 43:392-399. 21. Lemieux G A, Yarema K J, Jacobs C L, Bertozzi C R. Exploiting differences in sialoside expression for selective targeting of MRI contrast reagents. Journal of the American Chemical Society 1999; 121:4278-4279. 22. Casellas P, Galiegue S, Basile A S. Peripheral benzodiazepine receptors and mitochondrial function. Neurochemistry International 2002; 40:475-486. 23. Hardwick M, Fertikh D, Culty M, Li H, Vidic B, Papadopoulos V. Peripheral-type benzodiazepine receptor (PBR) in human breast cancer: Correlation of breast cancer cell aggressive phenotype with PBR expression, nuclear localization, and PBR-mediated cell proliferation and nuclear transport of cholesterol. Cancer Research 1999; 59:831-842. 24. Papadopoulos V. Peripheral-Type Benzodiazepine Diazepam Binding Inhibitor Receptor—Biological Role in Steroidogenic Cell-Function. Endocrine Reviews 1993; 14:222-240. 25. Alho H, Varga V, Krueger K E. Expression of Mitochondrial Benzodiazepine Receptor and Its Putative Endogenous Ligand in Cultured Primary Astrocytes and C-6 Cells—Relation to Cell-Growth. Cell Growth & Differentiation 1994; 5:1005-1014. 26. Diorio D, Welner S A, Butterworth R F, Meaney M J, Suranyicadotte B E. Peripheral Benzodiazepine Binding-Sites in Alzheimers-Disease Frontal and Temporal Cortex. Neurobiology of Aging 1991; 12:255-258. 27. Messmer K, Reynolds G P. Increased peripheral benzodiazepine binding sites in the brain of patients with Huntington's disease. Neuroscience Letters 1998; 241:53-56. 28. Vowinckel E, Reutens D, Becher B, Verge G, Evans A, Owens T, et al. PK11195 binding to the peripheral benzodiazepine receptor as a marker of microglia activation in multiple sclerosis and experimental autoimmune encephalomyelitis. Journal of Neuroscience Research 1997; 50:345-353. 29. Benavides J, Cornu P, Dennis T, Dubois A, Hauw J J, Mackenzie E T, et al. Imaging of Human-Brain Lesions with an Omega-3 Site Radioligand. Annals of Neurology 1988; 24:708-712. 30. Cornu P, Benavides J, Scatton B, Hauw J J, Philippon J. Increase in Omega-3 (Peripheral-Type Benzodiazepine) Binding-Site Densities in Different Types of Human Brain-Tumors—a Quantitative Autoradiography Study. Acta Neurochirurgica 1992; 119:146-152. 31. Shavaleev N M, Pope S J A, Bell Z R, Faulkner S, Ward M D. Visible-light sensitisation of near-infrared luminescence from Yb(III), Nd(III) and Er(III) complexes of 3,6-bis(2-pyridyl)tetrazine. Dalton Transactions 2003:808-814. 32. Werts M H V, Verhoeven J W, Hofstraat J W. Efficient visible light sensitisation of water-soluble near-infrared luminescent lanthanide complexes. Journal of the Chemical Society-Perkin Transactions 2 2000:433-439. 33. Werts M H V, Hofstraat J W, Geurts F A J, Verhoeven J W. Fluorescein and eosin as sensitizing chromophores in near-infrared luminescent ytterbium(III), neodymium(III) and erbium(III) chelates. Chemical Physics Letters 1997; 276:196-201. 34. Faulkner S, Pope S J A. Lanthanide-sensitized lanthanide luminescence: Terbium-sensitized ytterbium luminescence in a trinuclear complex. Journal of the American Chemical Society 2003; 125:10526-10527. 35. Bromiley A, Welch A, Chilcott F, Waikar S, McCallum S, Dodd M, et al. Attenuation correction in PET using consistency conditions and a three-dimensional template. Ieee Transactions on Nuclear Science 2001; 48:1371-1377. 36. Couper G W, McAteer D, Wallis R, Welch A, Norton M, Park K G M. Quantification of FDG-PET scans in patients with oesophageal and gastric cancer. A study of 40 patients. British Journal of Surgery 2002; 89:64-64. 37. Couper G W, Wallis F, Welch A, Sharp P F, Park K G M, Cassidy J. The role of FDG-PET in the early detection of response of colorectal liver metastases to chemotherapy. Gut 2002; 50:A107-A107. 38. Dehdashti F, Flanagan F L, Mortimer J E, Katzenellenbogen J A, Welch M J, Siegel B A. Positron emission tomographic assessment of “metabolic flare” to predict response of metastatic breast cancer to antiestrogen therapy. European Journal of Nuclear Medicine 1999; 26:51-56. 39. Oyama N, Kim J, Jones L A, Mercer N M, Engelbach J A, Sharp T L, et al. MicroPET assessment of androgenic control of glucose and acetate uptake in the rat prostate and a prostate cancer tumor model. Nuclear Medicine and Biology 2002; 29:783-790. 40. Oyama N, Miller T R, Dehdashti F, Siegel B A, Fischer K C, Michalski J M, et al. C-11-acetate PET imaging of prostate cancer: Detection of recurrent disease at PSA relapse. Journal of Nuclear Medicine 2003; 44:549-555. 41. Smith I C, Welch A, Chilcott F, Soloviev D, Waikar S, Hutcheon A W, et al. F-18-FDG PET may predict the pathological response of breast cancer to primary chemotherapy. Journal of Nuclear Medicine 1999; 40:137p-137p. 42. Smith I C, Welch A E, Hutcheon A W, Miller I D, Payne S, Chilcott F, et al. Positron emission tomography using [F-18]-fluorodeoxy-D-glucose to predict the pathologic response of breast cancer to primary chemotherapy. Journal of Clinical Oncology 2000; 18:1676-1688. 43. Manning H C, Goebel T, Marx J N, Bornhop D J. Facile, efficient conjugation of a trifunctional lanthanide chelate to a peripheral benzodiazepine receptor ligand. Organic Letters 2002; 4:1075-1078. 44. 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[0132] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the Specification and Example be considered as exemplary only, and not intended to limit the scope and spirit of the invention.
[0133] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as reaction conditions, and so forth used in the Specification and Claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the Specification and Claims are approximations that may vary depending upon the desired properties sought to be determined by the present invention.
[0134] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the experimental or example sections are reported as precisely as possible. Any numerical value, however, inherently contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
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Compounds and methods related to NIR molecular imaging, in-vitro and in-vivo functional imaging, therapy/efficacy monitoring, and cancer and metastatic activity imaging. Compounds and methods demonstrated pertain to the field of peripheral benzodiazepine receptor imaging, metabolic imaging, cellular respiration imaging, cellular proliferation imaging as targeted agents that incorporate signaling agents.
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TECHNICAL FIELD
[0001] The present invention relates to new isolated human antibodies raised against peptides being derivatives of apolipoprotein B, in particular antibodies to be used for immunization therapy for treatment of atherosclerosis, method for their preparation, and method for passive immunization using said antibodies.
[0002] In particular the invention includes:
[0003] The use of any isolated antibody raised against an oxidized form of the peptides listed in table 1, in particular MDA-modified peptides, preferably together with a suitable carrier and adjuvant as an immunotherapy or “anti-atherosclerosis “vaccine” for prevention and treatment of ischemic cardiovascular disease.
BACKGROUND OF THE INVENTION
[0004] The protective effects of humoral immunity are known to be mediated by a family of structurally related glycoproteins called antibodies. Antibodies initiate their biological activity by binding to antigens. Antibody binding to antigens is generally specific for one antigen and the binding is usually of high affinity. Antibodies are produced by B-lymphocytes. Blood contains many different antibodies, each derived from a clone of B-cells and each having a distinct structure and specificity for antigen. Antibodies are present on the surface of B-lymphocytes, in the plasma, in interstitial fluid of the tissues and in secretory fluids such as saliva and mucous on mucosal surfaces.
[0005] All antibodies are similar in their overall structure, accounting for certain similarities in physico-chemical features such as charge and solubility. All antibodies have a common core structure of two identical light chains, each about 24 kilo Daltons, and two identical heavy chains of about 55-70 kilo Daltons each. One light chain is attached to each heavy chain, and the two heavy chains are attached to each other. Both the light and heavy chains contain a series of repeating homologous units, each of about 110 amino acid residues in length which fold independently in a common globular motif, called an immunoglobulin (Ig) domain. The region of an antibody formed by the association of the two heavy chains is hydrophobic. Antibodies, and especially monoclonal antibodies, are known to cleave at the site where the light chain attaches to the heavy chain when they are subjected to adverse physical or chemical conditions. Because antibodies contain numerous cysteine residues, they have many cysteine-cysteine disulfide bonds. All Ig domains contain two layers of beta-pleated sheets with three or four strands of anti-parallel polypeptide chains.
[0006] Despite their overall similarity, antibody molecules can be divided into a small number of distinct classes and subclasses based on physicochemical characteristics such as size, charge and solubility, and on their behavior in binding to antigens. In humans, the classes of antibody molecules are: IgA, IgD, IgE, IgG and IgM. Members of each class are said to be of the same isotype. IgA and IgG isotypes are further subdivided into subtypes called IgA1, IgA2 and IgG1, IgG2, IgG3 and IgG4. The heavy chains of all antibodies in an isotype share extensive regions of amino acid sequence identity, but differ from antibodies belonging to other isotypes or subtypes. Heavy chains are designated by the letters of the Greek alphabet corresponding to the overall isotype of the antibody, e.g., IgA contains alpha., IgD contains delta., IgE contains epsilon., IgG contains .gamma., and IgM contains .mu. heavy chains. IgG, IgE and IgD circulate as monomers, whereas secreted forms of IgA and IgM are dimers or pentamers, respectively, stabilized by the J chain. Some IgA molecules exist as monomers or trimers.
[0007] There are between 10 8 and 10 10 structurally different antibody molecules in every individual, each with a unique amino acid sequence in their antigen combining sites. Sequence diversity in antibodies is predominantly found in three short stretches within the amino terminal domains of the heavy and light chains called variable (V) regions, to distinguish them from the more conserved constant (C) regions.
[0008] Atherosclerosis is a chronic disease that causes a thickening of the innermost layer (the intima) of large and medium-sized arteries. It decreases blood flow and may cause ischemia and tissue destruction in organs supplied by the affected vessel. Atherosclerosis is the major cause of cardiovascular disease including myocardial infarction, stroke and peripheral artery disease. It is the major cause of death in the western world and is predicted to become the leading cause of death in the entire world within two decades.
[0009] The disease is initiated by accumulation of lipoproteins, primarily low-density lipoprotein (LDL), in the extracellular matrix of the vessel. These LDL particles aggregate and undergo oxidative modification. Oxidized LDL is toxic and cause vascular injury. Atherosclerosis represents in many respects a response to this injury including inflammation and fibrosis.
[0010] In 1989 Palinski and coworkers identified circulating autoantibodies against oxidized LDL in humans. This observation suggested that atherosclerosis may be an autoimmune disease caused by immune reactions against oxidized lipoproteins. At this time several laboratories began searching for associations between antibody titers against oxidized LDL and cardiovascular disease. However, the picture that emerged from these studies was far from clear. Antibodies existed against a large number of different epitopes in oxidized LDL, but the structure of these epitopes was unknown. The term “oxidized LDL antibodies” thus referred to an unknown mixture of different antibodies rather than to one specific antibody. T cell-independent IgM antibodies were more frequent than T-cell dependent IgG antibodies.
[0011] Antibodies against oxidized LDL were present in both patients with cardiovascular disease and in healthy controls. Although some early studies reported associations between oxidized LDL antibody titers and cardiovascular disease, others were unable to find such associations. A major weakness of these studies was that the ELISA tests used to determine antibody titers used oxidized LDL particles as ligand. LDL composition is different in different individuals, the degree of oxidative modification is difficult both to control and assess and levels of antibodies against the different epitopes in the oxidized LDL particles can not be determined. To some extent, due to the technical problems it has been difficult to evaluate the role of antibody responses against oxidized LDL using the techniques available so far, but, however, it is not possible to create well defined and reproducable components of a vaccine if one should use intact oxidized LDL particles.
[0012] Another way to investigate the possibility that autoimmune reactions against oxidized LDL in the vascular wall play a key role in the development of atherosclerosis is to immunize animals against its own oxidized LDL. The idea behind this approach is that if autoimmune reactions against oxidized LDL are reinforced using classical immunization techniques this would result in increased vascular inflammation and progressive of atherosclerosis. To test this hypothesis rabbits were immunized with homologous oxidized LDL and then induced atherosclerosis by feeding the animals a high-cholesterol diet for 3 months.
[0013] However, in contrast to the original hypothesis immunization with oxidized LDL had a protective effect reducing atherosclerosis with about 50%. Similar results were also obtained in a subsequent study in which the high-cholesterol diet was combined with vascular balloon-injury to produce a more aggressive plaque development. In parallel with our studies several other laboratories reported similar observations. Taken together the available data clearly demonstrates that there exist immune reactions that protect against the development of atherosclerosis and that these involves autoimmunity against oxidized LDL.
[0014] These observations also suggest the possibility of developing an immune therapy or “vaccine” for treatment of atherosclerosis-based cardiovascular disease in man. One approach to do this would be to immunize an individual with his own LDL after it has been oxidized by exposure to for example copper. However, this approach is complicated by the fact that it is not known which structure in oxidized LDL that is responsible for inducing the protective immunity and if oxidized LDL also may contain epitopes that may give rise to adverse immune reactions.
[0015] The identification of epitopes in oxidized LDL is important for several aspects:
[0016] First, one or several of these epitopes are likely to be responsible for activating the anti-atherogenic immune response observed in animals immunized with oxidized LDL. Peptides containing these epitopes may therefore represent a possibility for development of an immune therapy or “atherosclerosis vaccine” in man. Further, they can be used for therapeutic treatment of atheroschlerosis developed in man.
[0017] Secondly, peptides containing the identified epitopes can be used to develop ELISAs able to detect antibodies against specific structure in oxidized LDL. Such ELISAs would be more precise and reliable than ones presently available using oxidized LDL particles as antigen. It would also allow the analyses of immune responses against different epitopes in oxidized LDL associated with cardiovascular disease.
[0018] U.S. Pat. No. 5,972,890 relates to a use of peptides for diagnosing atherosclerosis. The technique presented in said U.S. patent is as a principle a form of radiophysical diagnosis. A peptide sequence is radioactively labelled and is injected into the bloodstream. If this peptide sequence should be identical with sequences present in apolipoprotein B it will bind to the tissue where there are receptors present for apolipoprotein B. In vessels this is above all atherosclerotic plaque. The concentration of radioactivity in the wall of the vessel can then be determined e.g., by means of a gamma camera. The technique is thus a radiophysical diagnostic method based on that radioactively labelled peptide sequences will bound to their normal tissue receptors present in atherosclerotic plaque and are detected using an external radioactivity analysis. It is a direct analysis method to identify atherosclerotic plaque. It requires that the patient be given radioactive compounds.
[0019] Published studies (Palinski et al., 1995, and George et al., 1998) have shown that immunisation against oxidised LDL reduces the development of atherosclerosis. This would indicate that immuno reactions against oxidised LDL in general have a protecting effect. The results given herein have, however, surprisingly shown that this is not always the case. E.g., immunisation using a mixture of peptides #10, 45, 154, 199, and 240 gave rise to an increase of the development of atherosclerosis. Immunisation using other peptide sequences, e.g., peptide sequences #1, and 30 to 34 lacks total effect on the development of atherosclerosis. The results are surprising because they provide basis for the fact that immuno reactions against oxidised LDL, can protect against the development, contribute to the development of atherosclerosis, and be without any effect at all depending on which structures in oxidised LDL they are directed to. These findings make it possible to develop immunisation methods, which isolate the activation of protecting immuno reactions. Further, they show that immunisation using intact oxidised LDL could have a detrimental effect if the particles used contain a high level of structures that give rise to atherogenic immuno reactions.
[0020] The technique of the present invention is based on quite different principles and methods. In accordance with claim 1 the invention relates to antibodies raised against oxidized fragments of apolipoprotein B, which antibodies are used for immunisation against cardiovascular disease.
[0021] As an alternative to active immunisation, using the identified peptides described above, passive immunisation with pre-made antibodies directed to the same peptides is an attractive possibility. Such antibodies may be given desired properties concerning e.g. specificity and crossreactivity, isotype, affinity and plasma halflife. The possibility to develop antibodies with predetermined properties became apparent already with the advent of the monoclonal antibody technology (Milstein and Köhler, 1975 Nature, 256:495-7). This technology used murine hybridoma cells producing large amounts of identical, but murine, antibodies. In fact, a large number of preclinical, and also clinical trials were started using murine monoclonal antibodies for treatment of e.g. cancers. However, due to the fact that the antibodies were of non-human origin the immune system of the patients recognised them as foreign and developed antibodies to them. As a consequence the efficacy and plasma half-lives of the murine antibodies were decreased, and often side effects from allergic reactions, caused by the foreign antibody, prevented successful treatment.
[0022] To solve these problems several approaches to reduce the murine component of the specific and potentially therapeutic antibody were taken. The first approach comprised technology to make so called chimearic antibodies where the murine variable domains of the antibody were transferred to human constant regions resulting in an antibody that was mainly human (Neuberger et al. 1985, Nature 314:268-70). A further refinement of this approach was to develop humanised antibodies where the regions of the murine antibody that contacted the antigen, the so called Complementarity Determining Regions (CDRs) were transferred to a human antibody framework. Such antibodies are almost completely human and seldom cause any harmful antibody responses when administered to patients. Several chimearic or humanised antibodies have been registered as therapeutic drugs and are now widely used within various indications (Borrebaeck and Carlsson, 2001, Curr. Opin. Pharmacol. 1:404-408).
[0023] Today also completely human antibodies may be produced using recombinant technologies. Typically large libraries comprising billions of different antibodies are used. In contrast to the previous technologies employing chimearisation or humanisation of e.g. murine antibodies this technology does not rely on immunisation of animals to generate the specific antibody. In stead the recombinant libraries comprise a huge number of pre-made antibody variants why it is likely that the library will have at least one antibody specific for any antigen. Thus, using such libraries the problem becomes the one to find the specific binder already existing in the library, and not to generate it through immunisations. In order to find the good binder in a library in an efficient manner, various systems where phenotype i.e. the antibody or antibody fragment is linked to its genotype i.e. the encoding gene have been devised. The most commonly used such system is the so called phage display system where antibody fragments are expressed, displayed, as fusions with phage coat proteins on the surface of filamentous phage particles, while simultaneously carrying the genetic information encoding the displayed molecule (McCafferty et al., 1990, Nature 348:552-554). Phage displaying antibody fragments specific for a particular antigen may be selected through binding to the antigen in question. Isolated phage may then be amplified and the gene encoding the selected antibody variable domains may optionally be transferred to other antibody formats as e.g. full length immunoglobulin and expressed in high amounts using appropriate vectors and host cells well known in the art.
[0024] The format of displayed antibody specificities on phage particles may differ. The most commonly used formats are Fab (Griffiths et al., 1994. EMBO J. 13:3245-3260) and single chain (scFv) (Hoogenboom et al., 1992, J Mol Biol. 227:381-388) both comprising the variable antigen binding domains of antibodies. The single chain format is composed of a variable heavy domain (VH) linked to a variable light domain (VL) via a flexible linker (U.S. Pat. No. 4,946,778). Before use as analytical reagents, or therapeutic agents, the displayed antibody specificity is transferred to a soluble format e.g. Fab or scFv and analysed as such. In later steps the antibody fragment identified to have desireable characteristics may be transferred into yet other formats such as full length antibodies.
[0025] Recently a novel technology for generation of variability in antibody libraries was presented (WO98/32845, Soderlind et al., 2000, Nature BioTechnol. 18:852-856).
[0026] Antibody fragments derived from this library all have the same framework regions and only differ in their CDRs. Since the framework regions are of germline sequence the immunogenicity of antibodies derived from the library, or similar libraies produced using the same technology, are expected to be particularly low (Soderlind et al., 2000, Nature BioTechnol. 18:852-856). This property is expected to be of great value for therapeutic antibodies reducing the risk for the patient to form antibodies to the administered antibody thereby reducing risks for allergic reactions, the occurrence of blocking antibodies, and allowing a long plasma half-life of the antibody. Several antibodies derived from recombinant libraries have now reached into the clinic and are expected to provide therapeutic drugs in the near future.
[0027] Thus, when met with the challenge to develop therapeutic antibodies to be used in humans the art teaches away from the earlier hybridoma technology and towards use of modern recombinant library technology (Soderlind et al., 2001, Comb. Chem. & High Throughput Screen. 4:409-416). It was realised that the peptides identified (PCT/SE02/00679), and being a integral part of this invention, could be used as antigens for generation of fully human antibodies with predetermined properties. In contrast to earlier art (U.S. Pat. No. 6,225,070) the antigenic structures i.e. the peptides used in the present invention were identified as being particularly relevant as target sequences for therapeutic antibodies (PCT/SE02/00679). Also, in the present invention the antibodies are derived from antibody libraries omitting the need for immunisation of lipoprotein deficient mice to raise murine antibodies (U.S. Pat. No. 6,225,070). Moreover, the resulting antibodies are fully human and are not expected to generate any undesired immunological reaction when administered into patients.
[0028] The peptides used, and previously identified (PCT/SE02/00679) are the following:
TABLE 1 A. High IgG, MDA-difference P 11. FLDTVYGNCSTHFTVKTRKG P 25. PQCSTHILQWLKRVHANPLL P 74. VISIPRLQAEARSEILAHWS B. High IgM, no MDA-difference P 40. KLVKEALKESQLPTVMDFRK P 68. LKFVTQAEGAKQTEATMTFK P 94. DGSLRHKFLDSNIKFSHVEK P 99. KGTYGLSCQRDPNTGRLNGE P 100. RLNGESNLRFNSSYLQGTNQ P 102. SLTSTSDLQSGIIKNTASLK P 103. TASLKYENYELTLKSDTNGK P 105. DMTFSKQNALLRSEYQADYE P 177. MKVKIIRTIDQMQNSELQWP C. High IgG, no MDA difference P 143. IALDDAKINFNEKLSQLQTY P 210. KTTKQSFDLSVKAQYKKNKH D. NHS/AHP, IgG-ak > 2, MDA-difference P 1. EEEMLENVSLVCPKDATRFK P 129. GSTSHHLVSRKSISAALEHK P 148. IENIDFNKSGSSTASWIQNV P 162. IREVTQRLNGEIQALELPQK P 252. EVDVLTKYSQPEDSLIPFFE E. NHS/AHP, IgM-ak > 2, MDA-difference P 301. HTFLIYITELLKKLQSTTVM P 30. LLDIANYLMEQIQDDCTGDE P 31. CTGDEDYTYKIKRVIGNMGQ P 32. GNMGQTMEQLTPELKSSILK P 33. SSILKCVQSTKPSLMIQKAA P 34. IQKAAIQALRKMEPKDKDQE P 100. RLNGESNLRFNSSYLQGTNQ P 107. SLNSHGLELNADILGTDKIN P 149. WIQNVDTKYQIRIQIQEKLQ P 169. TYISDWWTLAAKNLTDFAEQ P 236. EATLQRIYSLWEHSTKNHLQ F. NHS/AHP, IgG-ak < 0.5, no MDA-difference P 10. ALLVPPETEEAKQVLFLDTV P 45. IEIGLEGKGFEPTLEALFGK P 111. SGASMKLTTNGRFREHNAKF P 154. NLIGDFEVAEKINAFRAKVH P 199. GHSVLTAKGMALFGEGKAEF P 222. FKSSVITLNTNAELFNQSDI P 240. FPDLGQEVALNANTKNQKIR or an active site of one or more of these peptides.
[0029] In Table 1 above, the following is due:
[0030] (A) Fragments that produce high levels of IgG antibodies to MDA-modified peptides (n=3),
[0031] (B) Fragments that produce high levels of IgM antibodies, but no difference between native and MDA-modified peptides (n=9),
[0032] (C) Fragments that produce high levels of IgG antibodies, but no difference between native and MDA-modified peptides (n=2),
[0033] (D) Fragments that produce high levels of IgG antibodies to MDA-modified peptides and at least twice as much antibodies in the NHP-pool as compared to the AHP-pool (n=5),
[0034] (E) Fragments that produce high levels of IgM antibodies to MDA-modified peptides and at least twice as much antibodies in the NHP-pool as compared to the AHP-pool (n=11), and
[0035] (F) Fragments that produce high levels of IgG antibodies, but no difference between intact and MDA-modified peptides but at least twice as much antibodies in the AHP-pool as compared to the NHP-pool (n=7).
SUMMARY OF THE INVENTION
[0036] The present invention relates to the use of at least one recombinant human antibody or an antibody fragment thereof directed towards at least one oxidized fragment of apolipoprotein B in the manufacture of a pharmaceutical composition for therapeutical or prophylactical treatment of atherosclerosis by means of passive immunization.
[0037] Further the invention relates to the recombinant preparation of such antibodies, as well as the invention relates to method for passive immunization using such antibodies raised using an oxidized apolipoprotein B fragement, as antigen, in particular a fragemnt as identified above.
[0038] The present invention utilises an isolated antibody fragment library to generate specific human antibody fragments against oxidized, in particular MDA modified peptides derived from Apo B100. Identified antibody fragments with desired characteristics may then rebuilt into full length human immunoglobulin to be used for therapeutic purposes.
BRIEF DESCRIPTION OF THE DRAWINGS
[0039] FIGS. 1A-1C are ELISA results from Screen II;
[0040] FIGS. 2A-2F are graphs of dose response for ELISAs;
[0041] FIG. 3 are the DNA sequences of various regions;
[0042] FIGS. 4A and 4B are light and heavy-chain vectors;
[0043] FIG. 5 is a graph of ELISA results;
[0044] FIG. 6 is a graph of Oil Red O Stained area in aortas;
[0045] FIG. 7 is a graph of Oil Red O stained area in aortas versus antibody product;
[0046] FIGS. 8 a and 8 b are graphs of LDL uptake; and
[0047] FIG. 9 are graphs of the Ratio MDA/na LDL and ApoB
DETAILED DESCRIPTION OF THE INVENTION
[0048] Below will follow a detailed description of the invention examplified by, but not limited to, human antibodies derived from an isolated antibody fragment library and directed towards two MDA modified peptides from ApoB 100.
EXAMPLE 1
[0049] Selection of scFv Against MDA Modified Peptides IEIGL EGKGF EPTLE ALFGK (P45. Table 1) and KTTKQ SFDLS VKAQY KKNKH (P210. Table 1).
[0050] The target antigens were chemically modified to carry Malone-di-aldehyde (MDA) groups on lysines and histidines. The modified peptides were denoted IEI (P45) and KTT (P210).
[0051] Selections were performed using BioInvent's n-CoDeR™ scFv library for which the principle of construction and production have been described in Soderlind et al. 2000, Nature BioTechnology. 18, 852-856. Briefly, CDRs are isolated from human immunoglobulin genes and are shuffled into a fixed framework. Thus variability in the resulting immunoglobulin variable regions is a consequence of recombination of all six CDRs into the fixed framework. The framework regions are all germline and are identical in all antibodies. Thus variability is restricted to the CDRs which are all natural and of human origin. The library contains approximately 2×10 10 independent clones and a 2000 fold excess of clones were used as input for each selection. Selections were performed in three rounds. In selection round 1, Immunotubes (NUNC maxisorb 444202) were coated with 1.2 ml of 20 μg/ml MDA-modified target peptides in PBS (137 mM NaCl, 2.7 mM KCl, 4.3 mM Na 2 HPO 4 , 1.4 mM KH 2 PO 4 ) with end over end agitation at +4° C. over night. The tubes were then blocked with TPBSB5% (5 % BSA, 0.05% Tween 20, 0.02 % sodium Azide in PBS) for 30 minutes and washed twice with TPBSB3% (3 % BSA, 0.05% Tween 20, 0.02 % sodium Azide in PBS) before use. Each target tube was then incubated with approximately 2×10 13 CFU phages from the n-CodeR™ library in 1.8 ml TPBSB3% for 2 h at room temperature, using end over end agitation. The tubes were then washed with 15×3 ml TPBSB3% and 2×1 ml PBS before the bound phages were eluted with 1 ml/tube of 2 mg/ml trypsin (Roche, 109819) for 30 minutes at room temperature. This procedure takes advantage of a specific trypsin site in the scFv-fusion protein to release the phage from the target. The reaction was stopped by the addition of 100 μl of Aprotein (0.2 mg/ml, Roche, cat.236624), and the immunotubes were washed with 300 μl PBS, giving a final volume of 1.4 ml.
[0052] For amplification of the selected phage E. Coli HB101F′ cells were grown exponentially in 10 ml of LB medium (Merck, cat. 1.10285) to OD 600 =0.5 and infected with the selected and eluted phage principally as described (Soderlind et al., 2000, Nature BioTechnol. 18, 852-856. The resulting phage supernatant was then precipitated by addition of ¼volume of 20% PEG 6000 in 2.5 M NaCl and incubated for 5 h at +4° C. The phages were then pelleted by centrifugation for 30 minutes, 13000×g, re-suspended in 500 μl PBS and used in selection round 2.
[0053] The amplified phagestock was used in selection round 2 in a final volume of 1.5 ml of 5 % BSA, 0.05% Tween 20, 0.02 % sodium Azide in PBS. Peptide without MDA modification (4×10 −7 M) was also included for competition against binders to MDA-unmodified target peptide. The mixture was incubated in immunotubes prepared with antigen as described above, except that the tubes were blocked with 1% Casein instead of TPBSB3%. The incubations and washing of the immunotubes were as described for selection 1. Bound phages were then eluted for 30 minutes using 600 μl of 100 mM Tris-Glycine buffer, pH 2.2. The tubes were washed with additional 200 μl glycin buffer and the eluates were pooled and then neutralised with 96 μl of 1 M Tris-HCl, pH 8.0. The samples were re-natured for 1 h at room temperature and used for selection round 3.
[0054] For selection round 3, BSA, Tween 20 and Sodium Azide were added to the renaturated phage pool to a final concentration of 3 %, 0.05% and 0.02%, respectively. Competitor peptides, MDA modified unrelated peptides as well as native target peptides without modification were added to a concentration of 1×10 −7 M. The phage mixtures (1100 μl) were added to immunotubes coated with target antigen as described in selection 1 and incubated over night at 4° C. with agitation. The tubes were then washed with 3×3 ml TPBSB 3%, 5×3 ml PBS and eventually bound phages were eluted using trypsin as described in selection round 1 above. Each eluate was infected to 10 ml of logarithmically growing HB101F′ in LB containing 100 μg/ml ampicillin, 15 μg/ml tetracycline, 0.1% glucose, and grown over night at 30° C., 200 rpm in a shaker incubator.
[0055] The over night cultures were used for mini scale preparation of plasmid DNA, using Biorad mini prepp Kit (Cat. 732 6100). To remove the phage gene III part from the expression vector, 0.25 μg of the plasmid DNA was cut for 2 h at 37° C. using 2.5 U Eag-1 (New England Biolabs, cat. R050) in the buffer recommended by the supplier. The samples were then heat inactivated for 20 minutes at 65° C. and ligated over night at 16° C. using 1 U T4 DNA ligase in 30 μl of 1×ligase buffer (Gibco/BRL). This procedure will join two Eag-1 sites situated on opposite sides of the phage gene III fragment, thus creating a free scFv displaying a terminal 6×his tag. After ligation the material was digested for 2 h at 37° C. in a solution containing 30 ul ligation mix, 3.6 μl 10 x REACT3 stock, 0.4 μl 1 M NaCl, 5 μl H 2 O 2 , in order to destroy clones in which the phage gene III segment had been religated. Twenty (20) ng of the final product were transformed into chemical competent Top10F′ and spread on 500 cm 2 Q-tray LA-plates (100 μg/ml Amp, 1% glucose), to enable the picking of single colonies for further screening.
[0056] Screening of the n-CoDeR™ scFv Library for Specific Antibody Fragments Binding t0 MDA Modified Peptides from Apolipoprotein B-100
[0057] In order to identify scFv that could discriminate between MDA modified IEI (P45) peptide and native IEI and between MDA modified KTT (P210) and native KTT respectively screenings were performed on bacterial supernatants from selected scFv expressing clones.
[0058] Colony picking of single clones, expression of scFv and screening number 1 was performed on BioInvent's automatic system according to standard methods. 1088 and 831 single clones selected against the MDA modified IEI and KTT peptides respectively were picked and cultured and expressed in micro titre plates in 100 μl LB containing 100 μg ampicillin/ml.
[0059] For screening number 1 white Assay plates (Greiner 655074) were coated with 54 pmol peptide/well in coating buffer (0.1 M Sodium carbonate, pH 9.5), either with MDA modified peptide which served as positive target or with corresponding unmodified peptide which served as non target. In the ELISA the expressed scFv were detected through a myc-tag situated C-terminal to the scFv using 1 μg/ml of anti-c-myc monoclonal (9E10 Roche 1667 149) in wash buffer. As a secondary antibody Goat-anti-mouse alkaline phosphatase conjugate (Applied Biosystems Cat # AC32ML) was used at 25000 fold dilution. For luminescence detection CDP-Star Ready to use with Emerald II Tropix (Applied Biosystems Cat # MS100RY) were used according to suppliers recommendation.
[0060] ScFv clones that bound MDA modified peptide but not native peptide were re expressed as described above and to screening another time in a luminescent ELISA (Table 2 and FIG. 1 ). Tests were run both against directly coated peptides (108 pmol/well coated with PBS) and the more physiological target, LDL particles (1 μg/well coated in PBS +1 mM EDTA) containing the ApoB-100 protein with and without MDA modification were used as targets. Positive clones were those that bound oxidised LDL and MDA modified peptide but not native LDL or peptide. The ELISA was performed as above except that the anti-His antibody (MaBO50 RαD) was used as the detection antibody. Twelve IEI clones and 2 KTT clones were found to give more than three fold higher luminescence signal at 700 nm for the MDA modified form than for the native form both for the peptide and LDL.
[0061] The identified clones were further tested through titration against a fixed amount (1 μg/well) of MDA LDL and native LDL in order to evaluate the dose response of the scFv ( FIG. 2 ).
TABLE 2 Screening results. The number of clones tested in each screening step for each target. The scored hits in percent are shown within brackets. Target IEI KTT Screening Tested Clones 1088 831 number 1 Scored Hits 64 33 (%) (5.9%) (4.0%) Screening Tested Clones 64 33 number 2 Scored Hits 12 2 (%) (1.1%) (0.2%) Dose Tested Clones 12 2 response Scored Hits 8 2 (%) (0.7%) (0.2%)
[0062] The sequences of the chosen scFv clones were determined in order to find unique clones. Bacterial PCR was performed with the Boeringer Mannheim Expand kit using primers (5′-CCC AGT CAC GAC GTT GTA AAA CG-3′) and (5′-GAA ACA GCT ATG AAA TAC CTA TTG C-3′) and a GeneAmp PCR system 9700 (PE Applied system) using the temperature cycling program 94° C. 5 min, 30 cycles of 94° C. 30s, 52° C. for 30s and 68° C. for 2min and finally 5 min at 68 min. The sequencing reaction was performed with the bacterial PCR product (five fold diluted) as template, using Big Dye Terminator mix from PE Applied Biosystems and the GeneAmp PCR system 9700 (PE Applied system) and the temperature cycling program 25 cycles of 96° C. 10s, 50° C. for 5s and 60° C. for 4 min. The extension products were purified according to the supplier's instructions and the separation and detection of extension products was done by using a 3100 Genetic analyser (PE Applied Biosystems). The sequences were analysed by the in house computer program. From the sequence information homologous clones and clones with inappropriate restriction sites were excluded, leaving six clones for IgG conversion. The DNA sequence of the variable heavy (VH) and variable light (VL) domains of the finally selected clones are shown in FIG. 3 .
EXAMPLE 2
Transfer of genes Encoding the Variable Parts of Selected scFv to Full Length Human IgG1 Vestors.
[0063] Bacteria containing scFv clones to be converted to Ig-format were grown over night in LB supplemented with 100 μg/ml ampicillin. Plasmid DNA was prepared from over night cultures using the Quantum Prep, plasmid miniprep kit from Biorad (# 732-6100). The DNA concentration was estimated by measuring absorbance at 260nm, and the DNA was diluted to a concentration of 2 ng/μl. VH and VL from the different scFv-plasmids were PCR amplified in order to supply these segments with restriction sites compatible with the expression vectors (see below). 5′ primers contain a BsmI and 3′ primers contain a BsiWI restriction enzyme cleavage site (shown in italics). 3′ primers also contained a splice donor site (shown in bold).
[0064] Primers for amplification of VH-segments:
(SEQ. ID. NO: 13) 5′VH: 5′-GGT GTGCATTC CGAGGTGCAGCTGTTGGAG (SEQ. ID. NO: 14) 3′VH: 5′-GA CGTACG ACTCACCT GAGCTCACGGTGACCAG
[0065] Primers for amplification of VL-segments:
(SEQ. ID. NO: 15) 5′VL: 5′-GGT GTGCATTC CCAGTCTGTGCTGACTCAG (SEQ. ID. NO: 16) 3′VL: 5′-GA CGTACG TTCT ACTCACCT AGGACCGTCAGCTT
[0066] PCR was conducted in a total volume of 50 μl, containing 10ng template DNA, 0.4 μM 5′ primer, 0.4 μM 3′ primer and 0.6 mM dNTP (Roche, #1 969 064). The polymerase used was Expand long template PCR system (Roche # 1 759 060), 3.5 u per reaction, together with each of the supplied buffers in 3 separate reactions. Each PCR amplification cycle consisted of a denaturing step at 94° C. for 30 seconds, an annealing step at 55° C. for 30 seconds, and an elongating step at 68° C. for 1.5 minutes. This amplification cycle was repeated 25 times. Each reaction began with a single denaturing step at 94° C. for 2 minutes and ended with a single elongating step at 68° C. for 10 minutes. The existence of PCR product was checked by agarose gel electrophoresis, and reactions containing the same amplified material (from reactions with different buffers) were pooled. The PCR amplification products were subsequently purified by spin column chromatography using S400-HR columns (Amersham-Pharmacia Biotech # 27-5240-01).
[0067] Four (4) μl of from each pool of PCR products were used for TOPO TA cloning (pCR 2.1 TOPO, InVitrogen #K4550-01) according to the manufacturers recommendations. Bacterial colonies containing plasmids with inserts were grown over night in LB supplemented with 100 μg/ml ampicillin and 20 μg/ml kanamycin. Plasmid DNA was prepared from over night cultures using the Quantum Prep, plasmid miniprep kit from Biorad (# 732-6100). Plasmid preparations were purified by spin column chromatography using S400-HR columns (Amersham-Pharmacia Biotech # 27-5240-01). Three plasmids from each individual VH and VL cloning were subjected to sequence analysis using BigDye Cycle Sequencing (Perkin Elmer Applied Biosystem, # 4303150). The cycle sequencing program consisted of a denaturing step at 96° C. for 10 seconds, an annealing step at 50° C. for 15 seconds, and an elongating step at 60° C. for 4 minutes. This cycle was repeated 25 times. Each reaction began with a single denaturing step at 94° C. for 1 minute. The reactions were performed in a volume of 10 μl consisting of 1 μM primer (5′-CAGGAAACAGCTATGAC), 3 μl plasmid DNA and 4 μl Big Dye reaction mix. The reactions were precipitated according to the manufacturers recommendations, and samples were run on a ABI PRISM 3100 Genetic Analyzer. Sequences were compared to the original scFv sequence using the alignment function of the OMIGA sequence analysis software (Oxford Molecular Ltd).
[0068] Plasmids containing VH and VL segments without mutations were restriction enzyme digested. To disrupt the pCR 2.1 TOPO vector, plasmids were initially digested with DraI (Roche # 1 417 983) at 37° C. for 2 hours. Digestions were heat inactivated at 70° C. for 20 minutes and purified by spin column chromatography using S400-HR columns (Amersham-Pharmacia Biotech # 27-5240-01). The purified DraI digestions were subsequently digested with BsmI (Roche # 1 292 307) and BsiWI (Roche # 1 388 959) at 55° C. over night. Digestions were purified using phenol extraction and precipitation. The precipitated DNA was dissolved in 10 μl H 2 O and used for ligation.
[0069] The expression vectors were obtained from Lars Norderhaug (J. Immunol. Meth. 204 (1997) 77-87). After some modifications, the vectors ( FIG. 4 ) contain a CMV promoter, an Ig-leader peptide, a cloning linker containing BsmI and BsiWI restriction sites for cloning of VH/VL, genomic constant regions of IgG1(heavy chain (HC) vector) or lambda (light chain (LC) vector), neomycin (HC vector) or methotrexate (LC vector) resistance genes for selection in eukaryotic cells, SV40 and ColEI origins of replication and ampicillin (HC vector) or kanamycin (LC vector) resistance genes for selection in bacteria.
[0070] The HC and LC vectors were digested with BsmI and BsiWI, phosphatase treated and purified using phenol extraction and precipitation. Ligation were set up at 16° C. over night in a volume of 10 μl, containing 100 ng digested vector, 2 μl digested VH/VL-pCR 2.1 TOPO vector (see above), 1 U T4 DNA ligase (Life Technologies, # 15224-025) and the supplied buffer. 2 μl of the ligation mixture were subsequently transformed into 50 μl chemocompetent top10F′ bacteria, and plated on selective (100 μg/ml ampicillin or 20 μg/ml kanamycin) agar plates.
[0071] Colonies containing HC/LC plasmids with VH/VL inserts were identified by colony PCR:
Forward primer: 5′-ATGGGTGACAATGACATC Reverse primer: 5′-AAGCTTGCTAGCGTACG
[0072] PCR was conducted in a total volume of 20 μl, containing bacterias, 0.5 μM forward primer, 0.5 μM reverse primer and 0.5 mM dNTP (Roche, #1 969 064). The polymerase used was Expand long template PCR system (Roche # 1 759 060), 0.7 U per reaction, together with the supplied buffer #3. Each PCR amplification cycle consisted of a denaturing step at 94° C. for 30 seconds, an annealing step at 52° C. for 30 seconds, and an elongating step at 68° C. for 1.5 minutes. This amplification cycle was repeated 30 times. Each reaction began with a single denaturing step at 94° C. for 2 minutes and ended with a single elongating step at 68° C. for 5 minutes. The existence of PCR product was checked by agarose gel electrophoresis. Colonies containing HC/LC plasmids with VH/VL inserts were grown over night in LB supplemented with 100 μg/ml ampicillin or 20 μg/ml kanamycin. Plasmid DNA was prepared from over night cultures using the Quantum Prep, plasmid miniprep kit from Biorad (# 732-6100). Plasmid preparations were purified by spin column chromatography using S400-HR columns (Amersham-Pharmacia Biotech # 27-5240-01). To confirm the integrity of the DNA sequence, three plasmids from each individual VH and VL were subjected to sequence analysis using BigDye Cycle Sequencing (Perkin Elmer Applied Biosystem, # 4303150). The cycle sequencing program consisted of a denaturing step at 96° C. for 10 seconds, an annealing step at 50° C. for 15 seconds, and an elongating step at 60° C. for 4 minutes. This cycle was repeated 25 times. Each reaction began with a single denaturing step at 94° C. for 1 minute. The reactions were performed in a volume of 10 μl consisting of 1 μM primer (5′-AGACCCAAGCTAGCTTGGTAC), 3 μl plasmid DNA and 4 μl Big Dye reaction mix. The reactions were precipitated according to the manufacturers recommendations, and samples were run on a ABI PRISM 3100 Genetic Analyzer. Sequences were analysed using the OMIGA sequence analysis software (Oxford Molecular Ltd). The plasmid DNA was used for transient transfection of COS-7 cells (see below) and were digested for production of a joined vector, containing heavy and light chain genes on the same plasmid.
[0073] Heavy and light chain vectors containing VH and VL segments originating from the same scFv were cleaved by restriction enzymes and ligated: HC- and LC-vectors were initially digested with MunI (Roche # 1 441 337) after which digestions were heat inactivated at 70° C. for 20 minutes and purified by spin column chromatography using S200-HR columns (Amersham-Pharmacia Biotech # 27-5120-01). HC-vector digestions were subsequently digested with NruI (Roche # 776 769) and LC-vector digestions with Bst1107I (Roche # 1 378 953). Digestions were then heat inactivated at 70° C. for 20 minutes and purified by spin column chromatography using S400-HR columns (Amersham-Pharmacia Biotech # 27-5240-01). 5 μl of each digested plasmid were ligated at 16° C over night in a total volume of 20 μl, contaning 2 U T4 DNA ligase (Life Technologies, # 15224-025) and the supplied buffer. 2 μl of the ligation mixture were subsequently transformed into 50 μl chemocompetent top10F′ bacteria, and plated on selective (100 μg/ml ampicillin and 20 μg/ml kanamycin) agar plates.
[0074] Bacterial colonies were grown over night in LB supplemented with 100 μg/ml ampicillin and 20 μg/ml kanamycin. Plasmid DNA was prepared from over night cultures using the Quantum Prep, plasmid miniprep kit from Biorad (# 732-6100). Correctly joined vectors were identified by restriction enzyme digestion followed by analyses of fragment sizes by agarose gel-electrophoreses
[0075] Plasmid preparations were purified by spin column chromatography using S400-HR columns (Amersham-Pharmacia Biotech # 27-5240-01) and used for transient transfection of COS-7 cells.
[0076] COS-7 cells (ATCC # CRL-1651) were cultured at 37° C. with 5% CO 2 in Dulbeccos MEM, high glucose +Glutamaxl (Invitrogen # 31966021), supplementd with 0.1 mM non-essential amino acids (Invitrogen # 11140035) and 10% fetal bovine sera (Invitrogen # 12476-024, batch # 1128016). The day before transfection, the cells were plated in 12-well plates (Nunc, # 150628) at a density of 1.5×10 5 cells per well.
[0077] Prior to transfection, the plasmid DNA was heated at 70° C. for 15 minutes. Cells were transfected with 1 μg HC-plasmid +1 μg LC-plasmid, or 2 μg joined plasmid per well, using Lipofectamine 2000 Reagent (Invitrogen, # 11668019) according to the manufacturers recommendations. 24 hours post transfection, cell culture media was changed and the cells were allowed to grow for 5 days. After that, medium was collected and protein production was assayed for using ELISA.
[0078] Ninetysix (96)-well plates (Costar # 9018, flat bottom, high binding) were coated at 4° C. over night by adding 100 μl/well rabbit anti-human lamda light chain antibody (DAKO, # A0193) diluted 4000 times in coatingbuffer (0.1 M sodium carbonate, pH 9.5). Plates were washed 4 times in PBS containing 0.05% Tween 20 and thereafter blocked with 100 μl/well PBS+3% BSA (Albumin, fraction V, Roche # 735108) for 1 h. at room temperature. After washing as above, 100 μl/well of sample were added and incubated in room temperature for 1 hour. As a standard for estimation of concentration, human purified IgG1 (Sigma, # I5029) was used. Samples and standard were diluted in sample buffer (1× PBS containing 2% BSA and 0.5% rabbit serum (Sigma # R4505). Subsequently, plates were washed as described above and 100 μl/well of rabbit anti-human IgG (y-chain) HRP-conjugated antibody (DAKO, # P214) diluted 8000 times in sample buffer was added and incubated at room temperature for 1 hour. After washing 8 times with PBS containing 0.05% Tween 20, 100 μl/well of a substrate solution containing one OPD tablet (10 mg, Sigma # P8287,) dissolved in 15 ml citric acid buffer and 4.5 μl H 2 O 2 (30%) was added. After 10 minutes, the reaction was terminated by adding 150 μl/well of 1M HCI. Absorbance was measured at 490-650 nm and data was analyzed using the Softmax software.
[0079] Bacteria containing correctly joined HC- and LC-vectors were grown over night in 500 ml LB supplemented with ampicillin and kanamycin. Plasmid DNA was prepared from over night cultures using the Quantum Prep, plasmid maxiprep kit from Biorad (# 732-6130). Vectors were linearized using PvuI restriction enzyme (Roche # 650 129). Prior to transfection, the linearized DNA was purified by spin column chromatography using S400-HR columns (Amersham-Pharmacia Biotech # 27-5240-01) and heated at 70° C for 15 minutes.
EXAMPLE 3
[0080] Stable Transfection of NSO Cells Expressing Antibodies Against MDA Modified Peptides from Apolipoprotein B-100.
[0081] NSO cells (ECACC no. 85110503) were cultured in DMEM (cat nr 31966-021, Invitrogen) supplemented with 10% Fetal Bovine Serum (cat no. 12476-024, lot: 1128016, Invitrogen) and 1X NEAA (non-essential amino acids, cat no. 11140-053, Invitrogen). Cell cultures are maintained at 37° C. with 5% CO 2 in humidified environment.
[0082] DNA constructs to be transfected were four constructs of IEI specific antibodies (IEI-A8, IEI-D8, IEI-E3, IEI-G8), two of KTT specific antibodies (KTT-B8, KTT-D6) and one control antibody (JFPA12).The day before transfection, the cells were trypsinized and counted, before plating them in a T-75 flask at 12×10 6 cells/flask. On the day of transfection, when the cells were 85-90% confluent, the cells were plated in 15 ml DMEM+1× NEAA+10% FBS (as above). For each flask of cells to be transfected, 35-40 μg of DNA were diluted into 1.9 ml of OPTI-MEM I Reduced Serum Medium (Cat no. 51985-026, lot: 3062314, Invitrogen) without serum. For each flask of cells, 114 μl of Lipofectamine 2000 Reagent (Cat nr. 11668-019, lot: 1116546, Invitrogen) were diluted into 1.9 ml OPTI-MEM I Reduced Serum Medium in another tube and incubated for 5 min at room temperature. The diluted DNA was combined with the diluted Lipofectamine 2000 Reagent (within 30 min) and incubated at room temperature for 20 min to allow DNA-LF2000 Reagent complexes to form.
[0083] The cells were washed with medium once and 11 ml DMEM+1X NEAA+10% FBS were added. The DNA-LF2000 Reagent complexes (3.8 ml) were then added directly to each flask and gently mixed by rocking the flask back and forth. The cells were incubated at 37° C in a 5% CO 2 incubator for 24 h.
[0084] The cells were then trypsinized and counted, and subsequently plated in 96-well plates at 2×10 4 cells/well using five 96-well plates/construct. Cells were plated in 100μl well of DMEM +1× NEAA +10% FBS (as above) containing G418-sulphate (cat nr.10131-027, lot: 3066651, Invitrogen) at 600 μg/ml. The selection pressure was kept unchanged until harvest of the cells.
[0085] The cells were grown for 12 days and assayed for antibody production using ELISA. From each construct cells from the 24 wells containing the highest amounts of IgG were transferred to 24-well plates and were allowed to reach confluency. The antibody production from cells in these wells was then assayed with ELISA and 5-21 pools/construct were selected for re-screening (Table 3). Finally cells from the best 1-4 wells for each construct were chosen. These cells were expanded successively in cell culture flasks and finally transferred into triple layer flasks (500 cm2) in 200 ml of (DMEM+1× NEM+10% Ultra low IgG FBS (cat.no. 16250-078, lot.no. 113466, Invitrogen)+G418 (600 μg/ml)) for antibody production. The cells were incubated for 7-10 days and the supernatants were assayed by ELISA, harvested and sterile filtered for purification.
EXAMPLE 4
Production and Purification of Human IaG1
[0086] Supernatants from NSO cells transfected with the different IgG1 antibodies were sterile filtered using a 0.22 μm filter and purified using an affinity medium MabSelect™ with recombinant protein A, (Cat. No. 17519901 Amersham Biosciences).
[0087] Bound human IgG1 was eluted with HCL-glycine buffer pH 2.8. The eluate was collected in 0.5 ml fractions and OD 280 was used to determine presence of protein. The peak fractions were pooled and absorbance was measured at 280nm and 320nm. Buffer was changed through dialysis against a large volume of PBS. The presence of endotoxins in the purified IgG-1 preparations was tested using a LAL test (QCL-1000 R , cat. No. 50-647U Bio Whittaker). The samples contained between 1 and 12 EU/ml endotoxin. The purity of the preparations were estimated to exceed 98% by PAGE analysis.
TABLE 3 Summary of Production and Purification of human IgG1 Volume culture Total IgG1 in Total IgG1 supernatant supernatant Purified Clone name (ml) (mg) (mg) Yield (%) IEI-A8 600 68 42 61.8 IEI-D8 700 45 21 46.7 IEI-E3 700 44.9 25.6 60 IEI-G8 600 74 42.4 57.3 KTT-B8 1790 77.3 37.6 48.6 KTT-D6 1845 47.8 31.8 66.5 JFPA12 2000 32.2 19.2 59.6
[0088] The purified IgG1 preparations were tested in ELISA for reactivity to MDA modified and un-modified peptides ( FIG. 5 ) and were then used in functional in vitro and in vivo studies.
EXAMPLE 5
Analysis of Possible Anti-Atherogenic Effect of Antibodies are Performed Both in Experimental Animals and in Cell Culture Studies.
[0089] 1. Effect of antibodies on atherosclerosis in apolipoprotein E knockout (apo E-) mice. Five weeks old apo E- mice are fed a cholesterol-rich diet for 15 weeks. This treatment is known to produce a significant amount of atherosclerotic plaques in the aorta and carotid arteries. The mice are then given an intraperitoneal injection containing 500 μg of the respective antibody identified above. Control mice are given 500 μg of an irrelevant control antibody or PBS alone. Treatments are repeated after 1 and 2 weeks. The mice are sacrificed 4 weeks after the initial antibody injection. The severity of atherosclerosis in the aorta is determined by Oil Red O staining of flat preparations and by determining the size of subvalvular atherosclerotic plaques. Collagen, macrophage and T cell content of subvalvular atherosclerotic plaques is determined by Masson trichrome staining and cell-specific immunohistochemistry. Quantification of Oil Red O staining, the size of the subvalvular plaques, trichrome staining and immunohistochemical staining is done using computer-based image analysis.
[0090] In a first experiment the effect of the antibodies on development of atherosclerosis was analysed in apo E−/− mice fed a high-cholesterol diet. The mice were given three intraperitoneal injections of 0.5 mg antibody with week intervals starting at 21 weeks of age, using PBS as control. They were sacrificed two weeks after the last antibody injection, and the extent of atherosclerosis was assessed by Oil Red O staining of descending aorta flat preparations. A pronounced effect was observed in mice treated with the IEI-E3 antibody, with more than 50% reduction of atherosclerosis as compared to the PBS group (P=0.02) and to a control group receiving a human IgGI antibody (FITC8) directed against a non-relevant fluorescein isothiocynate (FITC) antigen (P=0.03) ( FIG. 6 ). The mice tolerated the human antibodies well and no effects on the general health status of the mice were evident.
[0091] To verify the inhibitory effect of the IEI-E3 antibody on development of atherosclerosis we then performed a dose-response study. The schedule was identical to that of the initial study. In mice treated with IEI-E3 antibodies atherosclerosis was reduced by 2% in the 0.25 mg group (n.s.), by 25% in the 0.5 mg group (n.s.) and by 41% (P=0.02) in the 2.0 mg group as compared to the corresponding FITC antibody-treated groups ( FIG. 7 ).
[0092] 2. Effect of antibodies on neo-intima formation following mechanical injury of carotid arteries in apo E- mice. Mechanical injury of arteries results in development of fibro-muscular neo-intimal plaque within 3 weeks. This plaque resembles morphologically a fibro-muscular atherosclerotic plaque and has been used as one model for studies of the development of raised lesion. Placing a plastic collar around the carotid artery causes the mechanical injury. Five weeks old apo E- mice are fed a cholesterol-rich diet for 14 weeks. The mice are then given an intraperitoneal injection containing 500 μg of the respective antibody. Control mice are given 500 μg of an irrelevant control antibody or PBS alone. The treatment is repeated after 7 days and the surgical placement of the plastic collar is performed 1 day later. A last injection of antibodies or PBS is given 6 days after surgery and the animals are sacrificed 15 days later. The injured carotid artery is fixed, embedded in paraffin and sectioned. The size of the neo-intimal plaque is measured using computer-based image analysis.
[0093] 3. Effect of antibodies on uptake of oxidized LDL in cultured human macrophages. Uptake of oxidized LDL in arterial macrophages leading to formation of cholesterol-loaded macrophage foam cells is one of the most characteristic features of the atherosclerotic plaque. Several lines of evidence suggest that inhibiting uptake of oxidized LDL in arterial macrophages represent a possible target for treatment of atherosclerosis. To study the effect of antibodies on macrophage uptake of oxidized c are pre-incubated with 125 I-labeled human oxidized LDL for 2 hours. Human macrophages are isolated from blood donor buffy coats by centrifugation in Ficoll hypaque followed by culture in presence of 10% serum for 6 days. The cells are then incubated with medium containing antibody/oxidized LDL complexes for 6 hours, washed and cell-associated radioactivity determined in a gamma-counter. Addition of IEI-E3 antibodies resulted in a five-fold increase in the binding (P=0.001) and uptake (P=0.004) of oxidized LDL compared to FITC-8 into macrophages, but had no effect on binding or uptake of native LDL ( FIGS. 8 a and 8 b ).
[0094] 4. Effect of antibodies on oxidized LDL-dependent cytotoxicity. Oxidized LDL is highly cytotoxic. It is believed that much of the inflammatory activity in atherosclerotic plaques is explained by cell injury caused by oxidized LDL. Inhibition of oxidized LDL cytotoxicity thus represents another possible target for treatment of atherosclerosis. To study the effect of antibodies on oxidized LDL cytotoxicity cultured human arterial smooth muscle cells are exposed to 100 ng/ml of human oxidized LDL in the presence of increasing concentrations of antibodies (0-200 ng/ml) for 48 hours. The rate of cell injury is determined by measuring the release of the enzyme LDH.
[0095] The experiment shown discloses an effect for a particular antibody raised against a particular peptide, but it is evident to the one skilled in the art that all other antibodies raised against the peptides disclosed will behave in the same manner.
[0096] The antibodies of the present invention are used in pharmaceutical compositions for passive immunization, whereby the pharmaceutical compositions primarily are intended for injection, comprising a solution, suspension, or emulsion of a single antibody or a mixture of antibodies of the invention in a dosage to provide a therapeutically or prophylactically active level in the body treated. The compositions may be provided with commonly used adjuvants to enhance absorption of the antibody or mixture of antibodies. Other routes of administration may be the nasal route by inhaling the antibody/antibody mixture in combination with inhalable excipients.
[0097] Such pharmaceutical compositions may contain the active antibody in an amount of 0.5 to 99.5% by weight, or 5 to 90% by weight, or 10 to 90% by weight, or 25 to 80% by weight, or 40 to 90% by weight.
[0098] The daily dosage of the antibody, or a booster dosage shall provide for a therapeutically or prophylactically active level in the body treated to reduce or prevent signs and sympthoms of atherosclerosis by way of passive immunization. A dosage of antibody according to the invention may be 1 μg to 1 mg per kg bodyweight, or more.
[0099] The antibody composition can be supplemented with other drugs for treating or preventing atherosclerosis or heart-vascular diseases, such as blood pressure lowering drugs, such as beta-receptor blockers, calcium antagonists, diurethics, and other antihypertensive agents.
[0100] FIG. 9 shows binding of isolated scFv to MDA modified ApoB100 derived peptides and to a MDA modified control peptide of irrelevant sequence. Also depicted are the ratios between binding of the scFv to MDA modified and native ApoB100 protein and human LDL respectively. Columns appear in the order they are defined from top to bottom in right hand column of the respective subfigure.
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The present invention relates to passive immunization for treating or preventing atherosclerosis using an isolated human antibody directed towards at least one oxidized fragment of apolipoprotein B in the manufacture of a pharmaceutical composition for therapeutical or prophylactical treatment of atherosclerosis by means of passive immunization, as well as method for preparing such antibodies, and a method for treating a mammal, preferably a human using such an antibody to provide for passive immunization.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates generally to aids for teaching the fundamentals of spiking and serving a volleyball. More specifically, it relates to automatic ball feeding devices.
2. Description of Prior Art
It is well known to those persons acquainted with the sport of volleyball that a teaching aid for this purpose has been developed in the past and is available on the market. It teaches correct arm swing, extension, approach and jump technique to learning players and corrects poor habits of advanced players. However, the device is a manually worked by a second person replacing a volleyball thereupon after each spiking action by a player. This is accordingly in need of an improvement.
SUMMARY OF THE INVENTION
Therefore, it is a principal object of the present invention to provide a volleyball spiking tee that accomplishes all the same teaching fundamentals described above, and which additionally feeds the balls automatically so that no second person is needed for reloading the device after each spiking action; and which can be all done by the player alone before he starts to play.
Other objects are to provide a volleyball spiking tee which is simple in design, inexpensive to manufacture, rugged in construction, easy to use and efficient in operation.
These and other objects will be readily evident upon a study of the following Specification and the accompanying Drawing.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a fragmentary perspective view of a spiking machine, shown in accordance with the present invention;
FIG. 2 is a side elevational view of the invention;
FIG. 3 is a top plan view of the invention;
FIG. 4 is a cross-sectional view, taken along line 4--4 of FIG. 2, and
FIG. 5 is a longitudinal view of an adjustable support post, used in conjunction with the invention.
DETAILED DESCRIPTION
Referring now to the Drawing in greater detail, the reference numeral 10 represents a volleyball spiking tee incorporating the invention wherein there is a cage or rack 11 upon which a plurality of volleyballs 12 are stored in a row. The rack is made from several spaced apart, generally "U"-shaped ribs 13 and which are attached to a plurality of elongated rods 14 extending thereacross. The ribs and rods are made of anodized aluminum and the attachment may be made by weld. The rack thus forms a chute or trough in which the balls are supported.
The rack is supported in elevated position upon a downwardly extending post assembly 15 that includes a pair of small flat plates 16 between which a portion of the lower rods are sandwiched and the plates are bolted together by bolts 17 extending therebetween. A vertically downward sleeve 18 is welded to an underside of the lower plate which extends horizontally thereupon. A spacer 19 is placed between the rear portion of the lower plate and an underside of the frame so that the frame thus inclines downwardly toward its front at approximately eight degrees so that the balls roll freely toward the front end.
A ball dispensing unit 20 is formed at the front end of the rack by means of the lowermost rods being longer so to form a pair of forwardly extending, equally spaced apart, track rails 21 upon which the balls can roll. A forward terminal end of the rails are slightly bent arcuately downward, and a rubber hose 22 is slid on each, the hoses projecting a short distance beyond the rod ends, as shown, for the balls to roll thereacross. Also the uppermost rods are made longer so to form a pair of forwardly extending arms 23 which at their terminal end are "U"-shaped and converge together for being inserted into an end of a cylindrically shaped stopper 24 made of styrofoam, and which serves to stop the forwardly rolling ball and hold it therebetween and upon the tips of the hoses which are spaced at proper distance therefrom for preventing the ball to drop down therebetween during the free roll of the ball, but from which it can be readily dislodged by the player during a playing action.
After a ball is thus removed, a next ball resting thereagainst, automatically rolls down into the discharging seat 25 formed between the face of the stopper and the hose tips.
The invention also includes means for a person to move a group of balls out of the rack storage area 26 and into the discharge area 27 ready for automatically feeding to the discharge seat. This includes a tension coil spring 28 attached across the rib at the exit end of the rack, and a nylon cord 29 attached to the center of the spring extending through an eyelet 30 on a cross-bar 31 between the upper ends of the rib, so that when the cord is pulled, the spring is lifted up out of the way, allowing balls to roll out of the rack.
The post assembly also includes a post 32 insertable into the sleeve 18, the post including a post adjustment handle 33 on a side plate 34 attached on a side of the post.
While various changes may be made in the detail construction, it is understood that such changes will be within the spirit and scope of the present invention as is defined by the appended claims.
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A volleyball storage and dispensing device, including a storage rack upon an upright post, and a ball dispensing station at its front that lightly holds a volleyball between a styrofoam stop and tips of a pair of rubber hoses.
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CROSS-REFERENCE TO RELATED APPLICATIONS
Not applicable
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not applicable
INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISC
Not applicable
BACKGROUND OF THE INVENTION
1. Field of the Invention
A floatation apparatus is disclosed for supporting and propelling a user(s) on the water particularly while snorkeling. The apparatus may include a frame configured to support and propel a user, with the frame being buoyed in the water by an arrangement of floats that are each connected to the frame by an arm.
2. Description of Related Art
A variety of devices are commercially available to assist snorkeling and/or SCUBA diving enthusiasts in the enjoyment of their sport. The most common of these devices are diving planes and sleds. Planes and sleds are, however, ill suited for those that may wish to participate in or host dedicated snorkeling activities. Planes that function as portable submersible devices are, for example, designed to travel for significant periods of time at depth underwater. This makes them of little practical use to a snorkeler, who must routinely remain at or near the surface of breath. Many planes and sleds also come with the added expense of a boat, which is required to pull the device through the water. Therefore, it would be advantageous to have a standalone dedicated apparatus for snorkelers that has independent source of propulsion. Such a device could, for example, be used by guests of hotels and resorts who would like to experience snorkeling but do not know how to SCUBA dive or how to use a towed dive plane or sled.
U.S. Pat. No. 2,948,251 to Replogle discloses a diving plane for towing one or more divers at various depths beneath the surface of the water. Wendt teaches an operator controlled towed underwater sled in U.S. Pat. No. 3,101,691. An apparatus to be towed behind a motor boat while permitting controlled motion beneath the water and on the surface of the water is taught by Nutting in U.S. Pat. No. 3,139,055.
Vlad teaches a water vehicle on which a rider may be towed by a boat either on or beneath the surface of the water in U.S. Pat. No. 3,638,598. A highly controllable water sled device having an adjustable buoyancy feature is taught by Willat in U.S. Pat. No. 4,361,103. U.S. Pat. No. 4,624,207 to King discloses an underwater diving plane towed by a boat and ridden by a diver.
U.S. Pat. No. 5,134,955 to Manfield discloses a submersible two passenger dive sled. An underwater diving plane is taught by Carter in U.S. Pat. No. 5,178,090. Culpepper teaches a submersible aquatic sled capable of towing a diver both on and below the surface of the water in U.S. Pat. No. 5,605,111.
A towable and steerable diver aid is disclosed in U.S. Pat. No. 6,145,462 to Aquino. U.S. Pat. No. 6,561,116 to Linjawi discloses a sub-aqua device for towing a person through the water. Arthur teaches a towable underwater kite for towing riders on or through the water in U.S. Pat. No. 6,612,254.
The foregoing examples of the related art and limitations related therewith are intended to be illustrative and not exclusive. Other limitations of the related art will become apparent to those skilled in the art upon a reading of the specification and a study of the drawings.
BRIEF SUMMARY OF THE INVENTION
This invention is directed to a flotation apparatus including a frame configured to support an individual sitting or lying in a prone position. A plurality (preferably six) of elongated arms are each pivotally attached at a proximal end thereof to the frame with a buoyant float positioned on a distal end of each arm for enhanced stability. Preferably, a propulsion apparatus is mounted to the frame and a control apparatus for operating the propulsion apparatus in a prone or a seated position is provided.
The following embodiments and aspects thereof are described and illustrated in conjunction with systems, tools and methods which are meant to be exemplary and illustrative and not limiting in scope. In various embodiments one or more of the above-described problems have been reduced or eliminated while other embodiments are directed to other improvements. In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent by reference to the drawings and by study of the following descriptions.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)
FIG. 1 is a perspective view of an embodiment of the flotation apparatus.
FIG. 2 is another perspective view of an embodiment of FIG. 1 .
FIG. 3 is a top plan view of FIG. 1 .
FIG. 4 is a bottom plan view of FIG. 1 .
FIG. 5 is a right side elevation view of FIG. 1 .
FIG. 6 is a front elevation view of FIG. 1 .
FIG. 7 is a rear elevation view of FIG. 1 .
FIG. 8 is a perspective view of FIG. 1 showing the arms and attached buoyant floats in a downward orientation.
FIG. 9 is a view of FIG. 8 showing the arms and attached buoyant floats in an upward stored orientation.
FIG. 10 is an enlarged perspective view of an arm mount assembly.
FIG. 11 is an exploded view of FIG. 10 .
FIG. 12 is a section view in the direction of arrows 12 - 12 in FIG. 10 .
FIG. 13 is an enlarged perspective view of the front portion of the apparatus 10 .
FIG. 14 is a section view in the direction of arrows 14 - 14 in FIG. 13 .
FIG. 15 is a side elevation view of FIG. 1 showing a user in a prone position with the addition of a canopy overhead.
FIG. 16 is a simplified schematic view of the propulsion and control system.
Exemplary embodiments are illustrated in reference figures of the drawings. It is intended that the embodiments and figures disclosed herein are to be considered to be illustrative rather than limiting.
DETAILED DESCRIPTION OF THE INVENTION
Nomenclature
10 . flotation apparatus
12 . frame
14 . flotation assembly
16 . propulsion motor
18 . propulsion motor
20 . control system
22 . aluminum tube
24 . user support netting
26 . upright support
28 . interior space
30 . arm
32 . arm
34 . arm
36 . arm mount assembly
38 . arm mount assembly
40 . arm mount assembly
42 . shrouded propeller
44 . rear wheel
46 . container
48 . front wheel
50 . buoyant float
52 . top plate
54 . arm mounting plate
56 . bolt
57 . nut
58 . bottom plate
60 . locking pin
62 . retainer
64 . fixed mounting plate
66 . cavity
68 . locking pin aperture
70 . left joystick
72 . right joystick
74 . alternate left joystick
76 . alternate right joystick
78 . facial opening
80 . mounting flange
82 . viewing box
84 . neck clearance
86 . transparent viewing bottom
90 . canopy
92 . upright support
94 . canopy bow
96 . canopy canvas
98 . upright support
A flotation apparatus is provided that may be used for carrying a snorkeler(s) on a body of water. The apparatus may include a frame configured to support and propel a user in a prone position, with the frame being buoyed in the water by an arrangement of floats that are each connected to the frame by an articulatable arm. A propulsion system may be included for driving the apparatus, with a control system also being provided to operate the propulsion system. In operation, the arms (with associated floats) may be pivoted down from a storage positioned and fixed in positioned relative to the frame and then the entire apparatus may be placed in a body of water. Once on the water, the frame will be located on or proximate the surface depending on the position in which the arms were fixed. A user may then lay in a prone and facedown position along the frame such that the user's body and face are supported at a constant position above or at a depth below the surface. Then, using the control system, the user may activate the propulsion system and drive the apparatus across the surface of the water.
Referring now to FIGS. 1 to 7 , an apparatus 10 is provided that may be used for carrying a snorkeler(s) on a body of water as shown in FIG. 15 . The apparatus 10 may include a frame shown generally at numeral 12 configured to support and propel a user in a prone or seated position, with the frame 12 being buoyed in the water by an arrangement of floats 50 that are each connected to the frame 12 on either side thereof by articulatable arms 30 , 32 and 34 .
A propulsion system including battery-powered trolling motors 16 and 18 may be included for driving the apparatus 10 , with a control system 20 also being provided to operate the propulsion system 16 / 18 . In operation, the arms 30 , 32 and 34 with associated floats 50 may be pivoted down from a storage position in the direction of arrows A, B and C in FIG. 8 and fixed in position relative to the frame 12 and then the entire apparatus 10 may be placed in a body of water. Once on the water, the frame 12 will be located on or proximate to the surface of the water depending on the angular position in which the arms 30 , 32 and 34 were fixed (described below). A user then may lie in a prone and facedown position along the frame 12 , as shown in FIG. 15 , such that the user's body and face are supported at a constant position above or at a depth below the surface. Then, using the control system 20 for the apparatus 10 , the user may activate the propulsion system 16 / 18 and drive the apparatus 10 across the surface of the water.
Note that each of the arms 30 , 32 and 34 may be independently positioned to accommodate a load in balance or to achieve a desired angular orientation of the frame 12 to the surface of the water. Note further that any propulsion apparatus may be viewed as optional, allowing for arm or finned leg propulsion by the user, particularly in a prone position.
The frame 12 of the apparatus 10 may be substantially planar in dimension and formed by configuring and welding together the forward ends of an approximately 2″ diameter aluminum tube 22 . The forward end of the frame 12 may be formed by joining the ends of tube 22 together at an acute angle best seen in FIG. 4 to define an interior space 28 of the frame 12 . From this apex or forward end, the tube 22 may taper outward and extend about 3′ to an approximate midpoint of the frame 12 . At the midpoint, side of the tube 22 may be configured to form an obtuse angle relative to the interior space 28 . The tube 22 may then taper inward for about 3.5° to a rearward end of the frame 12 where the tube 22 is bent transversely and may be a length of about 2′ so that the frame 12 as a whole takes on a generally five-sided configuration. Thus, in one non-limited example, an embodiment of the frame 12 may have an overall length of about 6′7″ and a maximum width of about 2′6″. The interior space 28 of the frame 12 may be covered with a predetermined selection of fabric, mesh or netting 24 that extends across the frame 12 and is secured in space around the tube 22 by lacing 24 a to support a user lying lengthwise of the frame 12 or seated. Wheels 44 and 48 may also be mounted to the frame 12 proximate the ends for use in rolling the apparatus 10 over land when not in use.
Arm mount assemblies 36 , 38 and 40 may be welded or otherwise fixed to and along either side of the frame 12 at predetermined locations along the tube 22 proximate the forward end, the rearward end 32 , and at or proximate the widest or midpoint of the frame 12 . Referring to FIGS. 10 to 12 , each of the mount assemblies 36 , 38 and 40 may be substantially disc-like in configuration and, by using mount assembly 38 (left-hand) as an example, include a movable front mounting plate 54 and a fixed rear mounting plate 64 . The mounting plates 54 and 64 may also each include a center aperture—as will be discussed infra—for engagement with a bolt 56 to support one of the arms 32 . In addition, a series of cavities 66 may be defined proximate the perimeter of each mounting plate 64 and used for receiving a pin 60 a extending from a proximal end of a threaded locking pin 60 threadably engaged into threaded aperture 68 a to hold each arm 32 in desired position relative to the frame 12 .
Each arm 30 , 32 and 34 of the apparatus 10 may articulate in the direction of arrows A, B and C with respect to the frame 12 as seen in FIG. 2 . For example, as shown, each arm 30 , 32 and 34 may be pivoted up and down on (and also removably connected to) its corresponding mount assembly 36 , 38 and 40 . Also, like the frame 12 , each arm 16 may be constructed from a 2″ diameter aluminum tube or, preferably 2″ square aluminum tube. However, other materials that meet the requisite strength and rust resistance characteristics may be used. The arms 30 , 32 and 34 may also each have a length of between 1′ and 6′, or longer.
Still referring to FIGS. 10 to 12 , the arm mounting plate 54 attached to the proximal end of each arm may be substantially disc-like in configuration and include a rear face that is engageable with the front face of the fixed mounting plate 64 connected to the frame 12 . Each arm 30 , 32 and 34 may be folded up for storage by moving or pivoting the arms in the direction of arrows A′, B′ and C′ and tilting the motors 16 and 18 up in the direction of arrow E relative to the frame 12 as shown in FIG. 9 . The front face of fixed mounting plate 64 , for example, may include a bolt 56 that is moveably received and supported through the center aperture of the mount assembly 36 of the frame 12 . The bolt 56 may thus be extended through the apertures of the mount assembly 36 and tightened into nut 57 to hold each arm 32 in a user predetermined position relative to the frame 12 .
An opposite end 54 of each arm 16 may be curved downwardly into a substantially vertical orientation so that, as described infra, it may be fitted with a float 14 . To further insure the quick and secure selected angular orientation of each of the arms 32 as seen by example in FIGS. 10 to 12 , a hand-operated locking pin 60 threaded through aperture 68 in the mounting plate 54 aligns with one of three series of cavities 66 a , 66 b and 66 c by the moveable angular orientation of the arm 32 . The rounded distal end 60 a of locking pin 60 forms an alignment pin 60 a which positively engages in one of the cavities 66 . Note that cavities 66 a are provided in a sequence which would correspond to the normal in-use positioning of the arm 32 , cavities 66 b are in an array and orientation around the periphery of fixed mounting plate 64 corresponding to the stored orientation of each of the arms 32 , while cavities 66 c are provided for orienting each of the arms positioned on the opposite side of frame 12 in an angular orientation so as to make the fixed mounting plates 64 ambidextrous. Note that threaded locking pin 60 may be replaced by a spring-biased locking pin which is locked and unlocked by a push-pull motion for quicker arm position readjustment.
The float(s) 50 of the apparatus 10 may be constructed as inflatable rubber, hollow sealed plastic shells, or foam type floats. For example, each float 50 may include a rubber torus (i.e., “doughnut”) shaped inner tube float having a diameter of about 16″ and a height of 10″. As best seen in FIGS. 3 and 4 , each float 50 may thus be fitted about the distal end of an arm 30 , 32 or 34 and secured in position by top and bottom plates 52 and 58 and that are secured to the distal end of each arm above and below the float 50 by retainer 62 .
The optional propulsion system 16 / 18 of the apparatus 10 may include one or more batteries ( FIG. 16 ) and a shrouded propeller 42 of each motor 16 and 18 with each battery being positioned in an aluminum container 46 mounted to the frame 12 and extending outboard of the frame 12 . (Alternately, water jets (not shown) may be mounted outboard of the containers 46 on a support (not shown) of frame 12 . Each support may include one or more water intake ports for the jet(s) and one or more exhaust ports.) The motors 16 and 18 (or the jets not shown) may then be controlled by the control system 20 ( FIGS. 13 and 16 ) positioned in another aluminum container positioned proximate the forward end of the frame 12 . As seen in FIG. 16 , the control system 20 may feature a pair of joysticks 70 and 72 that extend downwardly through the bottom of the aluminum container and operate to control the motors 16 and 18 (or thrust of the jets not shown). A second pair of joysticks 74 and 76 may be located at the tops of containers 46 for a user in a seated position.
Referring now to FIG. 8 , the vertical positioning of the frame 12 and the user support netting 24 may be raised by the lowering in the direction of arrows A, B and C of each of the arms 30 , 32 and 34 and fixing the selected orientation as previously described with respect to FIGS. 10 to 12 . In a furthermost downwardly orientation of each of the floats 50 , the user support netting 24 will position the body of the user well above the surface of the water.
Referring in more detail to FIG. 15 , the preferred embodiment of the invention will also include a canopy 90 having upright pole supports 92 and 98 connected between supports attached to the frame 12 and a tubular canopy bow 94 . Moreover, with the user positioned in a prone position with the hands in a supported position gripping the upright support members 26 ( FIG. 13 ), the thumbs of the user may easily have access to the joysticks 70 and 72 to steer and propel the apparatus 10 . The face-down orientation of the head of the user comfortably fits into and is supported by a viewing box 74 supported on frame 12 by mounting flange 80 best seen in FIGS. 13 and 14 . The viewing box 82 includes a neck clearance 84 and a facial opening 78 which positions the eyes of the viewer above a transparent viewing bottom 86 which will typically be submerged for clear underwater viewing.
While a number of exemplary aspects and embodiments have been discussed above, those of skill in the art will recognize certain modifications, permutations and additions and subcombinations thereof. It is therefore intended that the following appended claims and claims hereinafter introduced are interpreted to include all such modifications, permutations, additions and subcombinations that are within their true spirit and scope.
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A flotation apparatus including a frame configured to support a snorkeler lying in a prone position. A plurality, preferably six, of elongated arms are each pivotally attached at a proximal end thereof to the frame with a buoyant float positioned on a distal end of each arm for enhanced stability. Preferably, a propulsion apparatus is mounted to the frame and a control apparatus for operating the propulsion apparatus in a prone position is provided.
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BACKGROUND OF THE INVENTION
Polycarbonates and their copolymers with polyesters are known thermoplastics valued for their optical clarity as well as their physical and thermal properties. Most of the monomers used to prepare these polymers are ultimately derived from petroleum. With the projected decline in global petroleum reserves over the coming decades, there is a strong desire to identify renewable sources of starting materials for polycarbonate-polyester copolymers. Particularly for applications in which the use of an article molded from a polycarbonate-polyester copolymer is fleeting, there is also a desire for polycarbonate-polyester copolymers with biodegradable linkages that facilitate structural decomposition of the article. There is therefore a desire for new polycarbonate-polyester copolymers that can be prepared using renewable starting materials and that include biodegradable linkages.
BRIEF DESCRIPTION OF THE INVENTION
The above-described and other drawbacks are alleviated by a polycarbonate-polyester block copolymer, comprising: a polycarbonate block having the structure
wherein each occurrence of R 1 is independently a C 6 -C 60 divalent hydrocarbon group, provided that at least 60% of the R 1 groups comprise aromatic moieties; Y is —O— or —O—R 2 —R 3 —O—; each occurrence of R 2 is independently a C 6 -C 18 arylene group; each occurrence of R 3 is independently a C 1 -C 12 alkylene group; and n is 2 to about 200; and an aliphatic polyester block having the structure
wherein each occurrence of R 4 and R 5 is independently hydrogen or C 1 -C 12 alkyl; each occurrence of p is independently 0, 1, 2, 3, 4, or 5; and q is 2 to about 1,000.
Another embodiment is a polycarbonate-polylactide block copolymer, comprising: a polycarbonate block having the structure
wherein n 1 is about 20 to about 200; and a polylactide block having the structure
wherein q 1 is about 50 to about 500.
Another embodiment is a polycarbonate-polyester diblock copolymer having the structure
wherein each occurrence of R 1 is independently a C 6 -C 60 divalent hydrocarbon group, provided that at least 60% of the R 1 groups comprise aromatic moieties; R 2 is a C 6 -C 18 arylene group; R 3 is a C 1 -C 12 alkylene group; each occurrence of R 4 and R 5 is independently hydrogen or C 1 -C 12 alkyl; R 6 is C 6 -C 18 aryl; each occurrence of p is independently 0, 1, 2, 3, 4, or 5; n is 2 to about 200; and q is 2 to about 1,000.
Another embodiment is a polycarbonate-polyester triblock copolymer having the structure
wherein each occurrence of R 1 is independently a C 6 -C 60 divalent hydrocarbon group, provided that at least 60% of the R 1 groups comprise aromatic moieties; each occurrence of R 2 is independently a C 6 -C 18 arylene group; each occurrence of R 3 is independently a C 1 -C 12 alkylene group; each occurrence of R 4 and R 5 is independently hydrogen or C 1 -C 12 alkyl; each occurrence of p is independently 0, 1, 2, 3, 4, or 5; n is 2 to about 200; and each occurrence of q is 2 to about 1,000.
Another embodiment is a polycarbonate-polyester diblock copolymer having the structure
wherein each occurrence of R 1 is independently a C 6 -C 60 divalent hydrocarbon group, provided that at least 60% of the R 1 groups comprise aromatic moieties; R 2 is a C 6 -C 18 arylene group; R 3 is a C 1 -C 12 alkylene group; each occurrence of R 4 and R 5 is independently hydrogen or C 1 -C 12 alkyl; each occurrence of p is independently 0, 1, 2, 3, 4, or 5; each occurrence of R 6 is independently a C 6 -C 18 aryl group; n is 2 to about 200; q is 2 to about 1,000; and x is 0 or 1.
Another embodiment is a polycarbonate-polyester triblock copolymer having the structure
wherein each occurrence of R 1 is independently a C 6 -C 60 divalent hydrocarbon group, provided that at least 60% of the R 1 groups comprise aromatic moieties; each occurrence of R 2 is independently a C 6 -C 18 arylene group; each occurrence of R 3 is independently a C 1 -C 12 alkylene group; each occurrence of R 4 and R 5 is independently hydrogen or C 1 -C 12 alkyl; each occurrence of p is independently 0, 1, 2, 3, 4, or 5; each occurrence of R 6 is independently a C 6 -C 18 aryl group; n is 2 to about 200; each occurrence of q is 2 to about 1,000; and x is 0 or 1.
Another embodiment is a polycarbonate-polylactide diblock copolymer having the structure
wherein n 1 is about 20 to about 200; and q 1 is about 50 to about 500.
Another embodiment is a polycarbonate-polylactide triblock copolymer having the structure
wherein n 1 is about 20 to about 200; and each occurrence of q 1 is about 50 to about 500.
Another embodiment is a polycarbonate-polylactide diblock copolymer having the structure
wherein n 1 is about 20 to about 200; and q 1 is about 50 to about 500.
Another embodiment is a polycarbonate-polylactide triblock copolymer having the structure
wherein n 1 is about 20 to about 200; and each occurrence of q 1 is about 50 to about 500.
Another embodiment is a composition, comprising: a polycarbonate; and a polycarbonate-polyester block copolymer comprising a polycarbonate block having the structure
wherein each occurrence of R 1 is independently a C 6 -C 60 divalent hydrocarbon group, provided that at least 60% of the R 1 groups comprise aromatic moieties; Y is —O— or —O—R 2 —R 3 —O—; each occurrence of R 2 is independently a C 6 -C 18 arylene group; each occurrence of R 3 is independently a C 1 -C 12 alkylene group; and n is 2 to about 200; and an aliphatic polyester block having the structure
wherein each occurrence of R 4 and R 5 is independently hydrogen or C 1 -C 12 alkyl; each occurrence of p is independently 0, 1, 2, 3, 4, or 5; and q is 2 to about 1,000.
Another embodiment is a method of preparing a polycarbonate-polyester block copolymer, comprising: conducting a ring-opening polymerization of an aliphatic cyclic ester in the presence of a polycarbonate to form an uncapped polycarbonate-polyester block copolymer; wherein the polycarbonate has the structure
wherein each occurrence of R 1 is independently a C 6 -C 60 divalent hydrocarbon group, provided that at least 60% of the R 1 groups comprise aromatic moieties; each occurrence of R 2 is independently a C 6 -C 18 arylene group; each occurrence of R 3 is independently a C 1 -C 12 alkylene group; Y 1 is C 6 -C 18 aryl or —R 2 —R 3 —OH; and n is 2 to about 200.
Another embodiment is a method of preparing a polycarbonate-polylactide block copolymer, comprising: conducting a ring-opening polymerization of a lactide in the presence of a polycarbonate to form an uncapped polycarbonate-polylactide block copolymer; wherein the polycarbonate has the structure
wherein R 9 is
and n 1 is about 20 to about 200.
These and other embodiments, including articles comprising the block copolymers or block copolymer-containing compositions, are described in detail below.
DETAILED DESCRIPTION OF THE INVENTION
The present inventors have discovered that polycarbonate-polyester block copolymers can be prepared by ring-opening polymerization of a cyclic ester in the presence of a polycarbonate with at least one alcohol end group. Many of the cyclic esters suitable for use in the method can be derived from renewable resources. For example, the cyclic dimers known as lactides can be derived from corn.
One embodiment is a polycarbonate-polyester block copolymer, comprising: a polycarbonate block having the structure
wherein each occurrence of R 1 is independently a C 6 -C 60 divalent hydrocarbon group, provided that at least 60% of the R 1 groups comprise aromatic moieties; Y is —O— or —O—R 2 —R 3 —O—; each occurrence of R 2 is independently a C 6 -C 18 arylene group; each occurrence of R 3 is independently a C 1 -C 12 alkylene group; and n is 2 to about 200; and an aliphatic polyester block having the structure
wherein each occurrence of R 4 and R 5 is independently hydrogen or C 1 -C 12 alkyl; each occurrence of p is independently 0, 1, 2, 3, 4, or 5; and q is 2 to about 1,000.
In the context of the polycarbonate block, the number of repeat units n can be 2 to about 200, specifically about 20 to about 200, more specifically about 20 to about 100, still more specifically about 20 to about 50. With respect to the divalent group R 1 in the polycarbonate repeat unit, at least about 60 percent of the total number of R 1 groups contain aromatic moieties, and the balance thereof are aliphatic or alicyclic. In one embodiment, each R 1 is a C 6 -C 30 aromatic group, which is a group that contains at least one aromatic moiety. R 1 can be derived from a dihydroxy compound of the formula HO—R 1 —OH, in particular a dihydroxy compound of the formula
HO-A 1 -Y 1 -A 2 -OH
wherein each of A 1 and A 2 is a monocyclic divalent aromatic group and Y 1 is a single bond or a bridging group having one or more atoms that separate A 1 from A 2 . In an exemplary embodiment, one atom separates A 1 from A 2 . In one specific embodiment, the polycarbonate is a linear homopolymer derived from bisphenol A, in which each of A 1 and A 2 is p-phenylene and Y 1 is isopropylidene. In this embodiment, R 1 has the structure
In some embodiments, each R 1 can be derived from a dihydroxy aromatic compound of the formula
wherein R a and R b each represent a halogen or C 1 -C 12 alkyl group and can be the same or different; and y and z are each independently integers of 0, 1, 2, 3, 4, or 5. It will be understood that R a is hydrogen when y is 0, and likewise R b is hydrogen when z is 0. Also, X a represents a bridging group connecting the two hydroxy-substituted aromatic groups, where the bridging group and the hydroxy substituent of each C 6 arylene group are disposed ortho, meta, or para to each other on the C 6 arylene group. In one embodiment, the bridging group X a is single bond, —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, or a C 1 -C 18 unsubstituted or substituted hydrocarbylene group. As used herein, the term “hydrocarbyl”, whether used by itself, or as a prefix, suffix, or fragment of another term, refers to a residue that contains only carbon and hydrogen. The residue can be aliphatic or aromatic, straight-chain, cyclic, bicyclic, branched, saturated, or unsaturated. It can also contain combinations of aliphatic, aromatic, straight chain, cyclic, bicyclic, branched, saturated, and unsaturated hydrocarbon moieties. However, when the hydrocarbyl residue is described as substituted, it may, optionally, contain heteroatoms such as halogens, oxygen, nitrogen, sulfur, silicon, or phosphorous over and above the carbon and hydrogen members of the substituent residue. The C 1 -C 18 hydrocarbylene group can be disposed such that the C 6 arylene groups connected thereto are each connected to a common alkylidene carbon or to different carbons of the C 1 -C 18 hydrocarbylene group. In one embodiment, y and z are each 1, and R a and R b are each a C 1 -C 3 alkyl group, specifically methyl, disposed meta to the hydroxy group on each arylene group.
In one embodiment, X a is a substituted or unsubstituted C 3 -C 18 cycloalkylidene; a C 1 -C 25 alkylidene of formula —C(R c )(R d )— wherein R e and R d are each independently hydrogen, C 1 -C 12 alkyl, C 3 -C 12 cycloalkyl, C 7 -C 12 arylalkyl, C 1 -C 12 heteroallyl, or cyclic C 7 -C 12 heteroarylalkyl, or a group of the formula —C(═R e )— wherein R e is a divalent C 1 -C 12 hydrocarbon group. Exemplary groups of this type include methylene, cyclohexylmethylene, ethylidene, neopentylidene, and isopropylidene, as well as 2-[2.2.1]-bicycloheptylidene, cyclohexylidene, cyclopentylidene, cyclododecylidene, and adamantylidene. A specific example wherein X a is a substituted cycloalkylidene is the cyclohexylidene-bridged, alkyl-substituted bisphenol of the formula
wherein R a′ and R b′ are each independently C 1 -C 12 alkyl, R g is C 1 -C 12 alkyl or halogen, r and s are each independently 1 to 4, and t is 0 to 10. In a specific embodiment, at least one of each of R a′ and R b′ are disposed meta to the cyclohexylidene bridging group. The substituents R a′ , R b′ , and R g may, when comprising an appropriate number of carbon atoms, be straight chain, cyclic, bicyclic, branched, saturated, or unsaturated. In an embodiment, R a′ and R b′ are each independently C 1 -C 4 alkyl, R g is C 1 -C 4 allyl, r and s are each 1, and t is 0 to 5. In another specific embodiment, R a′ , R b′ and R g are each methyl, r and s are each 1, and t is 0 or 3. The cyclohexylidene-bridged bisphenol can be the reaction product of two moles of o-cresol with one mole of cyclohexanone. In another exemplary embodiment, the cyclohexylidene-bridged bisphenol is the reaction product of two moles of a cresol with one mole of a hydrogenated isophorone (for example, 1,1,3-trimethyl-3-cyclohexane-5-one). Such cyclohexane-containing bisphenols, for example the reaction product of two moles of a phenol with one mole of a hydrogenated isophorone, are useful for making polycarbonate polymers with high glass transition temperatures and high heat distortion temperatures. Cyclohexyl bisphenol-containing polycarbonates, or a combination comprising at least one of the foregoing with other bisphenol polycarbonates, are supplied by Bayer Co. under the APEC® trade name.
In another embodiment, X a is a C 1 -C 18 alkylene group, a C 3 -C 18 cycloalkylene group, a fused C 6 -C 18 cycloalkylene group, or a group of the formula —B 1 —W—B 2 — wherein B 1 and B 2 are the same or different C 1 -C 6 alkylene group and W is a C 3 -C 12 cycloalkylidene group or a C 6 -C 16 arylene group.
X a can also be a substituted C 3-18 cycloalkylidene of the formula
wherein R r , R p , R q , and R t are independently hydrogen, halogen, oxygen, or a C 1 -C 12 unsubstituted or substituted hydrocarbyl group; I is a direct bond, a carbon, or a divalent oxygen, sulfur, or —N(Z)- where Z is hydrogen, halogen, hydroxy, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, or C 1 -C 12 acyl; h is 0, 1, or 2, provided that h is 0 when I is a direct bond, a divalent oxygen, sulfur, or —N(Z)-; j is 1 or 2; i is 0 or 1; and k is 0, 1, 2, or 3, provided that at least two of R r , R p , R q , and R t taken together are a fused cycloaliphatic, aromatic, or heteroaromatic ring. It will be understood that where the fused ring is aromatic, the ring as shown in the preceding structure will have an unsaturated carbon-carbon linkage where the ring is fused. When k is one and i is 0, the ring as shown in the preceding structure contains 4 carbon atoms, when k is 2, the ring as shown in the preceding structure contains 5 carbon atoms, and when k is 3, the ring contains 6 carbon atoms. In one embodiment, two adjacent groups (for example, R q and R t taken together) form an aromatic group, and in another embodiment, R q and R t taken together form one aromatic group and R r and R p taken together form a second aromatic group. When R q and R t taken together form an aromatic group, R p can be a double-bonded oxygen atom, that is, a ketone.
Other useful aromatic dihydroxy compounds of the formula HO—R 1 —OH include compounds of the formula
wherein each R h is independently a halogen atom, a C 1 -C 10 hydrocarbyl such as a C 1 -C 10 alkyl group, a halogen-substituted C 1 -C 10 alkyl group, a C 6 -C 10 aryl group, or a halogen-substituted C 6 -C 10 aryl group, and n is 0 to 4. In some embodiments, the halogen is bromine.
Some illustrative examples of specific aromatic dihydroxy compounds include the following: 4,4′-dihydroxybiphenyl, 1,6-dihydroxynaphthalene, 2,6-dihydroxynaphthalene, bis(4-hydroxyphenyl)methane, bis(4-hydroxyphenyl)diphenylmethane, bis(4-hydroxyphenyl)-1-naphthylmethane, 1,2-bis(4-hydroxyphenyl)ethane, 1,1-bis(4-hydroxyphenyl)-1-phenylethane, 2-(4-hydroxyphenyl)-2-(3-hydroxyphenyl)propane, bis(4-hydroxyphenyl)phenylmethane, 2,2-bis(4-hydroxy-3-bromophenyl)propane, 1,1-bis (hydroxyphenyl)cyclopentane, 1,1-bis(4-hydroxyphenyl)cyclohexane, 1,1-bis(4-hydroxyphenyl)isobutene, 1,1-bis(4-hydroxyphenyl)cyclododecane, trans-2,3-bis(4-hydroxyphenyl)-2-butene, 2,2-bis(4-hydroxyphenyl)adamantane, alpha, alpha′-bis(4-hydroxyphenyl)toluene, bis(4-hydroxyphenyl)acetonitrile, 2,2-bis(3-methyl-4-hydroxyphenyl)propane, 2,2-bis(3-ethyl-4-hydroxyphenyl)propane, 2,2-bis(3-n-propyl-4-hydroxyphenyl)propane, 2,2-bis(3-isopropyl-4-hydroxyphenyl)propane, 2,2-bis(3-sec-butyl-4-hydroxyphenyl)propane, 2,2-bis(3-t-butyl-4-hydroxyphenyl)propane, 2,2-bis(3-cyclohexyl-4-hydroxyphenyl)propane, 2,2-bis(3-allyl-4-hydroxyphenyl)propane, 2,2-bis(3-methoxy-4-hydroxyphenyl)propane, 2,2-bis(4-hydroxyphenyl)hexafluoropropane, 1,1-dichloro-2,2-bis(4-hydroxyphenyl)ethylene, 1,1-dibromo-2,2-bis(4-hydroxyphenyl)ethylene, 1,1-dichloro-2,2-bis(5-phenoxy-4-hydroxyphenyl)ethylene, 4,4′-dihydroxybenzophenone, 3,3-bis(4-hydroxyphenyl)-2-butanone, 1,6-bis(4-hydroxyphenyl)-1,6-hexanedione, ethylene glycol bis(4-hydroxyphenyl)ether, bis(4-hydroxyphenyl)ether, bis(4-hydroxyphenyl)sulfide, bis(4-hydroxyphenyl)sulfoxide, bis(4-hydroxyphenyl)sulfone, 9,9-bis(4-hydroxyphenyl)fluorine, 2,7-dihydroxypyrene, 6,6′-dihydroxy-3,3,3′,3′-tetramethylspiro(bis)indane (“spirobiindane bisphenol”), 3,3-bis(4-hydroxyphenyl)phthalimide, 2,6-dihydroxydibenzo-p-dioxin, 2,6-dihydroxythianthrene, 2,7-dihydroxyphenoxathin, 2,7-dihydroxy-9,10-dimethylphenazine, 3,6-dihydroxydibenzofuran, 3,6-dihydroxydibenzothiophene, and 2,7-dihydroxycarbazole, resorcinol, substituted resorcinol compounds such as 5-methyl resorcinol, 5-ethyl resorcinol, 5-propyl resorcinol, 5-butyl resorcinol, 5-t-butyl resorcinol, 5-phenyl resorcinol, 5-cumyl resorcinol, 2,4,5,6-tetrafluoro resorcinol, 2,4,5,6-tetrabromo resorcinol, or the like; catechol; hydroquinone; substituted hydroquinones such as 2-methyl hydroquinone, 2-ethyl hydroquinone, 2-propyl hydroquinone, 2-butyl hydroquinone, 2-t-butyl hydroquinone, 2-phenyl hydroquinone, 2-cumyl hydroquinone, 2,3,5,6-tetramethyl hydroquinone, 2,3,5,6-tetra-t-butyl hydroquinone, 2,3,5,6-tetrafluoro hydroquinone, 2,3,5,6-tetrabromo hydroquinone, and the like, as well as combinations comprising at least one of the foregoing dihydroxy compounds.
Further examples of bisphenol compounds include 1,1-bis(4-hydroxyphenyl)methane, 1,1-bis(4-hydroxyphenyl)ethane, 2,2-bis(4-hydroxyphenyl)propane (hereinafter “bisphenol A” or “BPA”), 2,2-bis(4-hydroxyphenyl)butane, 2,2-bis(4-hydroxyphenyl)octane, 1,1-bis(4-hydroxyphenyl)propane, 1,1-bis(4-hydroxyphenyl)n-butane, 2,2-bis(4-hydroxy-1-methylphenyl)propane, 1,1-bis(4-hydroxy-t-butylphenyl)propane, 3,3-bis(4-hydroxyphenyl)phthalimidine, 2-phenyl-3,3-bis(4-hydroxyphenyl)phthalimidine (PPPBP), and 1,1-bis(4-hydroxy-3-methylphenyl)cyclohexane (DMBPC). Combinations comprising at least one of the foregoing dihydroxy compounds can also be used. The polycarbonate block may also comprise a polysiloxane-polycarbonate copolymer.
The polycarbonate block includes an R 2 group and an R 3 group at each end. Each occurrence of R 2 is independently a C 6 -C 18 arylene group, and each occurrence of R 3 is independently a C 1 -C 12 alkylene group. In some embodiments, R 2 is unsubstituted or substituted phenylene (including 1,2-phenylene, 1,3-phenylene, and 1,4-phenylene), and R 3 is C 1 -C 6 alkylene. In some embodiments, R 2 is 1,4-phenylene, and R 3 is methylene.
The block copolymer includes at least one aliphatic polyester block having the structure
wherein each occurrence of R 4 and R 5 is independently hydrogen or C 1 -C 12 alkyl; each occurrence of p is independently 0, 1, 2, 3, 4, or 5; and q is 2 to about 1,000, specifically about 10 to about 800, more specifically about 20 to about 600. In some embodiments, each occurrence of R 4 and R 5 is hydrogen, and p has a value of 1, 2, 3, or 4. In some embodiments, each occurrence of R 4 is hydrogen, each occurrence of R 5 is hydrogen or methyl, and p is 0. In these embodiments, the polyester block is a polyglycolide (R 5 is hydrogen) or a polylactide (R 5 is methyl). When R 4 and R 5 are different, the carbon atom to which they are attached is chiral, and it may have any possible stereochemistry. For example, when R 4 is hydrogen and R 5 is methyl and p is 0, the polyester block may be a poly(L-lactide), a poly(D-lactide), or poly(rac-actide). In some embodiments, each occurrence of R 4 and R 5 is hydrogen and p is 3; in these embodiments, the polyester block is poly(6-valerolactone). In some embodiments, each occurrence of R 4 and R 5 is hydrogen and p is 4; in these embodiments, the polyester block is poly(ε-caprolactone).
In addition to the polycarbonate block and the polyester block, the polycarbonate-polyester block copolymer can, optionally, further comprising an end group (especially an end group bound to the polyester block) having the structure
wherein R 6 is a C 6 -C 18 aryl group; and x is 0 or 1. As demonstrated in the working examples below, such aromatic carbonate end groups thermally stabilize the block copolymer. Specific end groups include, for example,
In addition to the polycarbonate block and the polyester block, the polycarbonate-polyester block copolymer can, optionally, further comprising an end group (especially an end group bound to the polycarbonate block) that is a C 6 -C 18 aryl group. Specific C 6 -C 18 aryl groups include, for example,
The polycarbonate-polyester block copolymer can be a diblock copolymer. That is, its polymer blocks can consist of one polycarbonate block and one polyester block. Alternatively, the polycarbonate-polyester block copolymer can be a triblock copolymer. That is, its polymer blocks can consist of one polycarbonate block, and two polyester blocks.
One embodiment is a polycarbonate-polylactide block copolymer, comprising: a polycarbonate block having the structure
wherein n 1 is about 20 to about 200; and a polylactide block having the structure
wherein q 1 is about 50 to about 500. This block copolymer can be a diblock copolymer in which the polymer blocks consist of one polycarbonate block and one polylactide block. Alternatively, it can be a triblock copolymer in which the polymer blocks consist of one polycarbonate block and two polylactide blocks. The polycarbonate-polylactide block copolymer may further comprise an end group having the structure
For example, the polycarbonate-polylactide block copolymer can comprise two end groups each independently having the structure
In addition to being described in terms of its component polymer blocks, the polycarbonate-polyester block copolymer may be described in terms of its complete structure. For example, in some embodiments, the polycarbonate-polyester block copolymer is a diblock copolymer having the structure
wherein each occurrence of R 1 is independently a C 6 -C 60 divalent hydrocarbon group, provided that at least 60% of the R 1 groups comprise aromatic moieties; R 2 is a C 6 -C 18 arylene group; R 3 is a C 1 -C 12 alkylene group; each occurrence of R 4 and R 5 is independently hydrogen or C 1 -C 12 alkyl; R 6 is C 6 -C 18 aryl; each occurrence of p is independently 0, 1, 2, 3, 4, or 5; n is 2 to about 200, specifically about 10 to about 100, more specifically about 20 to about 50; and q is 2 to about 1,000, specifically about 10 to about 500, more specifically about 50 to about 500, more specifically about 100 to about 500, even more specifically about 150 to about 500.
In another embodiment, the polycarbonate-polyester block copolymer is an uncapped triblock copolymer having the structure
wherein each occurrence of R 1 is independently a C 6 -C 60 divalent hydrocarbon group, provided that at least 60% of the R 1 groups comprise aromatic moieties; each occurrence of R 2 is independently a C 6 -C 18 arylene group; each occurrence of R 3 is independently a C 1 -C 12 alkylene group; each occurrence of R 4 and R 5 is independently hydrogen or C 1 -C 12 alkyl; each occurrence of p is independently 0, 1, 2, 3, 4, or 5; n is 2 to about 200, specifically about 10 to about 100, more specifically about 20 to about 50; and each occurrence of q is 2 to about 1,000, specifically about 10 to about 500, more specifically about 50 to about 500, more specifically about 100 to about 500, even more specifically about 150 to about 500.
In another embodiment, the polycarbonate-polyester block copolymer is a capped diblock copolymer having the structure
wherein each occurrence of R 1 is independently a C 6 -C 60 divalent hydrocarbon group, provided that at least 60% of the R 1 groups comprise aromatic moieties; R 2 is a C 6 -C 18 arylene group; R 3 is a C 1 -C 12 alkylene group; each occurrence of R 4 and R 5 is independently hydrogen or C 1 -C 12 alkyl; each occurrence of p is independently 0, 1, 2, 3, 4, or 5; each occurrence of R 6 is independently a C 6 -C 18 aryl group; n is 2 to about 200, specifically about 10 to about 100, more specifically about 20 to about 50; q is 2 to about 1,000, specifically about 10 to about 500, more specifically about 50 to about 500, more specifically about 100 to about 500, even more specifically about 150 to about 500; and x is 0 or 1.
In another embodiment, the polycarbonate-polyester block copolymer is a capped triblock copolymer having the structure
wherein each occurrence of R 1 is independently a C 6 -C 60 divalent hydrocarbon group, provided that at least 60% of the R 1 groups comprise aromatic moieties; each occurrence of R 2 is independently a C 6 -C 18 arylene group; each occurrence of R 3 is independently a C 1 -C 12 alkylene group; each occurrence of R 4 and R 5 is independently hydrogen or C 1 -C 12 alkyl; each occurrence of p is independently 0, 1, 2, 3, 4, or 5; each occurrence of R 6 is independently a C 6 -C 18 aryl group; n is 2 to about 200, specifically about 10 to about 100, more specifically about 20 to about 50; each occurrence of q is 2 to about 1,000, specifically about 10 to about 500, more specifically about 50 to about 500, more specifically about 100 to about 500, even more specifically about 150 to about 500; and x is 0 or 1.
In another embodiment, the polycarbonate-polyester block copolymer is an uncapped polycarbonate-polylactide diblock copolymer having the structure
wherein n 1 is about 20 to about 200; and q 1 is about 50 to about 500.
In another embodiment, the polycarbonate-polyester block copolymer is an uncapped polycarbonate-polylactide triblock copolymer having the structure
wherein n 1 is about 20 to about 200; and each occurrence of q 1 is about 50 to about 500.
In another embodiment, the polycarbonate-polyester block copolymer is a capped polycarbonate-polylactide diblock copolymer having the structure
wherein n 1 is about 20 to about 200; and q 1 is about 50 to about 500.
In another embodiment, the polycarbonate-polyester block copolymer is a capped polycarbonate-polylactide triblock copolymer having the structure
wherein n 1 is about 20 to about 200; and each occurrence of q 1 is about 50 to about 500.
Other embodiments include methods of preparing the polycarbonate-polyester block copolymer. Thus, one embodiment is a method of preparing a polycarbonate-polyester block copolymer, comprising: conducting a ring-opening polymerization of an aliphatic cyclic ester in the presence of a polycarbonate containing at least one alcohol end group to form an uncapped polycarbonate-polyester block copolymer; wherein the polycarbonate has the structure
wherein each occurrence of R 1 is independently a C 6 -C 60 divalent hydrocarbon group, provided that at least 60% of the R 1 groups comprise aromatic moieties; each occurrence of R 2 is independently a C 6 -C 18 arylene group; each occurrence of R 3 is independently a C 1 -C 12 alkylene group; Y 1 is C 6 -C 18 aryl or —R 2 —R 3 —OH; and n is 2 to about 200, specifically about 10 to about 100, more specifically about 20 to about 50.
Aliphatic cyclic esters suitable for use in the method include, for example, glycolide, lactides (including L,L-lactide, D,D-lactide, and rac-lactide), β-propiolactone, β-butyrolactone, γ-butyrolactone, δ-valerolactone, ε-caprolactone, and mixtures thereof. In some embodiments, the cyclic ester is L,L-lactide or rac-lactide.
The ring-opening polymerization is typically conducted in the presence of a catalyst. Suitable catalysts include, for example, stannous ethoxide, stannous n-butoxide, stannous octoate, magnesium ethoxide, aluminum isopropoxide, zinc n-butoxide, titanium n-butoxide, zirconium n-propoxide, dibutyltin dimethoxide, tributyltin methoxide, and mixtures thereof. Enzymatic catalysts can also be used. In some embodiments, the catalyst comprises comprising stannous octoate (also known as stannous 2-ethylhexanoate; CAS Reg. No. 301-10-0).
The ring-opening polymerization may be conducted in solution (that is, in the presence of a solvent), or in “bulk” or “melt” (that is, in the absence of a solvent). Solvents suitable for use in solution ring-opening polymerization include, for example, chlorinated solvents (including methylene chloride), tetrahydrofuran, benzene, toluene, and the like, and mixtures thereof.
The method can, optionally, further include capping the uncapped polycarbonate-polyester block copolymer. Suitable capping agents include, for example, aryl chloroformates (such as phenyl chloroformate), aromatic acid halides (such as benzoyl chloride and toluoyl chlorides), aromatic anhydrides (such as benzoic anhydride), and mixtures thereof.
One embodiment is a method of preparing a polycarbonate-polylactide block copolymer, comprising: conducting a ring-opening polymerization of a lactide in the presence of a polycarbonate with at least one alcohol end group to form an uncapped polycarbonate-polylactide block copolymer; wherein the polycarbonate has the structure
wherein R 9 is
and n 1 is about 20 to about 200, specifically about 10 to about 100, more specifically about 20 to about 50. The method can, optionally, further comprise reacting the uncapped polycarbonate-polylactide block copolymer with phenyl chloroformate to form a phenyl carbonate-capped polycarbonate-polylactide block copolymer.
Other embodiments include compositions comprising the polycarbonate-polyester block copolymer. For example, one embodiment is a composition, comprising: a polycarbonate; and a polycarbonate-polyester block copolymer comprising a polycarbonate block having the structure
wherein each occurrence of R 1 is independently a C 6 -C 60 divalent hydrocarbon group, provided that at least 60% of the R 1 groups comprise aromatic moieties; Y is —O— or —O—R 2 —R 3 —O—; each occurrence of R 2 is independently a C 6 -C 18 arylene group; each occurrence of R 3 is independently a C 1 -C 12 alkylene group; and n is 2 to about 200, specifically about 10 to about 100, more specifically about 20 to about 50; and an aliphatic polyester block having the structure
wherein each occurrence of R 4 and R 5 is independently hydrogen or C 1 -C 12 alkyl; each occurrence of p is independently 0, 1, 2, 3, 4, or 5; and q is 2 to about 1,000, specifically about 10 to about 500, more specifically about 50 to about 500, more specifically about 100 to about 500, even more specifically about 150 to about 500. Polycarbonates that are suitable for blending with the polycarbonate-polyester block copolymer include those comprising repeating units having the structure
wherein R 1 has the same definition used above in the context of the polycarbonate block of the polycarbonate-polyester block copolymer. The polycarbonate can have an intrinsic viscosity, as determined in chloroform at 25° C., of about 0.3 to about 1.5 deciliters per gram (dl/gm), specifically about 0.45 to about 1.0 dl/gm. The polycarbonates can have a weight average molecular weight of about 10,000 to about 200,000 atomic mass units, specifically about 20,000 to about 100,000 atomic mass units, as measured by gel permeation chromatography (GPC) using a crosslinked styrene-divinylbenzene column and calibrated to polycarbonate references. GPC samples are prepared at a concentration of about 1 milligram/milliliter, and are eluted at a flow rate of about 1.5 milliliters/minute. The composition can comprise the polycarbonate and the polycarbonate-polyester block copolymer in a weight ratio of about 1:99 to about 99:1, specifically about 10:90 to about 90:10, more specifically about 20:80 to about 80:20. The composition comprising the polycarbonate and the polycarbonate-polyester block copolymer may be prepared by polymer blending methods known in the art, including solution blending and melt blending (for example, melt kneading in an extruder).
Other embodiments include articles comprising the polycarbonate-polyester block copolymer or a composition comprising the polycarbonate-polyester block copolymer. The polycarbonate-polyester block copolymer is particularly useful for fabricating articles including mobile phone A-covers (front covers), shavers, razors, notebooks, automotive and transportation parts, medical parts and housings, and disposable packaging.
The invention is further illustrated by the following non-limiting examples.
EXAMPLE 1
This example describes the preparation of a polycarbonate. The following were added into a 80 L continuously stirred tank reactor (CSTR) equipped with an overhead condenser and a recirculation pump with a flow rate of 40 L/minute: (a) Bisphenol A (5000 grams, 21.9 mole); (b) methylene chloride (26.7 L); (c) deionized water (13.5 liters), (d) 4-hydroxybenzyl alcohol (81.7 grams, 0.66 mole) (e) sodium gluconate (10 grams); and (f) triethylamine (30 grams). Phosgene (2862 grams, 28.9 moles) was added at a rate of 165 grams/minute with simultaneous addition of base (50 weight percent NaOH in deionized water) to maintain the pH of the reaction between 9 and 10. After the complete addition of phosgene, the reaction mixture was purged with nitrogen gas, and the organic layer was extracted. The organic extract was washed once with dilute hydrochloric acid (HCl), and subsequently washed with deionized water by centrifugation. The organic layer was precipitated from methylene chloride into hot steam. The polymer was dried under hot nitrogen before analysis. The polycarbonate product displayed the following characteristics: weight average molecular weight (M w )=27,000, polydispersity index (PDI; M w /M n )=2.4; T g =153° C.
EXAMPLE 2
This example describes the preparation of a partially capped polycarbonate. The following were added into a 80 liter CSTR equipped with an overhead condenser and a recirculation pump with a flow rate of 40 liters/minute: (a) bisphenol A (5,000 grams, 21.9 moles); (b) methylene chloride (26.7 liters); (c) deionized water (13.5 liters), (d) 4-hydroxybenzyl alcohol (61.3 grams, 0.49 moles) (e) paracumylphenol (35.9 grams, 0.17 moles), (f) sodium gluconate (10 grams); and (g) triethylamine (30 grams). Phosgene (2862 grams, 165 grams/minute, 28.9 moles) was added with simultaneous addition of base (50 weight percent NaOH in deionized water) to maintain the pH of the reaction between 9 and 10. After the complete addition of phosgene, the reaction mixture was purged with nitrogen gas, and the organic layer was extracted. The organic extract was washed once with dilute hydrochloric acid (HCl), and subsequently washed with deionized water by centrifugation. The organic layer was precipitated from methylene chloride into hot steam. The polymer was dried under hot nitrogen before analysis. The polycarbonate product displayed the following characteristics: M w =34,800, PDI=3.95; T g =153° C. It should be noted that polycarbonate product is expected to be a mixture of polycarbonate molecules with two 4-hydroxymethylphenyl end groups, one 4-hydroxymethylphenyl end group and one 4-cumylphenyl end group, and two 4-cumylphenyl end groups.
EXAMPLE 3
This example describes the preparation of a polycarbonate-polylactide block copolymer using a solution polymerization method.
In general, of polycarbonate-polyester copolymers were prepared by solution (that is, in the presence of solvent) or bulk (or melt; that is, in the absence of solvent) ring-opening polymerization of a cyclic ester in the presence of a polycarbonate and a catalyst for the ring-opening polymerization. The polycarbonate starting materials were crushed using a mortar and pestle and dried in an oven set at 110° C. for at least four hours. The cyclic ester monomers were kept in a refrigerator when not being used. Stannous octoate (Sn(Oct) 2 ; CAS Reg. No. 301-10-1) was used as the catalyst for the reactions. All glassware was dried overnight in an oven set at 180° C. All reactions were performed under N 2 .
In a typical reaction, 10.0 grams of racemic lactide (rac-LA; CAS Reg. No. 95-96-5; 0.07 moles), 5 grams of crushed polycarbonate from Example 1 (0.044 millimoles), and 100 milliliters of toluene were added to a 3-necked round bottom flask equipped with a magnetic stir bar, a condenser, and a N 2 inlet and outlet. The solution and contents were allowed to heat to reflux until all of the reactants were completely dissolved. Once dissolved, 2.6 grams (0.56 millimoles) of a Sn(Oct) 2 catalyst solution diluted in toluene was injected into the reaction flask. The reaction was allowed to stir for 1 hour. The solution was allowed to cool, and the product was dissolved in methylene chloride and precipitated drop-wise into methanol. The precipitate was dried in an oven set at 110° C. The M w was measured to be 35,880 g/mol and PDI was 1.47 (relative to polycarbonate standards).
EXAMPLE 4
This example describes the preparation of a polycarbonate-polylactide block copolymer using a solution polymerization method. In a typical reaction, 5.0 grams of rac-LA (0.035 moles), 5 grams of crushed polycarbonate from Example 1 (0.044 millimoles), and 100 milliliters of toluene were added to a 3-necked round bottom flask equipped with a magnetic stir bar, a condenser, and a N 2 inlet and outlet. The solution and contents were allowed to heat to reflux until all of the reactants were completely dissolved. Once dissolved, 2.6 grams (0.56 millimoles) of a Sn(Oct) 2 catalyst solution diluted in toluene was injected into the reaction flask. The reaction was allowed to stir for 1 hour. The solution was allowed to cool, and the product was dissolved in methylene chloride and precipitated drop-wise into methanol. The precipitate was dried in an oven set at 110° C. The M w was measured to be 51,317 g/mol and PDI was 1.4 (relative to polycarbonate standards).
EXAMPLE 5
This example describes the preparation of a polycarbonate-polylactide block copolymer using a melt polymerization method. In a typical reaction, 10.0 grams of dry polycarbonate from Example 2 (1.6 millimoles) and 10.0 grams of rac-LA (0.07 mole) were charged to a 3-necked round bottom flask equipped with an overhead mechanical stirrer and a N 2 inlet and outlet. The flask was submersed into an oil bath thermostatted to 155° C., and the contents in the flask were stirred until completely melted. Once the contents were melted, a catalytic amount of Sn(Oct) 2 was added to the flask (0.25-0.5 millimole Sn(Oct) 2 ). The reaction mixture was allowed to stir for 1 hour. After the allotted time, the flask and contents were allowed to cool, and the product was dissolved in CH 2 Cl 2 and precipitated slowly into stirring methanol. The solid was dried in an oven set at 110° C. before further characterization. The M w was measured to be 28,356 g/mol and PDI was 4.7 (relative to polycarbonate standards). Although it was unexpected that the product M w values would be less than that for the polycarbonate starting material, this may be attributable to an offset between gel permeation chromatography retention times for the polycarbonate standards and product block copolymers, which have different solubility parameters in the eluent, methylene chloride.
EXAMPLE 6
This example describes the preparation of a polycarbonate-polylactide block copolymer using a melt polymerization method. 5.0 grams of dry polycarbonate from Example 2 (0.8 millimoles) and 10.0 grams of rac-LA (0.07 moles) were charged to a 3-necked round bottom flask equipped with an overhead mechanical stirrer and a N 2 inlet and outlet. The flask was submersed into an oil bath thermostatted to 160° C., and the contents in the flask were stirred until completely melted. Once the contents were melted, a catalytic amount of Sn(Oct) 2 was added to the flask (0.25-0.5 millimole Sn(Oct) 2 ). The polymerization was allowed to stir for 1 hour. After the allotted time, the flask and contents were allowed to cool, and the product was dissolved in CH 2 Cl 2 and precipitated slowly into stirring methanol. The solid was dried in an oven set at 110° C. before further characterization. The M w was measured to be 38,398 g/mol and PDI was 1.5 (relative to polycarbonate standards).
EXAMPLE 7
This example describes the preparation of a polycarbonate-polylactide block copolymer using a melt polymerization method. Into a 1 L 3-necked round bottom flask equipped with an overhead mechanical stirrer, a thermocouple, and a N 2 inlet and outlet was charged 125.0 grams of the polycarbonate from Example 2 (20 millimoles) and 125.0 grams of L,L-lactide (0.87 moles). The flask was place in a heating mantle and the thermocouple was plugged into a variable control temperature device set to a temperature of 190° C. The contents in the flask were stirred until completely melted. Once the contents were melted, a catalytic amount of Sn(Oct) 2 was added to the flask (5.0 millimoles Sn(Oct) 2 ). The polymerization was allowed to stir for 2 hours. After the allotted time, the flask and contents were allowed to cool, and the product was dissolved in CH 2 Cl 2 and precipitated slowly into stirring methanol. The solid was dried in an oven set at 110° C. before further characterization. The M w was measured to be 25,801 g/mol and PDI was 3.8 (relative to polycarbonate standards).
EXAMPLE 8
This example describes chain end modification of a polycarbonate-polylactide block copolymer. Prior to the reaction, the polycarbonate-polylactide block copolymer prepared in Example 3 was dried in an oven set at 110° C. overnight. Into a 3-necked round bottom flask was charged 5 grams of the polycarbonate-polylactide block copolymer (0.41 millimoles hydroxy groups theoretically, 30 milliliters of tetrahydrofuran (THF), and 0.12 grams of phenyl chloroformate (0.77 millimoles). The reactants were allowed to stir under N 2 , and then 0.1 grams of triethylamine (1.0 millimole) was added drop wise by syringe into the flask. The triethylammonium hydrochloride (TEA-HCl) precipitate was filtered and disposed, and the product was precipitated drop-wise into stirring excess methanol. The material was dried in an oven set at 110° C. The M w was measured to be 38,370 g/mol and PDI was 1.6 (relative to polycarbonate standards).
EXAMPLE 9
This example describes chain end modification of a polycarbonate-polylactide block copolymer. The Example 5 polycarbonate-polylactide block copolymer was transformed into a phenyl carbonate capped polycarbonate-polylactide block copolymer using the method described in Example 8. The M w was measured to be 29,110 g/mol and PDI was 2.5 (relative to polycarbonate standards).
EXAMPLE 10
This example describes chain end modification of a polycarbonate-polylactide block copolymer. Into a 1 L 3-necked round bottom flask, 80.0 grams of the Example 8 polycarbonate-polylactide block copolymer (26.8 millimoles total hydroxy groups), 500 milliliters of THF, and 4.2 grams phenyl chloroformate (26.8 millimoles) was combined and stirred until completely dissolved. Using a syringe, 3 grams of triethylamine (30 millimoles) was added drop-wise to the flask. The TEA-HCl precipitate was filtered, and the polymer was concentrated by removing approximately 250 milliliters of THF under vacuum. The polymer was precipitated into stirring methanol (1 liter). The M w was measured to be 20,953 g/mol and PDI was 3.1 (relative to polycarbonate standards).
Characterization of Polycarbonate-Polylactide Copolymers
In the above examples, several variables were adjusted to achieve a broad range of materials for testing. The monomer to initiator ratio was varied to control the molecular weight of the lactide block, and this directly affected the polycarbonate-polylactide reaction due to the fact that the initiator was one of the copolymer blocks. The reactions were done in solution or in bulk for the ring opening polymerization, and the bulk was preferred for ease of work-up. The kinetics of the ring opening of the lactide in bulk are well known, and most reaction mixtures stopped stirring within 5 to 10 minutes of the addition of Sn(Oct) 2 catalyst due to the high viscosity of the materials in the melt, which developed quickly upon addition of the Sn(Oct) 2 catalyst. Table 1 displays the properties for the materials synthesized. Glass transition temperature (T g ) and melting temperature (T m ) values were measured by differential scanning calorimetry (DSC). Onset degradation temperatures were measured by thermal gravimetric analysis (TGA) and defined as the temperature at which 99 weight percent of the material remains. Mole percent lactic acid was determined by proton nuclear magnetic resonance spectroscopy ( 1 H NMR) using integrated values of the methane protons of poly(lactic acid) versus the aromatic protons of poly(bisphenol A carbonate).
TABLE 1
Onset of
Degradation
Mole % lactic
Temperature
acid in
Entry
M w
PDI
(° C.)
T g (° C.)
copolymer
Ex. 1
27,000
2.4
459
153
0
Ex. 2
34,800
4.0
459
153
0
Ex. 3
35,880
1.5
220
121
53
Ex. 4
51,320
1.4
262
134
24
Ex. 5
28,360
3.4
256
50; 121
70
Ex. 6
38,370
1.6
262
124
43
Ex. 7
25,800
3.8
258
n/m
78
Ex. 8
38,400
1.5
169
57
77
Ex. 9
29,110
2.5
283
123
54
Ex. 10
20,950
3.1
281
86; (T m = 196)
79
The results indicate that the thermal decomposition temperatures were lower in the copolymers as compared to the polycarbonates of Examples 1 and 2. On the other hand, phenyl carbonate-capped polycarbonate-polylactide copolymers showed a significantly higher onset of decomposition temperatures that the non-capped copolymers. See, for example, the phenyl carbonate-capped block copolymer of Example 6 (262° C.) versus the corresponding uncapped block copolymer of Example 3 (220° C.); and the phenyl carbonate-capped block copolymer of Example 9 (283° C.) versus the corresponding uncapped block copolymer of Example 5 (256° C.).
EXAMPLE 10
This example illustrates the preparation of films comprising the polycarbonate-polylactide block copolymers. The polycarbonate-polylactide block copolymers of Examples 3 to 9 were pressed into films, and the films were translucent to opaque, indicating phase separation/immiscibility of the polylactide and polycarbonate components. In contrast, films prepared from the Example 1 and Example 2 polycarbonates were transparent. In FIG. 1, the transmission electron microscopic image for the Example 1 polycarbonate shows a single continuous phase. Also in FIG. 1, the image for the Example 4 polycarbonate-polylactide block copolymer shows a two-phase system. The lighter images in the TEM image for the polycarbonate-polylactide represent the polylactide domains, which are on the order of 10 to 100 nanometers in size. Most of the polylactide domains have a small, circular particle size, indicative of the controlled nature of the ring opening polymerization and corresponding narrow molecular weight distribution.
This written description uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to make and use the invention. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal language of the claims.
All cited patents, patent applications, and other references are incorporated herein by reference in their entirety. However, if a term in the present application contradicts or conflicts with a term in the incorporated reference, the term from the present application takes precedence over the conflicting term from the incorporated reference.
All ranges disclosed herein are inclusive of the endpoints, and the endpoints are independently combinable with each other.
The use of the terms “a” and “an” and “the” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Further, it should further be noted that the terms “first,” “second,” and the like herein do not denote any order, quantity, or importance, but rather are used to distinguish one element from another. The modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes the degree of error associated with measurement of the particular quantity).
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A polycarbonate-polyester block copolymer includes a polycarbonate block and a polyester block, each having specific structures. The block copolymer can be prepared, at least in part, from renewable feedstocks. In some forms, the block copolymer includes biodegradable segments that facilitate structural breakdown of objects molded from the block copolymer. Methods of preparing the block copolymer are described as are compositions that include it and articles prepared from it.
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The invention described herein was made in the course of, or under, a grant from the National Institutes of Health.
BACKGROUND OF THE INVENTION
During a study of Caribbean sponges, several sponges of the genus Agelas were examined and all gave ethanolic extracts having antimicrobial activity, in agreement with previous reports. Burkholder, P. R. in "Biology and Geology of Coral Reefs, Biology I"; Jones, O. A.; Endean, R., Eds.; Academic Press: New York, 1973; p. 144. Prior studies by Minale et al., Minale, L.; Cimino, G.; de Stefano, S.; Sodano, G. Prog. Chem. Nat. Prod. 1976, 33, 1 resulted in the identification of 4,5-dibromo-2-cyanopyrrole as the antimicrobial constituent of the Mediterranean sponge Angelas oroides. A. oroides also contained 4,5-dibromopyrrole-2-carboxylic acid, Forenza, S. L.; Minale, L.; Riccio, R.; Fattorusso, E. Chem. Commum. 1971, 1129, the corresponding amide, and oroidin having the formula: ##STR2##
According to this invention, we have now discovered the major antimicrobial constituent of Agelas sceptrum (Lamarck), Agelas conifera, Agelas schmidti, an unknown sponge species from Canton atoll in the South Pacific (collection No. 78-012) and an unknown sponge, Axinella sp., from Belize which have been found to possess superior antimicrobial properties.
SUMMARY OF THE INVENTION
Briefly, the present invention comprises a novel antimicrobial agent having the formula: ##STR3## the free amine of the above compound, other tautomers, other salts and amides of said free amine, and each of said compounds associated with water of crystallization.
It is an object of this invention to provide a novel antimicrobial agent.
It is also a further object of this invention to provide a novel preparation of the antimicrobial agent.
These and other objects and advantages of this invention will be apparent from the detailed description which follows.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The source of the compound of the above formula is from Agelas sceptrum (Lamarck), Agelas conifera, Agelas schmidti, an unknown sponge species from Canton atoll in the South Pacific, and an unknown sponge, Axinella sp., from Belize.
The dihydrochloride can be converted to the free amine by reaction with a stoichiometric amount of a base such as sodium hydroxide which eliminates two moles of HCl. The diamide can be formed by reaction of the free amine with a stoichiometric amount of a lower aliphatic monocarboxylic acid anhydride. For example, the diacetate of the free amine is obtained by reaction of the free amine with two moles of acetic anhydride. Other such acids containing from 1 to about 10 carbon atoms can be used. Salts other than the dihydrochloride can be made by neutralization of the free amine with mineral acids such as dilute sulfuric acid.
The compound, as isolated, is normally associated with several moles of water as water of crystallization. The invention comprehends all such compounds with or without water of crystallization.
The following example is intended solely to illustrate the invention and should not be regarded as limiting in any way. In the Example, the parts and percentages are by weight unless otherwise indicated.
EXAMPLE
Agelas sceptrum, collected at Glover Reef, Belize, was maintained frozen until required. The lyophilized sponge was extracted sequentially with hexane, dichloromethane, and methanol. The acetone-insoluble portion of the methanolic extract was twice chromatographed on Sephadex LH-20 using first methanol then 1:1 methanol/chloroform as eluants to obtain a fraction containing the antimicrobial material. This fraction was chromatographed on a LiChrosorb DIOL column using 1:1 methanol/chloroform as eluant to obtain oroidin (0.01% dry weight) and a compound of the formula: ##STR4## (0.1% dry weight). The compound of the foregoing formula is hereinafter referred to as a sceptrin. Traces of a colored impurity were removed by passing an aqueous solution of sceptrin through Sephadex G-10, after which it was crystallized from water. Sceptrin, mp. 215°-225° C. (dec.), [α] D -7.4° (c 2.5, MeOH), had the molecular formula C 22 H 24 Br 2 N 10 O 2 .2HCl.nH 2 O. The elemental analysis of a sample dried at 110° C. over P 2 O 5 required one molecule of water per sceptrin molecule while the x-ray study indicated three water molecules per sceptrin. The electron impact mass spectrum did not show a molecular ion but the field desorption mass spectrum contained a triplet at m/z 619, 621, 623 (C 22 H 25 Br 2 N 10 O 2 ) + . The following spectral data indicated that sceptrin was a symmetrical dimer of oroidin: IR (KBr) 3350, 1680, 1625 cm -1 ; UV (MeOH) 265 nm (ε 20,850); 1 H NMR (DMSO-d 6 ) δ 2.29 (b s, 1 H), 3.10 (d, 1 H, J=8 Hz), 3.42 (b s, 2 H), 6.66 (s, 1 H), 6.97 (s, 1 H), 6.99 (s, 1 H), 7.33 (b s, 2 H), 8.59 (b t, 1 H, J≈5 Hz); 13 C NMR (D 2 O) δ 160.8 (s), 145.7 (s), 123.9 (s), 121.6 (d), 111.6 (d), 108.3 (d), 95.2 (s), 41.6, 40.9, 36.9.
Sceptrin crystallized in the monoclinic crystal class and accurate cell constants determined by a least-squares fit of 15 high angle reflections were a=19.788(8), b=13.337(4), and c=13.725(7) A and β=122.69(2)°. Systematic extinctions (h+k=2n), a calculated density of 1.63 g/cm 3 , and the presence of chirality were uniquely accomodated by the space group C2 with four molecules of C 22 H 26 Br 2 Cl 2 N 10 O 2 .3H 2 O per unit cell. All unique diffraction maxima with 2θ≦100° were collected on a computer-controlled four-circle diffractometer using graphite monochromated CuKα (1.54178 A) radiation and a variable speed ω-scan technique. Of the 2172 unique reflections surveyed in this fashion, 1697 (78%) were judged observed [F o ≧3 (F o )] after correction for Lorentz, polarization, and background effects.
A phasing model was achieved by standard heavy-atom procedures. The following library of crystallographic programs was used: Germain, G., Main, P.; Woolfson, M. M. Acta Cryst. 1970, B24, 274 (MULTAN); Hubbard, C. R.; Quicksall, C. O.; Jacobson, R. A. "The Fast Fourier Algorithm and the programs ALFF, ALFFDP, ALFFT and FRIEDEL", USAEC Report IS-2625; Institute for Atomic Research, Iowa State University, Ames, Ia, 1971; Busing, W. R.; Martin, K. O.; Levy, H. A. "A Fortran Crystallographic Least Squares Program", USAEC Report ORNL-TM-305; Oak Ridge National Laboratory, Oak Ridge, Tn., 1965; Johnson, C. "ORTEP: A Fortran Thermal-Ellipsoid Plot Program", USAEC Report ORNL-3794; Oak Ridge, Tn. 1965. The deconvolution of the Patterson synthesis gave the Br positions. The remaining non-hydrogen atoms were located in subsequent electron density maps. Full-matrix least-squares refinement with anisotropic temperature factors for the non-hydrogen atoms, isotropic hydrogens, and anomolous dispersion corrections have converged to a standard crystallographic residual of 0.090 for the structure and 0.094 for the enantiomer.
The two-fold axis of the sceptrin molecule is coincident with the crystallographic two-fold axis. Thus, only half of the atoms in one molecule are independent and the asymmetric unit of the cell contains two such independent C 11 H 13 BrClN 5 O groups. A drawing of the final x-ray model for one molecule of sceptrin is given. Bond distances and angles agree well with generally accepted values.
Antimicrobial assays of the crude extracts of six Agelas samples revealed the presence of active compounds in all samples. However, when the crude extracts were partitioned between ethyl acetate and water, A. sceptrum was particularly distinguished by the strong antimicrobial activity of the aqueous phase.
Sceptrin exhibited antimicrobial activity against Staphylococcus aureus (MIC 15 μg/ml), Bacillus subtilis, Candida albicans, Pseudomonas aeruginosa, Alternaria sp. (fungus), and Cladosporium cucumerinum. The antimicrobial activity of sceptrin was considerably greater than that recorded for oroidin.
Acute toxicity studies in mice indicated that sceptrin was not toxic at a level of 50 milligrams per kilogram.
The novel antimicrobial agent can be administered to humans in tablet or capsule form. The drug can also be blended with conventional excipients and the like prior to tableting. The drug can also be formulated into parenteral solutions for injection using the usual liquid pharmaceutical carriers.
Having fully described the invention, it is intended that it be limited only by the lawful scope of the appended claims.
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A novel antimicrobial agent having the formula: ##STR1## The new antimicrobial agent may exist as the dihydrochloride salt, as shown or as tautomers of the structure, or in the form of other salts and derivatives such as amides and is normally associated with water of crystallization.
The novel antimicrobial agent is obtained from Agelas sceptrum, Agelas conifera, Agelas schmidti, an unknown sponge species from Canton atoll and an unknown sponge Axinella sp., from Belize.
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RELATED APPLICATIONS
This application is a continuation of U.S. patent application Ser. No. 12/762,000 filed on Apr. 16, 2010, the entire content of which is hereby incorporated by reference herein.
BACKGROUND
The present invention generally relates to the field of paper shredders, and specifically to paper shredders that have a mechanism for removing staples and paper clips prior to shredding.
Paper shredders are commonly used to shred documents in order to preserve the confidentiality of the information on the documents. Shredders come in a variety of sizes, from large industrial shredders capable of shredding stacks of sheets of paper at one time, to personal and office shredders that can shred up to several sheets at one time.
Personal and office shredders are commonly designed to have paper hand fed into the shredder. These shredders include a slot, typically on the top of the shredder, and sheets of paper are fed into the slot. While these shredders are often designed to accommodate staples and paper clips, it is desirable to remove staples and paper clips prior to shredding in order to prevent damage to or jamming of the shredder
Some shredders are designed to accommodate a stack of paper for shredding. These shredders commonly pull sheets of paper from the bottom of a stack for shredding several sheets at a time. When shredding a stack of paper, staples or paper clips can be embedded in the stack, and thus it is impractical to remove all staples and paper clip prior to shredding. While these shredders can often accommodate staples and paper clips, it would be desirable to have a system for removing staples and paper clips from sheets of paper within a stack prior to shredding.
SUMMARY OF THE INVENTION
The present invention provides a paper shredder that facilitates the removal of staples and paper clips from sheets within a stack prior to shredding. The shredder includes a housing, cutters positioned in the housing, and a feeder base adapted to support a stack of paper. The feeder base includes a feeder slot. The feeder base further includes a first aperture on one side of the feeder slot, the first aperture providing a first communication pathway between a top surface of the feeder base and a waste area below the feeder base, and a second aperture on a same side of the feeder slot as the first aperture, the second aperture providing a second communication pathway between the top surface of the feeder base and the waste area below the feeder base. The first and second communication pathways are separated from one another.
In one aspect, the first and second communication pathways are separated from one another by a portion of the feeder base. The first aperture facilitates the stack of paper supported on the feeder base folding over at a corner corresponding to the first aperture, the second aperture facilitates the stack of paper supported on the feeder base folding over at a corner corresponding to the second aperture, and the portion of the feeder base separating the first and second communication pathways supports the stack of paper between the first and second apertures.
In another aspect, the first and second apertures are each positioned at a different corner of the feeder base and are each completely surrounded by the feeder base.
The present invention also provides a shredder having a housing, cutters positioned in the housing, and a feeder base coupled to the housing and adapted to support a stack of paper. The feeder base includes a feeder slot through which paper passes for shredding in the cutters. The feeder base is integrally-formed as one piece having a front portion, a rear portion, and a sidewall along first and second sides and spanning the feeder slot.
Other aspects of the invention will become apparent by consideration of the detailed description and accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates a paper shredder embodying the present invention.
FIG. 2 is an exploded view of the shredder of FIG. 1 .
FIG. 3 is an exploded view of a feeder assembly of the shredder of FIG. 1 .
FIG. 4 is a section view taken along line 4 - 4 of FIG. 1 .
FIG. 5 is a perspective view of the shredder of FIG. 1 with the feeder assembly removed.
FIG. 6 is a top view of the shredder shown in FIG. 5 .
FIG. 7 is a section view taken along line 7 - 7 in FIG. 6 .
FIG. 8 is a top view of a shredder that is an alternate embodiment of the present invention.
FIG. 9 is a bottom perspective view of a feeder assembly of the shredder of FIG. 10 .
FIG. 10 is a side view of a pressure plate and feeder base of the second embodiment.
FIG. 11 is a perspective section view of a rear feeder base taken along line 11 - 11 in FIG. 10 .
DETAILED DESCRIPTION
Before any embodiments of the invention are explained in detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the following drawings. The invention is capable of other embodiments and of being practiced or of being carried out in various ways.
The illustrated shredder includes a housing 20 , a litter bin 22 positioned in the housing 20 , a top cover 24 mounted on top of the housing 20 , an engine assembly 26 mounted in the top cover 24 , a feeder base 28 mounted on the top cover 24 , and a feeder assembly 30 pivotally mounted to the feeder base 28 . By pivoting the feeder assembly 30 upward, a stack of paper 32 can be placed on the feeder base 28 in preparation for shredding. The feeder assembly 30 is then closed, and the shredding operation is performed by pulling bottom sheets of the stack of paper 32 through the feeder base 28 and into the engine assembly 26 . The paper passes through rotary cutters 34 ( FIG. 8 ) in the engine assembly 26 , which shred the paper and drop it into a waste area where the litter bin 22 is positioned. After shredding is completed, the litter bin 22 can be slid out the front of the housing 20 for disposal.
The feeder assembly 30 is shown in more detail in FIGS. 2-4 . The feeder assembly 30 includes a feeder door 40 pivotally mounted to the feeder base 28 and moveable between a lowered position and a raised position. The illustrated feeder door 40 is a one-piece door that substantially covers the entire feeder base and is pivoted about an axis at one end of the feeder door 40 . Two turn springs 42 bias the feeder door 40 toward the raised position. A catch button 44 and latch 46 are mounted on the free end of the feeder door 40 . The catch button 44 is positioned within an opening 48 in the feeder door 40 and is designed to be moveable vertically from a released position to a pressed position. The latch 46 is mounted for horizontal movement relative to the feeder door 40 between a latched position, where it engages a lip 50 ( FIG. 4 ), and an unlatched position. A pair of latch springs 52 bias the latch 46 toward the latched position and, due to a camming interface 54 ( FIG. 4 ) between the latch 46 and the catch button 44 , such bias of the latch 46 also biases the catch button 44 toward the released position. When the catch button 44 is not pressed, it is in the released position and the latch 46 is in the latched position, which will hold the feeder door 40 in its lowered position relative to the top cover 24 . When the catch button 44 is moved toward the pressed position, the latch 46 will be moved toward the unlatched position, which will release engagement between the latch 46 and the lip 50 , and will allow the feeder door 40 to pivot upward to the raised position.
The feeder assembly 30 further includes a pressure plate 56 mounted adjacent the bottom surface of the feeder door 40 . The pressure plate 56 is a one-piece member that includes a series of posts 60 that are dimensioned to slide within corresponding openings 62 in the feeder door 40 such that the pressure plate 56 can float vertically relative to the feeder door 40 . A series of push springs 64 bias the pressure plate 56 away from the feeder door 40 . Pressure rollers 66 are mounted to the pressure plate 56 and are aligned on opposing sides of a central portion of the pressure plate 56 . The pressure rollers 66 can each rotate about axes A 1 relative to the pressure plate 56 , but their rotational axes A 1 are fixed relative to each other. The pressure rollers 66 are designed to apply pressure to a top sheet of a stack of sheets positioned on the feeder base. It should be understood that, in some embodiments, the pressure plate could be made of multiple members. For example, the pressure plate could include a front plate and a rear plate that are completely separate or that are hinged together to allow some degree of independent movement. This would facilitate upward movement of one of the plates (e.g., to accommodate the passage of a staple) while maintaining downward pressure of the other plate (to keep pressure on the stack of paper).
The illustrated feeder base 28 comprises a front portion 70 and a rear portion 72 , each of which includes an inner end 74 an outer end 76 . Each of the inner ends 74 includes a series of notches 78 that are dimensioned to receive a series of rubber rollers 80 that are part of the engine assembly 26 and are substantially aligned with the pressure rollers 66 . The rubber rollers 80 protrude slightly above a top surface of the feeder base 28 and are rotated by the engine assembly 26 to frictionally draw sheets of paper through a feeder slot 84 and into the rotary cutters 34 . This action is facilitated by the one-piece pressure plate that spans the feeder slot, and by downward pressure provided by the pressure rollers 66 positioned on opposing sides of the feeder slot 84 . As such, when the paper is being drawn into the cutters 34 , the paper moves toward the feeder slot 84 . The rear portion 72 of the feeder base 28 includes hinges 86 that pivotally support the feeder door 40 for pivoting about an axis A 2 . It should be understood that, in some embodiments, the feeder base 28 could be made of a single member (see FIG. 11 ) instead of separate front and rear portions.
Each of the front portion 70 and the rear portion 72 of the feeder base 28 includes two apertures 90 that provide an opening between the top surface of the feeder base 28 (which supports a stack of paper 32 in preparation for shredding) and the waste area where the litter bin 22 is positioned below the feeder base 28 . Each aperture 90 is positioned at a corner of the feeder base 28 . That is, each aperture 90 is approximately aligned with a corner of a sheet of paper positioned on the stack.
A staple plate 92 is secured to the feeder base 28 adjacent each of the apertures 90 . As best shown in FIGS. 5-6 , each staple plate 92 is positioned at an oblique angle relative to the feeder slot 84 and relative to a side edge 94 of the feeder base 28 . In the illustrated embodiment, the staple plates 92 include an edge 96 positioned above a plane defined by the top surface of the feeder base 28 . The illustrated edge 96 faces the aperture 90 and is at an angle α ( FIG. 6 ) of about 10 degrees relative to the feeder slot 84 and relative to the side edge 94 of the feeder base 28 . As used herein, a “staple plate” is used as a convenient term to describe a plate that can be used to separate a staple S ( FIG. 6 ), paper clip, or other paper-fastening device from a sheet or sheets of paper. The staple plate 92 need not have a straight edge, but instead could have an edge with an angle that varies relative to the feed slot 84 . In this regard, the angle of the edge of the staple plate 92 at any point shall be considered the tangent to the edge at that point. It should also be noted that, while the illustrated embodiment of FIGS. 1-9 utilizes the edge 96 of the staple plate 92 to define a portion of the aperture 90 , the staple plate 92 could be eliminated, in which case the “edge” would be defined by a portion of the feeder base 28 (see, e.g., the second embodiment of FIG. 10 ).
By positioning the edge 96 of the staple plate 92 at an oblique angle α relative to the feeder slot 84 , the bottom sheets 97 of paper will move in a direction that is oblique to the edge 96 of the staple plate 92 . This orientation causes the corner of a stapled stack of paper to fold over in a dog-eared fashion, as shown in FIG. 7 . When in this position, further movement of the bottom sheets 97 of paper toward the feeder slot (to the right in FIG. 7 ) causes the bottom sheets 97 to peel away from the staple S. If not for the dog-eared corner, the bottom sheets 97 would need to shear through the staple S, which is more difficult to do consistently and often causes the entire stapled stack of paper to be sucked into the feeder slot and into the cutters, which can cause a jam. After the bottom sheets 97 tear away from the staple S, the next several sheets are pulled into the feeder slot 84 , and the operation continues as described above. When the last several sheets of a staple stack are pulled into the feeder slot 84 , the staple S will be slid toward the feeder slot 84 and into engagement with the edge 96 of the staple plate 92 , where it should be held in place while the remaining sheets are torn away from the staple S. The staple S (and any small pieces of paper attached to the staple S) will then fall through the aperture 90 and into the litter bin 22 .
FIGS. 8-10 illustrate an alternate embodiment of the present invention. The illustrated shredder 200 has a feeder base 202 that is similar to the feeder base 28 of FIGS. 1-7 , with the exception of the size and shape of the openings. More specifically, the openings 204 of the second embodiment do not include a staple plate 92 . In addition, the edge of the opening 204 includes a compound angle having an inner first section 206 at an oblique angle β of about ten degrees relative to the feeder slot 208 , and an outer second section 210 at an angle γ of about twenty-eight degrees relative to the feeder slot 208 . This configuration has been found to enhance the ability of sheets of paper to peel-away from a stapled stack. That is, the steeper angle in the outer section 210 has been found to enhance the ability of a stack of sheets to fold over at the corner, thereby facilitating peeling of the lowest sheets of the stack away from the staple, as described above and illustrated in FIG. 7 . In this embodiment, it has been found that the edge of the opening is sufficient to remove paper clips. In addition, because the cutters are designed to handle staples, it is acceptable if the last few sheets (the top sheets) in a stack of stapled sheets pull the staple into the cutters.
Referring to FIGS. 9-10 , the feeder assembly 212 of the second embodiment includes a pressure plate 214 that is substantially shorter than the support surface 216 of the feeder base 202 that supports the stack of paper prior to shredding. More specifically, referring to FIG. 12 , the pressure plate 214 has a length 218 perpendicular to the feeder slot 208 of about 144 mm, compared to a corresponding length 220 of the support surface 216 of about 284 mm. As a result, the pressure plate 214 has a length that is about 50% of the length of the support surface 216 . In addition, the pressure plate 214 does not overlap with the openings 204 and the inner and outer sections 206 , 210 of the edge of the openings 204 that engage and slide paper clips off of stacks of sheets (best shown in broken lines in FIG. 10 ). This shorter pressure plate 214 functions to apply most of the pressure in the area of the feeder slot 208 , so that the pressure of the paper on the rubber rollers 80 is enhanced. In addition, this design reduces lifting of the pressure plate when a stack of stapled sheets is folded at the corner (see FIG. 7 ). Such lifting of the pressure plate will result in a loss of friction on the rubber rollers 80 , which can cause the shredder to slip (i.e., fail to draw sheets into the cutter due to insufficient friction between the rubber rollers 80 and the bottom sheet). As noted above in connection with the first embodiment, the pressure plate 214 can be made of multiple members. For example, the pressure plate 214 could be made from two members that are evenly positioned on opposing sides of the feeder slot and are coupled together by a hinged link. In such an embodiment with multiple pressure plate members, the above-referenced length and size of the pressure plate would be determined by looking at the combined or effective footprint of the pressure plate members.
FIG. 11 illustrated an alternative embodiment for a feeder base 230 that is a one-piece design. More specifically, the front and rear portions 232 , 234 of the feeder base 230 are connected by an integrally-formed side wall 236 along each side. In addition, the feeder base 230 includes a deflection member in the form of a plate 240 positioned in each opening 242 and tilted relative to horizontal. Each illustrated plate 240 will deflect paper clips that fall off the stacks of sheet being shredded, and will direct those paper clips into smaller ports 244 for falling into the litter bin (not shown in FIG. 11 ). These plates 240 guide the paper clips around other components of the shredder (e.g., the motor and circuit board). In addition, each of the front and rear portions 232 , 234 of the feeder base 230 includes a recessed portion 246 that will retain some paper clips that slide off and do not fall into the opening 242 . This facilitates the saving and reusing of paper clips.
Various features of the invention are set forth in the following claims.
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A paper shredder includes a housing, cutters positioned in the housing, and a feeder base adapted to support a stack of paper. The feeder base includes a feeder slot. The feeder base further includes a first aperture on one side of the feeder slot, the first aperture providing a first communication pathway between a top surface of the feeder base and a waste area below the feeder base, and a second aperture on a same side of the feeder slot as the first aperture, the second aperture providing a second communication pathway between the top surface of the feeder base and the waste area below the feeder base. The first and second communication pathways are separated from one another.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of co-pending commonly owned U.S. Provisional Application No. 60/401,867, filed Aug. 8, 2002, entitled Vinyl Siding Locking Tool. Priority is claimed under 35 U.S.C. §119(e). The contents of the same are expressly incorporated herein by reference.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not Applicable
AUTHORIZATION PURSUANT TO 37 C.F.R. § 1.71(d)(e)
A portion of the disclosure of this patent document contains material which is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure, as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates generally to the field of application of siding, particularly vinyl siding, to buildings, and more particularly to tools employed to secure one row of siding to an adjacent row of siding.
2. Description of the Related Art
Tools are available to crimp vinyl siding. Presently tools crimp the top of the piece of siding against an inside piece of utility trim. A positive lock is not always attained. This is a particular problem regarding achieving a secure connection between the top horizontal row of vinyl siding and the row immediately below, which row is typically the highest nailed piece of siding. A poor lock to the utility trim results in the top piece of siding loosening and falling away from the top nailed horizontal row of vinyl siding.
Tin snips have been employed with a twisting motion in an attempt to provide a more secure attachment however, the technique is difficult to teach to workers. Therefore, there exists a need for method and apparatus for more efficiently securing adjacent pieces of vinyl siding in general, and the top piece of siding to the top nailed piece of siding in particular.
BRIEF SUMMARY OF THE INVENTION
The present invention discloses a hand tool for locking together adjacent vinyl siding strips. First and second handles, bearing first and second jaws, are pivotally attached. A first jaw forms a channel, and the second jaw supports a crimp bolt. A portion of a siding strip is disposed between the jaws. Actuation of the jaws moving the crimp bolt against the vinyl strip pushes the strip into the channel forming crimps, which crimps facilite formation of a positive lock with an adjacent strip.
Other objects, advantages, and novel features of the present invention will become apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
FIG. 1 is an elevational view of the vinyl siding locking tool of this invention;
FIG. 2 is an enlarged, perspective view showing the crimp bolt portion of the vinyl siding locking tool;
FIG. 3 is an elevational view showing application of the tool to a siding strip;
FIG. 4 is a fragmentary, perspective view showing the siding strip after engagement by the tool;
FIG. 5 is an enlarged, fragmentary, partly sectional view showing engagement of the siding strip by the tool;
FIG. 6 is a vertical sectional view showing interlocking of two typical vinyl siding strips; and
FIG. 7 is an enlarged fragmentary sectional view illustrating attachment of adjacent vinyl strips after operation of the tool of this invention on the same.
DETAILED DESCRIPTION OF THE INVENTION
Referring now to the drawings, wherein like reference numerals designate identical or corresponding parts throughout the several views, FIG. 1 shows the vinyl siding locking tool of this invention generally at ( 11 ) and further in FIG. 3 employed to operate on a vinyl siding strip ( 13 ).
Referring again to FIG. 3 , the tool ( 11 ) includes a first handle member ( 15 ) having a first hand grip ( 16 ) and a second handle member ( 17 ) having a second hand grip ( 18 ). The handle members ( 15 , 18 ) are pivotally connected by a bolt ( 19 ). A bias spring ( 20 ) is mounted to bolt ( 19 ) and engages the handle members ( 15 , 17 ).
A first jaw member ( 22 ) projects from first handle member ( 15 ) to the opposite side of the pivot bolt ( 19 ). Referring again to FIG. 1 , the first jaw member ( 22 ) includes a U-shaped side wall ( 23 ). A transverse member ( 24 ) partially spans the side wall ( 23 ). The side wall ( 23 ) and transverse member ( 24 ) form an open channel ( 25 ).
Referring again to FIG. 3 , a second jaw member ( 26 ) projects from second handle ( 17 ) to the opposite side of pivot bolt ( 19 ). Second jaw member includes a U-shaped side wall ( 27 ). A transverse wall ( 28 ) spans the side wall ( 27 ). A crimp bolt ( 29 ) projects through, and is supported by transverse wall ( 28 ).
Referring now to FIG. 2 , the crimp bolt ( 29 ) includes a shaft ( 30 ) along the length thereof. A head ( 32 ) is fixed to one end of shaft ( 30 ) and has grooves ( 33 ) formed therein for engagement by a screw driver or the like. Referring also to FIG. 1 , when the head ( 32 ) is viewed in end elevation, the periphery thereof is a rounded triangular shape, defining a tapered area ( 36 ) and an opposite wider area ( 37 ). As can be seen in FIG. 3 , in side elevation, the slope of the tapered area ( 36 ) from the periphery to the grooves ( 33 ) is less than the slope of the wider area ( 37 ) from the periphery to the grooves ( 33 ).
The crimp bolt ( 29 ) is threaded through a bore ( 35 ) formed in transverse wall ( 28 ) such that the head ( 32 ) is positioned in the space between the first and second jaw members ( 22 , 26 ). Rotation of the crimp bolt ( 29 ) is employed to adjust the operating position of the head ( 32 ) between the first and second jaw members ( 22 , 26 ). The crimp bolt ( 29 ) is positioned such that the tapered area ( 36 ) is directed toward second jaw ( 26 ) and the wider area ( 37 ) is directed toward first jaw ( 22 ). Preferably the crimp bolt ( 29 ) is disposed at an angle to the long axis of second jaw member ( 26 ) on the order of 40° to 50°.
Referring next to FIG. 4 , a double declination vinyl siding strip ( 13 ) is shown having the upper portion cut off at ( 41 ) to form the top siding strip ( 40 ) which abuts against the J-trim (not shown) at the top of the wall of the house or other building being sided. Crimps ( 42 ) have been formed in panel lip ( 54 ) of siding strip ( 40 ) to facilitate a positive lock with the highest nailed siding strip ( 13 ). FIGS. 3 and 5 show application of the tool ( 11 ) to form the crimps ( 42 ). The crimps ( 42 ) preferably are formed toward the top edge of panel lip ( 54 ).
Referring to FIG. 6 , two double declination vinyl siding strips ( 13 ) are shown connected in conventional fashion. Each strip ( 13 ) normally has a nailing flange ( 46 ) having an upper or top lip portion ( 47 ). Depending from the nailing flange ( 46 ) is a channel portion ( 48 ) which opens upwardly and to the rear of the strip ( 13 ). Immediately below is a companion channel ( 49 ) opening downwardly and to the front side of the strip ( 13 ). Upper panel declination ( 50 ) extends downwardly from channel ( 49 ) to an upper shoulder area ( 51 ) formed to create a lap appearance. Lower panel declination ( 52 ) extends downwardly from upper shoulder ( 51 ), terminating at a lower shoulder ( 53 ) extending toward the back side of strip ( 13 ). An upwardly extending panel lip ( 54 ) is formed along the inwardly disposed edge of lower shoulder ( 53 ). The panel lip ( 54 ) of an upper siding strip ( 13 ) fits into the channel ( 49 ) of a lower siding strip ( 13 ) in the conventional case.
Referring to FIG. 7 , the top siding strip ( 40 ) is shown attached to the highest nailed siding strip ( 55 ). The crimps ( 42 ) formed in panel lip ( 54 ) of top strip ( 40 ) span the channel ( 49 ) of the highest nailed strip ( 55 ). Positive engagement of the wall surfaces of channel ( 49 ) by the crimp ( 42 ) provides a positive lock between the top siding strip ( 40 ) and the top nailed siding strip ( 55 ). This obviates any need for the utility trim piece commonly employed in the art.
The industrial applicability of the vinyl siding locking tool ( 11 ) is believed to be apparent from the foregoing description. Although only exemplary embodiments of the invention have been described in detail above, those skilled in the art will readily appreciate the many modifications are possible without materially departing from the novel teachings and advantages of this invention. Accordingly, all such modifications are intended to be included within the scope of this invention as defined in the following claims.
In the claims, means-plus-function clauses are intended to cover both equivalent structures and structural equivalents of the structures described herein as performing the claimed function.
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A hand tool is provided for securing adjacent vinyl siding strips. First and second handles, bearing first and second jaws, are pivotally attached. A first jaw forms a channel, and the second jaw supports a crimp bolt. A portion of one siding strip is disposed between the jaws. Actuation of the jaws moving the crimp bolt against the vinyl strip pushes the strip into the channel forming crimps on the strip, which crimps facilitate formation of a positive lock with an adjacent strip.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The invention relates to a signal evaluation method for detecting QRS complexes in electrocardiogram (ECG and IEGM) signals.
[0003] 2. Background Art
[0004] Regarding the background of the invention, it can be stated that the automatic analysis of ECG signals is playing an increasingly larger role in perfecting the functionality of cardiac pacemakers and defibrillators. Newer models of implantable cardiac devices of this type accordingly also offer the capability to perform an ECG analysis. The detection of QRS complexes and R spikes in ECG signals plays an extremely important role in this context. This significance results from the many and diverse applications for the information concerning the time of occurrence of the QRS complex, for example when examining the heart rate variability, in the classification and data compression, and as the base signal for secondary applications. QRS complexes and R spikes that are not detected at all or detected incorrectly pose problems with respect to the efficiency of the processing and analysis phases following the detection.
[0005] A wide overview of known signal evaluation methods for detecting QRS complexes in ECG signals can be found in the technical essay by Friesen et al. “A Comparison of the Noise Sensitivity on Nine QRS Detection Algorithms” in IEEE Transaction on Biomedical Engineering, Vol. 37, No. 1, January 1990, pages 85-98. The signal evaluation algorithms presented there are based throughout on an evaluation of the amplitude, the first derivation of the signal, as well as its second derivation. For the presented algorithms, the essay distinguishes between those that perform an analysis of the amplitude and the first derivation, those that analyze only the first derivation, and those that take into consideration the first and second derivation. To summarize briefly, all algorithms check whether the given signal parameter exceeds or falls short of any predetermined thresholds, after which, if such an event occurs, the occurrence of additional defined events is checked based on a predefined pattern, and if certain criteria are fulfilled, the conclusion is drawn that a QRS complex is present.
[0006] Another aspect in the signal evaluation for detecting QRS complexes needs to be taken into account when methods of this type are implemented in implanted cardiac devices. In view of the natural limitations of these devices regarding their energy supply and computing capacity, it is important that the detection of QRS complexes can be performed with the simplest possible algorithms with the fewest possible mathematical operations on the basis of whole numbers instead of real numbers.
[0007] Signal processing methods from the fields of linear and non-linear filtering, wavelet transformation, artificial neural networks and genetic algorithms have also been applied in the QRS detection. With large signal-noise distances and non-pathological signals, i.e., when good signal conditions are present, these evaluation methods produce reliable results. When no such conditions were present, the efficiency of the evaluation processes could drop drastically, which, of course, is not acceptable with regard to the reliable operation of a pacemaker.
[0008] Finally, QRS detection on the basis of zero crossing counts is known from Applicant's prior German patent application no. 100 11 733.3 which has however been published subsequently. It comprises the following process steps:
[0009] sampling of the signal and conversion into discrete signal values in chronological order;
[0010] high-pass filtering of the sampled signal values;
[0011] determining the sign of each signal value;
[0012] continuous checking of the signs of consecutive signal values for the presence of a zero crossing between two consecutive signal values;
[0013] determining the number of zero crossings in a defined segment of the consecutive signal values; and
[0014] comparing the determined number of zero crossings to a defined threshold value, with a lower deviation from the threshold value signifying the presence of a QRS complex in the defined segment of the signal curve.
[0015] So as to in this case obtain a significantly high number of zero crossings in the range outside the QRS complexes, a high-frequency overlay signal of low amplitude as compared to the amplitude of the QRS complex is added to the high- or band-pass filtered and squared ECG signal.
[0016] Of course, this way of proceeding conflicts with the demand, explained at the outset, for simplest possible algorithms.
SUMMARY OF THE INVENTION
[0017] Based on the described problems, the invention has as its object to present a signal evaluation method for detecting QRS complexes in ECG signals that can be used with a comparatively low computing capacity and also with problematic signal conditions while producing reliable detection results. This object is met with the process steps according to the invention as follows:
[0018] sampling of the ECG signal and conversion into discrete signal values of chronological order;
[0019] comparing the signal values to a threshold function adaptively determined therefrom;
[0020] determining a frequency number within a defined segment of the consecutive signal values, by which preferably the absolute values of the signal values fall short of the threshold function;
[0021] comparing the determined frequency number to a defined threshold, wherein an undershoot of the threshold is significant for the presence of a QRS complex in the defined segment of the ECG signal.
[0022] The core element of the inventive method is the application of a threshold comparison and a subsequent frequency count, based on utilizing the morphology of the QRS complex. The QRS complex in the ECG signal is characterized by a relatively high-amplitude oscillation that markedly guides the signal curve away from the regularly noisy and offset-actuated zero line of the electrocardiogram. The frequency of this short oscillation lies within a range in which other signal components, such as the P and T wave, exert only minor influence and can be removed preferably by pre-filtering—for example high-pass or band-pass filtering. After suppression of these low-frequency signal components, signal fluctuations result around the zero line, due to higher-frequency noise, that dominate the ECG signal in the range where no QRS complex occurs. The QRS complex then appears in this signal context as a slow, high-amplitude oscillation of only short duration that significantly leads away from the zero line of the ECG signal. If the signal values are compared to a threshold function representative of the signal noise, the amounts of the signal values outside the QRS complex mostly undershoot this threshold function. In this regard, the frequency number is great by which the amounts of the signal values undershoot the threshold function. In the range of the QRS complex, the amounts of the signal values significantly exceed the threshold function. Consequently, a small frequency number of undershoots of the threshold is found in the course of the QRS complex. So the QRS complex can be selected by comparison of the determined frequency number with a defined threshold value. An undershoot of the threshold value signifies the overshoot of the threshold function that is typical of the QRS complex.
[0023] The method, according to the invention, of QRS complex detection has proven robust with regard to noise interference and easy to implement with respect to the computing technology. In this regard, it is particularly suitable for implementation in the real time analysis of ECG signal morphologies in cardiac pacemakers.
[0024] The previously mentioned high-pass filtering is performed preferably with a low pass frequency of 18 Hz. In this way, the low-frequency components, such as the P and T waves as well as a base line drift, can be suppressed. Furthermore, the QRS complex thus becomes the signal component with the lowest frequency that dominates the signal during its occurrence.
[0025] To increase the sign-noise distance, provision may furthermore be made to square the signal values prior to comparing them to the threshold function and the frequency number. As a result, smaller signal values are weakened relative to larger signal values, which further improves the detectability of the QRS complex.
[0026] The value of the threshold function is preferably determined adaptively from a flowing determination of the average of the band-pass filtered and squared signal values.
[0027] Details of the method according to the invention will become apparent from the ensuing description of a exemplary embodiment, taken in conjunction with the drawing.
BRIEF DESCRIPTION OF THE DRAWING
[0028] [0028]FIG. 1 is a highly schematic illustration of the signal curve of a QRS complex in an ECG signal; and
[0029] [0029]FIG. 2 is a structural diagram of the signal evaluation method according to the invention for detecting QRS complexes in ECG signals.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0030] As seen in FIG. 1, an idealized QRS complex consists of a relatively high-amplitude oscillation about the zero line 1 that initially guides the ECG signal 4 , in the Q spike 6 , away from the zero line 1 in a negative direction. Afterwards the ECG signal 4 is guided, in the R spike 5 , into the positive range with a steep rise and with a subsequent steep drop back into the negative range while forming the S spike 7 .
[0031] In reality, the ECG signal 4 is accompanied by a certain level of noisiness, as indicated in FIG. 1 by the dashed signal curve. If this noisy signal is sampled and converted into discrete signal values of chorological order and band-pass filtered, these signal values can be compared to the threshold function K(n) that is diagrammatically illustrated in FIG. 1 as a crisscrossed line. As can be derived clearly and by way of model from FIG. 1, the value of the ECG signal in the range outside the QRS complex mostly falls short of this threshold function K(n). In the range N 1 for instance, significantly high frequencies result for signal values |x(n)| below the threshold function K(n).
[0032] In the range of the Q spike 6 , the value of the ECG signal deviates very strongly from the threshold function K(n) in the positive direction. The frequency number D(n) within the segment N 2 of the QRS complex 6 for this event is considerably smaller than the frequency number D(n) within the segment N 1 . In this regard, the frequency number D(n) may be utilized for detecting the QRS complex, the presence of which is detected when the frequency number D(n) undershoots a defined threshold Θ.
[0033] Emphasis must be laid on the fact that a gist of the invention as compared to the prior art resides in that, based on the detection of the mentioned frequency number found and the comparison thereof to a defined threshold, the amplitude of the ECG signal is not checked as to whether a certain threshold is absolutely exceeded for conclusion therefrom on the QRS complex; this is the prior art way of proceeding. Rather, sort of a check is carried out as to how long the ECG signal clearly remains on a side of the threshold function that speaks in favor of the presence of a QRS complex. Only the presence of a certain duration of this condition is used as a conclusion that points to the presence of a QRS complex. Consequently, strong measuring fluctuations of only short duration are not detected as (false) QRS complexes (so-called false positive errors).
[0034] The detailed sequence of the inventive evaluation method will be explained in detail, based on FIG. 2.
[0035] The ECG signal 4 is sampled and converted into discrete signal values x(n) of chronological order. The sampling rate may be f t =360 Hz, for example, i.e., the ECG signal is converted into a sequence of 360 measuring values per second. The sampled ECG signal x(n) is then subjected, on the input side, to a band-pass filtering BP that serves to remove all the signal components that do not belong to the QRS complex. This includes P and T waves as well as high-frequency noise that may originate, for example, from the bioelectrical muscle activity. The applied filter BP is linear-phase, non-recursive and has a band-pass characteristic with the pass frequencies f g1 =18 Hz and f g2 =27 Hz as well as the limiting cutoff frequencies f s1 =2 Hz and f s2 =50 Hz. The filter order is FO=26. The group delay of the band-pass filter BP accordingly corresponds to 13 sampling values and must be taken into consideration when determining the time of the occurrence of the QRS complex.
[0036] The signal values x f (n) attained in this manner are subsequently squared in a squaring step QS according to the following relation:
|x f (n)| 2
[0037] The values x fq (n) thus prepared from the original signal values x(n) by a kind of computation of an absolute value are fed to a comparator complex HZ that compares these signal values to a threshold function K(n) adaptively determined therefrom. The process complex that is concerned with the determination of the threshold function K(n) is designated by AS in FIG. 2. In this complex, an appropriate value for the function coefficients K(n) is adaptively estimated from the signal values x fq (n). To this end, the band-pass filtered and squared signal values are recursively determined by flowing averaging by the aid of a memory factor λ k (0<λ k <1),
K ( n )=λ k K ( n− 1)+(1−λ k ) x fq ( n )· c
[0038] with c being a constant.
[0039] Empirically, λ k =0,98 and c=8 result as appropriate values.
[0040] The averaging time given by the memory factor λ k substantially determines the adaptation rate of this estimate, with too short as well as too long averaging signals affecting the efficiency of the signal evaluation method.
[0041] In the process complex HZ, the signal values x fq (n) are compared to the threshold function K(n)—as mentioned. In doing so, the direction is found in which the signal values x fq (n) deviate from the threshold function K(n). A frequency number D(n) within this defined segment N is determined therefrom, representing the number or frequency of events for which the signal values x fq (n) fall short of the threshold function. In a favorable way of calculating, D(n) may also be determined recursively via
D ( n ) = λ D D ( n - 1 ) + ( 1 - λ D ) d ( n ) mit d ( n ) = { 0 f u ¨ r x fq ( n ) ≥ k ( n ) 1 f u ¨ r x fq ( n ) < k ( n )
[0042] A smaller amount of the frequency number D(n) indicates that the amount of the ECG signal 4 durably exceeds the threshold function K(n), which is a reliable parameter for the presence of the QRS complex.
[0043] In the course of the method according to the invention, a threshold Θ still has to be determined, the undershoot of which significantly indicates the presence of a QRS complex in the defined segment of the ECG signal 4 . Θ(n) is recursively computed from D(n) by
Θ( n )=λ θ Θ( n− 1)+(1−λ θ ) D ( n )
[0044] with a memory factor 0<λ θ <1 being used. This memory factor for example can be selected to be λ θ =0,99. If D(n) falls short of the threshold Θ, a QRS complex has been detected, otherwise it has not.
[0045] The job of checking whether the above requirement has been fulfilled takes place in the decision stage according to FIG. 2.
[0046] The evaluation method according to the invention can be realized by implementation based on a software-based solution in the form of a corresponding evaluation program but also by a realization based on a hardware-based solution by means of a corresponding electronic evaluation assembly.
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A signal evaluation method for detecting QRS complexes in electrocardiogram (ECG) signals comprises the following steps:
sampling of the ECG signal ( 4 ) and conversion into discrete signal values (x(n)) in chronological order;
comparing the signal values (x f (n), x fq (n)) to a threshold function (K(n)) adaptively determined therefrom;
determining a frequency number (D(n)) within a defined segment of the consecutive signal values, by which signal values (x f (n), x fq (n)) preferably fall short of the threshold function (K(n));
comparing the determined frequency number (D(n)) to a defined threshold (Θ), wherein an undershoot of the threshold (Θ) is significant for apresence of a QRS complex ( 5, 6, 7 ) in the defined segment of the ECG signal ( 4 ).
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FIELD OF THE DISCLOSURE
[0001] The invention relates generally to a connector assembly for a tool and handle.
BACKGROUND
[0002] Flow through tools typically include an extension pole having a hose connected at a first pole end and a tool connected at a second pole end. Alternatively, flow through tools include a tool directly connected to a hose. Liquid is delivered through the pole and/or hose and into the tool. The tool can be any suitable tool for dispensing water including but not limited to a watering wand, a brush, and a mop. Such tools deliver the liquid to a surface so that the surface can easily be watered, rinsed, washed, painted, or the like.
[0003] In general, two methods have been used to ensure that the tool is secured to the pole. In a first example, the tool is integral with the pole, i.e., the tool and pole are manufactured as a single article. This construction is deficient in that it does not allow the user to replace the tool on the pole.
[0004] In a second example, the pole can include a threaded element or similar structure at its second end such that the tool can be removably attached to the pole. While this addresses the disadvantage noted above, the tool may rotate relative to the pole due to the forces applied to the tool during use. Further, it is difficult to properly align the tool angle relative to the pole when typical threaded engagements are used. The user must turn the tool onto the pole until a water-tight connection is achieved. However, this may not result in a proper orientation of the tool relative to the pole, especially if the tool has been overtightened several times.
BRIEF DESCRIPTION OF THE DRAWINGS
[0005] Exemplary aspects and features of quick release assemblies in accordance with the disclosure are described and explained in greater detail below with the aid of the drawing figures in which:
[0006] FIG. 1 depicts an exploded view of an implement including a quick release assembly.
[0007] FIG. 2 depicts a detail view of an alternative quick release assembly.
[0008] FIG. 3 depicts a cut-away view of the quick release assembly shown in FIG. 2 .
[0009] FIG. 4 depicts a cut-away view of the quick release assembly of FIG. 3 after assembly.
[0010] FIG. 5 depicts a cross sectional view of an assembly tip.
[0011] FIG. 6A depicts a cross sectional view of an alternative assembly tip.
[0012] FIG. 6B depicts a perspective view of the assembly tip shown in FIG. 6A .
[0013] FIG. 7 depicts a cross sectional view of an additional alternative assembly tip.
[0014] FIG. 8A depicts a perspective view of an additional alternative assembly tip.
[0015] FIG. 8B depicts a cross sectional view of the assembly tip shown in FIG. 8A taken along line 8 B- 8 B.
[0016] FIG. 9A depicts a perspective view of an additional exemplary assembly tip.
[0017] FIG. 9B depicts a cross sectional view of the assembly tip shown in FIG. 9A taken along line 9 B- 9 B.
[0018] FIG. 10A depicts a perspective view of an additional exemplary quick release assembly.
[0019] FIG. 10B depicts a cross sectional view taken of the quick release assembly shown in FIG. 10A taken along line 10 B- 10 B.
[0020] FIG. 11 depicts a perspective view of an additional alternate example of a quick release assembly.
DETAILED DESCRIPTION
[0021] Referring now to FIG. 1 , an exploded view of an implement 20 is shown. The implement 20 includes an extension pole 22 , a quick release assembly 24 , and a tool 26 . The extension pole 22 is exemplified as an elongate, hollow tube with an inner flow-through channel 28 extending throughout its length. The pole 22 has a rear end 30 and a front end 32 and generally extends along a longitudinal axis X. A liquid source such as a hose (not shown) can be attached to the pole 22 at the rear end 30 in order to introduce liquid into the pole 22 such that it can flow from the rear end 30 through the inner channel 28 to the front end 32 . While a pole 22 is shown here, the quick release assembly may alternatively be directly connected to a hose.
[0022] The quick release assembly 24 includes a tip 34 and a base 36 . The tip 34 has a front section 38 and a rear section 40 . The rear section 40 of the tip 34 can be inserted into the front end 32 of the pole 22 (or directly into a hose) and is thereby secured to the pole 22 . In this example, the rear section 40 is T-shaped to match the T-shaped channel in the pole 22 , but the pole 22 and tip 34 can use other complementary cross sections. Such a T-section configuration is beneficial however, in that it can help to prevent rotation of the pole 22 relative to the tip 34 . The tip 34 may be attached to the pole 22 in several ways, including but not limited to adhesives, screws, rivets, and crimping. As will be discussed in greater detail herein, a button assembly 42 is disposed in the front section 38 of the tip 34 .
[0023] The base 36 includes a receiving portion 44 , an aperture 46 , and a threaded plug 48 . The receiving portion 44 has a profile that matches the front section 38 of the tip 34 . As will be more clearly described herein, the base 36 and tip 34 can be connected to form the quick release assembly 24 by inserting the front section 38 of the tip 34 into the receiving portion 44 of the base 36 along the longitudinal axis X. The button assembly 42 extends through the aperture 46 , thereby preventing separation of the tip 34 and base 36 . To remove the base 36 from the tip 34 , the button assembly 42 is depressed downwardly, and the tip 34 is pulled out from the base 36 .
[0024] The tool 26 shown in FIG. 1 is a brush head that includes an attachment section 50 , a body 52 , and a set of bristles 54 extending outwardly from the body 52 . The brush head 26 can be coupled to the base 36 by turning the attachment section 50 , which includes grooves (not shown) on the interior surface thereof for receiving the threads of the threaded plug 48 of the base 36 . Alternatively, the brush head 26 can be coupled to the base 36 by adhesive bonding or integral manufacture of the brush 26 and base 36 . Further, other tools can be used including but not limited to water wands, spray nozzles, brushes, and squeegees. When alternate tools are needed, the releasable locking mechanism permits a quick and easy release of one tool, and the addition of a new tool.
[0025] As described in further detail below, both the tip 34 includes an inner channel 35 and the base 36 include an inner channel 37 extending the length of the respective part. Further, the brush 26 or other tool can include a similar inner channel 39 . In use of the implement 20 , the liquid source directs a liquid through the inner channel 28 of the pole 22 , through the channel 35 of the tip 34 , through the channel 37 of the base 36 , through the channel 39 of the brush 26 and onto the bristles 54 . The liquid on the bristles 54 can then be used to wash, rinse, or paint a surface. The liquid can be water, paint, liquid soap, or any other liquid.
[0026] Referring now to FIG. 2 , a detail view of an alternative quick release assembly 60 is shown. The quick release assembly 60 is identical to the quick release assembly 24 except for the features specifically noted herein. The assembly 60 includes a tip 62 and a base 64 . The tip 62 includes a rear section 66 with a rear end 68 and a front section 70 with a front end 72 . The front section 70 is attached to the rear section 66 at a shoulder 74 . The rear section 66 of the tip 62 is cylindrical in shape, and not T-shaped as shown in FIG. 1 . The cylindrical shape of the rear section 66 allows it to be attached to a pole, or directly to a liquid source having a circular flow through channel such as a hose. The rear section 66 includes a circumferential groove 76 in which a gasket (not shown) can be disposed. The gasket helps to provide a water-tight seal between the pole or hose and the tip 62 .
[0027] The front section 70 is a plug 78 including a top piece 80 and a bottom piece 82 . The top piece 80 generally has the shape of a paralleleipiped, while the bottom piece 82 has a generally cylindrical shape. The top piece 80 includes a button assembly 84 that allows the tip 62 to be releasably locked to the base 64 . The button assembly 84 includes a button 86 that is biased by a biasing element, here a spring (see FIG. 1 ), to an extended position away from the longitudinal axis X. As exemplified, the button 86 includes a sloped front side 88 and a generally vertical rear side 90 .
[0028] An inner channel 92 extends from the front end 72 to the rear end 68 of the tip 62 . The inner channel 92 allows fluid to flow through the tip 62 from the pole (or other liquid source) to the base 64 . The inner channel 92 is disposed in the bottom piece 82 of the front section 70 .
[0029] The base 64 includes a rear section 94 with a rear end 96 . A receiving section 98 is disposed in the rear section 94 of the base 64 and has a shape substantially similar to that of the plug 78 of the tip 62 , with a rectangular section 100 and a circular section 102 . The receiver 98 defines an upper boundary 104 . An aperture 106 extends through the base 64 from the receiver 98 . The aperture 104 is sized and shaped to receive the button 86 .
[0030] The complementary shapes of the tip plug 78 and the base receiver 98 allows the plug 78 to be inserted into the receiver 98 . The depressible button 86 , in its normal biased position, extends to a height above that of the upper boundary 104 of the receiver 98 . During insertion of the tip 62 into the base 64 , a user may manually depress the button 86 while pushing the tip 62 and base 64 together along the longitudinal axis X. Alternatively, the user may simply insert the plug 78 of the tip 62 into the receiver 64 , and allow the force of the upper boundary 104 against the sloped front side 88 of the button 86 to automatically depress the button 86 as the plug 78 is inserted into the receiver 98 .
[0031] Upon complete insertion of the plug 78 of the tip 62 into the receiver 98 of the base 64 , the depressible button 86 extends through the aperture 106 under the force of the spring. In other words, the button 86 “snaps-up” through the aperture 106 . The button 86 releasably locks the tip 62 and base 64 together and thereby prevents separation of these components. To disassemble the tip 62 from the base 64 , a user may simply depress the button 86 while simultaneously pulling the tip 62 and base 64 apart in opposite directions.
[0032] The depth of insertion of the plug 78 into the receiver 98 may be limited by the engagement of the rear end 96 of the base 64 with the shoulder 74 of the tip 62 . Such frictional contact may also help to stabilize the connection of the tip 62 relative to the base 64 . Additionally or alternatively, the depth of insertion can be limited by the depressible button 86 on the tip 62 and the aperture 106 .
[0033] While the plug 78 in this example includes a top piece 80 and a bottom piece 82 , the plug 78 can generally be any non-circular shape as such shapes prevent rotation of the plug 78 relative to the base 64 . For example, the plug 78 can be triangular, rectangular, octagonal, or any other non-circular shape. The plug 78 could also be generally circular with certain other elements disposed thereon to prevent rotation, such as a keyway or wings. Such configurations are considered to be non-circular. In each of the above examples, the plug 78 and the receiver 98 have complementary shapes such that the plug 78 can be inserted into the receiver 98 and rotation is prevented between the plug 78 the receiver 98 . Additionally, unlike conventional threaded attachment mechanisms, the tip 62 and the base 64 do not loosen when a torque is applied about the longitudinal axis to one or more of the tip and the base.
[0034] Referring now to FIG. 3 , a quick release assembly 110 is shown in cross-section view. The quick release assembly 110 is the same as the quick release assembly 60 in form and function except as specifically noted herein. The quick release assembly 110 includes a tip 112 and a base 114 . The tip 112 includes a front section 116 with a front end 118 and a rear section 120 with a rear end 122 . An annular rib 124 is disposed on the front end 118 . An inner channel 126 extends in longitudinal direction X along the length of the tip 112 from the rear end 120 to the front end 116 .
[0035] The front section 116 includes a button assembly 128 generally similar to the button assemblies previously described. The button assembly 128 includes a depressible button 130 with a front side 132 and a back side 134 . However, the button 130 does not have a sloped front side like button 84 . Instead, the front side 132 is generally vertical. The back side 134 is generally vertical. The button 130 has at its base a flange 136 extending outwardly. The button assembly 128 also includes a spring 138 that provides an upwardly biasing force (i.e., +y-axis) on the button 130 . A collar 140 having edges 142 can be press-fit into the tip 112 to trap the button 130 in the tip 112 by engaging the flanges 136 of the button 130 . Alternatively, the collar 140 may be an integral part of the tip 112 which is formed with the tip 112 in a molding process or a machining process. The button collar 140 may also be an extruded undercut in the tip 112 that prevents the button 130 from “popping out” of place.
[0036] Similar to FIGS. 1 and 2 , the base 114 includes a receiver 144 that accepts the tip 112 . The base receiver 144 defines an upper boundary 146 , and a tapered surface 148 extends downwardly from the upper boundary 146 . Similar to the previously described quick release assemblies, and as best shown in FIG. 3 , the base 114 includes an inner channel 150 extending forward from the receiver 144 . A gasket 152 can be disposed on the end of the inner channel 150 in the receiver 144 to ensure that liquid flow though the inner channel 150 of the quick release assembly 110 does not leak into the receiver 144 of the base 114 . As in the previously described bases, the base 114 includes an aperture 154 .
[0037] During insertion of the tip 112 into the base 114 , the tapered surface 148 provides a contact interface with the button 130 of less than ninety-degrees. Such a lessened angle of interface allows the tapered surface 148 to automatically depress the button 130 when the user pushes the tip 112 and base 114 together along the longitudinal axis X. However, when the tip 112 is coupled to the base 114 , and the button 130 is extended in the aperture 154 (see FIG. 4 ), the back side 134 of the button is generally parallel with a back-end 156 of the aperture 154 such that the button 130 is prevented from being automatically depressed when the tip 112 and base 114 experience a separating force along the longitudinal axis X. Preferably, separation of the tip 112 from the base 114 includes the user depressing the button 130 while simultaneously applying a separating force on the tip 112 and base 114 along the longitudinal axis X.
[0038] Upon coupling the tip 112 to the base 114 , the front section 116 of the tip 112 is inserted into and locked in the receiver 144 of the base 114 . The annular rib 124 on the front end 118 of the tip 112 bears against the gasket 152 in the receiver 144 of the base 114 such that the inner channel 126 of the tip 112 is in fluid communication with the inner channel 150 of the base 114 . Specifically, any fluid flowing through the inner channel 126 of the tip 112 will flow through the inner channel 150 of the base 114 without any of the fluid leaking into the receiver 144 . Thus, it is typically desirable for the front section 116 of the tip 112 to fit snugly in the receiver 144 .
[0039] FIG. 5 illustrates a quick release tip 160 , which includes a front section 162 and a rear section 164 . The rear section 164 may be any shape to fit a pole or hose. The front section 162 includes a first button 166 and a second button 168 . Such a tip 160 requires a base (not shown) with a receiver that includes two apertures through which the first and second buttons can extend. While two buttons 166 , 168 are shown, the tip 160 can include any number of buttons around the periphery of the tip.
[0040] FIGS. 6A and 6B illustrate a quick release tip 170 , which includes a front section 172 , a rear section 174 , and an inner channel 176 extending the entire length. Similar to the embodiments previously described, the rear section 174 may be any shape to fit a pole or hose. The front section 172 includes a bottom piece 178 and a top piece 180 . The top piece 180 includes a button assembly 182 that functions generally similarly to the previous examples. The button assembly 182 includes a button 184 that is biased upwardly by a spring 186 . The button assembly 182 further includes a hinge 188 at its back side 190 . The button 184 includes a flange 192 , and the top piece 180 includes a retention post 194 that engages the flange 192 so that the spring 186 maintains the button 184 in the extended position shown in FIGS. 6A and 6B . As can be seen in FIG. 6B , the top piece 180 and the bottom piece 178 create a non-circular profile for the front section 172 that, when inserted into a coordinated receiver of a base, restrict rotation between the tip 170 and a base. To remove the tip 170 from a base, the user an depress the button 184 as in previous examples.
[0041] FIG. 7 illustrates a further example of a quick release tip 200 , which includes a front section 202 and a rear section 204 . Similar to the embodiments previously described, the rear section 204 may be any shape to fit a pole or hose. Instead of a button assembly, the front section in this example includes a projecting tab 206 attached by a strip 208 . The strip 208 may be made of a flexible material such that the strip 208 acts as a spring and the projecting tab 206 can pivot about the strip 208 and return to its extended position upon the release of any force upon the projecting tab 206 . In an example, the strip 208 can be a thermoplastic polymer. In another example, the entire tip 200 can be made from such a polymer.
[0042] Referring now to FIGS. 8A and 8B , perspective view and a side section view of a quick release tip 210 , respectively, are shown. The tip in FIG. 8A is coupled to an extension pole 211 . As in some of the previously described embodiments, the top piece 212 on the front section 214 includes a collar 216 that engages the flanges 218 of the button 220 to capture the button 220 . However, a side rail 222 of the collar 216 is slidably removable in a side groove 224 in the collar 216 . Accordingly, the button assembly 228 can be assembled by removing the side rail 222 , inserting the button 220 and spring 230 with the flanges 218 under the collar 216 , and replacing the side rail 222 . The side rail 222 can be held in place by an interference snap-fit engagement, a suitable retention bracket (not shown), an adhesive bond (in which case it would not be removable), or other known methods.
[0043] Similarly, FIGS. 9A and 9B illustrate a perspective view and a front section view of a quick release tip 240 , respectively. In this exemplified quick release tip, a front rail 242 is removable from the collar 244 . In all other repsects, it is similar to the quick release tip 210 shown in FIGS. 8A and 8B .
[0044] FIGS. 10A and 10B illustrate a perspective view and a side section view of a quick release assembly 250 . A base 252 may include a front section 254 with a front end 256 and a rear section 258 with a rear end 260 . FIGS. 10A and 10B illustrate the rear section 258 attached to a pole 262 . In this example, the front end 256 of the base 252 may include a receiver 264 . A button assembly 266 is generally disposed in the receiver 264 and includes a button 268 , a collar 270 capturing the button 268 , a spring 272 biasing the button 268 toward the longitudinal axis X, and a tab 274 connected to the button 268 . The user may pull the tab 274 away from the longitudinal axis X against the force of the spring 272 to move the button 268 in a similar direction, thereby permitting the removal of the tip 276 from the base 252 .
[0045] The tip 276 includes a rear section 278 sized and shaped to be inserted into the receiver 264 . The rear section 278 has a rear end 280 and an inner channel 282 extending throughout its length, and includes a plug 284 with an engagement ledge 286 and a platform 288 . The platform 288 and the engagement ledge 286 each have a flat surface 290 , 292 . A gasket 294 is disposed on the rear end 280 surrounding the inner channel 282 .
[0046] When the tip 276 is assembled to the base 252 , the button 268 extends toward the longitudinal axis X, with the button 268 bearing against the platform 288 past the engagement ledge 286 . Accordingly, the engagement ledge 286 bearing against the rear side of the button 268 restricts the tip 276 from moving longitudinally relative to the base 252 . Further, the flat surface 290 of the engagement ledge 286 bears against a flat internal surface 296 of the receiver 264 , and the flat surface 292 of the platform 288 bears against the button 268 . These interactions restrict the tip 276 from rotating relative to the base 252 .
[0047] To separate the tip 276 from the base 252 , a user pulls up on the tab 274 away from the longitudinal axis X which raises the button 268 above the engagement ledge 286 . The assembly 250 may then separate when the user pulls the base 252 and tip 276 in opposite directions of the longitudinal axis X.
[0048] FIG. 11 illustrates a perspective view of an additional example of an implement 300 with a tip 308 and a base 310 . The tip 308 is connected to an extendible pole 304 that is fully described in U.S. patent application Ser. No. ______, the contents of which are included herein by reference. The pole 304 is sealed on its rear end by a handle 306 , and therefore does not allow a liquid such as paint, water or other liquid to be introduced into and flow through its interior as in the previous examples.
[0049] The tip 308 and the base 310 are constructed similarly as in FIG. 2 , except that neither the tip 308 nor the base 310 includes an inner channel. While, of course, the tip 308 and the base 310 can include inner channels as in previous examples, it is not required because the pole 304 in this example has no provision to allow a liquid to flow through its interior to the tip 308 and base 310 (due to the sealing by the handle 306 ).
[0050] A paint roller 312 is shown integrally connected to the base 310 in FIG. 11 , but other tools can be used with the implement 300 . The base 310 and the paint roller 312 can be secured to and removed from the tip 308 as in previous examples. After the base 310 is removed from the tip 308 , a second base (not shown) similar to the base 310 can then be disposed on the tip 308 . The second base can have a different type of tool such as a paint brush (not shown) attached to it. Furthermore, a base similar to base 310 with virtually any type of tool attached to it could be disposed on the tip 308 and used. For example, in addition to the already mentioned paint roller and paint brush, other tools such as a broom, squeegee, pik, other kinds of brushes, and the like can be connected to a base and used. Thus, the implement 300 allows for the quick interchangeability of tools.
[0051] A variety of materials may be used to manufacture the quick release tip and the base including but not limited to die cast zinc, aluminum, stainless steel, and a variety of thermoplastic resins. Thermoplastic polymers such as, for example, polyesters, nylons, polypropylenes, and mixtures thereof are specific materials that can be used to fabricate the tip and the base.
[0052] Although the foregoing text sets forth a detailed description of numerous different embodiments of a quick-tip system, the scope of coverage of this patent is not limited thereto. On the contrary, the detailed description is to be construed as exemplary only and does not describe every embodiment of a quick-tip system.
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A quick-release connector assembly includes a tip including a plug, a depressible member proximate the plug, and a biasing element upwardly biasing the member; and a base having a receiver and an aperture, the receiver being complementary to the plug, the base further including a connector section configured to secure a tool. The tip is releasably lockable to the base by the insertion of the plug into the receiver and the extension of the member through the aperture, and when the tip is locked with the base, the base is prohibited from rotating relative to the tip.
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FIELD OF THE INVENTION
The present invention relates to a set of aerodynamic surfaces for an aircraft, and to an aircraft comprising at least one such set of aerodynamic surfaces.
BACKGROUND OF THE INVENTION
It is known that a fixed aerodynamic surface of an aircraft (such as a wing, a horizontal stabilizer or a vertical stabilizer) is extended at the rear by at least one mobile flap (such as an aileron, an elevator, a rudder, etc.) able to form a mobile trailing-edge part for said aerodynamic surface.
It is also known that such mobile flaps are controlled by actuators mounted on the fixed aerodynamic surfaces. Of course, said actuators have to be designed for the forces they need to develop in order to move said flaps, it being necessary for these forces to overcome the aerodynamic forces applied to said flaps. Because these flaps can rotate, these aerodynamic forces generate, with respect to the hinge of said flaps, a resistive moment generally known as a “hinge moment”.
However, because said actuators are heavy components, they have to be specified just sufficient to do the job in order to limit the mass of the aircraft, and this means that the hinge moment has to be known with accuracy.
Furthermore, in a new aircraft development program, said actuators have to be defined very early on because they themselves undergo a lengthy development process. Now, hinge moments of an aircraft under development are not only difficult to predict with sufficient preciseness for the actuators to be specified optimally, but also vary greatly with changes in the geometry of the aircraft during the development process.
Hence, in practice, margins of safety are created in the specifying of said actuators so as to guarantee that the flaps will work in spite of the uncertainties in prediction and the possible variations in geometry. As a result, the actuators are always overspecified.
In an attempt to remedy the aforementioned disadvantages, proposals have already been made for external trailing-edge tabs to be arranged on control surfaces, these working by modifying the shape of said control surfaces. Such external tabs are detrimental to the aerodynamic performance of the aircraft because they increase the drag. In addition, the compensation they afford has constantly to be adjusted according to the phase of flight or the angle of the control surfaces. Furthermore, these external tabs are located at the trailing edge of the control surfaces and therefore add additional weight making said control surfaces sensitive to aerostatic flutter.
Elsewhere, document U.S. Pat. No. 2,630,988 already discloses a set of aerodynamic surfaces for aircraft, comprising at least:
one fixed aerodynamic surface delimited by two external walls which, at the rear, converge toward one another and between which a spar is positioned, said external walls and said spar delimiting a box section that is open to the rear and runs in the overall direction of the span of said fixed aerodynamic surface; a mobile flap, the front part of which is articulated about an axis of rotation with respect to said fixed aerodynamic surface and which extends said external walls, thereby forming a mobile trailing-edge part for said fixed aerodynamic surface; actuating means, housed in said box section and able to cause said mobile flap to rotate; and a vane, positioned in that part of said box section that is free of said actuating means and on the opposite side of said axis of rotation to said flap, said vane rotating as one with said flap and running in the overall direction of the span of said fixed aerodynamic surface, said vane dividing said box section into two chambers at least substantially isolated from one another and each comprising one of said external walls.
In a set of aerodynamic surfaces such as this, each chamber is in pressure-wise communication with the aerodynamic flow over the corresponding external wall of said box structure via the slot that there is by design between the rear part of said fixed aerodynamic surface and said mobile flap.
Thus, in theory, said vane is subjected to a pressure differential similar to the one applied to said flap and, because it is positioned on the opposite side of the axis of rotation therefrom, it generates an antagonistic moment opposing the hinge moment, thus decreasing the latter accordingly.
However, experience has shown that said pressure communication slot is unable, at said vane, to guarantee a pressure differential that can actually be used to generate such an antagonistic moment able optimally to oppose the hinge moment.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to overcome this disadvantage by providing self-adaptive compensation that is directly proportional to the aerodynamic forces that give rise to the hinge moment.
To this end, according to the invention, the set of aerodynamic surfaces of the type recalled hereinabove comprises, in each external wall of said mobile flap, at least one pressure tapping able to place the corresponding chamber in pressure-wise communication with the aerodynamic flow over the corresponding external wall of said box section.
These pressure tappings may be distributed along the chord of the flap and connected to said chambers via ducts in said mobile flap. The location and number of said pressure tappings are determined so that irrespective of the location at which a pressure variation liable to alter the hinge moment occurs, this variation is transmitted to the corresponding chamber. Presetable nonreturn valves may possibly be provided in said ducts, in order best to regulate the pressure differential applied to said vane.
Thus, across the vane, there is a pressure differential proportional to the differential between the external walls of the flap. This pressure differential leads to the creation of a hinge moment antagonistic to that of the flap. There is therefore an overall reduction in the force that the actuator needs to develop and the level of reduction can easily be evaluated because it is in direct proportion:
to the ratio of surface areas between the vane and the flap, and to any possible setting of the device that controls the pressure differential.
It must be noted that the present invention:
does not affect the external lines of the aircraft, or the performance thereof; concentrates the added mass forward of the axis of articulation of the flap, thus encouraging static balancing thereof and contributing to the reduction in flutter; makes it possible to reduce the magnitude of the hinge moments, resulting in a reduction in the size of the actuators; and allows the hinge moments to be tailored to the capability of the actuators, thus guaranteeing that the flaps will work even if there is a change in the magnitude of the hinge moment.
In order to provide relative pressure-wise isolation between the two chambers of the box section while at the same time allowing the flap-vane assembly to rotate freely about said axis of rotation, it is advantageous:
for the front edge of said vane to be straight and parallel to said axis of rotation of the flap, for that face of said spar that faces toward said flap to be cylindrical about said axis of rotation of said flap, and for said front edge of the vane to be in sealed sliding contact with said cylindrical face; and for the lateral edges of said vane to be straight and orthogonal to said axis of rotation of said flap, for said box section to comprise flat partitions orthogonal to said axis of rotation, and for said lateral edges of the vane to be in sealed sliding contact with such flat partitions.
The present invention also relates to an aircraft comprising at least one such set of aerodynamic surfaces as specified hereinabove.
BRIEF DESCRIPTION OF THE DRAWINGS
The figures of the attached drawing will make it easy to understand how the invention may be embodied. In these figures, identical references denote elements that are similar.
FIG. 1 is a schematic and partial plan view, with cutaway, of the rear part of a fixed aerodynamic surface provided with a mobile flap, the latter comprising a vane according to the provisions of the present invention.
FIGS. 2 and 3 are schematic sections on II-II and III-III of FIG. 1 , respectively.
DETAILED DESCRIPTION OF THE INVENTION
The exemplary embodiment of the invention, illustrated in FIGS. 1 to 3 , depicts the rear part of a fixed aerodynamic surface 1 , which may be a wing or horizontal stabilizer, and a mobile flap 2 , which may be a control surface controlling roll (an aileron) or an elevator. It will be understood, from reading that which follows, that the embodiment of FIGS. 1 to 3 is merely one exemplary embodiment and that the present invention can be applied mutatis mutandis to some other type of aerodynamic surface and mobile flap, for example to a vertical stabilizer and its rudder.
The rear part of the fixed aerodynamic surface 1 is delimited by external walls 3 and 4 which converge toward one another toward the rear and between which there is positioned a spar 5 . In the example depicted, the external walls 3 and 4 correspond respectively to the extrados and to the intrados of said fixed aerodynamic surface. The external walls 3 and 4 and the spar 5 delimit a box section 6 open toward the rear and running in the overall direction of the span E of said fixed aerodynamic surface.
Via its front part, the mobile flap 2 is articulated for rotation about an axis of rotation X-X with respect to said rear part of the fixed aerodynamic surface 1 , the axis X-X having the overall direction of the span E.
The mobile flap 2 comprises an external wall 7 and an external wall 8 which respectively extend the external walls 3 and 4 of said rear part 1 of the fixed aerodynamic surface. The external walls 7 and 8 converge toward one another to form a trailing edge 9 . This trailing edge 9 of the flap 2 therefore forms a mobile trailing edge part for said fixed aerodynamic surface 1 .
Housed inside the box section 6 are actuating means 10 , articulated to said flap 2 at 11 and able to cause this flap to rotate about the axis X-X as symbolized in FIG. 2 by the double-headed arrows 12 , 13 and by the positions of said flap 2 shown in dotted line.
The part 6 . 10 of the box section 6 in which the actuating means 10 are located is delimited by one of the flat partitions 14 , orthogonal to the axis of rotation X-X, provided inside said box section 6 .
Furthermore, that face 15 of the part of the spar 5 that lies facing the flap 2 and is positioned in the part 6 . 16 of the box section 6 , outside of the part 6 . 10 thereof, is cylindrical about the axis of rotation X-X.
Positioned in said part 6 . 16 of the box section 6 is a vane 16 secured to the forward part of said flap 2 , so that it rotates as one therewith. The vane 16 lies on the opposite side of the axis of rotation X-X to the flap 2 and runs in the overall direction of the span E of said fixed aerodynamic surface.
The vane 16 has an at least approximately rectangular shape and its straight lateral edges 17 (which are orthogonal to the axis X-X) lie, in a way that has not been depicted, in sealed sliding contact with respective flat walls 14 . In addition, the front edge 18 of the vane 16 (which is straight and parallel to the axis X-X) is also in sealed sliding contact (in a way that has not been depicted) with the cylindrical face 15 of the spar 5 .
Thus, the vane 16 divides the part 6 . 16 of the box section 6 into two chambers 6 . 16 E and 6 . 16 I which are substantially isolated from one another and which remain so as the flap 2 rotates about its axis of rotation X-X, whereas their volumes vary in opposite directions as a result of the concomitant rotation of said vane 16 .
The chamber 6 . 16 E lies on the same side as the external walls 3 and 7 and is in pressure-wise communication with the aerodynamic flow 19 flowing over these external walls, by virtue of the slot 20 that separates said external walls 3 and 7 . One or a plurality of pressure tappings 21 are also provided in the external wall 7 of the flap 2 , at least one duct 22 being made in said flap to place the chamber 6 . 16 E in communication with each of said pressure tappings 21 . Thus, the same pressure is applied to the face 16 . 3 of the vane 16 that faces toward the external wall 3 as is applied to the external wall 7 of the flap 2 .
The chamber 6 . 16 I is positioned on the same side as the external walls 4 and 8 and is in pressure-wise communication with the aerodynamic flow 23 20 flowing over these external walls by virtue of the slot 24 that separates said external walls 4 and 8 . One or a plurality of pressure tappings 25 are also provided in the external wall 8 of the flap 2 , at least one duct 26 being made in said flap in order to place the chamber 6 . 16 I in communication with each of said pressure tappings 25 . Thus, the same pressure is applied to the face 16 . 4 of the vane 16 that faces toward the external wall 4 as is applied to the external wall 8 of the flap 2 .
Presetable nonreturn valves 27 and 28 may be provided in the ducts 22 and 26 respectively, in order best to regulate the pressure differential applied to said vane 16 .
From the foregoing, it will therefore have been readily understood that the vane 16 and the flap 2 are submitted to the same pressure differential and generate opposing moments about the axis X-X.
As a result, the force that the actuating means 10 have to provide in order to cause the flap 2 to turn is smaller and the magnitude of the antagonistic moment generated by the vane 16 can be adjusted by varying the surface area of this vane.
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Disclosed is a set of aerodynamic surfaces for an aircraft. There is included in the set a fixed aerodynamic surface delimited by two external walls which, at the rear, converge toward one another. A mobile flap extends the external walls, forming a mobile trailing-edge. An actuator is positioned so as to cause the mobile flap to rotate. A vane runs in the overall direction of the span of the fixed aerodynamic surface, and rotates with the flap.
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BACKGROUND OF THE INVENTION
The present invention relates to a method, a circuit arrangement and an apparatus for a non-contacting real time determination of velocities of one or a plurality of movements at an object in a direction perpendicular to a coherent radiation impinging on the object, with the scattered light of the coherent radiation producing a spatial speckle pattern over a speckle spectrum, and with the speckle pattern becoming time dependent due to the movements at the object.
If a laser beam of wavelength λ impinges on an object in the x direction, and the average distance Δx between scatter centers is >>λ, the scattered light forms a granular structure, called speckles. This is the case, for example, on all normal surfaces. The intensity distribution of the speckles is irregular. Certain mathematical interrelationships exist for the statistic distribution of the speckles. These mathematical interrelationships do not depend on the characteristics of the object, as long as the requirement of Δx>>λ is met.
With the laser at rest and the object at rest, the speckle pattern is stationary. Under certain conditions of mutual position of laser, object and observation point, the speckle pattern moves as a whole if the object itself moves. This results in a specific speckle velocity V s which, in suitable cases, is proportional to the velocity of the object. One way to record speckle movement is to measure the light intensity of the scattered light on an effective detector surface which is small compared to the average speckle size σ.
Such a detector produces a signal I proportional to the light intensity on its surface and there now exist various ways to determine the speckle velocity from the time-dependent form, I(t), of that signal. One of these methods is the so-called correlation method. Here, the incident light intensities are detected at two spatially separate locations and the resulting intensity signals are recorded. Two time dependencies result for the intensity. Both intensity time dependencies are stored. The correlation function calculated therefrom has a peak from whose position the speckle velocity can be determined.
The drawback of this method is that it requires a large amount of electronic equipment and that the velocity is not determined in real time (Pusey, J. Phys. D 9 (1976) page 1399). In principle, this method does not utilize any specific speckle characteristic.
Only a single time dependent signal I(t) is required for the method employing time integration of the signal I(t). Initially, average values N i are formed from the speckle intensity signal I(t) by way of integration over a succession of time intervals, with a computer calculating the standard deviation S and an overall average N. The quotient of both values, S/N, is a non-linear measure for the speckle velocity. The drawback of this method is again the high costs for the electronic computer and the fact that it is not a real-time method. In principle, the fact that the contrast of the speckle signal is known to go toward zero with increasing integration time, is utilized here (J. Ohtsubo, T. Asakura, Opt. Quant. Electr. 8 (1976) 523).
An earlier patent application, in the Federal Republic of Germany, No. P 3,242,771.9, discloses the so-called speckle counting process. This method counts the points of intersection between the intensity signal I(t) and a threshold level S. The threshold level S is set to be proportional to the average intensity value I. The advantage of this method is that the costs for electronic equipment are reduced and the method has real-time characteristics.
However, the drawback of this method is that noise is superposed on the speckle signal. Particularly at low velocities, this noise results in erroneous measurements because the velocity indicated is too high. In principle, this method utilizes the speckle characteristic that the time interval Δt between two counts has an average Δt which is given by Δt being approximately const·σ/V. None of the prior art methods is suitable to separate superposed velocities.
SUMMARY OF THE INVENTION
It is an object of the present invention to record the movement of a speckle pattern in such a manner that the resulting data permit a determination of the speckle velocity independently of other superposed velocities. In particular, it is an object of the invention to determine the blood circulation velocity near the skin surface or in other parts of the human body.
The above and other objects are achieved, according to the invention, by a method and apparatus for determining the velocity of an object in a given direction without contacting the object, by directing coherent radiation to the object in a direction substantially perpendicular to the given direction to cause radiation to be scattered from the object to produce a speckle pattern exhibiting a speckle spectrum, the speckle pattern at a location spaced from the object having a time dependency which is a function of movement of the object, detecting the speckle pattern intensity at the location spaced from the object, producing a first signal representative of the detected speckle intensity, and producing, from the first signal, a velocity-dependent intensity signal having a value which is weighted as a function of the frequency of the first signal.
The method according to the invention takes advantage of the fact that, for an object at rest, I(t)=constant and no frequencies unequal to 0 occur. If the object moves, then frequencies unequal to zero do occur. Thus, measuring the intensity of the signal, which is normally an electrical signal, at frequencies unequal to zero is a measure for the velocity v s . The invention particularly utilizes the fact that the speckle pattern as a whole has a granular structure. If a change is made to not simply determine the intensity above a frequency ν 0 , but to first suitably modify the signal, then the intensity formation produces a measured value which is proportional to velocity v s . This measure resides in that the amplitudes A(υ) of the spectrum must first be amplified by a factor which is proportional to υ.
On the basis of the specific shape of the speckle spectrum, the intensity of the thus formed signal is proportional to velocity v s . This proportionality has been proven by theoretical derivation and experimental data.
Due to the intensity formation, measured value P is also proportional to the average intensity I at the point of observation. To avoid interference resulting from laser output intensity fluctuations and changes in reflection conditions, such interference can be eliminated by dividing the measured value by the average light intensity I.
The advantage of the method is that the cost of the required electronic equipment can be kept low. The frequency dependent weighting is effected by time differentiation and the intensity formation by a power meter.
It is also not absolutely necessary to simultaneously measure the total intensity. In the worst case, the dependency is linear with variations in intensity. If thus great differences in velocity are to be measured and, on the other hand, a stable laser is available, this can be omitted.
In the above-described, previously proposed speckle counting method described in Federal Republic of Germany Application No. P 3,242,771.9, this is not the case. In that method, the counting rate is very sensitively dependent upon threshold S and thus on the measured average intensity I.
An important condition for speckle formation is that the laser light is scattered at scatter centers which have an average distance Δx>>λ. In normal moving objects, all scatter centers move at the same velocity. However, when observing blood flow near the skin surface of a living subject, the scatter centers may have different velocities. The resulting speckle pattern now moves under the influence of the velocity, v H , of the skin surface and of the velocity, v B , of the red blood cells. Since this is a coherent superposition of two speckle patterns according to the two velocities, a new speckle pattern is created which in appearance does not differ from the speckle pattern of a normal object. Only its behavior over time is different.
With the prior art speckle methods it is not possible to separate these two velocity components from one another or to separate even other such velocities. With these methods, the result would simply be that either a slightly higher velocity is indicated without it being possible to distinguish whether this was the result of increased skin velocity or increased movement of the blood. In any case, in no experiments was it possible to determine a difference between skin through which blood flowed and skin through which no blood flowed.
In the first-mentioned prior art methods, there probably exists no possibility at all to determine, in principle, a difference between skin through which blood flows and skin through which no blood flows. Even if this were possible, such a method could not be used in practice, because the measuring periods are very long and the amount of apparatus required would be too large.
Since the major portion of the light is scattered over the skin surface and the skin cells, the movement of the speckle pattern is also primarily determined by the skin velocity v H . Only a small portion of the light penetrates into the blood vessels and is there scattered back to return back to the outside. Therefore, the proportion of blood movement in the respective speckle pattern is always low.
If a strip of textile were glued to the skin and then a measurement were made or the blood supply to one part of the skin were suppressed, an approximate measured value for the skin velocity would result. The spectrum of signal I(t) for such a measurement is composed of a superposition of a plurality of velocities. Measurement at the skin at a location where blood flow occurs produces a spectrum in which high frequencies are more prevalent compared to measurements made at skin through which no blood flows. This permits the conclusion that the average velocity v B of the movement of blood is higher than the average velocity, v H , of the movement of skin.
Roughly, the spectrum can be composed of two parts: movement of the skin and movement of the blood. Due to the difference between the average velocities v H and v B , it is now possible to separate the signal components associated with these two velocities. A signal amplitude representation is formed only of that portion of the spectrum signal whose frequency lies above υ g , and the portion with a frequency less than υ g is suppressed. In the spectrum, this would correspond to integration over a frequency interval of υ g to infinity.
In principle, the separation of the two velocity ranges is possible even with intensity formation of the electrical signal without the use of weighted amplification. The frequency dependent amplification increases the signal differences between skin through which blood flows and skin through which no blood flows.
There exists no uniform definition of blood flow. However, it is considered to be appropriate to set the blood flow to be proportional to the velocity and the quantity of the blood, respectively. Thus, the method permits a determination of blood flow since the signal is proportional to the velocity, because of the frequency dependent weighting and also proportional to the quantity of moving blood. If more moving blood enters into the area through which the laser light penetrates, the signal becomes larger of course.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a simplified pictorial view of a measuring arrangement for carrying out the present invention.
FIG. 2 is a block diagram of a circuit for producing velocity information according to the invention.
FIGS. 3a through 3h are waveform diagrams illustrating the operation of the circuit of FIG. 2, FIGS. 3a, c, e and g being signal vs. time waveforms and FIGS. 3b, d, f and h being frequency spectrum diagrams.
FIGS. 4-6 are diagrams illustrating the measurement results achieved with the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
FIG. 1 is a pictorial illustration of a measuring arrangement or device with which velocity can be determined. A laser beam 15 is directed to a measuring point 5 on an object 6. Due to the surface roughness of object 6, the light scattered therefrom forms a granular pattern, i.e. speckles, where the average size σ of the speckles at the locus of observation 16 is determined only by the wavelength λ of the light employed (e.g. He-Ne laser, λ=633 nm), the size of the beam spot of beam 15 at point 5 and the distance from measuring point 5 to locus 16. With a suitable optical arrangement, the speckle pattern moves as a whole so that a speckle velocity v s can be defined.
For small angles between laser beam 15 and the optical axis 14 of the observation device there exists a simple relationship as described above.
The speckles are detected at an aperture 30 which, in order to substantially maintain the speckle contrast, is smaller than the average speckle size σ. In order to obtain a small angle between laser beam 15 and observation device optical axis 14, and to additionally assure flexible access to the desired measuring points, light conductors, or optical fibers, 7, 8, 10 are utilized. The beam from a laser 1 is focussed through a lens 2 into an optical fiber, or fiber bundle, 3. The exciting beam is highly divergent so that it is collimated by lens 4 to form beam 15 which is directed toward measuring point 5 on object 6.
The diameter, D, of the beam spot at measuring point 5 must be as small as possible so that the speckle size σ reaches the maximum size required for detection. Yet, the distance between measuring point 5 and the locus of observation 16 must not be too large because then the available light intensity would not be sufficient for detection. On the other hand, the diameter D must not depend greatly on the distance between lens 4 and object 6 because then even a slight change in the distance would result in a great change in speckle size σ, which would again bring about an error in the velocity measurement. The beam profile must therefore have a long, narrow waist 17. This is brought about by carefully matching the divergence of the laser beam exiting from optical fiber 3, the focal length of lens 4 and the distance between lens 4 and the end of optical fiber 3. Thus the diameter of the beam 15 does not change considerably within e.g. a distance from 55 to 65 mm in front of the lens.
Fiber bundle 7 forms part of the detection system and starts at locus of observation 16, which is as close as possible to the end of light conductor 3 and to lens 4 to keep the angle small between the incident laser beam 15 and the direction of observation 14. To detect speckle movement and produce therefrom a time dependent speckle intensity signal I(t), a single fiber 10 of bundle 7 leads from locus 16 to a light detector 11. Since the effective diameter of the individual fiber 10 is the effective aperture 30 for the speckle detection, the distance between measuring point 5 and locus of observation 16 must be selected such that the speckle size σ is somewhat larger than the diameter of fiber 10.
If the object 6 moves, the speckles move past the end of the individual fiber 10 so that light detector 11, e.g. a photomultiplier, at the end of the individual fiber 10 indicates time-dependent speckle intensity I(t). The individual fiber 10 is disposed in the center of the remaining fibers 8 of bundle 7. Fibers 8 form a bundle which leads to a further detector 9. Since fiber bundle 8 is composed of approximately 400 individual fibers each having a diameter equal to the speckle size σ, and since the light incident on those fibers is measured in a common detector 9, the signal produced by detector 9 represents the average speckle intensity I at the same location at which speckle intensity I is measured with the aid of detectior 11. The quality of the average formation G is given by
Gα√N,
where
G is the standard deviation of the average values divided by the mean of the average values,
N is the number of the optical fibers with a diameter equal to the speckle size 6, and
α means proportional to.
A tubus 18 serves to maintain the optimum distance between measuring head 19 and object 6. A filter 12 permits only light at the laser wavelength to pass and thus reduces the noise on the input signals to detectors 9 and 11 caused by scattered light of other wavelengths. Measuring head 19 carries the output end of fiber 3, as well as lens 4, the fiber bundle at locus 16 and filter 12.
I(t) is thus the time-dependent signal of the speckle intensity whose spectrum is determined by the spatial spectrum of the speckle pattern and by the velocity of the object.
Prerequisite for use of the method according to the present invention is that the intensity I(t) be determined by means of a detector 11 whose effective measuring surface area is smaller than the average speckle size. The effective surface area may be defined by the detector itself, by a small aperture placed onto it or, as in the embodiment of FIG. 1, by the cross section of the associated light conductor.
In contrast to the speckle counting method, the velocity determination procedure is not sensitively dependent on the total intensity of the scattered light. Therefore, it is not necessary, in principle, to determine total intensity. If the total light intensity fluctuates by no more than 5%, the determined velocity also contains an error of 5%. But this possible error can also be compensated.
Simultaneous measurement of the laser light intensity and a mathematical division operation eliminates the influence of fluctuations in laser light intensity. Simultaneous measurement of the total intensity of the scattered light and division also eliminates the influence produced by changes in reflection from object 6.
Simultaneous measurement of the total intensity of the scattered light I at the same location as the determination of speckle intensity I also eliminates the influence of direction dependent scattering.
I and I can be determined in various ways, e.g. by means of a beam splitter or by means of a glass fiber arrangement as shown in FIG. 1. The benefit of the glass fiber arrangement is its good maneuverability, which is particularly important in connection with measurements on the skin.
If in a stationary speckle pattern, the speckle pattern is scanned by means of a small aperture 30, a locus dependency I r (y) results with a local spectrum.
r indicates that I r is a space dependent function.
y is a space coordinate.
The function I y (y) could be obtained by scanning the speckle pattern.
The local spectrum of the speckle pattern is generally known from the literature. If now the speckle pattern moves at a velocity V and is observed at one location, a time-dependent light intensity I(t) results behind the aperture at I(t)=I r (vt).
v is the velocity.
I is a time-dependent function.
To illustrate the occurrence in connection with the speckle pattern, let us observe a sine-shaped light intensity distribution which is brought past the aperture at a velocity V S . The sine-shaped intensity has a locus dependency ##EQU1## The corresponding time dependency is ##EQU2## Obviously a high velocity results in the occurrence of higher frequencies in both time-dependent functions. In these functions i indicates functions concerning the example with a sine-shaped light intensity,
I o is the amplitude and y o is the wave length in space of the sine-shaped light intensity distribution.
In order to incorporate the velocity in the amplitude, a one-time time differentiation is made. ##EQU3## where
v is the velocity (see above),
y o is the wavelength in space (see above).
Now the intensity of the signal I(t) is determined to obtain the velocity. ##EQU4## P(v) is defined by this equation.
For the illustrated embodiment, the following calculations then apply: ##EQU5## (P i (v) is the equivalent function to P(v), now applied for the example with the sine-shaped light intensity. ##EQU6## M i (v) is defined by the first equation. It follows that M i (v) is proportional to velocity v.
For the speckle pattern, the value P(v) can be calculated only as the statistical average because the local spectrum of the speckles is known.
According to one theorem (the Power theorem), the following applies: ##EQU7##
This is the square of the Fourier transform of I(t), the "power spectrum".
ν is the frequency. ##EQU8##
This is so because in the spectrum, time differentiation corresponds to a multiplication with the frequency. 1/v results from a type of substitution rule. ##EQU9## This is the spectrum of the spatial speckle pattern known from literature. The expression is inserted to get the following equation. ##EQU10## where I is the average intensity and σ is the average speckle size. ##EQU11## This results in: ##EQU12## A comparison with the result of the sine-shaped intensity shows:
y.sub.o =√3σ
Time averaging, i.e. the intensity determination, corresponds to integration of the spectrum. If two velocities are superposed, skilled selection of the frequency intervals makes it possible to effect a separation. The position of the frequency interval could be obtained by interpreting the spectra of the speckle intensity signal I(t). For example, measuring at the skin a separation of the blood flow velocity from other moving objects (body, skin, other cells . . . ) is achieved by selecting an intervall from 50 Hz to 1500 Hz.
If now only given frequency intervals are utilized for the intensity formation, the velocity measurements are separated. A reduction to practice is realized in that the time-dependent signal is changed by means of active filters. It is known, for example, that a highpass filter suppresses the low frequencies and thus serves to detect high velocities. The same applies correspondingly for a lowpass filter and low velocities.
The measured value M(v s ) can be realized by means of the electronic circuit shown in FIG. 2, with FIGS. 3a through 3h showing the functions of the individual components in the circuit arrangement.
The signal I(t) from detector 11 is amplified in amplifier 20. This signal has the time dependency shown in FIG. 3a and the spectrum A(ν) shown in FIG. 3b. The signal from amplifier 20 passes through a linear filter 21 or a differentiating member, respectively, in which it is amplified proportionally to frequency ν by means of an adjustable proportionality constant, producing the output signal and spectrum shown in FIGS. 3c and 3d. The simplest way to realize this is in the form of an RC member as a passive component. Higher demands for linearity and dynamics can be met by an active circuit.
Noise from photomultiplier and laser are superposed on the speckle signal. Active lowpass filter 23 serves to constrict the observed frequency range, e.g. to a limit frequency ν T , without adversely affecting linearity, if limit frequency ν T is greater than the maximum frequency of I which is fixed by speckle size σ and the maximum velocity. The output signal of lowpass filter 23 and related spectrum are shown in FIGS. 3g and 3h.
In practice, an RMS power/DC converter 24 performs an integration and determines the total intensity, P, of the time-dependent signal. In principle, the integration is a "specific" integration over time of the time-dependent signal. However, it is mire clearly seen in the spectrum in which a frequency integration is effected over a certain frequency interval. The value of the integrated signal from converter 24 is mathematically divided in divider 26 by an average intensity signal I which is derived from detector 9 and amplified in amplifier 25. The result of this division then represents the measured value M(v S ). After time integration in integrator 28, which determines the accuracy of the measurement, M(v S ) is displayed in display device 29.
The noise from photomultiplier nd laser does of course also occur in the frequency range under observation. This share of measured signal M(v s ) can be eliminated by generating a fixed, settable signal value F in a signal generator 27 and subtracting value F from the quotient of P/I.
Since the influence of the blood flow movement is best determined in the higher frequency portion, the average velocity of inadvertent body movement is less than that of the movement of the blood. This difference is utilized for the separation of the two velocities. An active highpass filter 22 whose output signal and spectrum, respectively, are shown for limit frequency υ H in FIGS. 3e and 3f, is connected into the circuit for this purpose. On the one hand, this filter 22 must sharply separate the two velocity ranges, i.e., it must have a sharp edge. On the other hand, in order to maintain linearity, it must be frequency independent for frequencies above υ H . For example, the filter 22 may be given by a 4-pole Butterworth filter with a cut-off-frequency at 50 Hz.
If the plane of observation varies by ±5 mm from its nominal position, no change appears in the velocity signal in the circuit arrangement or apparatus according to FIG. 1. The linearity achieved with the method according to the invention is shown in FIG. 4. Deviations at slower velocities are the result of the beam spot not being square as in the theoretical derivation but having an e -x .spsp.2 profile and the speckle movement being measured by means of an aperture which is not negligibly small compared to the speckle size.
In FIG. 4 the circles are measuring values A (in Volts) by the equipment at different velocities of a test object. The different sensitivities indicated by the slope of the two lines are achieved by applying speckle patterns of different speckle size 6.
The time dependence of the flow of blood, with the blood supply suppressed during time interval ΔT, is shown in FIG. 5 and the change in blood movement due to the use of a circulation enhancing ointment is shown in FIG. 6.
In practice, it may turn out to be appropriate to note that, in the determination of a value B indicating the flow of blood, other weightings bring about more easily distinguished or more stable measured values than the weightings discussed above. Weighting proportional to ν 2 or ν 3 would emphasize, in particular, the proportion of high velocities. Moreover, a step-type filter, a suitable highpass filter, which, on the one hand, suppresses the frequencies in the spectrum near zero, which are caused by the proportion of constant light in the speckle intensity, and, on the other hand, amplifies the remainder independently of frequency, can be used to generate a measured signal which indicates, for example, the amount of blood movement independently of velocity.
These weightings can be realized with a modified circuit arrangement. Amplification proportional to ν 2 would correspond to twice performed differentiation, and amplification proportional to ν 3 would require a special amplifier having such a characteristic. Filter 21 would then have to be more generalized to an element which amplifies the signal with specific frequency weighting.
Measurements made according to the method of the invention indicate that velocities up to several 100 microns per second can be detected. This lower limit is given by the available measuring aperture 30 of several microns in diameter, since in this way a minimum size is set for the speckles. To measure higher velocities, it is necessary to broaden the covered frequency range, so that the noise increases. This again can be compensated for by increasing the laser intensity.
For an exemplary embodiment of the invention see FIGS. 1 and 2. Specification of the components:
1: 7 mW HeNe-Laser, 633 nm
2: 80 mm focal-length lens
3: Optical fiber, diameter 0.3 mm
4: 16 mm focal-length lens
5: Diameter of the laser-spot 1.5 mm
7: Fiber bundle of 400 fibers with 70 μm diameter each
8: Fiber bundle leading to photocell 9
9: Silicon photocell with a sensitive area of 1.2×1.2 mm 2
10: Single fiber leading to the photomultiplier
11: Photomultiplier with a bialkali cathode
12: 633 nm interference filter
20: Amplifier with variable gain (≈10)
21: Differentiator with a characteristic frequency f d =210 Hz
22: Active high pass filter, 4-pole Butterworth, cut-off-frequency 50 Hz
24: 2% accuracy RMS/DC-Converter (Root-Mean-Square Processing)
25: Amplifier with variable gain (≈100)
26: 2% accuracy divider
28: Integratior with variable time-constants from 0.1 s to 4 s
30: Effective aperture for speckle-detection given by the diameter of one fiber: 70 μm
Angle between beam 15 and axis 14: 15°
Distance lens 4-aperture 30: 220 mm
Distance lens 4-laser spot 5: 60 mm
23: Active lowpass filter, 4-pole Butterworth, cut-off-frequency 1500 Hz
It will be understood that the above description of the present invention is susceptible to various modifications, changes and adaptations, and the same are intended to be comprehended within the meaning and range of equivalents of the appended claims.
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Method and apparatus for determining the velocity of an object in a given direction without contacting the object, by: directing coherent radiation to the object in a direction substantially perpendicular to the given direction to cause radiation to be scattered from the object to produce a speckle pattern exhibiting a speckle spectrum, the speckle pattern at a location spaced from the object having a time dependency which is a function of movement of the object, detecting the speckle pattern intensity at the location spaced from the object, producing a first signal representative of the detected speckle intensity, and producing, from the first signal, a time-dependent intensity signal having a value which is weighted as a function of the frequency of the first signal.
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TECHNICAL FIELD
The present invention relates to a golf ball, and more specifically, to an improved golf ball which has channel to contribute to the continuous flow of air through dimples of the ball during its flying.
BACKGROUND OF THE INVENTION
Every golf ball has many dimples on its surface, whose arrangement, size, shape, and depth determine various flying characteristics. Generally, to arrange dimples on a ball its surface is to be divided into spherical polyhedrons whose purpose is to keep the symmetry of ball, get uniform repelling power of pneumatic dynamics on dimples, and thus obtain certain flying stability. Dimples also have a variety of patterns like circle, oval, spheroid, and polygon, among which circular or circular plus partially oval dimples are most frequently used, And their sizes are either uniform or different, and it is the same with their depths.
As for the ball with dimples which are of circle or of circle plus partial oval, by the way, it is impossible to see maximum fly or flying stability as expected in terms of its characteristics of the optimum construction and arrangement of demples and properties of matter. It is because it flies in back spin to make circular dimples located at the back and both sides of ball subject to partial vacuum leading to excessive drag (to pull ball against its ongoing direction), in other words it loses much of energy to be transmitted to it when hit. Back spin, however, is likely to give lift to golf ball helping it fly higher and longer, which is an antinomic situation of the loss of energy due to excessive drag described above.
Accordingly, it is an object of the present invention to minimize drag, obtain proper lift, and maintain original properties of golf ball to maximize its fly.
SUMMARY OF THE INVENTION
The basic concept of the present invention is to provide golf ball having channel which allows the flow of air through adjacent dimples, circular or oval or both, having distinct borders and being independent (hereinafter referred to as "air connection channel") to contribute to the continuous flow of air through dimples of the golf ball during its flying. Then the channel would swiftly disperse to next dimples the vacuum generated during its flying in back spin, which minimizes drag contributing to the improvement of fly and flying stability.
Further objects and advantages of the present invention will become apparent from the following detailed description and accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 shows the surface of an invented golf ball looked from a pole.
FIG. 2 shows the surface of an invented golf ball looked from a pole, an example of polyhedron composition as in FIG. 1.
FIG. 3 shows the surface of an invented golf ball looked from a pole, an example of polyhedron composition as in FIG. 1.
FIG. 4 is a development figure describing a typical pattern of air connection channel (dark squares marlsed X) connecting dimples in accordance with the invention.
FIG. 5 is same as FIG. 4, a development figure describing another pattern of air connection channel (dark squares marked X) connecting dimples, however except that some dimples have air connection channels but other do not, indicating various ways of connecting dimples using air connection channels in this invention.
FIGS. 6-13 demonstrate how many air connection channels a dimple has, if dimples on a ball are connected with air connection channels and the dimple is contiguous to a plurality of dimples.
FIG. 14 depicts sections of two dimples, as air connection channels are formed, as well as the way of determining the depth and diameter of two dimples whose diameters are different each other and the depth and length of their air connection channels, as both dimples are connected via air connection channel.
FIG. 15 shows the way of determining the proper depth, length, and width of air connection channels for dimples, various shapes of sections of air connection channels (marked X1, X2, X3, and X4), and real patterns of sections after air connection channels are made to the left picture.
DETAILED DESCRIPTION OF THE INVENTION
FIG. 1 shows the surface of an invented golf ball looked from a pole, which is divided into composition of spherical polyhedrons to arrange dimples on it, resulting in air connection channels connecting dimples one another (darlk squares marked X) and successive, rather than independent, gathering of dimples. Though only some dark squares are marked X in this figure, all of them are air connection channels. In fact, these dark parts have two sides belonging to a circular arc and other two sides rather resembling straight lines, and this shape of the square applies to all other ones described below.
FIG. 2 shows the surface of an invented golf ball looked from a pole, an example of polyhedron composition as in FIG. 1, which arranges dimples and forms air connection channels for connecting them by dividing the surface of ball by 20 or 20-12 sides. It is a figure showing an example of well completed ball according to the invention.
FIG. 3 shows the surface of an invented golf ball looked from a ploe, an example of polyhedron composition as in FIG. 1, which arranges dimples and forms air connection channels for connecting them by dividing the surface of ball by 8 or 6-8 sides. It is a figure showing an example of well completed ball according to the invention.
FIG. 4 is a development figure describing a typical pattern of air connection channel (dark squares marked X) connecting dimples; again, only some dark squares are marked X in this figure, but all of them are air connection channels. In fact, these dark parts have two sides belonging to a circular arc and other two sides rather resembling straight lines, and this shape of the square applies to all other ones described below.
FIG. 5 is same as FIG. 4, a development figure describing a typical pattern of air connection channel (dark squares marked X) connecting dimples, however except that some dimples have air connection channels but other do not, indicating various ways of connecting dimples using air connection channels in this invention; again, only some dark squares are marked X in this figure, but all of them are air connection channels. In fact, these dark parts have two sides belonging to a circular arc and other two sides rather resembling straight lines, and this shape of the square applies to all other ones described below.
FIG. 6 demonstrates that a dimple marked A-1 has four air connection channels, if dimples on a ball are connected with air connection channels and it is contiguous to four dimples.
FIG. 7 demonstrates that a dimple marked A-2 has five air connection channels, if dimples on a ball are connected with air connection channels and it is contiguous to five dimples.
FIG. 8 demonstrates that a dimple marked A-3 has six air connection channels, if dimples on a ball are connected with air connection channels and it is contiguous to six dimples.
FIG. 9 demonstrates that a dimple marked A-4 has seven air connection channels, if dimples on a ball are connected with air connection channels and it is contiguous to seven dimples.
FIG. 10 demonstrates that a dimple marked A-5 has eight air a connection channels, if dimples on a ball are connected with air connection channels and it is contiguous to eight dimples.
FIG. 11 demonstrates that a dimple marked A-6 has two air connection channels, if dimples on a ball are connected with air connection channels and it is contiguous to four dimples.
FIG. 12 demonstrates that a dimple marked A-7 has three air connection channels, if dimples on a ball are connected with air connection channels and it is contiguous to six dimples.
FIG. 13 demonstrates that a dimple marked A-8 has four air connection channels, if dimples on a ball are connected with air connection channels and it is contiguous to eight dimples.
As the way of making air connection channels and their patterns and sizes are described in FIGS. 14 and 15, the channel is made by drawing a line connecting the center of each dimple between adjourning ones and establishing certain width W from the line. The limitations of W are as follows: If a dimple whose diameter is D is close by several dimples, either all of them may have each one's air connection channel as in FIGS. 6, 7, 8, 9, and 10 or only some of them may have them as in FIGS. 11, 12, and 13; if there are N air connection channels, the sum of each W around the dimple whose diameter is D is recommended to be not more than 70% of the circumference L of the dimple. Here, the type of diameter of the dimple may be one and the same or 2 to 10 kinds. And W of one air connection channel X is recommended to be between 0.1 mm and 4 mm.
For the length of air connection channel, W is obtained by establishing a random, short diameter d1, to a dimple whose diameter is D1 and establishing another random, short diameter, d2, to a dimple whose diameter is D2, while the length is by connecting random each two points located on d1 and d2 in parallel, as in FIG. 14. And it is recommended to be not longer than 5 mm. The random, short diameter of d in a dimple whose diameter is D shall be determined, as shown in FIG. 15 to be more than 50% of D, because it would face more air resistance during its flying and its flying stability would be reduced, if it is less than 50%. For the depth of air connection channels, the depth of a random, short diameter d would be h, as that of a dimple whose diameter is D is H, as in FIGS. 14 and 15; h is recommended to be less than 70% of H or 1.2 mm. If h is deeper than it, it would disturb the air flow in dimples to worsen its flying stability.
A channel having a curved bottom has a different depth at different locations along its bottom surface. Also, a channel having inward curved sides has one width at the upper end and a lower width at the bottom end. Also, the length of a channel will vary depending upon whether it is measured along the exterior of the golf ball or along the bottom of the channel to the point where it enters a curved bottom dimple surface.
The sections of air connection channels may have various patterns such as X1, X2, X3, and X4 as shown in FIG. 15, which have basic relations with the depth of dimples. Generally speaking, square pattern is recommended for the dimple with shallow depth, while half-circle for the one with deep depth. In short, one should consider the depth of dimples in choosing its pattern. A dimple may share air connection channels either with all of its adjoining dimples as in FIGS. 6, 7, 8, 9, and 10 or with only some of its adjoining dimples-with no channels for remaining dimples as in FIGS. 11, 12, and 13. It is closely related with the arrangement of dimples--that all have air connection channels or that only some have channels depends on what kind of solid, uniform size or different size/shape, forms the spherical polyhedrons divided from sphere. In other words, the arrangement of dimples on a golf ball shall be determined considering air flow and if all of the dimples are uniform or not.
As such, a golf ball was invented to increase its fly sharply and reduce drag outstandingly, as in FIGS. 2 and 3, by executing air connection channels in it.
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A golf ball defining a spherical surface divided into spherical polyhedrons to form dimples thereon, characterized in that at least some of the dimples are connected to one another via air connection channels no more than 4 mm wide no more than 5 mm long, and no more than 1.2 mm deep the channel depth being less that 70% of the depth of the dimples.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit from U.S. Application No. 60/497,617, filed Aug. 25, 2003, which is incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to the treatment of neoplasms such as cancer.
[0003] Cancer is a disease marked by the uncontrolled growth of abnormal cells. Cancer cells have overcome the barriers imposed in normal cells, which have a finite lifespan, to grow indefinitely. As the growth of cancer cells continue, genetic alterations may persist until the cancerous cell has manifested itself to pursue a more aggressive growth phenotype. If left untreated, metastasis, the spread of cancer cells to distant areas of the body by way of the lymph system or bloodstream, may ensue, destroying healthy tissue.
[0004] The treatment of cancer has been hampered by the fact that there is considerable heterogeneity even within one type of cancer. Some cancers, for example, have the ability to invade tissues and display an aggressive course of growth characterized by metastases. These tumors generally are associated with a poor outcome for the patient. Ultimately, tumor heterogeneity results in the phenomenon of multiple drug resistance, i.e., resistance to a wide range of structurally unrelated cytotoxic anticancer compounds, J. H. Gerlach et al., Cancer Surveys, 5:25-46 (1986). The underlying cause of progressive drug resistance may be due to a small population of drug-resistant cells within the tumor (e.g., mutant cells) at the time of diagnosis, as described, for example, by J. H. Goldie and Andrew J. Coldman, Cancer Research, 44:3643-3653 (1984). Treating such a tumor with a single drug can result in remission, where the tumor shrinks in size as a result of the killing of the predominant drug-sensitive cells. However, with the drug-sensitive cells gone, the remaining drug-resistant cells can continue to multiply and eventually dominate the cell population of the tumor. Therefore, the problems of why metastatic cancers develop pleiotropic resistance to all available therapies, and how this might be countered, are the most pressing in cancer chemotherapy.
[0005] Anticancer therapeutic approaches are needed that are reliable for a wide variety of tumor types, and particularly suitable for invasive tumors. Importantly, the treatment must be effective with minimal host toxicity.
[0006] The brain is well protected from outside influences by the blood-brain barrier, which prevents the free entry of many circulating molecules, cells or micro-organisms into the brain interstitial space. However, this is not true for many drugs, such as phenothiazines, which penetrate the blood-brain barrier. While desirable for the treatment of brain disorders or brain tumors, when used to treat peripheral disorders (e.g., cancers localized outside the brain), the brain is exposed to the phenothiazine without any therapeutic benefit and with the possibility of adverse effects. Side effects most frequently reported with phenothiazine compounds are extrapyramidal symptoms including pseudo-parkinsonism, dystonia, dyskinesia, akathisia, oculogyric crises, opisthotonos, and hyperreflexia. New drugs and drug formulations that treat cancer without significant exposure to the brain can provide effective cancer treatment with reduced side effects and a greater therapeutic index.
SUMMARY OF THE INVENTION
[0007] The invention provides formulations and structural modifications for phenothiazine compounds which result in altered biodistributions, thereby reducing the occurrence of side effects associated with this class of drug.
[0008] The invention features a phenothiazine conjugate including a phenothiazine covalently attached via a linker to a bulky group of greater than 200 daltons or a charged group of less than 200 daltons. The phenothiazine conjugate has anti-proliferative activity in vivo and reduced activity in the central nervous system in comparison to the parent phenothiazine.
[0009] Desirably, the phenothiazine conjugate is described by formula (I):
[0010] In formula (I), R 2 is selected from the group consisting of: CF 3 , halogen, OCH 3 , COCH 3 , CN, OCF 3 , COCH 2 CH 3 , CO(CH 2 ) 2 CH 3 , S(O) 2 CH 3 , S(O) 2 N(CH 3 ) 2 , and SCH 2 CH 3 ; A 1 is selected from the group consisting of G 1 ,
each of R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently H, OH, F, OCF 3 , or OCH 3 ; R 32 , R 33 , R 34 , and R 35 , are each, independently, selected from H or C 1-6 alkyl; W is selected from the group consisting of: NO,
and G 1 is a bond between the phenothiazine and the linker.
[0013] The linker L is described by formula (II):
G 1 -(Z 1 ) o -(Y 1 ) u -(Z 2 ) s -(R 9 )-(Z 3 ) t -(Y 2 ) v -(Z 4 ) p -G 2 (II)
[0014] In formula (II), G 1 is a bond between the phenothiazine and the linker, G 2 is a bond between the linker and the bulky group or between the linker and the charged group, each of Z 1 , Z 2 , Z 3 , and Z 4 is, independently, selected from O, S, and NR 39 ; R 39 is hydrogen or a C 1-6 alkyl group; each of Y 1 and Y 2 is, independently, selected from carbonyl, thiocarbonyl, sulphonyl, phosphoryl or similar acid-forming groups; o, p, s, t, u, and v are each independently 0 or 1; and R 9 is C 1-10 alkyl, C 1-10 heteroalkyl, C 2-10 alkenyl, a C 2-10 alkynyl, C 5-10 aryl, a cyclic system of 3 to 10 atoms, or a chemical bond linking G 1 -(Z 1 ) o -(Y 1 ) u -(Z 2 ) s - to -(Z 3 ) t -(Y 2 ) v -(Z 4 ) p -G 2 .
[0015] The bulky group can be a naturally occurring polymer or a synthetic polymer. Natural polymers that can be used include, without limitation, glycoproteins, polypeptides, or polysaccharides. Desirably, when the bulky group includes a natural polymer, the natural polymer is selected from alpha-1-acid glycoprotein and hyaluronic acid. Synthetic polymers that can be used as bulky groups include, without limitation, polyethylene glycol, and the synthetic polypetide N-hxg.
[0016] The bulky group may also include another therapeutic agent. Desirably, the therapeutic agent conjugated to the phenothiazine of formula (I) via a linker of formula (II) is a compound of formula (III):
[0017] In formula (III), B 1 is selected from
wherein each of X and Y is, independently, O, NR 19 , or S; each of R 14 and R 19 is, independently, H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, or C 1-7 heteroalkyl; each of R 15 , R 16 , R 17 , and R 18 is, independently, H, halogen, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, alkoxy, arlyoxy, or C 1-7 heteroalkyl; p is an integer between 2 and 6, inclusive; each of m and n is, independently, an integer between 0 and 2, inclusive; each of R 10 and R 11 is
wherein R 21 is H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, acyl, or C 1-7 heteroalkyl; R 20 is H, OH, or acyl, or R 20 and R 21 together represent
wherein each of R 23 , R 24 , and R 25 is, independently, H, halogen, trifluoromethyl, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, alkoxy, arlyoxy, or C 1-7 heteroalkyl; each of R 26 , R 27 , R 28 , and R 29 is, independently, H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, or C 1-7 heteroalkyl; and R 30 is H, halogen, trifluoromethyl, OCF 3 , NO 2 , C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, alkoxy, arlyoxy, or C 1-7 heteroalkyl; each of R 12 and R 13 is, independently, H, Cl, Br, OH, OCH 3 , OCF 3 , NO 2 , and NH 2 , or R 12 and R 13 together form a single bond; and G 2 is a bond between the compound of formula (III) and the linker.
[0021] The charged group can be a cation or an anion. Desirably, the charged group is a polyanion having at least three negatively charged moieties or a polycation having at least three positively charged moieties.
[0022] The invention features a method for inhibiting passage across the blood-brain barrier of a phenothiazine by covalent attachment of a bulky group of greater than 200 daltons or a charged group of less than 200 daltons. The group increases the size, or alters the charge, of the phenothiazine sufficiently to inhibit passage across the blood-brain barrier without destroying the antiproliferative activity of the phenothiazine covalently attached to the group.
[0023] The invention also features liposomal composition that includes an effective amount of a phenothiazine conjugate described herein.
[0024] In another aspect, the invention features a liposomal composition that includes (a) a compound of formula (IV):
or a pharmaceutically acceptable salt thereof, wherein R 42 is selected from the group consisting of: CF 3 , halogen, OCH 3 , COCH 3 , CN, OCF 3 , COCH 2 CH 3 , CO(CH 2 ) 2 CH 3 , S(O) 2 CH 3 , S(O) 2 N(CH 3 ) 2 , and SCH 2 CH 3 ;
R 49 is selected from the group consisting of:
each of R 41 , R 43 , R 44 , R 45 , R 46 , R 47 , and R 48 is independently H, OH, F, OCF 3 , or OCH 3 ; and W is selected from the group consisting of: NO,
(b) an antiproliferative agent, wherein each are present in amounts that together are sufficient to inhibit the growth of a neoplasm.
[0029] Preferably, the compound of formula (IV) is acepromazine, chlorpromazine, cyamemazine, fluphenazine, mepazine, methotrimeprazine, methoxypromazine, perazine, perphenazine, prochlorperazine, promethazine, propiomazine, thiethylperazine, thiopropazate, thioridazine, trifluoperazine, or triflupromazine.
[0030] The liposomal formulation, desirably, contains an anti-proliferative agent of formula (V):
or a pharmaceutically acceptable salt thereof. In formula (V), B 2 is
wherein each of X and Y is, independently, O, NR 59 , or S; each of R 54 and R 59 is, independently, H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, or C 1-7 heteroalkyl; each of R 55 , R 56 R 57 and R 58 is, independently, H, halogen, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, alkoxy, arlyoxy, or C 1-7 heteroalkyl; p is an integer between 2 and 6, inclusive; each of m and n is, independently, an integer between 0 and 2, inclusive; each of R 50 and R 51 is
wherein R 61 is H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, acyl, or C 1-7 heteroalkyl; R 62 is H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, acyl, alkoxy, aryloxy, or C 1-7 heteroalkyl; and R 60 is H, OH, or acyl, or R 60 and R 61 together represent
wherein each of R 63 , R 64 , and R 65 is, independently, H, halogen, trifluoromethyl, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, alkoxy, arlyoxy, or C 1-7 heteroalkyl; each of R 66 , R 67 , R 68 , and R 69 is, independently, H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, or C 1-7 heteroalkyl; and R 30 is H, halogen, trifluoromethyl, OCF 3 , NO 2 , C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, alkoxy, arlyoxy, or C 1-7 heteroalkyl; each of R 52 and R 53 is, independently, H, Cl, Br, OH, OCH 3 , OCF 3 , NO 2 , and NH 2 , or R 52 and R 53 together form a single-bond.
[0035] Compounds of formula (V) useful in the methods and compositions of the invention include pentamidine, propamidine, butamidine, heptamidine, nonamidine, stilbamidine, hydroxystilbamidine, diminazene, dibrompropamidine, 2,5-bis(4-amidinophenyl)furan, 2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime, 2,5-bis(4-amidinophenyl)furan-bis-O-4-fluorophenyl, 2,5-bis(4-amidinophenyl)furan-bis-O-4-methoxyphenyl, 2,4-bis(4-amidinophenyl)furan, 2,4-bis(4-amidinophenyl)furan-bis-O-methylamidoxime, 2,4-bis(4-amidinophenyl)furan-bis-O-4-fluorophenyl, 2,4-bis(4-amidinophenyl)furan-bis-O-4-methoxyphenyl, 2,5-bis(4-amidinophenyl) thiophene, 2,5-bis(4-amidinophenyl) thiophene-bis-O-methylamidoxime, 2,4-bis(4-amidinophenyl)thiophene, and 2,4-bis(4-amidinophenyl)thiophene-bis-O-methylamidoxime.
[0036] In one embodiment of the liposomal formulation, the compound of formula (IV) is chlorpromazine, perphenazine or promethazine and the compound of formula (V) is pentamidine, 2,5-bis(4-amidinophenyl)furan, or 2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime.
[0037] The invention also features a liposomal formulation that includes (a) a first compound selected from prochlorperazine, perphenazine, mepazine, methotrimeprazine, acepromazine, thiopropazate, perazine, propiomazine, putaperazine, thiethylperazine, methopromazine, chlorfenethazine, cyamemazine, perphenazine, norchlorpromazine, trifluoperazine, thioridazine (or a salt of any of the above), and dopamine D2 antagonists (e.g., sulpride, pimozide, spiperone, ethopropazine, clebopride, bupropion, and haloperidol), and, (b) a second compound selected from pentamidine, propamidine, butamidine, heptamidine, nonamidine, stilbamidine, hydroxystilbamidine, diminazene, benzamidine, phenamidine, dibrompropamidine, 1,3-bis(4-amidino-2-methoxyphenoxy)propane, phenamidine, amicarbalide, 1,5-bis(4′-(N-hydroxyamidino)phenoxy)pentane, 1,3-bis(4′-(N-hydroxyamidino)phenoxy)propane, 1,3-bis(2′-methoxy-4′-N -hydroxyamidino)phenoxy)propane, 1,4-bis(4′-(N-hydroxyamidino)phenoxy)butane, 1,5-bis(4′-(N-hydroxyamidino)phenoxy)pentane, 1,4-bis(4′-(N-hydroxyamidino)phenoxy)butane, 1,3-bis(4′-(4-hydroxyamidino)phenoxy)propane, 1,3-bis(2′-methoxy-4′-(N-hydroxyamidino)phenoxy)propane, 2,5-bis[4-amidinophenyl]furan, 2,5-bis[4-amidinophenyl]furan-bis-amidoxime, 2,5-bis[4-amidinophenyl]furan-bis-O-methylamidoxime, 2,5-bis[4-amidinophenyl]furan-bis-O-ethylamidoxime, 2,5-bis(4-amidinophenyl)furan-bis-O-4-fluorophenyl, 2,5-bis(4-amidinophenyl)furan-bis-O-4-methoxyphenyl, 2,4-bis(4-amidinophenyl)furan, 2,4-bis(4-amidinophenyl)furan-bis-O-methylamidoxime, 2,4-bis(4-amidinophenyl)furan-bis-O-4-fluorophenyl, 2,4-bis(4-amidinophenyl)furan-bis-O-4-methoxyphenyl, 2,5-bis(4-amidinophenyl) thiophene, 2,5-bis(4-amidinophenyl) thiophene-bis-O-methylamidoxime, 2,4-bis(4-amidinophenyl)thiophene, 2,4-bis(4-amidinophenyl)thiophene-bis-O-methylamidoxime, 2,8-diamidinodibenzothiophene, 2,8-bis(N-isopropylamidino)carbazole, 2,8-bis(N-hydroxyamidino)carbazole, 2,8-bis(2-imidazolinyl)dibenzothiophene, 2,8-bis(2-imidazolinyl)-5,5-dioxodibenzothiophene, 3,7-diamidinodibenzothiophene, 3,7-bis(N-isopropylamidino)dibenzothiophene, 3,7-bis(N-hydroxyamidino)dibenzothiophene, 3,7-diaminodibenzothiophene, 3,7-dibromodibenzothiophene, 3,7-dicyanodibenzothiophene, 2,8-diamidinodibenzofuran, 2,8-di(2-imidazolinyl)dibenzofuran, 2,8-di(N-isopropylamidino)dibenzofuran, 2,8-di (N-hydroxylamidino)dibenzofuran, 3,7-di(2-imidazolinyl)dibenzofuran, 3,7-di(isopropylamidino)dibenzofuran, 3,7-di(N-hydroxylamidino)dibenzofuran, 2,8-dicyanodibenzofuran, 4,4′-dibromo-2,2′-dinitrobiphenyl, 2-methoxy-2′-nitro-4,4′-dibromobiphenyl, 2-methoxy-2′-amino-4,4′-dibromobiphenyl, 3,7-dibromodibenzofuran, 3,7-dicyanodibenzofuran, 2,5-bis(5-amidino-2-benzimidazolyl)pyrrole, 2,5-bis[5-(2-imidazolinyl)-2-benzimidazolyl]pyrrole, 2,6-bis[5-(2-imidazolinyl)-2-benzimidazolyl]pyridine, 1-methyl-2,5-bis(5-amidino-2-benzimidazolyl)pyrrole, 1-methyl-2,5-bis[5-(2-imidazolyl)-2-benzimidazolyl]pyrrole, 1-methyl-2,5-bis[5-(1,4,5,6-tetrahydro-2-pyrimidinyl)-2-benzimidazolyl]pyrrole, 2,6-bis(5-amidino-2-benzimidazoyl)pyridine, 2,6-bis[5-(1,4,5,6-tetrahydro-2-pyrimidinyl)-2-benzimidazolyl]pyridine, 2,5-bis(5-amidino-2-benzimidazolyl)furan, 2,5-bis-[5-(2-imidazolinyl)-2-benzimidazolyl]furan, 2,5-bis-(5-N-isopropylamidino-2-benzimidazolyl)furan, 2,5-bis-(4-guanylphenyl)furan, 2,5-bis(4-guanylphenyl)-3,4-dimethylfuran, 2,5-bis {p-[2-(3,4,5,6-tetrahydropyrimidyl)phenyl]}furan, 2,5-bis[4-(2-imidazolinyl)phenyl]furan, 2,5[bis-{4-(2-tetrahydropyrimidinyl)}phenyl]-3-(p-tolyloxy)furan, 2,5[bis{4-(2-imidazolinyl)}phenyl]-3-(p-tolyloxy)furan, 2,5-bis {4-[5-(N-2-aminoethylamido)benzimidazol-2-yl]phenyl}furan, 2,5-bis[4-(3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)phenyl]furan, 2,5-bis[4-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl)phenyl]furan, 2,5-bis(4-N,N-dimethylcarboxhydrazidephenyl)furan, 2,5-bis{4-[2-(N-2-hydroxyethyl)imidazolinyl]phenyl}furan, 2,5-bis[4-(N-isopropylamidino)phenyl]furan, 2,5-bis{4-[3-(dimethylaminopropyl)amidino]phenyl}furan, 2,5-bis {4-[N-(3-aminopropyl)amidino]phenyl}furan, 2,5-bis[2-(imidzaolinyl)phenyl]-3,4-bis(methoxymethyl)furan, 2,5-bis[4-N-(dimethylaminoethyl)guanyl]phenylfuran, 2,5-bis {4-[(N-2-hydroxyethyl)guanyl]phenyl}furan, 2,5-bis[4-N-(cyclopropylguanyl)phenyl]furan, 2,5-bis[4-(N,N-diethylaminopropyl)guanyl]phenylfuran, 2,5-bis{4-[2-(N-ethylimidazolinyl)]phenyl}furan, 2,5-bis {4-[N-(3-pentylguanyl)]}phenylfuran, 2,5-bis[4-(2-imidazolinyl)phenyl]-3-methoxyfuran, 2,5-bis[4-(N-isopropylamidino)phenyl]-3-methylfuran, bis[5-amidino-2-benzimidazolyl]methane, bis[5-(2-imidazolyl)-2-benzimidazolyl]methane, 1,2-bis[5-amidino-2-benzimidazolyl]etbane, 1,2-bis[5-(2-imidazolyl)-2-benzimidazolyl]ethane, 1,3-bis[5-amidino-2-benzimidazolyl]propane, 1,3-bis[5-(2-imidazolyl)-2-benzimidazolyl]propane, 1,4-bis[5-amidino-2-benzimidazolyl]propane, 1,4-bis[5-(2-imidazolyl)-2-benzimidazolyl]butane, 1,8-bis[5-amidino-2-benzimidazolyl]octane, trans-1,2-bis[5-amidino-2-benzimidazolyl]ethene, 1,4-bis[5-(2-imidazolyl)-2-benzimidazolyl]-1-butene, 1,4-bis[5-(2-imidazolyl)-2-benzimidazolyl]-2-butene, 1,4-bis[5-(2-imidazolyl)-2-benzimidazolyl]-1-methylbutane, 1,4-bis[5-(2-imidazolyl)-2-benzimidazolyl]-2-ethylbutane, 1,4-bis[5-(2-imidazolyl)-2-benzimidazolyl]-1-methyl-1-butene, 1,4-bis[5-(2-imidazolyl)-2-benzimidazolyl]-2,3-diethyl-2-butene, 1,4-bis[5-(2-imidazolyl)-2-benzimidazolyl]-1,3-butadiene, 1,4-bis[5-(2-imidazolyl)-2-benzimidazolyl]-2-methyl-1,3-butadiene, bis[5-(2-pyrimidyl)-2-benzimidazolyl]methane, 1,2-bis[5-(2-pyrimidyl)-2-benzimidazolyl]ethane, 1,3-bis[5-amidino-2-benzimidazolyl]propane, 1,3-bis[5-(2-pyrimidyl)-2-benzimidazolyl]propane, 1,4-bis[5-(2-pyrimidyl)-2-benzimidazolyl]butane, 1,4-bis[5-(2-pyrimidyl)-2-benzimidazolyl]-1-butene, 1,4-bis[5-(2-pyrimidyl)-2-benzimidazolyl]-2-butene, 1,4-bis[5-(2-pyrimidyl)-2-benzimidazolyl]-1-methylbutane, 1,4-bis[5-(2-pyrimidyl)-2-benzimidazolyl]-2-ethylbutane, 1,4-bis[5-(2-pyrimidyl)-2-benzimidazolyl]-1-methyl-1-butene, 1,4-bis[5-(2-pyrimidyl)-2-benzimidazolyl]-2,3-diethyl-2-butene, 1,4-bis[5-(2-pyrimidyl)-2-benzimidazolyl]-1,3-butadiene, and 1,4-bis[5-(2-pyrimidyl)-2-benzimidazolyl]-2-methyl-1,3-butadiene, 2,4-bis(4-guanylphenyl)pyrimidine, 2,4-bis(4-imidazolin-2-yl)pyrimidine, 2,4-bis[(tetrahydropyrimidinyl-2-yl)phenyl]pyrimidine, 2-(4-[N-1-propylguanyl]phenyl)-4-(2-methoxy-4-[N-1-propylguanyl]phenyl)pyrimidine, 4-(N-cyclopentylamidino)-1,2-phenylene diamine, 2,5-bis-[2-(5-amidino)benzimidazoyl]furan, 2,5-bis[2-{5-(2-imidazolino)}benzimidazoyl]furan, 2,5-bis[2-(5-N-isopropylamidino)benzimidazoyl]furan, 2,5-bis[2-(5-N-cyclopentylamidino)benzimidazoyl]furan, 2,5-bis[2-(5-amidino)benzimidazoyl]pyrrole, 2,5-bis[2-{5-(2-imidazolino)}benzimidazoyl]pyrrole, 2,5-bis[2-(5-N-isopropylamidino)benzimidazoyl]pyrrole, 2,5-bis[2-(5-N-cyclopentylamidino)benzimidazoyl]pyrrole, 1-methyl-2,5-bis[2-(5-amidino)benzimidazoyl]pyrrole, 2,5-bis[2-{5-(2-imidazolino)}benzimidazoyl]-1-methylpyrrole, 2,5-bis[2-(5-N-cyclopentylamidino)benzimidazoyl]-1-methylpyrrole, 2,5-bis[2-(5-N-isopropylamidino)benzimidazoyl]thiophene, 2,6-bis[2-{5-(2-imidazolino)}benzimidazoyl]pyridine, 2,6-bis[2-(5-amidino)benzimidazoyl]pyridine, 4,4′-bis[2-(5-N-isopropylamidino)benzimidazoyl]-1,2-diphenylethane, 4,4′-bis[2-(5-N-cyclopentylamidino)benzimidazoyl]-2,5-diphenylfuran, 2,5-bis[2-(5-amidino)benzimidazoyl]benzo[b]furan, 2,5-bis[2-(5-N-cyclopentylamidino)benzimidazoyl]benzo[b]furan, 2,7-bis[2-(5-N-isopropylamidino)benzimidazoyl]fluorine, 2,5-bis[4-(3-(N-morpholinopropyl)carbamoyl)phenyl]furan, 2,5-bis[4-(2-N,N-dimethylaminoethylcarbamoyl)phenyl]furan, 2,5-bis[4-(3-N,N-dimethylaminopropylcarbamoyl)phenyl]furan, 2,5-bis[4-(3-N-methyl-3-N-phenylaminopropylcarbamoyl)phenyl]furan, 2,5-bis[4-(3-N,N 8 ,N 11 -trimethylaminopropylcarbamoyl)phenyl]furan, 2,5-bis[3-amidinophenyl]furan, 2,5-bis[3-(N-isopropylamidino)amidinophenyl]furan, 2,5-bis[3(N-(2-dimethylaminoethyl)amidino]phenylfuran, 2,5-bis[4-(N-2,2,2-trichloroethoxycarbonyl)amidinophenyl]furan, 2,5-bis[4-(N-thioethylcarbonyl) amidinophenyl]furan, 2,5-bis[4-(N-benzyloxycarbonyl)amidinophenyl]furan, 2,5-bis[4-(N-phenoxycarbonyl)amidinophenyl]furan, 2,5-bis[4-(N-(4-fluoro)-phenoxycarbonyl)amidinophenyl]furan, 2,5-bis[4-(N-(4-methoxy)phenoxycarbonyl)amidinophenyl]furan, 2,5-bis[4(1-acetoxyethoxycarbonyl)amidinophenyl]furan, and 2,5-bis[4-(N-(3-fluoro)phenoxycarbonyl)amidinophenyl]furan, or a salt of any of the above.
[0038] Alternatively, the second compound can be a functional analog of pentamidine, such as netropsin, distamycin, bleomycin, actinomycin, daunorubicin, or a compound that falls within a formula provided in any of U.S. Pat. Nos. 5,428,051; 5,521,189; 5,602,172; 5,643,935; 5,723,495; 5,843,980; 6,008,247; 6,025,398; 6,172,104; 6,214,883; and 6,326,395, or U.S. Patent Application Publication Nos. US 2001/0044468 A1 and US 2002/0019437 A1.
[0039] The invention also features a method for treating a patient who has a neoplasm, or inhibiting the development of a neoplasm in a patient who is at risk for developing a neoplasm. The method includes the step of administering to the patient an effective amount of any of the phenothiazine conjugates, phenothiazine formulations, or combinations described herein.
[0040] In another aspect, the invention features a method for treating a patient who has a neoplasm, or inhibiting the development of a neoplasm in a patient who is at risk for developing a neoplasm by administering to the patient a pharmaceutical composition that includes a phenothiazine conjugate of formula (I) and a compound of formula (V), wherein each are administered in amounts that together are sufficient to treat a neoplasm in a patient.
[0041] The combination of a compound of formula (I) and a compound of formula (V) can be administered within thirty days of each other. Preferably, all treatments are administered within fourteen or ten days of each other, more preferably within five days of each other, and most preferably within twenty-four hours of each other or even simultaneously. The compounds can be administered by the same or different routes. Exemplary routes of administration include intravenous, intramuscular, subcutaneous, inhalation, rectal, buccal, topical, or oral administration. These compounds are administered in amounts that, when administered together to a patient having a neoplasm, reduce cell proliferation in the neoplasm.
[0042] Depending on the type of cancer and its stage of development, the combination therapy can be used to treat cancer, to slow the spreading of the cancer, to slow the cancer's growth, to kill or arrest cancer cells that may have spread to other parts of the body from the original tumor, to relieve symptoms caused by the cancer, or to prevent cancer in the first place. Combination therapy can also help people live more comfortably by eliminating cancer cells that cause pain or discomfort.
[0043] The administration of a combination of the present invention allows for the administration of lower doses of each compound, providing similar efficacy and lower toxicity compared to administration of either compound alone. Alternatively, such combinations result in improved efficacy in treating neoplasms with similar or reduced toxicity.
[0044] Cancers treated according to any of the methods of the invention can be, for example, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (Hodgkin's disease, non-Hodgkin's disease), Waldenstrom's macroglobulinemia, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, meningioma, melanoma, neuroblastoma, and retinoblastoma. Preferably, the cancer being treated is lung cancer, especially lung cancer attributed to squamous cell carcinoma, adenocarinoma, or large cell carcinoma, colorectal cancer, ovarian cancer, especially ovarian adenocarcinoma, prostate cancer; gastric cancer, esophageal cancer, head and neck cancer, or thyroid cancer.
[0045] The invention features a method of promoting investment in a company conducting or planning in vivo studies on a pharmaceutical composition including a phenothiazine conjugate, phenothiazine formulation, or combination described herein. The method includes the step of disseminating information about the identity, therapeutic use, toxicity, efficacy, or projected date of governmental approval of the pharmaceutical composition.
[0046] The invention also features a method of promoting investment in a company conducting or planning in vivo studies on a therapeutic method described herein. The method of promoting includes the step of disseminating information about the dosing regimen, toxicity, efficacy, or projected date of governmental approval of the therapeutic method.
[0047] As used herein “identity” refers to an identifier intended to convey the identity of a compound described herein. The identifier can be, for example, a structure, diagram, figure, chemical name, common name, tradename, formula, reference label, or any other identifier that conveys the identity of the compound to a person.
[0048] By “in vivo studies” is meant any study in which a compound of the invention is administered to a mammal, including, without limitation, non-clinical studies, e.g., to collect data concerning toxicity and efficacy, and clinical studies.
[0049] By “projected date of governmental approval” is meant any estimate of the date on which a company will receive approval from a governmental agency to sell, e.g., to patients, doctors, or hospitals, a pharmaceutical composition including a compound of the invention. A governmental approval includes, for example, the approval of a new drug application by the Food and Drug Administration, among others.
[0050] As used herein, the terms “cancer” or “neoplasm” or “neoplastic cells” is meant a collection of cells multiplying in an abnormal manner. Cancer growth is uncontrolled and progressive, and occurs under conditions that would not elicit, or would cause cessation of, multiplication of normal cells. The terms also encompass the original site of proliferation (“primary tumor or cancer”) and invasion of other tissues, or organs beyond the primary site (“metastisis”) by neoplastic cells.
[0051] By “inhibits the growth of a neoplasm” is meant measurably slows, stops, or reverses the growth rate of the neoplasm or neoplastic cells in vitro or in vivo. Desirably, a slowing of the growth rate is by at least 20%, 30%, 50%, or even 70%, as determined using a suitable assay for determination of cell growth rates (e.g., a cell growth assay described herein). Typically, a reversal of growth rate is accomplished by initiating or accelerating necrotic or apoptotic mechanisms of cell death in the neoplastic cells, resulting in a shrinkage of the neoplasm.
[0052] As used herein, the term “treating” refers to administering a pharmaceutical composition for prophylactic and/or therapeutic purposes. To “prevent disease” refers to prophylactic treatment of a patient who is not yet ill, but who is susceptible to, or otherwise at risk of, a particular disease. To “treat disease” or use for “therapeutic treatment” refers to administering treatment to a patient already suffering from a disease to improve the patient's condition. Thus, in the claims and embodiments, treating is the administration to a mammal either for therapeutic or prophylactic purposes.
[0053] The term “administration” or “administering” refers to a method of giving a dosage of a pharmaceutical composition to a mammal, wherein the phenothiazine, phenothiazine conjugate, or phenothiazine combination is administered by a route selected from, without limitation, inhalation, ocular administration, nasal instillation, parenteral administration, dermal administration, transdermal administration, buccal administration, rectal administration, sublingual administration, perilingual administration, nasal administration, topical administration and oral administration. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, and intramuscular administration. The preferred method of administration can vary depending on various factors, e.g., the components of the pharmaceutical composition, site of the potential or actual disease and severity of disease.
[0054] By “an effective amount” is meant the amount of a compound, or combination according to the invention, required to inhibit the growth of the cells of a neoplasm in vivo. The effective amount of active compound(s) used to practice the present invention for therapeutic treatment of neoplasms (i.e., cancer) varies depending upon the manner of administration, the age, body weight, sex, race, vital organ function, and general health of the subject. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an “effective” amount.
[0055] By “parent phenothiazine” is meant the phenothiazine which is modified by conjugation to a bulky group or a charged group.
[0056] By “reduced CNS activity” for a phenothiazine conjugate is meant that the ratio of AUC brain (area under the curve in brain tissue) to AUC blood (area under the curves in whole blood) is reduced for the phenothiazine conjugate in comparison to the parent phenothiazine administered under the same conditions. The AUC calculation includes the administered compound and any metabolites thereof having antiproliferative activity. Desirably the AUC brain /AUC blood ratio is reduced by 5%, 10%, 20%, 30% 40%, 50%, 60%, 70%, 80%, 90%, or even 95%.
[0057] As used herein, “targeting” of neoplasms refers to a phenothiazine conjugate which increases the ratio of AUC neoplasm (area under the curve in neoplasm tissue) to AUC blood (area under the curve in whole blood) for the phenothiazine conjugate in comparison to the parent phenothiazine administered under the same conditions. Phenothiazine-containing formulations may also be targeted to a neoplasm, e.g., liposomal formulations, pegylated formulations, or microencapsulated formulations, resulting in an increase in the AUC neoplasm /AUC blood ratio for the formulation in comparison to the phenothiazine administered as a non-particulate formulation. Neoplasm targeting, with concomitant long neoplasm exposure times, can increase the proportion of neoplasm that do not move into cell cycle dvision when drug concentrations are high. Desirably the AUC neoplasm /AUC blood ratio is increased by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or even 95%.
[0058] By “linked through the ring nitrogen” is meant that the charged group, bulky group, or linker is covalently attached to a substituent of ring nitrogen as identified below.
[0059] By “phenothiazine” is meant any compound having a phenothiazine ring structure or related ring structure as shown below. Thus, ring systems for which the ring sulfur atom is oxidized, or replaced by O, NH, CH 2 , or CH═CH are encompassed by the generic description “phenothiazine.” For all of the ring systems show below, phenothiazines include those ring substitutions and nitrogen substitutions provide for in formulas (I) and (IV).
[0060] By “charged group” is meant a group comprising three or more charged moieties.
[0061] By “charged moiety” is meant a moiety which loses a proton at physiological pH thereby becoming negatively charged (e.g., carboxylate, or phosphate), a moiety which gains a proton at physiological pH thereby becoming positively charged (e.g., ammonium, guanidinium, or amidinium), a moiety that includes a net formal positive charge without protonation (e.g., quaternary ammonium), or a moiety that includes a net formal negative charge without loss of a proton (e.g., borate, BR 4 − ).
[0062] In the generic descriptions of compounds of this invention, the number of atoms of a particular type in a substituent group is generally given as a range, e.g., an alkyl group containing from 1 to 7 carbon atoms or C 1-7 alkyl. Reference to such a range is intended to include specific references to groups having each of the integer number of atoms within the specified range. For example, an alkyl group from 1 to 7 carbon atoms includes each of C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , and C 7 . A C 1-7 heteroalkyl, for example, includes from 1 to 6 carbon atoms in addition to one or more heteroatoms. Other numbers of atoms and other types of atoms may be indicated in a similar manner.
[0063] As used herein, the terms “alkyl” and the prefix “alk-” are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e., cycloalkyl. Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 6 ring carbon atoms, inclusive. Exemplary cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. The alkyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. Exemplary alkyls include, without limitation, methyl; ethyl; n-propyl; isopropyl; cyclopropyl; cyclopropylmethyl; cyclopropylethyl; n-butyl; iso-butyl; sec-butyl; tert-butyl; cyclobutyl; cyclobutylmethyl; cyclobutylethyl; n-pentyl; cyclopentyl; cyclopentylmethyl; cyclopentylethyl; 1-methylbutyl; 2-methylbutyl; 3-methylbutyl; 2,2-dimethylpropyl; 1-methylpropyl; 1,1-dimethylpropyl; 1,2-dimethylpropyl; 1-methylpentyl; 2-methylpentyl; 3-methylpentyl; 4-methylpentyl; 1,1-dimethylbutyl; 1,2-dimethylbutyl; 1,3-dimethylbutyl; 2,2-dimethylbutyl; 2,3-dimethylbutyl; 3,3-dimethylbutyl; 1-ethylbutyl; 2-ethylbutyl; 1,1,2-trimethylpropyl; 1,2,2-trimethylpropyl; 1-ethyl-1-methylpropyl; 1-ethyl-2-methylpropyl; and cyclohexyl.
[0064] By “alkenyl” is meant a branched or unbranched hydrocarbon group containing one or more double bonds. An alkenyl may optionally include monocyclic or polycyclic rings, in which each ring desirably has from three to six members. The alkenyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. Exemplary alkenyls include, without limitation, vinyl; allyl; 2-cyclopropyl-1-ethenyl; 1-propenyl; 1-butenyl; 2-butenyl; 3-butenyl; 2-methyl-1-propenyl; 2-methyl-2-propenyl; 1-pentenyl; 2-pentenyl; 3-pentenyl; 4-pentenyl; 3-methyl-1-butenyl; 3-methyl-2-butenyl; 3-methyl-3-butenyl; 2-methyl-1-butenyl; 2-methyl-2-butenyl; 2-methyl-3-butenyl; 2-ethyl-2-propenyl; 1-methyl-1-butenyl; 1-methyl-2-butenyl; 1-methyl-3-butenyl; 2-methyl-2-pentenyl; 3-methyl-2-pentenyl; 4-methyl-2-pentenyl; 2-methyl-3-pentenyl; 3-methyl-3-pentenyl; 4-methyl-3-pentenyl; 2-methyl-4-pentenyl; 3-methyl-4-pentenyl; 1,2-dimethyl-1-propenyl; 1,2-dimethyl-1-butenyl; 1,3-dimethyl-butenyl; 1,2-dimethyl-2-butenyl; 1,1-dimethyl-2-butenyl; 2,3-dimethyl-2-butenyl; 2,3-dimethyl-3-butenyl; 1,3-dimethyl-3-butenyl; 1,1-dimethyl-3-butenyl and 2,2-dimethyl-3-butenyl.
[0065] By “alkynyl” is meant a branched or unbranched hydrocarbon group containing one or more triple bonds. An alkynyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members. The alkynyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxy, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. Exemplary alkynyls include, without limitation, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-hexene-1-ynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl; 1-methyl-2-propynyl; 1-methyl-2-butynyl; 1-methyl-3-butynyl; 2-methyl-3-butynyl; 1,2-dimethyl-3-butynyl; 2,2-dimethyl-3-butynyl; 1-methyl-2-pentynyl; 2-methyl-3-pentynyl; I-methyl-4-pentynyl; 2-methyl-4-pentynyl; and 3-methyl-4-pentynyl.
[0066] By “C 2-6 heterocyclyl” is meant a stable 5- to 7-membered monocyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of 2 to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O, and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxy, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be covalently attached via any heteroatom or carbon atom which results in a stable structure, e.g., an imidazolinyl ring may be linked at either of the ring-carbon atom positions or at the nitrogen atom. A nitrogen atom in the heterocycle may optionally be quaternized. Preferably when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. Heterocycles include, without limitation, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl. Preferred 5 to 6 membered heterocycles include, without limitation, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl.
[0067] By “C 6-12 aryl” is meant an aromatic group having a ring system comprised of carbon atoms with conjugated π electrons (e.g., phenyl). The aryl group has from 6 to 12 carbon atoms. Aryl groups may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members. The aryl group may be substituted or unsubstituted. Exemplary subsituents include alkyl, hydroxy, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, fluoroalkyl, carboxyl, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, monosubstituted amino, disubstituted amino, and quaternary amino groups.
[0068] By “C 7-14 alkaryl” is meant an alkyl substituted by an aryl group (e.g., benzyl, phenethyl, or 3,4-dichlorophenethyl) having from 7 to 14 carbon atoms.
[0069] By “C 3-10 alkheterocyclyl” is meant an alkyl substituted heterocyclic group having from 7 to 14 carbon atoms in addition to one or more heteroatoms (e.g., 3-furanylmethyl, 2-furanylmethyl, 3-tetrahydrofuranylmethyl, or 2-tetrahydrofuranylmethyl).
[0070] By “heteroalkyl” is meant a branched or unbranched alkyl, alkenyl, or alkynyl group having a number of carbon atoms, e.g., from 1 to 7 carbon atoms, in addition to 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O, S, and P. Heteroalkyls include, without limitation, tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides. A heteroalkyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has three to six members. The heteroalkyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, hydroxyalkyl, carboxyalkyl, and carboxyl groups.
[0071] By “acyl” is meant a chemical moiety with the formula R—C(O)—, wherein R is selected from C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, or C 1-7 heteroalkyl.
[0072] By “halogen” is meant bromine, chlorine, iodine, or fluorine.
[0073] By “fluoroalkyl” is meant an alkyl group that is substituted with a fluorine.
[0074] By “perfluoroalkyl” is meant an alkyl group consisting of only carbon and fluorine atoms.
[0075] By “carboxyalkyl” is meant a chemical moiety with the formula —(R)—COOH, wherein R is selected from C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, or C 1-7 heteroalkyl.
[0076] By “hydroxyalkyl” is meant a chemical moiety with the formula —(R)—OH, wherein R is selected from C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, or C 1-7 heteroalkyl.
[0077] By “alkoxy” is meant a chemical substituent of the formula —OR, wherein R is selected from C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, or C 1-7 heteroalkyl.
[0078] By “aryloxy” is meant a chemical substituent of the formula —OR, wherein R is a C 6-12 aryl group.
[0079] By “alkylthio” is meant a chemical substituent of the formula —SR, wherein R is selected from C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 2-6 heterocyclyl, C 6-12 aryl, C 7-14 alkaryl, C 3-10 alkheterocyclyl, or C 1-7 heteroalkyl.
[0080] By “arylthio” is meant a chemical substituent of the formula —SR, wherein R is a C 6-12 aryl group.
[0081] By “quaternary amino” is meant a chemical substituent of the formula —(R)—N(R′)(R″)(R′″) + , wherein R, R′, R″, and R′″ are each independently an alkyl, alkenyl, alkynyl, or aryl group. R may be an alkyl group linking the quaternary amino nitrogen atom, as a substituent, to another moiety. The nitrogen atom, N, is covalently attached to four carbon atoms of alkyl and/or aryl groups, resulting in a positive charge at the nitrogen atom.
[0082] By an “antiproliferative agent” is meant a compound that, individually, inhibits the growth of a neoplasm. Antiproliferative agents of the invention include alkylating agents, platinum agents, antimetabolites, topoisomerase inhibitors, antitumor antibiotics, antimitotic agents, aromatase inhibitors, thymidylate synthase inhibitors, DNA antagonists, farnesyltransferase inhibitors, pump inhibitors, histone acetyltransferase inhibitors, metalloproteinase inhibitors, ribonucleoside reductase inhibitors, TNF alpha agonists and antagonists, endothelin A receptor antagonists, retinoic acid receptor agonists, immunomodulators, hormonal and antihormonal agents, photodynamic agents, and tyrosine kinase inhibitors. Antiproliferative agents that can be administered in combination with any phenothiazine conjugate or combination of phenothiazine conjugate and compound of formula (V) or combination of phenothiazine of formula (IV) and compound of formula (V) described herein. Antiproliferative agents include those agents listed in Table 1.
TABLE 1 Alkylating agents cyclophosphamide lomustine busulfan procarbazine ifosfamide altretamine melphalan estramustine phosphate hexamethylmelamine mechlorethamine thiotepa streptozocin chlorambucil temozolomide dacarbazine semustine. carmustine Platinum agents cisplatin carboplatinum oxaliplatin ZD-0473 (AnorMED) spiroplatinum, lobaplatin (Aeterna) carboxyphthalatoplatinum, satraplatin (Johnson Matthey) tetraplatin BBR-3464 (Hoffmann-La Roche) ormiplatin SM-11355 (Sumitomo) iproplatin AP-5280 (Access) Antimetabolites azacytidine tomudex gemcitabine trimetrexate capecitabine deoxycoformycin 5-fluorouracil fludarabine floxuridine pentostatin 2-chlorodeoxyadenosine raltitrexed 6-mercaptopurine hydroxyurea 6-thioguanine decitabine (SuperGen) cytarabin clofarabine (Bioenvision) 2-fluorodeoxy cytidine irofulven (MGI Pharma) methotrexate DMDC (Hoffmann-La Roche) idatrexate ethynylcytidine (Taiho) Topoisomerase amsacrine rubitecan (SuperGen) inhibitors epirubicin exatecan mesylate (Daiichi) etoposide quinamed (ChemGenex) teniposide or mitoxantrone gimatecan (Sigma-Tau) irinotecan (CPT-11) diflomotecan (Beaufour-Ipsen) 7-ethyl-10-hydroxy-camptothecin TAS-103 (Taiho) topotecan elsamitrucin (Spectrum) dexrazoxanet (TopoTarget) J-107088 (Merck & Go) pixantrone (Novuspharma) BNP-1350 (BioNumerik) rebeccamycin analogue (Exelixis) CKD-602 (Chong Kun Dang) BBR-3576 (Novuspharma) KW-2170 (Kyowa Hakko) Antitumor dactinomycin (actinomycin D) amonafide antibiotics doxorubicin (adriamycin) azonafide deoxyrubicin anthrapyrazole valrubicin oxantrazole daunorubicin (daunomycin) losoxantrone epirubicin bleomycin sulfate (blenoxane) therarubicin bleomycinic acid idarubicin bleomycin A rubidazone bleomycin B plicamycinp mitomycin C porfiromycin MEN-10755 (Menarini) cyanomorpholinodoxorubicin GPX-100 (Gem Pharmaceuticals) mitoxantrone (novantrone) Antimitotic paclitaxel SB 408075 (GlaxoSmithKline) agents docetaxel E7010 (Abbott) colchicine PG-TXL (Cell Therapeutics) vinblastine IDN 5109 (Bayer) vincristine A 105972 (Abbott) vinorelbine A 204197 (Abbott) vindesine LU 223651 (BASF) dolastatin 10 (NCI) D 24851 (ASTAMedica) rhizoxin (Fujisawa) ER-86526 (Eisai) mivobulin (Warner-Lambert) combretastatin A4 (BMS) cemadotin (BASF) isohomohalichondrin-B (PharmaMar) RPR 109881A (Aventis) ZD 6126 (AstraZeneca) TXD 258 (Aventis) PEG-paclitaxel (Enzon) epothilone B (Novartis) AZ10992 (Asahi) T 900607 (Tularik) IDN-5109 (Indena) T 138067 (Tularik) AVLB (Prescient NeuroPharma) cryptophycin 52 (Eli Lilly) azaepothilone B (BMS) vinflunine (Fabre) BNP-7787 (BioNumerik) auristatin PE (Teikoku Hormone) CA-4 prodrug (OXiGENE) BMS 247550 (BMS) dolastatin-10 (NIH) BMS 184476 (BMS) CA-4 (OXiGENE) BMS 188797 (BMS) taxoprexin (Protarga) Aromatase aminoglutethimide exemestane inhibitors letrozole atamestane (BioMedicines) anastrazole YM-511 (Yamanouchi) formestane Thymidylate pemetrexed (Eli Lilly) nolatrexed (Eximias) synthase inhibitors ZD-9331 (BTG) CoFactor ™ (BioKeys) DNA antagonists trabectedin (PharmaMar) mafosfamide (Baxter International) glufosfamide (Baxter International) apaziquone (Spectrum Pharmaceuticals) albumin + 32P (Isotope Solutions) O6 benzyl guanine (Paligent) thymectacin (NewBiotics) edotreotide (Novartis) Farnesyltransferase arglabin (NuOncology Labs) tipifarnib (Johnson & Johnson) inhibitors lonafarnib (Schering-Plough) perillyl alcohol (DOR BioPharma) BAY-43-9006 (Bayer) Pump inhibitors CBT-1 (CBA Pharma) zosuquidar trihydrochloride (Eli Lilly) tariquidar (Xenova) biricodar dicitrate (Vertex) MS-209 (Schering AG) Histone tacedinaline (Pfizer) pivaloyloxymethyl butyrate (Titan) acetyltransferase SAHA (Aton Pharma) depsipeptide (Fujisawa) inhibitors MS-275 (Schering AG) Metalloproteinase Neovastat (Aeterna Laboratories) CMT-3 (CollaGenex) inhibitors marimastat (British Biotech) BMS-275291 (Celltech) Ribonucleoside gallium maltolate (Titan) tezacitabine (Aventis) reductase inhibitors triapine (Vion) didox (Molecules for Health) TNF alpha virulizin (Lorus Therapeutics) revimid (Celgene) agonists/antagonists CDC-394 (Celgene) Endothelin A atrasentan (Abbott) YM-598 (Yamanouchi) receptor antagonist ZD-4054 (AstraZeneca) Retinoic acid fenretinide (Johnson & Johnson) alitretinoin (Ligand) receptor agonists LGD-1550 (Ligand) Immunomodulators interferon dexosome therapy (Anosys) oncophage (Antigenics) pentrix (Australian Cancer Technology) GMK (Progenics) ISF-154 (Tragen) adenocarcinoma vaccine (Biomira) cancer vaccine (Intercell) CTP-37 (AVI BioPharma) norelin (Biostar) IRX-2 (Immuno-Rx) BLP-25 (Biomira) PEP-005 (Peplin Biotech) MGV (Progenics) synchrovax vaccines (CTL Immuno) β-alethine (Dovetail) melanoma vaccine (CTL Immuno) CLL therapy (Vasogen) p21 RAS vaccine (GemVax) Hormonal and estrogens prednisone antihormonal conjugated estrogens methylprednisolone agents ethinyl estradiol prednisolone chlortrianisen aminoglutethimide idenestrol leuprolide hydroxyprogesterone caproate goserelin medroxyprogesterone leuporelin testosterone bicalutamide testosterone propionate; fluoxymesterone flutamide methyltestosterone octreotide diethylstilbestrol nilutamide megestrol mitotane tamoxifen P-04 (Novogen) toremofine 2-methoxyestradiol (EntreMed) dexamethasone arzoxifene (Eli Lilly) Photodynamic talaporfin (Light Sciences) Pd-bacteriopheophorbide (Yeda) agents Theralux (Theratechnologies) lutetium texaphyrin (Pharmacyclics) motexafin gadolinium (Pharmacyclics) hypericin Tyrosine Kinase imatinib (Novartis) kahalide F (PharmaMar) Inhibitors leflunomide (Sugen/Pharmacia) CEP-701 (Cephalon) ZD1839 (AstraZeneca) CEP-751 (Cephalon) erlotinib (Oncogene Science) MLN518 (Millenium) canertinib (Pfizer) PKC412 (Novartis) squalamine (Genaera) phenoxodiol () SU5416 (Pharmacia) trastuzumab (Genentech) SU6668 (Pharmacia) C225 (ImClone) ZD4190 (AstraZeneca) rhu-Mab (Genentech) ZD6474 (AstraZeneca) MDX-H210 (Medarex) vatalanib (Novartis) 2C4 (Genentech) PKI166 (Novartis) MDX-447 (Medarex) GW2016 (GlaxoSmithKline) ABX-EGF (Abgenix) EKB-509 (Wyeth) IMC-IC11 (ImClone) EKB-569 (Wyeth) Miscellaneous agents SR-27897 (CCK A inhibitor, Sanofi-Synthelabo) BCX-1777 (PNP inhibitor, BioCryst) tocladesine (cyclic AMP agonist, Ribapharm) ranpirnase (ribonuclease stimulant, Alfacell) alvocidib (CDK inhibitor, Aventis) galarubicin (RNA synthesis inhibitor, Dong-A) CV-247 (COX-2 inhibitor, Ivy Medical) tirapazamine (reducing agent, SRI International) P54 (COX-2 inhibitor, Phytopharm) N-acetylcysteine (reducing agent, Zambon) CapCell ™ (CYP450 stimulant, Bavarian Nordic) R-flurbiprofen (NF-kappaB inhibitor, Encore) GCS-100 (gal3 antagonist, GlycoGenesys) 3CPA (NF-kappaB inhibitor, Active Biotech) G17DT immunogen (gastrin inhibitor, Aphton) seocalcitol (vitamin D receptor agonist, Leo) efaproxiral (oxygenator, Allos Therapeutics) 131-I-TM-601 (DNA antagonist, TransMolecular) PI-88 (heparanase inhibitor, Progen) eflornithine (ODC inhibitor, ILEX Oncology) tesmilifene (histamine antagonist, YM BioSciences) minodronic acid (osteoclast inhibitor, Yamanouchi) histamine (histamine H2 receptor agonist, Maxim) indisulam (p53 stimulant, Eisai) tiazofurin (IMPDH inhibitor, Ribapharm) aplidine (PPT inhibitor, PharmaMar) cilengitide (integrin antagonist, Merck KGaA) rituximab (CD20 antibody, Genentech) SR-31747 (IL-1 antagonist, Sanofi-Synthelabo) gemtuzumab (CD33 antibody, Wyeth Ayerst) CCI-779 (mTOR kinase inhibitor, Wyeth) PG2 (hematopoiesis enhancer, Pharmagenesis) exisulind (PDE V inhibitor, Cell Pathways) Immunol ™ (triclosan oral rinse, Endo) CP-461 (PDE V inhibitor, Cell Pathways) triacetyluridine (uridine prodrug, Wellstat) AG-2037 (GART inhibitor, Pfizer) SN-4071 (sarcoma agent, Signature BioScience) WX-UK1 (plasminogen activator inhibitor, Wilex) TransMID-107 ™ (immunotoxin, KS Biomedix) PBI-1402 (PMN stimulant, ProMetic LifeSciences) PCK-3145 (apoptosis promotor, Procyon) bortezomib (proteasome inhibitor, Millennium) doranidazole (apoptosis promotor, Pola) SRL-172 (T cell stimulant, SR Pharma) CHS-828 (cytotoxic agent, Leo) TLK-286 (glutathione S transferase inhibitor, Telik) trans-retinoic acid (differentiator, NIH) PT-100 (growth factor agonist, Point Therapeutics) MX6 (apoptosis promotor, MAXIA) midostaurin (PKC inhibitor, Novartis) apomine (apoptosis promotor, ILEX Oncology) bryostatin-1 (PKC stimulant, GPC Biotech) urocidin (apoptosis promotor, Bioniche) CDA-II (apoptosis promotor, Everlife) Ro-31-7453 (apoptosis promotor, La Roche) SDX-101 (apoptosis promotor, Salmedix) brostallicin (apoptosis promotor, Pharmacia) ceflatonin (apoptosis promotor, ChemGenex)
[0083] Compounds useful in the invention include those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, solvates, and polymorphs, thereof, as well as racemic mixtures of the compounds described herein.
[0084] Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.
DETAILED DESCRIPTION
[0085] We have discovered methods of improving the therapeutic index of phenothiazines and drug combinations including phenothiazines. This can be achieved by liposomal formulation or by conjugation of the phenothiazine to a charged or bulky group. The invention provides peripherally acting phenothiazine conjugates which have reduced CNS activity and enhanced neoplasm uptake in comparison their parent phenothiazines. The phenothiazine conjugates described herein have three characteristic components: a phenothiazine covalently tethered, via a linker, to a group that is bulky or charged.
[heading-0086] Phenothiazines
[0087] Phenothiazines which can be modified to inhibit passage across the blood-brain barrier include, without limitation, acepromazine, cyamemazine, fluphenazine, mepazine, methotrimeprazine, methoxypromazine, perazine, pericyazine, perimethazine, perphenazine, pipamazine, pipazethate, piperacetazine, pipotiazine, prochlorperazine, promethazine, propionylpromazine, propiomazine, sulforidazine, thiazinaminiumsalt, thiethylperazine, thiopropazate, thioridazine, trifluoperazine, trimeprazine, thioproperazine, trifluomeprazine, triflupromazine, chlorpromazine, chlorproethazine, those compounds in PCT application WO02/057244, and those compounds in U.S. Pat. Nos. 2,415,363; 2,519,886; 2,530,451; 2,607,773; 2,645640; 2,766,235; 2,769,002; 2,784,185; 2,785,160; 2,837,518; 2,860,138; 2,877,224; 2,921,069; 2,957,870; 2,989,529; 3,058,979; 3,075,976; 3,194,733; 3,350,268; 3,875,156; 3,879,551; 3,959,268; 3,966,930; 3,998,820; 4,785,095; 4,514,395; 4,985,559; 5,034,019; 5,157,118; 5,178,784; 5,550,143; 5,595,989; 5,654,323; 5,688,788; 5,693,649; 5,712,292; 5,721,254; 5,795,888; 5,597,819; 6,043,239; and 6,569,849, each of which is incorporated herein by reference. Structurally related phenothiazines having similar antiproliferative properties are also intended to be encompassed by this group, which includes any compound of formula (IV), described above.
[0088] The structures of several of the above-mentioned phenothiazines are provided in Table 2. These are structural examples of parent phenothiazines which can be modified as described herein to achieve a reduction in CNS activity. Phenothiazine conjugates of the invention are prepared by modification of an available functional group present in the parent phenothiazine. Alternatively, the substituent at the ring nitrogen can be removed from the parent phenothiazine prior to conjugation with a bulky group or a charged group.
TABLE 2
[0089] Phenothiazine compounds can be prepared using, for example, the synthetic techniques described in U.S. Pat. Nos. 2,415,363; 2,519,886; 2,530,451; 2,607,773; 2,645640; 2,766,235; 2,769,002; 2,784,185; 2,785,160; 2,837,518; 2,860,138; 2,877,224; 2,921,069; 2,957,870; 2,989,529; 3,058,979; 3,075,976; 3,194,733; 3,350,268; 3,875,156; 3,879,551; 3,959,268; 3,966,930; 3,998,820; 4,785,095; 4,514,395; 4,985,559; 5,034,019; 5,157,118; 5,178,784; 5,550,143; 5,595,989; 5,654,323; 5,688,788; 5,693,649; 5,712,292; 5,721,254; 5,795,888; 5,597,819; 6,043,239; and 6,569,849, each of which is incorporated herein by reference.
[heading-0090] Linkers
[0091] The linker component of the invention is, at its simplest, a bond between a phenothiazine and a group that is bulky or charged. The linker provides a linear, cyclic, or branched molecular skeleton having pendant groups covalently linking a phenothiazine to a group that is bulky or charged.
[0092] Thus, the linking of a phenothiazine to a group that is bulky or charged is achieved by covalent means, involving bond formation with one or more functional groups located on the phenothiazine and the bulky or charged group. Examples of chemically reactive functional groups which may be employed for this purpose include, without limitation, amino, hydroxyl, sulfhydryl, carboxyl, carbonyl, carbohydrate groups, vicinal diols, thioethers, 2-aminoalcohols, 2-aminothiols, guanidinyl, imidazolyl, and phenolic groups.
[0093] The covalent linking of a phenothiazine and a group that is bulky or charged may be effected using a linker which contains reactive moieties capable of reaction with such functional groups present in the phenothiazine and the bulky or charged group. For example, a hydroxyl group of the phenothiazine may react with a carboxyl group of the linker, or an activated derivative thereof, resulting in the formation of an ester linking the two.
[0094] Examples of moieties capable of reaction with sulfhydryl groups include α-haloacetyl compounds of the type XCH 2 CO— (where X=Br, Cl or I), which show particular reactivity for sulfhydryl groups, but which can also be used to modify imidazolyl, thioether, phenol, and amino groups as described by Gurd, Methods Enzymol. 11:532 (1967). N-Maleimide derivatives are also considered selective towards sulfhydryl groups, but may additionally be useful in coupling to amino groups under certain conditions. Reagents such as 2-iminothiolane (Traut et al., Biochemistry 12:3266 (1973)), which introduce a thiol group through conversion of an amino group, may be considered as sulfhydryl reagents if linking occurs through the formation of disulphide bridges.
[0095] Examples of reactive moieties capable of reaction with amino groups include, for example, alkylating and acylating agents. Representative alkylating agents include:
(i) α-haloacetyl compounds, which show specificity towards amino groups in the absence of reactive thiol groups and are of the type XCH 2 CO— (where X=Cl, Br or I), for example, as described by Wong Biochemistry 24:5337 (1979); (ii) N-maleimide derivatives, which may react with amino groups either through a Michael type reaction or through acylation by addition to the ring carbonyl group, for example, as described by Smyth et al., J. Am. Chem. Soc. 82:4600 (1960) and Biochem. J. 91:589 (1964); (iii) aryl halides such as reactive nitrohaloaromatic compounds; (iv) alkyl halides, as described, for example, by McKenzie et al., J Protein Chem. 7:581 (1988); (v) aldehydes and ketones capable of Schiff's base formation with amino groups, the adducts formed usually being stabilized through reduction to give a stable amine; (vi) epoxide derivatives such as epichlorohydrin and bisoxiranes, which may react with amino, sulfhydryl, or phenolic hydroxyl groups; (vii) chlorine-containing derivatives of s-triazines, which are very reactive towards nucleophiles such as amino, sufhydryl, and hydroxyl groups; (viii) aziridines based on s-triazine compounds detailed above, e.g., as described by Ross, J. Adv. Cancer Res. 2:1 (1954), which react with nucleophiles such as amino groups by ring opening; (ix) squaric acid diethyl esters as described by Tietze, Chem. Ber. 124:1215 (1991); and
(x) α-haloalkyl ethers, which are more reactive alkylating agents than normal alkyl halides because of the activation caused by the ether oxygen atom, as described by Benneche et al., Eur. J. Med. Chem. 28:463 (1993).
[0106] Representative amino-reactive acylating agents include:
(i) isocyanates and isothiocyanates, particularly aromatic derivatives, which form stable urea and thiourea derivatives respectively; (ii) sulfonyl chlorides, which have been described by Herzig et al., Biopolymers 2:349 (1964); (iii) acid halides; (iv) active esters such as nitrophenylesters or N-hydroxysuccinimidyl esters; (v) acid anhydrides such as mixed, symmetrical, or N-carboxyanhydrides; (vi) other useful reagents for amide bond formation, for example, as described by M. Bodansky, Principles of Peptide Synthesis, Springer-Verlag, 1984; (vii) acylazides, e.g. wherein the azide group is generated from a preformed hydrazide derivative using sodium nitrite, as described by Wetz et al., Anal. Biochem. 58:347 (1974); and (viii) imidoesters, which form stable amidines on reaction with amino groups, for example, as described by Hunter and Ludwig, J. Am. Chem. Soc. 84:3491 (1962). Aldehydes and ketones may be reacted with amines to form Schiff's bases, which may advantageously be stabilized through reductive amination. Alkoxylamino moieties readily react with ketones and aldehydes to produce stable alkoxamines, for example, as described by Webb et al., in Bioconjugate Chem. 1:96 (1990).
[0115] Examples of reactive moieties capable of reaction with carboxyl groups include diazo compounds such as diazoacetate esters and diazoacetamides, which react with high specificity to generate ester groups, for example, as described by Herriot, Adv. Protein Chem. 3:169 (1947). Carboxyl modifying reagents such as carbodiimides, which react through O-acylurea formation followed by amide bond formation, may also be employed.
[0116] It will be appreciated that functional groups in the phenothiazine and/or the bulky or charged group may, if desired, be converted to other functional groups prior to reaction, for example, to confer additional reactivity or selectivity. Examples of methods useful for this purpose include conversion of amines to carboxyls using reagents such as dicarboxylic anhydrides; conversion of amines to thiols using reagents such as N-acetylhomocysteine thiolactone, S-acetylmercaptosuccinic anhydride, 2-iminothiolane, or thiol-containing succinimidyl derivatives; conversion of thiols to carboxyls using reagents such as α-haloacetates; conversion of thiols to amines using reagents such as ethylenimine or 2-bromoethylamine; conversion of carboxyls to amines using reagents such as carbodiimides followed by diamines; and conversion of alcohols to thiols using reagents such as tosyl chloride followed by transesterification with thioacetate and hydrolysis to the thiol with sodium acetate.
[0117] So-called zero-length linkers, involving direct covalent joining of a reactive chemical group of the phenothiazine with a reactive chemical group of the bulky or charged group without introducing additional linking material may, if desired, be used in accordance with the invention. For example, the ring nitrogen of the phenothiazine can be linked directly via an amide bond to the charged or bulky group.
[0118] Most commonly, however, the linker will include two or more reactive moieties, as described above, connected by a spacer element. The presence of such a spacer permits bifunctional linkers to react with specific functional groups within the phenothiazine and the bulky or charged group, resulting in a covalent linkage between the two. The reactive moieties in a linker may be the same (homobifunctional linker) or different (heterobifunctional linker, or, where several dissimilar reactive moieties are present, heteromultifunctional linker), providing a diversity of potential reagents that may bring about covalent attachment between the phenothiazine and the bulky or charged group.
[0119] Spacer elements in the linker typically consist of linear or branched chains and may include a C 1-10 alkyl, a heteroalkyl of 1 to 10 atoms, a C 2-10 alkene, a C 2-10 alkyne, C 5-10 aryl, a cyclic system of 3 to 10 atoms, or —(CH 2 CH 2 O) n CH 2 CH 2 —, in which n is 1 to 4.
[0120] In some instances, the linker is described by formula (III):
G 1 -(Z 1 ) o -(Y 1 ) u -(Z 2 ) s -(R 9 )-(Z 3 ) t -(Y 2 ) v -(Z 4 ) p -G 2 (III)
[0121] In formula (III), G 1 is a bond between the phenothiazine and the linker, G 2 is a bond between the linker and the bulky group or between the linker and the charged group, each of Z 1 , Z 2 , Z 3 , and Z 4 is, independently, selected from O, S, and NR 39 ; R 39 is hydrogen or a C 1-10 alkyl group; each of Y 1 and Y 2 is, independently, selected from carbonyl, thiocarbonyl, sulphonyl, phosphoryl or similar acid-forming groups; o, p, s, t, u, and v are each independently 0 or 1; and R 9 is C 1-10 alkyl, C 1-10 heteroalkyl, C 2-10 alkenyl, a C 2-10 alkynyl, C 5-10 aryl, a cyclic system of 3 to 10 atoms, or a chemical bond linking G 1 -(Z 1 ) o -(Y 1 ) u -(Z 2 ) s - to -(Z 3 ) t -(Y 2 ) v -(Z 4 ) p -G 2 .
[heading-0122] Bulky Groups
[0123] The function of the bulky group is to increase the size of the phenothiazine sufficiently to inhibit passage across the blood-brain barrier. Bulky groups capable of inhibiting passage of the phenothiazine across the blood-brain barrier include those having a molecular weight greater than 200, 300, 400, 500, 600, 700, 800, 900, or 1000-daltons. Desirably, these groups are attached through the ring nitrogen of the phenothiazine.
[0124] Desirably, a bulky group is selected which enhances the cellular or neoplasm uptake of the conjugate. For example, certain peptides enable active translocation across the plasma membrane into cells (e.g., RKKRRQRRR, the Tat(49-57) peptide). Exemplary peptides which promote cellular uptake are disclosed, for example, by Wender et al., Proc. Natl. Acad. Sci. USA 97(24):13003-8 (2000) and Laurent et al., FEBS Lett 443(1):61-5 (1999), incorporated herein by reference. An example of a charged bulky group which facilitates cellular uptake is the polyguanidine peptoid (N-hxg) 9 , shown below. Each of the nine guanidine side chains is a charged guanidinium cation at physiological pH.
[0125] The bulky group may also be charged. For example, bulky groups include, without limitation, charged polypeptides, such as poly-arginine (guanidinium side chain), poly-lysine (ammonium side chain), poly-aspartic acid (carboxylate side chain), poly-glutamic acid (carboxlyate side chain), or poly-histidine (imidazolium side chain).
[0126] A charged polysaccharide that may also be used to promote neoplasm uptake of the phenothiazine conjugate. One polysaccharide useful for neoplasm targeting is hyaluronic acid or a low molecular weight fragments thereof (e.g. where n is 6-12, see structure below). Certain neoplasms, including many that are found in the lung, overexpress the CD44 cell-surface marker. CD44 is found at low levels on epithelial, hemopoietic, and neuronal cells and at elevated levels in various carcinoma, melanoma, lymphoma, breast, colorectal, and lung neoplasm cells. This cell surface receptor binds to hyaluronic acid. Hyaluronic acid is a major component of the extracellular matrix, and CD44 is implicated in the metabolism of solubilized hyaluronic acid. CD44 appears to regulate lymphocyte adhesion to cells of the high endothelial venules during lymphocyte migration, a process that has many similarities to the metastatic dissemination of solid neoplasms. It is also implicated in the regulation of the proliferation of cancer cells. Hyaluronic acid conjugates can gain access to the neoplasm cells subsequent to extravasating into the neoplasm from the circulation, resulting in an enhanced concentration of the conjugate within the neoplasm. See, for example, Eliaz et al., Cancer Research 61:2592 (2001) and references cited therein.
[0127] The bulky group can be an antiproliferative agent used in the combinations of the invention. Such conjugates are desirable where the two agents should have matching pharmacokinetic profiles to enhance efficacy and/or to simplify the dosing regimen. Desirably, the antiproliferative agent is a compound of formula (V), above. Antiproliferatives that can be conjugates to a phenothiazine compound include pentamidine, shown below, as well as 1,3-bis(4-amidino-2-methoxyphenoxy)propane, phenamidine, amicarbalide, 1,5-bis(4′-(N-hydroxyamidino)phenoxy)pentane, 1,3-bis(4′-(N -hydroxyamidino)phenoxy)propane, 1,3-bis(2′-methoxy-4′-(N-hydroxyamidino)phenoxy)propane, 1,4-bis(4′-(N-hydroxyamidino)phenoxy)butane, 1,5-bis(4′-(N-hydroxyamidino)phenoxy)pentane, 1,4-bis(4′-(N-hydroxyamidino)phenoxy)butane, 1,3-bis(4′-(4-hydroxyamidino)phenoxy)propane, 1,3-bis(2′-methoxy-4′-(N-hydroxyamidino)phenoxy)propane, 2,5-bis[4-amidinophenyl]furan, 2,5-bis[4-amidinophenyl]furan-bis-amidoxime, 2,5-bis[4-amidinophenyl]furan-bis-O-methylamidoxime, 2,5-bis[4-amidinophenyl]furan-bis-O-ethylamidoxime, 2,5-bis(4-amidinophenyl)furan-bis-O-4-fluorophenyl, 2,5-bis(4-amidinophenyl)furan-bis-O-4-methoxyphenyl, 2,4-bis(4-amidinophenyl)furan, 2,4-bis(4-amidinophenyl)furan-bis-O-methylamidoxime, 2,4-bis(4-amidinophenyl)furan-bis-O-4-fluorophenyl, 2,4-bis(4-amidinophenyl)furan-bis-O-4-methoxyphenyl, 2,5-bis(4-amidinophenyl) thiophene, 2,5-bis(4-amidinophenyl) thiophene-bis-O-methylamidoxime, 2,4-bis(4-amidinophenyl)thiophene, 2,4-bis(4-amidinophenyl)thiophene-bis-O-methylamidoxime, 2,8-diamidinodibenzothiophene, 2,8-bis(N-isopropylamidino)carbazole, 2,8-bis(N-hydroxyamidino)carbazole, 2,8-bis(2-imidazolinyl)dibenzothiopbene, 2,8-bis(2-imidazolinyl)-5,5-dioxodibenzothiophene, 3,7-diamidinodibenzothiophene, 3,7-bis(N-isopropylamidino)dibenzothiophene, 3,7-bis(N-hydroxyamidino)dibenzothiophene, 3,7-diaminodibenzothiophene, 3,7-dibromodibenzothiophene, 3,7-dicyanodibenzothiophene, 2,8-diamidinodibenzofuran, 2,8-di(2-imidazolinyl)dibenzofuran, 2,8-di(N-isopropylamidino)dibenzofuran, 2,8-di(N-hydroxylamidino)dibenzofuran, 3,7-di(2-imidazolinyl)dibenzofuran, 3,7-di(isopropylamidino)dibenzofuran, 3,7-di(N-hydroxylamidino)dibenzofuran, 2,8-dicyanodibenzofuran, 4,4′-dibromo-2,2′-dinitrobiphenyl, 2-methoxy-2′-nitro-4,4′-dibromobiphenyl, 2-methoxy-2′-amino-4,4′-dibromobiphenyl, 3,7-dibromodibenzofuran, 3,7-dicyanodibenzofuran, 2,5-bis(5-amidino-2-benzimidazolyl)pyrrole, 2,5-bis[5-(2-imidazolinyl)-2-benzimidazolyl]pyrrole, 2,6-bis[5-(2-imidazolinyl)-2-benzimidazolyl]pyridine, 1-methyl-2,5-bis(5-amidino-2-benzimidazolyl)pyrrole, 1-methyl-2,5-bis[5-(2-imidazolyl)-2-benzimidazolyl]pyrrole, 1-methyl-2,5-bis[5-(1,4,5,6-tetrahydro-2-pyrimidinyl)-2-benzimidazolyl]pyrrole, 2,6-bis(5-amidino-2-benzimidazoyl)pyridine, 2,6-bis[5-(1,4,5,6-tetrahydro-2-pyrimidinyl)-2-benzimidazolyl]pyridine, 2,5-bis(5-amidino-2-benzimidazolyl)furan, 2,5-bis-[5-(2-imidazolinyl)-2-benzimidazolyl]furan, 2,5-bis-(5-N-isopropylamidino-2-benzimidazolyl)furan, 2,5-bis-(4-guanylphenyl)furan, 2,5-bis(4-guanylphenyl)-3,4-dimethylfuran, 2,5-bis {p-[2-(3,4,5,6-tetrahydropyrimidyl)phenyl]}furan, 2,5-bis[4-(2-imidazolinyl)phenyl]furan, 2,5[bis-{4-(2-tetrahydropyrimidinyl)}phenyl]-3-(p-tolyloxy)furan, 2,5[bis{4-(2-imidazolinyl)}phenyl]-3-(p-tolyloxy)furan, 2,5-bis {4-[5-(N-2-aminoethylamido)benzimidazol-2-yl]phenyl}furan, 2,5-bis[4-(3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)phenyl]furan, 2,5-bis[4-(4,5,6,7-tetrahydro-1H-1,3-diazepin-2-yl)phenyl]furan, 2,5-bis(4-N,N-dimethylcarboxhydrazidephenyl)furan, 2,5-bis{4-[2-(N-2-hydroxyethyl)imidazolinyl]phenyl}furan, 2,5-bis[4-(N-isopropylamidino)phenyl]furan, 2,5-bis{4-[3-(dimethylaminopropyl)amidino]phenyl}furan, 2,5-bis {4-[N-(3-aminopropyl)amidino]phenyl}furan, 2,5-bis[2-(imidzaolinyl)phenyl]-3,4-bis(methoxymethyl)furan, 2,5-bis[4-N-(dimethylaminoethyl)guanyl]phenylfuran, 2,5-bis {4-[(N-2-hydroxyethyl)guanyl]phenyl}furan, 2,5-bis[4-N-(cyclopropylguanyl)phenyl]furan, 2,5-bis[4-(N,N-diethylaminopropyl)guanyl]phenylfuran, 2,5-bis{4-[2-(N-ethylimidazolinyl)]phenyl}furan, 2,5-bis {4-[N-(3-pentylguanyl)]}phenylfuran, 2,5-bis[4-(2-imidazolinyl)phenyl]-3-methoxyfuran, 2,5-bis[4-(N-isopropylamidino)phenyl]-3-methylfuran, bis[5-amidino-2-benzimidazolyl]methane, bis[5-(2-imidazolyl)-2-benzimidazolyl]methane, 1,2-bis[5-amidino-2-benzimidazolyl]ethane, 1,2-bis[5-(2-imidazolyl)-2-benzimidazolyl]ethane, 1,3-bis[5-amidino-2-benzimidazolyl]propane, 1,3-bis[5-(2-imidazolyl)-2-benzimidazolyl]propane, 1,4-bis[5-amidino-2-benzimidazolyl]propane, 1,4-bis[5-(2-imidazolyl)-2-benzimidazolyl]butane, 1,8-bis[5-amidino-2-benzimidazolyl]octane, trans-1,2-bis[5-amidino-2-benzimidazolyl]ethene, 1,4-bis[5-(2-imidazolyl)-2-benzimidazolyl]-1-butene, 1,4-bis[5-(2-imidazolyl)-2-benzimidazolyl]-2-butene, 1,4-bis[5-(2-imidazolyl)-2-benzimidazolyl]-1-methylbutane, 1,4-bis[5-(2-imidazolyl)-2-benzimidazolyl]-2-ethylbutane, 1,4-bis[5-(2-imidazolyl)-2-benzimidazolyl]-1-methyl-1-butene, 1,4-bis[5-(2-imidazolyl)-2-benzimidazolyl]-2,3-diethyl-2-butene, 1,4-bis[5-(2-imidazolyl)-2-benzimidazolyl]-1,3-butadiene, 1,4-bis[5-(2-imidazolyl)-2-benzimidazolyl]-2-methyl-1,3-butadiene, bis[5-(2-pyrimidyl)-2-benzimidazolyl]methane, 1,2-bis[5-(2-pyrimidyl)-2-benzimidazolyl]ethane, 1,3-bis[5-amidino-2-benzimidazolyl]propane, 1,3-bis[5-(2-pyrimidyl)-2-benzimidazolyl]propane, 1,4-bis[5-(2-pyrimidyl)-2-benzimidazolyl]butane, 1,4-bis[5-(2-pyrimidyl)-2-benzimidazolyl]-1-butene, 1,4-bis[5-(2-pyrimidyl)-2-benzimidazolyl]-2-butene, 1,4-bis[5-(2-pyrimidyl)-2-benzimidazolyl]-1-methylbutane, 1,4-bis[5-(2-pyrimidyl)-2-benzimidazolyl]-2-ethylbutane, 1,4-bis[5-(2-pyrimidyl)-2-benzimidazolyl]-1-methyl-1-butene, 1,4-bis[5-(2-pyrimidyl)-2-benzimidazolyl]-2,3-diethyl-2-butene, 1,4-bis[5-(2-pyrimidyl)-2-benzimidazolyl]-1,3-butadiene, and 1,4-bis[5-(2-pyrimidyl)-2-benzimidazolyl]-2-methyl-1,3-butadiene, 2,4-bis(4-guanylphenyl)pyrimidine, 2,4-bis(4-imidazolin-2-yl)pyrimidine, 2,4-bis[(tetrahydropyrimidinyl-2-yl)phenyl]pyrimidine, 2-(4-[N-1-propylguanyl]phenyl)-4-(2-methoxy-4-[N-1-propylguanyl]phenyl)pyrimidine, 4-(N-cyclopentylamidino)-1,2-phenylene diamine, 2,5-bis-[2-(5-amidino)benzimidazoyl]furan, 2,5-bis[2-{5-(2-imidazolino)}benzimidazoyl]furan, 2,5-bis[2-(5-N-isopropylamidino)benzimidazoyl]furan, 2,5-bis[2-(5-N-cyclopentylamidino)benzimidazoyl]furan, 2,5-bis[2-(5-amidino)benzimidazoyl]pyrrole, 2,5-bis[2-{5-(2-imidazolino)}benzimidazoyl]pyrrole, 2,5-bis[2-(5-N-isopropylamidino)benzimidazoyl]pyrrole, 2,5-bis[2-(5-N-cyclopentyl amidino)benzimidazoyl]pyrrole, 1-methyl-2,5-bis[2-(5-amidino)benzimidazoyl]pyrrole, 2,5-bis[2-{5-(2-imidazolino)}benzimidazoyl]-1-methylpyrrole, 2,5-bis[2-(5-N-cyclopentylamidino)benzimidazoyl]-1-methylpyrrole, 2,5-bis[2-(5-N-isopropylamidino)benzimidazoyl]thiophene, 2,6-bis[2-{5-(2-imidazolino)}benzimidazoyl]pyridine, 2,6-bis[2-(5-amidino)benzimidazoyl]pyridine, 4,4′-bis[2-(5-N-isopropylamidino)benzimidazoyl]-1,2-diphenylethane, 4,4′-bis[2-(5-N-cyclopentylamidino)benzimidazoyl]-2,5-diphenylfuran, 2,5-bis[2-(5-amidino)benzimidazoyl]benzo[b]furan, 2,5-bis[2-(5-N-cyclopentylamidino) enzimidazoyl]benzo[b]furan, 2,7-bis[2-(5-N-isopropylamidino)benzimidazoyl]fluorene, 2,5-bis[4-(3-(N-morpholinopropyl)carbamoyl)phenyl]furan, 2,5-bis[4-(2-N,N-dimethylaminoethylcarbamoyl)phenyl]furan, 2,5-bis[4-(3-N,N-dimethylaminopropylcarbamoyl)phenyl]furan, 2,5-bis[4-(3-N-methyl-3-N-phenylaminopropylcarbamoyl)phenyl] furan, 2,5-bis[4-(3-N,N 8 ,N 11 -trimethylaminopropylcarbamoyl)phenyl]furan, 2,5-bis[3-amidinophenyl]furan, 2,5-bis[3-(N-isopropylamidino)amidinophenyl]furan, 2,5-bis[3(N-(2-dimethylaminoethyl)amidino]phenylfuran, 2,5-bis[4-(N-2,2,2-trichloroethoxycarbonyl)amidinophenyl]furan, 2,5-bis[4-(N-thioethylcarbonyl) amidinophenyl]furan, 2,5-bis[4-(N-benzyloxycarbonyl)amidinophenyl]furan, 2,5-bis[4-(N-phenoxycarbonyl)amidinophenyl]furan, 2,5-bis[4-(N-(4-fluoro)-phenoxycarbonyl)amidinophenyl]furan, 2,5-bis[4-(N-(4-methoxy)phenoxycarbonyl)amidinophenyl]furan, 2,5-bis[4(1-acetoxyethoxycarbonyl)amidinophenyl]furan, or 2,5-bis[4-(N-(3-fluoro)phenoxycarbonyl)amidinophenyl]furan.
[0128] Methods for making any of the foregoing compounds are described in U.S. Pat. Nos. 5,428,051; 5,521,189; 5,602,172; 5,643,935; 5,723,495; 5,843,980; 6,008,247; 6,025,398; 6,172,104; 6,214,883; and 6,326,395, an U.S. Patent Application Publication Nos. US 2001/0044468 A1 and US 2002/0019437 A1.
[0129] The conjugate comprising, for example, a phenothiazine (A) and pentamidine (B), can be linked, without limitation, as dimers, trimers, or tetramers, as shown below.
Charged Groups
[0131] The function of the charged group is to alter the charge of the phenothiazine sufficiently to inhibit passage across the blood-brain barrier. Desirably, charged groups are attached through the ring nitrogen of the phenothiazine.
[0132] A charged group may be cationic or an anionic. Charged groups include 3, 4, 5, 6, 7, 8, 9, 10, or more negatively charged moieties and/or 3, 4, 5, 6, 7, 8, 9, 10, or more positively charged moieties. Charged moieties include, without limitation, carboxylate, phosphodiester, phosphoramidate, borate, phosphate, phosphonate, phosphonate ester, sulfonate, sulfate, thiolate, phenolate, ammonium, amidinium, guanidinium, quaternary ammonium, and imidazolium moieties.
[heading-0133] Phenothiazine Conjugates
[0134] The phenothiazine conjugates of the present invention can be designed to largely remain intact in vivo, resisting cleavage by intracellular and extracellular enzymes or, through the selection of the appropriate linkers, can be designed to degrade in vivo. For example, the linker can include one or more ester bonds susceptible to hydrolysis by esterases, amide bonds susceptible to hydrolysis by amidases, and/or phosphate bonds susceptible to hydrolysis by phosphatases.
[0135] Phenothiazine conjugates are further described by any one of formulas (VI) to (IX), shown below.
[0136] In formulas (VI)-(IX), R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and W are as described above. L is a linker of formula (II), described above. B is a bulky or charged group, as described above.
[heading-0137] Therapy
[0138] The compositions of the invention are useful for the treatment of neoplasms. Therapy may be performed alone or in conjunction with another therapy (e.g., surgery, radiation therapy, chemotherapy, immunotherapy, anti-angiogenesis therapy, or gene therapy). For example, useful antiproliferative agents that can be used in conjunction with the compositions of the invention include those listed in Table 1.
[0139] The duration of the combination therapy depends on the type of disease or disorder being treated, the age and condition of the patient, the stage and type of the patient's disease, and how the patient responds to the treatment. Therapy may be given in on-and-off cycles that include rest periods so that the patient's body has a chance to recovery from any as yet unforeseen side-effects. Therapy may also be given for a continuous period.
[0140] Examples of cancers and other neoplasms include, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (Hodgkin's disease, non-Hodgkin's disease), Waldenstrom's macroglobulinemia, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, gastric cancer, esophageal cancer, bead and neck cancer, thyroid cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodenriglioma, schwannoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).
[heading-0141] Formulation of Pharmaceutical Compositions
[0142] The administration of phenothiazine conjugates may be by any suitable means that results in a concentration of the compound that, combined with the other component, is anti-neoplastic upon reaching the target region. The compound may be contained in any appropriate amount in any suitable carrier substance, and is generally present in an amount of 0.1-95% by weight of the total weight of the composition. The composition may be provided in a dosage form that is suitable for the oral, parenteral (e.g., intravenously, intramuscularly, intra-arteriol, subcutaneous), rectal, cutaneous, nasal, vaginal, inhalant, skin (patch), buccal or ocular administration route. Thus, the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols.
[0143] Methods well known in the art for making formulations are found, for example, in “Remington: The Science and Practice of Pharmacy” (20th ed., ed. A. R. Gennaro A R., 2000, Lippincott Williams & Wilkins). Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds. Nanoparticulate formulations (e.g., biodegradable nanoparticles, solid lipid nanoparticles, liposomes) may be used to control the biodistribution of the compounds. Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycolate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel. The concentration of the compound in the formulation will vary depending upon a number of factors, including the dosage of the drug to be administered, and the route of administration.
[0144] The compound of the invention may be optionally administered as a pharmaceutically acceptable salt, such as a non-toxic acid addition salts or metal complexes that are commonly used in the pharmaceutical industry. Examples of acid addition salts include organic acids such as acetic, lactic, pamoic, maleic, citric, malic, ascorbic, succinic, benzoic, palmitic, suberic, salicylic, tartaric, methanesulfonic, toluenesulfonic, or trifluoroacetic acids or the like; polymeric acids such as tannic acid, carboxymethyl cellulose, or the like; and inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid phosphoric acid, or the like. Metal complexes include calcium, zinc, iron, and the like.
[0145] Administration of compounds in controlled release formulations is useful where the compound of formula I has (i) a narrow therapeutic index (e.g., the difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect is small; generally, the therapeutic index, TI, is defined as the ratio of median lethal dose (LD50) to median effective dose (ED50)); (ii) a narrow absorption window in the gastro-intestinal tract; or (iii) a short biological half-life, so that frequent dosing during a day is required in order to sustain the plasma level at a therapeutic level.
[0146] Many strategies can be pursued to obtain controlled release in which the rate of release outweighs the rate of metabolism of the therapeutic compound. For example, controlled release can be obtained by the appropriate selection of formulation parameters and ingredients, including, e.g., appropriate controlled release compositions and coatings. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes.
[0147] Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose and sorbitol), lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc).
[0148] Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium.
[heading-0149] Liposomal Formulations
[0150] Phenothiazine conjugates, and phenothiazine combinations can be incorporated into liposomal carriers for administration. The liposomal carriers are composed of three general types of vesicle-forming lipid components. The first includes vesicle-forming lipids which will form the bulk of the vesicle structure in the liposome.
[0151] Generally, these vesicle-forming lipids include any amphipathic lipids having hydrophobic and polar head group moieties, and which (a) can form spontaneously into bilayer vesicles in water, as exemplified by phospholipids, or (b) are stably incorporated into lipid bilayers, with its hydrophobic moiety in contact with the interior, hydrophobic region of the bilayer membrane, and its polar head group moiety oriented toward the exterior, polar surface of the membrane.
[0152] The vesicle-forming lipids of this type are preferably ones having two hydrocarbon chains, typically acyl chains, and a polar head group. Included in this class are the phospholipids, such as phosphatidylcholine (PC), PE, phosphatidic acid (PA), phosphatidylinositol (PI), and sphingomyelin (SM), where the two hydrocarbon chains are typically between about 14-22 carbon atoms in length, and have varying degrees of unsaturation. The above-described lipids and phospholipids whose acyl chains have a variety of degrees of saturation can be obtained commercially, or prepared according to published methods. Other lipids that can be included in the invention are glycolipids and sterols, such as cholesterol.
[0153] The second general component includes a vesicle-forming lipid which is derivatized with a polymer chain which will form the polymer layer in the composition. The vesicle-forming lipids which can be used as the second general vesicle-forming lipid component are any of those described for the first general vesicle-forming lipid component. Vesicle forming lipids with diacyl chains, such as phospholipids, are preferred. One exemplary phospholipid is phosphatidylethanolamine (PE), which provides a reactive amino group which is convenient for coupling to the activated polymers. An exemplary PE is distearyl PE (DSPE).
[0154] The preferred polymer in the derivatized lipid, is polyethyleneglycol (PEG), preferably a PEG chain having a molecular weight between 1,000-15,000 daltons, more preferably between 2,000 and 10,000 daltons, most preferably between 2,000 and 5,000 daltons. Other hydrophilic polymers which may be suitable include polyvinylpyrrolidone, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyl methacrylamide, polymethacrylamide and polydimethylacrylamide, polylactic acid, polyglycolic acid, and derivatized celluloses, such as hydroxymethylcellulose or hydroxyethylcellulose.
[0155] Additionally, block copolymers or random copolymers of these polymers, particularly including PEG segments, may be suitable. Methods for preparing lipids derivatized with hydrophilic polymers, such as PEG, are well known e.g., as described in U.S. Pat. No. 5,013,556.
[0156] The third general vesicle-forming lipid component, which is optional, is a lipid anchor by which a targeting moiety is anchored to the liposome, through a polymer chain in the anchor. Additionally, the targeting group is positioned at the distal end of the polymer chain in such a way so that the biological activity of the targeting moiety is not lost. The lipid anchor has a hydrophobic moiety which serves to anchor the lipid in the outer layer of the liposome bilayer surface, a polar head group to which the interior end of the polymer is covalently attached, and a free (exterior) polymer end which is or can be activated for covalent coupling to the targeting moiety. Methods for preparing lipid anchor molecules of this types are described below.
[0157] The lipids components used in forming the liposomes are preferably present in a molar ratio of about 70-90 percent vesicle forming lipids, 1-25 percent polymer derivatized lipid, and 0.1-5 percent lipid anchor. One exemplary formulation includes 50-70 mole percent underivatized PE, 20-40 mole percent cholesterol, 0.1-1 mole percent of a PE-PEG (3500) polymer with a chemically reactive group at its free end for coupling to a targeting moiety, 5-10 mole percent PE derivatized with PEG 3500 polymer chains, and 1 mole percent alpha-tocopherol.
[0158] The liposomes are preferably prepared to have substantially homogeneous sizes in a selected size range, typically between about 0.03 to 0.5 microns. One effective sizing method for REVs and MLVs involves extruding an aqueous suspension of the liposomes through a series of polycarbonate membranes having a selected uniform pore size in the range of 0.03 to 0.2 micron, typically 0.05, 0.08, 0.1, or 0.2 microns. The pore size of the membrane corresponds roughly to the largest sizes of liposomes produced by extrusion through that membrane, particularly where the preparation is extruded two or more times through the same membrane. Homogenization methods are also useful for down-sizing liposomes to sizes of 100 nm or less.
[0159] The liposomal formulations of the present invention include at least one surface-active agent. Suitable surface-active agents useful for the formulation of the phenothiazine conjugates, and phenothiazine combinations described herein, including compounds belonging to the following classes: polyethoxylated fatty acids, PEG-fatty acid diesters, PEG-fatty acid mono-ester and di-ester mixtures, polyethylene glycol glycerol fatty acid esters, alcohol-oil transesterification products, polyglycerized fatty acids, propylene glycol fatty acid esters, mixtures of propylene glycol esters and glycerol esters, mono- and diglycerides, sterol and sterol derivatives, polyethylene glycol sorbitan fatty acid esters, polyethylene glycol alkyl ethers, sugar esters, polyethylene glycol alkyl phenols, polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty acid esters, lower alcohol fatty acid esters, and ionic surfactants. Commercially available examples for each class of excipient are provided below.
[0160] Polyethoxylated fatty acids may be used as excipients for the formulation of the phenothiazine conjugates, and phenothiazine combinations described herein. Examples of commercially available polyethoxylated fatty acid monoester surfactants include: PEG 4-100 monolaurate (Crodet L series, Croda), PEG 4-100 monooleate (Crodet O series, Croda), PEG 4-100 monostearate (Crodet S series, Croda, and Myrj Series, Atlas/ICI), PEG 400 distearate (Cithrol 4DS series, Croda), PEG 100, 200, or 300 monolaurate (Cithrol ML series, Croda), PEG 100, 200, or 300 monooleate (Cithrol MO series, Croda), PEG 400 dioleate (Cithrol 4DO series, Croda), PEG 400-1000 monostearate (Cithrol MS series, Croda), PEG-1 stearate (Nikkol MYS-1EX, Nikko, and Coster K1, Condea), PEG-2 stearate (Nikkol MYS-2, Nikko), PEG-2 oleate (Nikkol MYO-2, Nikko), PEG-4 laurate (Mapeg® 200 ML, PPG), PEG-4 oleate (Mapeg® 200 MO, PPG), PEG-4 stearate (Kessco® PEG 200 MS, Stepan), PEG-5 stearate (Nikkol TMGS-5. Nikko), PEG-5 oleate (Nikkol TMGO-5, Nikko), PEG-6 oleate (Algon OL 60, Auschem SpA), PEG-7 oleate (Algon OL 70, Auschem SpA), PEG-6 laurate (Kessco® PEG300 ML, Stepan), PEG-7 laurate (Lauridac 7, Condea), PEG-6 stearate (Kessco® PEG300 MS, Stepan), PEG-8 laurate (Mapeg® 400 ML, PPG), PEG-8 oleate (Mapeg® 400 MO, PPG), PEG-8 stearate (Mapeg® 400 MS, PPG), PEG-9 oleate (Emulgante A9, Condea), PEG-9 stearate (Cremophor S9, BASF), PEG-10 laurate (Nikkol MYL-10, Nikko), PEG-10 oleate (Nikkol MYO-10, Nikko), PEG-12 stearate (Nikkol MYS-10, Nikko), PEG-12 laurate (Kessco® PEG 600 ML, Stepan), PEG-12 oleate (Kessco®V PEG 600 MO, Stepan), PEG-12 ricinoleate (CAS # 9004-97-1), PEG-12 stearate (Mapeg® 600 MS, PPG), PEG-15 stearate (Nikkol TMGS-15, Nikko), PEG-15 oleate (Nikkol TMGO-15, Nikko), PEG-20 laurate (Kessco® PEG 1000 ML, Stepan), PEG-20 oleate (Kessco® PEG 1000 MO, Stepan), PEG-20 stearate (Mapeg®& 1000 MS, PPG), PEG-25 stearate (Nikkol MYS-25, Nikko), PEG-32 laurate (Kessco® PEG 1540 ML, Stepan), PEG-32 oleate (Kesscog PEG 1540 MO, Stepan), PEG-32 stearate (Kessco® PEG 1540 MS, Stepan), PEG-30 stearate (Myrj 51), PEG-40 laurate (Crodet L40, Croda), PEG-40 oleate (Crodet 040, Croda), PEG-40 stearate (Emerest® 2715, Henkel), PEG-45 stearate (Nikkol MYS-45, Nikko), PEG-50 stearate (Myrj 53), PEG-55 stearate (Nikkol MYS-55, Nikko), PEG-100 oleate (Crodet 0-100, Croda), PEG-100 stearate (Ariacel 165, ICI), PEG-200 oleate (Albunol 200 MO, Taiwan Surf.), PEG-400 oleate (LACTOMUL, Henkel), and PEG-600 oleate (Albunol 600 MO, Taiwan Surf.). Formulations of the phenothiazine conjugates, and phenothiazine combinations according to the invention may include one or more of the polyethoxylated fatty acids above.
[0161] Polyethylene glycol fatty acid diesters may also be used as excipients for the formulation of the phenothiazine conjugates, and phenothiazine combinations described herein. Examples of commercially available polyethylene glycol fatty acid diesters include: PEG-4 dilaurate (Mapeg® 200 DL, PPG), PEG-4 dioleate (Mapeg®200 DO, PPG), PEG-4 distearate (Kessco® 200 DS, Stepan), PEG-6 dilaurate (Kessco® PEG 300 DL, Stepan), PEG-6 dioleate (Kessco® PEG 300 DO, Stepan), PEG-6 distearate (Kessco® PEG 300 DS, Stepan), PEG-8 dilaurate (Mapeg® 400 DL, PPG), PEG-8 dioleate (Mapeg® 400 DO, PPG), PEG-8 distearate (Mapeg® 400 DS, PPG), PEG-10 dipalmitate (Polyaldo 2PKFG), PEG-12 dilaurate (Kessco® PEG 600 DL, Stepan), PEG-12 distearate (Kessco® PEG 600 DS, Stepan), PEG-12 dioleate (Mapeg® 600 DO, PPG), PEG-20 dilaurate (Kessco® PEG 1000 DL, Stepan), PEG-20 dioleate (Kessco® PEG 1000 DO, Stepan), PEG-20 distearate (Kessco® PEG 1000 DS, Stepan), PEG-32 dilaurate (Kessco® PEG 1540 DL, Stepan), PEG-32 dioleate (Kessco® PEG 1540 DO, Stepan), PEG-32 distearate (Kessco®& PEG 1540 DS, Stepan), PEG-400 dioleate (Cithrol 4DO series, Croda), and PEG-400 distearate Cithrol 4DS series, Croda). Formulations of the phenothiazine conjugates, and phenothiazine combinations according to the invention may include one or more of the polyethylene glycol fatty acid diesters above.
[0162] PEG-fatty acid mono- and di-ester mixtures may be used as excipients for the formulation of the phenothiazine conjugates, and phenothiazine combinations described herein. Examples of commercially available PEG-fatty acid mono- and di-ester mixtures include: PEG 4-150 mono, dilaurate (Kessco® PEG 200-6000 mono, Dilaurate, Stepan), PEG 4-150 mono, dioleate (Kessco® PEG 200-6000 mono, Dioleate, Stepan), and PEG 4-150 mono, distearate (Kessco® 200-6000 mono, Distearate, Stepan). Formulations of the phenothiazine conjugates, and phenothiazine combinations according to the invention may include one or more of the PEG-fatty acid mono- and di-ester mixtures above.
[0163] In addition, polyethylene glycol glycerol fatty acid esters may be used as excipients for the formulation of the phenothiazine conjugates, and phenothiazine combinations described herein. Examples of commercially available polyethylene glycol glycerol fatty acid esters include: PEG-20 glyceryl laurate (Tagat® L, Goldschmidt), PEG-30 glyceryl laurate (Tagat® L2, Goldschmidt), PEG-15 glyceryl laurate (Glycerox L series, Croda), PEG-40 glyceryl laurate (Glycerox L series, Croda), PEG-20 glyceryl stearate (Capmul® EMG, ABITEC), and Aldo® MS-20 KFG, Lonza), PEG-20 glyceryl oleate (Tagat® 0, Goldschmidt), and PEG-30 glyceryl oleate (Tagat® O2, Goldschmidt). Formulations of the phenothiazine conjugates, and phenothiazine combinations according to the invention may include one or more of the polyethylene glycol glycerol fatty acid esters above.
[0164] Alcohol-oil transesterification products may also be used as excipients for the formulation of the phenothiazine conjugates, and phenothiazine combinations described herein. Examples of commercially available alcohol-oil transesterification products include: PEG-3 castor oil (Nikkol CO-3, Nikko), PEG-5,9, and 16 castor oil (ACCONON CA series, ABITEC), PEG-20 castor oil, (Emalex C-20, Nihon Emulsion), PEG-23 castor oil (Emulgante EL23), PEG-30 castor oil (Incrocas 30, Croda), PEG-35 castor oil (lncrocas-35, Croda), PEG-38 castor oil (Emulgante EL-65, Condea), PEG-40-castor oil (Emalex C-40, Nihon Emulsion), PEG-50 castor oil (Emalex C-50, Nihon Emulsion), PEG-56 castor oil (Eumulgin® PRT 56, Pulcra SA), PEG-60 castor oil (Nikkol CO-60TX, Nikko), PEG-100 castor oil, PEG-200 castor oil (Eumulgin® PRT 200, Pulcra SA), PEG-5 hydrogenated castor oil (Nikkol HCO-5, Nikko), PEG-7 hydrogenated castor oil (Cremophor WO7, BASF), PEG-10 hydrogenated castor oil (Nikkol HCO-10, Nikko), PEG-20 hydrogenated castor oil (Nikkol HCO-20, Nikko), PEG-25 hydrogenated castor oil (Simulsol® 1292, Seppic), PEG-30 hydrogenated castor oil (Nikkol HCO-30, Nikko), PEG-40 hydrogenated castor oil (Cremophor RH 40, BASF), PEG-45 hydrogenated castor oil (Cerex ELS 450, Auschem Spa), PEG-50 hydrogenated castor oil (Emalex HC-50, Nihon Emulsion), PEG-60 hydrogenated castor oil (Nikkol HCO-60, Nikko), PEG-80 hydrogenated castor oil (Nikkol HCO-80, Nikko), PEG-100 hydrogenated castor oil (Nikkol HCO-100, Nikko), PEG-6 corn oil (Labrafil® M 2125 CS, Gattefosse), PEG-6 almond oil (Labrafil® M 1966 CS, Gattefosse), PEG-6 apricot kernel oil (Labrafil® (M 1944 CS, Gattefosse), PEG-6 olive oil (Labrafil® M 1980 CS, Gattefosse), PEG-6 peanut oil (Labrafil® M 1969 CS, Gattefosse), PEG-6 hydrogenated palm kernel oil (Labrafil® M 2130 BS, Gattefosse), PEG-6 palm kernel oil (Labrafil® M 2130 CS, Gattefosse), PEG-6 triolein (Labrafil® M 2735 CS, Gattefosse), PEG-8 corn oil (Labrafil® WL 2609 BS, Gattefosse), PEG-20 corn glycerides (Crovol M40, Croda), PEG-20 almond glycerides (Crovol A40, Croda), PEG-25 trioleate (TAGAT®TO, Goldschmidt), PEG-40 palm kernel oil (Crovol PK-70), PEG-60 corn glycerides (Crovol M70, Croda), PEG-60 almond glycerides (Crovol A70, Croda), PEG-4 caprylic/capric triglyceride (Labrafac® Hydro, Gattefosse), PEG-8 caprylic/capric glycerides (Labrasol, Gattefosse), PEG-6 caprylic/capric glycerides (SOFTIGEN®767, Huls), lauroyl macrogol-32 glyceride (GELUCIRE 44/14, Gattefosse), stearoyl macrogol glyceride (GELUCIRE 50/13, Gattefosse), mono, di, tri, tetra esters of vegetable oils and sorbitol (SorbitoGlyceride, Gattefosse), pentaerythrityl tetraisostearate (Crodamol PTIS, Croda), pentaerythrityl distearate (Albunol DS, Taiwan Surf.), pentaerythrityl tetraoleate (Liponate PO-4, Lipo Chem.), pentaerythrityl tetrastearate (Liponate PS-4, Lipo Chem.), pentaerythrityl tetracaprylate tetracaprate (Liponate PE-810, Lipo Chem.), and pentaerythrityl tetraoctanoate (Nikkol Pentarate 408, Nikko). Also included as oils in this category of surfactants are oil-soluble vitamins, such as vitamins A, D, E, K, etc. Thus, derivatives of these vitamins, such as tocopheryl PEG-1000 succinate (TPGS, available from Eastman), are also suitable surfactants. Formulations of the phenothiazine conjugates, and phenothiazine combinations according to the invention may include one or more of the alcohol-oil transesterification products above.
[0165] Polyglycerized fatty acids may also be used as excipients for the formulation of the phenothiazine conjugates, and phenothiazine combinations described herein. Examples of commercially available polyglycerized fatty acids include: polyglyceryl-2 stearate (Nikkol DGMS, Nikko), polyglyceryl-2 oleate (Nikkol DGMO, Nikko), polyglyceryl-2 isostearate (Nikkol DGMIS, Nikko), polyglyceryl-3 oleate (Caprol® 3GO, ABITEC), polyglyceryl-4 oleate (Nikkol Tetraglyn 1-O, Nikko), polyglyceryl-4 stearate (Nikkol Tetraglyn 1-S, Nikko), polyglyceryl-6 oleate (Drewpol 6-1-O, Stepan), polyglyceryl-10 laurate (Nikkol Decaglyn 1-L, Nikko), polyglyceryl-10 oleate (Nikkol Decaglyn 1-O, Nikko), polyglyceryl-10 stearate (Nikkol Decaglyn 1-S, Nikko), polyglyceryl-6 ricinoleate (Nikkol Hexaglyn PR-15, Nikko), polyglyceryl-10 linoleate (Nikkol Decaglyn 1-LN, Nikko), polyglyceryl-6 pentaoleate (Nikkol Hexaglyn 5-O, Nikko), polyglyceryl-3 dioleate (Cremophor G032, BASF), polyglyceryl-3 distearate (Cremophor GS32, BASF), polyglyceryl-4 pentaoleate (Nikkol Tetraglyn 5-O, Nikko), polyglyceryl-6 dioleate (Caprol® 6G20, ABITEC), polyglyceryl-2 dioleate (Nikkol DGDO, Nikko), polyglyceryl-10 trioleate (Nikkol Decaglyn 3-O, Nikko), polyglyceryl-10 pentaoleate (Nikkol Decaglyn 5-O, Nikko), polyglyceryl-10 septaoleate (Nikkol Decaglyn 7-O, Nikko), polyglyceryl-10 tetraoleate (Caprol® 10G4O, ABITEC), polyglyceryl-10 decaisostearate (Nikkol Decaglyn 10-IS, Nikko), polyglyceryl-101 decaoleate (Drewpol 10-10-O, Stepan), polyglyceryl-10 mono, dioleate (Caprol® PGE 860, ABITEC), and polyglyceryl polyricinoleate (Polymuls, Henkel). Formulations of the phenothiazine conjugates, and phenothiazine combinations according to the invention may include one or more of the polyglycerized fatty acids above.
[0166] In addition, propylene glycol fatty acid esters may be used as excipients for the formulation of the phenothiazine conjugates, and phenothiazine combinations described herein. Examples of commercially available propylene glycol fatty acid esters include: propylene glycol monocaprylate (Capryol 90, Gattefosse), propylene glycol monolaurate (Lauroglycol 90, Gattefosse), propylene glycol oleate (Lutrol OP2000, BASF), propylene glycol myristate (Mirpyl), propylene glycol monostearate (LIPO PGMS, Lipo Chem.), propylene glycol hydroxystearate, propylene glycol ricinoleate (PROPYMULS, Henkel), propylene glycol isostearate, propylene glycol monooleate (Myverol P-06, Eastman), propylene glycol dicaprylate dicaprate (Captex® 200, ABITEC), propylene glycol dioctanoate (Captex® 800, ABITEC), propylene glycol caprylate caprate (LABRAFAC PG, Gattefosse), propylene glycol dilaurate, propylene glycol distearate (Kessco® PGDS, Stepan), propylene glycol dicaprylate (Nikkol Sefsol 228, Nikko), and propylene glycol dicaprate (Nikkol PDD, Nikko). Formulations of the phenothiazine conjugates, and phenothiazine combinations according to the invention may include one or more of the propylene glycol fatty acid esters above.
[0167] Mixtures of propylene glycol esters and glycerol esters may also be used as excipients for the formulation of the phenothiazine conjugates, and phenothiazine combinations described herein. One preferred mixture is composed of the oleic acid esters of propylene glycol and glycerol (Arlacel 186). Examples of these surfactants include: oleic (ATMOS 300, ARLACEL 186, ICI), and stearic (ATMOS 150). Formulations of the phenothiazine conjugates, and phenothiazine combinations according to the invention may include one or more of the mixtures of propylene glycol esters and glycerol esters above.
[0168] Further, mono- and diglycerides may be used as excipients for the formulation of the phenothiazine conjugates, and phenothiazine combinations described herein. Examples of commercially available mono- and diglycerides include: monopalmitolein (C16:1) (Larodan), monoelaidin (C18:1) (Larodan), monocaproin (C6) (Larodan), monocaprylin (Larodan), monocaprin (Larodan), monolaurin (Larodan), glyceryl monomyristate (C14) (Nikkol MGM, Nikko), glyceryl monooleate (C18:1) (PECEOL, Gattefosse), glyceryl monooleate (Myverol, Eastman), glycerol monooleate/linoleate (OLICINE, Gattefosse), glycerol monolinoleate (Maisine, Gattefosse), glyceryl ricinoleate (Softigen® 701, Huls), glyceryl monolaurate (ALDO® MLD, Lonza), glycerol monopalmitate (Emalex GMS-P, Nihon), glycerol monostearate (Capmul® GMS, ABITEC), glyceryl mono- and dioleate (Capmul® GMO-K, ABITEC), glyceryl palmitic/stearic (CUTINA MD-A, ESTAGEL-G18), glyceryl acetate (Lamegin® EE, Grunau GmbH), glyceryl laurate (Imwitor® 312, Huls), glyceryl citrate/lactate/oleate/linoleate (Imwitor® 375, Huls), glyceryl caprylate (Imwitor® 308, Huls), glyceryl caprylate/caprate (Capmul® MCM, ABITEC), caprylic acid mono- and diglycerides (Imwitor® 988, Huls), caprylic/capric glycerides (Imwitor® 742, Huls), Mono- and diacetylated monoglycerides (Myvacet® 9-45, Eastman), glyceryl monostearate (Aldo® MS, Arlacel 129, ICI), lactic acid esters of mono and diglycerides (LAMEGIN GLP, Henkel), dicaproin (C6) (Larodan), dicaprin (C10) (Larodan), dioctanoin (C8) (Larodan), dimyristin (C14) (Larodan), dipalmitin (C16) (Larodan), distearin (Larodan), glyceryl dilaurate (C12) (Capmul® GDL, ABITEC), glyceryl dioleate (Capmul® GDO, ABITEC), glycerol esters of fatty acids (GELUCIRE 39/01, Gattefosse), dipalmitolein (C16:1) (Larodan), 1,2 and 1,3-diolein (C18:1) (Larodan), dielaidin (C18:1) (Larodan), and dilinolein (C18:2) (Larodan). Formulations of the phenothiazine conjugates, and phenothiazine combinations according to the invention may include one or more of the mono- and diglycerides above.
[0169] Sterol and sterol derivatives may also be used as excipients for the formulation of the phenothiazine conjugates, and phenothiazine combinations described herein. Examples of commercially available sterol and sterol derivatives include: cholesterol, sitosterol, lanosterol, PEG-24 cholesterol ether (Solulan C-24, Amerchol), PEG-30 cholestanol (Phytosterol GENEROL series, Henkel), PEG-25 phytosterol (Nikkol BPSH-25, Nikko), PEG-5 soyasterol (Nikkol BPS-5, Nikko), PEG-10 soyasterol (Nikkol BPS-10, Nikko), PEG-20 soyasterol (Nikkol BPS-20, Nikko), and PEG-30 soyasterol (Nikkol BPS-30, Nikko). Formulations of the phenothiazine conjugates, and phenothiazine combinations according to the invention may include one or more of the sterol and sterol derivatives above.
[0170] Polyethylene glycol sorbitan fatty acid esters may also be used as excipients for the formulation of the phenothiazine conjugates, and phenothiazine combinations described herein. Examples of commercially available polyethylene glycol sorbitan fatty acid esters include: PEG-10 sorbitan laurate (Liposorb L-10, Lipo Chem.), PEG-20 sorbitan monolaurate (Tween® 20, Atlas/ICI), PEG-4 sorbitan monolaurate (Tween® 21, Atlas/ICI), PEG-80 sorbitan monolaurate (Hodag PSML-80, Calgene), PEG-6 sorbitan monolaurate (Nikkol GL-1, Nikko), PEG-20 sorbitan monopalmitate (Tween® 40, Atlas/ICI), PEG-20 sorbitan monostearate (Tween® 60, Atlas/ICI), PEG-4 sorbitan monostearate (Tween®) 61, Atlas/ICI), PEG-8 sorbitan monostearate (DACOL MSS, Condea), PEG-6 sorbitan monostearate (Nikkol TS106, Nikko), PEG-20 sorbitan tristearate (Tween® 65, Atlas/ICI), PEG-6 sorbitan tetrastearate (Nikkol GS-6, Nikko), PEG-60 sorbitan tetrastearate (Nikkol. GS-460, Nikko), PEG-5 sorbitan monooleate (Tween® 81, Atlas/ICI), PEG-6 sorbitan monooleate (Nikkol TO-106, Nikko), PEG-20 sorbitan monooleate (Tween®& 80, Atlas/ICI), PEG-40 sorbitan oleate (Emalex ET 8040, Nihon Emulsion), PEG-20 sorbitan trioleate (Tween® 85, Atlas/ICI), PEG-6 sorbitan tetraoleate (Nikkol GO-4, Nikko), PEG-30 sorbitan tetraoleate (Nikkol GO-430, Nikko), PEG-40 sorbitan tetraoleate (Nikkol GO-440, Nikko), PEG-20 sorbitan monoisostearate (Tween® 120, Atlas/ICI), PEG sorbitol hexaoleate (Atlas G-1086, ICI), polysorbate 80 (Tween® 80, Pharma), polysorbate 85 (Tween® 85, Pharma), polysorbate 20 (Tween® 20, Pharma), polysorbate 40 (Tween® 40, Pharma), polysorbate 60 (Tween® 60, Pharma), and PEG-6 sorbitol hexastearate (Nikkol GS-6, Nikko). Formulations of the phenothiazine conjugates, and phenothiazine combinations according to the invention may include one or more of the polyethylene glycol sorbitan fatty acid esters above.
[0171] In addition, polyethylene glycol alkyl ethers may be used as excipients for the formulation of the phenothiazine conjugates, and phenothiazine combinations described herein. Examples of commercially available polyethylene glycol alkyl ethers include: PEG-2 oleyl ether, oleth-2 (Brij 92/93, Atlas/ICI), PEG-3 oleyl ether, oleth-3 (Volpo 3, Croda), PEG-5 oleyl ether, oleth-5 (Volpo 5, Croda), PEG-10 oleyl ether, oleth-10 (Volpo 10, Croda), PEG-20 oleyl ether, oleth-20 (Volpo 20, Croda), PEG-4 lauryl ether, laureth-4 (Brij 30, Atlas/ICI), PEG-9 lauryl ether, PEG-23 lauryl ether, laureth-23 (Brij 35, Atlas/ICI), PEG-2 cetyl ether (Brij 52, ICI), PEG-10 cetyl ether (Brij 56, ICI), PEG-20 cetyl ether (BriJ 58, ICI), PEG-2 stearyl ether (Brij 72, ICI), PEG-10 stearyl ether (Brij 76, ICI), PEG-20 stearyl ether (Brij 78, ICI), and PEG-100 stearyl ether (Brij 700, ICI). Formulations of the phenothiazine conjugates, and phenothiazine combinations according to the invention may include one or more of the polyethylene glycol alkyl ethers above.
[0172] Sugar esters may also be used as excipients for the formulation of the phenothiazine conjugates, and phenothiazine combinations described herein. Examples of commercially available sugar esters include: sucrose distearate (SUCRO ESTER 7, Gattefosse), sucrose distearate/monostearate (SUCRO ESTER 11, Gattefosse), sucrose dipalmitate, sucrose monostearate (Crodesta F-160, Croda), sucrose monopalmitate (SUCRO ESTER 15, Gattefosse), and sucrose monolaurate (Saccharose monolaurate 1695, Mitsubisbi-Kasei). Formulations of the phenothiazine conjugates, and phenothiazine combinations according to the invention may include one or more of the sugar esters above.
[0173] Polyethylene glycol alkyl phenols are also useful as excipients for the formulation of the phenothiazine conjugates, and phenothiazine combinations described herein. Examples of commercially available polyethylene glycol alkyl phenols include: PEG-10-100 nonylphenol series (Triton X series, Rohm & Haas) and PEG-15-100 octylphenol ether series (Triton N-series, Rohm & Haas). Formulations of the phenothiazine conjugates, and phenothiazine combinations according to the invention may include one or more of the polyethylene glycol alkyl phenols above.
[0174] Polyoxyethylene-polyoxypropylene block copolymers may also be used as excipients for the formulation of the phenothiazine conjugates, and phenothiazine combinations described herein. These surfactants are available under various trade names, including one or more of Synperonic PE series (ICI), Pluronic® series (BASF), Lutrol (BASF), Supronic, Monolan, Pluracare, and Plurodac. The generic term for these copolymers is “poloxamer” (CAS 9003-11-6). These polymers have the formula (X):
HO(C 2 H 4 O) a (C 3 H 6 O) b (C 2 H 4 O) a H (X)
where “a” and “b” denote the number of polyoxyethylene and polyoxypropylene units, respectively. These copolymers are available in molecular weights ranging from 1000 to 15000 daltons, and with ethylene oxide/propylene oxide ratios between 0.1 and 0.8 by weight. Formulations of the phenothiazine conjugates, and phenothiazine combinations according to the invention may include one or more of the polyoxyethylene-polyoxypropylene block copolymers above.
[0176] Polyoxyethylenes, such as PEG 300, PEG 400, and PEG 600, may be used as excipients for the formulation of the phenothiazine conjugates, and phenothiazine combinations described herein.
[0177] Sorbitan fatty acid esters may also be used as excipients for the formulation of the phenothiazine conjugates, and phenothiazine combinations described herein. Examples of commercially sorbitan fatty acid esters include: sorbitan monolaurate (Span-20, Atlas/ICI), sorbitan monopalmitate (Span-40, Atlas/ICI), sorbitan monooleate (Span-80, Atlas/ICI), sorbitan monostearate (Span-60, Atlas/ICI), sorbitan trioleate (Span-85, Atlas/ICI), sorbitan sesquioleate (Arlacel-C, ICI), sorbitan tristearate (Span-65, Atlas/ICI), sorbitan monoisostearate (Crill 6, Croda), and sorbitan sesquistearate (Nikkol SS-15, Nikko). Formulations of the phenothiazine conjugates, and phenothiazine combinations according to the invention may include one or more of the sorbitan fatty acid esters above.
[0178] Esters of lower alcohols (C 2 to C 4 ) and fatty acids (C 8 to C 18 ) are suitable surfactants for use in the invention. Examples of these surfactants include: ethyl oleate (Crodamol EO, Croda), isopropyl myristate (Crodamol IPM, Croda), isopropyl palmitate (Crodamol IPP, Croda), ethyl linoleate (Nikkol VF-E, Nikko), and isopropyl linoleate (Nikkol VF-IP, Nikko). Formulations of the phenothiazine conjugates, and phenothiazine combinations according to the invention may include one or more of the lower alcohol fatty acid esters above.
[0179] In addition, ionic surfactants may be used as excipients for the formulation of the phenothiazine conjugates, and phenothiazine combinations described herein. Examples of useful ionic surfactants include: sodium caproate, sodium caprylate, sodium caprate, sodium laurate, sodium myristate, sodium myristolate, sodium palmitate, sodium palmitoleate, sodium oleate, sodium ricinoleate, sodium linoleate, sodium linolenate, sodium stearate, sodium lauryl sulfate (dodecyl), sodium tetradecyl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, sodium taurocholate, sodium glycocholate, sodium deoxycholate, sodium taurodeoxycholate, sodium glycodeoxycholate, sodium ursodeoxycholate, sodium chenodeoxycholate, sodium taurochenodeoxycholate, sodium glyco cheno deoxycholate, sodium cholylsarcosinate, sodium N-methyl taurocholate, egg yolk phosphatides, hydrogenated soy lecithin, dimyristoyl lecithin, lecithin, hydroxylated lecithin, lysophosphatidylcholine, cardiolipin, sphingomyelin, phosphatidylcholine, phosphatidyl ethanolamine, phosphatidic acid, phosphatidyl glycerol, phosphatidyl serine, diethanolamine, phospholipids, polyoxyethylene-10 oleyl ether phosphate, esterification products of fatty alcohols or fatty alcohol ethoxylates, with phosphoric acid or anhydride, ether carboxylates (by oxidation of terminal OH group of, fatty alcohol ethoxylates), succinylated monoglycerides, sodium stearyl fumarate, stearoyl propylene glycol hydrogen succinate, mono/diacetylated tartaric acid esters of mono- and diglycerides, citric acid esters of mono-, diglycerides, glyceryl-lacto esters of fatty acids, acyl lactylates, lactylic esters of fatty acids, sodium stearoyl-2-lactylate, sodium stearoyl lactylate, alginate salts, propylene glycol alginate, ethoxylated alkyl sulfates, alkyl benzene sulfones, α-olefin sulfonates, acyl isethionates, acyl taurates, alkyl glyceryl ether sulfonates, sodium octyl sulfosuccinate, sodium undecylenamideo-MEA-sulfosuccinate, hexadecyl triammonium bromide, decyl trimethyl ammonium bromide, cetyl trimethyl ammonium bromide, dodecyl ammonium chloride, alkyl benzyldimethylammonium salts, diisobutyl phenoxyethoxydimethyl benzylammonium salts, alkylpyridinium salts, betaines (trialkylglycine), lauryl betaine (N-lauryl, N,N-dimethylglycine), and ethoxylated amines (polyoxyethylene-15 coconut amine). For simplicity, typical counterions are provided above. It will be appreciated by one skilled in the art, however, that any bioacceptable counterion may be used. For example, although the fatty acids are shown as sodium salts, other cation counterions can also be used, such as, for example, alkali metal cations or ammonium. Formulations of the phenothiazine conjugates, and phenothiazine combinations according to the invention may include one or more of the ionic surfactants above.
[0180] The excipients present in the formulations of the invention are present in amounts such that the carrier forms a clear, or opalescent, aqueous dispersion of the phenothiazine, phenothiazine conjugate, or phenothiazine combination sequestered within the liposome. The relative amount of a surface active excipient necessary for the preparation of liposomal or solid lipid nanoparticulate formulations is determined using known methodology. For example, liposomes may be prepared by a variety of techniques, such as those detailed in Szoka et al, 1980. Multilamellar vesicles (MLVs) can be formed by simple lipid-film hydration techniques. In this procedure, a mixture of liposome-forming lipids of the type detailed above dissolved in a suitable organic solvent is evaporated in a vessel to form a thin film, which is then covered by an aqueous medium. The lipid film hydrates to form MLVs, typically with sizes between about 0.1 to 10 microns.
[0181] Other established liposomal formulation techniques can be applied as needed. For example, the use of liposomes to facilitate cellular uptake is described in U.S. Pat. Nos. 4,897,355 and 4,394,448.
[heading-0182] Dosages
[0183] The dosage of each compound of the claimed combinations depends on several factors, including: the administration method, the neoplasm to be treated, the severity of the neoplasm, whether the neoplasm is to be treated or prevented, and the age, weight, and health of the patient to be treated. The phenothiazine conjugates, combinations, and formulations of the invention are administered to patients in therapeutically effective amounts. For example, an amount is administered which prevents, reduces, or eliminates the neoplasm. Typical dose ranges are from about 0.001 μg/kg to about 5 mg/kg of body weight per day. Desirably, a dose of between 0.001 μg/kg and 1 mg/kg of body weight, or 0.005 μg/kg and 0.5 mg/kg of body weight, is administered. The exemplary dosage of drug to be administered is likely to depend on such variables as the type and extent of the condition, the overall health status of the particular patient, the formulation of the compound, and its route of administration. Standard clinical trials may be used to optimize the dose and dosing frequency for any particular compound.
[0184] For combinations that include an anti-proliferative agent, the recommended dosage for the anti-proliferative agent is desirably less than or equal to the recommended dose as given in the Physician 's Desk Reference, 57 th Edition (2003).
[0185] As described above, the phenothiazine conjugates may be administered orally in the form of tablets, capsules, elixirs or syrups, or rectally in the form of suppositories. Parenteral administration of a compound is suitably performed, for example, in the form of saline solutions or with the compound incorporated into liposomes. In cases where the compound in itself is not sufficiently soluble to be dissolved, a solubilizer such as ethanol can be applied.
[0186] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods and compounds claimed herein are performed, made, and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention.
EXAMPLES
Example 1
Protection and Deprotection of Reactive Groups
[0187] The synthesis of phenothiazine conjugates may involve the selective protection and deprotection of alcohols, amines, ketones, sulfhydryls or carboxyl functional groups of the phenothiazine, the linker, the bulky group, and/or the charged group. For example, commonly used protecting groups for amines include carbamates, such as tert-butyl, benzyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 9-fluorenylmethyl, allyl, and m-nitrophenyl. Other commonly used protecting groups for amines include amides, such as formamides, acetamides, trifluoroacetamides, sulfonamides, trifluoromethanesulfonyl amides, trimethylsilylethanesulfonamides, and tert-butylsulfonyl amides. Examples of commonly used protecting groups for carboxyls include esters, such as methyl, ethyl, tert-butyl, 9-fluorenylmethyl, 2-(trimethylsilyl)ethoxy methyl, benzyl, diphenylmethyl, O-nitrobenzyl, ortho-esters, and halo-esters. Examples of commonly used protecting groups for alcohols include ethers, such as methyl, methoxymethyl, methoxyethoxymethyl, methylthiomethyl, benzyloxymethyl, tetrahydropyranyl, ethoxyethyl, benzyl, 2-napthylmethyl, O-nitrobenzyl, P-nitrobenzyl, P-methoxybenzyl, 9-phenylxanthyl, trityl (including methoxy-trityls), and silyl ethers. Examples of commonly used protecting groups for sulfhydryls, include many of the same protecting groups used for hydroxyls. In addition, sulfhydryls can be protected in a reduced form (e.g., as disulfides) or an oxidized form (e.g., as sulfonic acids, sulfonic esters, or sulfonic amides). Protecting groups can be chosen such that selective conditions (e.g., acidic conditions, basic conditions, catalysis by a nucleophile, catalysis by a lewis acid, or hydrogenation) are required to remove each, exclusive of other protecting groups in a molecule. The conditions required for the addition of protecting groups to amine, alcohol, sulfhydryl, and carboxyl functionalities and the conditions required for their removal are provided in detail in T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis (2 nd Ed.), John Wiley & Sons, 1991 and P. J. Kocienski, Protecting Groups, Georg Thieme Verlag, 1994.
[0188] In the examples that follow, the use of protecting groups is indicated in a structure by the letter P, where P for any amine, aldehyde, ketone, carboxyl, sulfhydryl, or alcohol may be any of the protecting groups listed above.
Example 2
Polyguanidine Conjugates of Phenothiazines
[0189] 2-(trifluoromethyl)phenothiazine (CAS 92-30-8, Aldrich Cat. No. T6,345-2) can be reacted with an activated carboxyl. Carboxyls can be activated, for example, by formation of an active ester, such as nitrophenylesters, N-hydroxysuccinimidyl esters, or others as described in Chem. Soc. Rev. 12:129, 1983 and Angew. Chem. Int. Ed. Engl. 17:569, 1978, incorporated herein by reference. For example, oxalic acid (Aldrich, catalogue number 24,117-2) can be attached as a linking group, as shown below in reaction 1.
[0190] The protecting group in the reaction product can be removed by hydrolysis. The resulting acid is available for conjugation to a bulky group or a charged group.
[0191] The polyguanidine peptoid N-hxg, shown below, can be prepared according to the methods described by Wender et al., Proc. Natl. Acad. Sci. USA 97(24): 13003-8, 2000, incorporated herein by reference.
[0192] The carboxyl derivative produced by the deprotection of the product of reaction 1 can be activated, vide supra, and conjugated to the protected precursor of N-hxg followed by the formation of the guanidine moieties and cleavage from the solid phase resin, as described by Wender ibid., to produce the polyguanidine prednisolone conjugate shown below.
[0193] The resulting phenothiazine conjugate includes a bulky group (FW 1,900 Da) which includes several positively charged moieties.
Example 3
Hyaluronic Acid Conjugates of a Phenothiazines
[0194] 2-Methylthiophenothiazine (CAS 7643-08-5, Aldrich Cat. No. 55,292-5) can be reacted a hydrazine-substituted carboxylic acid, which has been activated as shown in reaction 3.
[0195] The protecting group can be removed from the reaction product and the free hydrazine coupled to a carboxyl group of hyaluronic acid as described by, for example, Vercruysse et al., Bioconjugate Chem., 8:686, 1997 or Pouyani et al., J. Am. Chem. Soc., 116:7515, 1994. The structure of the resulting hydrazide conjugate is provided below.
[0196] In the phenothiazine conjugate above, the hyaluronic acid is approximately 160,000 Daltons in molecular weight. Accordingly, m and n are whole integers between 0 and 400. Conjugates of lower and higher molecular weight hyaluronic acid can be prepared in a similar fashion.
Example 4
PEG Conjugates of Phenothiazines
[0197] (10-piperadinylpropyl)phenothiazine can be conjugated to mono-methyl polyethylene glycol 5,000 propionic acid N-succinimidyl ester (Fluka, product number 85969). The resulting mPEG conjugate, shown below, is an example of a phenothiazine conjugate of a bulky uncharged group.
[0198] Conjugates of lower and higher molecular weight mPEG can be prepared in a similar fashion (see, for example, Roberts et al., Adv. Drug Delivery Rev. 54:459 (2002)).
[0199] Chlorpromazine can be conjugated to an activated PEG (e.g., a mesylate, or halogenated PEG compound) as shown in reaction 4.
Example 5
Pentamidine Conjugates of Phenothiazines
[0200] Pentamadine conjugates of phenothiazine can be prepared using a variety of conjugation techniques. For example, reaction 5 shows perimethazine, the alcohol activated in situ (e.g., using mesylchloride), followed by alkylation of pentamidine to form the conjugate product of the two therpeutic agents.
Example 6
Animal Assays
[0201] Animal assays to determine the reduction of side effects and/or reduced CNS activity are well known in the art and are standard measures for pharmacokinetic studies. For example, drug distribution can be assessed in an animal model as described in Tsuneizumi et al., Biol. Psychiatry, 1992, 32:817-834.
[0202] All publications and patents cited in this specification are incorporated herein by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.
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The invention provides formulations and structural modifications for phenothiazine compounds which result in altered biodistributions, thereby reducing the occurrence of adverse reactions associated with this class of drug.
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CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser. No. 12/752,697, filed Apr. 1, 2010, entitled “Modular Gastrointestinal Prostheses,” which claims the benefit under 35 U.S.C. §119 of U.S. Provisional Application 61/211,853, filed on Apr. 3, 2009, entitled “Modular Systems for Intra-Luminal Therapies within Hollow Body Organs,” which are incorporated herein by reference in their entirety for all purposes.
TECHNICAL FIELD
[0002] This invention relates to prosthetic implants placed within the gastrointestinal system, including the stomach, the esophagus and the intestines. In particular, it relates to implant systems having components implantable and removable using endoscopic techniques, for treatment of obesity, diabetes, reflux, and other gastrointestinal conditions.
BACKGROUND
[0003] Bariatric surgery procedures such as sleeve gastrectomy, the Rouen-Y gastric bypass (RYGB) and the bileo-pancreatic diversion (BPD) are surgical procedures to modify food intake and/or absorption within the gastrointestinal system to effect weight loss in obese patients. These procedures affect metabolic processes within the gastrointestinal system, by either short-circuiting certain natural pathways or creating different interaction between the consumed food, the digestive tract, its secretions and the neurohormonal system regulating food intake and metabolism. In the last few years there has been a growing clinical consensus, that obese diabetic patients who undergo bariatric surgery see a remarkable resolution of their Type-2 Diabetes Mellitus (T2DM) soon after the procedure. The remarkable resolution of diabetes after RYGB and BPD typically occurs too fast to be accounted for by weight loss alone, suggesting that there may be a direct impact on glucose homeostasis. The mechanism of this resolution of T2DM is not well understood, and it is quite likely that multiple mechanisms are involved.
[0004] One of the drawbacks of bariatric surgical procedures is that they require fairly invasive surgery, with potentially serious complications and long patient recovery periods. In recent years, there is an increasing amount of ongoing effort to develop minimally invasive procedures to mimic the effects of bariatric surgery using minimally invasive procedures. One such procedure involves the use of gastrointestinal implants that modify transport and absorption of food and organ secretions. For example, U.S. Pat. No. 7,476,256 describes an implant having a tubular sleeve with an anchor having barbs. While these implants may be delivered endoscopically, the implants offer the physician limited flexibility and are not readily removable or replaceable, as the entire implant is subject to tissue in-growth after implantation. Moreover, stents with active fixation means, such as barbs that penetrate in to the surrounding tissue, may potentially cause tissue necrosis and erosion of the implants through the tissue, which can lead to serious complications such as systemic infection.
SUMMARY
[0005] According to various embodiments, the present invention is an intra-luminal implant system for treating metabolic disorders such as obesity and diabetes, which provides far more flexible therapy alternatives than single devices to treat these disorders. These implant systems include components that can be selectively added or removed to mimic a variety of bariatric surgical procedures with a single basic construct. The fundamental building blocks of the system include anchoring implants that are placed within the GI system or some instances around particular organs. These low-profile implants are designed for long-term performance with minimal interference with normal physiological processes. Features of these anchoring implants allow them to act as docking stations for therapy implants designed for achieving certain metabolic modification goals. By using a combination of anchoring implants with corresponding tubular elements, it is possible to design therapies with particular metabolic modification goals or those that mimic currently practiced bariatric surgical procedures. This allows the physician to customize the therapy to the patient at the time of the initial procedure but also allows the flexibility to alter the therapy during the life-time of the patient by replacing individual components.
[0006] According to some embodiments, the invention includes a anchoring implant portion (docking element) including an expandable structure (e.g., a low profile stent or ring or fabric/elastomeric cuff) anchored within the esophagus, the gastro-esophageal junction, the pyloric junction, the duodenum or the jejunum and may have sleeve or graft extensions. The stents may be balloon expandable or self-expanding and anchor against the tissue with radial force. The rings could be made of self-expanding Nitinol and anchor to the tissue by entrapment of the tissue within the ring elements or by radial force. The cuffs could be either sutured or stapled or permanently or reversibly attached by other mechanical means to the tissue. The anchoring implant includes or is adapted to receive (e.g., endoscopically) features that enable docking functionality. The docking functionality of the stent, ring or cuff, for example, could take the form of magnetic elements, hooks, mating mechanical elements or structures (such as the stent braid or mesh) that are integral to the framework of the stent, ring or cuff or the sleeve or graft extension. The system also could be such that the docking functionality is not integral to the stent, ring or cuff but is introduced later by attaching other elements such as magnets, hooks, mating mechanical elements etc to the framework of the stent, ring, cuff or to the sleeve/graft extension of the above implants. Therapeutic implants, such as tubular sleeves or stent grafts are adapted to be reversibly attached to the anchoring implants. These therapeutic implants will have corresponding features (e.g., magnets, hooks, mechanical elements) to enable docking to the anchoring implants, so that the therapeutic implants can be reversibly attached to the anchoring implants. In some embodiments, the tubular implants will not be in contact with tissue to minimize or prevent tissue in-growth and facilitate easy removal with endoscopic instrumentation after long-term implantation.
[0007] According to various embodiments, the anchoring or docking implants comprise stents or covered stents (stent grafts) that promote tissue in-growth without penetrating into the tissue. Such stents may include, for example, a self-expanding laser cut stent with non-penetrating struts that engage the wall of the GI tract or a self-expanding stent braided with a Dacron type fabric covering of the right porosity would promote tissue in-growth and aid fixation.
[0008] According to various embodiments, the anchoring or docking implants comprise a double braided stent (e.g., having a spacing between the braids of 0.5 to 5.0 mm). This embodiment is optimized such that the outer braid could be securely anchored within tissue, but the tissue would not grow into the inner braid, which can then be used to anchor the replaceable implant.
[0009] According to various embodiments, the anchoring or docking implants are specifically designed to be constrained at certain anatomic locations. Such designs, for example, may include a double-flange shaped or dumbbell-shaped implants placed at the pyloric junction or barrel shaped stents placed within the duodenal bulb.
[0010] According to various embodiments, the replaceable therapeutic implants that dock to the anchoring implants take the form of long tubes that can selectively channel the flow of food and secretions from organs (e.g., the stomach, gall bladder, intestines and pancreas) to various destinations within the digestive tract. This diversion and bypass of food and organ secretions (e.g., insulin and incretin from the pancreas and bile from the gall bladder) could then be controlled by adjusting the design features of the system where the implants are placed within the GI tract. The implants could also include restrictive stoma type elements or anti-reflux valves. To divert food and secretions from the first part of the intestine, for example, an anchoring implant can be placed within the duodenal bulb or at the pyloric junction. Then, a thin tube about 1-2 feet in length with a funnel shaped proximal end and a rigid ring shaped distal end can be introduced into the proximal duodenum and docked to the permanent implant. It would be possible to later remove this by endoscopic means by simple undocking it from the anchoring implant. To restrict passage of food, a restrictive element such as one created by a tapered stepped tube or a stent or a stent graft can become the docking element and be reversibly attached to the docking station.
[0011] According to various embodiments, the docking means may include engaging/disengaging mechanical shape memory and super-elastic elements, attractive/repulsive and levitating magnetic mechanisms, loop-hoop fastener technologies etc. The systems may be deployed with functional docking components or those components would be attached to the permanent implants under endoscopic visual guidance. The docking means is designed so that the therapeutic implants can be easily deployed and securely affixed to the anchoring implants. According to various embodiment, the engaging elements of the docking system are arranged so that they do not impinge on the surrounding tissue, nor would be later covered with tissue layers. This facilitates disengaging the tubular sleeve elements from the stent with simple magnetic instruments or grasper type endoscopic instruments or funnel shaped retrieval basket catheters or using a draw-string type mechanism.
[0012] According to some embodiments, the anchoring element is integrated with a therapy component.
[0013] According to various embodiments, the present invention is a method of treating gastro-esophageal reflux disease (GERD) including placing a low-profile implant within the stomach, the esophagus, the intestine or at internal junctions of these organs or around these organs, and securely attaching to the implant other gastro-intestinal implants that permit bypass of food and organ secretions from one site within the gastro-intestinal tract to other sites within the gastro-intestinal tract.
[0014] While multiple embodiments are disclosed, still other embodiments of the present invention will become apparent to those skilled in the art from the following detailed description, which shows and describes illustrative embodiments of the invention. Accordingly, the drawings and detailed description are to be regarded as illustrative in nature and not restrictive.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 is a cross sectional view of a portion of the digestive tract in the body. A docking element is implanted in the duodenal bulb and a tubular implant (sleeve) is attached to the docking element and extended into the duodenum to the ligament of treitz.
[0016] FIG. 2 is a cross sectional view of a portion of the digestive tract in the body. An endoscope is inserted into the mouth, passing through the esophagus in to the stomach and the end of the scope is pointed to allow viewing of the pylorus.
[0017] FIG. 3 is a drawing of a typical endoscope used for diagnostic and therapeutic procedures in the gastro intestinal (GI) tract.
[0018] FIG. 4A is a drawing of an over the wire sizing balloon that can be used to measure the diameter of the pylorus, duodenal bulb, esophagus, pyloric antrum or other lumen in the GI tract.
[0019] FIG. 4B is a drawing of a monorail sizing balloon that can be used to measure the diameter of the pylorus, duodenal bulb, esophagus, pyloric antrum or other lumen in the GI tract.
[0020] FIG. 5 is a sectional view of a portion of the digestive tract in the body. An endoscope is inserted into the GI tract up to the pylorus. A sizing balloon is inserted through the working channel and into the area of the duodenal bulb. The balloon is inflated to measure the diameter of the duodenal bulb.
[0021] FIG. 6A is a drawing of a stent that can used as a docking element.
[0022] FIG. 6B is a drawing of a stent that can used as a docking element that has a polymer covering on the inside and outside.
[0023] FIG. 7 is a tubular implant that can be used to bypass the stomach, duodenum or other intestinal lumen.
[0024] FIG. 8 is a drawing of a delivery catheter for the docking element and tubular implant.
[0025] FIG. 9A is a cross sectional view of a portion of the digestive tract in the body. A delivery catheter with a docking element and tubular implant loaded onto the catheter are loaded onto an endoscope. The endoscope is then advanced through the esophagus, stomach and into the duodenal bulb.
[0026] FIG. 9B is a cross sectional view of a portion of the digestive tract in the body. A delivery catheter with a docking element and tubular implant loaded onto are loaded onto an endoscope. The endoscope is then advanced through the esophagus, stomach and into the duodenal bulb. The outer sheath of the delivery catheter is refracted to partially deploy the docking element into the duodenal bulb.
[0027] FIG. 10 is a drawing showing the docking element fully deployed into the duodenal bulb. The delivery catheter and endoscope has been has been removed to show clarity
[0028] FIG. 11 is a drawing showing the endoscope and delivery catheter advanced through the docking element into the duodenum up to the ligament of treitz.
[0029] FIG. 12 is a drawing showing the endoscope and delivery catheter advanced through the docking element into the duodenum up to the ligament of treitz. The outer sheath of the delivery catheter is retracted to partially expose the tubular implant.
[0030] FIG. 13 is a drawing showing the endoscope and delivery catheter advanced through the docking element into the duodenum up to the ligament of treitz. The outer sheath of the delivery catheter is retracted to partially expose the tubular implant. A balloon catheter is inserted through the working channel of the endoscope to the area of the partially exposed tubular implant. The balloon is inflated to temporarily secure the tubular implant to the duodenum.
[0031] FIG. 14 is a continuation of FIG. 13 where the outer sheath is retracted further to unsheath the tubular implant up to the duodenal bulb.
[0032] FIG. 15 is a continuation of FIG. 14 where the endoscope has been withdrawn to the duodenal bulb. The balloon on the balloon catheter is then deflated and the balloon catheter is withdrawn to the duodenal bulb. The balloon is then re-inflated to open up and secure the proximal end of the tubular implant to the inside diameter of the docking element.
[0033] FIG. 16 is a drawing of an alternative device and method for deploying the proximal end of the tubular element.
[0034] FIG. 17A is a cross sectional view of a portion of the digestive tract in the body. A docking element is implanted in the esophagus at the gastro-esophageal junction. The docking element serves as an anti-reflux valve.
[0035] FIG. 17B is a cross sectional view of a portion of the digestive tract in the body. A docking element is implanted in the esophagus at gastro-esophageal junction. The docking element serves as a restrictive stoma.
[0036] FIG. 18 is a cross sectional view of a portion of the digestive tract in the body. A docking element is implanted in the esophagus at gastro-esophageal junction. The docking element serves as an anti-reflux valve.
[0037] FIG. 19A is a stented sleeve with a stent used to hold open the sleeve. The sleeve located from the duodenal bulb to the ligament of treitz.
[0038] FIG. 19B is a stented sleeve with a stent used to hold open the sleeve. The sleeve located from the pylorus to the ligament of treitz.
[0039] FIG. 20 is a stented sleeve with a stent used to hold open the sleeve. The sleeve is located from the stomach antrum to the ligament of treitz.
[0040] FIG. 21A is a sectional view of a portion of the digestive tract in the body. A docking element is implanted in the esophagus at the gastro-esophageal junction. A docking element and tubular implant is implanted in the duodenum also.
[0041] FIG. 21B is a sectional view of a portion of the digestive tract in the body. A docking element is implanted in the esophagus at the gastro-esophageal junction. A docking element and tubular sleeve is implanted in the duodenum also. A third implant element bypasses the stomach.
[0042] FIG. 22A is a sectional view of a portion of the digestive tract in the body. A docking element is implanted in the esophagus at the gastro-esophageal junction. A second docking element and tubular implant is implanted from the esophageal implant to the ligament of treitz.
[0043] FIG. 22B is a sectional view of a portion of the digestive tract in the body. A docking element is implanted in the esophagus at gastro-esophageal junction. A docking element and tubular implant is implanted from the esophageal implant to the duodenal bulb.
[0044] FIG. 23A is a sectional view of a portion of the digestive tract in the body. A docking element and tubular implant is implanted in the esophagus at the gastro-esophageal junction. The modular implant has an anti-reflux valve. A second docking station and tubular implant is placed in the duodenal bulb and extends to the ligament of treitz. A third docking station and tubular implant connects the esophageal implant and the duodenal implant.
[0045] FIG. 23B is a sectional view of a portion of the digestive tract in the body. A docking element and tubular implant is implanted in the esophagus at the gastro-esophageal junction. The modular implant has an-anti reflux valve. A second docking station and tubular implant is placed in the pylorus and extends to the ligament of treitz. A third docking station and tubular implant connects the esophageal implant and the duodenal implant at the pylorus.
[0046] FIG. 24 is a sectional view of a portion of the digestive tract in the body. A docking element and tubular implant is implanted in the esophagus at gastro-esophageal junction. The modular implant has an-anti reflux valve. A second docking station and tubular implant is placed in the pyloric antrum and extends to the ligament of treitz. A third docking station and tubular implant connects the esophageal implant and the duodenal implant at the pyloric antrum.
[0047] FIG. 25 is a drawing of a delivery catheter with a docking element loaded onto it.
[0048] FIG. 26 is a drawing of a delivery catheter with the endoscope inserted through inner diameter of the delivery catheter.
[0049] FIG. 27 is a drawing of a delivery catheter which is designed to be inserted through the working channel of the endoscope.
[0050] FIG. 28 is a drawing of a delivery catheter with a docking element and tubular implant loaded onto it.
[0051] FIGS. 29-35 show a variety of stents that can be used as a docking element.
[0052] FIG. 36A is a drawing of a stent that can be used as a docking element.
[0053] FIG. 36B is a drawing of a stent that can be used as a docking element.
[0054] FIGS. 37-39 show docking elements.
[0055] FIG. 40A is an expandable ring that can attached to a sleeve to form a tubular implant.
[0056] FIG. 40B is an expandable ring that can attached to a sleeve to form a tubular implant.
[0057] FIG. 40C is an expandable ring that can attached to a sleeve to form a tubular implant.
[0058] FIG. 41 is a tubular implant that uses an expandable ring as in FIG. 40A , 40 B or 40 C as an anchoring means.
[0059] FIG. 42 is a tubular implant that uses an expandable ring as in FIG. 40A , 40 B or 40 C as an anchoring means. The tubular implant is placed and secured within a docking element.
[0060] FIG. 43 is a tubular implant that uses an expandable ring as in FIG. 40A , 40 B or 40 C as an anchoring means. The tubular implant is expanded and secured within the docking element.
[0061] FIG. 44 is a drawing of a docking element which uses hook and loop to secure the tubular implant to docking element.
[0062] FIG. 45A is a drawing of a tubular implant that has magnets in the wall to allow attachment to another tubular implant or to a docking element.
[0063] FIG. 45B is a drawing of a tubular implant that has magnets in the wall to allow attachment to another tubular implant or to a docking element, it has a female receptacle to allow attachment to a docking element or other tubular implant.
[0064] FIGS. 46A and 46B show tubular implants.
[0065] FIGS. 47A and 47B show tubular implants in which the sleeve has longitudinal or circumferential pleats, respectively.
[0066] FIGS. 48A and 48B show tubular implants or sleeves with a magnetic attachment means.
[0067] FIG. 49 is a drawing of a tubular implant or sleeve with barbs to attach to attach to tissue or to a docking element.
[0068] FIG. 50A is a drawing of a tubular implant or sleeve with pockets to insert magnets to allow attachment to a docking element or to another tubular implant.
[0069] FIG. 50B is a drawing of a tubular implant or sleeve with hooks to attach docking element or another tubular implant.
[0070] FIG. 51A is a conical or tapered shaped docking element or tubular implant.
[0071] FIG. 51B is a docking element or tubular implant with a stepped diameter.
[0072] FIG. 52 is a tubular implant that has hook and loop (velcro) attachment means to attach to a docking element or another tubular implant.
[0073] FIG. 53A is an over the wire balloon catheter for delivering and expanding balloon expandable stents for a docking element.
[0074] FIG. 53B is a rapid exchange balloon catheter for delivering and expanding balloon expandable stents for a docking element.
[0075] FIG. 54 shows a docking element design with a single-braided or laser-cut design placed at the pyloric junction.
[0076] FIG. 55 shows another docking element designed where the stomach side of docking element is more disk-like .
[0077] FIGS. 56 and 57 show docking elements of FIG. 55 and FIG. 56 covered with fabric or polymer sheets in areas where they contact tissue.
[0078] FIG. 58 shows a different design of the docking element placed within the pylorus, where two metallic elements (one on the stomach side and one on the duodenal side) are connected by a flexible sleeve element
[0079] FIG. 59 depicts the docking element of FIG. 58 where the flexible sleeve element has expanded with the opening of the pyloric valve.
[0080] FIG. 60 depicts another docking element design incorporating a flexible sleeve element.
[0081] FIG. 61 depicts a tubular implant which can be reversibly attached to various compatible docking elements described elsewhere such as those shown in FIGS. 54 through FIG. 58 .
[0082] FIG. 62 shows delivery of the tubular implant of FIG. 61 close to the docking element of FIG. 54 .
[0083] FIG. 63 depicts the docking element and the tubular element mated together upon release from the delivery catheter
[0084] FIG. 64 shows where the tubular element is now attached to the docking element of FIG. 58
[0085] FIG. 65 shows a situation where the tubular element is attached to the docking element of FIG. 58 on the stomach portion of the docking element.
[0086] FIGS. 66-78 show schematic views of various stages of an implantation method according to embodiments of the invention.
[0087] While the invention is amenable to various modifications and alternative forms, specific embodiments have been shown by way of example in the drawings and are described in detail below. The intention, however, is not to limit the invention to the particular embodiments described. On the contrary, the invention is intended to cover all modifications, equivalents, and alternatives falling within the scope of the invention as defined by the appended claims
DETAILED DESCRIPTION
[0088] FIG. 1 is a schematic, sectional view of an embodiment of the invention implanted in a portion of a human digestive tract. As a person ingests food, the food enters the mouth 100 , is chewed, and then proceeds down the esophagus 101 to the lower esophageal sphincter at the gastro-esophageal junction 102 and into the stomach 103 . The food mixes with enzymes in the mouth 100 and in the stomach 103 . The stomach 103 converts the food to a substance called chyme. The chyme enters the pyloric antrum 104 and exits the stomach 103 through the pylorus 106 and pyloric orifice 105 . The small intestine is about 21 feet long in adults. The small intestine is comprised of three sections. The duodenum 112 , jejunum 113 and ileum (not shown). The duodenum 112 is the first portion of the small intestine and is typically 10-12 inches long. The duodenum 112 is comprised of four sections: the superior, descending, horizontal and ascending. The duodenum 112 ends at the ligament of treitz 109 . The papilla of vater 108 is the duct that delivers bile and pancreatic enzymes to the duodenum 112 . The duodenal bulb 107 is the portion of the duodenum which is closest to the stomach 103 .
[0089] As shown in FIG. 1 , a docking or anchoring element 110 is implanted in the duodenal bulb 107 and a tubular or therapy implant 111 is attached to the docking element and extended into the duodenum 112 to the ligament of treitz 109 . In this embodiment, magnets 135 on the docking element 110 and magnets 136 on the tubular implant 111 are magnetically attracted to each other and thereby secure the docking element 110 to the therapy implant 111 . According to various exemplary embodiments, the anchoring element 110 includes an expandable structure (e.g., a stent or ring) adapted for anchoring within the duodenal bulb and has a diameter of between about 20 and about 40 mm in its unrestrained expanded configuration. In these embodiments, the magnets 135 on the docking or anchoring element 110 serve as a docking feature for releasably coupling with the magnets 136 of the tubular implant 111 .
[0090] FIG. 2 is a schematic view of a portion of the digestive tract in a human body. An endoscope 114 has been inserted through the mouth 100 , esophagus 101 , the gastro-esophageal junction 102 and into the stomach 103 . The endoscope 114 further extends into the pyloric antrum 104 to allow visualization of the pylorus 106 .
[0091] FIG. 3 is a drawing of an endoscope 114 . Endoscopes 114 are commonly used for diagnostic and therapeutic procedures in the gastrointestinal (GI) tract. The typical endoscope 114 is steerable by turning two rotary dials 115 to cause deflection of the working end 116 of the endoscope. The working end of the endoscope 116 or distal end, typically contains two fiber bundles for lighting 117 , a fiber bundle for imaging 118 (viewing) and a working channel 119 . The working channel 119 can also be accessed on the proximal end of the endoscope. The light fiber bundles and the image fiber bundles are plugged into a console at the plug in connector 120 . The typical endoscope has a working channel, for example, having a diameter in the 2 to 4 mm diameter range. It may, for example having a working channel having a diameter in the 2.6 to 3.2 mm range. The outside diameter of the endoscopes are typically in the 8 to 12 mm diameter range depending on whether the endoscope is for diagnostic or therapeutic purposes.
[0092] FIG. 4A is a partial sectional view of an over the wire sizing balloon 121 that is used to measure the diameter of the pylorus 106 , duodenal bulb 107 , esophagus 102 , pyloric antrum 104 or other lumen in the GI tract. The sizing balloon is composed of the following elements: a proximal hub 122 , a catheter shaft 124 , a distal balloon component 125 , radiopaque marker bands 126 , a distal tip 127 , a guide wire lumen 128 , and an inflation lumen 129 . The distal balloon component 125 can be made, for example, from silicone, silicone polyurethane copolymers, latex, nylon 12, PET (Polyethylene terphalate) Pebax (polyether block amide), polyurethane, polyethelene, polyester elastomer or other suitable polymer. The distal balloon component 125 can be molded into any desired shape, including for example a cylindrical shape, a dog bone shape, or a conical shape. The distal balloon component 125 can be made compliant or noncompliant. The distal balloon component 125 can be bonded to the catheter shaft 124 with glue, heat bonding, solvent bonding, laser welding or any suitable means. The catheter shaft can be made from silicone, silicone polyurethane copolymers, latex, nylon 12, PET (Polyethylene terphalate) Pebax (polyether block amide), polyurethane, polyethylene, polyester elastomer or other suitable polymer. Section A-A (shown at the top portion of FIG. 4A ) is a cross section of the catheter shaft 124 . The catheter shaft 124 is shown as a dual lumen extrusion with a guide wire lumen 128 and an inflation lumen 129 . The catheter shaft 124 can also be formed from two coaxial single lumen round tubes in place of the dual lumen tubing. The balloon is inflated by attaching a syringe (not shown) to luer fitting side port 130 . The sizing balloon accommodates a guidewire through the guidewire lumen from the distal tip 127 through the proximal hub 122 . The sizing balloon 121 can be filled with a radiopaque dye to allow visualization and measurement of the size of the anatomy with a fluoroscope. In the embodiment of FIG. 4A , the sizing balloon 121 has two or more radiopaque marker bands 126 located on the catheter shaft to allow visualization of the catheter shaft and balloon position. The marker bands 126 also serve as fixed known distance reference point that can be measured to provide a means to calibrate and determine the balloon diameter with the use of the fluoroscope. The marker bands can be made from tantalum, gold, platinum, platinum iridium alloys or other suitable material.
[0093] FIG. 4B is a partial sectional view of a rapid exchange sizing balloon 134 that is used to measure the diameter of the pylorus 106 , duodenal bulb 107 , esophagus 102 , pyloric antrum 104 or other lumen in the GI tract. The sizing balloon is composed of the following elements: a proximal luer 131 , a catheter shaft 124 , a distal balloon component 125 , radiopaque marker bands 126 , a distal tip 127 , a guide wire lumen 128 , and an inflation lumen 129 . The materials of construction will be similar to that of the sizing balloon 121 of FIG. 4A . The guide wire lumen 128 does not travel the full length of the catheter, it starts at the distal tip 127 and exist out the side of the catheter at distance shorter that that the shorter that the overall catheter length. A guide wire 132 is inserted into the balloon catheter to illustrate the guidewire path through the sizing balloon 134 . As shown in FIG. 4B , the sizing balloon catheter shaft changes section along its length from a single lumen at section B-B 133 to a dual lumen at section A-A at 124 .
[0094] FIG. 5 is a schematic view of a portion of the digestive tract in the body. An endoscope 114 is inserted into the GI tract up to the pylorus 106 . A sizing balloon 121 is inserted through the working channel 119 of the endoscope and into the area of the duodenal bulb 107 . The sizing balloon 121 is inflated with contrast agent. The diameter of the duodenal bulb 107 is measured with a fluoroscope.
[0095] FIG. 6A shows various views of a stent that can used as a docking or anchoring element. The stents of this invention can be comprised, for example, of any one or more of the following materials: Nickel titanium alloys (Nitinol), Stainless steel alloys: 304, 316L, BioDur® 108 Alloy, Pyromet Alloy® CTX-909, Pyromet® Alloy CTX-3, Pyromet® Alloy 31 , Pyromet® Alloy CTX-1, 21Cr-6Ni-9Mn Stainless, 21 Cr- 6 Ni- 9 Mn Stainless, Pyromet Alloy 350, 18Cr-2Ni-12Mn Stainless, Custom 630 (l7Cr-4Ni) Stainless, Custom 465® Stainless, Custom 455® Stainless Custom 450® Stainless, Carpenter 13-8 Stainless, Type 440C Stainless, Cobalt chromium alloys—MP35N, Elgiloy, L605, Biodur® Carpenter CCM alloy, Titanium and titanium alloys, Ti-6Al-4V/ELI and Ti-6Al-7Nb, Ti-15Mo Tantalum, Tungsten and tungsten alloys, Pure Platinum , Platinum-Iridium alloys, Platinum-Nickel alloys, Niobium, Iridium, Conichrome, Gold and Gold alloys. The stent may also be comprised of the following absorbable metals: Pure Iron and magnesium alloys. The stent may also be comprised of the following plastics: Polyetheretherketone (PEEK), polycarbonate, polyolefin's, polyethylene's, polyether block amides (PEBAX), nylon 6, 6-6, 12, Polypropylene, polyesters, polyurethanes, polytetrafluoroethylene (PTFE) Poly(phenylene sulfide) (PPS), poly(butylene terephthalate) PBT, polysulfone, polyamide, polyimide, poly(pphenylene oxide) PPO, acrylonitrile butadiene styrene (ABS), Polystyrene, Poly(methyl methacrylate) (PMMA), Polyoxymethylene (POM), Ethylene vinyl acetate , Styrene acrylonitrile resin, Polybutylene. The stent may also be comprised of the following absorbable polymeres: Poly (PGA), Polylactide (PLA), Poly(-caprolactone), Poly(dioxanone) Poly(lactide-coglycolide). Stent 137 stent according to various embodiments is laser cut from a round tubing or from a flat sheet of metal. The flat representation of the stent circumference is shown in item 138 . The flat representation of an expanded stent is shown in item 139 . The end view of the stent is shown 141 . Magnets 140 are attached to the stent on the outside diameter. The magnets may be attached to the stent by use of a mechanical fastener, glue, suture, welding, snap fit or other suitable means. The stent can be either balloon expandable or self expanding. The magnets may be located in middle of the stent or at the ends of the stent. Suitable materials for the magnets include: neodymium-iron-boron [Nd—Fe—B], samarium-cobalt [Sm—Co], alnico, and hard ferrite [ceramic] or other suitable material. In some embodiments, the magnets are encapsulated in another metal (e.g., titanium) or polymer to improve corrosion resistance and biocompatibility.
[0096] FIG. 6B shows various views of a stent that can used as a docking or anchoring element. Stent 142 may be laser cut from a round tubing or from a flat sheet of metal. The flat representation of the stent circumference is shown in item 143 . The flat representation of an expanded stent is shown in item 144 . The end view of the stent is shown 145 . Permanent magnets 140 are attached to the stent on the outside diameter. This stent is a covered stent. The stent covering is not shown on items 142 , 143 or 144 . The covering are shown on the end view which shows stent 145 . Stent may have an outside covering 146 , inside covering 147 or both. Suitable materials for the covering include but are not limited to: silicone, polyether block amides (PEBAX), polyurethanes, silicone polyurethane copolymers, nylon 12, polyethylene terphalate (PET), Goretex ePTFE, Kevlar, Spectra, Dyneena, polyvinyl chloride (PVC), polyethylene or polyester elastomers. The coverings may be dip coated onto the stent or they may be made as a separate tube and then attached to the stent by adhesives or mechanical fasteners such as suture, rivets or by thermal bonding of the material to the stent or another layer. The covering may also have drugs incorporated into the polymer to provide for a therapeutic benefit. The covering 146 or 147 may also be of biologic origin. Suitable biologic materials include but are not limited to: Amnion, Collagen Type I, II, III, IV, V, VI-Bovine, porcine, ovine, placental tissue or placental veins or arteries and small intestinal sub-mucosa.
[0097] FIG. 7 is a tubular therapy implant that can be used to bypass the stomach 103 , duodenum 112 or other intestinal lumens (e.g., a portion or all of the jejunum). The tubular implant is made of a thin wall tube 148 and a series of magnets 140 attached to the inside of the thin wall tube. According to other embodiments, the magnets 140 may be attached to the outside of the tube 148 . According to various embodiments, the magnets 140 are disposed about a circumference of the tube 148 such that the location of the magnets correspond to locations of corresponding magnets located on the anchoring or docking element. The tubular implants of this invention may be comprised, for example, of the following materials: silicone, polyether block amides (PEBAX), polyurethanes, silicone polyurethane copolymers, Nylon, polyethylene terphalate (PET), Goretex ePTFE, Kevlar, Spectra, Dyneena, polyvinyl chloride (PVC), polyethylene, polyester elastomers or other suitable materials. The thin wall tube length 149 may range from 1 inch in length up to 5 feet in length. The thickness of the thin walled tube will typically be in the range of 0.0001 inches to 0.10 inches. The diameter of the tubular implant will range from typically 25 to 35 mm, but may also range anywhere from 5 mm to 70 mm in diameter.
[0098] Exemplary tubular elements for performing intra-luminal gastrointestinal therapies, e.g., treating metabolic disorders, which may be used with the system of present invention include, for example, those elements disclosed in any of U.S. Pat. Nos. 4,134,405; 4,314,405; 4,315,509; 4,641,653; 4,763,653; and 5,306,300, each of which is hereby incorporated by reference in its entirety.
[0099] FIG. 8 is a schematic view of a delivery catheter for a delivering a self expanding docking or anchoring element 110 and tubular or therapy implant 111 , according to various embodiments of the invention. The delivery catheter is constructed with a central lumen 150 sufficiently large to allow the catheter to loaded be over the outside diameter of the endoscope 114 . The delivery catheter consists of an outer catheter 151 and an inner catheter 152 . To load the tubular implant onto the delivery catheter, the outer sheath handle 153 is retracted towards the inner catheter handle 154 until distance 155 (between the outer handle 153 and inner handle 154 ) is relatively small. The tubular implant 111 is then compressed around the inner catheter, and the outer sheath is partially closed by advancing the outer sheath handle 153 away from the inner sheath handle 154 . When the tubular implant is completely (or sufficiently) covered by the outer sheath or catheter 151 , the loading process is complete for the tubular implant. The delivery catheter also has a space on the inner catheter 151 for the docking or anchoring implant 110 to be loaded. As shown in FIG. 8 , the anchoring implant 110 is compressed around the distal portion of the inner catheter 152 . The outer sheath handle 153 is then advanced distally until it completely (or sufficiently) covers and retains the anchoring implant. In one embodiment, the tubular or therapy implant 111 is compressed over the inner catheter and the outer catheter is placed over the outside (left to right in FIG. 8 ) of the tubular implant 111 .
[0100] As further shown in FIG. 8 , according to exemplary embodiments, a stent retainer 159 is attached to the inner catheter. The stent retainer 159 acts to prevent the stent (e.g., the anchoring or docking implant 110 ) from releasing from the delivery catheter prematurely during deployment. The stent retainer is fastened to the inner catheter. The stent retainer 159 can be made from metal or plastic and can be made radiopaque by making from it from a radiopaque material such as tantalum. The stent retainer has a complementary shape that holds the tips on the stent and does not allow the stent to move distally or forward until the outer sheath 151 is fully retracted to the stent retainer 159 .
[0101] The catheter has a side port 156 which allows the space between the inner and outer sheaths to be flushed with saline. The outer sheath 151 and inner sheath 152 may be made from made from a simple single layer polymer extrusion such as from polyethylene or PTFE. The outer sheath may also be constructed in the following manner. The sheath inner diameter surface is constructed of a thin wall PTFE liner 157 . A layer of reinforcement 158 is placed over the PTFE liner, the reinforcement is preferably either a braid of wire or a coil of wire. The wire cross section can be either round or rectangular. The preferred material for the wire is a metal such as 316 or 304 stainless steel or Nitinol or other suitable material. The wire diameters are typically in the 0.0005 inch to 0.010 inch diameter range. The outer jacket material is preferably reflowed into the reinforcement layer by melting the material and flowing it into the spaces in between the braided wire or the coil wires.
[0102] FIGS. 9A-16 shows a series of steps in the implantation of the apparatus herein disclosed, according to an exemplary embodiment. FIG. 9A is a schematic view of a portion of the digestive tract in the body. A delivery catheter with a docking element 110 and tubular implant 111 loaded onto the catheter are loaded over the outside of an endoscope. The endoscope is then advanced through the esophagus, stomach, such that a distal portion is located in the pylorus or the duodenal bulb. FIG. 9B is a schematic view of a portion of the digestive tract in the body. As shown, a delivery catheter with a docking element 110 and tubular implant 111 loaded onto the catheter are loaded onto an endoscope. The endoscope is then advanced through the esophagus, stomach and into the duodenal bulb. The outer sheath or catheter 151 is then retracted by moving outer handle 153 towards inner handle 154 to deploy the docking or anchoring element 110 . FIG. 10 is a schematic view of a portion of the digestive tract in the body. The drawing shows the docking element 110 fully deployed into the duodenal bulb 107 . The delivery catheter and endoscope have been has been removed to show clarity.
[0103] FIG. 11 is a schematic view showing the delivery catheter (of FIG. 9 ), wherein the docking element is fully deployed, further advanced into the duodenum 112 until the distal end of the delivery catheter is disposed at or near the ligament of treitz 109 . Next, as shown in FIG. 12 , the outer sheath 151 of the delivery catheter is refracted slightly (e.g., 1-3 centimeters) to expose the distal portion of the tubular implant 111 . Also, the tubular implant 111 is advanced forward slightly (e.g., 1-5 centimeters), such that a sufficient amount of the distal end of the tubular implant 111 is disposed beyond the distal most portion of both the inner sheath 152 and the outer sheath 151 . In some embodiments, this is accomplished by use of a third intermediate sleeve to apply a distal force to the tubular implant 111 . In other embodiments, after deploying the anchoring element, the physician removes the endoscope from the patient, loads the tubular implant with a sufficient amount extending distally, then advances the endoscope to the appropriate locations and deploys the tubular implant 111 .
[0104] Then, in FIG. 13 , a sizing balloon 121 has been inserted through the working channel 119 on endoscope 114 . The sizing balloon 121 is advanced slightly (e.g., 1-2 inches) beyond the distal end of the endoscope 114 but still inside of the tubular implant 111 . The sizing balloon 121 is then inflated with saline or contrast agent to generate sufficient radial force to hold the tubular implant 111 in place in the duodenum 112 near the ligament of treitz 109 .
[0105] Next, as shown in FIG. 14 , the outer sheath 151 is retracted further to expose much or most (e.g., all but 1-3 centimeters) of the tubular implant 111 . The outer sheath 151 end is now located at or near the pylorus 106 . Then, a shown in FIG. 15 , the distal end of the endoscope 114 has been pulled back to the pyloric orifice 105 and the sizing balloon 121 has been deflated and repositioned at a location near the proximal end of the tubular implant 111 . The sizing balloon 121 is then reinflated to force or urge the proximal end of the tubular implant 111 into contact with the docking element 110 , such that the magnets 140 on the tubular sleeve are now in contact with the magnets 140 on the docking element. The magnetic attraction between the magnets 140 secures the tubular implant 111 to the docking element 110 . The endoscope 114 is then removed and the procedure is complete.
[0106] FIG. 16 shows an alternative embodiment for securing the proximal end of the tubular implant 111 to the docking element 110 . As shown, according to various embodiments, a Nitinol conical and tubular shaped forceps 160 are attached to the inner catheter near the proximal end of where the tubal implant is loaded on the delivery catheter. The Nitinol forceps 160 are configured to have an elastic memory in the open state. When the outer sheath 151 is full refracted the conical forceps open and in turn urge open the proximal end of the tubular implant 111 to seat the magnets on the tubular implant 111 to the magnets on the docking station 110 .
[0107] At some point during or after implantation of the docking element 110 or the tubular implant 111 , the physician may wish to remove one or both components. Either or both components may be readily removed using any of a number of techniques generally known in the art. One such technique for removing or extracting the stent or stent-like portion of the docking element 110 or the tubular implant 111 involves use of a retrieval hook and a collapsing sheath or overtube. One such exemplary system is disclosed in EP 1 832 250, which is hereby incorporated by reference in its entirety. Other removal or extraction systems are disclosed, for example in each of U.S. Publication 2005/0080480, U.S. Pat. No. 5,474,563, and U.S. Pat. No. 5,749,921, each of which is hereby incorporated by reference in its entirety.
[0108] FIG. 17A is a schematic view of a portion of the digestive tract in the body. A docking element 160 is implanted in the esophagus at gastro-esophageal junction 102 . The docking element serves as an anti-reflux valve when the tube 161 is compressed flat by pressure in the stomach 103 . FIG. 17B is a schematic view of a portion of the digestive tract in the body. A docking element 162 is implanted in the esophagus at gastro-esophageal junction 102 . The docking element 162 has a neck or narrow portion having an inside diameter less than the diameter of the native gastro-esophageal junction. Due to this reduced diameter, the docking element 162 serves as a restrictive stoma. FIG. 18 is a schematic view of a portion of the digestive tract in the body. A docking element 164 is implanted in the esophagus at gastro-esophageal junction 102 . A tubular implant 165 is attached to the docking element 164 . The tubular implant can have bi-leaflet reflux valve 166 , a tri-leaflet reflux valve 167 , a quad-leaflet reflux valve 168 , a penta-leaflet reflux valve 169 , a six-leaflet reflux valve 170 or seven-leaflet reflux valve.
[0109] FIG. 19A is a schematic view showing an alternative embodiment of the invention, wherein a docking element is not used but a stented sleeve 171 is used. A stent is used to hold open the sleeve and anchor it. The sleeve extends from a proximal end in or near the duodenal bulb 107 to a distal end at or near the ligament of treitz 109 . Those of skill in the art will understand that, in the stented-sleeve construct above, the stent and the sleeve could be mechanically pre-attached, such as by sutures or other chemical and mechanical bonding in which case the expansion of the stent results in anchoring of the stented sleeve structure on to the tissue. On the other hand, the stent could also reside freely within the sleeve at its end and when expanded could press the sleeve against the tissue to anchor it. All the stents and delivery catheters herein disclosed may also be used to deliver and anchor a stented sleeve or deliver a stent within a sleeve to anchor it on to surrounding tissue.
[0110] FIG. 19B is an alternative embodiment of the invention wherein a docking element is not used but a stented sleeve 172 is used. A stent is used to hold open the sleeve and anchor it. As shown, in this embodiment, the sleeve extends from a proximal end at or near the pylorus 106 to a distal end at or near the ligament of treitz 109 . Those of skill in the art will understand that in the stented-sleeve construct above the stent and the sleeve could be mechanically pre-attached, such as by sutures or other chemical and mechanical bonding in which case the expansion of the stent results in anchoring of the stented sleeve structure on to the tissue. On the other hand the stent could also reside freely within the sleeve at its end and when expanded could press the sleeve against the tissue to anchor it. All the stents and delivery catheters herein disclosed may also be used to deliver and anchor a stented sleeve or deliver a stent within a sleeve to anchor it on to surrounding tissue.
[0111] FIG. 20 is an alternative embodiment of the invention wherein a docking element is not used but a stented sleeve 172 is used. A stent is used to hold open the sleeve and anchor it. As shown, in this embodiment, the sleeve extends from a proximal end in the pyloric antrum 104 to a distal end at or near the ligament of treitz 109 . Those of skill in the art will understand that in the stented-sleeve construct above the stent and the sleeve could be mechanically pre-attached, such as by sutures or other chemical and mechanical bonding in which case the expansion of the stent results in anchoring of the stented sleeve structure on to the tissue. On the other hand the stent could also reside freely within the sleeve at its end and when expanded could press the sleeve against the tissue to anchor it. All of the stents and delivery catheters herein disclosed may also be used to deliver and anchor a stented sleeve or deliver a stent within a sleeve to anchor it on to surrounding tissue.
[0112] FIG. 21A shows an embodiment of the invention wherein a first docking (or anchoring) element 174 or a stented sleeve is implanted in the gastro-esophageal junction 102 and a second docking (or anchoring) element 175 or stented sleeve is implanted in the duodenal bulb 107 . FIG. 21B shows an embodiment of the invention wherein a first docking element 174 or a stented sleeve is implanted in the gastro-esophageal junction 102 , a second docking element 175 or stented sleeve in the duodenal bulb 107 , and a third docking element and tubular implant 176 is implanted to bypass the stomach from 174 to 175 .
[0113] FIG. 22A is an alternative embodiment of the invention wherein a first docking element 178 is implanted in the gastro-esophageal junction 102 , a second docking element 177 and tubular implant is implanted extending from the docking element 178 to a distal end at or near the ligament of treitz. FIG. 22B is an alternative embodiment of the invention wherein a first docking element 178 is implanted in the gastro-esophageal junction 102 , a second docking element 179 and tubular implant is implanted from the 178 docking element to the duodenal bulb 107 .
[0114] FIG. 23A is an alternative embodiment of the invention wherein a first docking element 180 , having an anti-reflux valve, is implanted in the gastro-esophageal junction 102 , a second docking element 181 and tubular implant is implanted from the duodenal bulb 107 to a location at or near the ligament of treitz. A third docking element 182 and tubular implant is implanted from the docking element 180 to the docking element 181 . FIG. 23B is an alternative embodiment of the invention wherein a first docking element 180 with an anti-reflux valve is implanted in the gastro-esophageal junction 102 , a second docking element 183 and tubular implant is implanted from a the pylorus 106 to the ligament of treitz. A third docking element 184 and tubular implant is implanted from the 183 docking to the 184 docking element.
[0115] FIG. 24 is an alternative embodiment of the invention wherein a first docking element 185 with an anti-reflex valve is implanted in the gastro-esophageal junction 102 , a second docking element 186 and tubular implant is implanted from the pyloric antrum 104 to the ligament of treitz. A third docking element and tubular implant 187 is implanted from the docking element 185 to the docking element 186 . As shown, the implant 187 includes a stent or stent-like anchoring element, which is adapted for delivery in a compressed configuration and to engage the first docking element 185 in an expanded configuration.
[0116] FIG. 25 is a schematic view of a delivery catheter for a self expanding docking element 110 , according to embodiments of the invention. As shown in FIG. 25 , the catheter is preloaded with the docking element but not the tubular implant. The delivery catheter is constructed with a central lumen 150 sufficiently large to allow the catheter to loaded be over the outside diameter of an endoscope. The delivery catheter consists of an outer catheter 151 and an inner catheter 152 . To load the tubular implant onto the delivery catheter the outer sheath handle 153 is retracted towards the inner catheter handle 154 until distance 155 is sufficiently small. Once the tubular implant is loaded over the inner catheter, the outer sheath is partially closed by advancing the outer sheath handle away from the inner sheath handle 154 . The outer sheath 151 is then advanced further until the tubular implant is completely (or sufficiently) covered by the outer sheath.
[0117] The delivery catheter also has a space on the inner catheter for the implant 110 to be loaded. Attached to the inner catheter is a stent retainer 159 . The purpose of the stent retainer 159 is to prevent the stent from releasing from the delivery catheter prematurely during deployment. The stent retainer is fastened to the inner catheter. The stent retainer 159 can be made from metal or plastic and can be made radiopaque by making from it from a radiopaque material such as tantalum. The stent retainer has a complementary shape that holds the tips on the stent and does not allow the stent to move distally or forward until the outer sheath 151 is fully retracted to the stent retainer 159 . The catheter has a side port 156 which allows the space between the inner and outer sheaths to be flushed with saline. The outer sheath 151 and inner sheath 152 may be made from made from a simple single layer polymer extrusion such as from polyethylene or PTFE. The outer sheath may also be constructed in the following manner. The sheath inner diameter surface is constructed of a thin wall PTFE liner 157 . A layer of reinforcement 158 is placed over the PTFE liner, the reinforcement is preferably either a braid of wire or a coil of wire. The wire cross section can be either round or rectangular. The preferred material for the wire is a metal such as 316 or 304 stainless steel or Nitinol or other suitable material. The wire diameters are typically in the 0.0005 inch to 0.010 inch diameter range. The outer jacket material is preferably reflowed into the reinforcement layer by melting the material and flowing it into the spaces in between the braided wire or the coil wires.
[0118] FIG. 26 is a schematic view showing the delivery catheter for the apparatus disclosed loaded over an endoscope. FIG. 27 is a schematic view of an alternative delivery catheter for a self expanding docking element 110 , tubular implant 111 or for both 110 and 111 on the same catheter. The delivery catheter is constructed with a smaller outside diameter to allow the catheter to be inserted through the working channel of the endoscope 114 . The delivery catheter consists of an outer catheter 151 and an inner catheter 152 . Attached to the inner catheter is a stent retainer 159 . The purpose of the stent retainer 159 is to prevent the stent from releasing from the delivery catheter prematurely during deployment. The stent retainer is fastened to the inner catheter. The stent retainer 159 can be made from metal or plastic and can be made radio-opaque by making from it from a radio-opaque material such as tantalum. The stent retainer has a complementary shape that holds the tips on the stent and does not allow the stent to move distally or forward until the outer sheath 151 is fully retracted to the stent retainer 159 .
[0119] The catheter has a side port 156 which allows the space between the inner and outer sheaths to be flushed with saline. The outer sheath 151 and inner sheath 152 may be made from made from a simple single layer polymer extrusion such as from polyethylene or PTFE. The outer sheath may also be constructed in the following manner. The sheath inner diameter surface is constructed of a thin wall PTFE liner 157 . A layer of reinforcement 158 is placed over the PTFE liner, the reinforcement is preferably either a braid of wire or a coil of wire. The wire cross section can be either round or rectangular. The preferred material for the wire is a metal such as 316 or 304 stainless steel or Nitinol or other suitable material. The wire diameters are typically in the 0.0005 inch to 0.010 inch diameter range. The outer jacket material is preferably reflowed into the reinforcement layer by melting the material and flowing it into the spaces in between the braided wire or the coil wires. The outside diameter of this catheter will range typically from 1 mm to 4 mm. The catheter can be constructed to be an over the wire catheter or a rapid exchange catheter. For a rapid exchange design the guidewire will enter the central lumen of the distal end of the catheter and exit at point 188 . For an over the wire catheter design the guidewire will enter the central lumen of the distal end of the catheter and exit at point 189 .
[0120] FIG. 28 is a schematic view of an alternative embodiment drawing of a delivery catheter for a self expanding docking element 110 and tubular implant 111 . As shown in FIG. 28 , the tubular implant is located distal to the docking element. The delivery catheter could also be used for delivery of a stented sleeve construct where the sleeve and stent are integrated together into one implant. The delivery catheter is constructed with a central lumen 150 large enough to allow the catheter to loaded be over the outside diameter of the endoscope 114 . The delivery catheter consists of an outer catheter 151 and an inner catheter 152 . To load the tubular implant onto the delivery catheter, the outer sheath handle 153 is retracted towards the inner catheter handle 154 until distance 155 is a sufficiently small. The outer sheath is then partially closed by advancing the outer sheath handle away from the inner sheath handle 154 . The outer sheath 151 is then further advanced until the tubular implant is completely (or sufficiently) covered by the outer sheath. The delivery catheter also has a space on the inner catheter for the modular implant 110 to be loaded. Attached to the inner catheter is a stent retainer 159 . The purpose of the stent retainer 159 is to prevent the stent from releasing from the delivery catheter prematurely during deployment. The stent retainer is fastened to the inner catheter. The stent retainer 159 can be made from metal or plastic and can be made radio-opaque by making from it from a radioopaque material such as tantalum. The stent retainer has a complementary shape that holds the tips on the stent and does not allow the stent to move distally or forward until the outer sheath 151 is fully retracted to the stent retainer 159 .
[0121] The catheter has a side port 156 which allows the space between the inner and outer sheaths to be flushed with saline. The outer sheath 151 and inner sheath 152 may be made from made from a simple single layer polymer extrusion such as from polyethylene or PTFE. The outer sheath may also be constructed in the following manner. The sheath inner diameter surface is constructed of a thin wall PTFE liner 157 . A layer of reinforcement 158 is placed over the PTFE liner, the reinforcement is preferably either a braid of wire or a coil of wire. The wire cross section can be either round or rectangular. The preferred material for the wire is a metal such as 316, 304 stainless steel, Nitinol or other suitable material. The wire diameters are typically in the 0.0005 inch to 0.010 inch diameter range. The outer jacket material is preferably reflowed into the reinforcement layer by melting the material and flowing the melted polymer into the spaces in between the braided wire or the coiled wires.
[0122] FIG. 29 is a drawing of a stent that can used as a docking element. Stent 137 stent is preferably laser cut from a round metal tubing or from a flat sheet of metal. The flat representation of the stent circumference is shown in item 138 . The flat representation of an expanded stent is shown in item 139 . The end view of the stent is shown 141 . Magnets 140 are attached to the stent on the inside diameter. The magnets may be attached to the stent by use of a mechanical fastener, glue, suture, welding, snap fit or other suitable means. The stent can be either balloon expandable or self expanding. The magnets may be located in middle of the stent or at the ends of the stent. Suitable materials for the magnets include, for example, neodymium-iron-boron [Nd—Fe—B], samarium-cobalt [Sm—Co], alnico, and hard ferrite [ceramic] or other suitable material. The stent may be balloon expanded or self expanding.
[0123] FIG. 30 is a drawing of a stent that can be used as a docking or anchoring element 110 . The stent can be laser cut from metal tubing or from a flat sheet of metal. The stent can also be braided or woven from round or flat wire. As shown in FIG. 30 , the stent has a double-layer mesh construction and it can a have separation between the two layers to allow other mechanical elements attached to mating tubular implant to mechanically interlock with the stent without exerting any anchoring force against the tissue.
[0124] In the picture shown, the stent has a narrowed diameter in the midpoint of the length this will provide for the stent to anchor more securely in anatomical locations such as the pylorus 106 . According to other embodiments, the stent has a cylindrical or other shape of double layer construction like a dumbbell shape. The mesh of the stent may be left open or it may be covered with a suitable material previously disclosed in this application. Magnets or other mechanical means for attachment of a tubular implant may be incorporated as disclosed in this application. The stent may be balloon expanded or self expanding. The mesh of the stent may be left open or it may be covered with a suitable material previously disclosed in this application. While the preferred embodiment of the above stent is a double-layer mesh construction, other single or multi-layer constructs which create hollow space within the structure to permit interlocking with other tubular implants could also be used. The space between the two mesh layers of the stent also help prevent or minimize tissue in-growth reaching the second (i.e., inner) layer of the stent and likewise from reaching an tubular or therapy implant coupled to the inner layer of the stent. Preventing or minimizing such tissue in-growth facilitates safe and easy removal (or replacement) of any such tubular or therapy implant.
[0125] FIG. 31A is a drawing of a stent that can be used as a docking or anchoring element. The stent can be braided from round or flat wire. As depicted in FIG. 31A , the stent is in the expanded state. The mesh of the stent may be left open or it may be covered with a suitable material, as previously disclosed in this application. The stent may be balloon expanded or self expanding. The mesh of the stent may be left open or it may be covered with a suitable material previously disclosed in this application. FIG. 31B is a drawing of a stent that can be used as a docking element. The stent can be braided from round or flat wire. As depicted in FIG. 31B , the stent is in the expanded state. The stent may include magnets 140 attached to the stent. The magnets may be on the inside diameter, outside diameter, both the inside or outside diameter or incorporated into the wall. The magnets can be used as a means to attach a tubular implant such as 111 . The mesh of the stent may be left open or it may be covered with a suitable material previously disclosed in this application. The stent may be balloon expanded or self expanding. The mesh of the stent may be left open or it may be covered with a suitable material, as previously disclosed in this application.
[0126] FIG. 32A is a drawing of a stent that can be used as a docking or anchoring element. The stent may be laser cut from round metal tubing or from a flat sheet of metal. The central portion of the stents diameter may be set to a smaller diameter to provide increased resistance to stent migration. The stent may be balloon expanded or self expanding. The mesh of the stent may be left open or it may be covered with a suitable material previously disclosed in this application. FIG. 32B is a drawing of a stent that can be used as a docking element. The stent may be laser cut from round metal tubing or from a flat sheet of metal. The central portion of the stents diameter may be shaped to an hour glass shape to provide increased resistance to stent migration. As shown in FIG. 32B , the stent has hoops 190 at the end of the stent. The hoops may be used to interlock with a stent retainer 159 on the inner catheter 152 to prevent premature deployment for the sheath is full y retracted. Radiopaque markers 191 can be attached to the end of the stent to increase the radiopacity of the stent. A metal insert may be pressed or swaged into the hoops 190 . The insert may be made from a high atomic density material such as tantalum, gold, platinum or iridium. The insert may take form of a disk or sphere and may be plastically deformed to fill the hoop cavity. The stent may be balloon expanded or self expanding. The mesh of the stent may be left open or it may be covered with a suitable material previously disclosed in this application.
[0127] FIG. 33A is a drawing of a stent that can be used as a docking element. Stent is preferably laser cut from round metal tubing or from a flat sheet of metal. The stent may be balloon expanded or self expanding. The mesh of the stent may be left open or it may be covered with a suitable material previously disclosed in this application. FIG. 33B is a drawing of a stent that can be used as a docking element. Stent is preferably laser cut from round metal tubing or from a flat sheet of metal. The stent may be balloon expanded or self expanding. The mesh of the stent may be left open or it may be covered with a suitable material previously disclosed in this application.
[0128] FIG. 34A is a drawing of a coil stent that can be used as a docking element. Stent is preferably made from round or flat wire. The stent is preferably self expanding, but may be made to be balloon expandable. The stent also may be laser cut into a coil from tubing. The preferred material for the stent is Nitinol. The mesh of the stent may be left open or it may be covered with a suitable material previously disclosed in this application. The stent has a hoop 192 at each end of the coil. The stent can be wound down onto a catheter by inserting a pin into the hoops on each end of the stent and rotating the pins in opposite directions to cause the stent to wind down onto the catheter. FIG. 34B is a drawing of a coil stent that can be used as a docking element. The stent is preferably made from round or flat wire. The stent is preferably self expanding, but may be made to be balloon expandable. The stent also may be laser cut into a coil from tubing. The preferred material for the stent is Nitinol. The mesh of the stent may be left open or it may be covered with a suitable material previously disclosed in this application. The stent has a hoop 192 at each end of the coil. The stent can be wound down onto a catheter by inserting a pin into the hoops on each end of the stent and rotating the pins in opposite directions to cause the stent to wind down onto the catheter. The stent has magnets 140 and the coil of the stent. The magnets can be used as an attachment means to a tubular implant.
[0129] FIG. 35 is a drawing of a coil stent that can be used as a docking element. The stent is preferably made from wire or sheet Nitinol metal. Several stents in series adjacent to each other can be used to form the docking element.
[0130] FIG. 36A is a drawing of a stent that can be used as a docking element. Stent is preferably laser cut from round metal tubing or from a flat sheet of metal. The stent is shaped to a conical shape to provide increased resistance to stent migration and to more closely fit the anatomy. The stent may be balloon expanded or self expanding. The mesh of the stent may be left open or it may be covered with a suitable material previously disclosed in this application. FIG. 36B is a drawing of a stent that can be used as a docking element. Stent is preferably laser cut from round metal tubing or from a flat sheet of metal. The stent is shaped to a have a stepped diameter to provide increased resistance to stent migration and to more closely fit the anatomy. The stent may be balloon expanded or self expanding. The mesh of the stent may be left open or it may be covered with a suitable material previously disclosed in this application.
[0131] FIG. 37 shows schematic views of a docking element. The docking element is composed of three primary components: A stent 194 , a sleeve material 193 and magnets 140 . The stent can be self expanding or balloon expandable. The sleeve can be any suitable material, as was previously disclosed in this application. The magnets may be attached to the sleeve by adhesive or mechanical fasteners such as rivets, screws, suture or mechanical interlocking
[0132] FIG. 38 shows schematic views of a docking element. The docking element is composed of four primary components: A stent 194 , a sleeve material 193 , radio-opaque markers 196 and pockets 195 . The stent can be self expanding or balloon expandable. The sleeve can be made from any suitable material, as was previously disclosed in this application. The pockets 195 are like small sleeves that are created in the sleeve material 194 . The pockets 195 may be made by sewing or by the use of a mechanical fastener. The pockets 195 form receptacles to hold magnets or other fasteners that will be delivered to the pocket, such that the docking element may be assembled in-situ. This design allows much larger magnetic or mechanical fastening elements to be incorporated into the docking element. A guide wire may be inserted into the pockets and the magnets or fasteners can be advanced over the guide wire into the pocket under endoscopic guidance. The sleeve may have holes 197 cut into it to allow some fluid transfer through the docking element if desired.
[0133] FIG. 39 is a drawing of a docking element. The docking element is composed of four primary components: A stent 194 , a sleeve material 193 , radio-opaque markers 196 and hooks 198 . The stent can be self expanding or balloon expandable. The sleeve can be made from any suitable material as was previously disclosed in this application. The hooks 198 are made from metal or plastic and are attached by adhesive, mechanical means or integrated into the sleeve material. The hooks serve as a docking feature for coupling with a corresponding feature on a tubular implant. The sleeve may have holes 197 in it to allow some fluid transfer through the docking element if desired.
[0134] FIGS. 40A-40C show expandable rings that can be attached to a sleeve to form a tubular implant 111 . The rings can be made of metal or plastic and can be self expanding or balloon expandable. In various embodiments, the rings are made of Nitinol. The expandable rings serve as coupling feature that operate to releasably couple the tubular implant 111 to a docking feature on the docking or anchoring element 110 .
[0135] FIG. 41 is a drawing of a tubular implant. The implant is composed of sleeve material 193 , expandable ring 199 , and a radiopaque marker 196 . The sleeve can be any suitable material as was previously disclosed in this application and the expandable ring can be of any suitable design as disclosed in FIGS. 40A-40C . Holes 197 can be cut into the sleeve to allow drainage through the sleeve. The expandable ring can be fastened to the sleeve by mechanical fasteners such as suture, wire, clips, or by adhesive or other suitable means. FIG. 42 is drawing of a tubular implant with expandable ring 199 and sleeve material 193 placed expanded and anchored to a docking or anchoring element(such as, for example, the anchoring element shown in FIG. 30 ). FIG. 43 is drawing of a tubular implant with expandable ring 199 and sleeve material 193 placed expanded and anchored to a docking element. The docking element is a modification to FIG. 30 . The docking element has the two layers of braid or material, but is it cylindrical without the hour glass shape of FIG. 30 . In both FIGS. 42 and 43 the coupling feature of the tubular implant is configured to releasably couple to the inner portion of the stent (i.e., the docking feature) of the docking or anchoring element.
[0136] FIG. 44 shows a docking element composed of three primary components: A stent 194 , a sleeve material 193 and hook and loop fastener (velcro) 200 or 201 . The stent can be self expanding or balloon expandable. The hook and loop fastener may be sewn or glued onto the sleeve material. The tubular implant that fastens to the docking element of this construction must have the hook fastener if the docking station has the loop fastener or vice-versa.
[0137] FIG. 45A is a drawing of a tubular implant. The tubular implant is designed to attach to another tubular implant or to a docking station by a magnetic attachment means. The tubular implant has magnets 140 embedded in the wall. Alternatively, the magnets could be located on either or both of the inner and outer walls. The magnets provide for an end-to-end connection method between components. FIG. 45B shows a tubular implant with a complementary end or female component to match with the male component of FIG. 45A .
[0138] FIGS. 46A shows a basic sleeve that is to be used as a component of a docking station, tubular implant, or for extending a tubular implant. The sleeve has radio-opaque markers 196 and may have holes in the sleeve 197 to allow some fluid flow thru the sleeve if required. FIG. 46B shows a basic sleeve that is to be used as a component of a docking station, tubular implant, or for extending a tubular implant. The sleeve has magnetic particles or ferromagnetic material 140 incorporated into the sleeve to allow attachment of the sleeve to a magnetic docking station or tubular implant.
[0139] FIG. 47A shows a basic sleeve that is to be used as a component of a docking station, tubular implant, or for extending a tubular implant. The sleeve has magnetic particles or ferromagnetic material 140 incorporated into the sleeve to allow attachment of the sleeve to a magnetic docking station or tubular implant. The sleeve also has longitudinal pleats 202 in the surface to allow it to collapse in diameter more uniformly and may help to reduce the loaded profile. The longitudinal pleats may be over the entire length or only a portion of the diameter or length. FIG. 47B shows a basic sleeve that is to be used as a component of a docking station, tubular implant, or for extending a tubular implant. The sleeve also has pleats around the circumference 203 . The circumferential pleats will allow the tubular implant or sleeve to bend easier without kinking.
[0140] FIG. 48A shows a tubular implant designed to attach to another tubular implant or to a docking station by a magnetic attachment means. The tubular implant has magnets 140 on the outside diameter. FIG. 48B shows a tubular implant designed to attach to another tubular implant or to a docking station by a magnetic attachment means. The tubular implant has magnets 140 in the wall thickness.
[0141] FIG. 49 shows a tubular implant that is constructed with a sleeve 193 material, and set of barbed hooks 204 . Hook 204 has 2 barbs per hook, hook 205 has one barb per hook, hook 206 has no barbs, hook 207 and 208 have different bend angles. The modular implant can attach to a docking element or directly to the anatomy or to another sleeve.
[0142] FIG. 50A shows a basic sleeve with pockets 195 . The basic sleeve may be used as part of a docking station or tubular implant. FIG. 50B shows a basic sleeve with hooks 198 . The sleeve may be used as part of a docking station or tubular implant. FIG. 51A is a basic sleeve with a conical diameter. The sleeve may be used as part of a docking station or tubular implant. FIG. 51B is a basic sleeve with a stepped diameter. The simple sleeve may be used as part of a docking station or tubular implant. FIG. 52 is a basic sleeve with hook and loop fastener (Velcro) on the outside diameter. The sleeve may be used as part of a docking station or tubular implant.
[0143] FIG. 53A is a balloon catheter for delivery of stents for docking elements or stented sleeves. The catheter is an over the wire design. FIG. 53B is a balloon catheter for delivery of stents for docking elements or stented sleeves. The catheter is of rapid exchange design.
[0144] FIG. 54 shows an enlarged view of the gastro-intestinal anatomy of the junction between the stomach and the duodenum, including the pyloric antrum 104 , the pylorus 106 , and the duodenal bulb 107 . A soft, braided docking or anchoring element 209 is placed at the pyloric junction (i.e., extending across the pylorus). As shown in FIG. 54 , the docking element is a variant of the element shown in FIG. 42 using a single braid. As shown, the docking element 209 is shaped such that it does not exert radial forces on the stomach wall or the duodenal wall for anchoring. It is retained within the pyloric junction due to its shape, which has an outer diameter larger than the maximum outer diameter of the pyloric orifice. As shown in FIG. 54 , the docking element 209 includes a proximal portion (i.e., the portion located in the pyloric antrum 106 ), a distal portion (i.e., the portion located in the duodenal bulb 107 , and a neck portion adapted to extend through the pylorus 106 . According to various embodiments, the proximal and distal portion are shaped such that each has an unconstrained diameter of between about 15 and about 25 millimeters, and the neck portion has an unconstrained diameter of between about 5 and about 15 millimeters. In some embodiments, the ratio of the diameter of the proximal portion to the diameter of the neck portion is between about 1.2 and about 5. According to various embodiments, the neck portion is formed with an unconstrained diameter smaller than a maximum diameter of the native pylorus, such that the neck portion operates to restrict flow from the stomach into the duodenum (i.e., to function as a restrictive stoma). In other embodiments, the neck portion is formed with an unconstrained diameter larger than a maximum diameter of the native pylorus, such that the neck portion does not restrict flow from the stomach into the duodenum (i.e., through the pylorus).
[0145] FIG. 55 shows another docking or anchoring element 210 having an alternate shape. In this instance, the proximal portion of the anchoring element 210 (i.e., the portion located on the pyloric antrum side) is more disk-like and serve as a pronounced anchoring/retaining flange for the device. In some embodiments, the anchoring element 210 has a maximum or unconstrained diameter slightly larger than an internal diameter of the pyloric antrum, such that the docking element 210 exerts a slight radial force on the wall of the pyloric antrum. In other embodiments, the unconstrained shape is such that the anchoring element 210 does not exert a radial force on the wall of the pyloric antrum. To minimize or prevent abrasive injury to tissue and tissue in-growth, and to provide for ease of replacement exemplary embodiments of the docking elements 209 and 210 could be covered with flexible woven fabric or nonwoven, extruded polymeric material used in synthetic medical grafts such as polyurethane, silicone, ePTFE, etc. FIGS. 56 and 57 show exemplary covered embodiments where the docking element includes a covering 211 .
[0146] According to various embodiments, one or both of the proximal portion and the distal portion of the anchoring element are sized or shaped such that at least a portion of the anchoring element has an unconstrained diameter larger than the diameter of the corresponding anatomical organ (e.g., the pyloric antrum or the duodenal bulb), such that when implanted the anchoring element exerts a radial force upon the wall of the organ.
[0147] FIG. 58 shows a different design of the docking element, where the docking element 213 now consists of separate proximal (i.e., stomach side) and distal (i.e., duodenal side) metallic braided elements connected by a flexible sleeve (tubular) element 212 . The flexible element 212 could be constructed of materials such as silicone, polyurethane, ePTFE, etc., which are resistant to stomach acid, enzymes and intestinal juices. The flexible element 212 is provides minimal interference to the opening and closing of the pyloric valve. FIG. 58 depicts the sleeve element in a somewhat compressed state (hence the drawing showing wrinkles to the sleeve 212 . FIG. 59 depicts the same docking element 213 where the pylorus 106 is now fully open and the sleeve element 212 is an expanded state. FIG. 60 depicts another docking element 214 where the flexible sleeve element 212 is attached to other docking structures such as the docking element 210 shown in FIG. 55 . According to various embodiments, the flexible element 212 has an outer diameter substantially similar to the maximum diameter of the native pylorus. The flexible element 212 , for example, may have a diameter of between about 5 and about 15 millimeters. According to other embodiments, the diameter of the flexible element 212 is set somewhat smaller than the maximum diameter of the pylorus, such that the flexible element 212 acts to restrict flow from the stomach into the duodenum. According to various embodiments, the neck portion is attached to the proximal and distal stent portions by a sewing technique.
[0148] FIG. 61 depicts a tubular implant 215 , which is a variant of the tubular implant of FIG. 41 . Here, the flexible sleeve portion is more stepped in shape, such as is shown in the tubular implant in FIG. 51B . The stepped portion of the tubular implant can serve the purpose of acting like a restrictive element for food passage, depending on the choice of dimensions of the inlet and outlet. The tubular element also has ring-like anchoring or coupling features 199 attached to its proximal end similar to the tubular element of FIG. 41 .
[0149] FIG. 62 depicts the ring like anchoring elements 199 of the tubular implant 215 of FIG. 61 constrained in a delivery catheter 216 as it is being withdrawn close to the docking element. FIG. 63 depicts the docking element and the tubular implant 215 mated together upon release from the delivery catheter. By withdrawing the delivery catheter while the tubular element is anchored in place, the ring like anchoring elements are released from the delivery catheter and expand to their unconstrained set shape and diameter. Upon such expansion, the fingers or protrusions of the coupling feature 199 engage the distal portion of the docking element. In these embodiments, the distal portion of the docking element is sized and shaped such that the protrusion of the coupling feature may extend through the openings (i.e., docking features) in the proximal portion, such that the coupling feature 199 of the tubular implant engages the docking or anchoring element. In addition to providing an anchoring function by resisting forces directed toward the pylorus or stomach, the distal portion of the docking element 209 further provides some amount of structural support to the tubular implant 215 , which help resist kinking, binding or twisting of the tubular implant.
[0150] FIG. 64 shows the tubular implant 215 attached to the docking element 213 using the same steps as outlined in FIGS. 62 and 63 . FIG. 65 shows a variant of the same concept where the tubular element 215 is now attached to the stomach side of the docking element 213 . Here, the delivery catheter will have to withdrawn through the pylorus before activating the release of the ring element.
[0151] While each of FIGS. 63-65 show a modular system in which a tubular implant is removably or releasably coupled with a docking or anchoring element, according to other embodiments, the tubular implant is structurally integrated with the docking or anchoring element (e.g., such as is shown in FIGS. 19-20 ). The tubular implant and docking element may be integrated using a variety of techniques, including for example adhesive bonding, mechanical fastening, sewing, and overmolding. Likewise, according to some embodiments, portions of the system are modular while other portions are integrally formed. For example, according to exemplary embodiments, the anchoring element and tubular implant located within the duodenum are integrally formed and the docking element and tubular implant located at the gastro-esophageal junction and within the stomach are modular.
[0152] FIGS. 66-78 show schematic views of various stages of an implantation method according to embodiments of the invention. FIG. 66 shows the initial stage of a minimally invasive method of implanting any of the various embodiments disclosed herein. As shown, the physician has advanced (e.g., endoscopically) a delivery system 300 to the pyloric antrum 104 . The delivery system 300 , according to some embodiments, includes an endoscope for visualization and a dual catheter system for securing the prostheses in a collapsed configuration. According to some embodiments, the delivery system 300 includes each of the components shown in and described with reference to FIG. 8 .
[0153] As shown in FIG. 67 , the physician has successfully guided the delivery system 300 through the pylorus 106 , such that a tip of the delivery system is located within the duodenal bulb 107 . Next, as shown in FIG. 68 , the physician has actuated the delivery system 300 (e.g, by retracting an outer sheath or catheter), so as to release a distal portion of the docking or anchoring element 110 in the duodenal bulb. As shown, the physician advances the delivery system 300 a sufficient distance to allow the distal portion to fully expand within the duodenal bulb 107 and a neck portion of the anchoring element 110 to expand within the opening of the pylorus 106 . Then, as shown in FIG. 69 , the delivery system 300 is further actuated to effect release of a proximal portion of the anchoring element 110 with the pyloric antrum 104 . As shown, at this stage, the anchoring element 110 is fully disengaged from the delivery system. As shown in FIG. 70 , the anchoring element is implanted across the pylorus 106 , such that the proximal portion of the anchoring element engages the proximal surface of the pylorus and the distal portion engages the distal surface of the pylorus.
[0154] Next, as shown in FIG. 71 , the delivery system 300 , which holds the tubular or therapy element 111 in a collapsed configuration, is advanced across the pylorus 106 into the duodenal bulb 107 . The delivery system 300 , as shown in FIG. 72 , is then advanced further down the duodenum (and, as desired, the jejunum), until the tip reaches the desired distal most implant location. Then, as shown in FIG. 73 , the physician actuates the delivery system 300 (e.g., by retracting an outer catheter), to release a distal portion of the therapy element 111 with the duodenum (or jejunum). Next, as shown in FIGS. 74-76 , the delivery system is further retracted such that the therapy element 111 is further released from the delivery system 300 . As shown in FIGS. 77-78 , the therapy element 111 is fully released from the delivery system 300 and has engaged the docking element 110 .
[0155] Various modifications and additions can be made to the exemplary embodiments discussed without departing from the scope of the present invention. For example, while the embodiments described above refer to particular features, the scope of this invention also includes embodiments having different combinations of features and embodiments that do not include all of the described features. Accordingly, the scope of the present invention is intended to embrace all such alternatives, modifications, and variations as fall within the scope of the claims, together with all equivalents thereof.
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A system for therapy within a gastrointestinal system includes anchoring or attachment functionality embodied in a low-profile implant technology and removable therapy components, which can be reversibly attached to these low-profile implants to accomplish various therapies. This design allows the physician to tailor the therapy to the patient's needs. The system has the potential to create conduits for diversion and/or restriction of food and organ secretions and to facilitate the treatment of metabolic disorders such as obesity and T2DM.
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BRIEF SUMMARY OF THE INVENTION
The invention relates to compounds of the formula: ##STR2## wherein a is a single bond and b is a double bond; or a is a double bond and b is a single bond; and enantiomers thereof; or a pharmaceutically acceptable salt thereof.
The compounds of the invention can be written as individual structures as follows: ##STR3##
More specifically, the compounds of the invention can be written as: ##STR4##
wherein a is a single bond, b is a double bond and c is a single bond that is in the plane of the page; or a is a double bond, b is a single bond and c is a single bond that is above the plane of the page; or a pharmaceutically acceptable salt thereof.
The compounds of the invention can be written as individual structures as follows: ##STR5## and have been given the trivial names wiedendioI-A (A) and wiedendioI-B (B).
In the structures shown just above, more of the stereochemistry of the chemical bonds are shown than in the flat formulas given ealier in the specification. In the structures shown just above, only the relative streochemistry for the compounds is known. The absolute stereochemistry for these compounds is not known. This point regarding relative and absolute stereochemistry is described in more detail below.
Atherosclerotic coronary artery disease (CAD) is the major cause of mortality in the United States and in the Western countries. One of the major reasons for developing CAD can be related to anabnormal lipoprotein profile. High serum cholesterol levels or high low density lipoprotein (LDL) cholesterol levels are a major risk factor for the disease. Recently, high density lipoprotein (HDL) cholesterol level have been found to be inversely correlated with CAD. HDL has also been to be found more strongly correlated with CAD than LDL. Finally, HDL has also been independently correlated with CAD, that is, whether or not you have high LDL. CasteIll, W. P. et al (1986) JAMA 256, P2835-2838 and Gordon, D. J. et al (89) Circulation 79, P 8-15.
Several factors have been identified as modifying factors of LDL and HDL. Among them, cholesteryl ester transfer protein (CETP) also known as LTP-I, is one that directly modifies the lipoproteins, especially HDL. CETP is a plasma glycoprotein with molecular weight about 70,000 dalton and it transfers cholesteryl ester from HDL to triglyceride rich lipoproteins such as LDL Glomset, J. A.,(1968) J. Lipid Res. 9, 155-167 and Morton, R. E., and Zilversmit, D. B. (1979) J. Lipid Res. 23, 1058-1967.
In families with CETP deficiency, HDL levels were inversely correlated with the plasma CETP concentration and LDL levels were reduced, and the family members are generally long lived Inazu, A., et al. (1990) N. Eng. J. of Med 323, p1234-1238 and Brown, M. L., et al. (1989) and Nature 342, p448-451. On the other hand, mice that were genetically manipulated to possess human CETP in the plasma showed decreased HDL cholesterol level Agelion, L., et al. (1991) J. Biol. Chem. 266, p10796-10801. Studies also showed that inhibition of CETP activity in animals with inhibitory antibody greatly increased HDL levels Whitlock, M. E., et al. (1989) J. Clin. Invest. 84, p129-137. The lipid transfer activity associated with LTP-I was also found to support sperm capacitation Ravnik, S. E., et al. (1993) Fertility and Sterility 59. p629-638. Results of these studies and others suggest that inhibition of plasma CETP activity can improve lipoprotein profile of dyslipidemic patients and generate an anti-atherogenic lipoprotein profile of normolipidemic individuals. In addition, inhibition of CETP activity may be useful as anti-fertility agents for males and females.
These compounds (A and B) are active in the cholesteryl ester transfer protein (CETP) assay described below, and therefore can improve the lipoprotein profile of dyslipidemic patients and generate an atherogenic lipoprotein profile of normolipidemic. In addition, inhibition of CETP activity may be useful as anti-fertility agents.
The invention also relates to compositions which comprise a compound of formula I, that is, A or B, and a pharmaceutically active carrier material.
The invention also relates to a method for treating a mammal afflicted with dyslipidemia which comprises administering an effective amount of a compound of formula A or B. The invention also relates to a method for reducing the fertility of a mammal which comprises administering an anti-fertility effective amount of a compound of formula A or B as an anti-fertility agent
The invention also comprises a method for preparing a compound of formula A or B, by extraction from the marine sponge Xestospongia cf. wiedenmayeri.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, a boldfaced line denotes a bond that is above the plane of the page. A dashed line denotes a bond that is below the plane of thepage. A straight line denotes a bond that is either within the plane of thepage, or whose stereochemistry is not specified. A wavy line denotes a bond whose stereochemistry is not specified.
The following is a description of the preparation of compounds of formula Aand B.
DESCRIPTION OF THE MARINE SPONGE
The compounds of the invention were extracted from a marine sponge which has the taxonomic identification Xestospongia cf. wiedenmayeri van Soest, 1980 (Phylum Porifera, Class Demospongiae, Order Haplosclerida, Family Petrosiidae). The sponge was collected by the Harbor Branch Oceanographic Institution, Inc of Fort Pierce, Fla. and given the sample number HRB 934 (HBOI/DMBR 2-VII-87-5-002). The sponge was collected by scuba diving at a depth of 37 meters from the fore reef escarpment off northwest Crooked Insland, Bahamas (latitude 22° 49.30'N, longitude 74°21.50'W). It was common in occurrence. The sponge was thickly encrusting to massive in morphology. The color in lefe was pinkish-tan externally, tan internally; in ethanol. it is reddish brown. The sponge isbrittle, fragile, and crumbly in life. After collection, a subsample of thesponge was preserved in ethanol as a taxonomic voucher; the remainder of the sponge was stored frozen at -20° C. The voucher specimen is currently deposited at Harbor Branch Oceanographic Museum, catalog number 003:00073. It is preserved in 70% ethanol with an expected shelf life of at least 30 years and is accessible to those skilled in the art for taxonomic identification purposes.
The description of Xestosoongia cf. wiedenmaveri can be found in van Soest,R. W. M. 1980. Marine sponges from Curacao and other Caribbean localities. Part II. Haplosclerida. Studies on the Fauna of Curacao and Other Caribbean Islands, 62(191): 1-173. The sample described in the paragraph above, differs from the published description of X. cf. wiedenmayeri in the possession of two categories of strongyles, with occasional tylote modifications, instead of the thick, oxeote spicules reported for X. cf. wiedenmayeri. Another difference is in the occurrence of this sponge in a deep reef environment; the specimen described in van Soest was reported tobe taken from mangrove roots and muddy environments.
The extraction process is set forth below and in FIG. 1.
Isolation of CETP inhibitors from HRB-934
A portion of the frozen sponge (26 g) was lyophilized to give 7.2 g of freeze-dried sponge. The dry sponge was ground to a powder and extracted with petroleum ether for 24 hours using a soxhlet extractor. The extract was evaporated to dryness under vacuum using a rotary evaporator to yield 492 mg of residue. Column chromatography of 471 mg of the residue on silica gel employing gradient elution from heptane to 4:1 chloroform/heptane gave three CETP-active fractions. Analysis of the fractions by thin layer chromatography revealed that the first CETP-activefraction contained impure A, and the second CETP-active fraction contained pure A. Rechromatography of the first fraction employing identical conditions resulted in resolution of A, which when added to the pure A obtained from the first silica column, yielded a total of 25 mg of A. The third CETP-active fraction from the first silica column was subjected to further chromatography using silica gel and a step gradient beginning with1:1 chloroform/heptane and continuing to 100% chloroform, and finally 1:9 methanol/chloroform.
This gave one CETP-active fraction which was found to be pure B (25 mg). ##STR6##
Compounds A and B have the physico-chemical characteristics set forth in tables 1,2 and 3 below.
TABLE 1______________________________________Physico-chemical properties of Compounds A and BSpectral Method Compound A Compound B______________________________________UV (heptane) 201 (17700), 199 (41400), 288λ.sub.max (e) 288 (640) (16100), 325 (9400)IR (film) cm.sup.-1 3498 br, 3340, 2945, 3500 br, 2934, 1596, 1615, 1492, 1288, 1498, 1466, 1377, 1385, 1258, 1181, 1316, 1258, 1208, 1085, 789, 728 1155, 758[α]D.sup.21.5 +121.0° -40.5°(chloroform)High resolution calculated: 345.2430 calculated: 345.2430peak matching by observed: 345.2410 observed: 345.2413FAB MS for the(M + H).sup.+ peak:Major chemical 345 (39), 344 (15), 345 (38), 344 (58),ionization mass 191 (38), 153 (100) 191 (53), 153 (100)spectral peaks:m/z (relativeabundance)______________________________________
TABLE 2______________________________________.sup.1 HNMR Chemical Shift Assignments* Compound A Compound BH-# δ(ppm) J(Hz) δ(ppm) J(Hz)______________________________________ 7 2.16 2H dd 8.9, 4.3 811 0.86 3H s 0.91 3H s12 1.03 3H s 0.91 3H s13 0.86 3H s 1.25 3H s14 1.72 3H s 1.03 3H d 7.615a 3.46 2H ABq 17.2 5.78 1H s15b 3.46 2H ABq 17.2 -- 4' 6.69 1H d 8.8 6.76 1H d 8.8 5' 6.30 1H d 8.8 6.36 1H d 8.8OMe 3.77 3H s 3.70 3H sOH 7.48 1H s 5.13 1H sOH 5.14 1H br s 4.97 1H s______________________________________*Assignments based on HETCOR and SINEPT Correlations. As used herein, SINEPT means Selective Insensitive Nuclei Enhanced Through Polarization Transfer; and HETCOR means Heteronuclear correlation.
TABLE 3______________________________________.sup.13 CNMR Chemical Shift Assignments*C# δCompd A δCompd B______________________________________1 35.9 t 38.8 t2 18.8 t 18.8 t3 41.6 t 42.0 t4 33.5 s 34.0 s5 51.7 d 55.1 d6 18.8 t 17.8 t7 33.6 t 34.2 t8 133.1 s 32.0 d9 143.7 s 164.3 s10 39.6 s 41.3 s11 33.3 q 33.4 q12 21.8 q 22.8 q13 20.0 q 21.9 q14 20.6 q 21.8 q15 24.8 t 112.6 d 1' 113.6 s 114.8 s 2' 140.3 s 139.7 s 3' 139.1 s 137.8 s 4' 110.8 d 109.7 d 5' 101.5 d 102.7 d 6' 150.7 s 151.0 sOMe 55.9 q 56.0 q______________________________________*Assignments based on HETCOR and SINEPT data, and comparison of these data to those reported in J. Org. Chem. 1986, 51, 4568-4573.
Based on the foregoing data, the structures shown below were assigned to the compounds A and B. ##STR7##
It is pointed out that the absolute stereochemistry for the above two compounds has not been determined, only the relative stereochemistry. Thus, for example, compound A may have the structure shown just above, or it may have the structure ##STR8##
Either one or the other of the above enantiomers of A is extracted from X. cf. wiedenmayeri but not both.
Similarly, compound B may have the structure shown above, or it may have the structure ##STR9##
Either one or the other of the above enantiomers of B is extracted from X. cf. wiedenmayeri, but not both.
The compounds of the invention may form pharmaceutically acceptable salts with organic and inorganic bases. Suitable organic bases include primary, secondary and tertiary alkyl amines, alkanolamines, aromatic amines, alkylaromatic amines and cyclic amines. Exemplary organic amines include the pharmaceutically acceptable bases selected from chloroprocaine, procaine, piperazine, glucamine, N-methylglucamine, N,N-dimethyl glucamine, ethylenediamine, diethanolamine, diisopropylamine, diethylamine, N-benzyl-2-phenylethylamine, N,N' dibenzyl-ethylenediamine, choline, clemizole, tris(hydroxymethyl) aminomethane, or D-glucosamine. The suitable inorganic bases include alkali metal hydroxides such as sodium hydroxide.
The following assay method was used to illustrate the biological activitiesof the compounds of the invention.
CETP ASSAY PROCEDURE
This assay used a commercially available CETP Scintillation Proximity Assaykit (Amersham TRKQ7015). In this assay, the transfer of [ 3 H]cholesteryl esters from high density lipoprotein (HDL) to biotinylated low density lipoproteins (LDL) was measured following incubation of donor and acceptor particles in the presence of recombinant CETP (rCETP; see Wang S. et al J. Biol. Chem. (1992) 267:1746-17490 which is herein incorporated by reference). Following incubation, the reaction was terminated and transfer was measured in a single step addition of streptavidin SPA beads, formulated in an assay terminal buffer (Amersham).The rate of increase in signal was proportional to the transfer of [ 3 H]cholesteryl ester by CETP.
To 96-well microtiter plates (DYNATECH Microlite) was pipetted 5 μl of sample (or buffer for blank) of appropriate dilution. For example, 5 μlof 20 μM compound A (IC 50 for A=2 μM) gave approximately 50% inhibition of transfer activity. The IC 50 for compound B=2.9 μM. As a control, 5 μl of CETP monoclonal antibody TP-1, 1:10 dilution fromascites was added. The reaction was started by adding 45 μl of the following mixtures to each well.
20 μl of assay buffer (from kit)
10 μl 3 H]Cholesteryl ester-HDL (from kit)
10 μl of biotinylated LDL (from kit)
5 μl of rCETP
The contents of the plate were mixed briefly by tapping the plate gently and then the plate was sealed with parafiim to prevent evaporation during the incubation. The plates were incubated at 37° C. for 4 hours. After incubation the reaction was stopped by adding 200 μl of streptavidin beads to each well. The beads were shaken gently before addition. The mixture was incubated at room temperature for 30 minutes to allow the assay to come to equilibrium with beads. Dpm were counted on a TopCount (Packard Instrument Company, Downers Grove, Ill.) (A conventionalscintillation counter with window settings fully open may also be used).
Based upon the foregoing biological data, it can be concluded that the compounds of the invention are useful as agents in the treatment of dyslipidemia. It can be concluded that the compounds of the invention are useful as anti-fertility agents for mammals.
In accordance with the invention, pharmaceutical compositions comprise, as the active ingredient, an effective amount of a compound of the formula A or B, and one or more non-toxic, pharmaceutically acceptable carriers or diluents. Examples of such carriers for use in the invention include ethanol, dimethylsulfoxide, glycerol, silica, alumina, starch equivalent carriers and diluents.
While effective amounts may vary as conditions in which such compositions are used may vary, a minimal dosage required for therapeutic activity is generally between about 1 and about 1000 milligrams, 1 to 4 times daily.
The compounds may be administered as a tablet, a capsule, solution, suspension or an aerosol. It may be administered orally, subcutaneously, intravenously, topically or by inhalation.
Therapeutic applications can be contemplated to be accomplished by any suitable therapeutic method and technique presently, or prospectively known to those skilled in the art.
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Compounds of the formula: ##STR1## wherein a is a single bond and b is a double bond; or a is a double bond and b is a single bond; and enantiomers thereof; or a pharmaceutically acceptable salt thereof are described. These compounds can improve lipoprotein profile of dyslipidemic patients and generate an anti-atherogenic lipoprotein profile of normolipidemic individuals. In addition, inhibition of CETP activity may be useful as antifertility agents.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] Not applicable.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not applicable.
FIELD OF THE INVENTION
[0003] The invention relates generally to movable step assemblies for recreational vehicles and in particular to an apparatus for extending and retracting a movable step assembly.
BACKGROUND OF THE INVENTION
[0004] Automatic step systems for recreational vehicles, motor homes, and the like are well known in the art. These systems are typically electrically-controlled and electrically-actuated to extend and retract an entryway step in response to a signal provided by an individual wishing to enter or exit the vehicle. One common system extends the step when the vehicle door is opened, and then retracts the step when the vehicle door is closed. Other systems offer a switch located just inside the vehicle door which controls the extension and retraction of the step. These systems also include a master power switch which can be used to lock the step in a given position.
[0005] Alternative systems incorporate a motor assembly for automatically-extending and retracting the step assembly. The motor rotates a pivot rod through a gear assembly which is coupled to the rod. The pivot rod moves a linkage assembly to extend and retract the steps. However, these systems can give the step a “spongy” or unstable feel. In addition, a load applied to the step tends to move the step towards the retracted position. Therefore, an improved mechanism for extending and retracting collapsible steps in recreational vehicles is needed.
SUMMARY OF THE INVENTION
[0006] The present invention provides an improved collapsible step assembly for recreational vehicles. In one aspect, the invention provides a movable step apparatus including a mounting frame, at least one step mounted to the frame through a linkage assembly with at least two non-parallel links and a pivot member having a longitudinal axis of rotation. A gravitational load on the step urges at least one of the links of the linkage assembly in the direction of rotation of the link toward extension of the step to press against a stop of the frame to react against the load.
[0007] In one aspect, the invention provides a movable step apparatus including a mounting frame, a motor mounted to the frame, at least one step mounted to the frame, a pivot member mounted to the frame, a linkage assembly, and a transmission assembly. The at least one step is mounted to the frame through the linkage assembly.
[0008] In use, the pivot member is rotatably mounted to the frame. The transmission assembly rotates the pivot member, the linkage assembly, and the at least one step between an extended position and a retracted position. Rotating the pivot member in a first direction moves the step to the extended position, and rotating the pivot member in an opposite direction moves the step to the retracted position.
[0009] Opposing ends of the pivot member are attached to the linkage assembly. The linkage assembly comprises a plurality of links pivotally connecting the frame to the at least one step. The linkage assembly also includes a link that is movable to contact a stop. When the at least one step is in the extended position, the link contacts the stop, and the stop reacts against the load applied to the at least one step.
[0010] The foregoing and other objects and advantages of the invention will appear in the detailed description which follows. In the description, reference is made to the accompanying drawings which illustrate a preferred embodiment of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 is a side plan view of a step assembly of the invention in an extended position;
[0012] FIG. 2 is a front, top perspective view of the step assembly in the extended position;
[0013] FIG. 3 is a rear, bottom perspective view of the step assembly in the extended position;
[0014] FIG. 4 is a side plan view of the step assembly in a retracted position;
[0015] FIG. 5 is a detail view of the drive portion of the step assembly in the extended position circumscribed by line 5 - 5 in FIG. 3 ;
[0016] FIG. 6 is a detail view of the drive portion of the step assembly of FIG. 5 but in the retracted position;
[0017] FIG. 7 is a detail cross sectional view of the step assembly in the extended position along line 7 - 7 in FIG. 3 ; and
[0018] FIG. 8 is a detail cross sectional view of the step assembly of FIG. 7 in the retracted position.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0019] The invention comprises a collapsible step assembly 10 for use with recreational vehicles. Referring to FIGS. 1-4 , the assembly 10 comprises a generally rectangular and planar upper step 12 , a lower step 14 , and a frame 16 . The steps 12 and 14 move between an extended position ( FIGS. 1 , 2 and 3 ) and a retracted position ( FIG. 4 ).
[0020] Each step 12 and 14 may be covered with a non-skid material (not shown) to increase the friction of their respective surfaces. The lengths of the steps 12 and 14 are approximately one-half of their respective widths.
[0021] Each step 12 and 14 also has arms 18 A and 18 B, respectively, which extend in a rearward direction from their outer edges. Arms 18 A and 18 B are symmetrically arrayed along each side of the assembly 10 . For simplicity, these components are only numbered on a single side of the assembly 10 in FIGS. 2 and 3 . Arms 18 A and 18 B are approximately equal in length to the steps 12 and 14 and may be reinforced by pieces of angle bar stock welded to them as illustrated on arm 18 A.
[0022] The frame 16 is generally box-like in shape and has open front, rear and bottom sides. The frame 16 includes a top bracket 17 and side brackets 21 . Each side bracket 21 includes a stop 19 , which is a pin that is welded, screwed or secured with a nut or other suitable fastener to the side bracket 21 . The purpose of stops 19 is explained below. The plane of the top bracket 17 is generally horizontal when the assembly 10 is properly installed on a recreational vehicle on level ground. The steps 12 and 14 are located below the frame 16 in the retracted position as shown in FIG. 4 . The frame 16 may also include a mounting assembly for attachment to a vehicle (not shown), or may be bolted, welded, or otherwise fixed to the vehicle.
[0023] As seen in FIG. 1 , when the assembly 10 is in the extended position, the steps 12 and 14 are generally parallel relative to each other and the top bracket 17 . As seen in FIG. 4 , when the assembly 10 is in the retracted position, the steps 12 and 14 are skewed rearward and downward at approximately 10 degrees and 15 degrees, respectively, relative to the top bracket 17 .
[0024] The steps 12 and 14 and the frame 16 are interconnected by a linkage assembly including three types of pivotable links; rearward links 20 , medial links 22 , and forward links 24 . The links 20 , 22 , and 24 comprise straight, flat metal strips having two opposing lower and upper ends symmetrically arrayed along each side of the assembly 10 . For simplicity, these components are only numbered on a single side of the assembly 10 in FIGS. 2 and 3 . The links 20 , 22 , and 24 pivot around each point of attachment between the extended and retracted positions. Rectangular support bracket 64 is secured to the medial links 22 to reinforce the assembly 10 during use. The forward links 24 may also include a support bracket to reinforce the assembly during use.
[0025] The rearward links 20 connect the upper step 12 to the frame 16 . As most easily seen in FIG. 1 , the upper ends of each rearward link 20 are pivotally mounted near the lower rearward corners of the side brackets 21 . The lower ends of each rearward link 20 are pivotally mounted near the rearward ends of the upper step arms 18 A. Each rearward link 20 also includes a tab 23 as most easily seen in FIG. 3 . The purpose of the tab 23 is explained below.
[0026] As seen in FIG. 1 , when the assembly 10 is in the extended position, the rearward links 20 are skewed downward and forward at approximately 15 degrees relative to the top bracket 17 . As seen in FIG. 4 , when the assembly 10 is in the retracted position, the rearward links 20 are skewed rearward and downward at approximately 35 degrees relative to the top bracket 17 .
[0027] The medial links 22 have a dogleg shape and pivotally connect the lower step 14 to the frame 16 and have approximate midpoints pivotally connected to the upper step 12 near the point where the step 12 meets the upper step arm 18 A. Each medial link 22 is approximately three times as long as and slightly wider than the rearward links 20 . The upper ends of the medial links 22 are pivotally mounted to the upper forward corners of the side brackets 21 . The lower ends of the medial links 22 are pivotally mounted near the ends of the lower step arms 18 B. The pivot rod 26 connects to the upper ends of the medial links 22 at opposing ends of the rod 26 .
[0028] As seen in FIG. 1 , when the assembly 10 is in the extended position, the medial links 22 are skewed forward and downward at approximately 70 degrees relative to the top bracket 17 and approximately straight down from step 12 . As seen in FIG. 4 , when the assembly 10 is in the retracted position, the medial links 22 are skewed rearward and downward at approximately 35 degrees relative to the top bracket 17 .
[0029] The forward links 24 connect the lower step 14 to the upper step 12 . The forward links 24 are approximately twice as long as the rearward links 20 and approximately half the length of the medial links 22 . The upper ends of the forward links 24 are pivotally mounted near the forward corners of the upper step 12 . The lower ends of the forward links 24 are pivotally mounted to the lower step 14 near the point where the lower step arm 18 B extends from the lower step 14 .
[0030] As seen in FIG. 1 , when the assembly 10 is in the extended position, the forward links 24 are skewed downward and slightly forward at approximately 85 degrees relative to the top bracket 17 . As seen in FIG. 4 , when the assembly 10 is in the retracted position, the forward links 24 are skewed rearward and downward at approximately 25 degrees relative to the top bracket 17 .
[0031] Referring to FIG. 3 , the assembly 10 also includes a pivot rod 26 extending transversely through the frame 16 . The longitudinal axis of the pivot rod 26 is generally perpendicular to the surface of the side brackets 21 . The pivot rod 26 connects to the upper ends of the medial links 22 at opposing ends of the rod 26 . As seen in FIGS. 5-8 , the pivot rod 26 also includes a short finger assembly 36 rigidly mounted to the rod 26 . The finger assembly 36 extends radially away from the longitudinal axis of the rod 26 . A link arm 38 with a fixed length is connected to the finger assembly 36 with a universal joint 40 . The universal joint 40 allows the finger assembly 36 and link arm 38 to pivot about generally vertical (about pivot 41 ) and horizontal (about the axis of the pin 35 extending through the two arms 36 ) axes relative to the fingers 36 .
[0032] The link arm 38 is swivelly-mounted to a horizontal drive gear 42 by a ball joint 39 at the end of crank arm 44 which is fixed to gear 42 . The gear 42 has teeth (not shown) which extend circumferentially along an arcuate edge portion of the gear 42 . The gear 42 is centrally and pivotally mounted with a second pivot pin 48 to a motor mounting plate 50 . The motor mounting plate 50 is mounted to the frame 16 . The gear teeth (not shown) engage a second drive gear (not shown) within housing 52 which extends from a lower side of a motor 54 . The motor 54 is also mounted to the motor mounting plate 50 .
[0033] As shown in FIGS. 5 and 7 , when the assembly 10 is in the extended position, the finger assembly 36 extends forward and downward relative to the pivot rod 26 , and the link arm 38 is horizontally rotated to a position below the pivot rod 26 . As shown in FIGS. 6 and 8 , when the assembly is in the retracted position, the finger assembly 36 extends rearward and downward relative to the rod 26 , and the link arm 38 is rotated to a position below the drive gear 42 .
[0034] The motor 54 rotates the segment gear 42 approximately 90 degrees between the extended and retracted positions. The particular drive for driving the gear within housing 52 that meshes with segment gear 42 may be a worm gear drive, although any suitable drive could be used to rotate rod 26 .
[0035] In use, the frame 16 of the assembly 10 is mounted to the underside of a vehicle adjacent to the doorway (not shown). Prior to use, the assembly 10 is in the retracted position so that the upper and lower steps 12 and 14 are recessed beneath the frame 16 , as shown in FIG. 4 . When the assembly 10 is actuated to move to the extended position, the motor 54 and associated drive train rotates the gear 42 clockwise approximately 90 degrees. As the gear 42 moves between these positions, the link arm 38 pushes the finger assembly 36 in a direction away from the gear 42 so that the rod 26 is rotated so as to extend the linkage assembly. This rotation causes the upper and lower steps 12 and 14 to move to the extended position.
[0036] When the step assembly 10 is in the extended position ( FIGS. 1 through 3 ), the tab 23 on the rearward link 20 engages the stop 19 on the side bracket 21 of the frame 16 . Applying a load to either step has a tendency to press the tab 23 on the rearward link 20 against the stop 19 , tending to rotate the link 20 further in the direction it rotates relative to the frame 16 when the step is extending, i.e., clockwise as viewed in FIG. 3 . That is, the size and orientation of the links results in a gravitational load on either step holding the step assembly 10 in the extended position, with the link 20 pressing against the stop 19 so that the stop 19 reacts against the load. Additionally, the assembly 10 can still support the load if the motor/drive unit is removed. This is possible since the stop 19 completely resists the load applied on either step. In addition, the step assembly 10 does not need to be preloaded since the applied gravitational load does not tend to move the assembly to the retracted position.
[0037] When the step assembly 10 is extended, the arm 44 engages a stop 47 , as shown in FIG. 5 . This stop 47 is engaged in addition to the tab 23 on the rearward link 20 engaging the stop 19 . The stop 47 is engaged after the tab 23 on the rearward link 20 engages the stop 19 . Therefore, play from the step assembly 10 is reduced since the arm 44 continues to move after the tab 23 on the rearward link 20 engages the stop 19 .
[0038] The stop 19 on the frame 16 may be a rotatable eccentric cam. If this is the case, rotating the stop 19 changes the extended position of the step assembly 10 . Dimensional uncertainties of the linkage assembly may cause the steps to be non-parallel or rotated at an angle with respect to the top bracket 17 of the frame 16 . The eccentric cam may be useful for making adjustments to ensure the steps are properly positioned if such problems occur. If the stop 19 is an eccentric cam, the stop 19 may also include a nut on the outer surface of the side bracket 21 for convenient adjustment of the stop 19 .
[0039] When the step assembly 10 is retracted, as shown in FIG. 4 , the upper step 12 is preferably pulled against bumpers 53 on each side of the frame 16 . The lower step 14 is also pulled against bumpers 55 on the bottom of the upper step 12 . In addition, the arm 44 moves near, but does not normally engage, a stop 49 , as shown in FIG. 6 .
[0040] Motion of the step assembly is preferably controlled by a current sensor. When the steps 12 and 14 contact bumpers 53 and 55 or the rearward link 20 contacts the stop 19 in the retracted or extended positions, respectively, the motor current will suddenly increase. The current sensor is capable of determining if a current threshold has been exceeded for the duration of a set time period. If such a current increase is sensed, the current sensor sends a signal to a controller to stop motion of the step assembly 10 . The current threshold and time period may be selected as appropriate for the current requirements of the motor 54 .
[0041] Of course, the description set out above is merely of an exemplary preferred version of the invention, and it is contemplated that numerous additions and modifications can be made. The example should not be construed as describing the only possible version of the invention, and the true scope of the invention will be defined by the claims.
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The present invention provides an improved collapsible step assembly for recreational vehicles. The movable step apparatus comprises a mounting frame, at least one step mounted to the frame through a linkage assembly, and a pivot rod with a longitudinal axis of rotation. In use, the pivot rod is rotatably mounted to the frame and rotates the linkage assembly and the at least one step between an extended position and a retracted position. Rotating the pivot rod in a first direction moves the step to the extended position, and rotating the pivot rod in the opposite direction moves the step to the retracted position. The linkage assembly includes a link which is movable in the direction of the link toward extension of the step to contact a stop of the frame that reacts against a gravitational load acting on the step.
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This is a continuation of application Ser. No. 08/121,264, filed Sep. 13, 1993, now abandoned.
FIELD OF THE INVENTION
The present invention relates to apparatus and methods for reducing the redox potential of substances and to various uses of such substances.
BACKGROUND OF THE INVENTION
It is well known that all biological systems live by undergoing oxidation and reduction reactions.
It is generally accepted that oxidation and the presence of an excess of hydroxyl free radicals produce degradation in certain biological systems in living organisms.
Specifically, scientific literature attributes certain cancers and other diseases such as Parkinsons disease to uncontrolled oxidation. Failure of the body's protective systems to quench the excess oxidizing free radicals leads to uncontrolled reactions resulting in such diseases.
It is known to improve water quality by electrolysis. A home unit for water improvement is manufactured and sold by Ange Systems, Inc. and distributed by Sanyo Trading Co., Ltd. in Tokyo, Japan and provides both acidic and alkaline water supplies. The acidic water is proposed for use in personal cleaning, to kill microorganisms, while the alkaline water is proposed for use as drinking water.
SUMMARY OF THE INVENTION
The present invention seeks to provide apparatus and methods for reducing the redox potential of substances and various uses of such substances.
It is appreciated that drinking water, especially chlorinated water, has a high concentration of oxidizing OH radicals expressed in high redox potential readings.
The present invention seeks to quench the hydroxyl free radicals by atomic hydrogen, to form water. The atomic hydrogen activity is provided via reducing water.
It is known that the active hydrogen in different antioxidants has different physical properties, such as its magnetic resonance, causing it to have different biological effects. Therefore, the hydrogen coming from a specific substance carries some characteristics of the substance it came from. It is also known that hydrogen atoms of a substance can be exchanged with hydrogen atoms in a solvent, such as water.
It is therefore another object of the present invention to form water in which one or more of the hydrogen atoms are of a predetermined character. In this manner, water can be improved qualitatively and quantitatively.
It is known that air oxidized by ozone, chlorine and the like is toxic to plants. The oxidative potential of the air stems from the formation of hydroxyl radicals upon reaction of the oxidizing matter with the moisture in the air and the water in the plants.
It is therefore another object of the present invention to reduce oxidizing fluids, such as air, by contact with atomic hydrogen or reducing water.
It is also an object of the present invention to provide a vehicle for preventing or slowing harmful oxidation in biological, organic and inorganic systems.
There is thus provided in accordance with a preferred embodiment of the present invention a method for improving water quality including the steps of:
providing a supply of water to be treated; and
decreasing the redox potential of the water principally by supplying thereto atomic hydrogen.
Preferably, the step of decreasing the redox potential comprises supplying molecular hydrogen to apparatus operative to convert the molecular hydrogen to atomic hydrogen.
The step of decreasing the redox potential may include the step of electrolysis.
In accordance with a preferred embodiment of the present invention, the step of supplying includes the step of supplying molecular hydrogen to a porous material which is operative to disassociate the molecular hydrogen into atomic hydrogen and to adsorb the atomic hydrogen.
There is also provided, in accordance with a preferred embodiment of the present invention a method for improving water quality including the steps of:
providing a supply of water to be treated; and
decreasing the redox-potential of the water by electrolysis employing a cathode and an anode, wherein water communicating with the anode and the cathode is not separated.
Additionally in accordance with a preferred embodiment of the present invention there is provided a method for improving water quality including the steps of:
providing a supply of water to be treated;
initially oxidizing the water; and
subsequently reducing the redox potential of the oxidized water.
Further in accordance with a preferred embodiment of the present invention there is provided a method for quenching the oxidizing free radicals of a substance including the steps of:
providing a supply of electron donors which following electron donation become oxidizers; and
providing a supply of a material rich in atomic hydrogen activity which immediately bonds with the oxidizers produced by electron donation so as to prevent the build up of a presence of oxidizers.
There is also provided in accordance with a preferred embodiment of the present invention a method for quenching the oxidizing free radicals of a substance including the steps of:
providing an anti-oxidant which is operative for producing reduction of the substance and which, upon producing reduction does not act as an oxidant.
Preferably the anti-oxidant is atomic hydrogen.
Preferably the porous material comprises a ceramic material, or a sistered material including a catalyst or graphite.
Additionally in accordance with a preferred embodiment of the present invention there is provided a method of improving air quality within an enclosure including the steps of:
reducing the redox potential of moisture in air to provide reducing air; and
supplying the reducing air to the enclosure.
Further in accordance with a preferred embodiment of the present invention there is provided a method of improving air quality including the step of quenching oxidizing substances in the air.
Preferably, the step of quenching comprises the step of quenching hydroxyl free radicals in the air.
Additionally in accordance with a preferred embodiment of the present invention there is provided a method of storing produce including the steps of:
maintaining produce in a controlled atmosphere; and
reducing the redox potential of the controlled atmosphere.
Further in accordance with a preferred embodiment of the present invention there is provided a method of growing plants including:
providing water having a redox potential;
providing a plant;
reducing the redox potential of the water to produce reduced redox potential water;
irrigating the plant with the reduced redox potential water.
Preferably the method of growing plants also includes the step of providing a spray of the reduced redox potential water thereby to provide a reduced redox potential atmosphere for the plant.
Additionally in accordance with a preferred embodiment of the present invention there is provided a method of soulless plant growth including the steps of:
providing water having a redox potential;
providing a plant;
reducing the redox potential of the water to produce reduced redox potential water;
providing the reduced redox potential water to the plant.
Preferably, the step of providing comprises the step of providing a water spray to the plant.
Further in accordance with a preferred embodiment of the present invention there is provided a method of reducing the redox potential of fluids including the steps of:
reduction of the redox potential of a liquid to produce a reduced redox potential liquid;
freezing the reduced redox potential liquid to produce frozen reduced redox potential liquid; and
supplying the frozen reduced redox potential liquid to a fluid for reduction of the redox potential thereof.
Additionally in accordance with a preferred embodiment of the present invention there is provided a method for improving water quality including the steps of:
killing microorganisms in the water by oxidizing the water; and
thereafter reducing the redox potential of the water.
Further in accordance with a preferred embodiment of the present invention there is provided a method of storing produce including the steps of:
providing a supply of water;
increasing the redox potential of part of the supply of water to provide oxidizing water;
reducing the redox potential of another part of the supply of water to provide reducing water;
humidifying air using the reducing water to produce reducing air;
washing produce using the oxidizing water;
thereafter rinsing the produce in the reducing water;
thereafter removing excess reducing water from the produce by directing a flow of the reducing air onto the produce; and
thereafter maintaining the produce in a controlled atmosphere containing the reduced air.
Further in accordance with a preferred embodiment of the present invention there is provided a method of disinfecting a liquid including the steps of:
supplying molecular oxygen and hydrogen to the liquid to create an excess of OH radicals for disinfection; and thereafter supplying molecular hydrogen to the liquid to reduce the redox potential thereof.
Additionally in accordance with a preferred embodiment of the invention there is provided a method of operating a spa including the steps of:
heating, disinfecting and reducing the redox potential of water by applying thereto an AC electrical current which produces partial electrolysis thereof; and
supplying the heated, disinfected and reduced water to a spa.
Further in accordance with a preferred embodiment of the present invention there is provided a method of providing a fluid with active hydrogen having selected characteristics including the steps of:
supplying hydrogen to a material having selected characteristics; and
causing exchange of hydrogen atoms between the material and the fluid, whereby the fluid receives hydrogen atoms from the material, which hydrogen atoms have the selected characteristics.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention will be understood and appreciated more fully from the following detailed description, taken in conjunction with the drawings in which:
FIG. 1 is a simplified illustration of apparatus for supplying atomic hydrogen to a fluid;
FIG. 2 is a simplified illustration of apparatus for reducing the redox potential of a liquid in accordance with one embodiment of the present invention;
FIGS. 3A and 3B are simplified illustrations of apparatus for reducing the redox potential of a gas in accordance with one embodiment of the present invention;
FIGS. 4A and 4B are simplified illustrations of apparatus for reducing the redox potential of a liquid in accordance with another embodiment of the present invention in two different variations;
FIG. 5 is a simplified illustration of apparatus for reducing the redox potential of a liquid in accordance with still another embodiment of the present invention, wherein a liquid is first oxidized and then reduced;
FIG. 6A is a simplified illustration of apparatus for reducing the redox potential of a liquid, wherein a liquid is first oxidized and then reduced in accordance with another embodiment of the invention;
FIG. 6B is a simplified illustration of a variation of the apparatus of FIG. 6A providing separate reducing and oxidizing functions;
FIG. 7 is a simplified illustration of a growing enclosure including apparatus for reducing the redox potential of the interior atmosphere thereof in accordance with an alternative embodiment of the present invention;
FIG. 8 is a simplified illustration of apparatus for producing fluids with characteristic hydrogen.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Reference is now made to FIG. 1, which is a simplified illustration of apparatus for supplying atomic hydrogen to a fluid. The apparatus preferably comprises a porous ceramic tube 10, typically formed of alumina and which is commercially available from Coors Ceramic Company of Golden, Colorado, under catalog number AL 998-L3. Molecular hydrogen from any suitable source, such as a gas cylinder or an electrolysis device, is supplied to the tube 10, via a conduit 12. A valve 14 and a pressure indicator 16 may be provided along conduit 12.
The porous ceramic tube 10 is preferably operative to prevent substantial diffusion of molecular hydrogen therethrough, thereby retaining pressurized molecular hydrogen therewithin over a relatively long time, even when valve 14 is closed. Atomic hydrogen, however, does become absorbed in pores of the tube 10, communicating with the outer surface thereof.
By causing fluid, such as a gas, e.g. air, or a liquid, e.g. water or a hydrocarbon fuel, to flow past tube 10, atomic hydrogen is supplied to the fluid, thus reducing the redox potential thereof, i.e. increasing the hydrogen activity of the fluid. Typical reductions of redox potential may be from about +300 mv to -150 mv for water, gasoline and air.
Reference is now made to FIG. 2 which shows the apparatus of FIG. 1 in a bath 18 or conduit of a liquid. The liquid is preferably stirred or otherwise caused to flow past the tube 10, for reducing the redox potential of the liquid in accordance with one embodiment of the present invention.
Reference is now made to FIGS. 3A and 3B, which are simplified illustrations of apparatus for reducing the redox potential of a gas in accordance with one embodiment of the present invention. It is seen that a plurality of tubes 10 are associated via a manifold 20 with a source of molecular hydrogen. A fan 22, or any other suitable device is provided for causing the gas to flow past the tubes 10. It is appreciated that the water vapor in the air picks up and reacts with the atomic hydrogen. In effect, the redox potential of the gas is thus reduced by reducing the redox potential of the liquid carried thereby.
Reference is now made to FIG. 4A which is a simplified illustration of apparatus for reducing the redox potential of a liquid in accordance with another embodiment of the present invention. A non-conductive housing 30 is provided with a liquid inlet 32 and a liquid outlet 34. A pair of respective negative and positive electrolysis electrodes 36 and 38 are located within the housing. By application of DC voltage across the electrodes 36 and 38, hydrogen is caused to be present on the negative electrode 36. This hydrogen is picked up by the liquid passing through housing 30. Oxygen and chlorine may be present on the positive electrode 38. Generally, the oxygen does not oxidize water. The chlorine strongly oxidizes the water by forming OH radicals. The net result, however, is reduction of the water.
Reference is now made to FIG. 4B which is a simplified illustration of apparatus for reducing the redox potential of a liquid in accordance with yet another embodiment of the present invention. A housing 29 is formed of stainless steel pipe and is associated with a liquid inlet element 31 and a liquid outlet element 33. The housing 29 is coupled to the negative terminal of a DC power supply 35 and serves as a negative electrode.
Disposed preferably concentrically within housing 29 is a stainless steel rod or pipe 37 which is mounted by a pair of insulating mounts 39 and is coupled to the positive terminal of power supply 35. Rod or pipe 37 serves as the positive electrode.
By application of DC voltage across the electrodes 29 and 37, hydrogen is caused to be present on the interior surface of housing 29. This hydrogen is picked up by the liquid passing through housing 29. Oxygen and chlorine may be present on the positive electrode 38. Generally, the oxygen does not oxidize water. The chlorine strongly oxidizes the water by forming OH radicals. The net result, however, is reduced water.
Reference is now made to FIG. 5 which is a simplified illustration of apparatus for reducing the redox potential of a liquid in accordance with still another embodiment of the present invention, wherein a liquid is first oxidized and then reduced. The apparatus comprises a pair of non-conducting housings 40 and 42 which are interconnected by a plurality of non-conducting electrochemical bridges 44, each of which may include a porous ceramic barrier 46. Each of housings 40 and 42 includes a liquid inlet and a liquid outlet, indicated respectively by reference numerals 48, 50 and 52, 54. A positive electrolysis electrode 56 is disposed within housing 40, while a negative electrolysis electrode 58 is disposed in housing 42.
The apparatus of FIG. 5, which is particularly suitable for disinfecting water, operates by causing water to enter housing 40 via inlet 48 and to be oxidized by electrode 56. The oxidized water, downstream of electrode 58, is supplied to an oxidation enhancement chamber 60, typically filled with activated carbon and ceramic beads. Chamber 60 provides high surface contact and dwelling time to enable the full oxidation of the water by the oxygen and chlorine produced by the operation of the positive electrode 56 on water, thereby to kill microorganisms therein.
The thus disinfected water is then supplied via inlet 52 to housing 42 wherein it is reduced. The reduced water from housing 42 is provided to a reduction enhancement chamber 62, typically filled with activated carbon and ceramic beads. Chamber 62 provides high surface contact and dwelling time to enable the full reduction of the water.
Reference is now made to FIG. 6A which is a simplified illustration of apparatus for reducing the redox potential of a liquid, wherein a liquid is first oxidized and then reduced in accordance with another embodiment of the invention. Here a housing 70 is formed of a conductor, such as stainless steel and defines a negative electrolysis electrode. Housing 70 is formed with a liquid inlet 72 and a liquid outlet 74. Disposed within housing 70 is a tube 76 formed of a porous ceramic material, which may be identical to that used in tube 10 described hereinabove.
A positive electrolysis electrode 78 is disposed interiorly of tube 76, so as to oxidize liquid entering through inlet 72. The oxidized liquid passes along a conduit 80 to the interior of housing 70, outside of tube 76, where it is reduced by hydrogen formed on the interior surface of housing 70, which operates as a negative electrode. Reduced, disinfected liquid, such as water is output at outlet 74. Alternatively, the ceramic tube 76 may be replaced by a fabric hose or similar device, which does not permit significant passage therethrough of liquid but does permit passage therethrough of electrical current.
Reference is now made to FIG. 6B which is a simplified illustration of a variation of the apparatus of FIG. 6A for reducing the redox potential of a liquid, wherein a liquid is first oxidized and then reduced in accordance with another embodiment of the invention. Here a housing 82 is formed of a conductor, such as stainless steel, and defines a negative electrolysis electrode. Housing 82 is formed with a liquid inlet 84 and a reduced cathodic liquid outlet 86. Disposed within housing 82 is a tube 88 formed of a porous ceramic material, which may be identical to that used in tube 10 described hereinabove. Tube 88 is formed with a liquid inlet 89 and an anodic water outlet 90.
A positive electrolysis electrode 92 is disposed interiorly of tube 88, so as to oxidize liquid entering through inlet 89. The oxidized liquid passes out through outlet 90. Liquid entering via inlet 84 is reduced by hydrogen formed on the interior surface of housing 82, which operates as a negative electrode. Reduced, cathodic liquid, such as water, is output at outlet 86. Alternatively, the ceramic tube 88 may be replaced by a fabric hose or similar device, which does not permit significant passage therethrough of liquid but does permit passage therethrough of electrical current.
Reference is now made to FIG. 7 which is a simplified illustration of a growing enclosure including apparatus for reducing the redox potential of the interior atmosphere thereof in accordance with an alternative embodiment of the present invention. It is seen that reducing water is employed not only for watering the plants, but also for spraying in the air, so as to reduce the redox potential of the interior atmosphere of the growing enclosure.
Reference is now made to FIG. 8 which is a simplified illustration of apparatus for characterizing hydrogen. Hydrogen is supplied to a container 100 typically formed of a porous ceramic material, such as that employed for tubes 10, described hereinabove. Disposed within container 100 is preferably a finely divided material, preferably an organic material or other active material which is a hydrogen donor, whose characteristics it is sought to obtain in atomic hydrogen. Hydrogen supplied to container 100 is exchanged with the hydrogen of the material contained in container 100 and the exchanged atomic hydrogen of the material collects on the outer surface of the container 100, so as to be able to be picked up by fluid, such as gas, or air, flowing therepast. The exchanged atomic hydrogen has characteristics of the material from which it was received, and thus, in effect contains information.
A number of examples of the invention will now be described:
EXAMPLE I--STRESS TOMATO PLANTS
Two sets of four trays of tomato plants were grown in a greenhouse in Patterson, Calif. The control tray was irrigated with well water whose measured redox potential was between 270 and 300 mv, while the test tray was irrigated with the same well water which had been treated using reducing equipment of the type illustrated in FIG. 4B. The measured redox potential of the test irrigation water was about 50 mv.
Both trays were not irrigated for three days. The lack of irrigation resulted in dehydration and browning of the plants in the control tray but did not result in browning or visible stress in the test plants.
EXAMPLE II--STRESS CAULIFLOWER PLANTS
Eight trays of cauliflower plants were grown in a greenhouse in Patterson, California. The control trays were irrigated with well water whose measured redox potential was between 270 and 300 mv, while the test trays were irrigated with the same well water which had been treated using reducing equipment of the type illustrated in FIG. 4B. The measured redox potential of the test irrigation water was about 50 mv. Both groups of trays grew normally for about three months and appeared to be identical.
Both sets of trays were not irrigated for three days. The lack of irrigation resulted in dehydration and browning of the plants in both the control trays and the test trays. Irrigation was then resumed as before. Most of the plants in the test trays returned nearly to their previous normal state, but none of the plants in the control trays revived.
EXAMPLE III--HIGH SALINITY STRESS CELERY PLANTS
Two identical beds of celery plants, each about 100 feet long and 12 feet wide and containing hundreds of thousands of plants, were grown in a greenhouse in Salinas, Calif. The control plants were irrigated with well water whose measured redox potential was between 270 and 300 mv, while the test plants were irrigated with the same well water which had been treated using reducing equipment of the type illustrated in FIG. 4B. The measured redox potential of the test irrigation water was about 50 mv.
Both groups of plants grew normally for about 6 weeks until salinity stress was noticed in the control plants. The salinity stress was expressed in yellowing of the control plants and damage to the roots of the control plants. No corresponding salinity stress was noticed in the test plants.
EXAMPLE IV--GROWTH AND VITALITY CAULIFLOWER PLANTS
Four trays of cauliflower plants were grown outdoors in Patterson, Calif. The control trays were irrigated with well water whose measured redox potential was between 270 and 300 mv, while the test trays were irrigated with the same well water which had been treated by boiling for two minutes and subsequent cooling to ambient temperature. The measured redox potential of the test irrigation water was about 100 mv. Both groups of trays grew normally for about one month and appeared to be identical.
Thereafter the control plants began to show signs of fatigue, loss of color, and susceptibility to attack by pests. The test plants did not show such fatigue or loss of color and showed less susceptibility to attack by pests.
EXAMPLE V--GROWTH AND VITALITY TOMATO PLANTS
Forty acres of tomato plants were grown in Five Points, Calif. Thirty-nine of the forty acres were irrigated with water whose measured redox potential was about 310 mv, while a control acre was irrigated with the same water which had been treated using reducing equipment of the type illustrated in FIG. 4B. The measured redox potential of the test irrigation water was about 45 mv. All plants were seeded in January, 1993. Irrigation began in April and proceeded for 8 hours once a week. Plants were harvested on Jul. 16, 1993.
Samples of fruit bearing plants were selected from both the control and the test acreage during harvest. The test plants were larger and heavier than the control plants. Although the number of tomatoes per plant was about the same for the control and test plants, the weight of the tomatoes in the test group was about 40% higher than that for the control group. The solid content, pH and other quality parameters were the same in both groups.
EXAMPLE VI--REDUCTION OF WATER BY ELECTROLYSIS
Well water at Patterson, Calif., having a redox potential of 312 mv was supplied to apparatus of the type illustrated in FIG. 4B at a rate of about 5 gallons per minute. The current was 20 Ampere and the voltage was 16 Volts. The water output had a measured redox potential of 45 mv. This water was supplied to a spa and was circulated therethrough and was also employed for irrigation.
EXAMPLE VII--REDUCTION OF WATER BY ELECTROLYSIS
Well water at Patterson, Calif., having a redox potential of 312 mv was supplied to apparatus of the type illustrated in FIG. 4B at a rate of about 5 gallons per minute. AC current was employed at 220 Volt. The water output had a measured redox potential of 45 mv. Operation of the apparatus of FIG. 4B using AC current provided heating of the water and disinfection thereof in addition to the reduction of the redox potential thereof. This water was supplied to a spa and was circulated therethrough and through the apparatus of FIG. 4B.
EXAMPLE VIII--REDUCTION OF WATER BY ELECTROLYSIS
Well water at Patterson, Calif., having a redox potential of 270 mv was supplied to apparatus of the type illustrated in FIG. 6A at a rate of about 1 gallon per minute. DC current was employed at 2 Amperes and a titanium electrode 78 was employed.
The water output had a measured redox potential of -50 mv.
EXAMPLE IX--REDUCTION OF WATER BY ELECTROLYSIS
Well water at Patterson, Calif., having a redox potential of 270 mv was supplied to apparatus of the type illustrated in FIG. 6B at a rate of about 1 gallon per minute. DC current was employed at 2 Amperes and a titanium electrode 78 was employed.
The water output at outlet 86 had a measured redox potential of 350 mv. The water output at outlet 90 had a measured redox potential of -460 mv.
EXAMPLE X--DECHLORINATION AND REDUCTION OF WATER BY ELECTROLYSIS
Well water at Patterson, Calif., having a redox potential of 270 mv was chlorinated with commercial chlorine solution. The redox potential of the chlorinated water was 690 mv. The chlorinated water was supplied to apparatus of the type illustrated in FIG. 6A at a rate of about 1 gallon per minute. DC current was employed at 2 Amperes and a titanium electrode 78 was employed.
The water output had a measured redox potential of 640 mv. This output was passed through an 8 inch long tube containing active carbon. The water output from the tube had a measured redox potential of -50 mv.
EXAMPLE XI--ICE CUBES OF REDUCING WATER
Hydrogen gas was bubbled into tap water using a sparger for about one minute. The measured redox potential of the tap water was reduced thereby from 295 mv to -50 mv. The thus reduced water was frozen into ice cubes and used subsequently in a variety of drinks. Melting of the ice cubes greatly reduced the redox potential of the drinks.
EXAMPLE XII--REDUCING WATER USING CERAMIC TUBE
Hydrogen was supplied under a pressure of 30 psi to a ceramic tube as illustrated in FIG. 2. Water was provided at a redox potential of 285 mv. Upon agitating the ceramic tube in the water, the redox potential of the water dropped to 85 mv.
EXAMPLE XIII--TRANSFER OF CHARACTERISTICS OF HYDROGEN
One gram of dry black pepper powder is placed in a ceramic tube as illustrated in FIG. 2. Hydrogen gas was supplied to the interior of the tube at a pressure of 25 psi. The water outside of the ceramic tube became slightly discolored and had a slight taste of pepper.
Part of the ceramic tube was left above the water line. Brown colored liquid droplets having a strong taste of pepper were found on the outer surface of the ceramic tube above the water line.
A control experiment identical to the foregoing but using nitrogen gas instead of hydrogen gas, produced none of the observed results.
EXAMPLE XIV--ENHANCEMENT OF HYDROCARBON FUEL
Hydrogen was sparged into regular unleaded gasoline. The redox potential of the gasoline was reduced from about 300 mv to -150 mv. This gasoline was employed in a lawnmower and an automobile and appeared to provide easier starting and more powerful operation.
It will be appreciated by persons skilled in the art that the present invention is not limited by what has been particularly shown and described hereinabove. Rather the scope of the present invention is defined only by the claims which follow:
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A method for improving water quality including the steps of providing a supply of water to be treated and decreasing the redox potential of the water principally by supplying thereto atomic hydrogen.
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This application is a National Stage Application of International Application Number PCT/GB2006/001695, filed May 9, 2006; which claims priority to Great Britain Application No. 0509442.0, filed May 9, 2005.
FIELD OF THE INVENTION
This invention relates to compounds and their use as affinity ligands.
BACKGROUND TO THE INVENTION
Fibrinogen is a dimeric protein, each half of which is composed of disulfide-bonded polypeptide chains designated Aα, Bβ and γ. In the liver, the genes for the Aα- and Bβ-chains encode single products of 610 and 461 amino acid residues, respectively. In contrast, alternative splicing of transcripts of the γ-chain gene yield γ-chain variants of slightly different lengths (411 and 427 residues), the shorter of which constitutes ˜90% of the final product. The predominant form of fibrinogen is secreted into the circulation with a molecular mass of ˜340 kDa. Following its secretion from the liver, the protein exists not only in plasma, but also in lymph and interstitial fluid. In healthy individuals, the concentration of fibrinogen in plasma is between 4 and 10 μM. Importantly, that concentration can increase by as much as much as 400% during times of physiological stress.
Fibrinogen is converted to fibrin by thrombin, a trypsin-like serine proteinase. Thrombin hydrolyzes at least two specific Arg-Gly bonds within fibrinogen. This process leads initially to the formation of fibrin protofibrils which can associate laterally, forming thicker fibres that, in turn, can associate to form even thicker and branched fibrin bundles. Such bundles are further stabilised by cross-links formed between Lys and Gln residues located within the α-chains of neighboring fibrin molecules, to form a 3-D meshwork capable of preventing or limiting blood flow. This process of cross-linking is catalysed by the enzyme Factor XIIIa.
Two types of congenital abnormalities of fibrinogen exist, afibrinogenemia and dysfibrinogenemia. Afibrinogenemia is a quantitative deficiency that results in bleeding diatheses. The term hypofibrinogenemia refers to a less severe fibrinogen deficiency. Dysfibrinogenemia is marked by functional abnormalities of fibrinogen that may result in either bleeding or thrombosis. Patients may be treated with fibrinogen concentrate or cryoprecipitate. Fibrinogen is also commonly used during surgery as an adjunct to hemostasis in the form of fibrin sealants. These are typically two-component systems comprising fibrinogen (e.g. in the form of fibrinogen concentrate) and thrombin in appropriate pharmaceutical compositions.
A concern in the administration of these partially purified forms of fibrinogen is the presence of contaminating proteins. An affinity-based purification method for the isolation of fibrinogen would therefore be useful. Such a purification method would be especially useful if it were able to isolate fibrinogen from non-depleted plasma, in a specific fashion, leaving all other protein components intact for further manipulation.
WO97/10887 discloses triazine-based compounds, useful as affinity adsorbents, of formula I
wherein R 1 is H, alkyl, hydroxyalkyl, cyclohexyl, NH 2 , phenyl, naphthyl, 1-phenylpyrazole, indazole, benzthiazole, benzoxazole or benzimidazole, any of which aromatic groups can be substituted with one or more of alkyl, alkoxy, acyloxy, acylamino, amino, NH 2 , OH, CO 2 H, sulphonyl, carbamoyl, sulphamoyl, alkylsulphonyl and halogen;
one X is N and the other is N, C—Cl or C—CN; Y is O, S or NR 2 ; Z is O, S or NR 3 ; R 2 and R 3 are each H, alkyl, hydroxyalkyl, benzyl or (5-phenylethyl; Q is benzene, naphthalene, benzthiazole, benzoxazole, 1-phenylpyrazole, indazole or benzimidazole; R 4 , R 5 and R 6 are each H, OH, alkyl, alkoxy, amino, NH 2 , acyloxy, acylamino, CO 2 H, sulphonic acid, carbamoyl, sulphamoyl, alkylsulphonyl or halogen; n is 0 to 6; p is 0 to 20; and A is a support matrix, optionally linked to the triazine ring by a spacer.
Compounds of formula I are disclosed as having affinity for proteins such as immunoglobulins, insulin, Factor VII or human growth hormone.
Compounds of related structure are disclosed in WO00/67900 and WO03/097112. They have affinity for endotoxins.
SUMMARY OF THE INVENTION
Surprisingly, it has been found that certain compounds, many of which are novel, are useful for affinity-based isolation of fibrinogen. These compounds are of formula II
wherein X, Y, Z, n and A are as defined for formula I above;
R 7 is a group bearing a positive charge at neutral pH; W is an optional linker; V is as described above for Q, but alternatively may be a nodal structure; and R 8 and R 9 are as defined for R 4 , R 5 and R 6 , but additionally include cyclic structures, or R 8 and R 9 are linked to form such a cyclic structure.
Further, compounds of the invention include the corresponding ligands, in which A is replaced by a functional group, linked directly or indirectly to the triazine ring, which can be immobilised on a support matrix. The terms “ligand” and “adsorbent” may be used interchangeably, below.
DESCRIPTION OF THE INVENTION
WO97/10887, WO00/67900 and WO03/097112 disclose how combinatorial libraries of ligands can be built on a solid support. Their disclosures, including examples of embodiments and procedures common to the present invention, are incorporated herein by reference. During the screening of a set of these combinatorial libraries with pooled human plasma as feedstock, a number of ligands were identified as being capable of selectively binding and eluting human fibrinogen.
Compounds of formula II, for use in the invention, can be prepared by procedures known to those skilled in the art. Such procedures are described in the 3 PCT publications identified above; they can be readily adapted to the preparation of new compounds.
WO97/10887 gives examples of A, including spacers or linkers L via which the triazine ring may be linked to a solid support M. As described in WO97/10887, such supports include agarose, silica, cellulose, dextran, starch, alginate, carrageenan, synthetic polymers, glass and metal oxides. Such materials may be activated before reaction to form an adsorbent of this invention.
L may be, for example, -T-(-V 1 —V 2 ) m —, wherein T is O, S or —NR 7 —; m is 0 or 1; V 1 is an optionally substituted hydrocarbon radical of 2 to 20 C atoms; and V 2 is O, S, —COO, —CONH—, —NHCO—, —PO 3 H—, —NH-arylene-SO 2 —CH 2 —CH 2 — or —NR 8 —; and R 7 and R 8 are each independently H or C 1-6 alkyl.
In compounds of the invention, R 7 is a group bearing a positive charge at neutral pH. Examples of such groups are guanidino, amidino etc. or derived from an amino acid such as alanine or phenylalanine.
W (if present) is an optional linker which may be an alkyl, cycloalkyl, oxyalkyl or aromatic ring structure, optionally substituted (e.g. with a carboxylic acid as in arginine or other).
V is as described above for Q, but alternatively may be a nodal structure. Examples of such structures include a simple tertiary amine or methine function, to permit the formation of, for example, a morpholino group.
R 8 and R 9 are as defined for R 4 , R 5 and R 6 , but additionally include cyclic structures, or R 8 and R 9 are linked to form such a cyclic structure. Examples of such cyclic structures include carbocyclic and heterocyclic rings, saturated, unsaturated or aromatic, typically containing 4 to 8 ring atoms of which 1, 2 or 3 are individually selected from N (or NH), O or S; an example is morpholine.
In a preferred embodiment of the invention, the fibrinogen-binding ligand or adsorbent is of formula III (which will be protonated at physiological pH)
In another preferred embodiment of the invention, the fibrinogen-binding ligand or adsorbent is of formula IV
In yet another preferred embodiment of the invention, the fibrinogen-binding ligand or adsorbent is represented by structure V
In a further preferred embodiment of the invention, the fibrinogen-binding ligand or adsorbent is represented by structure VI
In a most preferred embodiment of the invention, the fibrinogen-binding ligand or adsorbent is represented by structure VII
The fibrinogen-binding ligands and adsorbents described herein are useful for the purification of fibrinogen from complex mixtures including, but not limited to, human plasma and recombinant fermentation supernatants. This utility is demonstrated below in Example 7, by chromatography experiments using human pooled plasma.
The term “fibrinogen” is used herein to describe fibrinogen itself and also analogues that have the functional characteristics of fibrinogen, e.g. in terms of affinity to a given compound described herein. Thus, the analyte may be a protein that is a functional fragment of fibrinogen, or a structural analogue having one, more of all of the same binding sites, or a fusion protein.
The following Examples illustrate the invention.
Example 1
Synthesis of 4-(4-morpholino)anilinyl dichlorotriazine
Cyanuric chloride (16.1 g) was dissolved in tetrahydrofuran (130 mL) and cooled to 0° C. in an ice/salt bath. 4-(4-Morpholino)aniline (29.61 g) in THF (400 mL) was added to the solution of cyanuric chloride at such a rate that the temperature did not exceed 0° C. After addition was complete, the mixture was stirred at 0° C. for a further 30 minutes, before the solution was added to a mixture of ice (700 g) and water (1.5 L). The resulting solid was filtered off, washed with water (1 L), before being dried in a vacuum oven at 45° C. to constant weight (28.54 g).
Example 2
Synthesis of Adsorbent III
6% cross-linked Purabead agarose gel (1000 g settled in Reverse Osmosis (RO) water) was slurried with RO water (667 mL), 10 M sodium hydroxide (NaOH) (90 mL), and epichlorohydrin (127 mL). The slurry was stirred over 2 hours. After a sample was taken for analysis, the slurry was filtered, then washed with RO water (12×1 L). Analysis for epoxy groups showed that the gel was derivatised with 19.2 μmol epoxy groups per g of settled gel.
The gel was drained before RO water (400 mL) and 0.88 specific gravity aqueous ammonia solution (100 mL) were added. The mixture was stirred and heated to 40° C., then stirred at this temperature over 16 hours. After a sample was taken for analysis, the slurry was filtered, then washed with RO water (12×500 mL). TNBS analysis for amine groups showed that the gel was derivatised with 28.0 μmol amine groups per g of settled gel.
The settled, aminated gel (500 g) was suspended in 1 M potassium phosphate pH 7.0 (500 mL), then allowed to drain. To this gel were then added 1 M potassium phosphate pH 7.0 (125 mL) and RO water (125 mL). The slurry was stirred vigorously while acetone (250 mL) was added. After cooling in an ice/salt bath over 30 minutes, cyanuric chloride (12.5 g) in cold acetone (125 mL) was added in one portion. The mixture was stirred at 0° C. over 1 hour, before being washed with 50% aqueous acetone (5×500 mL), RO water (5×500 mL), 50% aqueous acetone (5×500 mL), and RO water (10×500 mL). The gel was allowed to settle under gravity, before a sample was taken for analysis. Analysis for chloride release indicated that the gel was derivatised with 26.1 μmol substituted dichlorotriazine per g of settled gel.
Settled gel from the previous stage (238 g) was slurried with RO water (138 mL) under ice/salt cooling, before 2-(4-morpholino)ethylamine (4.39 g) in cold (8° C.) RO water (95 mL) was added, such that the reaction temperature did not exceed 8° C. The mixture was then stirred at 8° C. over 1 hour. After a sample was taken for analysis, the slurry was filtered, then washed with RO water (10×250 mL). Analysis for chloride release indicated that the gel was derivatised with 23.8 μmol substituted monochlorotriazine per g of settled gel.
To 238 g (settled) of the gel was added agmatine sulfate (15.42 g) dissolved in RO water (200 mL-pH adjusted to pH 10, then made up to a final volume of 238 mL with RO water). The mixture was stirred at 60° C. overnight, while maintaining the pH at 10. After a sample of the supernatant was taken for analysis, the slurry was filtered, then washed with RO water (15×250 mL). Analysis for chloride release indicated that the gel had been derivatised with 17.0 μmol agmatine per g of settled gel.
The gel was incubated in a final concentration of 0.5 M NaOH/25% v/v aqueous ethanol overnight at 40° C., then washed with 0.5 M NaOH/25% v/v aqueous ethanol (5×250 mL). After the final wash was allowed to drain under gravity, 0.5 M NaOH/25% v/v aqueous ethanol (250 mL) was added and the mixture incubated at 40° C. overnight. The gel was then washed with 0.5 M NaOH/25% ethanol (5×250 mL), then RO water (10×250 mL). The gel was then incubated in a final concentration of 0.5 M NaOH overnight at 40° C., then washed with 0.5 M NaOH (5×250 mL). After the final wash was allowed to drain under gravity, 0.5 M NaOH (250 mL) was added and the mixture incubated at 40° C. overnight. The gel was then washed with 0.5 M NaOH (5×250 mL), then RO water (10×250 mL). After washing with 0.1 M PBS pH 7.0 (3×250 mL), the gel was washed a further time with RO water (10×250 mL), before storage in the cold room at 4° C. in 20% v/v aqueous ethanol.
Example 3
Synthesis of Adsorbent IV
6% cross-linked Purabead agarose gel (650 g settled in RO water) was slurried with RO water (438 mL), 10 M sodium hydroxide (NaOH) (59 mL), and epichlorohydrin (83 mL). The slurry was stirred over 2 hours. After a sample was taken for analysis, the slurry was filtered then washed with 12×1 L RO water. Analysis for epoxy groups showed that the gel was derivatised with 16.5 μmol epoxy groups per g of settled gel.
The gel was drained, before RO water (520 mL) and 0.88 specific gravity ammonia solution (130 mL) were added. The mixture was stirred and heated to 40° C., then stirred at this temperature over 16 hours. After a sample was taken for analysis, the slurry was filtered, then washed with RO water (12×1 L). TNBS analysis for amine groups showed that the gel was derivatised with 22.9 μmol amine groups per g of settled gel.
A 500 g portion of the settled, aminated gel was slurried with DMF (500 mL) then allowed to drain. This gel was then slurried with DMF (250 mL), and diisopropylethylamine (DIPEA) (11.0 mL) added with stirring. The mixture was stirred over 10 minutes, then 4-(4-morpholino)anilinyl dichlorotriazine (20.6 g) in DMF (250 mL) added in one portion. The mixture was stirred at room temperature over 3 hours. After a sample was taken for analysis, the slurry was filtered, then washed with 70% v/v aqueous DMF (4×150 mL), 50% DMF (2×150 mL), and RO water (10×150 mL). Analysis for chloride release indicated that the gel was derivatised with 20.2 μmol substituted monochlorotriazine per g of settled gel. Residual amine was undetectable by TNBS assay after derivatisation.
A 150 g (settled) portion of the gel was slurried in 1 M sodium borate buffer (150 mL) and the pH adjusted to 10 with 10 M sodium hydroxide. Arginine (5.50 g) was added in one portion. The mixture was stirred at 60° C. overnight, while maintaining the pH at 10. After a sample of the supernatant was taken for analysis, the slurry was filtered then washed with RO water (12×150 mL). Analysis for chloride release indicated that the gel had been derivatised with 22.4 μmol arginine per g of settled gel.
The gel was incubated in a final concentration of 0.5 M NaOH/25% v/v aqueous ethanol overnight at 40° C., then washed with 0.5 M NaOH/25% v/v aqueous ethanol (5×150 mL). After the final wash was allowed to drain under gravity, 0.5 M NaOH/25% v/v aqueous ethanol (150 mL) was added and the mixture incubated at 40° C. overnight. The gel was then washed with 0.5 M NaOH/25% ethanol (5×150 mL), then RO water (10×150 mL). The gel was then incubated in a final concentration of 0.5 M NaOH overnight at 40° C., then washed with 0.5 M NaOH (5×150 mL). After the final wash was allowed to drain under gravity, 0.5 M NaOH (150 mL) was added and the mixture incubated at 40° C. overnight. The gel was then washed with 0.5 M NaOH (5×150 mL), then RO water (10×150 mL). After washing with 0.1 M PBS pH 7.0 (3×150 mL), the gel was washed a further time with RO water (10×150 mL), before storage in the cold room in 20% v/v aqueous ethanol.
Example 4
Synthesis of Adsorbent V
6% cross-linked Purabead agarose gel (650 g settled in RO water) was slurried with RO water (438 mL), 10 M sodium hydroxide (NaOH) (59 mL), and epichlorohydrin (83 mL). The slurry was stirred over 2 hours. After a sample was taken for analysis, the slurry was filtered, then washed with RO water (12×1 L). Analysis for epoxy groups showed that the gel was derivatised with 16.5 μmol epoxy groups per g of settled gel.
The gel was drained before RO water (520 mL) and 0.88 specific gravity aqueous ammonia solution (130 mL) were added. The mixture was stirred and heated to 40° C., then stirred at this temperature over 16 hours. After a sample was taken for analysis, the slurry was filtered then washed with RO water (12×1 L). TNBS analysis for amine groups showed that the gel was derivatised with 22.9 μmol amine groups per g of settled gel.
A 500 g portion of the settled, aminated gel was slurried with DMF (500 mL), then allowed to drain. This gel was then slurried with DMF (250 mL), and DIPEA (11.0 mL) added with stirring. The mixture was stirred over 10 minutes, then 4-(4-morpholino)anilinyl dichlorotriazine (20.6 g) in DMF (250 mL) added in one portion. The mixture was stirred at room temperature over 3 hours. After a sample was taken for analysis, the slurry was filtered then washed with 70% v/v aqueous DMF (4×150 mL), 50% v/v aqueous DMF (2×150 mL), and RO water (10×150 mL). Analysis for chloride release indicated that the gel was derivatised with 20.2 μmol substituted monochlorotriazine per g of settled gel. Residual amine was undetectable by TNBS assay after derivatisation.
A 150 g (settled) portion of the gel was slurried in 1 M sodium borate buffer (150 mL) and the pH adjusted to 10 with 10 M sodium hydroxide. Arginine amide dihydrochloride (7.75 g) was added in one portion. The mixture was stirred at 60° C. overnight, while maintaining the pH at 10. The slurry was filtered, then washed with RO water (15×150 mL). Analysis for residual chloride of the washed and settled gel indicated that the gel had been derivatised to completion by arginine amide.
The gel was incubated in a final concentration of 0.5 M NaOH/25% v/v aqueous ethanol overnight at 40° C., then washed with 0.5 M NaOH/25% v/v aqueous ethanol (5×150 mL). After the final wash was allowed to drain under gravity, 0.5 M NaOH/25% v/v aqueous ethanol (150 mL) was added and the mixture incubated at 40° C. overnight. The gel was then washed with 0.5 M NaOH/25% v/v aqueous ethanol (5×150 mL), then RO water (10×150 mL). The gel was then incubated in a final concentration of 0.5 M NaOH overnight at 40° C., then washed with 0.5 M NaOH (5×150 mL). After the final wash was allowed to drain under gravity, 0.5 M NaOH (150 mL) was added and the mixture incubated at 40° C. overnight. The gel was then washed with 0.5 M NaOH (5×150 mL), then RO water (10×150 mL). After washing with 0.1 M PBS pH 7.0 (3×150 mL), the gel was washed a further time with RO water (10×150 mL), before storage in the cold room in 20% v/v aqueous ethanol.
Example 5
Synthesis of Adsorbent VI
6% cross-linked Purabead agarose gel (650 g settled in RO water) was slurried with RO water (438 mL), 10 M sodium hydroxide (NaOH) (59 mL), and epichlorohydrin (83 mL). The slurry was stirred over 2 hours. After a sample was taken for analysis, the slurry was filtered then washed with RO water (12×1 L). Analysis for epoxy groups showed that the gel was derivatised with 16.5 μmol epoxy groups per g of settled gel.
The gel was drained before RO water (520 mL) and 0.88 specific gravity ammonia solution (130 mL) were added. The mixture was stirred and heated to 40° C., then stirred at this temperature over 16 hours. After a sample was taken for analysis, the slurry was filtered then washed with 12×1 L RO water (12×1 L). TNBS analysis for amine groups showed that the gel was derivatised with 22.9 μmol amine groups per g of settled gel.
Settled aminated gel (70 g) was slurried in 1 M potassium phosphate (70 mL) and allowed to settle. 1 M potassium phosphate (20 mL) was then added, the mixture stirred vigorously, and acetone (10 mL) added. The mixture was cooled to 0° C. in an ice salt bath, before cyanuric chloride (1.75 g) in cold acetone (17.5 mL) was added in one portion. The slurry was stirred over 1 hour at 0-4° C., before being drained, then washed with 50% v/v aqueous acetone (5×70 mL), RO water (5×70 mL), with 50% v/v aqueous acetone (5×70 mL), and RO water (10×70 mL). Analysis revealed the attachment of 18.0 μmol dichlorotriazine groups per g of settled gel.
The dichlorotriazinyl agarose (55 g) was washed with 50% v/v aqueous DMF, then slurried in 50% v/v aqueous DMF (55 mL). 4-(4-Morpholino)aniline (1.23 g) was dissolved in 75% v/v aqueous DMF (15 mL) and cooled on ice, prior to addition to the dichlorotriazinyl agarose. The mixture was reacted at 4° C. over 60 mins. A sample of supernatant was taken after this time, before the gel was washed with 50% DMF (5×100 mL) and RO water (10×100 mL). Analysis of chloride ion released in the reaction indicated a loading of the amine of 20 6 μmol per g of settled gel.
A 37 g (settled) portion of the gel was slurried in 1 M sodium borate buffer (37 mL) and the pH adjusted to 9 with 10 M sodium hydroxide. 4-Aminobenzamidine dihydrochloride (1.93 g) was added in one portion. The mixture was stirred at 60° C. overnight, while maintaining the pH at 10. The slurry was filtered, then washed with RO water (15×150 mL). The gel was washed with RO water (10×150 mL), before storage in the cold room at 4° C. in 20% v/v aqueous ethanol.
Example 6
Synthesis of Adsorbent VII
6% cross-linked Purabead agarose gel (650 g settled in RO water) was slurried with RO water (438 mL), 10 M sodium hydroxide (NaOH) (59 mL), and epichlorohydrin (83 mL). The slurry was stirred over 2 hours. After a sample was taken for analysis, the slurry was filtered then washed with RO water (12×1 L). Analysis for epoxy groups showed that the gel was derivatised with 16.5 μmol epoxy groups per g of settled gel.
The gel was drained before RO water (520 mL) and 0.88 specific gravity ammonia solution (130 mL) were added. The mixture was stirred and heated to 40° C., then stirred at this temperature over 16 hours. After a sample was taken for analysis, the slurry was filtered then washed with RO water (12×1 L). TNBS analysis for amine groups showed that the gel was derivatised with 22.9 μmol amine groups per g of settled gel.
A 150 g portion of the settled, aminated gel was slurried with DMF (150 mL) then allowed to drain. This gel was then slurried with DMF (75 mL), and DIPEA (1.38 mL) added with stirring. The mixture was stirred over 10 minutes, then 4-(4-morpholino)anilinyl dichlorotriazine (2.58 g) in DMF (75 mL) added in one portion. The mixture was stirred at room temperature over 3 hours. After a sample was taken for analysis, the slurry was filtered then washed with 70% v/v aqueous DMF (4×150 mL), 50% v/v aqueous DMF (2×150 mL), and RO water (12×150 mL). Analysis for chloride release indicated that the gel was derivatised with 21.4 μmol substituted monochlorotriazine per g of settled gel. Residual amine analysis indicated that 0.8 μmol amine groups per g of settled gel remained after derivatisation.
A 132 g (settled) portion of the gel was slurried in 1 M sodium borate buffer (132 mL) and the pH adjusted to 10 with 10 M sodium hydroxide. Agmatine sulfate (3.73 g) was added in one portion. The mixture was stirred at 60° C. overnight, while maintaining the pH at 10. After a sample of the supernatant was taken for analysis, the slurry was filtered, then washed with RO water (15×150 mL). Analysis for chloride release indicated that the gel had been derivatised with 19.9 μmol agmatine per g of settled gel.
The gel was incubated in a final concentration of 0.5 M NaOH/25% v/v aqueous ethanol overnight at 40° C., then washed with 0.5 M NaOH/25% v/v aqueous ethanol (5×150 mL). After the final wash was allowed to drain under gravity, 0.5 M NaOH/25% v/v aqueous ethanol (150 mL) was added and the mixture incubated at 40° C. overnight. The gel was then washed with 0.5 M NaOH/25% v/v aqueous ethanol (5×150 mL), then RO water (10×150 mL). The gel was then incubated in a final concentration of 0.5 M NaOH overnight at 40° C., then washed with 0.5 M NaOH (5×150 mL). After the final wash was allowed to drain under gravity, 0.5 M NaOH (150 mL) was added and the mixture incubated at 40° C. overnight. The gel was then washed with 0.5 M NaOH (5×150 mL), then RO water (10×150 mL). After washing with 0.1 M PBS pH 7.0 (3×150 mL), the gel was washed a further time with RO water (10×150 mL), before storage in the cold room at 4° C. in 20% v/v aqueous ethanol.
Example 7
Chromatography on Human Plasma
Chromatography experiments were performed with each of Adsorbents III, IV, V, VI, and VII, using a 1 cm diameter, 10 mL column volume omnifit column using a Biologic LP chromatography system. The column was equilibrated with 5 column volumes of 13 mM sodium citrate, 140 mM sodium chloride pH 7.0 at 100 cm/hr. Human plasma (0.45 μm filtered, 100 mL) was then loaded at 50 cm/hr. Post-load wash was with 13 mM sodium citrate, 140 mM sodium chloride pH 7.0, to baseline absorbance. The column was then eluted with 0.3 M glycine, 0.5 M sodium chloride and 1% w/v sodium cholate pH 9.0, and sanitised with 2 M guanidine hydrochloride pH 7.0. The elution fraction was neutralised immediately with 0.4 M HCl prior to analysis. Load, non-bound, and elution fractions were analysed by nephelometry to determine binding and elution capacities. SDS PAGE was carried out to determine purity.
The purity of fibrinogen in each eluate was greater than 85%. Binding and elution capacities are presented in Table 1.
TABLE 1
Binding Capacity
Elution Capacity
Adsorbent
(mg/mL)
(mg/mL)
III
3.23
3.04
IV
2.76
0.28
V
6.43
3.77
VI
8.36
3.99
VII
17.97
15.04
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For the separation, removal, isolation, purification, characterization, identification or quantification of fibrinogen or a protein that is a fibrinogen analogue, an affinity adsorbent is used that is a compound of formula II wherein one X is N and the other is N, C—Cl or C—CN; Y is O, S or NR 2 ; 0 Z is O, S or NR 3 ; R 2 and R 3 are each H, alkyl, hydroxyalkyl, benzyl or &bgr; -phenylethyl; n is 0 to 6; A is a support matrix, optionally linked to the triazine ring by a spacer; R 7 is a group bearing a positive charge at neutral pH; W is an optional linker; V is an aromatic group; and R 8 and R 9 are each H, OH, alkyl, alkoxy, amino, NH 2 , acyloxy, acylamino, CO 2 H, sulphonic acid, carbamoyl, sulphamoyl, alkylsulphonyl or halogen or a cyclic structure such as a morpholino group, or R 8 and R 9 are linked to form such a cyclic structure.
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This application is a divisional of my co-pending application Ser. No. 07/565,451, filed Aug. 9, 1990 now U.S. Pat. No. 5,171,395.
BACKGROUND OF THE INVENTION
This invention relates to an improved device and method for adapting separable fasteners, particularly those of the hook and loop type, for attachment to other objects such as polyurethane foam seat cushions for automobiles, furniture and the like. In this method one portion of a separable fastener is incorporated into the foam object during the molding process for subsequent attachment to another object carrying the mating portion of the separable fastener. The fastener of this invention provides a greater degree of design flexibility both as to shape and depth of structure than prior art products.
DESCRIPTION OF THE PRIOR ART
Hook and loop separable fasteners, such as those sold by the assignee of this application under the trademark VELCRO® are well-known and used to join two members detachably to each other. This type fastener has two components. Each has a flexible substrate or sheet having one component of the fastening system on the surface thereof. One surface is typically comprised of resilient hooks while the other is comprised of loops and when the two surfaces are pressed together they interlock to form a releasable engagement.
Separable fasteners have in recent years been used in the manufacture of automobile seats, in the attachment of an upholstered seat cover, hereinafter called trim cover, to a polyurethane foam bun. One portion of the separable fastener is incorporated into the surface of the polyurethane seat bun during the foam molding process. The mating portion of the separable fastener is attached to the seat cover to provide releasable attachment to the foam seat bun. The separable fastener assembly used in the foam mold for incorporation in the bun surface typically comprises the hooked portion of the separable fastener system. This hook portion is characterized by a substrate carrying resilient hooks on one surface. The other surface of the substrate may act as an anchoring surface by a variety of methods well-known in the art. In some assemblies a magnetizable shim is often attached to the substrate to facilitate placement of the assembly in a trough of the mold cavity wall, which is equipped with magnets. A protective layer, usually in the form of a thin plastic film, may be placed over the resilient hooks to prevent incursion of foam into the hooks during the molding process, since significant foam contamination of the hooks would affect the ability to engage with the mating portion of the fastener attached to the seat trim cover. Fastening devices are applied to one surface of a clamshell mold; a chemical mixture, usually of a diisocyanate and a polyol, are injected into the mold; the upper surface of the mold is closed and clamped shut while the chemicals react and blow to form a flexible foam, well-known in the art.
The present state of the art relating to the attachment of such fastener means to foamed seat cushions and the like is generally represented by French patents 2,405,123, 2,423,666 and 2,466,330 as well as the following U.S. patents:
U.S. Pat. No. 4,470,857, issued Sep. 11, 1984 in the name of Stephen J. Casalou and assigned to R. A. Casalou, Inc.;
U.S. Pat. No. 4,563,380, issued Jan. 7, 1986 in the name of Philip D. Black and assigned to Minnesota Mining and Manufacturing Company;
U.S. Pat. No. 4,673,542, issued Jun. 16, 1987 in the name of Lauren R. Wigner and assigned to General Motors Corporation;
U.S. Pat. No. 4,693,921, issued Sep. 15, 1987 in the name of Patrick J. Billarant and Bruno Queval and assigned to Aplix;
U.S. Pat. No. 4,710,414, issued Dec. 1, 1987 in the name of Walter E. Northrup and Maurice E. Freeman and assigned to Minnesota Mining and Manufacturing Company;
U.S. Pat. No. 4,726,975, issued Feb. 23, 1988 in the name of Richard N. Hatch and assigned to Actief N. V. ABN Trust Co.; and
U.S. Pat. No. 4,842,916, issued Jun. 27, 1989 to Kunihiko Ogawa et al assigned to Kuraray Company Ltd., Kurashiki, Japan.
Such mold-in separable fastener assemblies presently in use, while proving to be superior means of attaching a seat cover to a foam bun, have presented several problems. One disadvantage of the separable fastener assemblies of the type disclosed in U.S. Pat. No. 4,673,542 is that the thin plastic film layer used to cover the hooks must be removed after the mold-in process, thus requiring an additional and somewhat painstaking step in the manufacture of the foam seat bun. It also requires an additional component in the manufacture of the assembly which must be attached to the separable fastener tape with an adhesive. In addition, an adhesive-backed tape is usually affixed to the film layer to assist in its removal. Other prior-art assemblies, including those disclosed in U.S. Pat. Nos. 4,726,975, 4,563,380 and 4,693,921 also employ a thin layer of film to prevent the incursion of foam into the projections of the separable fastener portion during mold-in.
French Patent 2,423,666 discloses a system for sealing the edges of the tape in the mold trough by jamming the edges into the trough. It is not believed that this system, which is particularly shown in FIG. 3 of the French patent, ever achieved any commercial success. French Patent 2,466,330 shows a fastening strip mounted, by some undefined means, probably an adhesive, on a spline positioned on the mold wall so as to extend into the interior of a mold cavity.
An additional disadvantage of most of the prior art products is that they are essentially straight, flat, thin, two dimensional parts intended to conform to the surface of the seat bun. The assignee of this application practices a modification of these limitations of the prior art by cutting segments of the flat straight strips and fitting them together in a way that they form shapes such as chevrons, wings or diagonals, said strip segments being held together by staples. Such assemblages, however, are incapable of forming smooth or sweeping curves which provide the fashion flexibility sought by designers. Neither do the flat two dimensional strips provide the capability for deep sculptured designs as described in pending U.S. patent application 07/475,687 filed Feb. 6, 1990 assigned to the assignee of this application. Heretofore, attempts to alter the seat appearance to achieve sculptured looks had to be accomplished through painstaking and expensive sewing of the trim cover. This is accomplished by the inclusion of special block of foam and seams arranged to provide the desired appearance after the trim cover is attached to the seat bun. But even with this method it is difficult to achieve certain desirable flowing or sweeping designs with a deep sculptured appearance.
BRIEF SUMMARY OF THE PRESENT INVENTION
In the present invention there is provided a novel fastener which, as in the prior art products, carries on one surface an area of outwardly extending fastener elements, preferably hooks. These fastening elements constitute one half of a touch fastening system. The other half of the fastening system is attached to the decorative upholstery constituting the outer decorative shell of the seat. Unlike prior art devices, however, the present invention utilizes a layer of precast foam to be positioned over a portion of the face of the fastening elements intended to be attached to the seat bun. The fastening elements are exposed by cutting out a portion of the precast foam layer or molding an opening in the desired shape into the cast foam. The foam layer may be shaped into any desirable shape by casting, cutting, sculpting or otherwise removing appropriate sections. The periphery of the sculpted foam slab is attached to the fastener by appropriate means, as will become clear below. The opening in the precast foam provides a wall which has a height considerably greater than the fastening elements and which defines the design to be incorporated into the seat bun. When the device is affixed to the mold by sliding the foam wall over a pedestal having a predetermined height extending into the mold volume and having a predetermined cross sectional dimension generally parallel to the interior mold surface as measured at a predetermined distance from said mold surface. The foam wall preferably defines an opening which engages the sides of said pedestal with a force sufficiently strong to resist any removal force caused by tendency of the foaming action to lift said foam wall during creation of said cushion and bonding of said forming cushion to said foam wall. To achieve this engagement with the pedestal, the foam wall preferably defines an opening which is smaller than said predetermined cross sectional dimension of said pedestal. This engagement is controlled by a number of factors such as height of wall (area of engagement), density of foam wall and size of opening relative to size of pedestal. The required engagement force is controlled by the nature of the foaming reaction and the resultant lifting force due to the seat bun foam formation.
The foam also provides protection for the fastener elements against contamination from the liquid molding chemicals without the need for protective covers. The mold-in device may be thick or thin or sculpted in any desirable set of tight or sweeping curves. It may be sculpted to have differing depths throughout its shape.
The sculpted foam may be affixed to the fastener sheet by any of the methods well-known in the art such as gluing, fusing, welding and the like or, alternatively, by engagement with a sheet of loop material laminated to the precast foam prior to sculpting.
The preferred outwardly facing hooks are positioned under the shaped foam and form a laminate with it. As viewed in the foamed seat bun, the hooks are located at the bottom of a trench formed by the cutout foam. After molding, the entire assembly forms an integral part of the seat giving the appearance of having been molded in the desired design as a part thereof, with the outwardly facing fastener elements disposed over the entire base of the opening formed in the precut foam.
After the seat bun is formed, the upholstered trim cover, containing on its inner surface companion fastening elements, is affixed to the bun by means of the incorporated mating element. The hook and loop closure firmly hold the two components together against slippage or distortion of the trim cover in service.
BRIEF DESCRIPTION OF THE DRAWINGS
In order to more fully understand the invention, reference is made to the following detailed drawings.
FIG. 1 and 1a are plan views of two embodiment of the invention.
FIG. 2 is a cross section through FIG. 1 taken along line A--A';
FIG. 3 is isometric view of a pedestal onto which the device of this invention is fitted in a mold;
FIG. 4 is a depiction of a mold containing the pedestal illustrated in FIG. 3 in conjunction with provision to apply prior art fastener strips in the manner well-known in the art;
FIG. 5 is a cross section of the device of this invention fitted to the pedestal of FIG. 3;
FIG. 6 illustrates a range of shapes molded into a single slab of foam forming the device of this invention;
FIG. 7 is a plan view of a completed seat bun produced from the mold of FIG. 4;
FIG. 8 is a cross sectional view of the seat bun of FIG. 7 along an arc through the bun along a trench formed therein from B to B'; and,
FIG. 9 is the cross section view of FIG. 8 illustrating the attachment of the trim cover to the fastening elements of the device of this invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now specifically to the drawings, FIG. 1 is a plan view of the device of this invention wherein a slab of foam, preferably polyurethane, is cut to an overall curved shape with an inner portion cut out to form an opening (2) through which strip of fastener elements (3) are exposed. The foam (1) makes up the walls (6) which define the opening (2) and may be of any desired depth or width. The shape selected may be varied at will and the opening shape need not correspond to the outer shape of the foam slab permitting the wall thickness to vary as illustrated in FIG. 1A. A thin sheet of fastening elements (4) (FIG. 2) is affixed to the lower side of the foam slab along the periphery surrounding the opening. The hooking elements (3) on the fastener sheet (4) are disposed inwardly to the foam and the sheet carrying the fastener elements serve to cover the lower end of the opening. The hooks at the bottom of the opening which defines the trench will engage the companion loop elements positioned on the inner side of an upholstery trim cover after the device is cast into a seat bun (5).
The opening defined by the walls of the device is designed to impart the desired design feature to the seat. Prior to casting the seat bun (5), the shaped mold-in device is fitted over a pedestal (7) built into the mold as shown in FIG. 4. FIG. 4 depicts a plan view of the lower section of a mold (8), well-known in the art, containing the pedestal (7) of FIG. 3. The mold may include other hook and loop fastening devices (9) such as those of the prior art, held in place by magnets as described in U.S. Pat. No. 4,673,542 to Lauren R. Wigner et al.
FIG. 3 depicts the pedestal (7) as a complex curve of dimensions designed to match the inner dimensions of a mold-in device, not shown. The mold-in device is placed over the pedestal (7) such that the wall surfaces (6) squeeze against the pedestal (7) and so that the foam wall surfaces (6) exert a slight pressure on the sidewalls (11) of the pedestal (2) (See FIG. 5). The fit is designed to furnish sufficient pressure to firmly retain the device in place throughout the seat bun foam pouring and foaming process. The engagement between the wall surfaces (6) and the sides (11) of the pedestal (7) also prevents the influx of liquid foaming chemicals into the opening (2).
The thickness of the foam defining the opening (2) can be made to match the height of the pedestal (7) or can be shorter or taller than the pedestal. If shorter than the pedestal, the space (12) would be created between the lower face (13) of the foam and the wall (10) of the mold (8) as shown in FIG. 5. This space (12) creates an undercut which allows the liquid foaming chemicals to flow under the outer surface of the device, the foam wall extending out from, the pedestal prior to the foaming and before the seat bun foam begins to rise. As the chemicals start to react they raise to fill the space (12) entrapping the fastener within the newly created seat bun foam of the seat bun (5).
Care must be taken that the force of the rising seat bun foam does not lift the foam wall from the pedestal. The fit of the mold-in device can be adjusted to exert greater or lesser force to assure that the device remains in its proper position or the height of the foam wall can be increased to provide greater holding force against the pedestal wall. It has been found that a force of 0.1 lbs per inch of wall length satisfactorily holds the foam in place on the pedestal for many practical molding conditions. Where the lifting force of the seat bun foam is slight, a force of less than 0.1 can be satisfactory. However, if a high lifting force is created by the seat bun foam a holding force greater than 0.1 lbs. per inch of wall will be necessary. If desired the pedestal surface may be grooved or roughened to increase the frictional engagement with the foam wall.
Table I shows the force in pounds required to overcome the friction of a section of precast cutout foam against a rod shaped pedestal using various dimensions of height and width. Varying thickness foam slab were cut into blocks approximately 2.25" square. Holes of differing diameter were die cut through the foam slabs. The cut out foam slabs were placed over a smooth aluminum rod 1.25" in diameter, simulating a pedestal. The force in pounds to slide the foam over the rod were recorded using an Instron tensile tester. The first foam tested was a low density foam of 0.95 #/cu ft with a compressive resistance given as ILD 32. The second foam tested was classified as a high density foam of 2.8 #/cu ft with a compressive resistance given as ILD 45.
TABLE I______________________________________(FORCE IN POUNDS TO REMOVE FOAMFROM 1.25" ROD)(Low Density .95 #/cu ft) HOLE DIAMETERFOAM THICKNESS 1.375" 1.25" 1.125" 1.00"______________________________________0.25" 0 N/A .08 .110.50" 0 .01 0.2 .311.00" 0 .02 .39 .712.00" 0 .02 .92 1.413.00" 0 .62 1.05 1.95______________________________________
TABLE II______________________________________(FORCE IN POUNDS TO REMOVE FOAMFROM 1.25" ROD)(High Density 2.8 #/CU/FT) HOLE DIAMETERFOAM THICKNESS 1.375" 1.25" 1.125" 1.00"______________________________________0.25" 0 .01 .14 .220.50" 0 .02 .36 .631.00" 0 -- .90 1.352.00" 0 .64 2.05 3.053.00" 0 .73 2.50 4.10______________________________________
It is readily apparent the dimensions of the cutout shape relative to the dimensions of the pedestal will depend upon the compressive force of the foam. It is possible to appropriately apply any desired foam to a pedestal by selecting its dimensions to apply sufficient force to the pedestal over which it is placed. I have found that a wall height of between 0.25" and 4" and preferably between 0.5" and 2.0" to be very satisfactory for holding the device onto the pedestal in a practical molding situation for many foam slabs found suitable for practicing this invention. As can be apparent from the above tables, both height of foam wall, density of foam and size of opening each independently affects the removal force.
The foam acts to replace the anchors of prior art products. By carefully selecting the foam to be compatible with the liquid chemicals of the molding compounds, it is possible to achieve anchoring forces substantially greater than prior art products.
Employing the arrangement whereby the lower face of the mold-in device (13) is raised above the face of the mold wall (10), that is providing an undercut (12) to allow the seat foam to anchor the mold-in device into the bun, greater force is required to tear the part from the finished bun than would be achieved solely by adhesion of the two foams to one another as occurs when the trench walls are sufficiently deep to rest upon the face of the mold.
The space (12) between the wall of the mold and the surface of the mold-in device (13) adds to the depth of the trench in the finished seat bun. Thus, it is possible to achieve very deep trenches without the need for using very thick foam slabs to create the mold-in device.
The instant invention is not restricted to a single trench in each section of precut foam. Any combination of patterns may be cut through the foam slab and a single sheet of fastener elements attached to the cut foam to create the mold-in device. In this way very complex parts can be designed without the need for loading separately many individual fastener segments into the mold. The single part device of this invention offers advantages in manufacturing efficiency when loading parts into molds on a production line.
Now turning to the preferred method for creating the configuration of the mold-in device of this invention. A pattern is cut into a slab of polyurethane foam, of the desired thickness, using any of the methods well-known in the art such as rotary dies, clicker presses flat dies or the like. I have found it especially useful to utilize a foam which already has laminated to it a sheet of fastener elements, said elements being disposed outwardly from the foam. I prefer that a sheet of loop material be laminated to the foam but it is possible to laminate hook material to the foam in the method contemplated. The choice will depend upon the selection of the fastener elements to be attached to the upholstery trim cover.
For purposes of illustration, below, loop material is laminated to the foam. By cutting the sections of the laminated foam through their entire thickness, including the attached loop elements, designs are formed in the slab. I then attach a sheet of hooks to the loops on the bottom face of the cutout foam. Alternatively, any appropriate adhesive may be used to attach the engaging elements to the foam slab. The hook elements are thus facing the foam, and in the sections cut out to create the trench, serve to close off the bottom of the trench with the hook elements disposed inwardly into the trench and in a position to engage loop elements on the trim cover. In this configuration, it will be realized the sheet of hook elements need not take on the shape of the trench nor even the overall shape of the device itself. In fact, it is not necessary to cover completely the underside of the foam; all that is required is sufficient overlap to permit engagement of the hook and loop around the periphery of the trench to adequately hold the hook elements in place with sufficient strength so as not to be pulled out when separating the trim cover as shown at 16 of FIG. 6. In general, I prefer the area of engagement to be at least equivalent to the area of the trench opening depending upon the relative engagement force of the loop of the trim cover to the engagement force of the loop laminated to the cut out foam slab. In any case, the engagement force between the foam slab laminate should exceed the engagement force between the device and the trim cover.
FIG. 8 shows a cross section of the seat bun of FIG. 7 along line B--B'. The trench (2) provides an opening with engaging elements (3) along its bottom surface (4). FIG. 9 illustrated the trim cover (14) engaged in place over seat bun (5) and engaged with elements (3) of the device of this invention with elements (15) attached to the trim cover. Any appropriate combination of engaging elements may be used for this purpose but I prefer hook elements be used in the seat bun and loop elements be used in the trim cover.
The following examples illustrate specific embodiments of the present invention.
EXAMPLE 1
A slab of polyurethane foam 8 inches by 6 inches and 1/2 inch thick laminated to a sheet of loop fastener elements, a commercial product sold by the assignee of the instant patent application under the trade name Velfoam® 3953, was used as the base of a device for molding into the foam seat buns. A portion of the foam was cut out through the entire thickness of the foam and the loop sheet to form a crescent curve design. A sheet of plastic hook material, the same dimensions as the foam slab, 8 inches by 6 inches, was attached to the loop elements of the Velfoam®. Alternatively it could be cut slightly larger than the outline of the cresent. The device was applied to a box shaped mold containing on its bottom face a pedestal of the shape of the cutout section of the foam slab except that the pedestal thickness was 1/16 inch greater than the dimensions of the opening in the foam. The height of the foam was slightly less than the 1.5 inch height of the pedestal. The device slid onto the pedestal with a slight resistance but it was possible to insert the piece to the full depth of the trench in the foam and the top of the pedestal was resting against the hook elements. The face of the device was resting approximately 1" above the face of the mold.
A mixture of chemicals used to create polyurethane seat bun foam consisting of MDI and a polyol and appropriate auxiliary ingredients was poured into the mold using a Cannon machine set for a pour time of 2 seconds. The lid of the mold was closed and the foaming chemicals allowed to react for a period of 10 minutes. The lid was raised, the foamed seat bun was removed from the mold. The density of the resulting product was approximately 2.5 lbs/cubic foot. The bun was crushed in a vacuum chamber through two cycles to release the blowing gases trapped in the seat bun foam cells and remove stresses in the poured bun which, unless released, will cause distortion of the bun shape.
The finished seat bun contained on its surface a trench in the shape of a crescent curve 11/2 inch deep with hook elements disposed outwardly from the bottom of the trench. All edges of the hook element layer were buried in the composite seat bun foam structure, resisting removal of the hook layer from the bun.
With the above formulation the bond between the seat bun foam walls defining the opening and the pedestal was sufficient to prevent lifting of the device from the pedestal during the foaming operation.
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In a device for incorporating a separable fastener in a foamed seat cushion during formation of the cushion in a mold, includes a sheet having fastener elements constituting one half of a touch fastener. A foam wall surrounds the fastening surface, the wall having a height considerably greater than the height of the fastening elements. The fastener is held on a pedestal having a predetermined height extending into the mold volume and having a predetermined cross sectional dimension generally parallel to the interior mold surface as measured at a predetermined distance from said mold surface. The foam wall defines an opening which engages the sides of said pedestal with a force sufficiently strong to resist any removal force caused by tendency of the foaming action to lift the foam wall during creation of the cushion and bonding of the forming cushion to the foam wall.
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BACKGROUND OF THE INVENTION
The present invention relates to an improvement in the adhesion and corrosion resistance of painted film applied over chemical conversion coatings on zinc or alloys thereof.
It has been well known that metallic articles having a surface of zinc or zinc alloy exhibit poor paint adhesion. In order to improve the adhesion, the surface has been treated to form a phosphate coating or a complex oxide coating. It has also been well known that a chromate coating applied on the surface of zinc or zinc alloy shows high corrosion resistance but poor adhesion of painted film and poor resistance against scratching as compared with phosphate coatings. In order to improve further the corrosion resistance of phosphate conversion coatings or complex oxide coatings, such coatings have been subjected to a post-treatment process with chromic acid in which the conversion coatings are treated with chromic acid, a dichromate or salts thereof.
The post-treatment process with chromic acid is inexpensive and affords excellent corrosion resistance. However, the toxic and deleterious environmental properties of chromium compounds have recently become serious problems. In order to alleviate the dangers of chromates, it would be desirable to eliminate the use of chromate compositions without sacrificing quality.
Post-treating compositions containing no chromate include those containing predominantly phytic acid as claimed in Japanese Patent Publication No. 43406/1973, those containing predominantly alpha-aminophosphoric acid or alpha-aminosulfonic acid as claimed in Japanese Patent Publication No. 78531/1975, aqueous solutions containing free fluoride ion or a complex ion thereof as claimed in U.S. Pat. No. 3,895,970 and tannic acid as claimed in Japanese Patent Publication No. 2902/1976. The corrosion prevention of metals with tannin has been studied for some years and reported by a number of investigators, especially by E. Knowles, T. White and the like. Such reports are summerized by Journal of the Oil Colour Chemistry Association, Vol. 41, pp. 10 (1956). While some effect can be achieved by such processes, the performance on zinc and alloys thereof is poor as compared with the post-treatment process with chromic acid. The application of such post-treatments over phosphate coatings on zinc may cause some deterioration of the corrosion resistance after painting and, in particular, may cause blisters in painted film as compared to the case where no post-treatment is employed.
SUMMARY OF THE INVENTION
It has now been found that when an aqueous solution of thiourea and a vegetable tannin is applied to conversion coatings on the surface of zinc or an alloy thereof, the corrosion resistance and adhesion of the subsequently painted film is comparable to that obtained via the post-treatment process with chromic acid.
DETAILED DESCRIPTION OF THE INVENTION
Thiourea compounds useful in the present invention include thiourea itself and derivatives thereof such as alkyl thiourea, e.g., dimethyl thiourea, diethyl thiourea, etc., guanyl thiourea and the like in a concentration from 0.1 to 20 g/l, preferably from 0.5 to 5 g/l. In general, suitable for use in the invention are thiourea compounds having the general formula: ##STR1## wherein each X is independently selected from the group consisting of hydrogen and alkyl and amidino groups of up to 4 carbon atoms. Substantially no effect will be achieved at a concentration of lower than 0.1 g/l. On the other hand, a concentration of higher than 20 g/l achieves no further improvement in results.
Tannin or tannic acid usable in the present invention may be any vegetable tannin, hydrolyzable or condensed, and may be partially hydrolyzed. Suitable tannins include depside tannin, gallotannin, chinese tannin, turkish tannin, hamamelitannin, tannic acid from acer ginnala, chebulinic acid, sumac tannin, chinese gallotannin, ellagitannin, catechin, catechin-tannin, and quebracho-tannic acid. The tannin may be used in a concentration from 0.1 to 20 g/l, preferably from 0.5 to 3 g/l.
The weight ratio of thiourea to tannin may range from 10:1 to 1:10, preferably from 3:1 to 1:3.
If the ratio of thiourea to tannin deviates markedly from the range of 10:1 to 1:10, blisters in subsequently painted film tend to be formed in the aqueous corrosion test.
The pH range of the treating solution according to the present process depends on the type of tannin, method and conditions of the application and the like but normally ranges from 2 to 10, preferably from 2.5 to 6.5. If the pH is higher than 10, the degradation of the tannin may occur, but if lower than 2 the reaction may occur too violently and dissolve the phosphate conversion coating. In order to adjust the pH of the treating solution, any commonly employed acidic or alkaline material may be used. Suitable acidic materials include inorganic acidic materials such as phosphoric acid, nitric acid, sulfuric acid, hydrofluoric acid, hydrochloric acid and the like and salts thereof and organic acidic materials such as oxalic acid, citric acid, malic acid, maleic acid, phthalic acid, lactic acid, tartaric acid, chloroacetic acid, acrylic acid and the like and salts thereof. Alkaline materials include inorganic and organic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, ammonia and amines such as ehtylamine, diethylamine, triethylamine, ethanolamine and the like.
For convenience in shipping, an aqueous concentrate may be prepared containing the thiourea and tannin compounds in the foregoing weight ratio with pH adjusted in the concentrate to enhance stability of the concentrate. Concentrate concentration of each component is in excess of 20 g/l, e.g., 10 wt. % or higher. For use, the concentrate is diluted with water to the desired concentration and pH adjusted, if necessary.
In general, metals subjected to this post-treatment are frequently dried without washing, but excessive soluble salts may be removed, if necessary, by washing with water.
The post-treatment solution may be applied over conversion coatings on zinc or zinc alloys by any conventional means such as spraying, immersion, brushing, roll coating, or flooding. The treatment is carried out by contacting the surface with the treating solution at a temperature of from ambient temperature to 90° C., preferably not in excess of 65° C.
The invention is illustrated by way of the following example:
EXAMPLE
Test panels of hot galvanized steel plate having a size of 100 mm×300 mm×0.3 mm and pretreated with chromic acid were polished 5 times by wet buffing to remove chromate adhered on the surface and then immersed in an aqueous solution of a surface conditioner containing titanium phosphate and passed between rubber rolls to remove excess solution. The test panels were sprayed with an aqueous zinc phosphatizing solution, washed with water, passed between rubber rolls to remove excess solution and then post-treated by immersion in an aqueous solution containing thiourea at a concentration of 2 g/l and gallotannin (available from Fuji Kagaku Kogyo Co. under the trade name of Tannic Acid AL) at a concentration of 1 g/l at 50° C. for 2 seconds, followed by passing between rubber rolls to remove excess solution and drying with hot air.
Thus treated, panels were then coated with an alkyd resin based paint via draw down bar and then baked in a hot air recycling oven at 280° C. for 50 seconds to obtain a coating thickness of about 6 microns.
Additional test panels were coated with a primer of epoxy resin and baked in a hot air recycling oven at 280° C. for 50 seconds to form a coating of about 4 microns thickness. The primed test panels were then coated with a top coating paint of acrylic resin type and then baked in a hot air recycling oven at 280° C. for 60 seconds to form a double coating having a total thickness of 14 microns.
The adhesion of the painted films was tested by the bending test in which two test pieces were bended to 180° and then folded completely by means of a vise and then applying and removing rapidly a cellophane tape and the results were then rated from 5 to 1.
Criterion for rating results of bending test were as follows:
5: No stripping
4: Not more than 5% stripping
3: Not more than 25% stripping
2: Not more than 50% stripping
1: More than 50% stripping
The salt-spray corrosion test was performed by scribing the test pieces to the depth to the base metal by means of a knife and then subjecting the panels to the salt spray test according to JIS-Z-2371 for 240 hours for the test panels coated with the single layer paint and for 1000 hours for the test pieces coated with two layers. After washing with water and drying, cellophane tape was applied and removed rapidly from the scribed portion of each test panel to measure the maximum width stripped off from the surface in mm and to observe the stripping-off of the painted film due to blisters in the film.
The aqueous corrosion test was performed by immersing the test panels into boiling water for 2 hours. Blisters were observed and the test panels rated by the bending test.
Blisters are rated as follows:
10--None
5--Blisters on a portion of the panel surface
0--Blisters on the entire panel surface.
COMPARATIVE EXAMPLES
For comparison purposes, panels were treated in an identical manner as above except for the post-treatment step.
Comparative Example 1A employed an aqueous solution of thiourea in a concentration of 2 g/l, Example 1B, an aqueous solution of gallotannin (available from Fuji Kagaku Kogyo Co. under the trade name of Tannin Acid AL) in a concentration of 2 g/l, Example 1C, a conventional aqueous solution of chromic acid at a concentration of 18 g/l, and Example 1D omitted the post-treatment entirely.
Results are presented in the Table.
TABLE__________________________________________________________________________ Single Layer Paint 240 Hr. Salt Spray Two Layer Paint Corrosion Width Aqueous Corrosion 1000 Hr. Salt SprayEXAMPLE Blisters (mm) Bending Blisters Bending (mm)__________________________________________________________________________1 10 0-0.5 4 10 4 0-11A 5 3 2 5 2 41B 5 3 2 5 2 31C 10 0-0.5 3-4 10 4 0-11D 0 5 2 0 2 5__________________________________________________________________________
As apparent from the data in the Table, the results obtained by the present process are comparable with those obtained by the conventional chromate process, except that the adhesion result obtained by the present process is somewhat superior to that obtained by the conventional process. Thus it is appreciated that the process according to the present invention can enhance the resolution of environmental pollution by replacing the conventional process employing chromic acid.
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An environmentally acceptable composition and process imparts improved corrosion resistance and paint adhesion to a conversion coated surface of zinc or zinc alloy. The coated surface is post-treated with an aqueous composition containing a thiourea compound and a vegetable tannin.
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RELATED APPLICATION(S)
[0001] This application is a continuation of U.S. application Ser. No. 12/745,136, which is the U.S. National Stage Application of International Application No. PCT/US2008/085114 filed on Dec. 1, 2008, published in English, which claims the benefit of U.S. Provisional Application No. 60/991,049, filed on Nov. 29, 2007. The entire teachings of the above application(s) are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Endoscopic mucosal resectioning (EMR) is acknowledged as a curative therapeutic modality in the treatment of early gastrointestinal cancers. Heretofore, submucosal injection with saline has been used to minimize complications during EMR. However, the duration of tissue elevation after saline injection is relatively short, and repeated injections are needed to perform EMR on large lesions. Notwithstanding the fact that solutions with high viscosity, such as hydroxypropyl methylcellulose (HPMC), have been used in EMR, an adequate solution to this problem has remained elusive.
SUMMARY OF THE INVENTION
[0003] One aspect of the invention relates to use of a composition comprising a purified inverse thermosensitive polymer in an endoscopic procedure for gastrointestinal mucosal resectioning. Another aspect of the invention relates to a method of gastrointestinal mucosal resectioning, comprising administering submucosally to a region of a gastrointestinal mucosa in a mammal an effective amount of a composition comprising a purified inverse thermosensitive polymer; and surgically resecting said region of gastrointestinal mucosa. Yet another aspect of the invention relates to a kit for use in gastrointestinal endoscopic mucosal resectioning, comprising a composition comprising a purified inverse thermosensitive polymer; a syringe; and instructions for use thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0004] FIG. 1 depicts graphically the viscosities of LeGoo Endo (a 20-25% aqueous solution of purified poloxamer 237) and a 20% aqueous solution of unpurified poloxamer 407 as a function of temperature.
[0005] FIG. 2 depicts graphically the viscosities of LeGoo Endo (a 20-25% aqueous solution of purified poloxamer 237) and a 2.0% aqueous solution of unpurified poloxamer 407 as a function of temperature.
DETAILED DESCRIPTION OF THE INVENTION
[0006] Endoscopic mucosal resection (EMR) represents a major advance in minimally invasive surgery in the gastrointestinal tract. EMR is based on the concept that endoscopy provides visualization and access to the mucosa, the innermost lining of the gastrointestinal tract—the site where most gastrointestinal cancers from the esophagus to the rectum have their origin. The method combines the therapeutic power of endoscopic surgery with the diagnostic power of pathology examination of resected tissue.
[0007] EMR first proliferated in Japan, where endoscopists were faced with a very high incidence of stomach cancer. This differs from most Western countries, including the United States, where colon cancer is a much more common disease. Most colon cancers arise in mucosal polyps, which project into the lumen of the colon, making them relatively easy to remove at endoscopy using wire loops to grasp the polyp base. The polyps are then excised with electric current, producing simultaneous cutting action and cauterization.
[0008] In contrast, in the stomach most cancers do not begin in polyps, but in only slightly elevated, flat, or slightly depressed mucosal dysplastic lesions. Such lesions are very difficult to grasp with a simple wire snare. Japanese endoscopists worked to develop a number of methods to elevate the diseased mucosal area so that snaring would be possible. Most of these techniques used fluid injection into the submucosa, the layer of the gastrointestinal tract immediately below the mucosa, to elevate the mucosa and allow it to he grasped with a snare. Unfortunately, the fluids used to date have not be optimal for the EMR because, for example, they are typically insufficiently viscous to provide a sufficiently durable, elevated surface. Were fluids available that were capable of providing the optimal durable, elevated mucosal surface, EMR could also be used effectively in the esophagus, where early cancer and premalignant dysplasia also tends to be nonpolypoid and fiat, and also in the colon, where it can be used to assist in removal of both small arid large flat or sessile polyps.
[0009] Unpurified inverse thermosensitive polymers could be considered for this indication, but unfortunately these polymers, which gel at body temperature, gel in the catheter used for injection because the catheter warms to body temperature soon after it is deployed within the colon or stomach.
[0010] Remarkably, a purified inverse thermosensitive polymer (LeGoo-endo™), which displays a rapid reversible liquid to gel transition, has now been shown to be efficacious as a submucosal injection solution in ex vivo and in vivo porcine models of human endoscopic gastrointestinal mucosal resectioning (EMR). The rapid reversible liquid to gel transition achieved as a result its purified nature allows LeGoo-endo to be liquid at room temperature and to gel only as it emerges from the catheter at the EMR site. The mucosal elevation obtained with LeGoo-endo™ was more durable than that obtained with other commonly used substances. Moreover, results with LeGoo-endo™ were not subject to significant variations in terms of size and consistency. LeGoo-endo™ performed well in in vivo colonic EMR. These results indicate that use of LeGoo-endo™ or other purified inverse thermosensitive polymers may increase the safety and efficiency of human EMR procedures,
[0011] In certain embodiments, the bleb the gel that provides the mucosal elevation) formed in vivo from the purified inverse thermosensitive polymer persists for about 30-180 minutes, about 45-150 minutes, about 60-120 minutes, about 75-100 minutes, about 90 minutes, about 80 minutes, about 70 minutes, about 60 minutes, about 50 minutes, about 40 minutes, or about 30 minutes.
[0012] In order to obtain the aforementioned results it was necessary to develop a method of injecting through a catheter into the colon or stomach a purified inverse thermosensitive polymer solution that transitions to a gel at body temperature. Among the challenges overcome was the fact that because the catheter quickly reaches body temperature while resident inside the body, the purified inverse thermosensitive polymer will gel inside the catheter prior to reaching the desired site for EMR. For example, due to gel formation in the catheter manual injection by pushing on the plunger of a syringe connected to a catheter is not workable, nor is injection assisted with a mechanical injector at pressures lower than 1200 psi; further, pressures higher than 1200 psi are precluded because they are sufficient to burst any conventional catheter. in other words, the method is not workable if the purified inverse thermosensitive polymer gels in the catheter (i.e., prior to reaching the EMR. site), and pressures that can be tolerated by conventional catheters are insufficient to deliver in fluid form the purified inverse thermosensitive polymer to the EMR site.
[0013] Remarkably, the delivery problems were solved with a system comprising a high-pressure needle catheter connected to a syringe filled with purified inverse thermosensitive polymer, wherein said high-pressure needle catheter is contained within an administration device (e.g., a syringe pump) that generates pressure on the plunger of the syringe, through a manual (e.g., screw), electrical or pressurized-gas mechanism. The higher pressures available and tolerated using said system have two functions: (a) pushing the viscous fluid through the catheter; and (b) allowing for a sufficiently rapid injection that purified inverse thermosensitive polymer entering the catheter from the room-temperature syringe constantly regulates the temperature of the catheter so that the polymer does not gel in the catheter during the residence time, and only gels after it emerges from the catheter and is brought into direct contact with the EMR site.
[0014] In sum, LeGoo-Endo—denoted “PS137-25” in the Figures—is an aqueous solution of purified poloxamer 237 with a viscosity at body temperature 3.9 times that of unpurified 20% poloxamer 407, allowing for the formation of a lasting bleb capable of withstanding the pressure exercised by the elastic mucosal membrane; moreover, the viscosities of LeGoo-Endo at 25 C and room temperature are less than a tenth of the viscosities of unpurified 20% poloxamer 407 at those temperatures, respectively, thereby preventing gel formation within the catheter during administration of LeGoo-Endo, in part because the catheter is continuously cooled by new LeGoo-Endo as it enters the catheter under pressure.
Inverse Thermosensitive Polymers
[0015] In general, the inverse thermosensitive polymers used in the methods of the invention, which become a gel at or about body temperature, can be injected into the patient's body in a liquid or soft gel form. The injected material once reaching body temperature undergoes a transition from a liquid or soft gel to a hard gel. The inverse thermosensitive polymers used in connection with the methods of the invention may comprise a block copolymer with inverse thermal gelation properties. In general, biocompatible, biodegradable block copolymers that exist as a gel at body temperature and a liquid at below body temperature may also be used according to the present invention. Also, the inverse thermosensitive polymer can include a therapeutic agent, such as anti-angiogenic agents, hormones, anesthetics, antimicrobial agents (antibacterial, antifungal, antiviral), anti-inflammatory agents, diagnostic agents, or wound healing agents. Similarly, low concentrations of dye (such as methylene blue) or fillers can be added to the inverse thermosensitive polymer.
[0016] The molecular weight of the inverse thermosensitive polymer may be between 1,000 and 50,000, or between 5,000 and 35,000. Typically the polymer is in an aqueous solution. For example, typical aqueous solutions contain about 5% to about 30% polymer, or about 10% to about 25%. The molecular weight of a suitable inverse thermosensitive polymer (such as a poloxamer or poloxamine) may be, for example, between 5,000 and 25,000, or between 7,000 and 20,000.
[0017] The pH of the inverse thermosensitive polymer formulation administered to the mammal is, generally, about 6.0 to about 7.8, which are suitable pH levels for injection into the mammalian body. The pH level may be adjusted by any suitable acid or base, such as hydrochloric acid or sodium hydroxide.
Poloxamers (Pluronics)
[0018] Notably, Pluronic® polymers have unique surfactant abilities and extremely low toxicity and immunogenic responses. These products have low acute oral and dermal toxicity and low potential for causing irritation or sensitization, and the general chronic and sub-chronic toxicity is low, In fact, Pluronic® polymers are among a small number of surfactants that have been approved by the FDA for direct use in medical applications and as food additives (BASF (1990) Pluronic® & Tetronic® Surfactants, BASF Co., Mount Olive, N.J.). Recently, several Pluronic® polymers have been found to enhance the therapeutic effect of drugs, and the gene transfer efficiency mediated by adenovirus. (March K L, Madison J E, Trapnell B C. “Pharmacokinetics of adenoviral vector-mediated gene delivery to vascular smooth muscle cells: modulation by poloxamer 407 and implication for cardiovascular gene therapy” Hum Gene Therapy 1995, 6, 41-53).
[0019] Poloxamers (or Pluronics), as nonionic surfactants, are widely used in diverse industrial applications, (Nonionic Surfactants: polyoxyalkylene block copolymers, Vol. 60, Nace V M, Dekker M (editors), New York, 1996. 280 pp.) Their surfactant properties have been useful in detergency, dispersion, stabilization, foaming, and emulsification. (Cabana A, Abdellatif A K, Juhasz 3, “Study of the gelation process of polyethylene oxide, polypropylene oxide-polyethylene oxide copolymer (poloxamer 407) aqueous solutions.” Journal of Colloid and Interface Science, 1997; 190: 307-312.) Certain poloxamines, e.g., poloxamine 1307 and 1107, also display inverse thermosensitivity,
[0020] Some of these polymers have been considered for various cardiovascular applications, as well as in sickle cell anemia, (Maynard C, Swenson R, Paris J A, Martin 35, Halistrom A P, Cerqueira M D, Weaver W D. Randomized, controlled trial of RheothRx (poloxamer 188) in patients with suspected acute myocardial infarction, RheothRx in Myocardial Infarction Study Group. Am Heart J. 1998 May 135 (5 Pt 1): 797-804; O'Keefe. J H, Crines C L, DeWood M A, Schaer G L, Browne K, Magorien R D, Kalbfleisch J M, Fletcher W O Jr, Bateman T M, Gibbons R J. Poloxamer-188 as an adjunct to primary percutaneous transluminal coronary angioplasty for acute myocardial infarction, Am J Cardiol. 1996 Oct. 1;78(7):747-750; and Orringer E P, Casella J F, Ataga K I, Koshy M, Adams-Graves P, Luchtman-Jones L, Wun T, Watanabe M, Shafer F, Kutlar A, Abboud M, Steinberg M, Adler B, Swerdlow P, Terregino C, Saccente S, Files B, Gallas S, Brown R, Wojtowicz-Praga S, Grindel J M, Purified poloxamer 188 for treatment of acute vasoocciusive crisis of sickle cell disease: A randomized controlled trial. JAMA. 2001 Nov. 7;286 (17):209942106.)
[0021] Importantly, several members of this class of polymer, e.g., poloxamer 188, poloxamer 407, poloxamer 338, poloxamines 1107 and 1307, show inverse thermosensitivity within. the physiological temperature range. (Qiu Y, Park K. Environment-sensitive hydrogels for drug delivery, Adv Drug Deliv Rev. 2001 Dec. 31;53(3):321-339; and Ron E S, Bromberg L E Temperature-responsive gels and thermogelling polymer matrices for protein and peptide delivery Adv Drug Deliv Rev. 1998 May 4;31(3;):197- 221.) in other words, these polymers are members of a class that are soluble in aqueous solutions at low temperature, but gel at higher temperatures, Poloxamer 407 is a biocompatible polyoxypropylene-polyoxyethylene block copolymer having an average molecular weight of about 12,500 and a polyoxypropylene fraction of about 30%; poloxamer 188 has an average molecular weight of about 8400 and a polyoxypropylene fraction of about 20%; poloxamer 338 has an average molecular weight of about 14,600 and a polyoxypropylene fraction of about 20%; poloxamine 1,107 has an average molecular weight of about 14,000, poloxamine 1307 has an average molecular weight of about 18,000. Polymers of this type are also referred to as reversibly gelling because their viscosity increases and decreases with an increase and decrease in temperature, respectively. Such reversibly gelling systems are useful wherever it is desirable to handle a material in a fluid state, but performance is preferably in a gelled or more viscous state. As noted above, certain poly(ethyleneoxide)/poly(propyleneoxide) block copolymers have these properties; they are available commercially as Pluronic® poloxamers and Tetronic® poloxamines (BASF, Ludwigshafen, Germany) and generically known as poloxamers and poloxamines, respectively. See U.S. Pat. Nos. 4,188,373, 4,478,822 and 4,474,751 (all of which are incorporated by reference).
[0022] The average molecular weights of the poloxamers range from about 1,000 to greater than 16,000 Daltons. Because the poloxamers are products of a sequential series of reactions, the molecular weights of the individual poloxamer molecules form a statistical distribution about the average molecular weight. in addition, commercially available poloxamers contain substantial amounts of poly(oxyethylene) homopolymer and poly(oxyethylene)/poly(oxypropylene diblock polymers. The relative amounts of these byproducts increase as the molecular weights of the component blocks of the poloxarner increase. Depending upon the manufacturer, these byproducts may constitute from about 15 to about 50% of the total mass of the polymer.
Purification of Inverse Thermosensitive Polymers
[0023] The inverse thermosensitive polymers may be purified using a process for the fractionation of water-soluble polymers, comprising the steps of dissolving a known amount of the polymer in water, adding a soluble extraction salt to the polymer solution, maintaining the solution at a constant optimal temperature for a period of time adequate for two distinct phases to appear, and separating physically the phases. Additionally, the phase containing the polymer fraction of the preferred molecular weight may be diluted to the original volume with water, extraction salt may be added to achieve the original concentration, and the separation process repeated as needed until a polymer having a narrower molecular weight distribution than the starting material and optimal physical characteristics can be recovered.
[0024] In certain embodiments, a purified poloxamer or poloxamine has a polydispersity index from about 1.5 to about 1.0. In certain embodiments, a purified poloxamer or poloxamine has a polydispersity index from about 1.2 to about 1.0.
[0025] The aforementioned process consists of forming an aqueous two-phase system composed of the polymer and an appropriate salt in water. In such a system, a soluble salt can be added to a single phase polymer-water system to induce phase separation to yield a high salt, low polymer bottom phase, and a low salt, high polymer upper phase. Lower molecular weight polymers partition preferentially into the high salt, low polymer phase, Polymers that can he fractionated using this process include polyethers, glycols such as poly(ethylene glycol) and poly(ethylene oxide)s, polyoxyalkyiene block copolymers, such as poloxamers, poloxamines, and polyoxypropylene/ polyoxybutylene copolymers, and other polyols, such as polyvinyl alcohol. The average molecular weight of these polymers may range from about 800 to greater than 100,000 Daltons. See U.S. Pat. No. 6,761,824 (incorporated by reference). The aforementioned purification process inherently exploits the differences in size and polarity, and therefore solubility, among the poloxamer molecules, the poly(oxyethylene) homopolymer and the poly(oxyethylene)/poly(oxypropylene) diblock byproducts. The polar fraction of the . poloxamer, which generally includes the lower molecular weight fraction and the byproducts, is removed allowing the higher molecular weight fraction of poloxamer to be recovered. The larger molecular weight purified poloxamer (an example of a purified inverse thermosensitive polymer) recovered by this method has physical characteristics substantially different from the starting material or commercially available poloxamer including a higher average molecular weight, lower polydispersity and a higher viscosity in aqueous solution.
[0026] Other purification methods may be used to achieve the desired outcome, For example, WO 92/16484 (incorporated by reference) discloses the use of gel permeation chromatography to isolate a fraction of poloxamer 188 that exhibits beneficial biological effects, without causing potentially deleterious side effects. The copolymer thus obtained had a. polydispersity index of 1.07 or less, and was substantially saturated, The potentially harmful side effects were shown to be associated with the low molecular weight, unsaturated portion of the polymer, while the medically beneficial effects resided in the uniform higher molecular weight material. Other similarly improved copolymers were obtained by purifying either the polyoxypropylene center block during synthesis of the copolymer, or the copolymer product itself (e.g., U.S. Pat. No. 5,523,492 and U.S. Pat. No. 5,696,298, both of which are incorporated by reference).
[0027] Further, a supercritical fluid extraction technique has been used to fractionate a polyoxyalkylene block copolymer as disclosed in U.S. Pat. No. 5,567,859 (incorporated by reference). A purified fraction was obtained, which was composed of a fairly uniform polyoxyalkylene block copolymer having a polydispersity of less than 1.17, According to this method, the lower molecular weight fraction was removed in a stream of carbon dioxide maintained at a pressure of 2200 pounds per square inch (psi) and a temperature of 40° C.
[0028] Additionally, U.S. Pat. No. 5,800,711 (incorporated by reference) discloses a process for the fractionation of polyoxyalkylene block copolymers by the batchwise removal of low molecular weight species using a salt extraction and liquid phase separation technique. Poloxamer 407 and poloxamer 188 were fractionated by this method. In each case, a copolymer fraction was obtained which had a higher average molecular weight and a lower polydispersity index as compared to the starting material. However, the changes in polydispersity index were modest and analysis by gel permeation chromatography indicated that some low-molecular-weight material remained. The viscosity of aqueous solutions of the fractionated polymers was significantly greater than the viscosity of the commercially available polymers at temperatures between 10° C. and 37° C., an important property for some medical and drug delivery applications. Nevertheless, some of the low molecular weight contaminants of these polymers are thought to cause deleterious side effects when used inside the body, making it especially important that they be removed in the fractionation process. As a consequence, polyoxyalkylene block copolymers fractionated by this process are not appropriate for all medical uses.
[0029] As mentioned above, the use of these polymers in larger concentrations in humans requires removal of lower molecular weight contaminants present in commercial preparations. As was demonstrated in U.S. Pat. No. 5,567,859 (incorporated by reference; Examples 8 & 9), the lower molecular weight contaminants are mostly responsible for the toxic effects seen. In a clinical trial using unpurified poloxamer 188, an unacceptable level of transient renal dysfunction was found (Maynard C, Swenson R, Paris J A, Martin J S, Hallstrom A P, Cerqueira M D, Weaver W D. Randomized, controlled trial of RheothRx (poloxamer 188) in patients with suspected acute myocardial infarction. RheothRx in Myocardial Infarction Study Group, Am Heart J. 1998 May 135(5 Pt 1):797-804), while another clinical trial using purified poloxamer 188 specifically mentioned that no renal dysfunction was found (Orringer E P, Casella J F, Ataga K I, Koshy M, Adams-Graves P, Luchtman-Jones L, Wun T, Watanabe M, Shafer F, Kutlar A, Abboud M, Steinberg M, Adler B, Swerdlow P, Terregino C, Saccente S. Files B, Ballas S. Brown R, Wojtowicz-Praga S, Grindel J M. Purified poloxamer 188 for treatment of acute vasoocclusive crisis of sickle cell disease: A randomized controlled trial. JAMA. 2001 Nov. 7;286(17):2099-2106.) Therefore, it seems imperative to utilize only fractionated poloxamers and poloxamines in EMR applications like the ones envisioned here. Furthermore, fractionation of these thermosensitive polymers leads to improved gels with stronger mechanical resistance and due to the improved thermosensitivity requires less polymer to achieve gelation (See for example U.S. Pat. No. 6,761,824 (incorporated by reference) on a purification scheme and the resultant viscosities).
[0000] Drug Delivery in Conjunction with EMR Using Purified Inverse Thermosensitive Polymers
[0030] Therapeutically effective use of many types of biologically active molecules has not been realized simply because methods are not available to effect delivery of therapeutically effective amounts of such substances into the particular cells of a patient for which treatment would provide therapeutic benefit. New ways of delivering drugs at the right time, in a controlled manner, with minimal side effects, and greater efficacy per dose are sought by the drug-delivery and pharmaceutical industries.
[0031] The reversibly gelling polymers used in the EMR methods of the invention have physico-chemical characteristics that make them suitable delivery vehicles for conventional small-molecule drugs, as well as new macromolecular (e.g., peptides) drugs or other therapeutic products. Therefore, the composition comprising the purified inverse thermosensitive polymer may further comprise a pharmaceutic agent selected to provide a pre-selected pharmaceutic effect. A pharmaceutic effect is one which seeks to treat the source or symptom of a disease or physical disorder. Pharmaceutics include those products subject to regulation under the FDA pharmaceutic. guidelines, as well as consumer products. Importantly, the compositions used EMR methods of the invention are capable of solubilizing and releasing bioactive materials. Solubilization is expected to occur as a result of dissolution in the bulk aqueous phase or by incorporation of the solute in micelles created by the hydrophobic domains of the poloxamer. Release of the drug would occur through diffusion or network erosion mechanisms.
[0032] Those skilled in the art will appreciate that the compositions used in the EMR methods of the invention may simultaneously be utilized to deliver a wide variety of pharmaceutic and personal care applications. To prepare a pharmaceutic composition, an effective amount of pharmaceutically active agent(s), which imparts the desirable pharmaceutic effect is incorporated into the reversibly gelling composition used in the EMR methods of the invention. Preferably, the selected agent is water soluble, which will readily lend itself to a homogeneous dispersion throughout the reversibly gelling composition. it is also preferred that the agent(s) is non-reactive with the composition. For materials, which are not water soluble, it is also within the scope of the EMR methods of the invention to disperse or suspend lipophilic material throughout the composition. Myriad bioactive materials may be delivered using the methods of the present invention; the delivered bioactive material includes anesthetics, antimicrobial agents (antibacterial, antifungal, antiviral), anti-inflammatory agents, diagnostic agents, and wound healing agents.
[0033] Because the reversibly gelling composition used in the methods of the present invention are suited for application under a variety of physiological conditions, a wide variety of pharmaceutically active agents may be incorporated into and administered from the composition. The pharmaceutic agent loaded into the polymer networks of the purified inverse thermosensitive polymer may be any substance having biological activity, including proteins, polypeptides, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, and synthetic and biologically engineered analogs thereof.
[0034] A vast number of therapeutic agents may he incorporated in the polymers used in the methods of the present invention. In general, therapeutic agents which may be administered via the methods of the invention include, without limitation; antiinfectives such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorexics; anti helmintics; antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants; antidiuretic agents; antidiarrheals; antihistamines; andinflammatory agents; antimigraine preparations; antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics, antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including calcium channel blockers and beta-blockers such as pindolol and antiarrhythmics; antihypertensives; diuretics; vasodilators including general coronary, peripheral and cerebral; central nervous system stimulants; cough and cold preparations, including decongestants; hormones such as estradiol and other steroids, including corticosteroids; hypnotics; immunosuppressives; muscle relaxants; parasympatholytics; psychostimulants; sedatives; and tranquilizers; and naturally derived or genetically engineered proteins, polysaccharides, glycoproteins, or lipoproteins. Suitable pharmaceuticals for parenteral administration are well known as is exemplified by the Handbook on Injectable Drugs, 6th Edition, by Lawrence A. Trissel, American Society of Hospital Pharmacists, Bethesda, Md., 1990.
[0035] The pharmaceutically active compound may be any substance having biological activity, including proteins, polypeptides, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, and synthetic and biologically engineered analogs thereof. The term “protein” is art-recognized and for purposes of this invention also encompasses peptides. The proteins or peptides may be any biologically active protein or peptide, naturally occurring or synthetic.
[0036] Examples of proteins include antibodies, enzymes, growth hormone and growth hormone-releasing hormone, gonadotropin-releasing hormone, and its agonist and antagonist analogues, somatostatin and its analogues, gonadotropins such as luteinizing hormone and follicle-stimulating hormone, peptide T, thyrocalcitonin, parathyroid hormone, glucagon, vasopressin, oxytocin, angiotensin I and II, bradykinin, kallidin, adrenocorticotropic hormone, thyroid stimulating hormone, insulin, glucagon and the numerous analogues and congeners of the foregoing molecules. The pharmaceutical agents may be selected from insulin, antigens selected from the group consisting of MMR. (mumps, measles and rubella.) vaccine, typhoid vaccine, hepatitis A vaccine, hepatitis B vaccine, herpes simplex virus, bacterial toxoids, cholera toxin B-subunit, influenza vaccine virus, bordetela pertussis virus, vaccinia virus, adenovirus, canary pox, polio vaccine virus, plasmodium falciparum, bacillus calmette geurin (BCG), klebsiella pneumoniae, HIV envelop glycoproteins and cytokins and other agents selected from the group consisting of bovine somatropine (sometimes referred to as BS), estrogens, androgens, insulin growth factors (sometimes referred to as IGF), interleukin I, interleukin II and cytokins. Three such cytokins are interferon-β, interferon-γ and tuftsin.
[0037] Examples of bacterial toxoids that may be incorporated in the compositions used in the EMR methods of the invention are tetanus, diphtheria, pseudomonas A, mycobacterium tuberculosis. Examples of that may be incorporated in the compositions used in the EMR methods of the invention are HIV envelope glycoproteins, e.g., gp 120 or gp 160, for AIDS vaccines. Examples of anti-ulcer H2 receptor antagonists that may be included are ranitidine, cimetidine and famotidine, and other anti-ulcer drugs are omparazide, cesupride and misoprostol, An example of a hypoglycaemic agent is glizipide,
[0038] Classes of pharmaceutically active compounds which can be loaded into that may be incorporated in the compositions used in the EMR methods of the invention include, but are not limited to, anti-AIDS substances, anti-cancer substances, antibiotics, immunosuppressants (e.g., cyclosporine) anti-viral substances, enzyme inhibitors, neurotoxins, opioids, hypnotics, antihistamines, lubricants tranquilizers, anti-convulsants, muscle relaxants and anti-Parkinson substances, anti-spasmodics and muscle contractants, miotics and anti-cholinergics, anti-glaucoma compounds, anti-parasite and/or anti-protozoal compounds, anti-hypertensives, analgesics, anti-pyretics and anti-inflammatory agents such as NSAIDs, local anesthetics, ophthalmics, prostaglandins, anti-depressants, anti-psychotic substances, anti-emetics, imaging agents, specific targeting agents, neurotransmitters, proteins, cell response modifiers, and vaccines.
[0039] Exemplary pharmaceutical agents considered to be particularly suitable for incorporation in the compositions used in the EMR methods of the invention include but are not limited to imidazoles, such as miconazole, econazole, terconazole, saperconazole, itraconazole, metronidazole, fluconazole, ketoconazole, and clotrimazole, luteinizing-hormone-releasing hormone (LHRH) and its analogues, nonoxynol-9, as GnRH agonist or antagonist, natural or synthetic progestrin, such as selected progesterone, 17- hydroxyprogeterone derivatives such as medroxyprogesterone acetate, and 19-nortestosterone analogues such as norethindrone, natural or synthetic estrogens, conjugated estrogens, estradiol, estropipate, and ethinyl estradiol, bisphosphonates including etidronate, alendronate, tiludronate, resedronate, clodronate, and pamidronate, calcitonin, parathyroid hormones, carbonic anhydrase inhibitor such as felbamate and dorzolamide, a mast cell stabilizer such as xesterbergsterol-A, lodoxamine, and cromolyn, a prostaglandin inhibitor such as diclofenac and ketorolac, a steroid such as prednisolone, dexamethasone, fluromethylone, rimexolone, and lotepednol, an antihistamine such as antazoline, pheniramine, and histiminase, pilocarpine nitrate, a beta-blocker such as levobunolol and timelol maleate. As will be understood by those skilled in the art, two or more pharmaceutical agents may he combined for specific effects. The necessary amounts of active ingredient can be determined by simple experimentation.
[0040] By way of example only, any of a number of antibiotics and antimicrobials may be included in the purified inverse thermnosensitive polymers used in the methods of the invention. Antimicrobial drugs preferred for inclusion in compositions used in the EMR methods of the invention include salts of lactam drugs, quinolone drugs, ciprofloxacin, norfloxacin, tetracycline, erythromycin, amikacin, triclosan, doxycycline, capreomycin, chlorhexidine, chlortetracycline, oxytetracycline, clindamycin, ethambutol, hexamidine isethionate, metronidazole, pentamidine, gentamicin, kanamycin, lineomYcin, methacycline, methenamine, minocycline, neomycin, netilmicin, paromomycin, streptomycin, tobramycin, miconazole and amanfadine and the like,
[0041] By way of example only, in the case of anti-inflammation, non-steroidal anti-inflammatory agents (MAIDS) may be incorporated in the compositions used in the EMR methods of the invention, such as propionic acid derivatives, acetic acid, fenamic acid derivatives, biphenylcarboxylic acid derivatives, oxicams, including but not limited to aspirin, acetaminophen, ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carporfen, and hucloxic acid and the like.
Exemplification
[0042] The invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention,
Ex Vivo
[0043] Gastric endoscopic mucosal resections (120) were performed in fresh ex vivo porcine stomachs using three different solutions: normal saline solution (n=40); HPMC (n=40); and Goo-endo™ (n=40). Each submucosal injection was performed by injecting 5 mL of solution by using a 10-mL syringe with a 25-gauge needle. After creating a visually adequate submucosal elevation, the needle was kept in position for a short time to block the puncture site and prevent premature escape of solution. The stomachs were placed on a thermal pad for assuring a constant temperature (35-37° C.). In all cases, the height and size of the bleb and the duration of the submucosal elevation were measured. When the elevation lasted visible in place 120 minutes, the test was finished.
[0044] The height of initial mucosal elevations was higher with LeGoo-endo™ (10.3+2.2 mm) than with saline (8.3+2.6 mm, p<0.01) and HPMC (9.05+2.3 mm, p=ns). No significant differences were observed regarding the large diameter of the elevations between LeGoo-endo™ (34.7+4.4 mm) and saline (36.7+4 mm) or HPMC (33.7+4 mm). All the submucosal elevations with LeGoo-endo™ lasted more than 120 minutes and the time was longer than with saline (20.9+11 min, p<0.01) and HPMC (89+32 min, p<0.01.). After 120 minutes in place, the elevations performed with LeGoo-endo™ showed no differences in size, shape and consistency.
In Vivo
[0045] Five EMR were performed in the colon of 2 pigs with LeGoo.endo™ using a 23-gauge scletotherapy needle with a syringe and a balloon dilator gun. LeGoo-endo™ was kept on ice during the intervention. Saline containing syringes were also kept on ice to cool the catheter immediately before poloxamer injections. After creating a visually adequate submucosal elevation, it was assessed as “small”, “medium” or “big”. Then, an “en bloc” resection of the lesion was performed using a needle knife or a polypectomy snare. All procedures were recorded and pictures were taken. In all cases, the size of the resected specimen was measured and surfaces were assessed by histologic evaluation.
[0046] The five EMR were located in the sigma between 18 and 25 cm from the anus margin. The height of initial mucosal elevation was large in 2 cases, medium in 2 cases, and small in 1 case. After the injection of the polymer, no reposition was needed. The mean volume injected was 6+2.5 mL (range, 3-10 mL) and the mean size of the specimen resected was 2.6+1.1 cm (range 0.9-4 cm). The mean time for the resection was 5+2 minutes (range, 2-8 minutes). During the resection, a large amount of gel was observed between the submucosa and the mucosa. No thermal injury was observed in the serosa surface and no perforations were reported. No changes were needed to electrocautery settings. In one case, a temporary bleeding from a submucosal vessel was observed. Histologic examination showed that submucosa layer was present in all the specimens.
Equivalents
[0047] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims. cm 1 - 20 . (canceled)
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One aspect of the invention relates to use of a composition comprising a purified inverse thermosensitive polymer in an endoscopic procedure for gastrointestinal mucosal resectioning in a mammal. Another aspect of the invention relates to a method of 5gastrointestinal mucosal resectioning, comprising administering submucosally to a region of a gastrointestinal mucosa in a mammal an effective amount of a composition comprising a purified inverse thermosensitive polymer; and surgically resecting said region of gastrointestinal mucosa. Yet another aspect of the invention relates to a kit for use in gastrointestinal endoscopic mucosal resectioning in a mammal, comprising a composition 10comprising a purified inverse thermosensitive polymer; a syringe; and instructions for use thereof.
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FIELD OF THE INVENTION
[0001] The invention relates to a kind of compound having anti-virus activity, more particularly to a kind of hepatitis C virus protease inhibitor.
BACKGROUND OF THE INVENTION
[0002] Viral hepatitis can be divided into seven types of A, B, C, D, E, F and G Hepatitis C is the most common one and is a kind of infectious disease targeting liver organs caused by hepatitis C virus (hepatitis C virus, HCV). About 3 percent of the global population has been infected with the hepatitis C virus.
[0003] Hepatitis C virus (HCV) is a positive-strand RNA of about 9.6 Kb including 5′ untranslated region (5′-UTR), open reading frame (ORF) and 3′ untranslated region (3′-UTR). ORF is translated into a polypeptide chain which is subsequently processed into at least 10 different proteins including one nucleocapsid protein, two envelope proteins (E1 and E2) and non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B).
[0004] At present, there are about 17 anti-HCV compounds (such as ABT-450, BMS-650032, BI 201335, TMC-435, GS 9256, ACH-1625, MK-7009, etc) which have been into the stage of the pre-clinical and clinical development. All of them are designed to target HCV NS3/4A serine protease inhibitors. For example, the drug boceprevir developed by the pharmaceutical giant Merck (Merck) and the drug telaprevir developed by Vertex Pharmaceuticals, Inc. (Vertex), both are designed to target NS3/4A serine protease of HCV, which were approved by U.S. FDA in 2011. Showed clinically is that the cure rate of both drugs combined with standard treatment can be increased to approximately 75%.
[0005] Nevertheless, these drugs are just the beginning. Researchers are developing drugs targeting to more than one biological characteristic of hepatitis C virus. These drugs by combined administration are expected to solve the drug-resistant problem of HCV.
SUMMARY OF THE INVENTION
[0006] The first aim of the present invention is to provide an anti-virus compound having the general formula (I), or a pharmaceutically acceptable prodrug, salt or hydrate thereof,
[0000]
[0000] wherein,
[0007] A is O, S, CH, NH or NR′, wherein, R′ is C 1 -C 6 alkyl substituted or unsubstituted by halogen which includes 0˜3 heteroatom(s) of O, S or N.
[0008] Ra, Rb, Rc and Rd independently is H, OH, halogen or —Y 1 —R m , Y 1 is linking bond, O, S, SO, SO 2 or NR n ; R m is hydrogen, or, R m is an unsubstituted substituent or one substituted by 1˜3 R m ′ which is selected from the following group: (C 1 -C 8 ) alkyl, N≡C—(C 1 -C 6 ) alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, (C 3 -C 7 ) cycloalkyl, (C 3 -C 7 cycloalkyl) (C 1 -C 6 ) alkyl, and 5˜6 membered aryl or heteroaryl including 0˜2 heteroatom(s) independently selected from N, O, S; R n is H, (C 1 -C 6 ) alkyl or (C 3 -C 6 ) cycloalkyl. Wherein, R m ′ is a substituent selected from the following group: halogen, (C 1 -C 6 ) alkyl substituted optionally by (C 1 -C 6 )alkyl-O— or (C 3 -C 6 )cycloalkyl-O—, (C 1 -C 6 ) haloalkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )alkyl-O—, heteroaryl, —NH 2 , (C 1 -C 4 alkyl)NH— and (C 1 -C 4 alkyl) 2 N—.
[0009] A 1 is NH or CH 2 .
[0010] A 2 is N, O or linking bond.
[0011] R 1 ′ is an unsubstituted substituent or one substituted by 1 to more R 1 ″ which is selected from the following group: C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, (aryl) C 1 -C 2 alkyl, C 3 -C 7 cycloalkyl, (C 3 -C 7 cycloalkyl) C 1 -C 2 alkyl, C 3 -C 7 cycloalkenyl, (C 3 -C 7 cycloalkenyl) C 1 -C 2 alkyl, heterocycloalkyl, (heterocycloalkyl) C 1 -C 2 alkyl, C 5 -C 10 heteroaryl and (C 5 -C 10 heteroaryl) C 1 -C 2 alkyl;
[0012] R 1 ″ is a substituent selected from the following group: halogen, OH, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, —NH 2 , (C 1 -C 6 alkyl)-NH— and —N(C 1 -C 6 alkyl) 2 ;
[0013] preferably, R 1 ′ is
[0000]
[0014] R 1 is hydrogen; or; R 1 linking covalently with R 3 together forms a C 5 -C 9 saturated or unsaturated hydrocarbon chain which can be inserted by 0˜2 heteroatom(s) independently selected from N, S and O, or which can be substituted by none or more halogen, O, S or —NR p R q , wherein, R p and R q independently is hydrogen or C 1 -C 6 alkyl; preferably, R 1 linking covalently with R 3 together forms a C 5 alkane chain.
[0015] R 3 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, heterocycloalkyl, (C 3 -C 7 cycloalkyl) C 1 -C 4 alkyl, (C 3 -C 7 cycloalkenyl) C 1 -C 4 alkyl, (heterocycloalkyl) C 1 -C 4 alkyl, C 2 -C 6 alkylacyl, (C 1 -C 4 alkyl) 1-2 (C 3 -C 7 ) cycloalkyl or (C 1 -C 6 alkyl) 1-2 amino.
[0016] R 4 is C 1 -C 10 alkoxycarbonyl, (C 1 -C 10 alkyl)-NHCO, (C 1 -C 10 alkyl) 2 NCO, aryl, heteroaryl or formyl substituted by 3˜7 membered cycloalkyl, heterocycloalkyl or cycloalkoxy, which may be unsubstituted or substituted by 1 to more R 4 ′; wherein, R 4 ′ is a substituent selected from the following group: halogen, OH, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, —NH 2 , (C 1 -C 6 alkyl)-NH— and —N(C 1 -C 6 alkyl) 2 , (C 1 -C 6 alkyl)-SO 2 —;
[0017] preferably, R 4 is
[0000]
[0000] wherein, Rx and Ry independently is F, Cl, C 1 -C 6 alkyl or C 1 -C 6 alkoxyl, Rz is C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 alkylformyl or (C 1 -C 6 alkyl)-SO 2 —.
[0018] When Z 3 links with O, Z 1 is N or CR Z1 , Z 2 is CR Z2 , wherein, R Z1 is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NH 2 , (C 1 -C 6 alkyl)NH or (C 1 -C 6 alkyl) 2 N, R Z2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl or heteroaryl; or R Z1 , R Z2 with carbon atoms linking with them together form a substituted or unsubstituted ring;
[0019] when Z 1 links with O, Z 2 is CH, Z 3 is C—Ar, Ar is a substituted or unsubstituted aryl or heteroaryl.
[0020] In one preferable embodiment of the present invention, when Z 3 links with O, preferably, R Z1 , R Z2 with carbon atoms linking with them together form a 6 membered aromatic ring substituted by Re, Rf, Rg and Rh, shown in formula (Ia),
[0000]
[0021] In formula (Ia),
[0022] A is O, S, CH, NH or NR′, wherein, R′ is C 1 -C 6 alkyl substituted or unsubstituted by halogen which includes 0˜3 heteroatom(s) of O, S or N.
[0023] Ra, Rb, Rc, Rd, Re, Rf, Rg and Rh independently is H, OH, halogen or —Y 1 —R m , Y 1 is linking bond, O, S, SO, SO 2 or NR n ; R m is hydrogen, or, R m is an unsubstituted substituent or one substituted by 1˜3 R m ′ which is selected from the following group: (C 1 -C 8 ) alkyl, N≡C—(C 1 -C 6 ) alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, (C 3 -C 7 ) cycloalkyl, (C 3 -C 7 cycloalkyl) (C 1 -C 6 ) alkyl, and 5˜6 membered aryl or heteroaryl including 0˜2 heteroatom(s) independently selected from N, O, S; R n is H, (C 1 -C 6 ) alkyl or (C 3 -C 6 ) cycloalkyl. Wherein, R m ′ is a substituent selected from the following group: halogen, (C 1 -C 6 ) alkyl substituted optionally by (C 1 -C 6 )alkyl-O— or (C 3 -C 6 )cycloalkyl-O—, (C 1 -C 6 ) haloalkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )alkyl-O—, heteroaryl, —NH 2 , (C 1 -C 4 alkyl)NH— and (C 1 -C 4 alkyl) 2 N—.
[0024] A 1 is NH or CH 2 .
[0025] A 2 is N, O or linking bond.
[0026] R 1 ′ is an unsubstituted substituent or one substituted by 1 to more R 1 ″ which is selected from the following group: C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, (aryl) C 1 -C 2 alkyl, C 3 -C 7 cycloalkyl, (C 3 -C 7 cycloalkyl) C 1 -C 2 alkyl, C 3 -C 7 cycloalkenyl, (C 3 -C 7 cycloalkenyl) C 1 -C 2 alkyl, heterocycloalkyl, (heterocycloalkyl) C 1 -C 2 alkyl, C 5 -C 10 heteroaryl and (C 5 -C 10 heteroaryl) C 1 -C 2 alkyl;
[0027] R 1 ″ is a substituent selected from the following group: halogen, OH, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, —NH 2 , (C 1 -C 6 alkyl)-NH— and —N(C 1 -C 6 alkyl) 2 ;
[0028] preferably, R 1 ′ is
[0000]
[0029] R 1 is hydrogen; or; R 1 linking covalently with R 3 together forms a C 5 -C 9 saturated or unsaturated hydrocarbon chain which can be inserted by 0˜2 heteroatom(s) independently selected from N, S and O, or which can be substituted by none or more halogen, O, S or —NR p R q , wherein, R p and R q independently is hydrogen or C 1 -C 6 alkyl; preferably, R 1 linking covalently with R 3 together forms a C 5 alkane chain.
[0030] R 3 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, heterocycloalkyl, (C 3 -C 7 cycloalkyl) C 1 -C 4 alkyl, (C 3 -C 7 cycloalkenyl) C 1 -C 4 alkyl, (heterocycloalkyl) C 1 -C 4 alkyl, C 2 -C 6 alkylacyl, (C 1 -C 4 alkyl) 1-2 (C 3 -C 7 ) cycloalkyl or (C 1 -C 6 alkyl) 1-2 amino.
[0031] R 4 is C 1 -C 10 alkoxycarbonyl, (C 1 -C 10 alkyl) 2 NHCO, (C 1 -C 10 alkyl) 2 NCO, aryl, heteroaryl or formyl substituted by 3˜7 membered cycloalkyl, heterocycloalkyl or cycloalkoxy, which may be unsubstituted or substituted by 1 to more R 4 ′; wherein, R 4 ′ is a substituent selected from the following group: halogen, OH, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, —NH 2 , (C 1 -C 6 alkyl)-NH— and —N(C 1 -C 6 alkyl) 2 , (C 1 -C 6 alkyl)-SO 2 —;
[0032] preferably, R 4 is
[0000]
[0000] wherein, Rx and Ry independently is F, Cl, C 1 -C 6 alkyl or C 1 -C 6 alkoxyl, Rz is C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 alkylformyl or (C 1 -C 6 alkyl)-SO 2 —.
[0033] In second preferably embodiment of the present invention, when Z 1 links with O, preferably, R 1 is hydrogen, R 3 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, heterocycloalkyl, (C 3 -C 7 cycloalkyl) C 1 -C 4 alkyl, (C 3 -C 7 cycloalkenyl) C 1 -C 4 alkyl, (heterocycloalkyl) C 1 -C 4 alkyl, C 2 -C 6 alkylacyl, (C 1 -C 4 alkyl) 1-2 (C 3 -C 7 ) cycloalkyl or (C 1 -C 6 alkyl) 1-2 amino. In this case, the general formula (I) turns into formula (Ib1),
[0000]
[0034] In formula (Ib1),
[0035] Ar is a substituted or unsubstituted aryl or heteroaryl, preferably, Ar is a 6 membered aryl or a 5˜6 membered heteroaryl which is substituted optionally by 1 or more R Ar ; wherein, R Ar is selected from the following substituent group: halogen, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 hydroxyalkyl and (C 1 -C 6 ) alkylamido.
[0036] A is O, S, CH, NH or NR′, wherein, R′ is C 1 -C 6 alkyl substituted or unsubstituted by halogen which includes 0˜3 heteroatom(s) of O, S or N.
[0037] Ra, Rb, Rc and Rd independently is H, OH, halogen or —Y 1 —R m , Y 1 is linking bond, O, S, SO, SO 2 or NR n ; R m is hydrogen, or, R m is an unsubstituted substituent or one substituted by 1˜3 R m ′ which is selected from the following group: (C 1 -C 8 ) alkyl, N≡C—(C 1 -C 6 ) alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, (C 3 -C 7 ) cycloalkyl, (C 3 -C 7 cycloalkyl) (C 1 -C 6 ) alkyl, and 5˜6 membered aryl or heteroaryl including 0˜2 heteroatom(s) independently selected from N, O, S;
[0038] R n is H, (C 1 -C 6 ) alkyl or (C 3 -C 6 ) cycloalkyl. Wherein, R m ′ is a substituent selected from the following group: halogen, (C 1 -C 6 ) alkyl substituted optionally by (C 1 -C 6 )alkyl-O— or (C 3 -C 6 )cycloalkyl-O—, (C 1 -C 6 ) haloalkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )alkyl-O—, heteroaryl, —NH 2 , (C 1 -C 4 alkyl)NH— and (C 1 -C 4 alkyl) 2 N—.
[0039] A 1 is NH or CH 2 .
[0040] A 2 is N, O or linking bond.
[0041] R 1 ′ is an unsubstituted substituent or one substituted by 1 to more R 1 ″ which is selected from the following group: C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, (aryl) C 1 -C 2 alkyl, C 3 -C 7 cycloalkyl, (C 3 -C 7 cycloalkyl) C 1 -C 2 alkyl, C 3 -C 7 cycloalkenyl, (C 3 -C 7 cycloalkenyl) C 1 -C 2 alkyl, heterocycloalkyl, (heterocycloalkyl) C 1 -C 2 alkyl, C 5 -C 10 heteroaryl and (C 5 -C 10 heteroaryl) C 1 -C 2 alkyl;
[0042] R 1 ″ is a substituent selected from the following group: halogen, OH, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, —NH 2 , (C 1 -C 6 alkyl)-NH— and —N(C 1 -C 6 alkyl) 2 ;
[0043] preferably, R 1 ′ is
[0000]
[0044] R 4 is C 1 -C 10 alkoxycarbonyl, (C 1 -C 10 alkyl)-NHCO, (C 1 -C 10 alkyl) 2 NCO, aryl, heteroaryl or formyl substituted by 3˜7 membered cycloalkyl, heterocycloalkyl or cycloalkoxy, which may be unsubstituted or substituted by 1 to more R 4 ′;
[0045] wherein, R 4 ′ is a substituent selected from the following group: halogen, OH, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, —NH 2 , (C 1 -C 6 alkyl)-NH— and —N(C 1 -C 6 alkyl) 2 , (C 1 -C 6 alkyl)-SO 2 —;
[0046] preferably, R 4 is
[0000]
[0000] wherein, Rx and Ry independently is F, Cl, C 1 -C 6 alkyl or C 1 -C 6 alkoxyl, Rz is C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 alkylformyl or (C 1 -C 6 alkyl)-SO 2 —.
[0047] In another preferably embodiment of the present invention, when Z 1 links with O, preferably, R 1 linking covalently with R 3 together forms a C 5 -C 9 saturated or unsaturated hydrocarbon chain which can be inserted by 0˜2 heteroatom(s) independently selected from N, S and O, or which can be substituted by none or more halogen, O, S or —NR p R q , wherein, R p and R q independently is hydrogen or C 1 -C 6 alkyl. In this case, A 1 is preferably CH 2 and the general formula (I) turns into formula (Ib2),
[0000]
[0048] In formula (Ib2),
[0049] Ar is a substituted or unsubstituted aryl or heteroaryl, preferably, Ar is a 6 membered aryl or a 5˜6 membered heteroaryl which is substituted optionally by 1 or more R Ar ; wherein, R Ar is selected from the following substituent group: halogen, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 hydroxyalkyl and (C 1 -C 6 ) alkylamido.
[0050] A is O, S, CH, NH or NR′, wherein, R′ is C 1 -C 6 alkyl substituted or unsubstituted by halogen which includes 0˜3 heteroatom(s) of O, S or N.
[0051] Ra, Rb, Rc and Rd independently is H, OH, halogen or —Y 1 —R m , Y 1 is linking bond, O, S, SO, SO 2 or NR n ; R m is hydrogen, or, R m is an unsubstituted substituent or one substituted by 1˜3 R m ′ which is selected from the following group: (C 1 -C 8 ) alkyl, N≡C—(C 1 -C 6 ) alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, (C 3 -C 7 ) cycloalkyl, (C 3 -C 7 cycloalkyl) (C 1 -C 6 ) alkyl, and 5˜6 membered aryl or heteroaryl including 0˜2 heteroatom(s) independently selected from N, O, S; R n is H, (C 1 -C 6 ) alkyl or (C 3 -C 6 ) cycloalkyl. Wherein, R m ′ is a substituent selected from the following group: halogen, (C 1 -C 6 ) alkyl substituted optionally by (C 1 -C 6 )alkyl-O— or (C 3 -C 6 )cycloalkyl-O—, (C 1 -C 6 ) haloalkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )alkyl-O—, heteroaryl, —NH 2 , (C 1 -C 4 alkyl)NH— and (C 1 -C 4 alkyl) 2 N—.
[0052] A 2 is N, O or linking bond.
[0053] R 1 ′ is an unsubstituted substituent or one substituted by 1 to more R 1 ″ which is selected from the following group: C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, (aryl) C 1 -C 2 alkyl, C 3 -C 7 cycloalkyl, (C 3 -C 7 cycloalkyl) C 1 -C 2 alkyl, C 3 -C 7 cycloalkenyl, (C 3 -C 7 cycloalkenyl) C 1 -C 2 alkyl, heterocycloalkyl, (heterocycloalkyl) C 1 -C 2 alkyl, C 5 -C 10 heteroaryl and (C 5 -C 10 heteroaryl) C 1 -C 2 alkyl;
[0054] R 1 ″ is a substituent selected from the following group: halogen, OH, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, —NH 2 , (C 1 -C 6 alkyl)-NH— and —N(C 1 -C 6 alkyl) 2 ; preferably, R 1 ′ is
[0000]
[0055] R 4 is C 1 -C 10 alkoxycarbonyl, (C 1 -C 10 alkyl)-NHCO, (C 1 -C 10 alkyl) 2 NCO, aryl, heteroaryl or formyl substituted by 3˜7 membered cycloalkyl, heterocycloalkyl or cycloalkoxy, which may be not substituted or substituted by 1 or more R 4 ′;
[0056] wherein, R 4 ′ is a substituent selected from the following group: halogen, OH, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, —NH 2 , (C 1 -C 6 alkyl)-NH— and —N(C 1 -C 6 alkyl) 2 , (C 1 -C 6 alkyl)-SO 2 —;
[0057] preferably, R 4 is
[0000]
[0000] wherein, Rx and Ry independently is F, Cl, C 1 -C 6 alkyl or C 1 -C 6 alkoxyl, Rz is C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 1 -C 6 alkylformyl or (C 1 -C 6 alkyl)-SO 2 —.
[0058] In the present invention, means that it can be double bond or single bond either.
[0059] In the present invention, the detailed compound is preferably as follows:
[0000]
[0060] The second aim of the present invention is to provide a pharmaceutical composition that comprises the compound having the general formula (I) of the present invention and pharmaceutically acceptable carrier(s). Wherein, the pharmaceutical composition of the present invention can also be used in combination with other anti-virus drugs such as interferon or ribavirin.
[0061] The third aim of the present invention is to provide a use of the compound of the present invention in preparation of a drug for preventing virus infection or antivirus, wherein, said virus is preferably hepatitis virus, more preferably hepatitis C virus.
[0062] The forth aim of the present invention is to provide a method where an effective amount of the compound of the present invention is administered to a patient infected with hepatitis virus, more preferably with HCV.
[0063] The synthesis process of the compound having the formula (I) of the present invention is as follows:
[0000]
[0064] Specifically, when Z 3 links with O, the synthesis of intermediate M that used to synthesize the compound having the formula (Ia) is as follows:
[0000]
[0065] Specifically, when Z 1 links with O, the synthesis of intermediate M that used to synthesize the compound having the formula (Ib1) and the formula (Ib2) is as follows:
[0000]
DETAILED DESCRIPTION OF THE INVENTION
Example 1
Intermediate 1 (Abbreviated as M1, Same as Following)
[0066]
Step S 1A : Synthesis of 1-(3-amino-benzofuran-2-yl)-ethanone (1A)
[0067] To a solution of 2-hydroxy-benzonitrile (1000 mmol) in DMF (dimethylformamide, 80 mL) was added K 2 CO 3 (207 g, 1.5 mol) portionwise under stirring, followed by 1-chloro-propan-2-one (139 g, 1.5 mol). After addition, the mixture was heated to 120° C. and stirred at that temperature for 2 hours. TLC showed the reaction was completed. The reaction mixture was cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate, washed with brine, dried and concentrated. The residue was washed with dichloromethane, filtered and dried to give 112 g of 1-(3-amino-benzofuran-2-yl)-ethanone (1A).
[0068] 1 H-NMR (DMSO): δ (ppm): 7.98 (d, J=8.0 Hz, 1H), 7.52 (m, 2H), 7.28 (dt, J=6.4, 1.6 Hz, 1H), 6.95 (brs, 2H), 2.37 (s, 3H). MS (ESI): M + +1=176.18.
Step S 1B : Synthesis of (E) 2-cinnamoyl-3-amino-benzofuran (1B)
[0069] To a solution of 1A (114 mmol) in MeOH (200 mL) was added NaOH (18.2 g, 445 mmol). The reaction was exothermic. After cooled to room temperature, benzaldehyde (14.5 g, 137 mmol) was added. The mixture was stirred overnight under N 2 . TLC monitored the reaction. After the reaction completed, the reaction mixture was poured into ice-water under stirring. The solids precipitated out and were collected by filtration, and dried to give 1B (26 g).
[0070] 1 H-NMR (DMSO): δ (ppm): 8.03 (d, J=8 Hz, 1H), 7.80 (dd, J1=7.6 Hz, J2=1.6 Hz, 2H), 7.70 (d, J=16 Hz, 1H), 7.55-7.59 (m, 3H), 7.47 (m, 3H), 7.44-7.48 (m, 3H). MS (ESI): M + +1=265.3.
Step S 1C : Synthesis of 2-phenyl-2,3-dihydrobenzofuron[3,2-b]pyridin-4(1H)-one (1C)
[0071] 1B (98 mmol) was dissolved in a mixture of AcOH (150 ml) and H 3 PO 4 (150 mL) The reaction mixture was heated to 120° C., and reacted under stirring for 4 hours. TLC monitored the reaction. After the reaction completed, the mixture was cooled and poured into ice-water, filtered and dried to give 1C (21 g).
[0072] 1 H-NMR (DMSO): δ (ppm): 7.98 (s, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.59 (q, J1=10.4 Hz, J2=7.6 Hz, 4H), 7.45 (t, J=7.2 Hz, 2H), 7.39 (t, J=7.4 Hz, 1H), 7.32 (m, 1H), 4.98 (dd, J1=14 Hz, J2=4.4 Hz, 1H), 2.86 (dd, J=14, 16.4 Hz, 1H), 2.57 (dd, J=16.4, 4.4 Hz, 1H). MS (ESI): M + +1=264.3.
Step S 1D : Synthesis of 2-phenyl-4-hydroxyl-benzo[4,5]furo[3,2-b]pyridine (1D)
[0073] To a solution of 1C (79.7 mmol) in 1,4-dioxane (100 mL) was added FeCl 3 .6H 2 O (110 g, 400 mmol). The mixture was refluxed for 3 hours. TLC showed the reaction completed. The mixture was cooled and poured into cold diluted hydrochloric acid aqueous solution under stirring. The solids were precipitated out and collected by filtration, dried to give 1D (14 g).
[0074] 1 H-NMR (DMSO-d 6 ): δ (ppm): 10.61 (s, 1H), 8.55 (s, 1H), 8.15 (d, J=7.6 Hz, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.55-7.63 (m, 4H), 7.38 (t, J=4.6 Hz, 1H), 7.33 (t, J=3.8 Hz, 1H). MS (ESI): M + 1=262.27.
Step S 1E : Synthesis of 4-chloro-2-phenyl-benzofuro[3,2-b]pyridine (M1)
[0075] 1D (53.6 mmol) was added to POCl 3 (90 mL), heated to dissolve and stirred at 110° C. for 2.5 hours. TLC showed the reaction completed. POCl 3 was evaporated under reduced pressure. The residue was cooled and poured into ice-water under stirring. The solids were collected by filtration and dried to give the desired product M1 (11.5 g).
[0076] 1 H-NMR (DMSO-d 6 ): δ (ppm): 8.29 (s, 1H), 8.22-8.27 (m, 3H), 7.91 (d, J=8.0 Hz, 1H), 7.76 (dt, J=8.2, 1.6 Hz, 1H), 7.49-7.59 (m, 4H). MS (ESI): M + +1=280.7.
Example 2
Intermediate 2 (M2)
[0077]
Step S 2A : Synthesis of 2-chloro-6-mercapto-benzonitrile (2A)
[0078] The solution of 2,6-dichloro-benzonitrile (20 mmol) in DMSO (dimethyl sulfoxide, 30 mL) was heated to 70° C., followed by addition of Na 2 S.9H 2 O portionwise under stirring. The mixture was stirred for 1 hour. TLC monitored the reaction. After the reaction completed, the mixture was cooled and extracted between water and ethyl acetate. The aqueous layer was acidified by hydrochloric acid to pH=3˜4 under stirring. The formed solids were collected by filtration and dried to give 2.3 g of 2-chloro-6-mercapto-benzonitrile (2A).
[0079] MS (ESI): M + +1=170.6.
Step S 2B : Synthesis of 1-(3-amino-4-chloro-benzothiophen-2-yl)-ethanone (2B)
[0080] The procedure was similar to step S 1A , while the starting material was 2-chloro-6-mercapto-benzonitrile (2A) in stead of 2-hydroxy-benzonitrile.
[0081] 1 H-NMR (DMSO-d 6 ): δ (ppm): 7.89 (dd, J=8 Hz, J=0.8 Hz, 1H), 7.84 (b, 2H), 7.53 (t, J=16 Hz, 1H), 7.45 (dd, J1=7.6 Hz, J2=1.2 Hz, 1H), 2.37 (s, 3H). MS (ESI): M + +1=226.7.
Step S 2C : Synthesis of (E) 2-cinnamoyl-3-amino-4-chloro-benzo[b]thiophene (2C)
[0082] The procedure was similar to step S 1B , while the starting material was 2B in stead of 1A.
[0083] 1 H-NMR (DMSO-d 6 ): δ (ppm): 8.19 (b, 2H), 7.92 (d, J=8.4 Hz, 1H), 7.79 (m, 2H), 7.70 (d, J=15.6 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.46-7.49 (m, 4H), 7.24 (d, J=15.6 Hz, 1H). MS (ESI): M + +1=315.8.
Step S 2D : Synthesis of 2-phenyl-9-chloro-2,3-dihydro-benzo[4,5]thieno[3,2-b]pyridin-4(1H)-one (2D)
[0084] The procedure was similar to step S 1C , while the starting material was 2C in stead of 1B.
[0085] MS (ESI): M + +1=314.8.
Step S 2E : Synthesis of 2-phenyl-9-chloro-4-hydroxyl-benzo[4,5]thieno[3,2-b]pyridine (2E)
[0086] The procedure was similar to step S 1D , while the starting material was 2D in stead of 1C.
[0087] 1 H-NMR (DMSO): δ (ppm): 11.95 (s, 1H), 8.24 (d, J=8.0 Hz, 2H), 8.12 (dd, J1=7.6 Hz, J2=0.8 Hz, 1H), 7.65 (dd, J=6.4, 1.2 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.52 (s, 1H), 7.49 (t, J=7.2 Hz, 1H). MS (ESI): M + +1=312.8.
Step S 2F : Synthesis of 4,9-dichloro-2-phenyl-benzo[4,5]thieno[3,2-b]pyridine (M2)
[0088] The procedure was similar to step S 1E , while the starting material was 2E in stead of 1D.
[0089] 1 H-NMR (DMSO): δ (ppm): 8.43 (s, 1H), 8.40 (dd, J=1.2, 7.6 Hz, 2H), 8.20 (dd, J1=7.6 Hz, J2=1.2 Hz, 1H), 7.73 (dd, J=1.2, 8.0 Hz, 1H), 7.68 (t, J=7.6 Hz, 1H), 7.59 (t, J=7.6 Hz, 2H), 7.53 (dt, J=2.0, 7.6 Hz, 1H). MS (ESI): M + +1=331.2.
Example 3
Intermediate 3 (M3)
[0090]
Step S 3A : Synthesis of 2-mercapto-benzonitrile (3A)
[0091] The procedure was similar to step S 2A , while the starting material was 2-fluoro-benzonitrile in stead of 2,6-dichloro-benzonitrile.
[0092] MS (ESI): M + +1=136.2.
Step S 3B : Synthesis of 1-(3-amino-benzo[b]thiophen-2-yl)-ethanone (3B)
[0093] The procedure was similar to step S 1A , while the starting material was 2-mercapto-benzonitrile (3A) in stead of 2-hydroxy-benzonitrile.
[0094] 1 H-NMR (DMSO-d 6 ): δ (ppm): 8.19 (d, J=8.4 Hz, 2H), 7.86 (t, J=7.0 Hz, 3H), 7.55 (t, J=7.2 Hz, 1H), 7.43 (t, J=7.2 Hz, 1H), 2.35 (s, 3H). MS (ESI):
[0095] M + +1=193.2.
Step S 3C : Synthesis of (E)-2-cinnamoyl 3-amino-benzo[b]thiophene (3C)
[0096] The procedure was similar to step S 1B , while the starting material was 3B in stead of 1A.
[0097] 1 H-NMR (DMSO-d 6 ): δ (ppm): 8.25 (m, 3H), 7.91 (d, J=8.4 Hz, 1H), 7.79 (d, J=15.6 Hz, 2H), 7.69 (d, J=7.2 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.46 (t, J=6.4 Hz, 4H), 7.23 (d, J=15.6 Hz, 1H). MS (ESI): M + +1=280.3.
Step S 3D : Synthesis of 2-phenyl-2,3-dihydro-benzo[4,5]thieno[3,2-b]pyridin-4(1H)-one (3D)
[0098] The procedure was similar to step S 1C , while the starting material was 2C in stead of 1B.
[0099] MS (ESI): M + +1=280.3.
[0100] Step S 3E : Synthesis of 2-phenyl-4-hydroxyl-benzothieno[3,2-b]pyridine (3E)
[0101] The procedure was similar to step S 1D , while the starting material was 3D in stead of 1C.
[0102] MS (ESI): M + +1=278.3.
Step S 3F : Synthesis of 4-chloro-2-phenyl-benzothieno[3,2-b]pyridine (M3)
[0103] The procedure was similar to step S 1F , while the starting material was 3E in stead of 1D.
[0104] 1 H-NMR (DMSO-d 6 ): δ (ppm): 8.54 (d, J=7.6 Hz, 1H), 8.35 (s, 1H), 8.34 (dd, J=1.6, 7.6 Hz, 1H), 8.20 (d, J=7.6 Hz, 1H), 7.74 (dt, J=7.2, 1.2 Hz, 1H), 7.68 (dt, J=7.6, 1.6 Hz, 1H), 7.51-7.60 (m, 3H). MS (ESI): M + +1=296.8.
Example 4
Intermediate 4 (M4)
[0105]
Step S 4A : Synthesis of 2-hydroxy-5-methoxy-benzaldehyde (4A)
[0106] To a mixture of MgCl 2 (3.48 g, 37.0 mmol), TEA (12.8 mL, 92.1 mmol) and paraformaldehyde (5 g, 167 mmol) in MeCN (100 mL) was added 4-methoxy-phenol (3 g, 24.2 mmol). The mixture was refluxed for 8 hours, cooled to room temperature, then poured into 5% HCl (300 mL), extracted with ethyl acetate (200 mL×3). The combined organic layer was dried, concentrated and purified by column chromatography on silica gel (ethyl acetate/n-hexane=1/5) to give 2.3 g of 2-hydroxy-5-methoxy-benzaldehyde (4A).
[0107] 1 H-NMR (DMSO-d 6 ): δ (ppm): 10.67 (s, 1H), 9.87 (s, 1H), 7.18 (dd, J1=8.8 Hz, J2=3.6 Hz, 1H), 7.02 (d, J=2.8 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 3.83 (s, 3H). MS (ESI): M + +1=153.15.
Step S 4B : Synthesis of 2-hydroxy-5-methoxy-benzonitrile (4B)
[0108] To a solution of 2-hydroxy-5-methoxy-benzaldehyde (10 g, 65.7 mmol) in 95% EtOH (30 mL) was added a solution of hydroxylamine hydrochloride (2.8 g, 78.8 mmol) in water (6 mL), followed a solution of NaOH (4 g, 98.8 mmol) in water. The mixture was stirred at room temperature for 2.5 hours, then extracted with ethyl acetate, dried over anhydrous Na 2 SO 4 and concentrated to give 12 g of solid. To the solid was added Ac 2 O (15 g, 146.9 mmol) and the mixture was refluxed for 20 min. TLC monitored the reaction. After the reaction completed, the mixture was poured into crash ice. Solids were precipitated out while stirring, which was collected by filtration and dried to give 9 g of 2-hydroxy-5-methoxy-benzonitrile (4B).
[0109] MS (ESI): M + +1=150.15.
Step S 4C : Synthesis of 1-(3-amino-5-methoxy-benzofuran-2-yl)-ethanone (4C)
[0110] The procedure was similar to step S 1A , while the starting material was 2-hydroxy-5-methoxy-benzonitrile (4B) in stead of 2-hydroxy-benzonitrile.
[0111] 1 H-NMR (DMSO-d 6 ): δ (ppm): 7.52 (d, J=2.4 Hz, 1H), 7.41 (d, J=9.2 Hz, 1H), 7.13 (dd, J=2.8, 9.2 Hz, 1H), 6.82 (s, 2H), 3.79 (s, 3H), 2.34 (s, 3H). MS (ESI): M + +1=208.23.
Step S 4D : Synthesis of (E)-2-cinnamoyl-3-amino-5-methoxy-benzofuran (4D)
[0112] The procedure was similar to step S 1B , while the starting material was 4C in stead of 1A.
[0113] MS (ESI): M + +1=294.32.
Step S 4E : Synthesis of 2-phenyl-8-methoxy-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (4E)
[0114] The procedure was similar to step S ic , while the starting material was 4D in stead of 1B.
[0115] MS (ESI): M + +1=294.32.
Step S 4F : Synthesis of 2-phenyl-4-hydroxyl-8-methoxy-benzofuro[3,2-b]pyridine (4F)
[0116] The procedure was similar to step S W , while the starting material was 4E in stead of 1C.
[0117] MS (ESI): M + +1=292.3.
Step S 4G : Synthesis of 4-chloro-8-methoxy-2-phenyl-benzofuro[3,2-b]pyridine (M4)
[0118] The procedure was similar to step S 1E , while the starting material was 4F in stead of 1D.
[0119] 1 H-NMR (DMSO-d 6 ): δ (ppm): 8.29 (s, 1H), 8.26 (dd, J1=6.8 Hz, J2=1.6 Hz, 2H), 7.83 (d, J=8.8 Hz, 1H), 7.70 (d, J=2.8 Hz, 1H), 7.55 (t, J=6.4 Hz, 2H), 7.51 (t, J=7.2 Hz, 1H), 7.31 (dd, J1=8.8 Hz, J2=2.8 Hz, 1H), 3.93 (s, 1H). MS (ESI): M + +1=310.75.
Example 5
Intermediate 5 (M5)
[0120]
Step S 5A : Synthesis of 5-chloro-2-hydroxy-benzonitrile (5A)
[0121] To a solution of 2-hydroxy-benzonitrile (5 g, 42 mmol) in chloroform (50 mL) was added 15 mL of a solution of NCS(N-chlorosuccinimide, 5.558 g, 44.1 mmol) in chloroform. The reaction mixture was refluxed overnight. TLC monitored the reaction. After the reaction completed, the mixture was poured into ice-water. The organic layer was washed with water, then stayed overnight.
[0122] The precipitated solids were collected by filtration. The filtrate was concentrated, recrystallized from chloroform and filtered to give a solid. The two batches of product were combined to give 4 g of 5-chloro-2-hydroxy-benzonitrile (5A).
[0123] 1 H-NMR (DMSO-d 6 ): δ (ppm): 11.44 (s, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.55 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.02 (d, J=9.2 Hz, 1H). MS (ESI):
[0124] M + +1=154.6.
Step S 5B : Synthesis of 1-(3-amino-5-chloro-benzofuran-2-yl)-ethanone (5B)
[0125] The procedure was similar to step S 1A , while the starting material was 5-chloro-2-hydroxy-benzonitrile (5A) in stead of 2-hydroxy-benzonitrile.
[0126] 1 H-NMR (DMSO-d 6 ): δ (ppm): 8.09 (q, 1H), 7.55 (t, J=1.2 Hz, 2H), 6.92 (b, 2H), 2.37 (s, 3H). MS (ESI): M + +1=212.6.
Step S 5C : Synthesis of (E)-2-cinnamoyl-3-amino-5-chloro-benzofuran (5C)
[0127] The procedure was similar to step S 1B , while the starting material was 5B in stead of 1A.
[0128] 1 H-NMR (DMSO-d 6 ): δ (ppm): 8.14 (m, 1H), 7.78-7.81 (m, 2H), 7.70 (d, J=15.6 Hz, 1H), 7.60 (m, 2H), 7.50 (d, J=15.6 Hz, 1H), 7.45-7.49 (m, 3H), 7.24 (b, 2H). MS (ESI): M + +1=298.7.
Step S 5D : Synthesis of 2-phenyl-8-chloro-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (5D)
[0129] The procedure was similar to step S ic , while the starting material was 5C in stead of 1B.
[0130] MS (ESI): M + +1=298.7.
Step S 5E : Synthesis of 2-phenyl-8-chloro-4-hydroxyl-benzofuro[3,2-b]pyridine (5E)
[0131] The procedure was similar to step S 1D , while the starting material was 5D in stead of 1C.
[0132] MS (ESI): M + +1=296.7.
Step S 5F : Synthesis of 4,8-dichloro-2-phenyl-benzo[4,5]furo[3,2-b]pyridine (M5)
[0133] The procedure was similar to step S 1E , while the starting material was 5E in stead of 1D.
[0134] 1 H-NMR (DMSO-d 6 ): δ (ppm): 8.37 (s, 1H), 8.30 (d, J=2.4 Hz, 1H), 8.25 (dd, J1=8.4 Hz, J2=1.6 Hz, 2H), 7.96 (d, J=8.8 Hz, 1H), 7.78 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.55 (dt, J=7.6, 1.6 Hz, 2H), 7.52 (t, J=7.6 Hz, 1H). MS (ESI): M + +1=315.2.
Example 6
Intermediate 6 (M6)
[0135]
Step S 6A : Synthesis of 1-(3-amino-5-bromo-benzofuran-2-yl)-ethanone (6A)
[0136] A mixture of 5-bromo-2-hydroxy-benzonitrile (15.06 g, 76.06 mmol), 1-chloro-propan-2-one (10.56 g, 114.09 mmol, 1.5 eq) and K 2 CO 3 (15.77 g, 114.09 mmol, 1.5 eq) was added to DMF (100 mL) The mixture was stirred at 90° C. for 2 hours. TLC monitored the reaction. After the reaction completed, the mixture was cooled to room temperature and poured into water (500 mL).
[0137] The yellow solids precipitated out were collected by filtration to give 1-(3-amino-5-bromo-benzofuran-2-yl)-ethanone (6A) (19.2 g, 99.36% yield).
[0138] 1 H-NMR (400 MHz, DMSO-d 6 ): δ (ppm): 8.24 (d, J=2.0 Hz, 1H), 7.64-7.67 (dd, J1=8.8 Hz, J2=2.0 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 6.91 (s, 2H), 2.37 (s, 3H).
Step S 6B : Synthesis of (Z)-2-cinnamoyl-3-amino-5-bromo-benzofuran (6B)
[0139] A mixture of 1-(3-amino-5-bromo-benzofuran-2-yl)-ethanone (19.2 g, 75.57 mmol), NaOH (12.09 g, 302.27 mmol, 4 eq) and benzaldehyde (10.42 g, 98.24 mmol, 1.3 eq) was added to MeOH (400 mL) The mixture was stirred at 45° C. for 48 hours. TLC monitored the reaction. After the reaction completed, the mixture was cooled to room temperature and poured into water (400 mL).
[0140] The yellow solids precipitated out were collected by filtration to give (Z)-2-cinnamoyl-3-amino-5-bromo-benzofuran (6B) (28 g, 100% yield).
[0141] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.29 (d, J=1.6 Hz, 1H), 7.78-7.80 (m, 2H), 7.68-7.72 (m, 2H), 7.57 (s, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.45-7.48 (m, 3H), 7.24 (s, 2H).
Step S 6C : Synthesis of 8-bromo-2-phenyl-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (6C)
[0142] A solution of (Z)-2-cinnamoyl-3-amino-5-bromo-benzofuran (28 g, 81.83 mmol) in AcOH (70 mL) and H 3 PO 4 (70 mL) was refluxed for 2 hours. TLC showed the reaction completed. The mixture was cooled to room temperature and poured into water (250 mL) The yellow solids precipitated out were collected by filtration to give 8-bromo-2-phenyl-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (6C) (23.8 g, 85% yield).
[0143] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.2 (d, J=1.6 Hz, 1H), 7.94 (s, 1H), 7.70-7.73 (dd, J1=9.2 Hz, J2=2.8 Hz, 1H), 7.56-7.59 (m, 3H), 7.44 (t, J=7.2 Hz, 3H), 7.37-7.40 (m, 1H), 4.97 (dd, J1=14.6 Hz, J2=4.8 Hz, 1H), 2.87 (dd, J1=16.4 Hz, J2=14.0 Hz, 1H), 2.54-2.60 (dd, J1=16.0 Hz, J2=4.4 Hz, 1H).
Step S 6D : Synthesis of 4-hydroxyl-8-bromo-2-phenyl-benzofuro[3,2-b]pyridine (6D)
[0144] A mixture of 8-bromo-2-phenyl-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (23.8 g, 69.55 mmol) and FeCl 3 .6H 2 O (112.78 g, 417.3 mmol) was added to 1,4-dioxane (300 mL) The mixture was refluxed for 16 hours. TLC showed the reaction completed. The mixture was cooled to room temperature and poured into ice-water (500 mL) The yellow solids precipitated out were collected by filtration to give 4-hydroxyl-8-bromo-2-phenyl-benzofuro[3,2-b]pyridine (6D) (15.7 g, 66.36% yield).
Step S 6E : Synthesis of 8-bromo-4-chloro-2-phenyl-benzofuro[3,2-b]pyridine (M6)
[0145] 4-hydroxyl-8-bromo-2-phenyl-benzofuro[3,2-b]pyridine (8.7 g, 25.72 mmol) was added to POCl 3 (100 mL) The mixture was refluxed for 4 hours. TLC showed the reaction completed. POCl 3 was evaporated under reduced pressure. The residue was poured into ice-water under stirring. The yellow solids precipitated out were collected by filtration to give 8-bromo-4-chloro-2-phenyl-benzofuro[3,2-b]pyridine (M6) (6.52 g, 71.01% yield).
[0146] 1 H-NMR (400 MHz, CDCl 3 ) δ 8.43 (s, 1H), 8.09 (d, J=7.2 Hz, 2H), 7.87 (s, 1H), 7.70-7.74 (dd, J1=8.8 Hz, J2=2.0 Hz, 1H), 7.53-7.59 (m, 3H), 7.47-7.51 (m, 1H).
Example 7
Synthesis of 7G
[0147]
Step S 7A : Synthesis of 2-chloro-3,6-dihydroxy-benzaldehyde (7A)
[0148] 2,5-dihydroxy-benzaldehyde (100 g, 0.725 mol) was dissolved in MeCN (1L). To the solution was added NCS(N-chlorosuccinimide, 106 g, 1.1 eq) in batches under N 2 protection. After addition completed, the mixture was stirred at room temperature overnight. TLC monitored the reaction. After the reaction completed, NaHSO 3 (38%, 500 mL) was added to the mixture, then extracted with ethyl acetate (3×600 mL) The organic layer was washed with water (2×600 mL) and brine (600 mL), dried over anhydrous MgSO 4 , concentrated to give a crude product, which was recrystallized to give the desired product 7A (25.6 g, 20.5% yield), as a yellow solid.
[0149] 1 H-NMR (400 MHz, DMSO-d 6 ): δ 11.09 (s, 1H), 10.34 (s, 1H), 9.94 (s, 1H), 7.23 (d, J=9.2 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H).
Step S 7B : Synthesis of (E)-2-chloro-3,6-dihydroxy-benzaldehyde oxime (7B)
[0150] A mixture of 7A (25.0 g, 144.87 mmol), hydroxylamine hydrochloride (12.08 g, 173.84 mmol, 1.2 eq) and NaOH (8.69 g, 217.3 mmol, 1.5 eq) in EtOH (200 mL) and H 2 O (100 mL) was stirred at room temperature overnight. TLC monitored the reaction. After the reaction completed, the mixture was extracted with ethyl acetate and concentrated to give a yellow solid 7B (34.2 g, 100% yield).
Step S 7c : Synthesis of 2-chloro-3-cyano-1,4-diacetoxy-benzene (7C)
[0151] 7B (34.2 g, 182.32 mmol) was dissolved in Ac 2 O (200 mL) The reaction mixture was refluxed for 24 hours under stirring. TLC monitored the reaction. After the reaction completed, the mixture was cooled to room temperature and poured into water (250 mL), extracted with ethyl acetate, concentrated and purified by column chromatography on silica gel to give product 7C (17.3 g, 37.2% yield).
Step S 7D : Synthesis of acetic acid 2-chloro-3-cyano-4-hydroxy-phenyl ester (7D)
[0152] 7C (13.8 g, 54.4 mmol) was dissolved in MeOH (80 ml) and dichloromethane (80 mL). To the solution was added K 2 CO 3 (7.52 g, 54.4 mmol, 1 eq). The reaction mixture was stirred at room temperature for 40 min. TLC monitored the reaction. After the reaction completed, the mixture was acidified by 1N hydrochloric acid to pH˜6, extracted with dichloromethane and concentrated to give white solid 7D (7.8 g, 67.76% yield).
[0153] 1 H-NMR (400 MHz, CDCl 3 ) δ 11.76 (s, 1H), 7.46 (d, J=9.2 Hz, 1H), 7.03 (d, J=9.2 Hz, 1H), 2.32 (s, 3H).
Step S 7E : Synthesis of 2-acetyl-3-amino-4-chloro-5-acetoxyl-benzofuran (7E)
[0154] To a solution of 7D (2.2 g, 10.4 mmol) in MeCN (20 mL) was added 1-chloro-propan-2-one (1.25 g, 13.52 mmol, 1.3 eq), followed by K 2 CO 3 (1.868 g, 13.52 mmol, 1.3 eq). The mixture was stirred at 90° C. for 40 min. TLC monitored the reaction. After the reaction completed, the mixture was quenched with water (100 mL) The white solids were precipitated out and collected by filtration and dried to give product 7E (3 g, 100% yield).
Step S 7F : Synthesis of 2-acetyl-3-amino-4-chloro-5-hydroxy-benzofuran (7F)
[0155] To a solution of 7E (12.8 g, 47.82 mmol) in MeOH (100 mL) was added a solution of saturated aqueous of K 2 CO 3 (6.61 g, 47.82 mmol, 1 eq.) dropwise. The mixture was stirred at room temperature overnight. TLC monitored the reaction. After the reaction completed, the mixture was acidified by 1N hydrochloric acid to pH˜6, extracted with ethyl acetate and concentrated to give white solid 7F (10.2 g, 94.54% yield).
[0156] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 10.14 (s, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.46 (s, 2H), 2.37 (s, 3H).
Step S 7G : Synthesis of 2-acetyl-3-amino-4-chloro-5-methoxyl-benzofuran (7G)
[0157] To a solution of 7F (0.5 g, 2.22 mmol) in DMF (5 mL) was added anhydrous CsF (1.01 g, 6.65 mmol, 3 eq), followed by MeI (0.377 g, 2.66 mmol, 1.2 eq) dropwise. The mixture was stirred at room temperature for 40 min. TLC monitored the reaction. After the reaction completed, the mixture was poured into water (25 mL) The white solids were precipitated out, collected by filtration and purified to give product 7G (0.33 g, 62.14% yield).
[0158] 1 H-NMR (400 MHz, CDCl 3 ) δ 7.50 (d, J=9.2 Hz, 1H), 7.42 (d, J=9.2 Hz, 1H), 6.51 (s, 2H), 3.89 (s, 3H), 2.38 (s, 3H).
Example 8
Intermediate 8 (M8)
[0159]
Step S 8A : Synthesis of 2-cinnamoyl-3-amino-4-chloro-5-methoxy-benzofuran (8A)
[0160] A mixture of 7G (1.5 g, 6.26 mmol), benzaldehyde (0.863 g, 8.14 mmol, 1.3 eq) and NaOH (1.0 g, 25.04 mmol, 4 eq) in MeOH (20 mL) was stirred at 45° C. for 24 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and poured into water (20 mL) The yellow solids precipitated out were collected by filtration and dried to give product 8A (1.9 g, 92.6% yield).
Step S 8B : Synthesis of 9-chloro-8-methoxy-2-phenyl-2,3-dihydrobenzofuro[3,2-b]pyridin-4(1H)-one (8B)
[0161] A mixture of 8A (1.9 g, 5.8 mmol) in AcOH (10 mL) and H 3 PO 4 (10 mL) was refluxed for 2 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and poured into water (20 mL) The yellow solids were precipitated out, collected by filtration and dried to give product 8B (1.78 g, 93.68% yield).
Step S 8C : Synthesis of 4-hydroxyl-9-chloro-8-methoxy-2-phenyl-benzofuro[3,2-b]pyridine (8C)
[0162] A mixture of 8B (1.78 g, 5.43 mmol) and FeCl 3 .6H 2 O (6.57 g, 32.58 mmol, 6 eq) was added to 1,4-dioxane (40 mL) The mixture was refluxed for 16 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and poured into water (50 mL) The brown solids were precipitated out, collected by filtration and dried to give product 8C (1.5 g, 84.8% yield).
Step S 8D : Synthesis of 4,9-dichloro-8-methoxy-2-phenyl-benzofuro[3,2-b]pyridine (M8)
[0163] A mixture of 8C (1.4 g, 4.3 mmol) in POCl 3 (20 mL) was refluxed for 2 hours. TLC monitored the reaction. After the reaction completed, POCl 3 was evaporated under reduced pressure. The residue was poured into ice-water. The yellow solids were precipitated out, collected by filtration and purified by column chromatography to give product M8 (1.22 g, 82.5% yield).
[0164] 1 H-NMR (400 MHz, CDCl 3 ) δ 8.16 (d, J=7.2 Hz, 2H), 7.88 (s, 1H), 7.44-7.55 (m, 4H), 7.19-7.22 (d, J=8.8 Hz, 1H), 4.02 (s, 3H).
Example 9
Intermediate 9 (M9)
[0165]
Step S 9A : Synthesis of (E)-1-(3-amino-4-chloro-5-methoxy-benzofuran-2-yl)-3-(2-isopropyl-thiazol-5-yl)-2-propen-1-one (9A)
[0166] 7G (3 g, 12.5 mmol) was dissolved in THF (tetrahydrofuran, 30 mL). To the solution was added 2-isopropyl-thiazole-5-carbaldehyde (2.33 g, 15 mmol, 1.2 eq), followed by crushed NaOH powder (1 g, 25 mmol, 2 eq). The reaction mixture was stirred at room temperature for 10 min. The solution became dark and some solids formed. The mixture was poured into ice-water under stirring.
[0167] The solids were collected by filtration, dried and purified by column chromatography on silica gel to give 3.5 g of pure product (9A).
[0168] 1 H-NMR (400 MHz, CDCl 3 ) δ 7.88 (d, J=16.0 Hz, 1H), 7.86 (s, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.21 (d, J=16.0 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.38 (s, 2H), 3.97 (s, 3H), 3.35 (m, 1H), 1.44 (d, J=7.2 Hz, 6H); ES-LCMS m/z N/A.
Step S 9B : Synthesis of 9-chloro-2-(2-isopropylthiazol-5-yl)-8-methoxy-1,2-dihydro-benzofuro[3,2-b]pyridin-4-one (9B)
[0169] 9A (3.5 g, 9.28 mmol) was added to MeCN (50 mL) and stirred at room temperature. To the mixture was added ZnCl 2 (1.91 g, 13.93 mmol, 1.5 eq), followed by AcOH (50 mL) and H 3 PO 4 (50 mL) The reaction mixture was heated to 80° C. and stirred overnight. After reaction completed, the mixture was cooled and poured into crushed ice under stirring, neutralized to pH=7-8, extracted with ethyl acetate, dried and concentrated to give 2.4 g of product (9B).
[0170] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 7.70 (s, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 5.56 (brs, 1H), 5.25 (dd, J=12.0, 4.8 Hz, 1H), 3.97 (s, 3H), 3.25-3.35 (m, 1H), 2.29-3.02 (m, 2H), 1.45 (d, J=7.0 Hz, 6H).
Step S 9C : Synthesis of 4-hydroxyl-9-chloro-2-(2-isopropyl-thiazol-5-yl)-8-methoxy-benzofuro[3,2-b]pyridine (9C)
[0171] The crude 9B (2.4 g, 6.9 mmol) was dissolved in THF (50 mL). To the solution was added activated MnO 2 (3.6 g, 40.4 mmol, 6 eq). The mixture was refluxed overnight. After reaction completed, the reaction mixture was cooled and filtered. The cake was washed well with THF and MeOH. The filtrate was concentrated and purified by column chromatography on silica gel to give 300 mg of pure product (9C).
[0172] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.23 (s, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.48 (s, 1H), 7.46 (d, J=8.8 Hz, 1H), 3.96 (s, 3H), 3.30 (m, 1H), 1.385 (d, J=7.3 Hz, 6H).
Step S 9D : Synthesis of 4,9-dichloro-2-(2-isopropyl-thiazol-5-yl)-8-methoxy-benzofuro[3,2-b]pyridine (M9)
[0173] A mixture of 9C (300 mg, 0.80 mmol) in POCl 3 (5 mL) was refluxed for 30 min. After reaction completed, POCl 3 was evaporated under reduced pressure. The residue was poured into crushed ice under stirring for 10 min. The solids were collected by filtration and dried to give 320 mg of crude product, which was dissolved in dichloromethane, purified by flash chromatography and concentrated to give 175 mg of pure product (M9).
[0174] 1 H-NMR (400 MHz, CDCl 3 ) δ 8.15 (s, 1H), 7.79 (s, 1H), 7.567 (d, J=8.8 Hz, 1H), 7.268 (d, J=8.8 Hz, 1H), 4.04 (s, 3H), 3.39 (m, 1H), 1.50 (d, J=7.2 Hz, 6H); ES-LCMS m/z N/A.
Example 10
Intermediate 10 (M10)
[0175]
Step S 10A : Synthesis of 1-(3-amino-4-chloro-5-methoxy-benzofuran-2-yl)-3-(2-isopropyl-thiazol-4-yl)-2-propen-1-one (10A)
[0176] A mixture of 7G (6.4 g, 26.7 mmol), 2-isopropyl-thiazole-4-carbaldehyde (4.8 g, 30.92 mmol, 1.16 eq) and NaOH (4.27 g, 106.8 mmol, 4 eq) in MeOH (200 mL) was stirred at 45° C. for 24 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and poured into water (200 mL) The yellow precipitates were collected by filtration and dried to give product 10A (9.96 g, 98.9% yield).
[0177] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.03 (s, 1H), 7.63 (s, 1H), 7.60 (d, J=9.2 Hz, 1H), 7.45-7.48 (d, J=9.2 Hz, 1H), 6.86 (s, 2H), 3.91 (s, 3H), 3.39 (m, 1H), 1.38 (d, J=6.4 Hz, 6H).
Step S 10B : Synthesis of 9-chloro-2-(2-isopropyl-thiazol-4-yl)-8-methoxy-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (10B)
[0178] 10A (9.96 g, 26.43 mmol) was dissolved in AcOH (50 mL) and H 3 PO 4 (50 mL). The solution was refluxed for 2 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and poured into water (200 mL) The brown precipitates were collected by filtration and dried to give product 10B (10.8 g), which was used for the next step directly.
Step S 10C : Synthesis of 4-hydroxyl-9-chloro-2-(2-isopropyl-thiazol-4-yl)-8-methoxy-benzofuro[3,2-b]pyridine (10C)
[0179] A mixture of 10B (10.3 g, 27.33 mmol, crude) and FeCl 3 .6H 2 O (33.04 g, 164.0 mmol, 6 eq) was added to 1,4-dioxane (300 mL) The mixture was refluxed for 16 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and poured into water (300 mL), extracted with ethyl acetate and concentrated to give a crude product 10C (8.75 g), which was used for the next step directly.
Step S 10D : Synthesis of 4,9-dichloro-2-(2-isopropyl-thiazol-4-yl)-8-methoxy-benzofuro[3,2-b]pyridine (M10)
[0180] The crude 10C (8.75 g, 23.34 mmol) was added to POCl 3 (200 mL) The mixture was refluxed for 2 hours. TLC monitored the reaction. After the reaction completed, POCl 3 was evaporated under reduced pressure. The residue was poured into crushed ice under stirring. The yellow solids were collected by filtration and purified by flash chromatography to give product M10 (0.66 g).
[0181] 1 H-NMR (400 MHz, CDCl 3 ) δ 8.36 (s, 1H), 8.17 (s, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 4.03 (s, 3H), 3.42 (m, 1H), 1.50 (d, J=6.0 Hz, 6H).
Example 11
Intermediate 11 (M11)
[0182]
Step S 11A : Synthesis of isobutyryl-thiourea (11A)
[0183] Thiourea (152 g, 2 mol) was dissolved in toluene (1520 mL). To the solution was added isobutyryl chloride (213 g, 2 mol) under mechanical stirring. The reaction mixture was refluxed for 3 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The filtrate was concentrated to dryness. The yellow solids were collected by filtration, washed with petroleum ether (100 mL×3) to appear white, dried in vacumm to give the desired product 11A (90 g, 30% yield) as a white solid (mp: 114˜116° C.).
[0184] 1 H-NMR (CDCl 3 ): δ 1.24 (d, J=6.0 Hz, 2×3H), δ 2.68 (m, J=6.93 Hz, 1H).
Step S 11B : Synthesis of 2-isobutyrylamino-thiazole-4-carboxylic acid ethyl ester (11B)
[0185] 11A (29.6 g, 0.2 mol) was dissolved in anhydrous EtOH (300 mL). To the solution was added 3-bromo-2-oxo-propionic acid (34 g, 0.17 mol). The mixture was refluxed for 2 hours, then cooled to room temperature, concentrated to dryness, dissolved with ethyl acetate, washed with saturated aqueous of NaHCO 3 . The organic layer was dried and concentrated to give a crude product 11B (48 g, 100% yield).
[0186] 1 H-NMR (CDCl 3 ): δ 1.356-1.373 (d, J=6.8 Hz, 2×3H), δ 2.828-2.845 (m, J=6.93 Hz, 1H), δ 8.094 (s, 1H), δ 10.026 (s, 1H), δ 11.605 (b, 1H).
Step S 11C : Synthesis of 2-isobutyrylamino-thiazole-4-methanol (11C)
[0187] 11B (0.73 g, 3 mmol) was dissolved in THF (14 mL). To the solution was added LiBH 4 (0.23 g, 10 mmol) in batches at room temperature. The reaction mixture was refluxed overnight, then quenched with 14 mL of anhydrous MeOH and concentrated to dryness. The residue was dissolved in dichloromethane and filtered. The filtrate was concentrated and dried to give a crude product 11C (0.48 g, 100% yield).
[0188] 1 H-NMR (CDCl 3 ): δ 1.32 (d, J=5.0 Hz, 2×3H), δ 2.58-2.73 (m, 1H), δ 4.68 (s, 2H), δ 6.82 (s, 1H).
Step S 11D : Synthesis of N-(4-formyl-thiazol-2-yl)-isobutyramide (11D)
[0189] 11C (0.5 g, 2.5 mmol) was dissolved in THF (10 mL). To the solution at room temperature was added activated MnO 2 (1.74 g, 20 mmol). The reaction mixture was refluxed overnight, then filtered. The filtrate was concentrated and dried to give a crude product 11D (0.25 g, 50% yield).
[0190] 1 H-NMR (CDCl 3 ): δ 1.32 (d, J=6.8 Hz, 6H), δ 2.58-2.73 (m, 1H), δ 7.88 (s, 1H), δ 9.88 (s, 1H), δ 10.24 (brs, 1H).
Step S 11E : Synthesis of N-{4-[3-(3-amino-4-chloro-5-methoxy-benzofuran-2-yl)-3-oxo-propenyl]-thiazol-2-yl}-isobutyramide (11E)
[0191] 7G (2.5 g, 10.4 mmol) was dissolved in THF (25 mL). To the solution was added 11D (2.4 g, 1.2 eq, 12.5 mmol), followed by crushed NaOH powder (0.8 g, 2 eq, 20.8 mmol). The reaction mixture was stirred at room temperature for about 1 hour and the solution was getting darker. After reaction completed, the mixture was poured into ice-water under stirring. The solids were collected by filtration, dried and purified by column chromatography on silica gel to give 2.6 g of pure product 11E.
[0192] 1 H-NMR (400 MHz, d-CDCl 3 ) δ 11.48 (brs, 1H), 7.64 (m, 2H), 7.26 (d, J=8.8 Hz, 1H), 7.23 (s, 1H), 7.18 (d, J=8.8 Hz, 1H), 6.41 (s, 2H), 3.96 (s, 3H), 2.78 (m, 1H), 1.31 (d, J=7.2 Hz, 6H).
Step S 11F : Synthesis of 9-chloro-2-(2-isobutyrylamino-thiazole-4-yl)-8-methoxy-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (11F)
[0193] To a mixture of 11E (2.6 g, 6.19 mmol) in MeCN (30 mL) was added ZnCl 2 (1.27 g, 1.5 eq, 9.3 mmol) at room temperature, followed by AcOH (30 mL) and H 3 PO 4 (30 mL) The reaction mixture was stirred 80° C. overnight. After reaction completed, the mixture was cooled and poured into crushed ice under stirring, neutralized to pH=7-8, extracted with ethyl acetate, dried and concentrated to give 1.6 g of crude product, which was purified by column chromatography on silica gel to give 500 mg of pure product (11F).
[0194] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 12.15 (s, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.134 (brs, 1H), 6.99 (s, 1H), 4.97 (m, 1H), 3.91 (s, 3H), 2.91 (m, 2H), 2.73 (m, 1H), 1.10 (d, J=7.2 Hz, 6H).
Step S 11G : Synthesis of 4-hydroxyl-9-chloro-2-(2-isobutyrylamino-thiazole-4-yl)-8-methoxy-benzofuro[3,2-b]pyridine (11G)
[0195] 11F (500 mg, 1.19 mmol) was dissolved in THF (tetrahydrofuran, 30 mL). To the solution was added activated MnO 2 (600 mg, 6 eq, 6.9 mmol). The mixture was refluxed for 48 hours. After reaction completed, the mixture was cooled and filtered. The cake was washed well with THF and MeOH. The filtrate was concentrated and purified by column chromatography on silica gel to give 300 mg of pure product (11G).
[0196] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 12.26 (s, 1H), 7.82 (s, 1H), 7.74 (d, J=9.6 Hz, 1H), 7.66 (s, 1H), 7.46 (d, J=9.6 Hz, 1H), 3.97 (s, 3H), 2.81 (m, 1H), 1.16 (d, J=7.2 Hz, 6H).
Step S 11H : Synthesis of 4,9-dichloro-2-(2-isobutyrylamino-thiazole-4-yl)-8-methoxy-2,3-dihydro-benzofuro[3,2-b]pyridine (M11)
[0197] A mixture of 11G (300 mg, 0.72 mmol) in POCl 3 (5 mL) was refluxed for 30 min. After reaction completed, POCl 3 was evaporated under reduced pressure. The residue was poured into crushed ice and stirred for 10 min. The solids were collected by filtration and dried to give 161 mg of product (M11).
[0198] 1 H-NMR (400 MHz, CDCl 3 ) δ 8.32 (s, 1H), 7.97 (s, 1H), 7.601 (d, J=8.8 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 4.06 (s, 3H), 2.99 (m, 1H), 1.3 (d, J=7.2 Hz, 6H).
Example 12
Synthesis of 12G
[0199]
Step S 12A : Synthesis of 2-bromo-3,6-dihydroxy-benzaldehyde (12A)
[0200] 2,5-dihydroxy-benzaldehyde (100 g, 0.72 mol) was dissolved in chlorform (1L). To the solution was added Na 3 PO 4 (77 g), followed by Br 2 (150 g, 0.94 mol) dropwise at room temperature. The mixture was stirred for 2.5 hours. To the reaction mixture was added aq.NH 4 Cl. The precipitated solid was collected by filtration, then dissolved in ethyl acetate, washed with water. The organic layer was dried over anhydrous Na 2 SO 4 , concentrated and purified by column chromatography on silica gel to give product 12A (90 g, 57.2% yield).
Step S 12B : Synthesis of 2-bromo-3,6-dihydroxy-benzaldehyde oxime (12B)
[0201] To a mixture of 2-bromo-3,6-dihydroxy-benzaldehyde (12A) (50 g, 0.23 mol) and hydroxylamine hydrochloride (19.2 g, 0.28 mol) was added 95% EtOH (500 mL), followed by NaOH (13.8 g, 0.345 mol). The reaction mixture was stirred at room temperature for 2 hours, then extracted with ethyl acetate and concentrated to give 2-bromo-3,6-dihydroxy-benzaldehyde oxime (12B) (45 g, 84.1% yield) as a solid.
Step S 12C : Synthesis of 2-bromo-3-cyano-1,4-diacetoxylbenzene (12C)
[0202] A mixture of 12B (45 g, 0.193 mol) and sodium acetate (3 g) in Ac 2 O (200 mL) was heated to reflux overnight. The reaction mixture was evaporated under reduced pressure to remove Ac 2 O. The residue was poured into water and stirred for 1 hour. The precipitated solids were collected by filtration and dried to give 12C (40 g, 69.1% yield).
[0203] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 7.79 (d, J=9.2 Hz, 1H), 7.61 (d, J=9.2 Hz, 1H), 2.40 (s, 3H), 2.38 (s, 3H).
Step S 12D : Synthesis of 2-bromo-3-cyano-4-hydroxy-phenyl acetate (12D)
[0204] 12C (15 g, 0.05 mol) was added to MeOH (52 ml) and dichloromethane (52 mL). To the mixture was added K 2 CO 3 (7 g, 0.05 mol) in batches at room temperature. The reaction mixture was stirred overnight at room temperture, then neutralized with diluted hydrochloric acid to pH=6-7, extracted with dichloromethane, dried over anhydrous Na 2 SO 4 and concentrated to give 12D (8 g, 62.1% yield).
[0205] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 11.75 (s, 1H), 7.44 (d, J=9.2 Hz, 1H), 7.06 (d, J=9.2 Hz, 1H), 2.31 (s, 3H).
Step S 12E : Synthesis of 2-acetyl-3-amino-4-bromo-5-acetoxyl-benzofuran (12E)
[0206] To a mixture of 12D (7 g, 0.027 mol) and 1-chloro-propan-2-one (3 mL) in DMF (30 mL) was added K 2 CO 3 (4.1 g, 0.029 mol). The reaction mixture was stirred at 90° C. for 1 hour. TLC monitored the reaction. After the reaction completed, the reaction mixture was cooled to room temperature and added dropwise to ice-water. The precipitated solids were collected by filtration to give a crude product 12E (6.8 g, 79.6% yield).
[0207] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 7.65 (d, J=9.2 Hz, 1H), 7.48 (d, J=9.2 Hz, 1H), 6.49 (s, 2H), 2.41 (s, 3H), 2.36 (s, 3H).
Step S 12F : Synthesis of 2-acetyl-3-amino-4-bromo-5-hydroxy-benzofuran (12F)
[0208] To a mixture of 12E (6.8 g, 0.021 mol) in MeOH (40 mL) and water (20 mL) was added K 2 CO 3 (4.5 g, 0.032 mol) in batches at room temperature. The reaction mixture was stirred at room temperature overnight, then neutralized with diluted hydrochloric acid to pH=6-7, extracted with ethyl acetate, dried and concentrated to give 12F (5.6 g, 95.1% yield).
Step S 12G : Synthesis of 2-acetyl-3-amino-4-bromo-5-methoxy-benzofuran (12G)
[0209] To a mixture of 12F (5.6 g, 0.020 mol) and CsF (9.5 g, 0.0625 mol) in THF (20 mL) was added MeI (2.9 g) dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour, then added dropwise into water. The solids were precipitated out dissolved in ethyl acetate and purified by column chromatography on silica gel to give 12G (2.4 g, 40.7% yield).
[0210] 1 H-NMR (400 MHz, CDCl 3 ) δ 7.58 (d, J=9.2 Hz, 1H), 7.41 (t, J=9.2 Hz, 1H), 6.41 (s, 2H), 3.89 (s, 3H), 2.38 (s, 3H).
Example 13
Intermediate 13 (M13)
[0211]
[0212] Step S 13A : Synthesis of 2-cinnamoyl-3-amino-4-bromo-5-methoxy-benzofuran (13A)
[0213] A mixture of 12G (2 g, 0.007 mol), benzaldehyde (1.6 g, 0.015 mol), NaOH (1.2 g) and formaldehyde (20 mL) was heated to 50° C. and reacted overnight, then added into water dropwise. The precipitated solids were collected by filtration to give 13A (2.6 g, 95% yield)
[0214] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 7.81 (m, 2H), 7.37 (d, J=15.6 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.56 (d, J=16.0 Hz, 1H), 7.44-7.50 (m, 4H), 6.82 (s, 2H), 3.91 (s, 3H).
Step S 13B : Synthesis of 9-bromo-8-methoxy-2-phenyl-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (13B)
[0215] A mixture of 13A (2.6 g, 0.0069 mol) in AcOH (10 mL) and H 3 PO 4 (10 mL) was heated to 90° C. and reacted for 2 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 13B (2 g, 76.9% yield).
[0216] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 7.61 (d, J=9.2 Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.43 (d, J=9.2 Hz, 1H), 7.33 (t, J=7.2 Hz, 2H), 6.83 (s, 1H), 4.99 (m, 1H), 3.91 (s, 3H), 2.75-2.87 (m, 2H).
Step S 13C : Synthesis of 4-hydroxyl-9-bromo-8-methoxy-2-phenyl-benzofuro[3,2-b]pyridine (13C)
[0217] A mixture of 13B (2.0 g, 0.0053 mol), FeCl 3 .6H 2 O (6 g) and 1,4-dioxane (20 mL) was heated to 110° C. and reacted overnight. After reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 13C (1.8 g, 90.4% yield).
[0218] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 11.79 (s, 1H), 8.17 (d, J=7.6 Hz, 2H), 7.08 (d, J=9.2 Hz, 1H), 7.51-7.54 (m, 3H), 7.42-7.46 (m, 2H), 3.95 (s, 3H).
Step S 13D : Synthesis of 9-bromo-4-chloro-8-methoxy-2-phenyl-benzofuro[3,2-b]pyridine (M13)
[0219] A mixture of 13C (1.8 g, 0.0048 mol) and POCl 3 (10 mL) was heated to 110° C. and reacted for 30 min. TLC monitored the reaction. After the reaction completed, POCl 3 in the mixture was evaporated. The residue was added dropwise into ice-water. The solids were collected by filtration and purified by a short column chromatography to give M13 (1.5 g, 79.3% yield).
[0220] 1 H-NMR (400 MHz, CDCl 3 ) δ 8.23 (dd, J1=8.0 Hz, J2=1.6 Hz, 2H), 7.94 (s, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.55 (dt, J1=7.6 Hz, J2=0.8 Hz, 2H), 7.49 (t, J=7.2 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 4.04 (s, 3H).
Example 14
Intermediate 14 (M14)
[0221]
Step S 14A : Synthesis of (E)-1-(3-amino-4-bromo-5-methoxy-benzofuran-2-yl)-3-(2-isopropyl-thiazol-5-yl)-2-propen-1-one (14A)
[0222] A mixture of 12G (1.5 g, 5.2 mmol), 2-isopropyl-thiazole-5-carbaldehyde (1.2 g, 7.7 mmol) in THF (20 mL) was cooled to 0° C. To the mixture was added NaOH (1.5 g), then stirred at room temperature overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 14A (1.4 g, 62.9% yield).
Step S 14B : Synthesis of 9-bromo-2-(2-isopropyl-thiazol-5-yl)-8-methoxy-1,2-dihydro-benzofuro[3,2-b]pyridin-4-one (14B)
[0223] A mixture of 14A (1.4 g, 3.3 mmol), ZnCl 2 (6 g), MeCN (10 mL), AcOH (2 mL) and H 3 PO 4 (2 mL) was heated to 90° C. and reacted overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water, extracted with ethyl acetate and concentrated to give 14B (1.1 g, 78% yield).
Step S 14C : Synthesis of 4-hydroxyl-9-bromo-2-(2-isopropyl-thiazol-5-yl)-8-methoxy-dibenzofuran (14C)
[0224] A mixture of 14B (1.1 g, 2.6 mmol), MnO 2 (6 g) in THF (20 mL) was heated to 110° C. and reacted overnight, then filtered. The filtrate was concentrated to give 14C (0.8 g, 73% yield).
Step S 14D : Synthesis of 9-bromo-4-chloro-2-(2-isopropyl-thiazol-5-yl)-8-methoxy-benzofuro[3,2-b]pyridine (M14)
[0225] A mixture of 14C (0.8 g, 1.9 mmol) in POCl 3 (10 mL) was heated to 110° C. and reacted for 30 min. TLC monitored the reaction. After the reaction completed, POCl 3 in reaction mixture was evaporated. The residue was added dropwise into ice-water. The precipitated solids were collected by filtration and purified by short column chromatography to give M14 (0.16 g, 19% yield).
[0226] 1 H-NMR (400 MHz, CDCl 3 ) δ 8.19 (s, 1H), 7.81 (s, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 4.04 (s, 3H), 3.40 (m, 1H), 1.52 (d, J=7.2 Hz, 6H).
Example 15
Intermediate 15 (M15)
[0227]
Step S 15A : Synthesis of 1-(3-amino-4-bromo-5-methoxy-benzofuran-2-yl)-3-(2-isopropyl-thiazol-4-yl)-2-propen-1-one (15A)
[0228] A mixture of 12G (2 g, 7 mmol), 2-isopropyl-thiazole-4-carbaldehyde (2.2 g, 14.6 mmol), NaOH (1.5 g) and MeOH (20 mL) was heated to 50° C. and reacted overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 15A (2.8 g, 94.4% yield).
[0229] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.04 (s, 1H), 7.67 (d, J=9.2 Hz, 1H), 7.63 (s, 2H), 7.45 (d, J=9.2 Hz, 1H), 6.81 (s, 2H), 3.90 (s, 3H), 3.38 (m, 1H), 1.38 (d, J=6.4 Hz, 6H).
Step S 15B : Synthesis of 9-bromo-2-(2-isopropyl-thiazol-4-yl)-8-methoxy-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (15B)
[0230] A mixture of 15A (2.8 g, 6.6 mmol), AcOH (10 mL) and H 3 PO 4 (10 mL) was heated to 90° C. and reacted for 2 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 15B (2 g, 71.4% yield).
Step S 15c : Synthesis of 4-hydroxyl-9-bromo-2-(2-isopropyl-thiazol-4-yl)-8-methoxy-benzofuro[3,2-b]pyridine (15C)
[0231] A mixture of 15B (2.0 g, 4.7 mmol), FeCl 3 .6H 2 O (6 g) in 1,4-dioxane (20 mL) was heated to 110° C. and reacted overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 15C (1.2 g, 60.2% yield).
[0232] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.04 (s, 1H), 7.67 (d, J=9.2 Hz, 1H), 7.63 (s, 2H), 7.45 (d, J=9.2 Hz, 1H), 6.81 (s, 2H), 3.91 (s, 3H), 3.38 (m, 1H), 1.42 (d, J=6.4 Hz, 6H).
Step S 15D : Synthesis of 9-bromo-4-chloro-2-(2-isopropyl-thiazol-4-yl)-8-methoxy-benzofuro[3,2-b]pyridine (M15)
[0233] A mixture of 15C (1.2 g, 2.8 mmol) in POCl 3 (10 mL) was heated to 110° C. and reacted for 30 min. TLC monitored the reaction. After the reaction completed, POCl 3 in the reaction mixture was evaporated. The residue was added dropwise into ice-water. The precipitated solids were collected by filtration and purified by short column chromatography to give M15 (0.2 g, 16% yield).
[0234] 1 H-NMR (400 MHz, CDCl 3 ) δ 8.39 (s, 1H), 8.20 (s, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.24 (d, J=9.2 Hz, 1H), 4.04 (s, 3H), 3.40 (m, 1H), 1.50 (d, J=7.2 Hz, 6H).
Example 16
Intermediate 16 (M16)
[0235]
Step S 16A : Synthesis of 1-(3-amino-4-bromo-5-methoxy-benzofuran-2-yl)-3-(2-isobutyrylamino-thiazole-4-yl)-2-propen-1-one (16A)
[0236] A mixture of 12G (2 g, 7 mmol), 11D (2.8 g, 14.5 mmol) in THF (20 mL) was cooled to 0° C. To the mixture was added NaOH (2 g). The reaction mixture was reacted at room temperature overnight. TLC monitored the reaction. After reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 16A (2 g, 61% yield).
[0237] 1 H-NMR (400 MHz, CDCl 3 ) δ 9.80 (s, 1H), 7.65 (s, 1H), 7.35 (d, J=9.2 Hz, 1H), 7.23 (s, 1H), 7.16 (d, J=9.2 Hz, 1H), 6.52 (s, 2H), 3.96 (s, 3H), 2.73 (m, 1H), 1.38 (d, J=7.2 Hz, 6H).
Step S 16B : Synthesis of 9-bromo-2-(2-isobutyrylamino-thiazole-4-yl)-8-methoxy-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (16B)
[0238] A mixture of 16A (2 g, 4.3 mmol), ZnCl 2 (6 g), MeCN (10 mL), AcOH (2 mL) and H 3 PO 4 (2 mL) was heated to 90° C. and reacted overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water, extracted with ethyl acetate and concentrated to give 16B (1.1 g, 55% yield).
[0239] 1 H-NMR (400 MHz, DMSO-d 6 ) δ 10.21 (s, 1H), 7.43 (d, J=9.2 Hz, 1H), 7.17 (d, J=9.2 Hz, 1H), 6.92 (s, 1H), 5.99 (m, 1H), 5.03 (m, 1H), 3.96 (s, 3H), 2.93-3.09 (m, 2H), 2.69-2.74 (m, 1H), 1.33 (d, J=7.2 Hz, 6H).
Step S 16C : Synthesis of 4-hydroxyl-9-bromo-2-(2-isobutyrylamino-thiazole-4-yl)-8-methoxy-benzofuro[3,2-b]pyridine (16C)
[0240] A mixture of 16B (1.1 g, 2.3 mmol) and MnO 2 (6 g) in THF (20 mL) was heated to 110° C. and reacted overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was filtered and the filtrate was concentrated to give 16C (0.7 g, 63.9% yield).
Step S 16D : Synthesis of 9-bromo-4-chloro-2-(2-isobutyrylamino-thiazole-4-yl)-8-methoxy-benzofuro[3,2-b]pyridine (M16)
[0241] A mixture of 16C (0.7 g, 1.5 mmol) in POCl 3 (10 mL) was heated to 110° C. and reacted for 30 min. TLC monitored the reaction. After the reaction completed, POCl 3 in the reaction mixture was evaporated. The residue was added dropwise into ice-water. The precipitated solids were collected by filtration and purified by short column chromatography to give M16 (0.2 g, 27% yield).
[0242] 1 H-NMR (400 MHz, CDCl 3 ) δ 9.37 (s, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.63 (d, J=9.2 Hz, 1H), 7.24 (d, J=9.2 Hz, 1H), 4.04 (s, 3H), 2.72 (m, 1H), 1.50 (d, J=7.2 Hz, 6H).
Example 17
Intermediate 17 (M17)
[0243]
Step S 17A : Synthesis of 2-mercapto-4-fluoro-benzonitrile (17A)
[0244] The procedure was similar to step S 3A , while the starting material was 2,4-difluoro-benzonitrile in stead of 2-fluoro-benzonitrile.
Step S 17B : Synthesis of 1-(3-amino-6-fluoro-benzo[b]thiophen-2-yl)-ethanone (17B)
[0245] The procedure was similar to step S 3B , while the starting material was 17A in stead of 3A.
Step S 17C : Synthesis of (E)-2-cinnamoyl-3-amino-6-fluoro-benzo[b]thiophene (17C)
[0246] The procedure was similar to step S 3C , while the starting material was 17B in stead of 3B.
Step S 17B : Synthesis of 2-phenyl-7-fluoro-2,3-dihydro-benzothieno[3,2-b]pyridin-4(1H)-one (17D)
[0247] The procedure was similar to step S 3D , while the starting material was 17C in stead of 3C.
Step S 17E : Synthesis of 2-phenyl-7-fluoro-4-hydroxyl-benzothieno[3,2-b]pyridine (17E)
[0248] The procedure was similar to step S 3E , while the starting material was 17D in stead of 3D.
[0249] 17E: MS (ESI): M + +1=296.
Step S 17F : Synthesis of 4-chloro-7-fluoro-2-phenyl-benzothieno[3,2-b]pyridine (M17)
[0250] The procedure was similar to step S 3F , while the starting material was 17E in stead of 3E.
[0251] M17: MS (ESI): M + +1=314.
Example 18
Synthesis of 4-chloro-2-methoxycarbonyl-phenyl acetic acid methyl ester (18E)
[0252]
Step S BA : Synthesis of 2-carboxyl-phenyl acetic acid (18A)
[0253] K 2 Cr 2 O 7 (24.4 g, 83 mmol) was dissolved in water (360 mL). To the solution was added conc. H 2 SO 4 (133 g, 1.3 mol) dropwise slowly at 65° C., followed by 1H-indene (6.85 g, 56 mmol) dropwise. The reaction mixture was stirred at this temperture for 2 hours. The color of the solution changed from orange to blue, some solids were precipitated out on the bottle wall. The reaction mixture was cooled to below 0° C., and stirred for 2 hours, then filtered. The cake was washed with 1% aq.H 2 SO 4 and ice-water until the green color disappeared, then dried to give 7.6 g of 2-carboxyl-phenyl acetic acid (18A).
[0254] MS (ESI): M + +1=181.1.
Step S 18B : Synthesis of 2-carboxymethyl-5-nitro-benzoic acid (18B)
[0255] 2-carboxyl-phenyl acetic acid (3 g, 16.7 mmol) was added in batches to fuming HNO 3 (16 mL) under ice-salt bath while keeping the temperature under −3° C. The reaction mixture was reacted at that temperature for 2 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was added into ice (16 g) under stirring. The precipitated white solids were collected by filtration and dried to give 2.1 g of the desired product 2-carboxymethyl-5-nitro-benzoic acid (18B).
[0256] 1 H-NMR (DMSO-d 6 ): δ (ppm): 8.62 (d, J=2.8 Hz, 1H), 8.35-8.37 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 4.11 (s, 2H); MS (ESI):
[0257] M + +1=226.1.
Step S 18C : Synthesis of 2-methoxycarbonylmethyl-5-nitro-benzoic acid methyl ester (18C)
[0258] 2-carboxymethyl-5-nitro-benzoic acid (2 g, 8.8 mmol) was dissolved in MeOH (30 mL). To the solution was added SOCl 2 (2.64 g, 22.2 mmol) dropwise slowly at room temperature. The reaction mixture was refluxed for 2 hours. TLC monitored the reaction. After the reaction completed, the solvent in the reaction mixture was evaporated to dryness, which was used for the next step directly.
Step S 18D : Synthesis of 2-methoxycarbonylmethyl-5-amino-benzoic acid methyl ester (18D)
[0259] 2-methoxycarbonylmethyl-5-nitro-benzoic acid methyl ester (2.2 g, 8.8 mmol) was dissolved in MeOH (30 mL), then heated to 50° C. To the solution was added SnCl 2 (5.89 g, 31 mmol) in batches. The reaction mixture was stirred at this temperture for 1 day. TLC monitored the reaction. After the reaction completed, the solvent was evaporated. To the residue was added ethyl acetate and base, adjusted pH to 8-9, then filtered though celite and washed with ethyl acetate. The organic layer of the filtrate was collected and washed with water, dried over anhydrous Na 2 SO 4 and concentrated to give 1.3 g of 5-amino-2-methoxycarbonylmethyl-benzoic acid methyl ester (18D).
[0260] 1 H-NMR (DMSO-d 6 ): δ (ppm): 7.15 (d, J=2.8 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H), 6.72 (dd, J1=8 Hz, J2=2.8 Hz, 1H), 5.30 (s, 1H), 3.75 (s, 2H), 3.73 (s, 3H), 3.56 (s, 3H); MS (ESI): M + +1=224.2.
Step S 18E : Synthesis of 4-chloro-2-methoxycarbonyl-phenyl acetic acid methyl ester (18E)
[0261] 5-amino-2-methoxycarbonylmethyl-benzoic acid methyl ester (5 g, 22.4 mmol) was dissolved in hydrochloric acid (50 mL). To the solution was added dropwise aq.NaNO 2 (1.7 g, 24.6 mmol) at below 5° C. After addition completed, the color became maroon. Then CuCl (2.4 g, 24.6 mmol) solution was added to the reaction mixture. The reaction mixture was reacted at below 5° C. for 1 hour. The reaction mixture was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous Na 2 SO 4 , concentrated and purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) to give 2.3 g of 5-chloro-2-methoxycarbonylmethyl-benzoic acid methyl ester (18E).
[0262] 1 H-NMR (DMSO-d 6 ): δ (ppm): 7.88 (d, J=2.8 Hz, 1H), 7.64-7.66 (dd, J1=8 Hz, J2=2 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 4.00 (d, J=4.0 Hz, 2H), 3.80 (s, 3H), 3.60 (s, 3H); MS (ESI): M + +1=243.7.
Example 19
Intermediate 19 (M19)
[0263]
Step S 19A : Synthesis of 2-(4-chloro-2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (19A)
[0264] 18E (16.48 mmol) was dissolved in CCl 4 (50 mL), and was added NBS (N-bromosuccinimide, 3.23 g, 18.13 mmol), followed by catalytic amount of BPO (benzoyl peroxide). The reaction mixture was refluxed for about 20 hours under stirring. When no more product was produced any more, the reaction mixture was cooled and filtered. To the filtrate was added NBS (1.6 g, 8.24 mmol) and catalytic amount of BPO. The reaction mixture was refluxed for additional 10 hours. After the reaction completed, the mixture was cooled and filtered. The filtrate was concentrated to give 6.4 g of a crude product (19A), which was used directly for the next step.
Step S 19B : Synthesis of 3-chloro-benzofuro[3,2-c]isoquinoline-5-ol (19B)
[0265] A mixture of 19A (crude, 20.29 mmol) and 2-hydroxy-benzonitrile (20.29 mmol) in MeCN (100 mL) was stirred at room temperature. To the solution was added triethylamine (TEA, 20.44 g, 202.9 mmol) dropwise. After addition completed, the reaction was refluxed for 24 hours, then cooled. The precipitated solids were collected by filtration, washed with a small amount of MeCN, then washed with water several times until there was no TEA salt, dried to give pure product 19B (3.1 g).
[0266] 1 H-NMR (DMSO-d 6 ): δ (ppm): 12.63 (s, 1H), 8.28 (d, J=2.4 Hz, 1H), 8.04-8.07 (m, 2H), 7.95 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H); MS (ESI): M + +1=270.7.
Step S 19C : Synthesis of 3,5-dichloro-benzofuro[3,2-c]isoquinoline (M19)
[0267] A mixture of 19B (11.8 mmol) in POCl 3 (20 mL) was refluxed for 2 hours. After reaction completed, POCl 3 was evaporated under reduced pressure. The residue was added into crushed ice and stirred for 10 min. The solids were collected by filtration and dried to give 3.2 g of a crude product, which was dissolved in dichloromethane and purified by flash chromatography (petroleum ether 1:1) and concentrated to give a pure product M19 (3.1 g).
[0268] 1 H-NMR (DMSO-d 6 ): δ (ppm): 8.50 (d, J=8.8 Hz, 1H), 8.44 (s, 1H), 8.20 (d, J=7.6 Hz, 1H), 8.13 (dd, J1=9.2 Hz, J2=2.0 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.69 (t, J=7.4 Hz, 1H), 7.59 (t, J=7.4 Hz, 1H); MS (ESI): M + +1=289.1.
Example 20
Intermediate 20 (M20)
[0269]
Step S 20A : Synthesis of 2-(4-bromo-2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (20A)
[0270] The procedure was similar to step S 19A , while the starting material was 5-bromo-2-methoxycarbonylmethyl-benzoic acid methyl ester (the procedure of this compound was similar to 5-chloro-2-methoxycarbonylmethyl-benzoic acid methyl ester, while the starting material was CuBr in stead of CuCl) in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester.
[0271] MS (ESI): M + +1=367.
Step S 20B : Synthesis of 5-hydroxyl-3-bromo-benzofuro[3,2-c]isoquinoline (20B)
[0272] The procedure was similar to step S 19B , while the starting material was 20A in stead of 19A.
[0273] 1 H-NMR (DMSO-d 6 ): δ (ppm): 12.63 (s, 1H), 8.41 (d, J=1.6 Hz, 1H), 8.05 (d, J=8.0 Hz, 2H), 7.98 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.50-7.54 (t, J=7.6 Hz, 1H), 7.40-7.44 (t, J=7.6 Hz, 1H); MS (ESI):
[0274] M + +1=315.1.
Step S 20C : Synthesis of 3-bromo-5-chloro-benzofuro[3,2-c]isoquinoline (M20)
[0275] The procedure was similar to step S 19C , while the starting material was 20B in stead of 19B.
[0276] 1 H-NMR (DMSO-d 6 ): δ (ppm): 8.59 (d, J=1.6 Hz, 1H), 8.42 (d, J=8.8 Hz, 1H), 8.19-8.24 (m, 2H), 7.95 (d, J=8.0 Hz, 1H), 7.60 (dt, J=1.2, 7.6 Hz, 1H), 7.59 (t, J=7.6 Hz, 1H); MS (ESI): M + +1=333.6.
Example 21
Intermediate 21 (M21)
[0277]
Step S 21A : Synthesis of 2-(2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (21A)
[0278] The procedure was similar to step S 19A , while the starting material was 2-methoxycarbonylmethyl-benzoic acid methyl ester (commercialized) in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester (18E).
[0279] MS (ESI): M + +1=288.1.
Step S 21B : Synthesis of 5-hydroxyl-8-methoxy-benzofuro[3,2-c]isoquinoline (21B)
[0280] The procedure was similar to step S 19B , while the starting material 19A and 2-hydroxy-benzonitrile were replaced with 21A and 2-hydroxy-5-methoxy-benzonitrile, respectively.
[0281] 1 H-NMR (DMSO-d 6 ): δ (ppm): 12.32 (s, 1H), 8.34 (d, J=8.0 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.88 (t, J=8.4 Hz, 1H), 7.67 (d, J=9.2 Hz, 1H), 7.59-7.62 (m, 2H), 7.09 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 3.83 (s, 3H); MS (ESI):
[0282] M + +1=266.3.
Step S 21C : Synthesis of 8-methoxy-5-chloro-benzofuro[3,2-c]isoquinoline (M21)
[0283] The procedure was similar to step S 19C , while the starting material was 21B in stead of 19B.
[0284] 1 H-NMR (DMSO-d 6 ): δ (ppm): 8.50 (t, J=9.0 Hz, 2H), 8.12 (t, J=8.0 Hz, 1H), 7.96 (t, J=8.0 Hz, 1H), 7.86 (d, J=9.2 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.25 (dd, J1=9.2 Hz, J2=2.8 Hz, 1H), 3.93 (s, 3H); MS (ESI): M + +1=284.7.
Example 22
Intermediate 22 (M22)
[0285]
Step S 22A : Synthesis of 2-(2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (22A)
[0286] The procedure was similar to step S 19A , while the starting material was 2-methoxycarbonylmethyl-benzoic acid methyl ester (commercialized) in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester (18E).
Step S 22B : Synthesis of 5-hydroxyl-benzofuro[3,2-c]isoquinoline 1 (22B)
[0287] The procedure was similar to step S 19B , while the starting material was 22A in stead of 19A.
Step S 22C : Synthesis of 5-chloro-benzofuro[3,2-c]isoquinoline (M22)
[0288] The procedure was similar to step S 19C , while the starting material was 22B in stead of 19B.
[0289] 1 H-NMR (DMSO-d 6 ): δ (ppm): 8.48 (d, J=6.4 Hz, 2H), 8.20 (d, J=7.2 Hz, 1H), 8.12 (t, J=7.6 Hz, 1H), 7.90-7.95 (m, 2H), 7.68 (t, J=7.8 Hz, 1H), 7.58 (t, J=7.2 Hz, 1H), MS (ESI): M + +1=254.7.
Example 23
Intermediate 23 (M23)
[0290]
Step S 23A : Synthesis of 2-(2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (23A)
[0291] The procedure was similar to step S 19A , while the starting material was 2-methoxycarbonylmethyl-benzoic acid methyl ester (commercialized) in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester (18E).
Step S 23B : Synthesis of 5-hydroxyl-benzothieno[3,2-c]isoquinoline (23B)
[0292] The procedure was similar to step S 19B , while the starting material was 23A in stead of 19A, and used 2-mercapto-benzonitrile in stead of 2-hydroxy-benzonitrile.
Step S 23C : Synthesis of 5-chloro-benzothieno[3,2-c]isoquinoline (M23)
[0293] The procedure was similar to step S 19C , while the starting material was 23B in stead of 19B.
[0294] 1 H-NMR (DMSO-d 6 ): δ (ppm): 8.51 (d, J=8.4 Hz, 1H), 8.41 (m, 1H), 8.31 (dd, J1=7.2 Hz, J2=0.8 Hz, 1H), 8.24 (m, 1H), 8.09 (t, J=8.0 Hz, 1H), 7.96 (t, J=8.0 Hz, 1H), 7.65-7.68 (m, 2H); MS (ESI): M + +1=270.7.
Example 24
Intermediate 24 (M24)
[0295]
Step S 24A : Synthesis of 2-(2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (24A)
[0296] The procedure was similar to step S 19A , while the starting material was 2-methoxycarbonylmethyl-benzoic acid methyl ester in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester (18E).
Step S 24B : Synthesis of 5-hydroxyl-8-chloro-benzofuro[3,2-c]isoquinoline (24B)
[0297] The procedure was similar to step S 19B , while the starting material was 24A in stead of 19A, and used 5-chloro-2-hydroxy-benzonitrile in stead of 2-hydroxy-benzonitrile.
Step S 24C : Synthesis of 5,8-dichloro-benzofuro[3,2-c]isoquinoline (M24)
[0298] The procedure was similar to step S 19C , while the starting material was 24B in stead of 19B.
[0299] 1 H-NMR (DMSO-d 6 ): δ (ppm): 8.51 (t, J=17.2 Hz, 2H), 8.23 (d, J=2.0 Hz, 1H), 8.15 (t, J=16.0 Hz, 1H), 7.96-7.99 (m, 2H), 7.70 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H); MS (ESI): M + +1=289.1.
Example 25
Intermediate 25 (M25)
[0300]
Step S 25A : Synthesis of 2-(4-methoxyl-2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (25A)
[0301] The procedure was similar to step S 19A , while the starting material was 5-methoxyl-2-methoxycarbonylmethyl-benzoic acid methyl ester (commercialized) in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester (18E).
[0302] MS (ESI): M + +1=318.1.
Step S 25B : Synthesis of 5-hydroxyl-3-methoxy-benzofuro[3,2-c]isoquinoline (25B)
[0303] The procedure was similar to step S 19B , while the starting material was 25A in stead of 19A.
[0304] MS (ESI): M + +1=266.3.
Step S 25C : Synthesis of 3-methoxy-5-chloro-benzofuro[3,2-c]isoquinoline (M25)
[0305] The procedure was similar to step S 19C , while the starting material was 25B in stead of 19B.
[0306] 1 H-NMR (CDCl 3 ): δ (ppm): 8.336 (d, J=8.8 Hz, 1H), 8.242 (d, J=7.6 Hz, 1H), 7.746 (d, J=2.4 Hz, 1H), 7.711 (d, J=7.6 Hz, 1H), 7.53-7.58 (m, 2H), 7.48 (t, J=7.2 Hz, 1H), 4.06 (s, 3H); MS (ESI): M + +1=284.7.
Example 26
Intermediate 26 (M26)
[0307]
Step S 26A : Synthesis of 2-(4-chloro-2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (26A)
[0308] The procedure was similar to step 19A.
Step S 26B : Synthesis of 5-hydroxyl-3-chloro-8-methoxy-benzofuro[3,2-c]isoquinoline (26B)
[0309] The procedure was similar to step S 19B , while the starting material was 2-hydroxy-5-methoxy-benzonitrile in stead of 2-hydroxy-benzonitrile.
[0310] 1 H-NMR (DMSO-d 6 ): δ (ppm): 12.49 (s, 1H), 8.25 (d, J=2.0 Hz, 1H), 8.027 (d, J=8.8 Hz, 1H), 7.918 (dd, J1=8.8 Hz, J2=2 Hz, 1H), 7.669 (d, J=9.2 Hz, 1H), 7.587 (d, J=2.8 Hz, 1H), 7.097 (dd, J1=8.8 Hz, J2=2.8 Hz, 1H), 3.840 (s, 3H); MS (ESI): M + +1=300.7.
Step S 26C : Synthesis of 3,5-dichloro-8-methoxy-benzofuro[3,2-c]isoquinoline (M26)
[0311] The procedure was similar to step S 19C , while the starting material was 26B in stead of 19B.
[0312] 1 H-NMR (CDCl 3 ): δ (ppm): 8.502 (d, J=1.6 Hz, 1H), 8.360 (d, J=8.8 Hz, 1H), 8.871 (dd, J1=8.8 Hz, J2=1.6 Hz, 1H), 7.706 (s, J=2.4 Hz, 1H), 7.623 (d, J=9.2 Hz, 1H), 7.182 (dd, J1=9.2 Hz, J2=2.8 Hz, 1H), 3.964 (s, 3H);
[0313] MS (ESI): M + +1=319.2.
Example 27
Intermediate 27 (M27)
[0314]
Step S 27A : Synthesis of 2-(4-chloro-2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (27A)
[0315] The procedure was similar to step 19A.
Step S 27B : Synthesis of 3,8-dichloro-5-hydroxyl-benzofuro[3,2-c]isoquinoline 1 (27B)
[0316] The procedure was similar to step S 19B , while the starting material was 5-chloro-2-hydroxy-benzonitrile in stead of 2-hydroxy-benzonitrile.
[0317] 1 H-NMR (DMSO-d 6 ): δ (ppm): 12.539 (s, 1H), 8.246 (d, J=2.0 Hz, 1H), 8.039 (s, 1H), 8.028 (d, J=8.8 Hz, 1H), 7.926 (dd, J1=8.4 Hz, J2=2 Hz, 1H), 7.796 (d, J=8.8 Hz, 1H), 7.520 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H); MS (ESI): M + +1=305.1.
Step S 27C : Synthesis of 3,5,8-trichloro-benzofuro[3,2-c]isoquinoline (M27)
[0318] The procedure was similar to step S 19C , while the starting material was 27B in stead of 19B.
[0319] 1 H-NMR (CDCl 3 ): δ (ppm): 8.510 (d, J=2.0 Hz, 1H), 8.356 (d, J=8.8 Hz, 1H), 8.220 (d, J=1.6 Hz, 1H), 7.890 (dd, J1=8.8 Hz, J2=1.6 Hz, 1H), 7.655 (d, J=8.8 Hz, 1H), 7.540 (dd, J1=8.4 Hz, J2=2 Hz, 1H); MS (ESI):
[0320] M + +1=323.6.
Example 28
Intermediate 28 (M28)
[0321]
Step S 28A : Synthesis of 2-(4-methoxyl-2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (28A)
[0322] The procedure was similar to step S 19A , while the starting material was 5-methoxy-2-methoxycarbonylmethyl-benzoic acid methyl ester (commercialized) in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester (18E).
[0323] MS (ESI): M + +1=318.1.
Step S 28B : Synthesis of 5-hydroxyl-3-methoxy-8-chloro-benzofuro[3,2-c]isoquinoline (28B)
[0324] The procedure was similar to step S 19B , while the starting material was 28A in stead of 19A, and used 5-chloro-2-hydroxy-benzonitrile in stead of 2-hydroxy-benzonitrile.
Step S 28C : Synthesis of 3-methoxy-5,8-dichloro-benzofuro[3,2-c]isoquinoline (M28)
[0325] The procedure was similar to step S 19C , while the starting material was 28B in stead of 19B.
[0326] 1 H-NMR (CDCl 3 ): δ (ppm): 8.325 (d, J=8.8 Hz, 1H), 8.204 (d, J=2.0 Hz, 1H), 7.761 (d, J=2.4 Hz, 1H), 7.634 (d, J=8.8 Hz, 1H), 7.591 (dd, J1=8.8 Hz, J2=2 Hz, 1H), 7.495 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 4.070 (s, 3H);
[0327] MS (ESI): M + +1=319.1.
Example 29
Intermediate 29 (M29)
[0328]
Step S 29A : Synthesis of 2-(2-methoxycarbonyl-phenyl)-2-bromo-acetic acid methyl ester (29A)
[0329] The procedure was similar to step S 19A , while the starting material was 2-methoxycarbonylmethyl-benzoic acid methyl ester in stead of 5-chloro-2-methoxycarbonyl methyl-benzoic acid methyl ester (18E).
Step S 29B : Synthesis of 5-hydroxyl-9-fluoro-benzothieno[3,2-c]isoquinoline (29B)
[0330] The procedure was similar to step S 19B , while the starting material was 29A in stead of 19A, and used 4-fluoro-2-mercapto-benzonitrile in stead of 2-hydroxy-benzonitrile.
Step S 29C : Synthesis of 5-chloro-9-fluoro-benzothieno[3,2-c]isoquinoline (M29)
[0331] The procedure was similar to step S 19C , while the starting material was 29B in stead of 19B.
[0332] 1 H-NMR (CDCl 3 ): δ (ppm): 8.47 (d, J=8.4 Hz, 1H), 8.37 (m, 1H), 8.27 (d, J=8.0 Hz, 1H), 8.171 (d, J=8.4 Hz, 1H), 8.05 (dd, J1=8.0 Hz, J2=7.2 Hz, 1H), 7.49 (dd, J1=8.4 Hz, J2=8.0 Hz, 1H); MS (ESI): M + +1=288.
Example 30˜70
Synthesis of Compound Ik (k=1, 2, 3 . . . 13, 15 . . . 41, 42)
Synthetic Method A
[0333] A mixture of intermediate Mi (I=1, 2, 3, . . . 11, 13, . . . 17, 19, . . . or 29) (0.1 mmol), starting material A-j (j=I, II, or VI) (0.1 mmol) and t-BuOK (potassium tert-butoxide, 5 mmol) was cooled to 0° C. To the mixture was added DMSO (dimethyl sulfoxide, 5 mL), then warmed to room temperature within 20 min. TLC monitored the reaction. After the reaction completed, the reaction mixture was poured into ice-water, extracted with ethyl acetate (50 mL×3), dried over anhydrous Na 2 SO 4 , filtered, concentrated to dryness under reduced pressure and purified by preparative-TLC (silica gel, CH 2 Cl 2 : MeOH=100:5) to give desired product Ik.
Synthetic Method B
[0334] A mixture of starting material A-j (j=I, II, or VI) (1 mmol) and t-BuOK (5 mmol) was dissolved in THF (tetrahydrofuran) and DMSO (2 ml+2 mL) and cooled to 0° C. To the solution was added a solution of intermediate Mi (I=1, 2, 3, . . . 11, 13, . . . 17, 19, . . . or 29) (1 mmol) in THF/DMSO (2 ml, 1/1) dropwise within 5 min at 0° C. The reaction mixture was stirred at room temperature overnight, then poured into water, extracted with ethyl acetate, dried over anhydrous MgSO 4 and purified by preparative-HPLC.
[0000] wherein, A-j (j=I, II, or VI) (The references of preparation: 1) PCT Int. Appl., 2009140500, 19 Nov. 2009; 2) PCT Int. Appl., 2008008776, 17 Jan. 2008) was listed as follows:
[0000]
[0000]
TABLE 1
Synthetic
Example
Ik
A-j
Mi
method
Compoud Structure
M + + 1
30
1
A-II
M2
A
850.3
31
2
A-I
M21
A
816
32
3
A-II
M4
A
830
33
4
A-II
M5
A
834
34
5
A-I
M24
A
820.2
35
6
A-I
M22
A
786.3
36
7
A-II
M17
A
834.2
37
8
A-II
M6
A
878.2
38
9
A-II
M3
A
816.3
39
10
A-I
M28
A
820.2
40
11
A-II
M24
A
808.2
41
12
A-II
M28
A
808.2
42
13
A-III
M24
A
807.2
43
15
A-II
M21
A
804.3
44
16
A-I
M20
B
865.1
45
17
A-I
M19
B
820.3
46
18
A-I
M25
B
816.3
47
19
A-I
M26
B
850.2
48
20
A-IV
M19
B
820.2
49
21
A-IV
M4
A
842.3
50
22
A-IV
M8
A
876.3
51
23
A-II
M8
A
864.3
52
24
A-II
M10
B
913.3
53
25
A-II
M10
A
929.2
54
26
A-II
M15
A
973.2
55
27
A-II
M13
A
908.2
56
28
A-IV
M13
A
920.2
57
29
A-II
M19
B
808.2
58
30
A-II
M20
B
852.2
59
31
A-II
M25
B
804.3
60
32
A-II
M26
B
838.2
61
33
A-II
M27
B
842.2
62
34
A-II
M11
A
956.3
63
35
A-II
M16
A
1000.2
64
36
A-V
M1
A
822.3
65
37
A-VI
M1
A
810.3
66
38
A-II
M1
A
800.3
67
39
A-II
M9
A
929.2
68
40
A-II
M14
A
973.2
69
41
A-II
M23
A
780.2
70
42
A-II
M28
B
838.2
[0335] Compound 2
[0336] tert-butyl(2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-(8-methoxybenzofuro[3,2-c]isoquinolin-5-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl carbamate
[0337] 1 H-NMR (CDCl 3 ): δ (ppm): 10.29 (s, 1H), 8.33 (d, J=8.2 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.78 (t, J=7.6 Hz, 1H), 7.49-7.55 (m, 3H), 7.08 (d, J=9.0 Hz, 1H), 6.96 (s, 1H), 6.11 (s, 1H), 5.70 (dd, J=8.8, 8.0 Hz, 1H), 5.20 (m, 1H), 4.98 (t, J=9.6 Hz, 1H), 4.67-4.72 (m, 2H), 4.33 (m, 1H), 4.12 (d, J=9.3 Hz, 1H), 3.99 (s, 3H), 2.80-2.92 (m, 2H), 2.73-2.78 (m, 1H), 2.49-2.59 (brs, 1H), 2.28 (q, J=8.8 Hz, 1H), 1.70-1.95 (m, 3H), 1.55-1.65 (m, 1H), 1.40-1.52 (m, 7H), 1.28 (s, 10H), 1.08-1.15 (m, 2H), 0.91 (m, 1H); MS (ESI): M + +1=816.
[0338] Compound 3
[0339] tert-butyl(S)-1-(2S,4R)-2-(1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-(8-methoxy-2-phenylbenzofuro [3,2-b]pyridin-4-yloxy)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl carbamate
[0340] 1 H-NMR (CDCl 3 ): δ (ppm): 9.27 (s, 1H), 8.02 (d, J=6.8 Hz, 2H), 7.82 (d, J=2.5 Hz, 1H), 7.69 (s, 1H), 7.61-7.65 (m, 4H), 7.33 (d, J=9.2 Hz, 1H), 5.84 (brs, 1H), 5.71 (dd, J=18.3, 9.6 Hz, 1H), 5.30 (d, J=18.3 Hz, 1H), 5.13 (d, J=9.6 Hz, 1H), 4.56-4.62 (m, 2H), 3.95-4.18 (m, 2H), 3.94 (s, 3H), 2.91-2.97 (m, 1H), 2.71 (dd, J=6.7, 14.1 Hz, 1H), 2.57 (ddd, J=14.1, 10.8, 4.1 Hz, 1H), 2.23 (dd, J=8.1, 17.5 Hz, 1H), 1.89 (dd, J=5.5, 17.8 Hz, 1H), 1.45 (dd, J=5.3, 9.2 Hz, 1H), 1.21-1.27 (m, 2H), 1.10 (s, 11H), 1.02 (s, 9H); MS (ESI): M + +1=830.
[0341] Compound 4
[0342] tert-butyl(S)-1-((2S,4R)-4-(8-chloro-2-phenylbenzofuro[3,2-b]pyridin-4-yloxy)-2-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl carbamate
[0343] 1 H-NMR (CDCl 3 ): δ (ppm): 9.27 (s, 1H), 8.30 (s, 1H), 8.04 (d, J=8.4 Hz, 2H), 7.61-7.70 (m, 3H), 7.51-7.58 (m, 3H), 5.71-5.80 (m, 2H), 5.30 (d, J=16.7 Hz, 1H), 5.13 (d, J=10.4 Hz, 1H), 4.52-4.62 (m, 2H), 3.20 (s, 1H), 4.13 (d, J=10.0 Hz, 1H), 2.91-2.97 (m, 1H), 2.67 (dd, J=6.8, 13.9 Hz, 1H), 2.57 (ddd, J=14.1, 10.8, 4.1, 1H), 2.23 (dd, J=8.1, 17.5 Hz, 1H), 1.88 (dd, J=5.5, 17.8 Hz, 1H), 1.45 (dd, J=5.3, 9.2 Hz, 1H), 1.21-1.27 (m, 2H), 1.12 (s, 11H), 1.02 (s, 9H); MS (ESI): M + +1=834.
Example 71
Compound 14
[0344] Synthesis of (2S,4R)-1-(S)-2-tert-butyl-4-oxo-4-(piperidin-1-yl)butanoyl)-4-(8-chlorobenzofuro[3,2-c]isoquinolin-5-yloxy)-N-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropyl)pyrrolidine-2-carboxamide
[0000]
[0345] A mixture of compound 13 (40.4 mg, 0.05 mmol) and LiOH (5 eq) was dissolved in THF/MeOH/H 2 O (3 mL/3 mL/3 mL) and stirred at room temperature for 3 hours. TLC monitored the reaction. After the reaction completed, the reaction mixture was acidified with 1N hydrochloric acid to pH˜7, then extracted with ethyl acetate, dried over MgSO 4 , filtered and concentrated to dryness under reduced pressure. The residue was dissolved in dimethylfomamide, then piperidine (0.1 mmol),
[0346] o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.065 mmol) and N,N-diisopropyl ethylamine (0.2 mmol) were added. The reaction mixture was stirred at room temperature overnight, then poured into water, extracted with ethyl acetate (50 mL×3), dried over MgSO 4 and purified by flash chromatography to give desired product 14.
[0347] 1 H-NMR (CDCl 3 ): δ (ppm): 10.21 (s, 1H), 8.50 (d, J=8.4 Hz, 1H), 8.24 (d, J=8.0 Hz, 1H), 8.01 (brs, 1H), 7.82 (t, J=8.0 Hz, 1H), 7.54-7.60 (m, 2H), 7.43 (dt, J=8.8, 1.2 Hz, 1H), 7.14 (brs, 1H), 6.06 (brs, 1H), 5.75-5.83 (m, 1H), 5.25 (m, d, J=17.2 Hz, 1H), 5.13 (d, J=10.0 Hz, 1H), 4.63 (d, J=11.6 Hz, 1H), 4.51 (t, J=8.0 Hz, 1H), 4.14 (dd, J=8.8, 2.0 Hz, 1H), 3.63 (s, 2H), 3.05-3.20 (m, 2H), 2.86-3.00 (m, 2H), 2.68-2.73 (m, 1H), 2.57-2.63 (m, 1H), 2.35 (d, J=14.4 Hz, 1H), 2.06-2.13 (m, 1H), 1.99 (t, J=8.0 Hz, 1H), 1.43-1.60 (m, 5H), 1.28-1.42 (m, 4H), 0.9-1.10 (m, 11H); MS (ESI): M + +1=818.3.
Effect Example 1
In Vitro Inhibitory Activity of Compounds in HCV Replication in HCV Infected Human Hepatocellular Carcinoma Cells (Huh7.5.1)
[0348] The preparation of Huh7.5.1cells: Huh 7.5.1 cells were seeded at a 96-well plate with 37 and 5% CO 2 for 24 hours incubation.
[0349] Virus infection: Using the J399EM virus supernatants (moi≈0.1) to infect Huh7.5.1cells. At the same time, the no virus infected cell will be set up as the control. After 8 hours virus infection, the virus will be washed out with PBS.
[0350] Drug treatment: The different doses of samples (i.e. the compound Ik, wherein k=1, 2, 3, . . . 42) were added in J399EM infected Huh7.5.1 cells, the each dose for duplicate. At the same time the no sample added in wells will be set up as the control. The test dose of sample is starting from 25 nM or 400 nM, with quarter dilution, 5 doses of sample will be added in the test wells, respectively, then continued for 72 hours incubation.
[0351] HCV-EGFP fluorescence detection: After samples treatment for 72 hours, the autofluorescence of HCV-EGFP were measured by the luminometer with excitation of 488 nm, and emission of 516 nm. The related fluorescence unit (RFU) of samples will be read out and used for calculating the inhibitory rates of compounds in HCV replication.
Effect Example 2
The Inhibitory Activity of Compounds in the HCV Replicon System
[0352] HCV replicon cell-line: The Huh7 cells were transfected with pSGR-399LM replicon DNA and cultured in the DMEM containing 10% FBS and 0.5 mg/mL G418. The cells were split at 1:3 to 1:5 every 3-4 days. The transfected cells were seeded in 96-well plates and cultured at 37° C., 5% CO 2 for 24 hr.
[0353] Treatment with samples: To the HCV replicon Huh7 cells-line were added different concentration of the samples (i.e. compound Ik, wherein k=1, 2, 3 . . . 42), the each concentration for duplicate, and set no sample control wells. The concentration started at 400 nM, with quarter dilution to form five different concentrations of samples, that is 400 nM, 100 nM, 25 nM, 6.25 nM and 1.56 nM. The samples were added separately, and continued to incubated for 72 hr.
[0354] Fluorescence detection: After 72 hr treatment with sample, the cells were lysed and added with Renilla luciferase substrate to detect luminescent signal. The relative luminescent unit (RLU) in the luminometer was read out and used to calculate the inhibition rate of HCV.
[0000]
TABLE 2
HCV infected
human
HCV
hepatocellular
MS(ESI):
replicon system
carcinoma cells in
compound
M + + 1
EC 50 (nM)
vitro EC 50 (nM)
1
850
B
B
2
816
A
A
3
830
A
B
4
834
A
B
5
820
A
A
6
786
A
A
7
834
A
A
8
878
A
B
9
816
A
B
10
820
A
A
11
808
A
B
12
808
A
B
13
807
B
B
14
818
A
B
15
804
B
B
16
865
A
A
17
820
A
A
18
816
A
A
19
850
A
A
20
820
A
A
21
842
A
B
22
876
A
A
23
864
A
A
24
913
A
A
25
929
A
A
26
973
A
A
27
908
A
A
28
920
A
A
29
808
A
A
30
852
B
B
31
804
B
B
32
838
A
B
33
842
B
B
34
956
A
A
35
1000
A
A
36
822
A
B
37
810
B
B
38
800
A
A
39
929
A
A
40
973
A
A
41
780
—
—
42
838
—
—
A: EC 50 ≦ 100 nM,
B: 100 nM < EC 50 < 1000 nM
Effect Example 3
Pharmacokinetic Evaluation of the Compounds of this Invention
EXPERIMENTAL
[0355] Twenty healthy male Sprague-Dawley (SD) rats with body weight of 200-220 g were divided into 5 groups randomly and each group contains 4 rats. Before the experiment, rats were fasted for 12 h with free access to water. The compound Ik (wherein k=2, 5, 18, 34 or 38) of this invention was administered by oral gavage at a dose level of 10 mg/kg. The compounds were prepared with 0.5% CMC-Na containing 1% Tween 80. The dose volume was 10 mL/kg. The rats were afforded unlimited access to food after 2 h of dosing 0.3 mL of blood samples were collected at 0.25 h, 0.5 h, 1.0 h, 2.0 h, 3.0 h, 5.0 h, 7.0 h, 9.0 h, and 24.0 h, respectively, from postocular venous plexes of the rat. The blood samples were placed in heparin-containing tubes and immediately centrifuged at 11000 rpm for 5 min. Plasma was separated and refrigerated at −20° C. until analysis. LC-MS/MS methods were used to quantify plasma concentrations of the compound Ik. The pharmacokinetic parameters obtained are shown in Table 3.
[0000]
TABLE 3
Pharmacokinetic parameters of SD rats after oral administration
T max
C max
AUC 0−t
AUC 0−∞
t 1/2
F
Compound
(h)
(ng/mL)
(ng · h/mL)
(ng · h/mL)
(h)
(%)
I38
0.63 ± 0.25
150 ± 42
239 ± 81
243 ± 81
0.72 ± 0.30
8.7
I5
1.25 ± 0.50
560 ± 139
2882 ± 1720
3028 ± 1705
3.48 ± 1.09
17.1
I18
1.7 ± 0.6
623.3 ± 60.7
3218.5 ± 336.4
3266.8 ± 303.2
3.8 ± 1.0
36.1
I34
0.4 ± 0.2
11.4 ± 04.3
9.6 ± 0.9
11.0 ± 1.1
0.5 ± 0.3
1.6
I2
0.4 ± 0.1
49.7 ± 11.0
157.9 ± 49.8
1777.6 ± 53.7
3.1 ± 1.3
1.8
Experimental Conclusions
[0356] The compounds of this invention showed satisfied pharmacokinetic behaviour. For instance, Compound 118 was orally administered to SD rats at 10 mg/kg. The peak plasma concentration was at 1.7±0.6 h, with C max of 623±60.7 ng/mL, and the area under plasma concentration-time curves AUC 0-t was 3218.5±336.4 ng·h/mL, AUC 0-∞ was 3266.8±303.2 ng·h/mL. The elimination half-life t 1/2 was 3.8±1.0 h. The absolute bioavailability F approached to 36.1%.
INDUSTRIAL APPLICABILITY OF THE INVENTION
[0357] The compounds of the present invention have the excellent activity of anti-hepatitis C virus. The value EC 50 of the desired compounds for HCV replicon system (pSGR-399LM+Huh7.5) all are lesser than 1000 nM. A majority of compounds are lesser than 100 nM. The value EC 50 of the compounds for HCV infected human hepatocellular carcinoma cells (Huh7.5.1) in vitro all are lesser than 1000 nM also. And the compounds of this invention showed satisfied pharmacokinetic behaviour also.
|
A compound of general formula (I);
A is O, S, CH, NH or NR′, when O links with Z 3 , Z 1 is N or CR Z1 , Z 2 is CR Z2 , when Z 1 links with O, Z 2 is CH, Z 3 is C—Ar; Ra, Rb, Rc and Rd independently is H, OH, halogen or —Y 1 —R m ; A 1 is NH or CH 2 ; R 1 ′ is alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl; A 2 is N, O or linking bond; R 1 is hydrogen, or, R 1 linking covalently with R 3 forms C 5 -C 9 saturated or unsaturated hydrocarbon chain substituted by O or N; R 3 is alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted by cycloalkyl etc; R 4 is alkoxy-CO, alkyl-NHCO, (alkyl) 2 NCO, or formyl substituted by aryl, cycloalkyl, heterocycloalkyl.
| 2 |
RELATED APPLICATION
[0001] The present application is related to contemporaneously filed application serial no. ______ titled “Residue Managing Attachment for Primary Tillage Machine.”
TECHNICAL FIELD
[0002] The present invention relates to the field of agricultural tillage equipment and, more particularly, to a machine having particular utility as a primary fall tillage tool with the ability to leave the field suitably finished with minimal requirements for additional tillage prior to spring planting.
BACKGROUND AND SUMMARY
[0003] It is known in the art to provide single-pass tillage implements which perform both shallow and deeper, primary tillage in a single pass. Typically, gangs of concavo-convex discs are utilized to perform the shallow tillage, while behind the discs sturdy shanks with various types of points are utilized to perform the deeper tillage. The discs are also typically used to cut and bury residue, to varying degrees. Several conventional machines, in an effort to have the soil in a fairly level condition by the time of the next planting season, use cooperating pairs of discs behind the tillage shanks to fill in furrows left by the shanks. Such discs typically are positioned to engage the two ridges produced by each advancing shank and to converge the ridges back into the shank's furrow whereby to create a raised berm that will settle down to a more level condition over the winter months before the next spring planting season. Some conventional machines also provide coulters at the front of the machine for residue-cutting purposes.
[0004] In one aspect the present invention is intended to provide an improved single-pass primary fall tillage machine which leaves the field in better condition for spring planting operations than has heretofore been possible. The machine not only cuts and partially buries residue left from harvesting operations, but also provides both deep and shallow tillage while leaving a smoother, more level field with smaller clod size.
[0005] The present invention provides a number of novel features, both individually and in combination. In one preferred embodiment, the machine has a group of laterally spaced, deep tillage shanks that are preceded by a transversely extending group of flat, residue-cutting coulters. Following the shanks is a group of soil-conditioning, concavo-convex discs that pulverize, level, and smooth the soil. Preferably, although not necessarily, the coulters are preceded by a gang of freely rotating residue wheels that engage and orient residue transversely for better severance by the coulters. Preferably, the residue wheels are each independently mounted, free-floating, and gravity-biased downwardly. The coulters are pressed downwardly as a group by a hydraulic hold-down circuit that allows the coulters to penetrate the soil to the extent necessary to achieve a firm backstop against which the coulters may cut the residue. The depth of penetration of the coulters is thus made independent of the depth of the tillage shanks, which are controlled by transport wheels on the main frame of the machine.
[0006] The conditioning discs at the rear of the machine are preferably arranged in at least two transversely extending, parallel rows with the discs of a trailing row being more closely spaced and greater in number than those of the front row. Preferably, the spacing of the discs in the trailing row is less than the spacing between the shanks, while the spacing of the discs in the front row is the same as the spacing between the shanks. While the discs in the front row are indexed with the shanks and are located to move soil from the shank ridge laterally back into the furrow behind the shank, the discs in the trailing row, being more closely spaced and angled in the opposite direction, serve the function of reducing clod size, mixing, and leveling the soil to provide a finish suitable for spring planting. Preferably, the discs of the conditioner are all individually mounted on transverse beams by generally C-shaped mounts, with at least the mounts of the discs in the trailing row having their open ends facing forwardly to minimize plugging. Best results are obtained when the discs of the trailing row are fluted.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIG. 1 is a top plan view of a tillage machine constructed in accordance with the principles of the present invention;
[0008] FIG. 2 is a side elevational view of such machine shown in its lowered, working position;
[0009] FIG. 3 is a side elevational view of the machine similar to FIG. 2 but illustrating the machine in its raised, transport position;
[0010] FIG. 4 is an enlarged, top plan view of a bank of residue wheels that may be attached ahead of the residue cutting coulters of the machine to orient residue for most effective severance by the coulters;
[0011] FIG. 5 is an enlarged cross-sectional view of one of the residue wheel assemblies taken substantially along line 5 - 5 of FIG. 4 ;
[0012] FIG. 6 is a view of a residue wheel assembly similar to FIG. 5 and illustrating upper and lower limits of floating travel of the residue wheel;
[0013] FIG. 7 is an exploded view of a portion of the gang of residue wheels illustrating details of construction;
[0014] FIG. 8 is a fragmentary isometric view of the subframe that supports the conditioning discs at the rear of the machine;
[0015] FIG. 8 a is a fragmentary isometric view of the disc conditioner subframe taken from a different angle than FIG. 8 ;
[0016] FIG. 9 is a fragmentary isometric view of the front of the machine illustrating the manner in which the tool bar for the cutting coulters is mounted to the main frame and coupled with the hydraulic hold-down circuit;
[0017] FIG. 10 is a schematic, top plan view of the various tools of the machine illustrating the manner in which they work the residue and soil to produce the desired field finish;
[0018] FIG. 11 is a fragmentary cross-sectional view taken substantially along line 11 - 11 of FIG. 10 and illustrating the condition of the field immediately behind the tillage shanks;
[0019] FIG. 12 is a fragmentary cross-sectional view taken substantially along line 12 - 12 of FIG. 10 and illustrating the condition of the soil immediately behind the first row of rear conditioning discs;
[0020] FIG. 13 is a cross-sectional view taken substantially along line 13 - 13 of FIG. 10 and illustrating the condition of the soil immediately behind the trailing row of soil conditioning discs; and
[0021] FIG. 14 is a schematic diagram of the hydraulic hold-down circuit associate with the residue-cutting coulters of the machine.
DETAILED DESCRIPTION
[0022] The present invention is susceptible of embodiment in many different forms. While the drawings illustrate and the specification describes certain preferred embodiments of the invention, it is to be understood that such disclosure is by way of example only. There is no intent to limit the principles of the present invention to the particular disclosed embodiments.
[0023] The tillage machine disclosed herein by way of example has a mobile main frame 10 that includes a pair of rearwardly diverging beams 12 , 14 and a generally rectangular in plan box frame 16 rigidly affixed to beams 12 , 14 beneath the same. Wheel assemblies 18 and 20 are secured to box frame 16 and support frame 10 for over-the-ground travel. Wheel assemblies 18 and 20 may be raised and lowered relative to frame 10 by hydraulic cylinders 22 and 24 for shifting the machine between a lowered, field working position as in FIG. 2 and a raised transport position as in FIG. 3 . Cylinders 22 , 24 are connected at their upper ends to a pair of respective, somewhat upwardly arched, fixed structural members 26 and 28 and at their lower ends to the wheel assemblies 18 , 20 .
[0024] At the front end of frame 10 a generally triangular in plan hitch tongue 30 is pivotally connected to the beams 12 and 14 by horizontal pivots 32 to adapt hitch tongue 30 to swing upwardly and downwardly relative to main frame 10 . Hitch tongue 30 is provided with a clevis 34 or the like at its forwardmost end for coupling the machine to a towing tractor (not shown). A linkage 36 of known construction connects hitch tongue 30 with wheel assemblies 18 , 20 to maintain main frame 10 level during raising and lowering thereof, while hitch tongue 30 pivots between level and inclined conditions as illustrated in FIGS. 2 and 3 .
[0025] The main frame 10 is provided with a group or squadron of deep tillage shanks 38 that are disposed at spaced locations across the machine. Shanks 38 , including their lowermost points, may take a variety of different forms as well understood by those skilled in the art including, for example, parabolic deep till shanks, a combination of deep till and heavy-duty chisel shanks, or all chisel shanks. In a preferred embodiment, shanks 38 are arranged in two primary ranks, namely a front rank of five shanks across box frame 16 generally ahead of wheel assemblies 18 , 20 and a rear rank of four shanks across the rear of box frame 16 in alignment with the four ground wheels associated with wheel assemblies 18 and 20 . The shank pattern is such that the shanks of the rear rank are interposed between the shanks of the front rank on 18 inch spacing. No shank is closer than 36 inches on the same beam.
[0026] Mounted on main frame 10 forwardly of shanks 38 is a gang of flat residue-cutting coulters 40 . In a preferred embodiment, each coulter 42 of the gang 40 has a diameter of 25 inches, and coulters 42 are arranged on 9 inch spacing with every other coulter 42 in line with one of the shanks 38 . Coulters 42 cut through residue and penetrate hard soils ahead of shanks 38 so as to properly size the residue, reduce its tendency to collect and build up on shanks 38 , and prepare a slit for the upper portions of shanks 38 . Coulters 42 are freely rotatable about a common transverse axis 44 and are preferably provided with double beveled peripheral edges that provide a relatively sharp periphery for slicing through the residue.
[0027] Coulters 48 , as is well understood by those skilled in the art, are supported by a number of generally C-shaped mounts 46 secured to a common, transversely extending, tubular beam 48 . Beam 48 , in turn, is swingably secured to the front end of main frame 10 by a pair of lugs 50 and 52 as shown particularly in FIG. 9 . Lugs 50 , 52 are connected at their front ends to beams 12 , 14 of main frame 10 by horizontal pivots 54 and 56 also shown in FIG. 9 . To control up and down swinging movement of gang 40 , cross beam 48 is provided at its center with an upwardly projecting crank 58 operably coupled at its upper end with a down pressure hydraulic cylinder 60 . Hold-down cylinder 60 is connected at its rear end to box frame 16 and is operable not only to raise and lower gang 40 but to also maintain a constant live down pressure pushing gang 40 into the ground when the machine is in its working position of FIG. 2 . Hold-down cylinder 60 is thus operable to maintain coulters 42 down in the soil to a depth of penetration determined by the hardness of the soil itself, regardless of the particular depth at which the shanks 38 are running. In other words, during field operations, the depth of coulters 42 is independent of shanks 38 in that shanks 38 are fixed to frame 10 and are depth-controlled by wheels 18 , 20 , while coulter gang 40 is depth controlled by hold-down cylinder 60 that is operable to move gang 40 up and down relative to frame 10 and shanks 38 . A control circuit of which cylinder 60 is a part is illustrated in FIG. 14 and will hereinafter be described in more detail.
[0028] In a preferred embodiment of the invention, a residue managing attachment 62 is mounted on main frame 10 forwardly of coulter gang 40 . The primary function of attachment 62 is to engage and reorient residue if necessary so that stalks and other elongated items which might initially extend lengthwise of coulters 42 are turned sideways to facilitate severance by coulters 42 . Attachment 62 includes as its primary components a series of residue wheels 64 , one for each coulter 42 , which are arranged at an oblique angle relative to the path of travel of the machine and coulters 42 . Moreover, each residue wheel 64 is laterally offset with respect to the coulter for which it orients residue as shown in FIG. 1 . It will be noted in that figure that while each residue wheel 64 is aligned fore-and-aft with one particular coulter 42 , it diverts residue to the next left adjacent coulter for severance.
[0029] Details of construction of attachment 62 and residue wheels 64 are illustrated in FIGS. 4-7 . As illustrated in those figures in particular, each residue wheel 64 is of generally flat, plate-like construction with a plurality of generally radially outwardly projecting fingers 66 . Each finger 66 tapers outwardly to a pointed tip 68 and is curved slightly rearwardly with respect to the normal direction of rotation of wheel 64 during ground engagement and forward motion of the machine. Wheels 64 rotate in a counterclockwise direction viewing FIGS. 5 and 6 . It will be appreciated that wheels 64 may take other forms within the scope of the present invention, such as being of solid construction, but it has been found that spaced, rearwardly curved, pointed fingers work best.
[0030] The residue wheels 64 are all mounted for independent up and down swinging motion relative to one another but are carried by a common cross beam 70 that is suspended beneath the hitch tongue 30 . As illustrated particularly in FIGS. 1 and 9 , cross beam 70 is immovably affixed to main frame 10 by a pair of fore-and-aft arms 72 and 74 (arm 74 only being visible in FIG. 1 ), the rear ends of which are mounted on the pivots 32 . Each arm 72 has an upwardly and rearwardly projecting stabilizing ear 76 rigidly affixed thereto that is attached to mainframe 10 at pivot 54 so as to keep arms 72 from swinging up and down about pivots 32 .
[0031] Each residue wheel 64 is rotatably mounted to the outer end of a support arm 78 which is, in turn, swingably mounted at its inner end to the cross beam 70 . Pivotal mounting of each arm 78 to cross beam 70 is accomplished through a cooperating pair of generally triangular in plan brackets 80 that are spaced apart along cross beam 70 and project rearwardly therefrom. Each bracket 80 includes a triangular top wall 82 and a rectangular downturned sidewall 84 that lies in a plane disposed at an approximately 45° angle to the path of travel of the machine. Adjacent its inner end, each support arm 78 is provided with a generally S-shaped arm 86 that cooperates with the inner end of arm 78 to present a mounting yoke that receives a transverse pivot bolt 88 and a sleeve 90 encircling bolt 88 . Bolt 88 extends between the two sidewalls 84 of a pair of adjacent brackets 80 so as to swingably attach support arm 78 to cross beam 70 .
[0032] Residue wheels 64 are gravity-biased downwardly by their own weight. To prevent excessive downward movement, each arm 78 is provided with a forwardly projecting extension 92 that is disposed to abut the underside of overhead top wall 82 after a predetermined amount of downward movement of the outer end of arm 78 such that top wall 82 serves as a limit stop for downward movement of wheel 64 . At least several of the residue wheels 64 along beam 70 , i.e., those directly under hitch tongue 30 , are provided with stops to limit upward travel of those wheels. In this respect as illustrated in FIGS. 5, 6 and 7 , those particular brackets 80 may be provided with a generally L-shaped stop weldment 94 comprising a vertical plate 96 and a horizontal plate 98 . Vertical plate 96 has a hole 100 ( FIG. 7 ) adjacent its front end through which the bolt 88 passes, while horizontal plate 98 has a hole 102 adjacent its forward end through which a vertical bolt 104 passes. Pivot bolt 88 and vertical bolt 104 thus attach stop weldment 94 to bracket 80 , positioning horizontal plate 98 under extension 92 of arm 78 for engagement thereby at the end of the upward path of travel of wheel 64 as illustrated in FIG. 6 .
[0033] Each residue wheel 64 has a generally horizontally L-shaped shield 106 associated therewith that is adjustably secured to the rearmost end of the corresponding support arm 78 . Each shield 106 is formed from flat sheet material and has a forward leg 108 located between the wheel 64 and corresponding arm 78 . A hole 110 ( FIG. 7 ) in forward leg 108 receives the spindle 112 of the corresponding residue wheel 64 so that shield 106 can be pivoted upwardly and downwardly between adjusted positions. Retention in a selected position of adjustment is provided by a bolt 114 ( FIG. 7 ) at the forwardmost end of leg 108 that passes though an arcuate slot 116 in forward leg 108 . Manifestly, loosening of bolt 114 permits rocking adjustment of shield 106 about spindle 112 to the extent permitted by slot 116 , while tightening of bolt 114 effectively retains shield 106 in a selected position of adjustment. Each shield 106 further includes a rear leg 118 projecting rearwardly from the rearmost extremity of forward leg 108 parallel with the path of travel of the machine.
[0034] As illustrated in FIG. 1 , each shield 106 is generally aligned fore-and-aft with a corresponding one of the trailing coulters 42 . Thus, the shield is in position to receive residue from the next residue wheel to the right as viewed in FIG. 1 and to prevent such residue from moving leftwardly past shield 106 to the next left adjacent coulter 42 . This prevents an excessive amount of residue from being collected in front of any one coulter, which would impede the slicing ability of the coulter. The shield also has the effect of positioning the residue from the corresponding wheel 64 directly in front of its coulter for effective severance. Further, each shield 106 tends to lie on top of and pinch down the residue to prepare it for severance by the coulter and to cooperate in such severance.
[0035] Supported at the rear of the machine is a group 120 of concavo-convex conditioning discs that mix residue into the soil behind shanks 38 , reduce clod size, and level the field. The discs of the group are arranged in at least two transverse rows, namely a front row 122 and a trailing row 124 . In one preferred embodiment, the discs of front row 122 are 24-inch smooth discs on 18-inch spacing with the discs indexed with respect to shanks 38 . That is to say, as illustrated in FIGS. 1 and 10 , each front disc 126 is disposed somewhat laterally offset from a corresponding, forwardly disposed shank 38 so as to be in position to receive one of the ridges from such shank and displace it laterally back toward the furrow left by the shank. As illustrated, the discs 126 of front row 122 are all obliquely disposed with respect to the path of travel of the machine so as to effect such lateral soil displacement action. In this respect, although discs 126 have been oriented to throw the soil toward the right as the machine is viewed in plan in FIG. 1 , discs 126 could alternatively be angled in the opposite direction to throw the soil leftwardly, in which event the row 122 of discs would be displaced somewhat to the right of the position illustrated in FIG. 1 so that the rightmost disc would be outboard of the rightmost shank 38 .
[0036] On the other hand, the discs 128 of trailing row 124 are preferably 24-inch fluted discs on 10-inch or 12-inch spacing and are angled oppositely to the front discs 126 . Discs 128 of trailing row 124 are thus more closely spaced than shanks 38 and front discs 126 , and there are more of the trailing discs 128 than the front discs 126 . While front discs 126 cut clods and perform an initial leveling action by shifting some of the soil from a shank ridge into the furrow left by the shank, the trailing discs 128 function to reduce clod size still further and to leave a level field finish. Both front and trailing rows of discs 122 and 124 mix and partially bury residue into the soil. In the illustrated embodiment, the group 120 of conditioning discs is also provided with a set of rear, transversely extending reels 130 that further level and smooth the field, although such reels 130 are purely optional.
[0037] The discs 126 of front row 122 are all individually mounted for rotation about individual, transversely oblique axes rather than journalled on a common long shaft that is obliquely disposed. In this respect, each disc 126 has a generally C-shaped mount 132 that attaches the same to an overhead, tubular beam 134 extending perpendicular to the path of travel of the machine. Mounts 132 have open ends that face rearwardly with respect to the direction of travel of the machine.
[0038] Similarly, the discs 128 of trailing row 124 are mounted for rotating movement about individual transversely oblique axes rather than being mounted on an obliquely disposed common spindle or shaft. Each disc 128 is rotatably supported by a generally reversely C-shaped mount 136 that is attached at its upper end to a tubular beam 138 common to all of the discs 128 and extending in perpendicular relationship to the path of travel of the machine. It is to be noted that in contrast to front mounts 132 , rear mounts 136 have their open ends facing forwardly while their closed ends face rearwardly. This unorthodox orientation of rear mounts 136 has been found to be especially beneficial in keeping the trailing row of discs 124 from plugging in spite of the narrow spacing thereof compared to front discs 126 . While the flutes of trailing discs 128 sometimes tend to carry soil upwardly and rearwardly as the discs rotate counterclockwise viewing FIGS. 2 and 3 , the rearwardly disposed bodies of mounts 136 tend to block and deter further upward travel of soil and direct it back down to the ground. If the open ends of mounts 136 faced rearwardly as with the front row of discs 122 , there would be a greater tendency for uplifted soil from the closely spaced trailing discs 128 to be captured within the open areas defined by the C-shaped mounts 136 , contributing to plugging.
[0039] The disc beams 134 and 138 are both part of a subframe denoted broadly by the numeral 140 that is swingably attached to the rear end of main frame 10 for up and down swinging movement. Detailed views of subframe 140 are shown in FIGS. 8 and 8 a . As illustrated therein, subframe 140 is generally rectangular in plan and has a pair of upstanding generally triangular mounting plates 142 and 144 rigidly affixed thereto adjacent its front end at widely spaced locations thereon. Mounting plates 142 , 144 are provided with upper and lower corners 146 and 148 respectively which, in turn, are pivotally connected to upper and lower links 150 and 152 of respective four-bar linkages 154 and 156 . Each four-bar linkage 154 , 156 has an upper rear pivot connection 158 with plate corner 146 and a lower rear pivot connection 160 with lower plate corner 148 . At its forward end, each linkage 154 , 156 has an upper front pivot connection 162 with beam member 12 or 14 and a lower front pivot connection 164 with the same beam. Top links 150 are substantially the same length as lower links 152 such that as subframe 140 swings upwardly and downwardly, it remains generally level. Preferably, upper links 150 are in the nature of adjustable turnbuckles for selectively adjusting the length thereof.
[0040] The four-bar linkages 154 and 156 are rigidly interconnected by a torque tube 166 that spans the lower links 152 adjacent their rear ends. Two pairs of upstanding plates 168 and 170 are rigidly affixed to torque tube 166 adjacent opposite ends thereof. Each pair of plates 168 , 170 pivotally supports an inverted, generally L-shaped member 172 having a pivotal connection 174 with plates 168 , 170 adjacent its lower end. A stop 176 spans each pair of plates 168 , 170 adjacent their upper ends to limit forward swinging of L-member 172 . At its upper rear end, each L-member 172 is pivotally connected to the rod end of a hydraulic cylinder 178 that is pivotally connected at its anchor end to the subframe 140 .
[0041] As a result of this arrangement, when cylinders 178 are in a retracted condition with L-members 172 away from stops 176 , subframe 140 , and thus the group of finishing discs 120 , is free to float up and down to a limited extent as front and trailing discs 126 and 128 engage the ground during forward movement of the machine. Front and trailing discs 122 and 124 thus are gravitationally biased into the ground at this time. If it is desired to raise subframe 140 , cylinders 178 are utilized for this purpose. However, initially, there is a certain amount of lost motion involved as the L-members 172 are swung forwardly until reaching the stops 176 . Thereafter, further extension of cylinders 178 results in the entire subframe 140 and four-bar linkages 154 , 156 being raised upwardly relative to main frame 10 .
[0042] FIG. 14 illustrates a hydraulic hold-down circuit broadly denoted by the numeral 180 that includes the hold-down cylinder 60 for maintaining constant down pressure against the coulter gang 40 . The rod end 182 of cylinder 60 is connected to coulter gang 40 via crank 58 , while the anchor end 184 of cylinder 160 is connected to main frame 10 . The geometry is such that fluid pressure attempting to contract cylinder 60 causes down pressure to be applied against coulter gang 40 . If coulter gang 40 is out of the ground as illustrated in FIG. 3 when the machine is in its raised transport position, there is no resistance to downward swinging of coulter gang 40 , and cylinder 60 fully retracts to lower gang 40 to its fullest extent.
[0043] As illustrated in FIG. 14 , hold-down circuit 180 includes a pressure line 186 leading to the anchor end of cylinder 60 from a quick coupler 188 with the tractor hydraulic system (not shown). A return line 190 leads from the anchor end of cylinder 60 to another quick coupler 192 with the tractor hydraulic system. A control valve broadly denoted by the numeral 194 is interposed within supply line 186 between couplers 188 and cylinder 160 and is adapted to reduce the pressure of a constant supply of oil from the tractor. Valve 194 has an adjustable pressure reducing port 196 and internal valving that enables a portion of the flow that would otherwise pass through pressuring reducing port 196 to by-pass such port and exit valve 194 through by-pass line 198 that connects to return line 190 leading to tractor coupler 192 . Valve 194 also includes an internal relief valve and is fluidically connected to a gauge 200 for displaying the pressure of the fluid supplied to the rod end of cylinder 60 . One suitable valve for performing the desired pressure-reducing, by-pass, check and relief functions of valve 194 is available from Shoemaker Incorporated of Fort Wayne, Ind. as part no. 8136.
[0000] Operation
[0044] During field operations the machine is in the lowered operating position of FIG. 2 . As the machine is drawn forwardly, the cross beam 70 associated with the residue managing unit 62 knocks down standing residue, and residue wheels 64 engage and orient stalks transverse to the trailing coulters 42 . Coulters 42 , under the influence of cylinder 60 , penetrate the residue and soil until encountering sufficient resistance to preclude further downward movement thereof, thus being provided with an anvil-like backstop against which the residue can be cleanly severed into shorter lengths by the coulters 42 . Shanks 38 enter the slits prepared by coulters 42 and deeply till and fracture the soil creating, as illustrated in FIG. 11 , a series of furrows 202 bounded on opposite sides by ridges 204 of chunky soil and residue left by the wake of each shank 38 . This action is also illustrated in FIG. 10 . At this stage, relatively large chunks or clods 206 exist in the ridges 204 .
[0045] When the ridges 204 are engaged by the front row of conditioning discs 122 , the discs 126 thereof cut the clods 206 into smaller sizes to produce smaller clods 208 as illustrated in FIG. 12 . Furthermore, the discs 126 throw the soil and residue from ridges 204 rightwardly into furrows 202 so as to produce a relatively level condition as illustrated in FIG. 12 , at the same time performing a degree of mixing of the residue into the soil. When the soil is then engaged by the trailing row of conditioning discs 128 as illustrated in FIGS. 10 and 13 , the relatively closely spaced trailing discs 128 have the effect of further cutting the clods to produce yet smaller clods 210 , to further mix the residue and soil, and to significantly smooth and level the soil. Ideally, no ridges or berms are left when the machine of the present invention has completed its work within a field.
[0046] It will be noted as illustrated particularly in FIG. 13 , and as also seen in FIG. 1 , that the discs 128 of trailing row 124 progressively taper toward smaller diameters as the right end of the row is approached. In the illustrated embodiment, the next-to-last disc 128 on the right is smaller than the other discs to the left, while the rightmost disc at the end of the row 124 is even smaller than its next adjacent disc to the left. This helps prevent the formation of a berm at the right end of the trailing row of discs 124 . It will be further appreciated that the addition of reels such as the reels 130 to the conditioning discs 120 aids in further reducing clod size and leveling the field.
[0047] The inventor(s) hereby state(s) his/their intent to rely on the Doctrine of Equivalents to determine and assess the reasonably fair scope of his/their invention as pertains to any apparatus not materially departing from but outside the literal scope of the invention as set out in the following claims.
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A one-pass primary tillage machine provides a combination of shallow and deep tillage, residue cutting and mixing, and clod size reduction and leveling of the field to prepare the field for the next planting season. A front group of flat coulters slice through the residue to reduce its size, followed by deep shanks that improve the tilth of the soil to a point below the intended planting depth. Following the shanks, a group of concavo-convex conditioning discs mix the residue with the soil, reduce clod size, and level the field.
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BACKGROUND
1. Field of Invention
This invention relates to the use of synchronized pulsed magnetic field and light photon stimulation to excite human or animal tissue including nerves or acupuncture points for pain control or energetic enhancement purposes.
2. Description of Prior Art
Heretofore, electromagnetic stimulation of sensory nerves or acupuncture points has focused mainly on stimulation of nerve tracts for the purpose of promoting release of natural opiates or pain pathway blocks through gating mechanisms. Various forms of such stimulation have been tried such as application of voltages or currents to acupuncture needles, transcutaneous electrical nerve stimulation (TENS), pulsed magnetic field stimulation, local application of heat or cold, use of light radiation, and magnetic therapy. Prior art devices of this type include the use of low frequency magnetic pules as described in U.S. Pat. No. 6,234,953 B1, issued May 22, 2001. Application of voltages or currents to needles and TENS both involve passage of electrical current through superficial skin and tissue which is known to be prone to stimulation of pain fibers. The magnitude of stimulation is then limited to what a given subject can tolerate. Pulsed magnetic field stimulation relies on induced currents, which can largely avoid pain fiber stimulation and so is capable of higher levels of nerve stimulation. However, pulsed magnetic field stimulation at intensities high enough for neural stimulation requires cumbersome apparatus with a many limitations. These limitations arise from the high energy requirements and associated limitations of coil heat generation, time required for recharging of energy storage devices as capacitors, and physical apparatus size. Traditional acupuncture is postulated to also involve meridian pathways, which is not limited to known nerve tracts. These pathways are felt to involve body energy management and overall maintenance of health. While many different attempts have been made to stimulate or increase the energy level within these meridians, no scientifically acceptable means of assessing or measuring the energy states of body areas, acupuncture points, or meridians currently exists. The electrical potential, resistance, or impedance has been measured between acupuncture points or a given acupuncture point and surrounding tissue, but the known unreliability and lack of specificity of such measurements limited their use in energy state assessment. Some of these complications include: variable impedance of the overlying skin layer, contact potentials which change with minor perturbations, and complex nature of tissue impedance with frequency dependent properties. Thus, the effectiveness of any method in stimulating a given acupuncture point or changing the energy status of the meridian system and the body remains open to question and highly variable in result. The specific form of what constitutes the most effective way to stimulate specific acupuncture points or the meridian system electromagnetically then remains unclear. Pulsed magnetic field stimulation has been previously found to be able to stimulate nerves and even muscles in essentially a painless way. However, apparatus and procedures necessary to insure that the stimulus energy reaches the meridians or other parts of the body have not been previously described. Magnetic therapy involving applying permanent magnets to the body surface has been previously tried with positive therapeutic results, but this procedure is limited in application due to the necessity of constantly wearing magnets. Techniques for directly magnetizing the human or animal body as a form of magnetic therapy have not been previously described.
Prior work have also shown that other modes of sensory stimulation made in the vicinity of sources of pain can also be used to alleviate pain or also stimulate acupuncture points. Some of these modes include application of cold massage, light, pressure, and heat. In general, pain relief can be provided by a wide variety of sensory stimulation. Prior art applications of sensory stimulation include: application of monochromatic light and biofeedback as specified in U.S. Pat. No. 5,947,908 issued on Sep. 7, 1999, application of heat, light, sound, and VHF electromagnetic radiation for central nervous system stimulation as specified in U.S. Pat. No. 3,773,049 issued on Nov. 20, 1973, and application of acoustic, optical, mechanical, and/or electrical signals with increasing or decreasing frequency as specified in U.S. Pat. No. 5,108,361 issued on Apr. 28, 1992. Thus, a reasonable strategy to maximize pain relief is to combine as many modalities as possible. Some use has been made of combined modes such as pressure and electricity in electrical stimulation of needles or TENS and magnetic stimulation, but such combinations have not been previously fully exploited. Specifically, the combined use of pulsed magnetic field in synchrony with full spectrum pulsed light has not been tried for acupuncture point or body energy stimulation. From a quantum mechanical viewpoint, light and magnetic field can be considered as both photons, that can supply energy. Body tissue components have a magnetic moment that is capable of resonance and magnetization effects. Nuclear magnetic resonance and imaging is an example where this type of resonance is applied for a medical application. Prior art attempts at exploiting resonance include application of a fluctuating magnetic field to excite postulated ionic cyclotron resonance as specified in U.S. Pat. No. 5,067,940 issued on Nov. 26, 1991 and use of a complex frequency pulsed electromagnetic generator as specified in U.S. Pat. No. 5,908,444 issued on Jun. 1, 1999. Whether ion cyclotron resonance actually occurs in tissue has not been conclusively demonstrated to date, also the specific form of stimulation used in this approach does not fully exploit particle properties. The specific combination of light and magnetic field required for effectively exploiting these resonance or other effects for enhanced energetic stimulation of the human or animal body has not been previously described.
OBJECTS AND ADVANTAGES
Accordingly, to provide an effective way to photonically stimulate tissue and modify the energy level in the body, a stimulation device is needed which has specific characteristics which match the energy transporting mechanisms of the body. Magnetic stimulation has important advantages over electrical stimulation in being able to avoid stimulation of pain fibers and not required needle insertion or electrode application. The present invention was designed to incorporate magnetic in combination with light stimulation to permit energetic excitation in a manner that could be used by a patient for self-use or applied by a practitioner. Light and magnetic field is known to interact in a transient plasma state to produce unique energy waves that propagate in the longitudinal rather than in the customary transverse electric and magnetic field mode. The longitudinal mode of propagation is known by those skilled in the art to be associated with mechanical vibrations and to involve less propagation loss than the transverse electric and magnetic field mode. The preferred embodiment of the present inventive device incorporates a xenon flash tube that generates a transient plasma state. Energetic excitation involving internally induced currents is another of the advantages of the inventive method in that the externally induced currents present in many previous acupuncture stimulators is not required. Another object of the present invention is to permit magnetization of major body areas as a way to provide magnetic therapy without encumbering the subject with the necessity of constantly wearing permanent magnet. Another object of the present invention is to provide a way to verify the effectiveness of the stimulator in providing energy to the body and level of magnetization. Such a measurement also forms the basis for a diagnostic assessment of the health of the body area and a rationale for treatment by use of the stimulator to promote a normal status. Another object of the present invention is to incorporate auditory sensory stimulation simultaneously with magnetic and light stimulation as a way of increasing total sensory stimulation to enhance pain relief.
SUMMARY OF THE INVENTION
The present invention provides for the above stated objectives as well as others by providing an electromagnetic stimulation device, which generates combined repetitive pulses of light and magnetic field to promote propagation of energy in the body. The level of currents induced by the pulsed magnetic field stimulation alone is limited in magnitude to values below the expected normal threshold of nerve fiber stimulation. When previously described apparatus used for pulsed magnetic field stimulation is used under this constraint, in effective pain control results. Also, there have been no previously reports on energy propagation under these conditions. It will be apparent to those skilled in the art that conventional electromagnetic theory cannot justify the current rationale, but consideration of quantum electrodynamics effects is necessary. According to quantum theory, at least two major energy levels and associated frequencies are present in hydrated tissue and any magnetically sensitive material. Probabilities are connected with these levels that can be affected by the light and magnetic field levels. Nuclear magnetic and ionic resonances are possible in tissue by judicious choices of these levels and the frequencies involved. In general, a variety of magnetic resonant frequencies and wavelengths of light are necessary to promote effective energy transfer. The approach here is to satisfy these requirements by using broad-spectrum pulses of magnetic field and light to insure a stimulus with sufficient harmonic content to promote effective energy transfer. In addition, full spectrum light provided by a flash tube such as zenon is used to insure that the proper wavelength is present for such transfer to occur. A unique property of flash tube discharges is the transient creation of a plasma state. Plasma is created by the interaction of electrons and positive gas ions during a discharge. A plasma resonant frequency is generated during the discharge along with a longitudinally propagated wave. This wave is characterized by special properties known to those skilled in the art that allow the focusing of energy and control of plasma resonant frequency by using an externally applied magnetic field. Cyclotron resonance is known to be possible with plasma waves interacting with a directed magnetic field. The density of the gas within the gas tube determines the plasma resonant frequency. Density can then be chosen for maximum effectiveness of energetic stimulation by matching the resonant frequency of key cellular energetic processes such as those involved in ATP utilization. Thus, magnetic field and electric field can be simultaneously applied longitudinally in the desired direction of propagation. This is in contrast to conventional electromagnetic waves where the electric and magnetic fields are in the transverse mode that is perpendicular to the direction of propagation. In this way, resonance requirements for enhancement of energy stimulation can be met by providing stimuli which have temporal characteristics to meet resonance criteria for enhanced energy transfer, and full light spectrum to meet associated wavelength criteria for enhancement. Magnetic pulses of the stimulator provided for herein are generated by a capacitive discharge circuit where ordinary power line alternating current (50-60 Hz) or a battery powered oscillator signal is used to charge capacitors to steady levels. Individual stimulus pulses are formed by discharging these capacitors into a single or multiple coils using a switching device such as a silicon controlled rectifier and xenon flash tube for magnetic field and light generation. By appropriate choice of total circuit capacitance, coil inductance, and resistance a unidirectional magnetic field is generated. Pulses will be repeated according to a repetition rate that is set to obtain optimum magnetic field transfer. The coil system with or without the flash tube is mounted on a handle and connected with flexible wires to the main electronics unit to allow positioning of the coil and resultant magnetic field at various locations.
The present device allows for the creation of the proper conditions for multiple body tissue resonance to occur and exploits this condition to promote transmission of magnetic field into the meridian or other body system. Use of monopolar magnetic stimulation pulses and light pulses permit magnetization of target body areas which creates residual magnetic effects suitable for magnetic therapy even after the stimuli crease. The measurement of the magnitude of magnetic field at different areas of the body then provides a way to assess the effectiveness of stimulation as well as a basis of evaluating the state of the body energy system. Such measurements can be made during as well as before and following stimulation.
Preliminary studies performed indicate that the combined and simultaneous treatment of the inventive device provides a substantially greater degree of pain relief and energetic enhancement (degree of magnetization) than either magnetic or light stimulation alone.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING
The invention will now be described with reference to the accompanying drawings in which:
FIG. 1 is a schematic diagram of the apparatus;
FIG. 2 shows an embodiment where natural quartz crystal between the flash tube and body surface being stimulated.
DETAILED DESCRIPTION OF THE INVENTION
Referring to FIG. 1, the schematic block diagram of the inventive stimulating apparatus is illustrated. Magnetic stimulator coil 2 is coupled in an electrical series connection with a full spectrum flash tube 1 so that each share the same excitation current. Electrical circuits required for the flash tube excitation at adjustable rates are well known in the art. Excitation current is derived from discharging a capacitor 4 that is previously charged by high voltage supply 5 . On-off switch 9 connects high voltage supply 5 to AC or alternating current power. Alternatively, high voltage supply 9 can be powered by oscillator 8 which converts DC or direct current battery power to alternating current. The major innovations of the present apparatus include the addition of a stimulating coil 2 in series connection with the flash tube 1 and the synchronous use of both light and magnetic field pulses for energetic stimulation of the human body. Effective human energetic stimulation also require a unique specific combination of stimulator design characteristics. From a quantum mechanical viewpoint, both light and magnetic field can be considered as photonic energetic stimuli. Thus, the first advantage of a combined light and magnetic field stimulator is to be able to achieve higher total energy levels while still limiting the stimulus levels of both. This is significant because stimulation levels generally set the limit on device effectiveness. For example, in transcutaneous electrical nerve stimulation (TENS) the use of electrical stimulation usually leads to stimulation of pain fibers in the vicinity of the local site of stimulation. Although TENS effectiveness for relief of an existing pain improves as stimulation level increases, the additional stimulus site pain ultimately limits the level of pain control. In TENS, stimulus level is usually adjusted to the maximum that a given subject is willing to tolerate. In pulsed magnetic field stimulation (PMFS) pain fiber stimulation does not seem to present a problem, but the use of high levels will ultimately lead to stimulation of even motor nerves. Motor nerve stimulation would be undesirable when the objective of the stimulation is pain control. High level PMFS is also limited in the total possible treatment time due to heat buildup by the stimulating coil. Pulse repetition rates for high level PMFS is also limited to below about 1 per second due to recharge requirements. Pulse repetition rates up to 10 per second have been used with success with TENS, so the repetition rate limitation for high level PMFS undoubtedly limits effectiveness of this approach for pain control. The design approach of the present apparatus purposely limits coil stimulation in terms of the rate of current rise to below 10 8 ampere-turns per second maintained for 100 microseconds. The product of the two preceding numbers, 10,000 ampere-turns, sets the strength-duration threshold for motor neuron excitation. Application of this limit leads to significantly lower current requirements and permits the use of conventional flash tube circuits for coil excitation well known to those skilled in the art. Use of a xenon flash tube is advantageous because of the full spectrum and high output power property of such light. This facilitates meeting wavelength requirements of any resonance process involved in body energetics. The narrow pulse width of flash tube discharges also facilitates meeting resonant frequency requirements since narrow width pulses inherently have a wide frequency bandwidth. Relatively narrow width pulses are also used for magnetic stimulation that also have similar advantages for meeting magnetic resonance frequency requirements. Flash tube designs commonly use inductors in electrical series with the flash tube to improve the sharpness of light flashes. Light flash durations measured in microseconds are typical. The design approach here is to substitute the magnetic stimulation coil in place of such an inductor. In this way, the stimulation coil acts to shape the light pulse as well as provide a magnetic field for body stimulation. Electronic circuitry required to vary the repetition rate of pulses over a range of 1 to 100 pulses per second is well known to those skilled in the art and is represented in FIG. 1 as rate control 10 . Provision for rate control extends the capability of matching to body energetic resonant frequencies that have been postulated to occur within 1-100 cycles per second. Rate control 10 can be implemented by using variable resistive-capacitive current charging to conduction thresholds of neon tubes. Different repetition rates are then obtained by setting the resistance value with a potentiometer 11 shown in FIG. 1 . Rate control 10 output is connected to trigger generator 6 either directly or through a silicon controlled rectifier switch. Trigger generator 6 creates the high voltages required for flash tube conduction. Other standard timing circuits can be used as well and are well known to those skilled in the art. By choosing appropriate values of circuit parameters, a monopolar stimulus current which generates a positive magnetic field at the coil surface nearer to the body surface being stimulated. For example, a storage capacitance of 7 microfarads charged to 440 volts discharged through a coil inductance of 200 microhenries (corresponding approximately to 70 turns of AWG 12 enameled copper wire of average radius 0.75 inch) and 1 ohm flash tube resistance is expected to be associated with a peak current of 75 amps. The waveform for this case is monopolar with a stimulus rise time (10%-90% transition) less than 50 microseconds and the fall time (90%-10%) greater than 250 microseconds during recovery. The specific durations are not critical, and other durations could be used, however the rise time must be shorter than fall time to insure generation of induced current in the body primarily in one direction. During use, the magnetic stimulation coil 1 is positioned directly over or touching the body surface. The coil consists of multiple turns of wire made either around a non-magnetic coil form or flat-spiral arrangement. Non-magnetic coil forms that satisfy requirements could be made of polyurethane or nylon. Enamel coating or other non-magnetic and non-conducting material insulates coil wire. An air space is provided at the center of the coil that can be positioned for passage of light generated from flash coil 2 to the body surface. A curved handle 7 is attached to the stimulating coil 2 such that the handle curvature starts at the coil and curves towards the body surface as shown in FIG. 1 . The purpose of the curvature is to allow identification of the proper coil polarity by feel alone. Flash tube 1 is positioned in conjunction with a reflector 3 to direct light towards the body surface. Reflector 3 is made of polished aluminum or plastic with a reflecting or white surface. Flash tube 1 can be mounted together with stimulating coil 2 or separately as shown in FIG. 2 . [Depending on the purpose of stimulation, close proximity of light and magnetic stimulation over a common body surface could be advantageous or separate locations of light and magnetic field could be used.] A reflector positioned around the flash tube is used to concentrate light to specific spatial regions. Light emanating from the flash tube can be further enhanced in terms of conditions at a specific body surface by optical filtering which consist of positioning focusing lens or optically active materials such as quartz crystal between the flash tube and body surface during energy enhancement procedures. FIG. 2 shows such an embodiment where a natural quartz crystal 12 is positioned in the optical path between the flash tube 1 and the body region to be stimulated. The quartz crystal 12 in FIG. 2 is also placed within the magnetic field produced by coil 2 . The arrangement of FIG. 2 facilitates the interaction of light and magnetic field within quartz crystal 12 for enhanced stimulation effect on the body surface. The stimulating coil also serves the purpose of focusing longitudinal mode plasma electromagnetic waves for stimulation and provides a means to alter the resonant frequency of the plasma wave. The property of a directed magnetic field to focus plasma waves is well known to those skilled in the art. Quartz will also provide an additional way to focus and tune the plasma wave. Determining the effectiveness of various strategies can only be made based on a quantitative measurement. The index of energetic stimulation level used by the present approach is the degree of magnetization of the body area involved. Magnetic sensor 13 in FIG. 1 is a magnetometer or device for measuring magnetic field at levels comparable to the strength of the earth's magnetic field with a direct meter readout. Various types of sensor units can be used which include SQUIDS (superconducting quantum interference device), electron and proton resonance transducers, pickup coils and Hall effect sensors. The response time of such a sensor must be less than about 10 seconds time constant to permit measurements to be made minute by minute. Measurement of the degree of magnetization also includes tissue responses to plasma wave excitation that can occur at plasma resonance frequencies. Positioning magnetic sensor 13 directly over the body part of interest before and following application of stimulation with the present apparatus allows quantitation of the level of magnetization achieved as well as the persistence of magnetization. Such quantitation of effect is especially useful in dealing with assessing effects on uncooperative subjects or animals where verbal feedback is lacking. The ionic content of body tissues insures the existence of a net magnetic moment and persistence of a magnetic field following stimulation. The presence of a negative magnetic field near the body surface is felt to lead to positive therapeutic effects in terms of cellular repair and pain control. The present stimulation device generator a pulsed magnetic field over the body surface, which leads to an induced negative magnetic field, which persists even following stimulation when used as described above. The degree of magnetization and persistence reflects energy level of the body area, which will be affected by both magnetic and light stimulation.
The coil handle is provided with a curvature to permit identification by feel of coil direction. Provision can be made to change the direction of magnetic field by rotating the coil by 180 degrees or a switch. Auditory signals are also generated in synchrony with pulsed stimuli as an additional mode of sensory stimulation as well as an indication of stimulation. One method of auditory signal generation is to use coils that have a hard insulation such as enamel would loosely enough to permit the wires to make a clicking sound when current is pulsed through the coil. It would also be possible to use a signal derived from the stimulation trigger or output current to generate a sound in synchrony with stimulation using a loudspeaker. Simultaneous light and magnetic field stimulation is accomplished either with the flash tube placed in the vicinity or adjacent to the coil system. When a stimulation subject is not blindfolded, visual stimulation is also possible as an additional mode of sensory stimulation by the flash tube discharge. While the above description contains many specificities, these should not be construed as limitations on the scope of the invention, but as an exemplification of one preferred embodiment thereof. Many other variations are possible. A stimulating coil in the above description is referred to as an individual unit, yet it is clear to those skilled in the art that an inductive effect and magnetic field generation is possible from just the flash tube itself or wires used to interconnect components. Thus a possible embodiment which is fully compatible within the scope of the invention is one where a separate stimulating coil is not used. FIG. 2 shows an embodiment where the stimulating coil and flash tube are separately mounted. For an application where maximum portability is desired, combining the coil and flash tube into one hand held unit would be a preferred mode. Multiple coils or stimulating units could also be used in other embodiments to stimulate more than one body site at the same time. Multiple stimulating units could be used in synchronized or asynchronous manner using techniques familiar to those skilled in the art. Use of a xenon flash tube has been described as advantageous, but other sources of full spectrum pulsed light and/or plasma can be used. Accordingly, the scope of the invention should be determined not by the embodiments illustrated, but by the appended claims and their legal equivalents.
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An electromagnetic stimulation device that generates combined repetitive pulses of full spectrum light and magnetic field to promote propagation of energy and pain relief in the body. The level of currents induced by the pulsed magnetic field stimulation alone is limited in magnitude to values below the expected normal threshold of motor nerve stimulation. Broad spectrum pulses of light and magnetic field are used to satisfy multiple resonance and wavelength criteria for enhancing energy transfer. The measurement of the magnitude of induced magnetic field at different body sites is used for the assessment of effectiveness of stimulation.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention pertains to medical system for sampling and analyzing blood or any components of the blood for specific readings as to qualities of the blood. One specific use of the present invention is for sensing the accumulation of blood glucose for diabetics. The system is a portable, pocket-size, battery operated, diagnostic system for detection and measurement of blood qualities.
2. Description of the Prior Art
Prior art blood glucose devices have operated on the principle of taking blood from an individual by a variety of methods, such as by needle or lance. An individual then had to coat a paper strip carrying chemistry with the blood, and insert the blood-coated strip into a blood glucose meter or visual comparison against a color standard. There are numerous blood glucose meters on the market, but are instruments which consume space and are not pocketable. The instruments usually have to be carried in a large handbag, or an individual's briefcase, or left at home such as in the bathroom or the bedroom.
Further, the prior art medical apparatus for sensing blood glucose required that an individual have separately available a needle or lance for extracting blood from the individual, strips carrying blood chemistry for creating a chemical reaction with respect to the blood glucose and changing color, and a blood glucose meter for reading the change in color indicating the blood glucose level. The level of blood glucose, when measured by glucometer, is read from a strip carrying the blood chemistry through the well-known process of reflectometers for glucose oxidation.
Monitor/reagent strip systems that are now available on the market have multiple sequential steps that the patient must follow at exact time intervals. Each step is subject to error by the patient. As in most monitors, it is the patient's responsibility to periodically calibrate the monitor against known color standards; validate the efficacy of their reagent strips and technique by immersing the strips in a control solution of known glucose content; and, then comparing the color change visually against the color standard or by using a calibrated monitor.
In the prior art, the procedure for obtaining accurate results from the time a drop of blood is placed on a reagent strip pad to the time the pad color change is read in the monitor is as follows. The patient must stick himself/herself with a lancet. A drop of blood must be squeezed to the surface of the skin. The drop of blood must then be carefully placed on the reagent pad, making sure to cover the pad completely and the pad must never be touched by the finger of the patient to prevent contamination. Once the sample has been applied to the surface of the reagent pad, the patient must press a timer on the monitor. At the end of the timing, the patient must wipe, blot or wash the strip off, using a careful technique. And for most strips, the patient must place the reacted reagent strip into the monitor, and press a test button or close a hatch to obtain results. Prior art commercially available comparable reagent strips or monitors require operator intervention in a prescribed sequence at exact time intervals. The prior art is subject to operator error, sequence, timing, and technique errors. The prior art reagent strips are also subject to contamination which will affect accuracy of measurement.
The present invention overcomes the disadvantages of the prior art by providing a hand-held pocketable medical system which includes an attachable disposable probe package carrying a chemical reagent chemistry for extracting blood from an individual, delivering the blood to the blood sensing reagent, or vice versa, in the disposable needle package, and resulting in a read-out of a level such as blood glucose. The system includes a microcomputer which is software controlled by an internal program and, of course, provisions can be provided for external programming of the microcomputer. The computer controls all timing functions thereby eliminating human error.
SUMMARY OF THE INVENTION
One general purpose of the present invention is a portable, shirt-pocket-size, battery-operated diagnostic device/system for use by health professionals and/or lay patients for the detection and measurement of certain selected chemical agents or substances for the purpose of diagnosis and/or treatment of disease. The application is not restricted to use with human beings. It may also be extended to veterinary medicine animals. One first application is for insulin dependent and non-insulin dependent diabetics for the measurement of glucose in serum, plasma, and/or whole blood.
Another purpose of the present invention is to provide a hand-held pocketable medical system including an engaging disposable needle or lance probe carrying the blood sensing reagent for sensing readings of the blood, such as blood glucose level. The medical system is cost effective and simple to operate by an individual. The reading, such as an individual's glucose level, is displayed on an LCD display on the side of a tubular like pen barrel of the medical system which approximates the size of an ordinary ink pen which can be carried in an individual's shirt pocket. The disposable needle probe packages can be carried in a corresponding hollow tubular pencil carrying a plurality of disposable probe packages for use as needed. The tubular structure resembling a pen contains the hand-held pocketable medical system, and the tubular structure resembling a pencil carries the extra supply of disposable needles. The pen-and-pencil design provides for the utmost peace of mind for the individual.
According to one embodiment of the present invention, there is provided a hand-held pocketable medical system including mechanical or electromechanical pen like structure for actuating a needle in a disposable needle or lance probe package, and for enabling a blood sample inside a finger or on the finger surface to be transferred to blood sensing reagent chemistry, or the blood sensing chemistry to be transferred to the blood. The mechanical structure can assume a variety of spring actuated configurations and can further create a vacuum for drawing the blood outside of the finger. The disposable needle probe package frictionally engages onto a socket at the bottome of the tubular hand-held pocketable medical system such as by snapping, threading, or the like, in place, and is easily releasable and disposable after a single use. The hand-held tubular medical system includes photosensing electronics connected to a microcomputer or custom integrated circuit not only for analyzing the properties of the blood sensing chemistry in the disposable probe package, but also for displaying a readout and storing previous readouts. The electronics includes a verification sequence verifying operability of the electronics including sensing of a low battery condition, verifying the condition of an unused disposable needle package, verifying the presence of a blood sample and subsequently providing multiple readings to provide for an averaging of results. The result will not be displayed until the qualification sequence has been successfully sequenced through verification.
One significant aspect and feature of the present invention is a hand-held pocketable medical system referred to as a "Med Pen" or a "Med Pen Mosquito" which is used to extract a blood sample from the body, subject the sample to chemical analysis, and display the results to the individual. A disposable needle package, referred to as a "Med-Point" carries the blood sensing chemistry consisting of a reagent strip, as well as the needle either for delivering blood to the reagent or for causing the reagent to be delivered to the blood. Additional disposable needle packages can be carried in a corresponding structure similar to that of the medical apparatus referred to as a "Med Pencil."
Another significant aspect and feature of the present invention is a pen like structure which is mechanical, and actuates upon a predetermined amount of pressure being exerted on the skin of an individual's finger. Upon this pressure being sensed, the needle will be actuated down through an individual's skin for the subsequent result of enabling a blood sample to be taken from within the finger or blood sample to occur on the surface of the finger. In an alternative, a button can be pushed actuating the probe into the skin.
A further significant aspect and feature of the present invention is a hand-held pocketable medical system referred to as "Med-Pen Mosquito" which will provide blood glucose readings where the disposable needle probe package carries glucose-oxidase or like chemical reagent, whereby once the blood undergoes a colorometric or potentiometric action proportional to the blood glucose concentration, electronics through the reflectance colorimeter provide for subsequent processing of the photosensing of the blood chemistry for displaying of the results on an LCD display.
A further significant aspect and feature of the present invention is a hand-held pocketable medical system which can be utilized by an individual and only requires the engagement of a disposable needle probe package, subsequent actuation of the apparatus causing a subsequent display on a visual readout for the desired measurement.
Having thus described embodiments of the present invention, it is a principal object hereof to provide a pocketable medical system, including disposable needle packages, which carries blood sensing reagent which engage thereto providing a subsequent readout on a visual display of a quality of the blood.
One object of the present invention is to provide a hand-held pocketable medical diagnostic system denoted as a Med-Pen Mosquito, disposable medical probe as needle packages referred to as Med-Points or Med-Probes which engage onto the Med-Pen, and a hollow tubular pencil referred to as a Med-Pencil for carrying extra disposable needle Med-Point packages. The disposable needle packages carry blood sensing chemistry or chemistry for sensing components of the blood for qualities such as glucose level. Other qualities of any substance can also include urea nitrogen, hemoglobin, alcohol, protein or other qualities of the blood.
Another object of the present invention is a Med-Pen which is a reuseable device containing the electronics and software programming, mechanical apparatus, battery(s), sensor(s), and related circuitry that cause the functional operation to be performed. The Med-Point or Med-Probe is a disposable device containing a needle/lance to obtain a blood sample, typically from a person's finger or toe, and a chemical reagent that reacts with the presence of blood as a function of the amount of glucose present in blood. The chemical reagent is sealed inside the Med-Point probe housing or inside a specific housing for the chemical reagent obviating the effects of contamination (from fingers), moisture, and light, thus improving accuracy and precision of measurement by stabilizing the oxidation reduction or chemical reaction of the reagent prior to use. The sensor(s) in the Med-Pen/Point system measure/detect via colorometric and/or potentiometric analysis of the amount of glucose present. This analog data is converted to a digital readout display quantifying glucose in miligrams per deciliter (mg/dl) or MMOL/L.
An additional object of the present invention is a self-contained automatic system. Once the Med-Pen/Point is depressed against the finger (or other area), no further operator intervention may be required depending upon the specific embodiment. All operations and performance of the system are performed automatically and mechanically/electronically in the proper sequence. Accuracy and precision of the measurement is enhanced because errors due to operator interpretation, operator technique, timing of events, and are thereby removed from operator control and influence due to automatic operation. Pressure of the system against a skin surface of a predetermined amount based on spring constants or other predetermined conditions automatically starts the system and sequences the operations dependent upon the specific embodiment.
Still another object of the present invention is a medical system which is software based and software intelligent. The system is self-calibrating through control commands by the software.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Other objects and many of the attendant advantages of the present invention will be readily appreciated as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings, in which like reference numerals designate like parts throughout the figures thereof and wherein:
FIG. 1 illustrates a plan view of a hand-held pocketable medical system;
FIG. 2 illustrates an obverse view of FIG. 1;
FIG. 3 illustrates a plan view of the system operation;
FIG. 4 illustrates a cross-sectional view of a first embodiment;
FIG. 5 illustrates an electrical schematic block diagram;
FIG. 6 illustrates a cross-sectional view of a second embodiment;
FIG. 7 illustrates a cross-sectional view of a third embodiment;
FIG. 8 illustrates a cross-sectional view of a fourth embodiment;
FIG. 9 illustrates a cross-sectional view of a fifth embodiment, a capillary action medical system;
FIG. 10 illustrates a sectional view of a first medical point embodiment;
FIGS. 11-12 illustrate sectional views of a second medical point embodiment;
FIG. 13 illustrates a sectional view of a third medical point embodiment;
FIGS. 14-15 illustrate a sectional views of a fourth medical point embodiment;
FIG. 16 illustrates a plan view of a system self-calibrating medical point;
FIG. 17 illustrates a sectional view of a medical probe with self-contained optical sensors; and,
FIG. 18 is a flow chart of blood transfer to the reagent strip.
FIG. 1 illustrates a plan view of a hand-held pocketable medical system 10 and a disposable medical probe 12 with a needle or lance or the like carrying blood sensing reagent strip chemistry, all of the present invention. The hand-held pocketable medical system 10 includes a tubular cylindrical pen like member 14 and a clip 16 affixed to the top of the tubular member 14. The disposable medical probe 12 is a narrowing cylinder, and fits into a socket or similar coupling the cylindrical member as later described in detail. A visual electronic readout 18, such as an LCD or the like, including a plurality of digits displays numerical qualities of the blood, as later described in detail.
FIG. 2 illustrates an obverse plan view of FIG. 1 including an instruction panel 20 which can be affixed to the cylindrical tubular member 14 of the system 10.
FIG. 3 illustrates a plan view in perspective of the hand-held pocketable medical system 10, and a disposable medical probe 12 disengaged prior to use and after use. Extra disposable medical probes 12 can be stored in a hollow tubular pencil like cylindrical member 21 which would resemble a pencil like structure.
FIG. 4 illustrates a cross-sectional view of a first embodiment 30 of the medical system 10 prior to finger engagement. The embodiment 30 includes a casing member 32 which is a pen like tubular cylindrical member, and a core portion 34 disposed therein. A button member 36 includes two downwardly extending members 38 and 40 although the button action could be side actuated. An outer spring 42 is disposed between members 38 and 34, and an inner spring 44 is disposed between members 34 and 40. The outer spring 42 is held in position by members 68 and 70. The internal actuating spring 44 is held in position by the lower member 70 and the top of the button 36. Member 74 further limits travel of the button 36 in an upward manner and member 75 limits travel downwardly of button 36. Latch 76a and 76b provide for securing of the diaphragm housing core 46. Latches 47a and 47b are disposed at the lower portion of the downwardly extending member 40. A diaphragm housing core 46 positions in notches 48a and 48b in core part 34. A diaphragm 49 fits over the diaphragm housing core 46. An optical measurement means includes a light source such as LED 50 and a light sensor such as phototransistor 52 mounted in an adjacent and opposed relationship with respect to each other on the walls of the diaphragm housing core 46. The LED 50 and phototransistor 52 connect to an electronics unit 54, as later described in detail. The electronics unit 54 is powered by a battery 56 held in position in battery housing 58 by battery lid 60. A visual display, such as a LCD display 62, positions in a LCD housing 64 and is held therein by a clear viewing lens 66. The disposable probe package 12 includes a needle 90, a probe like supporting structure 92, and a reagent strip 94. The strip 94, while shown in a horizontal configuration, can be in other configurations such as vertical, etc. Release tube 96 which provides means for releasing actuator spring 44, positions in the lower portion of casing 32 and engages the inner surfaces of latches 76a and 76b.
FIG. 5 illustrates an electrical schematic block diagram 100 of the electrical circuitry for the electromechanical structure of FIG. 4. A microcomputer 102 or custom integrated circuit controls operation. A crystal 104 provides the clock signal to the microcomputer 102. A start switch 106 is actuated upon the pressure of the disposable needle 12 against the skin through pressure. An operational amplifier 108 takes an analog signal through to an A/D converter 110. A controller 112 controls power to the op amp 108 and the A/D convertor 110. A piezo electric chiming transducer 98 is connected to an internal clock of the microcomputer for chiming at preset times for medical readings. Switches 98a and 98b set the time. A personal computer 114 can connect by a cable 116 to a plug 118 for outputting stored readings. A recall switch 120 recalls each previous reading as the switch is depressed. A voice synthesizer 122 can also state the reading, the time, and the day. The microcomputer stores software to verify the electronics, verify the calibration procedural steps, and controls the measuring of the qualities as predetermined by the software commands. A power wake up switch or photoswitch 124 turns on the electronics when a probe 12 is inserted into the pen 10.
MODE OF OPERATION
The operation of the hand-held portable medical diagnostic system 10 will now be described in detail, particularly with later reference to sensing of glucose for an insulin type of diabetic individual. This is by way of example and for purposes of illustration only and not to be construed as limiting of the structure or mode of operation of the present invention.
Pushing button 36 loads inner actuator spring 44. The push button 36 locks in place by latch 47a and 47b and holds spring 44 in the compressed state as shown in FIG. 4. Diaphragm 49 is thereby compressed by diaphragm tensioner 51 which is a small projection on the central portion of core 34. By pushing the release tube 96 upward with an individual's finger, from which blood sample is to be taken, latches 76a and 76b are opened, and core 34 is forced downwardly by action of the inner actuator spring 44. Downward movement of core 34 drives the diaphragm housing core 46 with the probe 12 and needle 90 downwardly and simultaneously begins to load outer spring 42. Needle 90 punctures the finger. Downward motion of core 34 opens latches 47a and 47b so that push button 36 can return to its neutral position by being forced upward by further expansion of inner spring 44. Outer spring 42, coaxial to inner spring 44, then can push core 34 upwardly which releases the diaphragm 49, and creates a vacuum in diaphragm housing core 46. The vacuum draws blood up from ruptured capillaries in the finger through the needle 90 into the probe 92 whereupon the blood wets the reagent strip 94. Further upward movement of core part 34 pulls the diaphragm housing core 46 upward so that probe 92 and needle 90 retract from the finger. The diaphragm housing core 46 is then locked in place by the latch 76a and 76b, all mechanical action ends, and all elements are in a neutral position. The blood sample on reagent strip 94 is processed by chemical reaction inside reagent strip 94, and color change of strip is read from the opposite side of reagent strip 94 by reflection of light from LED 50 to the phototransistor 52. The signal is processed in electronics of FIG. 5 as later described in detail, and converted into a numeric value subsequently displayed on LCD 62 which reflects the glucose level of the blood sample. The disposable probe 12 is removed from the device by pulling of the probe causing the skirt of casing member 32 to expand, freeing the probe from the socket.
Further operation of the system is now described. A user attaches a Med-Point probe 12 to the Med-Pen system 10 which accomplishes two functions. The first is the Med-Pen and Med-Point are engaged and made ready for use. The second is the sensor(s) can sense predefined color bands/areas located inside Med-Point as the pen and point are mated, thus automatically calibrating through an algorithm in the software. This self calibration ensures accuracy of measurement before each use; eliminates the need for operator intervention and operator induced error; verifies that the chemical reagent inside Med-Point is the correct color, i.e., unreacted; and, causes the Med-Pen to provide a visual and/or audible alarm if the calibration "acceptance criteria" in the software is not satisfied.
The user places Med-Pen/Point on one's finger or other area from which blood sample is to be taken. The user pushes down one end of Med-Pen and holds down until a tactile response indicates Med-Pen/Point may be removed. The tactile response may be in various forms such as mechanical click from detent action or even an audible beep.
Med-Pen/Point performs all operations in the proper sequence and does not require user intervention. A blood sample is transported by vacuum and/or capillary action to the chemical reagent, and/or chemical reagent is transported to the blood sample on surface/within finger or other areas. The vacuum is created by the mechanical action/design of components in the Med-Pen probe. The capillary action is created by the physical dimensional design of the Med-Point probe as later described. An internal clock/timer in the computer is initiated on pressure being exerted in the system. The chemical reagent reacts with blood/glucose. The electronic sensor(s) can detect colorimetrically and/or photoimetrically the amount of glucose present in the blood sample by measuring the change in color of the chemical reagent and/or the conductivity/impedance of the chemical reagent, respectively. The chemical reaction between the reagent and the blood/glucose is time dependent. Multiple measurements are made at specified time intervals as dictated by an internal clock, thus achieving three results. There is improved accuracy due to the resolution of the measurements over shorter time intervals rather than a single measurement at (x) seconds as in the prior art. There is improved accuracy because multiple measurements can be averaged optionally throughout the high/low readings, etc. for linear or non-linear reactions and/or equations. There is faster response time for operator use; i.e., one doesn't have to wait 30-60 seconds for a reading. The system takes early readings and extrapolates. The Med-Pen system electronics converts the analog data to digital format, and displays a quantitative digital readout of glucose in whole blood expressed in mg/dl or MMOL/L.
The accuracy and precision of measurements is further enhanced because the chemical reaction of the chemical reagent is stabilized. The Med-Point housing or self-contained housing for the reagent chemistry can provide a barrier that insulates the chemical reagent from those parameters that accelerate the reaction; i.e., light, moisture, contaminants from fingertips such as salt, fluoride, etc.
The electronics operates on the reflectance colorometer principal where the blood on the reagent strip undergoes a colorometric or potentiometric reaction proportional to the blood glucose concentration. The electronics provides verification of the system, the chemistry of a reagent of an unused strip, the presence of a blood sample, and provides multiple readings to average the results. Several readings can be taken at specific intervals shortly after the blood reacts with the reagent strip. Once two measurements are made at two distinct time periods, the slope of the reaction of the chemistry can be calculated towards determining an actual final glucose value. In the alternative, the software of the microcomputer can control predetermined samplings at predetermined time intervals and average the result to determine the final glucose reading after a predetermined time period, such as 60 seconds. This improves the accuracy of the final reading. The readings can also be stored and either recalled by a switch on the side of the pen, or recalled by connecting the pen through an interconnecting cable to a personal computer for outputting the readings for specific times on specific days to a video display or stored for subsequent display or printout.
DESCRIPTION OF ALTERNATIVE EMBODIMENTS
FIG. 6 illustrates a cross-sectional view of a second embodiment of a medical pen 130. The medical pen 130 includes a housing 131, a button structure 132 including a spring seat 134, a central core 136 including a detent 137, a spring seat 138 and a rolling diaphragm 140 connected between points 142 and 144 of the core 136. Vertically linerally aligned upper actuator spring 146 and lower spring 148 are between spring seats 134 and 138, respectively, and 138 and 150. Upper latch 152 and lower latch 154 engage at point 156. A latch 158 is part of housing 131. A push button extension 160 extends downwardly from the push button 132. The electronics include a battery 164, a battery cover 166, and the microcomputer assembly 168. An LCD display 170 mounts to the internal portion of a battery cover 166 and includes a clear lens 171. A combined optical sensor 172 provides for illumination, as well as detection, of the color of the chemical change. A release tube 174 includes catches 176 and 178. A probe structure 180 includes a needle 182 and a reagent strip 184 and a probe housing 186.
MODE OF OPERATION
Pushing the button 132 downwardly loads spring 146 and locks button 132 in place by action of latch 158 in detent 137. Air inside button 132 is pushed out through core 136, the porous reagent strip 184, probe 186, and the needle 182. The finger from which blood sample is to be taken pushes the release tube 174 upwards, latch 158 is opened so that loaded actuator spring 146 can drive the core 136 down which loads spring 148 and drives needle 182 of probe 186 into finger. Needle 182 ruptures capillaries in finger. When the core 136 has moved all the way down, latch 154 clips into a detent 151 and releases the latch 152 from engagement at point 156. This releases button 132 which is forced back to the neutral position by spring 146. Upward movement of the button 132 creates a vacuum inside button 132 and the core 136 by action of rolling diaphragm 140, that vacuum then reaches probe 186 and needle 182 through porous reagent strip 184, thus sucking blood from capillaries in the finger into the needle 182 through the probe 186 so as to wet the reagent strip 184. Extension 160 of button 132 retracts latch 154 from detent 151 after a mechanical delay and finite time delay defined by distance between latch 158 and extension 160, thus releasing core 136 which is forced upwards by spring 148 which is then locked in place by latch 158. This action retracts probe 186 with needle 182 from finger.
The blood sample on the reagent strip 184 reacts with the reagents in the reagent strip 184 and the resulting color change is read from the opposite side by optical sensor 172, whose signals are converted by electronics into a numerical readout on display which reflects the glucose level of the blood sample. Disposable probe unit 180 is then removed from device.
DESCRIPTION OF ALTERNATIVE EMBODIMENT
FIG. 7 illustrates a cross-sectional view of a third embodiment 200. The medical pen 200, an alternative embodiment, includes a casing 202, a spring tensioner 204, a spring 206, a diaphragm tensioner 208, a diaphragm plunger 210, a diaphragm 212, all positioned about a diaphragm housing core 214. This embodiment operates with a single spring 206, which secures between the spring tensioner 204 and the diaphragm tensioner 208. A slide button 216 secures to the diaphragm tensioner 208. The spring tensioner 204 includes an extension 218 extending downwardly therefrom. The diaphragm tensioner 208 includes upper latches 220a and 220b and lower latches 222a and 222b. A release tube 224 secures at points 226a and 226b to the latches 222a and 222b and at junctions 228a and 228b. The probe 234 includes a needle 236 and a reagent strip 238. The electronics include an optical sensor 240, electronic circuitry 242, a battery 244 with a battery cover 246, and an LCD display 248 with a clear lens 250.
MODE OF OPERATION
The probe 234, needle 236, release tube 224, and reagent strip 238 are a single disposable unit which is inserted into the socket in the pen 200. Upward thrust of extension 218 at release tube 224 during insertion pushes spring tensioner 204 upward which loads spring 206. The disposable unit 234 locks into place by action of latch 222a and 222b. Upward thrust of a finger from which blood sample is to be taken opens junction 228a and 228b between release tube 224 and probe 234 because probe 234 stops at the fixed diaphragm housing core 214. Sudden release of the release tube 224 drives the needle 236 into the finger where it ruptures capillaries. At its upper stop, release tube 224 opens latch 220a and 222b on diaphragm tensioner 208 which is forced upward pulling the diaphragm plunger 210 and the diaphragm 212 upward, thus creating a vacuum inside fixed diaphragm housing core 214. The vacuum reaches needle 236 through diaphragm housing core 214 and draws blood from the finger through the needle 236 which wets the reagent strip 238.
The pen 200 has to be manually removed from the finger and reset by means of the slide button 216. The color change of reagent strip 238 is read from the opposite side by the optical sensor 240, and the electronics unit 242 converts the color change into a numerical readout on the display 248.
DESCRIPTION OF ALTERNATIVE EMBODIMENT
FIG. 8 illustrates a cross-sectional view of a fourth embodiment of a pen 250. The pen 250 includes a casing 252, a diaphragm plunger 254, a diaphragm tensioner 256, and a diaphragm 258. The diaphragm housing core 260 supports the diaphragm 258. Upper latch 262 and lower latches 264a and 264b secure to the diaphragm tensioner 256. A slide button 266 also mounts on the diaphragm tensioner. Internal to the casing 252 are the electronics 268, a battery 270, a screw-on battery cover 272, a display 274, such as an LCD display, and a clear plastic lens 276 inside the casing. Optical sensors 278 connect to the electronics 268. A disposable probe 280 including a needle 282 and a release tube 284 having latch detents 286a and 286b secured to latches 264a and 264b at junctions 288a and 288b. A reagent strip 290 mounts in the probe housing 292.
MODE OF OPERATION
FIG. 8 illustrates the diaphragm tensioner 256 being pushed downward, thus depressing diaphragm 258. Diaphragm tensioner 256 locks into place by the latches 262a and 262b. Probe 280 with the needle 282 and release tube 284 are then inserted and held in place by latches 264a and 264b. Upward thrust of the finger breaks the junction 288 between the probe 280 and the release tube 284 which exposes the needle 282. The needle 282 punctures the finger rupturing the capillaries. At its upper stop, the release tube 284 opens the latches 262a and 262b on the diaphragm tensioner 256 so that by action of the elastic diaphragm 258, the diaphragm tensioner 256 is pushed back. This creates a vacuum in the diaphragm housing core 260 which sucks blood from finger through needle 282 into the probe 280 where the blood wets reagent strip 290. The pen 250 is then manually removed and reset by means of the slide button 266 before the next use. The blood is chemically processed on the reagent strip 290 whose color change is optically read from the opposite side and converted in the electronics unit 268 into a visual readout on display 274. Probe 280 with release tube 284 and needle 282 are held by frictional engagement until removed and disposed of.
DESCRIPTION OF ALTERNATIVE EMBODIMENT
FIG. 9 illustrates a cross-sectional view of a fifth embodiment, a capillary action medical system 300. The capillary action medical system 300 includes a case 302 with a top 304, a knob 306 with a shaft 308, and a plunger 310 fits through a hole 312 in the top 304. A button 314 pivots about a point 316 and includes a latch 318. A lance holder 320 includes a lance 330 therein. An upper spring 332 fits between the top 304 and the top of the plunger 310. A lower spring 334 engages between the bottom of the lance holder 320 and surface 336. A probe 340 includes a capillary duct 342 and a reagent strip 344 therein. Optical sensor 346, microprocessor electronics 348 and an LCD display 350 mount on a board 352. A clear lens 354 fits into the case 302. Likewise, a battery 356 applies power to the electronics unit 348 and includes a battery cover 358.
MODE OF OPERATION
Pulling upwardly on knob 306 loads actuator spring 332, and the plunger 310 then locks in place by latch 318. Disposable unit 340 consisting of the lance 330, probe 340 and reagent strip 344 insert into the system 300. The top end of lance 330 is held by lance holders 320. Pushing the button 314 releases the latch 318. The plunger 310 is forced down, hitting lance holder 320. The lance 330 punctures the finger and ruptures capillary blood vessels. By action of the spring 334, the lance holder 320 returns immediately to its neutral position, retracting the lance 330. Blood starts accumulating in the wound channel, and forms a drop on the skin's surface which is drawn into capillary duct 342 by capillary action. Blood rests on the reagent strip 344 and starts the chemical reaction. Color change is then read from the opposite side by the optical sensors 346 connected to the electronics unit 348. The electronics unit converts signals to a digital readout on display 350.
ALTERNATIVE EMBODIMENTS OF MED POINT
FIG. 10 illustrates a sectional view of a first embodiment of a medical point 400. A release tube 402 triggers a mechanism in the system 10 which drives a needle 404 into the finger thereby rupturing capillary blood vessels. The blood which accumulates in the wound channel is drawn through the needle 404 into a probe 406 by a vacuum generated in the system, and subsequently onto a reagent strip 408 which can be porous.
FIGS. 11-12 illustrate a sectional view of embodiments of a medical point 420 having a release tube 422 which is triggered by the system which drives the needle 424 into the finger, thereby rupturing capillary blood vessels. The needle 424 is then retracted halfway in order to allow the blood to accumulate in the wound channel and to avoid being obstructed by the tissue. The blood which accumulates in the wound channel is then drawn through the halfway withdrawn needle into the probe 426 by the vacuum generated in the device and onto the porous reagent strip 428.
FIG. 13 illustrates a sectional view of a third medical point embodiment 440 where the needle 442 includes a side hole 444. The needle includes a side hole which provides that the blood can be drawn despite a potentially plugged tip of the needle such as by skin or flesh.
FIGS. 14-15 illustrate sectional views of a fourth medical point embodiment 460 where a needle 464 is enclosed by a side guide tube 466. The side guide tube touches the surface of the finger. After puncturing the finger, the needle 464 is fully retracted in the guide tube 466 and blood is drawn in through the guide tube and the needle as illustrated in FIG. 15. In the alternative, a lance can be utilized in lieu of the needle of FIGS. 14 and 15. The lance can even include a side hole to act as a carrier for carrying the blood in the side hole of the lance.
FIG. 16 illustrates a plan view of a selfcalibration medical point which includes automatic calibration strips for the optical sensors and microcomputer in the system. The medical point 500 includes color strips 502, 504, and 506 about a probe housing 508. Color strips 502-506 have different shades of grey which reflect three defined levels of glucose in the blood for purposes of calibration. During insertion of the Med-Point, the color strips are read by an optical sensor unit 514. Signals are coupled to the electronics unit for calibration of the Med-Point 500 prior the Med-Point reaching its final position. In the final position, the sensor 514 reads the strip 510, which is impregnated with blood through the needle 512.
FIG. 17 illustrates a section view of a medical probe 540 including an optical sensing unit 548 with contacts 550 and 552 mounted in a probe housing 542. A needle 544 connects to the reagent strip 546. The optical sensing unit 548 reads the reagent strip and provides electronic information to the Med-Pen device. The metallic contacts 550 and 552 connect the sensing device to the electronics in the Med-Pen. The entire unit is considered disposable based on low cost of volume integrated circuits.
One alternative embodiment of the present invention is that the blood chemistry can be positioned at the site of the blood rather than taking the blood to the blood chemistry reagent strip. Disposable structures can be provided which would snap in place, although a needle or capillary action would not be required in that the reagent strip would touch blood located on one's skin and commence the process. The mode of operation would be that as previously discussed in pushing the system downwardly so that the release tube would apply upper pressure causing a reagent strip to come into contact with the blood. While all of the previous embodiments have illustrated the blood flowing to the chemical sensing reagent strip, the alternative embodiment can take the reagent strip to the blood, such as by having the reagent strip positioned on a lower portion of the disposable probe. The permutations of whether the blood is taken to the reagent strip or the reagent strip is taken to blood, is illustrated in FIG. 18 in a flow chart diagram. The teachings of the present invention can be expanded such as by having the probe include structure for first pricking and bringing blood from below the skin to the surface of the skin, and then having structure for moving the reagent strip to the blood on the surface of the skin for subsequent transfer of the reagent strip to the blood.
|
Hand-held shirt-pocket portable medical diagnostic system for checking measurement of blood glucose, urea nitrogen, hemoglobin, blood components or other body qualities. The system includes the engagement of a disposable needle or lance probe package which carries a chemical reagent strip such as blood reacting chemistry. The system includes a pen structure having a visual readout, a microcomputer, and photosensing circuitry which measures the change of color of the blood reacting chemistry of the disposable probe package. The pen also includes a spring arrangement for actuating a needle or lance into the skin for transferring blood from a finger or other area to the chemical reagent strip. A disposable probe structure package includes configurations for transferring of the blood to the reagent strip of the reagent strip to the blood. The pen can also create a vacuum about a time period that the needle is penetrating the skin. The system includes a verification sequence of the electronics, the chemistry of an unused disposable probe package, the presence of blood sample and multiple readings to average results. The system can also be provided with provisions for storing a plurality of readings, communicating with a personal computer, and can act as an alarm and chime to indicate time periods for blood sensing.
| 2 |
FIELD OF THE INVENTION
[0001] Described herein are processes useful for preparing 5-lipoxygenase activating protein (FLAP) inhibitors and their intermediates. In particular, described herein are processes for preparing 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid, the anhydrous Form C polymorph of sodium 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionate, and intermediates useful in said processes.
BACKGROUND OF THE INVENTION
[0002] Leukotrienes are biological compounds formed from arachidonic acid in the leukotriene synthesis pathway. Leukotrienes are synthesized primarily by eosinophils, neutrophils, mast cells, basophils, dendritic cells, macrophages and monocytes. Leukotrienes have been implicated in biological actions including, by way of example only, smooth muscle contraction, leukocyte activation, cytokine secretion, mucous secretion, and vascular function.
[0003] FLAP is a member of the MAPEG (membrane associated proteins involved in eicosanoid and glutathione metabolism) family of proteins. FLAP is responsible for binding arachidonic acid and transferring it to 5-lipoxygenase. 5-Lipoxygenase can then catalyze the two-step oxygenation and dehydration of arachidonic acid, converting it into the intermediate compound 5-HPETE (5-hydroperoxyeicosatetraenoic acid), and in the presence of FLAP convert the 5-HPETE to Leukotriene A 4 (LTA 4 ). LTA 4 is converted to LTB 4 by LTA 4 hydrolase or, alternatively, LTA 4 is acted on by LTC 4 synthase, which conjugates LTA 4 with reduced glutathione (GSH) to form the intracellular product leukotriene C 4 (LTC 4 ). LTC 4 is transformed to leukotriene D 4 (LTD 4 ) and leukotrine E 4 (LTD 4 ) by the action of gamma-glutamyl-transpeptidase and dipeptidases. LTC 4 synthase plays a pivotal role as the only committed enzyme in the formation of cysteinyl leukotrienes.
[0004] Processes for preparing FLAP Inhibitors, in particular 3-[3-(tert-butylsulfanyl)-1[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid, and intermediates useful in the synthesis of FLAP inhibitors, have been described in International patent application WO 2007/056021.
[0005] International patent application WO 2007/056021 describes a linear process for the preparation of FLAP inhibitors. In particular, WO 2007/056021 describes a process for the preparation of 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid via the following Scheme A:
[0000]
[0006] PCT/US2009/44945 describes the Form C polymorph of sodium 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionate and a process for its preparation. The process comprises dissolving 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester in ethanol and tetrahydrofuran, and adding aqueous sodium hydroxide. The mixture is then heated for 16 hours, filtered and then concentrated. The concentrate is then reslurried by adding methyl-tert-butyl ether and heated for 5 hours with stirring. The solids are isolated by filtration and the product dried under vacuum at room temperature for 5 days.
[0007] PCT/US2009/44945 also describes a linear process for the preparation of alkyl esters of 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid via the following Scheme B:
[0000]
SUMMARY OF THE INVENTION
[0008] Described herein are processes useful for preparing 5-lipoxygenase activating protein (FLAP) inhibitors and their intermediates, for example as shown in Scheme C and Scheme D below. In particular, described herein are processes for preparing 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid, the anhydrous Form C polymorph of sodium 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionate, and intermediates useful in said processes.
[0009] Such processes offer advantages over the prior art in that they are convergent rather than linear. Convergent processes may allow for a reduced cycle time, as stages of the reaction scheme may be run in parallel, and an increase in throughput and overall yield. In one comparison, the process of the present invention as shown in Scheme C below, increased the overall chemical yield by a factor of approximately 8, compared to Scheme B of PCT/US2009/44945 beginning with the respective starting materials.
[0010] Furthermore, the amount of solvent used in the process of the present invention is reduced compared to Scheme A of WO 2007/056021 and Scheme B of PCT/US2009/44945, thus minimising waste and environmental impact. In particular, the processes of present invention avoid a number of solvents of concern, such as, dichloromethane and acetonitrile, dimethylformamide and 1,2-dimethoxyethane.
[0011] The process of the present invention avoids the use of highly undesirable agents such as aluminium chloride, again minimising environmental impact.
[0000]
[0000]
[0012] In one aspect of the invention, there is provided a process 1B for preparing the anhydrous Form C polymorph of a compound of formula (I)
[0000]
[0000] comprising
[0013] A) the reaction of a compound of formula (XV)
[0000]
[0000] or a salt thereof; with a compound of formula (XII)
[0000]
[0000] or a salt thereof;
in the presence of a base, and a solvent to produce a compound of formula (XVI)
[0000]
[0000] or a salt thereof;
[0014] B) followed by the reduction of a compound of formula (XVI) or a salt thereof with hydrogen in the presence of palladium in a solvent, to produce a compound of formula (VIII)
[0000]
[0000] or a salt thereof;
[0015] C) followed by the reaction of a compound of formula (VIII) or a salt thereof; with aqueous sodium nitrite in the presence of hydrochloric acid to form the diazonium salt followed by reduction of the diazonium salt to produce a compound of formula (VI)
[0000]
[0000] or a salt thereof;
[0016] D) the reaction of a compound of formula (XIII)
[0000]
[0000] or a salt thereof;
with a compound of formula (XIV)
[0000]
[0000] or a salt thereof;
in the presence of a base, aqueous alcoholic solvent and palladium on carbon to produce a compound of formula (X)
[0000]
[0000] or a salt thereof;
[0017] E) followed by the reaction of a compound of formula (X) or a salt thereof; with, when L is bromine, aqueous or anhydrous hydrogen bromide, or where L is chlorine, aqueous or anhydrous hydrogen chloride, cyanuric chloride, thionyl chloride, methane sulfonyl chloride, toluene sulfonyl chloride or phosphoryl chloride to produce a compound of formula (VII)
[0000]
[0000] wherein L is chlorine or bromine; or a salt thereof;
[0018] F) followed by the step of reacting a compound of formula (VII) or a salt thereof;
[0000] wherein L is chlorine or bromine;
with a compound of formula (VI) or a salt thereof;
in the presence of a base and solvent; to produce a compound of formula (IVa)
[0000]
[0000] or a salt thereof;
[0019] G) followed by the reaction of a compound of formula (IVa) or a salt thereof; with a compound of formula (Va)
[0000]
[0000] in the presence of an acid and a solvent to produce a compound of formula (IIIa)
[0000]
[0000] or a salt thereof;
[0020] H) followed by the reaction of a compound of formula (IIIa) or a salt thereof with an aqueous solution of a base to produce a compound of formula (II)
[0000]
[0021] I) followed by
(a) dissolving a compound of formula (II) in methanol and methyl-t-butylether in the presence of solid sodium hydroxide, followed by addition of methyl-t-butylether, wherein the solvent system in the reactant mixture contains 30% or less methanol; or (b) dissolving a compound of formula (II) in an alcohol which is ethanol or methanol and reacting with aqueous sodium hydroxide, followed by the addition of diisopropylether, wherein the aqueous content of the reaction mixture is ≦5% and the solvent system in the reactant mixture contains 30% or less ethanol or methanol by volume.
[0024] In another aspect of the invention, there is provided a process 1 for preparing a compound of formula (ID
[0000]
[0000] or a salt thereof;
comprising reacting a compound of formula (VII)
[0000]
[0000] or a salt thereof;
wherein L is a leaving group;
with a compound of formula (VI)
[0000]
[0000] or a salt thereof
in the presence of a base and solvent, and then converting to a compound of formula (II) or a salt thereof.
[0025] In another aspect of the invention, there is provided a process 2 for preparing a compound of formula (I)
[0000]
[0000] comprising the step of reacting a compound of formula (VII)
[0000]
[0000] or a salt thereof;
wherein L is a leaving group;
with a compound of formula (VI)
[0000]
[0000] or a salt thereof;
in the presence of a base and solvent, and then converting to a compound of formula (I).
[0026] In another aspect of the invention, we have found improved processes for preparing the Form C polymorph of sodium 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionate.
[0027] In one embodiment of the invention, there is provided a process 3 for preparing the anhydrous Form C polymorph of a compound of formula (I)
[0000]
[0000] comprising dissolving a compound of formula (II)
[0000]
[0000] in methanol and methyl-t-butylether in the presence of solid sodium hydroxide, followed by addition of methyl-t-butylether, wherein the solvent system in the reactant mixture contains 30% or less methanol by volume.
[0028] In an alternative embodiment of the invention there is provided a process 4 for preparing the anhydrous Form C polymorph of a compound of formula (I)
[0000]
[0000] comprising dissolving a compound of formula (II)
[0000]
[0000] in an alcohol which is methanol or ethanol and reacting with aqueous sodium hydroxide, followed by the addition of diisopropylether, wherein the aqueous content of the reaction mixture is ≦5% and the solvent system in the reactant mixture contains 30% or less methanol or ethanol by volume.
[0029] Processes 3 and 4 provide a direct means of crystallisation and avoids having to concentrate the mixture to dryness and then tritarate with methy-t-butylether. Thus the process may allow for greater control and more consistent particle size and physical properties. Furthermore, the use of solid sodium hydroxide in process 3 reduces the amount of water present and makes it easier to control hydrate formation.
[0030] In another aspect of the invention, there are provided processes for preparing key intermediates for use in the process for preparing FLAP inhibitors via a Fischer Indole reaction.
[0031] In one embodiment, there is provided a process 5 for preparing a compound of formula (III):
[0000]
[0000] wherein,
Z is selected from —[C(R 1 ) 2 ] m [C(R 2 ) 2 ] n , —[C(R 2 ) 2 ] n [C(R 1 ) 2 ] m O, —O[C(R 1 ) 2 ] m [C(R 2 ) 2 n , or —[C(R 1 ) 2 ] n OC(R 2 ) 2 ] n , wherein each
[0032] R 1 is independently H, —CF 3 , or —C 1 -C 6 alkyl or two R 1 on the same carbon may join to form an oxo (═O); and each
[0033] R 2 is independently H, —OH, —OMe, —CF 3 , or —C 1 -C 6 alkyl or two R 2 on the same carbon may join to form an oxo (═O);
[0034] m is 1 or 2; each
[0035] n is independently 0, 1, 2, or 3;
[0000] Y is a heteroaryl optionally substituted by halogen, —C 1 -C 6 alkyl, —C(O)CH 3 , —OH, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 fluoroalkyl, —C 1 -C 6 fluoroalkoxy or —C 1 -C 6 hydroxyalkyl; R 6 is L 2 -R 13 wherein
[0036] L 2 is a bond, O, S, —S(═O), —S(═O) 2 or —C(═O);
[0037] R 13 is —C 1 -C 6 alkyl wherein —C 1 -C 6 alkyl may be optionally substituted by halogen; R 7 is selected from —C 1 -C 6 alkyleneC(O)OC 1- C 6 alkyl, —C 1 -C 6 alkyleneC(O)OH and —C 1 -C 6 alkyl; R 11 is -L 10 -X-G 6 , wherein
[0038] L 10 is aryl or heteroaryl;
[0039] X is a bond, —CH 2 — or —NH—;
[0040] G 6 is aryl, heteroaryl, cycloalkyl or cycloheteroalkyl optionally substituted by 1 or 2 substituents independently selected from halogen, —OH, —CN, —NH 2 , —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 fluoroalkyl, —C 1 -C 6 fluoroalkoxy, —C(O)NH 2 and —NHC(O)CH 3 ;
[0000] R 12 is H or —C 1 -C 6 alkyl; or a
salt thereof;
comprising reacting a compound of formula (IV)
[0000]
[0000] or a salt thereof;
wherein Y, Z, R 11 and R 12 are as defined for a compound of formula (III) with a compound of formula (V)
[0000]
[0000] wherein R 6 and R 7 are as defined for the compound of formula (III) in the presence of an acid and solvent.
[0041] In another embodiment, there is provided a process 6 for preparing a compound of formula (IIIa)
[0000]
[0000] comprising reacting a compound of formula (IVa)
[0000]
[0000] or a salt thereof;
with a compound of formula (Va)
[0000]
[0000] in the presence of an acid and a solvent.
[0042] In another aspect of the invention there is provided a process 7 for preparing a compound of formula (II)
[0000]
[0000] or a salt thereof;
comprising a process for preparing a compound of formula (IIIa) as defined above, and then converting to a compound of formula (II) or a salt thereof.
[0043] In a further aspect of the invention there is provided a process 8 for preparing a compound of formula
[0000]
[0000] comprising a process for preparing a compound of formula (IIIa) as defined above, and then converting to a compound of formula (I).
BRIEF DESCRIPTION OF FIGURES
[0044] FIG. 1 presents a DSC thermogram of the Form C Polymorph of a Compound of Formula (I) produced via Step 8A (see Examples Section).
[0045] FIG. 2 presents an XRPD profile of the Form C Polymorph of a Compound of Formula (I) produced via Step 8A (see Examples Section).
DETAILED DESCRIPTION OF THE INVENTION
[0046] In one aspect of the invention, there is provided a process 1B for preparing the anhydrous Form C polymorph of a compound of formula (I)
[0000]
[0000] comprising
[0047] A) the reaction of a compound of formula (XV)
[0000]
[0000] or a salt thereof; with a compound of formula (XII)
[0000]
[0000] or a salt thereof;
in the presence of a base, and a solvent to produce a compound of formula (XVI)
[0000]
[0000] or a salt thereof;
[0048] B) followed by the reduction of a compound of formula (XVI) or a salt thereof with hydrogen in the presence of palladium in a solvent, to produce a compound of formula (VIII)
[0000]
[0000] or a salt thereof;
[0049] C) followed by the reaction of a compound of formula (VIII) or a salt thereof; with aqueous sodium nitrite in the presence of hydrochloric acid to form the diazonium salt followed by reduction of the diazonium salt to produce a compound of formula (VI)
[0000]
[0000] or a salt thereof;
[0050] D) the reaction of a compound of formula (XIII)
[0000]
[0000] or a salt thereof;
with a compound of formula (XIV)
[0000]
[0000] or a salt thereof;
in the presence of a base, aqueous alcoholic solvent and palladium on carbon to produce a compound of formula (X)
[0000]
[0000] or a salt thereof;
[0051] E) followed by the reaction of a compound of formula (X) or a salt thereof; with, when L is bromine, aqueous or anhydrous hydrogen bromide, or where L is chlorine, aqueous or anhydrous hydrogen chloride, cyanuric chloride, thionyl chloride, methane sulfonyl chloride, toluene sulfonyl chloride or phosphoryl chloride to produce a compound of formula (VII)
[0000]
[0000] wherein L is chlorine or bromine; or a salt thereof;
[0052] F) followed by the step of reacting a compound of formula (VII) or a salt thereof; wherein L is chlorine or bromine;
[0000] with a compound of formula (VI) or a salt thereof;
in the presence of a base and solvent; to produce a compound of formula (IVa)
[0000]
[0000] or a salt thereof;
[0053] G) followed by the reaction of a compound of formula (IVa) or a salt thereof;
[0000] with a compound of formula (Va)
[0000]
[0000] in the presence of an acid and a solvent to produce a compound of formula (IIIa)
[0000]
[0000] or a salt thereof;
[0054] H) followed by the reaction of a compound of formula (IIIa) or a salt thereof with an aqueous solution of a base to produce a compound of formula (II)
[0000]
[0055] I) followed by
(a) dissolving a compound of formula (II) in methanol and methyl-t-butylether in the presence of solid sodium hydroxide, followed by addition of methyl-t-butylether, wherein the solvent system in the reactant mixture contains 30% or less methanol; or (b) dissolving a compound of formula (II) in an alcohol which is ethanol or methanol and reacting with aqueous sodium hydroxide, followed by the addition of diisopropylether, wherein the aqueous content of the reaction mixture is ≦5% and the solvent system in the reactant mixture contains 30% or less ethanol or methanol by volume.
[0058] In another aspect of the invention, there is provided a process 1 for preparing a compound of formula (II)
[0000]
[0000] or a salt thereof;
comprising reacting a compound of formula (VII)
[0000]
[0000] or a salt thereof;
wherein L is a leaving group;
with a compound of formula (VI)
[0000]
[0000] or a salt thereof in the presence of a base and solvent, and then converting to a compound of formula (II) or a salt thereof.
[0059] In one embodiment there is provided a process 1 for preparing a compound of formula (II) or a salt thereof. In a further embodiment there is provided a process 1 for preparing a compound of formula (II).
[0060] In another aspect of the invention, there is provided a process 2 for preparing a compound of formula (I)
[0000]
[0000] comprising reacting a compound of formula (VII)
[0000]
[0000] or a salt thereof
wherein L is a leaving group;
with a compound of formula (VI)
[0000]
[0000] or a salt thereof in the presence of a base and solvent, and then converting to a compound of formula (I).
[0061] In one embodiment of process 1 or process 2, L is selected from chlorine and bromine. In another embodiment, L is bromine. In a further embodiment, L is chlorine.
[0062] In one embodiment of process 1 or process 2, the base is selected MOH, M 2 CO 3 and MHCO 3 wherein M is selected from Li (lithium), Na (sodium), K (potassium) and Cs (caesium); 1,8-diazabicyclo[5.4.0]undec-7-ene; and R′R″R″′N wherein R′, R″ and R″′ are each independently C 1 -C 6 alkyl. In another embodiment, the base is MOH. In another embodiment, the base is NaOH (sodium hydroxide). In another embodiment the base is KOH (potassium hydroxide). In another embodiment, the base is R′R″R″′N wherein R′, R″ and R″′ are each independently C 1 -C 6 alkyl. In a further embodiment, the base is R′R″R″′N and R′, R″ and R″′ are each ethyl.
[0063] In one embodiment of process 1 or process 2, the base is present to neutralise or part neutralise any acid. In one embodiment the pH of the mixture is ≧4.0. In another embodiment the pH of the mixture is from about 6 to 7.5.
[0064] In one embodiment of process 1 or process 2, the reaction is carried out at from about 15° C. to about 21° C. when L is bromine. In another embodiment of process 1 or process 2, the reaction is carried out at from about 40° C. to about 50° C. when L is chlorine.
[0065] In one embodiment of process 1 or process 2, the solvent is selected from water, C 1 -C 6 alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dichloromethane and mixtures thereof. In another embodiment, the solvent is selected from C 1 -C 6 alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dichloromethane and mixtures thereof. In another embodiment, the solvent is C 1 -C 6 alcohol. In another embodiment, the solvent is selected from ethanol, 1-propanol, 2-propanol, 2-butanol, sec-butanol and mixtures thereof. In another embodiment, the solvent is 2-propanol. In another embodiment, the solvent is 2-propanol and water. In a further embodiment, the solvent is tetrahydrofuran.
[0066] In one embodiment of process 1 or process 2, the compound of formula (VII) is in the form of a salt or as the free base. In another embodiment the compound of formula (VII) is the free base. In another embodiment the compound of formula (VII) is a salt. In another embodiment the compound of formula (VII) is a salt selected from hydrogen bromide, hydrogen chloride, hydrogen iodide, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and phosphate. In a further embodiment the compound of formula (VII) is a salt selected from hydrogen bromide and hydrogen chloride.
[0067] In one embodiment of process 1 or process 2, the compound of formula (VI) is in the form of a salt or as the free base. In another embodiment the compound of formula (VI) is the free base. In another embodiment the compound of formula (VI) is a salt. In a further embodiment the compound of formula (VI) is the dihydrogen chloride salt.
[0068] In another aspect of the invention, we have found improved processes for preparing the anhydrous Form C polymorph of a compound of formula (I)
[0000]
[0069] In one embodiment of the invention, there is provided a process 3 for preparing the anhydrous Form C polymorph of a compound of formula (I)
[0000]
[0000] comprising dissolving a compound of formula (II)
[0000]
[0000] in methanol and methyl-t-butylether in the presence of solid sodium hydroxide, followed by addition of methyl-t-butylether, wherein the solvent system in the reactant mixture contains 30% or less methanol by volume.
[0070] In one embodiment the reaction is seeded with the anhydrous Form C polymorph of the compound of formula (I). It should be noted that the anhydrous Form C polymorph of the compound of formula (I) will still be produced without seeding.
[0071] Such a process provides a direct means of crystallisation and avoids having to concentrate the mixture to dryness and then tritarate with methy-t-butylether. Thus the process may allow for greater control and more consistent particle size and physical properties. Furthermore, the use of solid sodium hydroxide reduces the amount of water present and makes it easier to control hydrate formation.
[0072] In one embodiment, the reaction is carried out at from about 48° C. to about 55° C. By carrying out the reaction at about 48° C. or above the chance of forming alternative polymorphs is significantly reduced. The about 55° C. limit is governed by the solvent boiling point.
[0073] In one embodiment, approximately 1.01 equivalents (relative to the compound of formula (II)) of sodium hydroxide is used in the reaction, this prevents the resulting product from being contaminated with excess starting material or sodium hydroxide.
[0074] It is possible to recover additional compound of formula (I) from the mother liquor and washes from process 3, by removal of methanol or methanol and methyl-t-butylether by distillation. It may also be possible to perform the same operation using, for example, pervaporation or vapour permeation as an alternative method of methanol removal. It may also be possible to combine the recovery of compound of formula (I) with the recovery of solvent via these latter processes. The additional compound of formula (I) may be the anhydrous Form C Polymorph and/or may require further processing in order to be suitable for clinical use. Such recovery processes should allow for an increase in yield, help reduce cost of goods, increase overall mass productivity and decrease the amount of waste associated with the process.
[0075] The recovery of methyl-t-butylether and methanol from a methyl-t-butylether/methanol solvent system may be possible. Such a mixture forms a low boiling azeotrope. Recovery by conventional distillation would require high energy input and would result in losses of methyl-t-butylether product to waste. Alternative technologies such as the use of membranes were investigated together with a hybrid involving distillation and a membrane process. With pervaporation/vapour permeation, liquid mixtures can be separated by selectively evaporating one component from the mixture through a membrane. The membrane only allows the component with the smallest molecular size to be evaporated. The use of a hybrid pervaporation/distillation unit represents the introduction of a low energy technology. Such membranes allow the recovery of methyl-t-butylether and methanol to the required purity (e.g. >99% w/w) and may be purchased from, for example, Sulzer Chemtech GmbH, Friedichsthaler Strasse 19, D-66540 Neunkirchen, Germany. Such solvent recovery would avoid incineration of solvent and hence a reduction in CO 2 emissions from fossil fuel combustion, and a reduction in cost of goods.
[0076] In one aspect of the invention, there is provided a process for preparing the anhydrous Form C polymorph of a compound of formula (I)
[0000]
[0000] followed by solvent recovery using a pervaporation membrane.
[0077] In one embodiment of the invention, there is provided a process 3A for preparing the anhydrous Form C polymorph of a compound of formula (I)
[0000]
[0000] comprising dissolving a compound of formula (II)
[0000]
[0000] in methanol and methyl-t-butylether in the presence of solid sodium hydroxide, followed by addition of methyl-t-butylether, wherein the solvent system in the reactant mixture contains 30% or less methanol by volume; followed by methanol removal using a pervaporation membrane.
[0078] In an alternative embodiment of the invention, there is provided a process 4 for preparing the anhydrous Form C polymorph of a compound of formula (I)
[0000]
[0000] comprising dissolving a compound of formula (II)
[0000]
[0000] in an alcohol which is ethanol or methanol and reacting with aqueous sodium hydroxide, followed by the addition of diisopropylether, wherein the aqueous content of the reaction mixture is ≦5% and the solvent system in the reactant mixture contains 30% or less ethanol or methanol by volume.
[0079] In one embodiment the reaction is seeded with the anhydrous Form C polymorph of the compound of formula (I). It should be noted that the anhydrous Form C polymorph of the compound of formula (I) will still be produced without seeding.
[0080] In this embodiment, the aqueous content is preferably kept to a minimum in order to avoid the formation of hydrates, whilst using enough water to ensure the solubility of the compound of formula (II).
[0081] In one embodiment, the alcohol is selected from methanol and ethanol. In a further embodiment the alcohol is ethanol.
[0082] In one embodiment, the process is conducted at from about 48° C. to about 78° C. By carrying out the reaction at about 48° C. or above the chance of forming alternative polymorphs is significantly reduced. The about 78° C. limit is governed by the solvent boiling point.
[0083] In one embodiment, the aqueous content of the reaction mixture is ≦3%. In a further embodiment, the aqueous content of the reaction mixture is ≦2%.
[0084] Such a process provides a direct means of crystallisation and avoids having to concentrate the mixture to dryness and then tritarate with methy-t-butylether. Thus the process may allow for a high degree of control and consistent particle size and physical properties.
[0085] In one embodiment, the compound of formula (II) may be prepared by ester hydrolysis comprising the reaction of a compound of formula (IIIa)
[0000]
[0000] with an aqueous solution of a base.
[0086] In one embodiment, the base is selected from MOH wherein M is selected from Li (lithium), Na (sodium), K (potassium) and Cs (caesium); M′(OH) 2 wherein M′ is selected from Ca (calcium) and Ba (barium). In a further embodiment, the base is NaOH (sodium hydroxide).
[0087] In one embodiment, the process is carried out in solvent selected from C 1 -C 6 alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran and mixtures thereof. In another embodiment, the process is carried out in a solvent selected from a tetrahydrofuran and ethanol mixture; a methyltetrahydrofuran and methanol mixture; and butanol. In a further embodiment, the process is carried out in a solvent which is a 2-methyltetrahydrofuran and 2-propanol mixture.
[0088] In a further aspect of the invention, there is provided a process for preparing key intermediates of formula (III), including compounds of formula (IIIa), as defined above, for use in the process for preparing FLAP inhibitors via a Fischer Indole reaction.
[0089] In one embodiment, there is provided a process 5 for preparing a compound of formula (III):
[0000]
[0000] wherein,
Z is selected from —[C(R 1 ) 2 ] m [C(R 2 ) 2 ] n , —[C(R 2 ) 2 ] n [C(R 1 ) 2 ] m O, —O[C(R 1 ) 2 ] m [C(R 2 ) 2 ] n , or —[C(R 1 ) 2 ] n O[C(R 2 ) 2 ] n , wherein each
[0090] R 1 is independently H, —CF 3 , or —C 1 -C 6 alkyl or two R 1 on the same carbon may join to form an oxo (═O); and each
[0091] R 2 is independently H, —OH, —OMe, —CF 3 , or —C 1 -C 6 alkyl or two R 2 on the same carbon may join to form an oxo (═O);
[0092] m is 1 or 2; each
[0093] n is independently 0, 1, 2, or 3;
[0000] Y is a heteroaryl optionally substituted by halogen, —C 1 -C 6 alkyl, —C(O)CH 3 , —OH, —C 3 -C 6 cycloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 fluoroalkyl, —C 1 -C 6 fluoroalkoxy or —C 1 -C 6 hydroxyalkyl; R 6 is L 2 -R 13 wherein
[0094] L 2 is a bond, O, S, —S(═O), —S(═O) 2 or —C(═O);
[0095] R 13 is —C 1 -C 6 alkyl wherein —C 1 -C 6 alkyl may be optionally substituted by halogen;
[0000] R 7 is selected from —C 1 -C 6 alkyleneC(O)OC 1 -C 6 alkyl, —C 1 -C 6 alkyleneC(O)OH and —C 1 -C 6 alkyl;
R 11 is -L 10 -X-G 6 , wherein
[0096] L 10 is aryl or heteroaryl;
[0097] X is a bond, —CH 2 — or —NH—;
[0098] G 6 is aryl, heteroaryl, cycloalkyl or cycloheteroalkyl optionally substituted by 1 or 2 substituents independently selected from halogen, —OH, —CN, —NH 2 , —C 1 -C 6 alkyl, —C 1 - C 6 alkoxy, —C 1 -C 6 fluoroalkyl, —C 1 -C 6 fluoroalkoxy, —C(O)NH 2 and —NHC(O)CH 3 ;
[0000] R 12 is H or —C 1 -C 6 alkyl; or a
salt thereof;
comprising the reaction of a compound of formula (IV)
[0000]
[0000] or a salt thereof;
wherein Y, Z, R 11 and R 12 are as defined for a compound of formula (III) with a compound of formula (V)
[0000]
[0000] wherein R 6 and R 7 are as defined for the compound of formula (III) in the presence of an acid and solvent.
[0099] In one embodiment, Z is —O[C(R 1 ) 2 ] m [C(R 2 ) 2 ] n , R 1 is H, m is 1 and n is 0.
[0100] In one embodiment, Y is heteroaryl optionally substituted by —C 1 -C 6 alkyl. In another embodiment, Y is pyridinyl optionally substituted by —C 1 -C 6 alkyl. In another embodiment, Y is pyridinyl optionally substituted by methyl. In a further embodiment, Y is 5-methyl-pyridinyl.
[0101] In one embodiment, R 13 is —C 1 -C 6 alkyl and L 2 is S, —S(═O) or —S(═O) 2 . In a further embodiment, R 13 is tert-butyl and L 2 is S.
[0102] In one embodiment, R 7 is C 1 -C 6 alkyleneC(═O)OC 1 -C 6 alkyl. In another embodiment, R 7 is C 4 alkyleneC(═O)OC 1-6 alkyl. In another embodiment, R 7 is —CH 2 C(CH 3 ) 2 C(═O)OC 1 -C 6 alkyl. In another embodiment, R 7 is —CH 2 C(CH 3 ) 2 C(═O)OCH 3 . In a further embodiment, R 7 is —CH 2 C(CH 3 ) 2 C(═O)OCH 2 CH 3 .
[0103] In one embodiment, L 10 is aryl, X is a bond and G 6 is heteroaryl. In another embodiment, L 10 is aryl, X is a bond and G 6 is heteroaryl substituted by —OH or —C 1 -C 6 alkoxy. In another embodiment, L 10 is aryl, X is a bond and G 6 is heteroaryl substituted by —OCH 3 or —OCH 2 CH 3 . In another embodiment, L 10 is phenyl, X is a bond and G 6 is heteroaryl substituted by —OCH 3 or —OCH 2 CH 3 . In another embodiment, L 10 is phenyl, X is a bond and G 6 is pyridinyl substituted by —OCH 3 or —OCH 2 CH 3 . In a further embodiment, L 10 is phenyl, X is a bond and G 6 is pyridinyl substituted by —OCH 2 CH 3 .
[0104] In another embodiment, there is provided a process 6 or preparing a compound of formula (IIIa)
[0000]
[0000] comprising the reaction of a compound of formula (IVa)
[0000]
[0000] or a salt thereof;
with a compound of formula (Va)
[0000]
[0000] in the presence of an acid and a solvent.
[0105] In one embodiment of process 5 or 6, the compound of formula (IV) or (IVa) is in the form of a salt or as the free base. In another embodiment, the compound of formula (IV) or (IVa) is the free base. In another embodiment, the compound of formula (IV) or (IVa) is a salt. In another embodiment, the compound of formula (IV) or (IVa) is a salt selected from hydrogen bromide, hydrogen chloride, hydrogen iodide, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, phosphate, citrate, tartrate, formate, acetate and propionate. In a further embodiment, the compound of formula (IV) or (IVa) is salt selected from hydrogen bromide and hydrogen chloride.
[0106] In one embodiment of process 5 or 6, the solvent is selected from a C 1 -C 6 alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, water and mixtures thereof. In another embodiment the solvent is selected from a C 1 -C 6 alcohol, tetrahydrofuran, 2-methyltetrahydrofuran and mixtures thereof. In another embodiment, the solvent is a C 1 -C 6 alcohol selected from ethanol, 2-propanol and mixtures thereof. In a further embodiment the solvent is a mixture of 2-methyltetrahydrofuran, 2-propanol and water.
[0107] In one embodiment of process 5 or 6, the acid is a carboxylic acid. In another embodiment, the carboxylic acid is selected from the group consisting of isobutyric acid, citric acid, tartaric acid, acetic acid, propanoic acid, butanoic acid, dibenzoyl tartaric acid (for example, dibenzoyl tartaric acid monohydrate or dibenzoyl tartaric acid anhydrous), ditoluoyl tartaric acid, malic acid, maleic acid, benzoic acid, 3-phenyl acetic acid, triphenylacetic acid, phtalic acid, 2-hydroxyphenylacetic acid, anthracene-9-carboxylic acid, methoxyacetic acid, tartronic acid, glutaric acid, oxalic acid, trichloroacetic acid, camphoric acid, ethylhexanoic acid, napthylacetic acid and mixtures thereof. In another embodiment, the carboxylic acid is selected from the group consisting of isobutyric acid, citric acid, tartaric acid, acetic acid, propanoic acid, butanoic acid, dibenzoyl tartaric acid (for example, dibenzoyl tartaric acid monohydrate or dibenzoyl tartaric acid anhydrous), ditoluoyl tartaric acid, malic acid, benzoic acid, 3-phenyl acetic acid, triphenylacetic acid, phtalic acid, 2-hydroxyphenylacetic acid, anthracene-9-carboxylic acid, methoxyacetic acid, tartronic acid, glutaric acid and mixtures thereof. In another embodiment, the carboxylic acid is selected from isobutyric acid, citric acid, tartaric acid, acetic acid, propanoic acid, butanoic acid, dibenzoyl tartaric acid (for example, dibenzoyl tartaric acid monohydrate), ditoluoyl tartaric acid and mixtures thereof. In a further embodiment, the acid is a carboxylic acid selected from dibenzoyl tartaric acid (for example, dibenzoyl tartaric acid monohydrate) and isobutyric acid.
[0108] In one embodiment of process 5 or 6, the acid is a mixture of two or more acids. In another embodiment the acid is dibenzoyl tartaric acid in mixture with a co-acid selected from citric acid, maleic acid, oxalic acid, trichloroacetic acid, sodium hydrogen sulphate, camphoric acid, phosphoric acid, potassium dihydrogen phosphate, ethylhexanoic acid, isobutyric acid and napthylacetic acid. In another embodiment the acid is dibenzoyl tartaric in mixture with a co-acid selected from citric acid, trichloroacetic acid, sodium hydrogen sulphate, isobutyric acid and napthylacetic acid. In a further embodiment the acid is dibenzoyl tartaric in mixture with citric acid.
[0109] In one embodiment of process 5 or 6, the reaction is carried out at from about 5° C. to about 70° C. In another embodiment, the reaction is carried out from about 30° C. to about 60° C. In a further embodiment, the reaction is carried out at from about 20° C. to about 50° C.
[0110] It may be possible to recover the acid (e.g. dibenzoyl tartaric acid) or acids (e.g. dibenzoyl tartaric acid and citric acid) by partial removal of residual solvent (e.g. 2-methyltetrahydrofuran) followed by acidification with an acid, such as hydrochloric acid. It may also be possible to extract the acid (e.g. dibenzoyl tartaric acid) or acids (e.g. dibenzoyl tartaric acid and citric acid) into a solvent (e.g. 2-methyltetrahydrofuran) at acidic pH and recycle into another reaction directly, or by crystallising from this solvent (e.g. toluene or benzene) and then re-using.
[0111] In another aspect of the invention there is provided a process 7 for preparing a compound of formula (II)
[0000]
[0000] or a salt thereof;
comprising a process for preparing a compound of formula (IIIa) as defined above, and then converting to a compound of formula (II) or a salt thereof.
[0112] In one embodiment there is provided a process 7 for preparing a compound of formula (II) or a salt thereof. In a further embodiment there is provided a process 7 for preparing a compound of formula (II).
[0113] In one aspect of the invention process 7 is telescoped, wherein the compound of formula (IIIa) is not isolated.
[0114] In one embodiment of the invention there is provided a telescoped process 7A for preparing a compound of formula (II)
[0000]
[0000] or a salt thereof;
comprising a process for preparing a compound of formula (IIIa) as defined above, followed by ester hydrolysis with a base, in the presence of a C 1 -C 6 alcohol and a tetrahydrofuran as solvent, and then converting to a compound of formula (II) or a salt thereof.
[0115] In one embodiment of the invention there is provided a telescoped process 8A for preparing a compound of formula (I)
[0000]
[0000] comprising a process for preparing a compound of formula (IIIa) as defined above, followed by ester hydrolysis with a base, in the presence of a C 1 -C 6 alcohol and a tetrahydrofuran as solvent, and then converting to a compound of formula (I).
[0116] In one embodiment of process 7A or process 8A, the reaction is carried out at from about 5° C. to about 70° C. In a further embodiment, the reaction is carried out at from about 30° C. to about 55° C.
[0117] In one embodiment, the base is selected from MOH wherein M is selected from Li (lithium), Na (sodium), K (potassium) and Cs (caesium); M′(OH) 2 wherein M′ is selected from Ca (calcium) and Ba (barium). In a further embodiment, the base is NaOH (sodium hydroxide).
[0118] In one embodiment the solvent is a mixture of a C 1 -C 6 alcohol and a tetrahydrofuran. In another embodiment the solvent is a mixture of a C 1 -C 6 alcohol and 2-methyltetrahydrofuran. In a further embodiment the solvent is a mixture of 2-propanol and 2-methyltetrahydrofuran.
[0119] 2-Methyltetrahydrofuran is known to be a ‘green’ alternative to tetrahydrofuran. Unlike tetrahydrofuran, 2-methyltetrahydrofuran is obtained from renewable sources such as agricultural by-products. Reduced miscibility with water when compared with tetrahydrofuran is also an advantage when considering solvent recovery opportunities.
[0120] It may be possible to recover the 2-methyltetrahydrofuran and 2-propanol solvent. A standard distillation would offer efficient separation but the use of a membrane separation as described above for Process 3, may offer an even more efficient recovery. Such solvent recovery would avoid incineration of solvent and hence a reduction in CO 2 emissions from fossil fuel combustion, and a reduction in cost of goods.
[0121] In a further aspect of the invention there is provided a process 8 for preparing a compound of formula (I)
[0000]
[0000] comprising a process for preparing a compound of formula (IIIa) as defined above, and then converting to a compound of formula (I).
[0122] Compounds of formula (V) and (Va) may be prepared using methods similar to those described in U.S. Pat. No. 5,288,743. Alternatively the compound of formula (Va) is commercially available and may be purchased from, for example, Aurora Screening Library.
[0123] Compounds of formula (IV) and (IVa) may be prepared using methods similar to those described in UK Patent Application No. GB 2 265 621A.
[0124] Alternatively, the compound of formula (IVa) may be prepared by the reaction of a compound of formula (VII)
[0000]
[0000] or a salt thereof;
wherein L is a leaving group;
with a compound of formula (VI)
[0000]
[0000] or a salt thereof;
in the presence of a base and a suitable solvent.
[0125] In one embodiment, L is selected from chlorine and bromine. In another embodiment, L is bromine. In a further embodiment, L is chlorine.
[0126] In one embodiment, the base is selected MOH, M 2 CO 3 and MHCO 3 wherein M is selected from Li (lithium), Na (sodium), K (potassium) and Cs (caesium); 1,8-diazabicyclo[5.4.0]undec-7-ene; and R′R″R″′N wherein R′, R″ and R″′ are each independently C 1 C 6 alkyl. In another embodiment, the base is MOH. In another embodiment the base is NaOH (sodium hydroxide). In another embodiment the base is KOH (potassium hydroxide). In another embodiment, the base is R′R″R″′N wherein R′, R″ and R″′ are each independently C 1 -C 6 alkyl. In a further embodiment, the base is R′R″R″′N and R′, R″ and R″′ are each ethyl.
[0127] In one embodiment, the base is present to neutralise or part neutralise any acid. In one embodiment the pH of the mixture is ≧4.0. In another embodiment the pH of the mixture is from about 6 to 7.5.
[0128] In one embodiment, the reaction is carried out at from about 15° C. to about 21° C. when L is bromine. In another embodiment, the reaction is carried out at from about 40° C. to about 50° C. when L is chlorine.
[0129] In one embodiment, there is provided a process for preparing a compound of formula (IVa) wherein the solvent is selected from water, C 1 -C 6 alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dichloromethane and mixtures thereof. In another embodiment, the solvent is C 1 -C 6 alcohol. In another embodiment, the solvent is selected from C 1 -C 6 alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dichloromethane and mixtures thereof. In another embodiment, the solvent is C 1 -C 6 alcohol. In another embodiment, the solvent is selected from ethanol, 1-propanol, 2-propanol, 2-butanol, sec-butanol and mixtures thereof. In another embodiment, the solvent is 2-propanol. In another embodiment, the solvent is 2-propanol and water. In another embodiment the solvent is water. In a further embodiment, the solvent is tetrahydrofuran.
[0130] In one embodiment, the compound of formula (VII) is in the form of a salt or as the free base. In another embodiment, the compound of formula (VII) is the free base. In another embodiment the compound of formula (VII) is a salt. In another embodiment, the compound of formula (VII) is a salt selected from hydrogen bromide, hydrogen chloride, hydrogen iodide, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and phosphate. In a further embodiment, the compound of formula (VII) is a salt selected from hydrogen bromide and hydrogen chloride.
[0131] In one embodiment, the compound of formula (VI) is in the form of a salt or as the free base. In another embodiment, the compound of formula (VI) is the free base. In another embodiment, the compound of formula (VI) is a salt. In a further embodiment, the compound of formula (VI) is the dihydrogen chloride salt.
[0132] The compound of formula (VI) may be prepared by the reaction of a compound of formula (VIII)
[0000]
[0000] or a salt thereof;
with aqueous sodium nitrite in the presence of hydrochloric acid to form the diazonium salt followed by reduction of the diazonium salt. In one embodiment, the diazonium salt is reduced with an agent selected from ascorbic acid, sodium sulphite, sodium metabisulfite and sodium hydrosulfite. In another embodiment, the diazonium salt is reduced with sodium hydrosulfite
[0133] In one embodiment, the compound of formula (VIII) is in the form of a salt or as the free base. In another embodiment, the compound of formula (VIII) is the free base. In another embodiment, the compound of formula (VIII) is a salt. In another embodiment, the compound of formula (VIII) is a salt selected from hydrogen bromide, hydrogen chloride, hydrogen iodide, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, phosphate, citrate, tartrate, formate, acetate and propionate. In a further embodiment, the compound of formula (VIII) is salt selected from hydrogen bromide and hydrogen chloride.
[0134] In one embodiment, the process by which the diazonium salt is formed is carried out at from about 0° C. to about 5° C.
[0135] In one embodiment the addition of sodium hydrosulfite is carried out at <10° C.
[0136] In one aspect of the invention the process for preparing a compound of formula (IV) and the process for preparing a compound of formula (VI) are telescoped, wherein the compound of formula (VI) is not isolated.
[0137] In one embodiment of the invention there is provided a telescoped process 1A for preparing a compound of formula (II)
[0000]
[0000] or a salt thereof;
comprising a process for preparing a compound of formula (VI) as defined above, followed by a process for preparing a compound of formula (IVa) as defined above, wherein the compound of formula (VI) is not isolated, and then converting to a compound of formula (II).
[0138] In one embodiment of the invention there is provided a telescoped process 2A for preparing a compound of formula (I)
[0000]
[0000] comprising a process for preparing a compound of formula (VI) as defined above, followed by a process for preparing a compound of formula (IVa) as defined above, wherein the compound of formula (VI) is not isolated, and then converting to a compound of formula (I).
[0139] The compound of formula (VIII) may be prepared by the reaction of a compound of formula (IX)
[0000]
[0000] or a salt thereof; with sodium hydroxide in an alcoholic solvent, such as ethanol. In one embodiment the mixture is heated under reflux. The hydrogen chloride salt may then be made by addition of hydrogen chloride in a non-aqueous solvent such as an alcohol, for example, 2-propanol.
[0140] The compound of formula (IX) may be prepared by the reaction of a compound of formula (XI)
[0000]
[0000] or a salt thereof; with a compound of formula (XII)
[0000]
[0000] or a salt thereof;
in the presence of a base, and a solvent. In one embodiment, the base is potassium carbonate. In one embodiment, the solvent is ethanol. In one embodiment, the reaction is heated under reflux.
[0141] Alternatively, the compound of formula (VIII) may be prepared by the reduction of a compound of formula (XVI)
[0000]
[0000] or a salt thereof; with hydrogen in the presence of palladium in a solvent, such as tetrahydrofuran. The hydrogen chloride salt may then be made by addition of hydrogen chloride in a non-aqueous solvent such as an alcohol, for example, 2-propanol.
[0142] The compound of formula (XVI) may be prepared by the reaction of a compound of formula (XV)
[0000]
[0000] or a salt thereof; with a compound of formula (XII)
[0000]
[0000] or a salt thereof;
in the presence of a base, and a solvent. In one embodiment, the base is potassium carbonate. In one embodiment, the solvent is dimethylsulfoxide. In one embodiment, the reaction is heated at from 60 to 70° C.
[0143] In one embodiment, the compound of formula (XII) is in the form of the hydrochloride salt. The compound of formula (XI) is commercially available and may be purchased from, for example, Aldrich, Fischer Scientific and Univar Limited.
[0144] The compound of formula (XV) is commercially available and may be purchased from, for example, Aldrich.
[0145] The compound of formula (XII) is commercially available and may be purchased from, for example, Anichem.
[0146] In one embodiment, the compound of formula (VII) is prepared via a nucleophilic substitution reaction comprising the reaction of a compound of formula (X)
[0000]
[0000] or a salt thereof;
with, when L is bromine, aqueous or anhydrous hydrogen bromide, or where L is chlorine, aqueous or anhydrous hydrogen chloride, cyanuric chloride, thionyl chloride or phosphoryl chloride. In another embodiment the compound of formula (VII) is prepared via a nucleophilic substitution reaction comprising the reaction of a compound of formula (X) or a salt thereof; with aqueous hydrogen bromide (wherein L is bromine) or hydrogen chloride (wherein L is chlorine). In a further embodiment the compound of formula (VII) is prepared via a nucleophilic substitution reaction comprising the reaction of a compound of formula (X) or a salt thereof; with cyanuric chloride (wherein L is chlorine).
[0147] In one embodiment, the compound of formula (X) is in the form of a salt or as the free base. In another embodiment, the compound of formula (X) is the free base. In another embodiment, the compound of formula (X) is a salt. In another embodiment, the compound of formula (X) is a salt selected from hydrogen bromide, hydrogen chloride, hydrogen iodide, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and phosphate. In a further embodiment, the compound of formula (X) is a salt selected from hydrogen bromide and hydrogen chloride.
[0148] When L is bromine, the process may be carried out at from about 44° C. to about 50° C. When L is chlorine, the chlorinating agent is added at 5 20° C. and the mixture then heated at from about 20° C. to about 35° C.
[0149] Alternatively the compound of formula (VII) may be prepared via a nucleophilic substitution reaction comprising the reaction of a compound of formula (X)
[0000]
[0000] or a salt thereof;
with acetic acid and hydrogen bromide.
[0150] In one embodiment, the compound of formula (X) is in the form of a salt or as the free base. In another embodiment, the compound of formula (X) is the free base. In another embodiment, the compound of formula (X) is a salt. In another embodiment, the compound of formula (X) is a salt selected from hydrogen bromide, hydrogen chloride, hydrogen iodide, p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate and phosphate. In a further embodiment, the compound of formula (X) is a salt selected from hydrogen bromide and hydrogen chloride.
[0151] The process may be carried out at from about 44° C. to about 50° C.
[0152] The compound of formula (X) may be prepared by a Suzuki cross-coupling reaction comprising the reaction of a compound of formula (XIII)
[0000]
[0000] or a salt thereof;
with a compound of formula (XIV)
[0000]
[0000] or a salt thereof;
in the presence of a base, aqueous alcoholic solvent and palladium on carbon. In one embodiment the mixture is heated under reflux. In another embodiment, the compound of formula (X) may be prepared by any suitable cross-coupling reaction known to one skilled in the art using appropriate starting materials for example, Kumada-Corriu, Suzuki-Miyaura, Negishi and Stille,
[0153] In one embodiment the reaction is seeded with the compound of formula (X). It should be noted that the compound of formula (X) will still be produced without seeding.
[0154] In one embodiment, the base is selected from sodium carbonate, sodium hydroxide and potassium carbonate. In a further embodiment, the base is sodium carbonate.
[0155] In one embodiment, the aqueous alcohol solvent is selected from methanol, ethanol and propanol. In a further embodiment, the aqueous alcohol solvent is ethanol.
[0156] The compound of formula (XIII) is commercially available and may be purchased from, for example, Archimica.
[0157] The compound of formula (XIV) is commercially available and may be purchased from, for example, Aldrich and Manchester Organics.
[0158] The term “aryl” refers to a C 5 -C 10 aromatic group which has at least one ring having a conjugated pi electron system and includes both monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups. Examples include phenyl and naphthalene.
[0159] The term “alkylene” refers to a divalent C 1 -C 6 straight or branched hydrocarbon chain.
[0160] The term “alkyl” as used herein as a group or a part of a group refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms. For example, C 1 -C 6 alkyl means a straight or branched alkyl containing at least 1, and at most 6, carbon atoms. Examples of “alkyl” as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, t-butyl and hexyl.
[0161] The term “alkoxy” as used herein as a group or a part of a group refers to a —O(alkyl) group, where “alkyl” is as defined herein.
[0162] The term “alcohol” as used herein refers to an alkyl group substituted by a hydroxyl (-OH) group, where “alkyl” is as defined herein. Examples of “alcohol” as used herein include, but are not limited to, methanol, ethanol, propanol and butanol.
[0163] The term “cycloalkyl” refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, partially unsaturated, or fully unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include the following moieties:
[0000]
[0000] and the like.
[0164] The term “cycloheteroalkyl” refers to a C 5 -C 6 cycloalkyl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Examples of cycloheteroalkyl groups include tetrahydropyran, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, morpholine, 1,4-dioxane, thiomorpholine, 1,4-oxathiane and 1,4-dithane.
[0165] The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromo or iodo.
[0166] The term “heteroaryl” refers to an aryl or biaryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. An N-containing “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. Examples of heteroaryl groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Illustrative examples of heteroaryl groups include the following moieties:
[0000]
[0000] and the like.
EXAMPLES
Abbreviations
[0000]
TBME methyl-tert-butylether
DMSO dimethylsulphoxide
min minutes
NMP N-methyl pyrrolidine
h hours
HPLC high performance liquid chromatography
IPA isopropyl alcohol
2-MeTHF 2-methyltetrahydrofuran
THF tetrahydrofuran
DSC differential scanning calorimetry
XRPD X-ray powder diffraction
When the term “degassed” is used, this refers to cycles of vacuum/nitrogen purging, with the number of cycles depicted in parentheses.
Step 1: 5-[4-(Hydroxymethyl)phenyl]-2-(ethyloxy)pyridine
[0178]
[0179] A suspension of 4-(hydroxymethyl)phenyl]boronic acid (14 kg), 5-bromo-2-(ethyloxy)pyridine (19.6 kg), sodium carbonate (11.4 kg) in ethanol (169.4L) and water (49.4L) was stirred under vacuum and then purged with nitrogen twice. A suspension of 10% palladium on carbon (50% wet, 4.6 kg) was added followed by water (7 L), and the suspension was degassed (3×) under nitrogen. The reaction mixture was heated to 63±3° C. and then heated to reflux and stirred for 5 h. The catalyst was filtered off at 57-63° C., and the cake washed with ethanol (28 L). The reaction was concentrated to ca.140 L by atmospheric distillation, cooled to 57±3° C. and water (28 L) added, maintaining >54° C. The reaction was cooled to 53±3° C. and seeded with 5-[4-(hydroxymethyl)phenyl]-2-(ethyloxy)pyridine (70 g) as a slurry in ethanol/water (1:1, 200 mL). After 2 h 10 min water (14 L) was added, maintaining the temperature at 53±3° C. and then cooled to 2±3° C. over about 4.5 hours followed by a 0.5h age. The product was isolated by filtration, washed with ethanol/water (1:1, 140 L) at 2±3° C., followed by water (3×93 L) and dried at 40-50° C. under vacuum to give the title product (19.0 kg, 90% th) as a white solid.
[0180] 1 H NMR (400 MHz, CHLOROFORM-D) δppm 8.19 (1H, d, J=2.4 Hz); 7.71 (1H, dd, J=8.6, 2.7 Hz); 7.41 (2H, d, J=8.2 Hz); 7.37 (2H, d, J=8.2 Hz); 6.75 (1H, d, J=8.8 Hz); 4.68 (2H, d, J=5.6 Hz); 4.36 (2H, q, J=7.1 Hz); 3.44 (1H, t, J=5.9 Hz); 1.40 (3H, t, J=7.1 Hz).
Step 2: 5-[4-(Bromomethyl)phenyl]-2-(ethyloxy)pyridine
[0181]
[0182] 5[4-(hydroxymethyl)phenyl]-2-(ethyloxy)pyridine (47 kg) was stirred and heated to 47±3° C. in hydrogen bromide (48 wt % aq., 709 kg). After about 7 h at this temperature the reaction was cooled to 20±3° C. over 2 h, water (470 L) was then added and the mixture stirred for 1 h. The product was isolated by filtration and the slurry was washed with water (472 kg), aqueous sodium bicarbonate (23.5 kg in 706 kg water) followed by a displacement wash of water (475 kg). The white solid was dried at 30±5° C. under vacuum to give the title product (58.15 kg, 97%) as a white solid.
[0183] 1 H NMR (400 MHz, DMSO-D6) δppm 8.49 (1H, d, J=2.4 Hz); 8.01 (1H, dd, J=8.7, 2.6 Hz); 7.66 (2H, d, J=8.3 Hz); 7.54 (2H, d, J=8.3 Hz); 6.89 (1H, d, J=8.8 Hz); 4.77 (2H, s); 4.36 (2H, q, J=7.0 Hz); 1.35 (3H, t, J=7.1 Hz).
Step 2A: 5-[4-(bromomethyl)phenyl]-2-(ethyloxy)pyridine hydrobromide
[0184] All weights, volumes and equivalents are relative to 5-[4-(hydroxymethyl)phenyl]-2-(ethyloxy)pyridine. 5[4-(hydroxymethyl)phenyl]-2-(ethyloxy)pyridine (0.910 kg) was heated to 45±3° C. in glacial acetic acid (2.5 vol, 2.28 L). 33wt % hydrogen bromide in acetic acid (2.4 vol, 2.18 L) was added maintaining the temperature below 55° C. After 4 h at 45±3° C., diisopropyl ether (3.0 vol, 2.70 L) was added and the mixture aged 30 min. Diisopropylether (7.0 vol, 6.37 L) was added then the slurry was cooled to 3±3° C. and stirred for 1 h. The product was isolated by filtration and washed three times with diisopropyl ether (6vol, 5.46 L). The material was dried at 40±5° C. under vacuum to give the title product (1.43 kg, 96%) as a white solid.
[0185] 1 H NMR (400 MHz, CHLOROFORM-D) δppm 8.65 (1H, d, J=2.20 Hz); 8.39 (1H, dd, J=9.05, 2.45 Hz); 7.52-7.58 (4H, m); 7.29 (1H, d, J=9.05 Hz); 4.83 (2H, q, J=6.93 Hz); 4.54 (2H, s); 1.61 (3H, t, J=7.09 Hz).
Step 2B: 5-[4-(chloromethvl)phenyl]-2-(ethyloxy)pyridine
[0186]
[0187] 5-[4-(Hydroxymethyl)phenyl]-2-(ethyloxy)pyridine (1.0 kg., 1.00 eq.) was dissolved in tetrahydrofuran (2.5 L) and dimethyl sulfoxide (0.5 L) under an atmosphere of nitrogen. The mixture was cooled to 0±3° C. and cyanuric chloride (320 g, 0.40 eq.) was added maintaining the internal temperature below 20° C. The mixture was heated to 23±3° C. and stirred until there was less than 2.0% a/a 5[4-(hydroxymethyl)phenyl]-2-(ethyloxy)pyridine by HPLC analysis. The slurry was filtered and the cake washed with tetrahydrofuran (0.5 L) and iso-propanol (5.0 L). Water (14 L) was added to the combined filtrate, maintaining the temperature below 35° C. The resulting slurry was cooled to 23±3° C., aged and filtered. The cake was washed with water (3×10 L), pulled dry and dried at 45±5° C. in a vacuum oven to give the title compound (959 g, 89%) as a white powder.
[0188] 1 H NMR (400 MHz, DMSO-d 6 ) d ppm 8.48 (1 H, d, J=2.45 Hz) 8.00 (1 H, dd, J=8.68, 2.57 Hz) 7.67 (2 H, d, J=8.07 Hz) 7.52 (2 H, d, J=8.07 Hz) 6.88 (1 H, d, J=8.56 Hz) 4.81 (2 H, s) 4.36 (2 H, q, J=7.09 Hz) 1.34 (3 H, t, J=6.97 Hz).
Step 3: 4-{[(5-Methylpyridin-2-yl)methyl]oxy}aniline dihydrochloride
[0189]
[0190] N-(4-Hydroxyphenyl)acetamide (25.0 kg) and potassium carbonate (50.0 kg) were mixed in ethanol (187.5 L) at 22±3° C. and 2-(chloromethyl)-5-methylpyridine hydrochloride (32.5 kg) was added portionwise at 22±3° C. The mixture was then heated to reflux for 15 h. The reaction was then cooled to 57±3° C. and water (162.5 L) added maintaining this temperature. The organic and aqueous phases were allowed to separate and the lower aqueous layer was removed. The organic layer was then washed with aqueous potassium carbonate (20% w/v, 114 kg) at 57±3° C. Sodium hydroxide (50% w/v, 57.8 kg) was then added together with ethanol (12.5 L) and the reaction stirred at reflux for about 38 h. The reaction was cooled to 57±3° C. and the lower aqueous phase was removed. The organic layer was concentrated to ˜125 L by atmospheric distillation, 2-butanol (250 L) was then added and the concentration repeated. The reaction was then cooled to 22±3° C., further 2-butanol (125 L) was added and the mixture washed with water (75 L) at 50±3° C., followed by aqueous sodium chloride (5% w/w, 78 kg) at 50±3° C. The reaction was concentrated to 125 L by atmospheric distillation, further 2-butanol (125 L) was then added and the concentration repeated. 2-Propanol (150 L) was then added followed by hydrogen chloride (5 M -6 M in 2-propanol, 89.5 kg) over 2 hours at 76±3° C. The resulting slurry was then cooled to 22±3° C. over about 3.5 h, aged for about 40 min and the product isolated by filtration, washed with 2-propanol (2×200 L) follow by TBME (200 L) and dried at 40-50° C. under vacuum to give the title product (40.25 kg, 85% th).
[0191] 1 H NMR (400 MHz, DMSO-D6) δppm 8.74 (1H, s); 8.28 (1H, dd, J=8.2, 1.3 Hz); 7.91 (1H, d, J=8.1 Hz); 7.38-7.42 (2H, m); 7.17-7.21 (2H, m); 5.46 (2H, s); 2.45 (3H, s).
Step 3A: Alternative Synthesis of 4-{[(5-methylpyridin-2-yl)methyl]oxy}aniline dihydrochloride
[0192] 4-Nitrophenol (43 kg) and potassium carbonate (150 kg) were slurried in dimethylsulfoxide (217 L) under an atmosphere of nitrogen. 2-(Chloromethyl)-5-methylpyridine hydrochloride (58 kg) was added to the slurry and the mixture heated to 65±3° C. and stirred for 3 h. Water (866 L) was added maintaining the temperature above 55° C., the slurry was aged for 1 h, cooled to 20±3° C. over 2 h and aged for 1 h. The slurry was filtered and the solid washed with water (433 L), followed by aqueous iso-propanol (50% v/v, 2×433L) and water (2×346 L). The cake was blown with 2 barg nitrogen for 6 h to yield 5-methyl-2-[(4-nitrophenoxy)methyl]pyridine.
[0193] The 5-methyl-2-[(4-nitrophenoxy)methyl]pyridine (86.2 kg)* was dissolved in tetrahydrofuran (700 L) and 10% palladium on carbon (50% aqueous paste, 1.7kg) was added. The vessel was purged with nitrogen before three vacuum/nitrogen cycles, followed by three vacuum/hydrogen cycles. An atmosphere of 2 barg hydrogen was placed on the vessel and the mixture stirred vigorously at 23±3° C. for 8 h and the mixture filtered to remove palladium. The filter was washed with tetrahydrofuran (350 L) followed by iso-propanol (350 L) and the combined filtrate distilled to 420 L. iso-Propanol (700 L) was added, the solution distilled to 420L vol and iso-propanol (980 L) added. Hydrochloric acid in iso-propanol (5.5 mol dm −3 , 156 L) was added over 1 h, maintaining the temperature at 70±3° C. The slurry was aged for 1 h, cooled to 20±3° C. over 3 h and aged for 1 h. The slurry was filtered and the product washed with iso-propanol (2×700L), methyl tert-butyl ether (560 L) and dried in a vacuum oven at 55° C. to yield the title product (79 kg, 88% th).
[0194] 1 H NMR (400 MHz, DMSO-D6) δppm 10.5 (2H, s, br); 8.70 (1H, s); 8.22 (1H, d, J=8.1 Hz); 7.86 (1H, d, J=8.1 Hz); 7.36-7.42 (2H, m); 7.15-7.22 (2H, m); 5.43 (2H, s); 2.44 (3H, s).
[0195] *KF analysis shows water content of 18.9%; dry weight equivalent 70 kg.
Steps 4 and 5: 2-(Ethyloxy)-5-(4-{[1-(4-{[(5-methylpyridin-2-yl)methyl]oxy}phenyl)hydrazino]methyl}phenyl)pyridine
[0196]
[0197] Aqueous sodium nitrite (39.0 kg, 33% w/w) was added at 0-5° C. to a solution of (4-{[(5-methylpyridin-2-yl)methyl]oxy}anilinedihydrochloride (39.0 kg in water 155.8 L) and aqueous hydrogen chloride (conc., 29.6 kg) and washed in with water (7.8 L). This solution was then added at 0-10° C. to a degassed (3×) slurry of sodium hydrosulfite (71 kg) and sodium hydroxide (2.7 kg) in water (155.8 L) followed by a line wash of water (12 L). The resulting mixture was stirred for about 30 min and then warmed to 18±3° C. 2-Propanol (306.5 kg) was added and the pH adjusted to 7.0 using sodium hydroxide (20% w/w, 150.6 kg) maintaining the temperature below 25° C. The layers were allowed to separate and the lower aqueous phase removed. Sodium hydroxide (10% w/w, 78.1 kg) was added followed by 5-[4-(bromomethyl)phenyl]-2-(ethyloxy)pyridine (39.8 kg) and a 2-propanol line wash (3.9 L), and the reaction stirred at 18±3° C. for about 3.5 h. Water (97.5 L) and methanol (195 L) were then added, the mixture stirred for about 12 h and the product isolated by filtration. The crude product was slurry washed with 2-propanol: water (1-1,390 L) followed by two washes with water (2× about 390 kg), then methanol (309 kg) and finally dried at 40-50° C. under vacuum to give the title product (46.45 kg, 77.6% th, ˜93-94% pure by HPLC).
[0198] 1 H NMR (500 MHz, DMSO-D6) δppm 8.44 (1H, d, J=2.4 Hz); 8.39 (1H, s); 7.97 (1H, dd, J=8.5, 2.7 Hz); 7.62 (1H, dd, J=7.9, 1.5 Hz); 7.59 (2H, d, J=8.2 Hz); 7.37 (3H, t, J=8.5 Hz); 6.97 (2H, d, J=9.2 Hz); 6.82-6.88 (3H, m); 5.02 (2H, s); 4.52 (2H, s); 4.34 (2H, q, J=7.0 Hz); 4.18 (2H, s); 2.29 (3H, s); 1.33 (3H, t, J=7.0 Hz).
Purification of 2-(ethyloxy)-5-(4-{[1-(4-{[5-methylpyridin-2-yl)methyl]oxy}phenyl)hydrazino]methyl}phenyl)pyridine
[0199] 2-(Ethyloxy)-5-(4-{[1-(4-{[(5-methyl-2-pyridinyl)methyl]oxy}phenyl)hydrazino]methyl}phenyl)pyridine (50.2 kg) was dissolved in degassed (3×) NMP (210 kg) at 45±3° C., methanol (502 L) was then added maintaining the batch temperature at 43±3° C. and then aged for 30min. The slurry was then cooled to 5±3° C. over about 3 h, aged for 1 h, filtered, washed with methanol (2×198 kg) and then dried at 40-50° C. under vacuum to give the title product (44.9 kg, 89% th).
[0200] 1 H NMR (500 MHz, DMSO-D6) δppm 8.45 (1H, d, J=2.1 Hz); 8.39 (1H, s) 7.97 (1H, dd, J=8.7, 2.6 Hz); 7.62 (1H, dd, J=8.1, 1.4 Hz); 7.59 (2H, d, J=8.2 Hz); 7.38 (3H, t, J=8.2 Hz); 6.98 (2H, d, J=9.2 Hz); 6.82-6.88 (3H, m); 5.03 (2H, s); 4.53 (2H, s); 4.34 (2H, q, J=7.0 Hz); 4.19 (2H, s); 2.29 (3H, s); 1.34 (3H, t, J=7.0 Hz).
Steps 4A and 5A: Alternative Synthesis of 2-(ethyloxy)-5-(4-{[1-(4-{[(5-methylpyridin-2-yl)methyl]oxy}phenyl)hydrazino]methyl}phenyl)pyridine
[0201] Sodium nitrite (2.47 g) was dissolved in water (10 mL) and added at 0-5° C. to a solution of 4-{[(5-methylpyridin-2-yl)methyl]oxy}aniline dihydrochloride (10 g in water 40 mL) and aqueous hydrogen chloride (conc., 6.4 mL). This solution was then added at <10° C. to a degassed slurry of sodium hydrosulfite (18.2 g) and sodium hydroxide (6.2 mL, 10 wt %) in water (34 mL). The resulting mixture was stirred for 10 min and then warmed to 18±3° C. 2-Propanol (100 mL) was added and the pH adjusted to 7.0 using sodium hydroxide (20 wt %) maintaining the temperature below 25° C. The layers were allowed to separate and the lower aqueous phase removed. Sodium hydroxide (10 wt %, 29 mL) was added followed by 5-[4-(bromomethyl)phenyl]-2-(ethyloxy)pyridine (12.6 g) and the reaction stirrer at 18±3° C. for >2 h. Water (20 mL) and methanol (50 mL) were then added and the product was isolated by filtration. The crude product was then washed with 2-propanol: water (1-1, 100 mL) followed by water (100 mL), and then methanol (100 mL) and finally dried at ca. 45° C. under vacuum to give the title product (11.5 g, 75% th).
[0202] 1 H NMR (400 MHz, CHLOROFORM-D) δppm 8.42 (1H, s); 8.36 (1H, d, J=2.45 Hz); 7.78 (1H, dd, J=8.56, 2.45 Hz); 7.47-7.54 (3H, m); 7.40 (3H, dd); 7.04-7.10 (2H, m); 6.91-7.00 (2H, m); 6.79 (1H, d, J=8.56 Hz); 5.14 (2H, s); 4.49 (2H, s); 4.40 (2H, q, J=7.09 Hz); 3.51 (2H, s); 2.34 (3H, s); 1.43 (3H, t, J=7.09 Hz).
Step 4B: Alternative Synthesis of 2-{[(4-hydrazinophenyl)oxy]methyl}-5-methylpyridine dihydrochloride
[0203]
[0204] Aqueous sodium nitrite (187.8 g in 0.76 L) was added at 0-5° C. to a solution of (4-{[(5-methylpyridin-2-yl)methyl]oxy}aniline dihydrochloride (760.2 g) and aqueous hydrogen chloride (conc., 487 mL) in water (3.04 L). This solution was then added at <10° C. to a degassed slurry of sodium hydrosulfite (1380 g) and sodium hydroxide (53.2 g) in water (3.04 L).
[0205] The resulting mixture was stirred for 30min and then warmed to 18±3° C. The product was extracted in to ethyl acetate (9.5 L) at pH 8-9 using 32% sodium hydroxide. The organic layer was washed with water (2.28 L) and then hydrogen chloride in IPA (5-6 m, 1.29 L) was added over 1 h. The batch was cooled to 5±3° C. over 2h, aged, filtered and the cake washed with IPA (7.6 L), then TBME (5.32 L) and finally dried at 25° C. under vacuum to give the title product (723 g, 90.4% th).
[0206] 1 H NMR (500MHz, DMSO-D6) δppm 10.22 (3H, s); 8.71 (1H, s); 8.24 (1H, d, J=7.93 Hz); 7.87 (1 H, d, J=8.24 Hz); 7.00-7.06 (4H, m); 5.37 (2H, s); 2.45 (3H, s).
Step 5B: Alternative Synthesis of 2-(ethyloxy)-5-(4-{[1-(4-{[(5-methylpyridin-2-yl)methyl]oxy}phenyl)hydrazino]methyl}phenyl)pyridine
[0207]
[0208] To a slurry of 2-{[4-hydrazinophenyl)oxy]methyl}-5-methylpyridine (400 g) in 2-propanol (3.8 L) was added sodium hydroxide (2M, 2 L) followed by 5-[4-(bromomethyl)phenyl]-2-(ethyloxy)pyridine (380 g) at 18±3° C. After 2 h methanol (2 L) and water (2 L) were added and the slurry cooled to 5±3° C. The slurry was filtered and washed with methanol (2 L), water (2 L), then finally methanol (3 L) before being dried at 45-55° C. under vacuum to give the title product (505 g, 87% th).
Purification of 2-(ethyloxy)-5-(4-{[1-(4-{[(5-methylpyridin-2-yl)methyl]oxy}phenyl)hydrazino]methyl}phenyl)pyridine
[0209] The crude product, 2-(ethyloxy)-5-(4-{[1-(4-{[(5-methylpyridin-2-yl)methyl]oxy}phenyl)hydrazino]methyl}phenyl)pyridine (495 g), was dissolved in degassed NMP (1.98 L) at 45±3° C., methanol (4.95 L) was then added maintaining the temperature at 40-48° C. After 30 min the slurry was cooled to 5±3° C. over 2 h, aged for 1 h and then filtered and washed with methanol (2×2.5L) then dried at 40-50° C. under vacuum to give the title product (411 g, 82.9%).
[0210] 1 H NMR (400 MHz, DMSO-D6) δppm 8.45 (1H, d, J=2.69 Hz); 8.39 (1H, d, J=2.20 Hz); 7.98 (1H, dd, J=8.68, 2.57 Hz); 7.62 (1H, dd, J=8.31, 1.96 Hz); 7.59 (2H, d, J=8.31 Hz); 7.38 (3H, t, J=7.46 Hz); 6.95-7.00 (2H, m); 6.84-6.88 (3H, m); 5.03 (2H, s); 4.53 (2H, s); 4.34 (2H, q, J=6.93 Hz); 4.20 (2H, s); 2.30 (3H, s); 1.34 (3H, t, J=7.09 Hz).
Steps 4B and 5B: Alternative Synthesis of 2-(ethyloxy)-5-(4-{[1-(4-{[(5-methylpyridin-2-yl)methyl]oxy}phenyl)hydrazino]methyl}phenyl)pyridine
[0211] Sodium nitrite (0.19 kg) was dissolved in water (0.8 L) and added at 0-5° C. to a solution of 4-{[(5-methylpyridin-2-yl)methyl]oxy}aniline dihydrochloride (0.80 kg) in water (3.2 L) and aqueous hydrogen chloride (conc., 0.51 L), washing in with further water (0.4 L). This solution was then added at 0±3° C. to a degassed (3×) slurry of sodium hydrosulfite (1.46 kg) and potassium hydroxide (0.080 kg) in water (3.2 L), washing in with further water (1.2 L). 2-Propanol (4 L), potassium hydroxide (1.10 kg) and 5-[4-(chloromethyl)phenyl]-2-(ethyloxy)pyridine (0.67 kg) were added and the reaction heated to 45±5° C. for ca. 4 h. Volatiles (ca. 4 L) were removed by distillation under vacuum and 2-methyltetrahydrofuran (9.6 L) was added. The reaction was heated to 63±3° C. and the lower aqueous phase removed. The organic phase was washed with water (3.2 L) at 63±3° C., then 2-propanol (9.6 L) was added at 55±5° C. The resulting slurry was cooled to 20±3° C. and the solids collected by filtration. The filter cake was washed twice with 2-propanol (4 L) and dried at ca. 45° C. under vacuum to give the title product (0.953 kg, 78% th.) with >99% area purity by HPLC.
[0212] 1 H NMR (400 MHz, CHLOROFORM-D) δppm 8.42 (1H, s); 8.36 (1H, d, J=2.45 Hz); 7.78 (1H, dd, J=8.56, 2.45 Hz); 7.47-7.54 (3H, m); 7.40 (3H, dd); 7.04-7.10 (2H, m); 6.91-7.00 (2H, m); 6.79 (1H, d, J=8.56 Hz); 5.14 (2H, s); 4.49 (2H, s); 4.40 (2H, q, J=7.09 Hz); 3.51 (2H, s); 2.34 (3H, s); 1.43 (3H, t, J=7.09 Hz).
Step 6: ethyl 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methylpyridin-2-yl)methoxy)-1H-indol-2-yl]-2,2-dimethyl-propanoate
[0213]
[0214] To a degassed slurry of 2-(ethyloxy)-5-(4-{[1-(4-{[(5-methylpyridin-2-yl)methyl]oxy}phenyl)hydrazino]methyl}phenyl)pyridine (43.0 kg) and ethyl 5-[(1,1-dimethylethyl)thio]-2,2-dimethyl-4-oxopentanoate (39.6 kg) in 2-propanol (344 L) was added a degassed slurry of dibenzoyl tartaric acid monohydrate (147.1 kg) in 2-propanol (344 L). The reaction was stirred at 25±3° C. for 6 h and then at 45±3° C. for 10 h. After this period the reaction was concentrated by atmospheric distillation to 731 L, and water (172 L) added. The reaction was clarified through a bed of celite and the celite washed with 2-propanol (86 L), water was added (86 L) before a further concentration to 989 L. The solution was seeded at 65±3° C. and cooled to 20±3° C. before filtration. The filter cake was washed with 2-propanol:water (2:1, 426 L) followed by ethanol (427 L) and then dried at 45-55° C. under vacuum to give the title product (48.7 kg, 75% th).
[0215] 1 H NMR (500 MHz, CHLOROFORM-D) δppm 8.42 (1H, s); 8.30 (1H, d, J=2.1 Hz); 7.69 (1H, dd, J=8.5, 2.4 Hz); 7.43-7.48 (2H, m); 7.38 (2H, d, J=8.2 Hz); 7.35 (1 H, d, J=2.1 Hz); 7.09 (1 H, d, J=8.9 Hz); 6.85-6.91 (3H, m); 6.74 (1 H, d, J=8.5 Hz); 5.42 (2H, s); 5.24 (2H, s); 4.37 (2H, q, J=7.1 Hz); 4.06 (2H, q, J=7.1 Hz); 3.32 (2H, s); 2.30 (3H, s); 1.39 (3H, t, J=7.0 Hz); 1.24 (15H, s); 1.17 (3H, t, J=7.2 Hz).
Step 6A: Alternative Synthesis of ethyl 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methylpyridin-2-yl)methoxy)-1H-indol-2-yl]-2,2-dimethyl-propanoate
[0216]
[0217] 2-(Ethyloxy)-5-(4-{[1-(4-{[(5-methylpyridin-2-yl)methyl]oxy}phenyl)hydrazino]methyl}phenyl)pyridine (70 g) and ethyl 5-[(1,1-dimethylethyl)thio]-2,2-dimethyl-4-oxopentanoate (62 g) were stirred in a mixture of ethanol (70 mL) and isobutyric acid (490 mL). The slurry was degassed and heated at 23-25° C. for 12 h and then heated to 40±3° C. over 12 h. After a further 9 h at this temperature the reaction was heated to 70° C. and ethanol (280 mL) added followed by water (490 mL). The temperature was then adjusted 75° C. and seeded. The resulting suspension was cooled to 5° C. and the product isolated by filtration. The solid was washed with ethanol (2×350 mL) at 5° C. and dried at 40° C. under vacuum to give the title product (76 g, 72% th).
[0218] 1 H NMR (400 MHz, DMSO-D6) δppm 8.39-8.42 (2H, m); 7.94 (1 H, dd, J=8.6, 2.4 Hz); 7.60 (1H, dd, J=7.9, 2.1 Hz); 7.55 (2H, d, J=8.3 Hz); 7.38 (1H, d, J=7.8 Hz); 7.30 (1H, d, J=9.0 Hz); 7.10 (1H, d, J=2.4 Hz); 6.90 (2H, d, J=8.1 Hz); 6.83 (2H, d, J=8.6 Hz); 5.50 (2H, s); 5.15 (2H, s); 4.32 (2H, q, J=7.0 Hz); 4.04 (2H, q, J=7.1 Hz); 3.25 (2H, s); 2.28 (3H, s); 1.32 (3H, t, J=7.1 Hz); 1.11-1.17 (18H, m).
Step 7: 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid
[0219]
[0220] To a suspension of ethyl 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methylpyridin-2-yl)methoxy)-1H-indol-2-yl]-2,2-dimethyl-propanoate (47.56 kg) in tetrahydrofuran (71 L) was added ethanol (41.8 L) and aqueous sodium hydroxide (46-48 wt %, 10.46 kg). The reaction was then heated at reflux for 1-2 h before cooling to 20±3° C. and clarified. The filter was washed with tetrahydrofuran (24 L) and the solution was then acidified with hydrochloric acid (2M) to pH 4. Water (143 L) was then added and the slurry cooled to 2±3° C. before isolation of the product by filtration. The filter cake was washed with 2:1 water:tetrahydrofuran (142.5 L) at 2±3° C. followed by ethyl acetate (143 L) and dried at 45-55° C. under vacuum to give the title product (44.5 kg, 97.7%).
[0221] 1 H NMR (400 MHz, DMSO-D6) δppm 8.39-8.44 (2H, m); 7.95 (1H, dd, J=8.7, 2.6 Hz); 7.61 (1H, dd, J=7.9, 1.3 Hz); 7.55 (2H, d, J=8.3 Hz); 7.40 (1H, d, J=7.8 Hz); 7.34 (1H, d, J=8.8 Hz); 7.13 (1H, d, J=2.2 Hz); 6.91 (2H, d, J=8.1 Hz); 6.81-6.87 (2H, m); 5.53 (2H, s); 5.16 (2H, s); 4.33 (2H, q, J=6.9 Hz); 3.24 (2H, s); 2.30 (3H, s); 1.33 (3H, t, J=7.0 Hz); 1.10-1.18 (15H, m).
Purification of 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid
[0222] 3-[3-(tert-Butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (1.35 kg) was dissolved in 2-butanone (20.0 L) and water (0.9 L volumes) at 75±3° C. The solution was cooled to 65° C. and filtered. The transfer lines were washed with 2-butanone (1.35 L) and the combined filtrate and wash concentrated by distillation at atmospheric pressure to leave a residual volume of 10 Lvolumes. The suspension was cooled to 0±3° C. and stirred for 1 h at this temperature. The product was collected by filtration, washed with 2-butanone (5.4 L) then ethyl acetate (2.7 L) and dried under vacuum at 50±5° C. to give the title product (1.26 kg, 94% th).
[0223] 1 H NMR (400 MHz, DMSO-D6) δppm 12.46 (1 H, br s); 8.39-8.44 (2H, m); 7.94 (1 H, dd, J=8.7, 2.6 Hz); 7.60 (1H, dd, J=7.9, 1.3 Hz); 7.54 (2H, d, J=8.3 Hz); 7.39 (1H, d, J=7.8 Hz); 7.33 (1H, d, J=8.8 Hz); 7.12 (1H, d, J=2.2 Hz); 6.91 (2H, d, J=8.2 Hz); 6.81-6.87 (2H, m); 5.52 (2H, s); 5.16 (2H, s); 4.32 (2H, q, J=6.9 Hz); 3.24 (2H, s); 2.39 (3H, s); 1.33 (3H, t, J=7.0 Hz); 1.14 (9H, s); 1.12 (6H, s).
Step 6B & 7A: 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid
[0224]
[0225] To a degassed slurry of 2-(ethyloxy)-5-(4-{[1-(4-{[(5-methylpyridin-2-yl)methyl]oxy}phenyl)hydrazino]methyl}phenyl)pyridine (1.0 kg) and ethyl 5-[(1,1-dimethylethyl)thio]-2,2-dimethyl-4-oxopentanoate (720 mL) in 2-MeTHF (4.0 L) was added dibenzoyl tartaric acid monohydrate (854 g), citric acid (436 g) and 2-MeTHF (1 L). The reaction was stirred at 30±2° C. for 6 h and then heated to 55±2° C. and held at this temperature until the reaction was complete. Water (3.25 L) and 10 wt % sodium hydroxide (3.25 L) was added to achieve pH 7 then the lower aqueous layer was discarded. The reaction was then concentrated by atmospheric distillation to 3.4 L, and 2-propanol (8.7 L) wad added. Sodium hydroxide (236 g) was added and the mixture heated at reflux for ca.4 h before cooling to 67±3° C. The solution was then acidified with hydrochloric acid (2.6 L, 2M) to pH 6. After ageing, water (0.8 L) was added and the slurry cooled to 45±3° C. before isolation of the product by filtration. The filter cake was washed with 1.0:3.5:1.5 2-MeTHF:2-propanol:water (6.0 L), then by 2-propanol (6 L) and dried at 45° C. under vacuum to give the title product (1.06 kg, 73%).
[0226] 1 H NMR (400 MHz, DMSO-D6) δppm 8.1-8.43 (2H, m); 7.95 (1 H, dd, J=8.7, 2.6 Hz); 7.61 (1H, dd, J=7.8, 1.3 Hz); 7.55 (2H, d, J=8.3 Hz); 7.40 (1H, d, J=7.8 Hz); 7.34 (1H, d, J=8.8 Hz); 7.13 (1H, d, J=2.4 Hz); 6.91 (2H, d, J=8.1 Hz); 6.83-6.86 (2H, m); 5.53 (2H, s); 5.16 (2H, s); 4.33 (2H, q, J=6.9 Hz); 3.24 (2H, s); 2.31 (3H, s); 1.33 (3H, t, J=7.0 Hz); 1.11-1.16 (15H, m).
Step 6C & 7B: 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid
[0227]
[0228] 2-(Ethyloxy)-5-(4-{[1-(4-{[(5-methylpyridin-2-yl)methyl]oxy}phenyl)hydrazino]methyl}phenyl)pyridine (46.0 kg) and ethyl 5-[(1,1-dimethylethyl)thio]-2,2-dimethyl-4-oxopentanoate (32.3 kg) were added to degassed (4×) 2-MeTHF (151 kg) and were washed in with 2-MeTHF (20 Kg) The degassing was then repeated (4×). Dibenzoyl tartaric acid monohydrate (39.3 kg) and citric acid (20.1 kg) were then added followed by a 2-MeTHF (22 kg) line rinse and the mixture degassed again (4×). The reaction was stirred at 30±2° C. for about 6 h and then heated to 55±2° C. and held at this temperature until the reaction was complete (about 15 h). Water (152 kg) and 10 wt % sodium hydroxide (167 kg) was added and the mixture stirred for about 1 h and then allowed to settle, the lower aqueous layer was discarded at 50±2° C. The reaction was then concentrated by atmospheric distillation to ˜155L. 2-Propanol (290 kg) and sodium hydroxide (10.6 kg) were added and the mixture heated at reflux until the reaction was complete (about 15 h). After cooling to 65-70° C., the solution was diluted with 2-propanol (32 kg) then neutralised with hydrochloric acid (123 kg, 2M). Water (55 L) was added and the slurry cooled to 42-45° C. and aged for about 4 h before the product was isolated by filtration. The filter cake was washed with 2-MeTHF:2-propanol:water (19.5 kg:64 kg:34 kg), then by 2-propanol (217 kg) and dried under vacuum to give the title product (50.4 kg, 76%).
[0229] 1 H NMR (400 MHz, DMSO-D6) δppm 8.38-8.43 (2H, m); 7.93 (1 H, dd, J=8.6, 2.7 Hz); 7.59 (1H, dd, J=8.0, 1.6 Hz); 7.54 (2H, d, J=8.12 Hz); 7.38 (1H, d, J=7.9 Hz); 7.32 (1H, d, J=8.9 Hz); 7.11 (1 H, d, J=2.2 Hz); 6.90 (2H, d, J=8.4 Hz); 6.80-6.86 (2H, m); 5.51 (2H, s); 5.15 (2H, s); 4.32 (2H, q, J=7.1 Hz); 3.24 (2H, s); 2.28 (3H, s); 1.31 (3H, t, J=7.0 Hz); 1.07-1.16 (15H, m)
Step 8: Sodium 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionate
Polymorph Form C
[0230]
[0231] 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (28.3 kg) was dissolved in ethanol (32.6 Kg) by the addition of sodium hydroxide (3.7 kg, 46-48%) in ethanol (8.5 L) and heating at 72° C. for about 25 min. The resulting solution was cooled to 55±3° C., diluted with diisopropylether (78 L), seeded with sodium 3[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionate Polymorph Form C (28 g) and stirred for about 1 hr. Further diisopropylether (280 L) was added and the contents were stirred at 55±3° C. for about 1 h. The contents were then cooled to 20±3° C. and stirred overnight (about 11 hours). The slurry was allowed to settle for ca 10 min before being filtered under nitrogen. The filter cake was washed with diisoproyl ether:ethanol (9:1, 84.5 L) followed by diisopropyl ether (85 L) and dried at 45-55° C. under vacuum to give the title product (25.75 kg, 88.0% th).
[0232] 1 H NMR (500 MHz, DMSO-D6) δppm 8.38-8.41 (2H, m); 7.93 (1 H, dd, J=8.54, 2.75 Hz); 7.59 (1H, dd, J=7.93, 1.53 Hz); 7.51 (2H, d, J=8.24 Hz); 7.38 (1H, d, J=7.93 Hz); 7.22 (1H, d, J=8.85 Hz); 7.08 (1H, d, J=2.44 Hz); 6.92 (2H, d, J=8.24 Hz); 6.82 (1H, d, J=8.54 Hz); 6.76 (1H, dd, J=8.85, 2.44 Hz); 5.67 (2H, s); 5.13 (2H, s); 4.31 (2H, q, J=7.02 Hz); 3.20 (2H, s); 2.28 (3H, s); 1.31 (3H, t, J=7.02 Hz); 1.13 (9H, s); 0.97 (6H, s).
Step 8A: Sodium 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionate
Polymorph Form C
[0233]
[0234] 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (2.43 g, 3.8 mmol, 0.97 wt), sodium hydroxide pellets (0.17 g, 4.4 mmol, 0.0697 wt) and TBME (8.75 ml, 3.5 vol) were charged into a vessel. The resulting slurry was heated to 50° C. over 10 min with stirring. After a further 35 min, methanol (3.75 ml, 1.5vol) was added and the slurry aged at 50° C. for 45 min. A solution was formed and 7:3 TBME:methanol (2.5 ml, 1 vol) was added to the vessel to simulate a line wash. TBME (7.5 ml, 3 vol) was charged to the vessel over 30 min. The solution was then seeded with a slurry of sodium 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionate Polymorph Form C (0.025 g, 0.038 mmol, 0.01 wt) in TBME (0.5 ml, 0.2 vol). The resulting slurry was aged at 50° C. for 1 h 15 min and then TBME (22.5 ml, 9 vol) was added over 1 h. The slurry was aged for a further hour at 50° C., filtered and washed with TBME (2×10 ml) and then dried at 50° C. in vacuo.
[0235] 1 H NMR (400 MHz, MeOH) δppm 8.36 (1H, s); 8.26 (1H, d, J=2.45 Hz); 7.85 (1H, dd, J=8.68, 2.57 Hz); 7.65 (1H, d, J=8.07 Hz); 7.47 (1H, d, J=8.07 Hz); 7.41 (2H, d, J=8.07 Hz); 7.12-7.17 (2H, m); 6.93 (2H, d, J=8.31 Hz); 6.77-6.83 (2H, m, J=8.74, 2.48, 2.48 Hz); 5.61 (2H, s); 5.17 (2H, s); 4.31 (2H, q, J=7.09 Hz); 2.34 (3H, s); 1.37 (3H, t, J=7.09 Hz); 1.17 (9H, s); 1.12 (6H, s).
[0236] DSC thermogram of the title product is shown in FIG. 1 .
[0237] The DSC thermogram was obtained using a TA Q2000 calorimeter. The sample was weighed into an aluminium pan and a pan lid pushed on top without sealing the pan. The experiment was conducted using a heating rate of 10° C. min −1 .
[0238] XRPD profile of the title product is shown in FIG. 2 .
[0239] The data was acquired on a PANalytical X′Pert Pro powder diffractometer using an XCelerator detector. The acquisition conditions were: radiation: Cu Kα, generator tension: 40 kV, generator current: 45 mA, start angle: 2.0° 2θ, end angle: 40.0° 2θ, step size: 0.0167° 2θ, time per step: 31.75 seconds. The sample was prepared by mounting a few milligrams of sample on a Si wafer (zero background) plate, resulting in a thin layer of powder. Characteristic XRPD angles and d-spacings are recorded in Table 1. The margin of error is approximately±0.1° 2θfor each of the peak assignments. Peak intensity may vary from sample to sample due to preferred orientation.
[0240] Peak positions were measured using Highscore software.
[0000]
TABLE 1
Characteristic XRPD peak positions and d-spacings
2θ/°
d-spacing/Å
3.5
25.0
4.2
21.0
7.0
12.6
7.7
11.5
8.4
10.6
9.6
9.2
10.5
8.4
11.6
7.6
12.9
6.8
17.5
5.1
19.3
4.6
20.9
4.2
24.0
3.7
|
The present invention provides processes useful for preparing 5-lipoxygenase activating protein (FLAP) inhibitors and their intermediates. In particular, processes for preparing 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid, the anhydrous Form C polymorph of sodium 3-[3-(tert-butylsulfanyl)-1-[4-(6-ethoxy-pyridin-3-yl)benzyl]-5-(5-methyl-pyridin-2-yl-methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionate, and intermediates useful in said processes are provided.
| 2 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the use of β3-adrenergic agonists for the treatment of glaucoma and ocular hypertension by topical or systemic administration in mammals. More particularly, it relates to the use of ophthalmological compositions containing an active amount of these β3-agonists or the pharmaceutical acceptable salts thereof for the treatment of glaucoma and ocular hypertension.
2. Description of the Prior Art
Glaucoma is an ocular disorder that causes functional or organic disturbances in the eyes due to continuous or repeated increase in intraocular pressure. Not only is there an increase in intraocular pressure, but also optic nerve cupping and visual field loss. Although the pathophysiological mechanism of open angle glaucoma is still unknown there is substantial evidence to suggest that the increased intraocular pressure is detrimental to the eye and that it is the most important factor causing degenerative damage in the retina. Primary open-angle glaucoma is an insidious, slowly progressive, bilateral condition. The condition is often asymmetric on presentation, however, so that one eye may have moderate or advanced damage and the fellow eye has minimal or no detectable damage. Most patients with primary open-angle glaucoma have elevated intraocular pressures in the range of 22 to 40 mm Hg. The cardinal features of open-angle glaucoma include elevated intraocular pressure, cupping and atrophy of the optic disc, and visual field loss. Individuals with intraocular pressures of 21 mm Hg or greater, normal visual fields, normal optic discs, open angles, and the absence of any ocular or systemic disorders contributing to the elevated intraocular pressures are referred to as having ocular hypertension. The concept of ocular hypertension is important because this set of findings occurs in 4% to 10% of the population over age 40. The term normal-tension glaucoma refers to typical glaucomatous optic disc cupping and visual field loss in eyes that have normal intraocular pressures, open angles, and the absence of any contributing ocular or systemic disorders. Normal tension glaucoma may be a consequence of the retina being unusually sensitive to pressure and therefore damage may occur at intraocular pressure levels otherwise considered physiologically normal. The clinical features of normal-tension glaucoma resemble primary open-angle glaucoma except for the absence of elevated intraocular pressure. Some authorities believe the visual field and optic disc changes are identical in normal-tension glaucoma and primary open-angle glaucoma, whereas others state subtle differences exist between the finding of the two conditions. If left untreated, glaucoma almost invariably leads to blindness. The course of the disease is typically slow with progressive loss of vision. Conventional therapy for glaucoma is based on lowering the intraocular pressure, either by drugs, laser therapy, or surgery. The treatment of glaucoma is required to reduce an intraocular pressure to the level adequate to maintain normal optic nerve functions.
Pilocarpine eye drops have been used extensively for the treatment of glaucoma. It is known however that pilocarpine eye drops not only reduce intraocular pressure but also act on the iris sphincter muscle and the ciliary muscle thereby causing side effects such as pupillary constriction, accommodative spasm as well as conjunctival congestion. Such side effects may invite very serious dangers particularly to persons operating motor vehicles. In the case of an elderly patient with cataracts, miosis will result in increased visual impairment.
Epinephrine eye drops are also associated with side effects such as conjunctival congestion, pain at the eyebrow and allergic blepharoconjunctivitis. The eye drops sometimes bring about increased intraocular pressure due to mydriasis.
Recently, beta blockers have become promising in this field, and timolol maleate, levobunolol hydrochloride and betaxolol hydrochloride are commercially available. These drugs are beta-adrenergic antagonists that are believed to work by blocking the β-adrenergic receptors in the ciliary epithelium and, thereby, decrease the production of aqueous humor, the clear fluid that circulates in the eye.
Drug therapy for glaucoma typically comprises topically instilled and/or orally administered medicines. Pilocarpine, epinephrine (and its prodrug form), and β-blockers are frequently used as topical drugs and carbonic anhydrase inhibitors are used via systemic administration. Because of the incidence of significant side-effects associated with conventional medical therapy for glaucoma, there is a serious problem with patient compliance. The discomfort of taking these medicines results in patients not following their treatment schedules.
The problems associated with present commercially available drugs has encouraged development of new agents for the treatment of glaucoma. There is thus a need for the development of new agents which avoids the shortcomings and problems of the presently available medicaments.
SUMMARY OF THE INVENTION
According to the present invention there is provided a method of treating glaucoma and ocular hypertension in a mammal comprising administering to the eye of the mammal or systemically, in an amount effective to reduce intraocular pressure, compounds which act as agonists at β 3 -adrenergic receptors (also known as β 3 -adrenoceptors). Such receptors have been described for example by J. R. S. Arch et. al., Nature, 309, 163-165 (1984); C. Wilson et. al., Eur J. Pharmacol., 100, 309-319 (1984); L. J. Emorine et. al, Science 245, 1118-1121 (1989); and A. Bianchetti et. al. Br. J. Pharmacol., 100, 831-839 (1990).
β 3 -adrenoceptors belong to the family of adrenoceptors which mediate the physiological actions of the hormones adrenaline and noradrenaline. Sub-types of the adrenoceptors, α 1 -, α 2 -, β 1 1-, β 2 -, and β 3 - can be identified on the basis of their pharmacological properties and physiological effects. Chemical agents which stimulate or block these receptors (but not ⊖ 3 ) are widely used in clinical medicine. More recently, emphasis has been placed upon specific receptor selectivity in order to reduce side effects caused, in part, by interactions with other receptors.
β 3 -adrenoceptors are known to occur in adipose tissue and the gastrointestinal tract. β 3 -adrenoceptor agonists have been found to be particularly useful as thermogenic anti-obesity agents and as anti-diabetic agents. Compounds which act as agonists at β 3 -adrenoceptors may be identified using standard tests. (see for instance C. Wilson et. al., supra).
It has now been found unexpectedly that compounds which act as agonists at β 3 -adrenoceptors are useful for the treatment of glaucoma and/or ocular hypertension by topical or systemic administration in mammals.
Accordingly the present invention provides a method of treatment of a mammal, including man, suffering from glaucoma or ocular hypertension which comprises administering to the subject an effective amount of a compound which acts as an agonist at β 3 -adrenoceptors.
In a preferred aspect of the present invention, there is provided a method of treatment of a mammal, including man, suffering from a condition of glaucoma and/or ocular hypertension which comprises topically administering to the subject an effective amount of a compound which acts as an agonist at β 3 -adrenoceptors.
In a particularly preferred aspect of the present invention, there is provided a method of treatment of a mammal, including man, suffering from a condition of glaucoma and/or ocular hypertension which comprises systemically administering to the subject orally an effective amount of a compound which acts as an agonist at β 3 -adrenoceptors.
A most particularly preferred aspect of the present invention is directed to the use of β 3 -agonist compounds which have a formula according to compounds I which are described in the present specification.
References in this specification to treatment include prophylactic treatment as well as treatment for the acute and chronic alleviation of symptoms.
Preferred compounds for use according to the invention are those compounds which act as agonists at β 3 -adrenoceptors described in published European Patent Specification Nos. 6735, 21636, 23385, 25331, 28105, 29320, 40000, 40915, 51917, 52963, 61907, 63004, 66351, 68669, 70133, 70134, 82665, 89154, 91749, 94595, 95827, 99707, 101069, 102213, 139921, 140243, 140359, 142102, 146392, 164700, 170121, 170135, 171519, 171702, 182533, 185814, 196849, 198412, 210849, 211721, 233686, 236624, 254532, 254856, 262785, 300290, 303546, 328251, 345591, 386603, 386920, 436435, 455006, 500443, 516349, and 556880;published UK Patent Specification No. 2133986; published PCT Patent Specification Nos. 84/00956, 84/03278, 84/04091, 90/13535 and 92/18461; U.S. Pat. Nos. 4391826, 4585796; published Belgian Patent Specification No. 900983 , published Japanese Patent Specification No. 86-145148, U.S. Pat. Nos. 5,061,727, 5,151,439, 4,707,497, 4,927,836 and application Ser. No. 010,973 filed Jan. 29, 1993.
A preferred group of β 3 -adrenoceptor agonists for use according to the present invention is that represented by the formula (I): ##STR2## or a physiologically acceptable salt or ester thereof, wherein R 4 represents one or more groups which may be the same or different and are selected from the group consisting of hydrogen, halogen, trifluoromethyl, C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 -alkylthio, alkoxycarbonyl, carboxyl, hydroxyalkyl, hydroxy, C 1-4 -alkylsulphonyl and C 1-4 -alkylsulphinyl; R 5 and R 6 each independently represent a hydrogen atom or a C 1-4 -alkyl group; R 7 and R 8 each independently represent a group selected from the group consisting of hydrogen, carboxy, alkoxycarbonyl, hydroxymethyl, --CH 2 --OCH 2 --CO 2 R 9 and --CH 2 --OCH 2 --CH 2 OR 9 , with the proviso that R 7 and R 8 do not both represent hydrogen; and R 9 is a hydrogen atom or a C 1 -C 4 alkyl group.
Particularly preferred β 3 -adrenoceptor agonists and physiologically acceptable salts or solvates thereof for use according to the present invention are listed below. It will be appreciated that where the above compounds of formula (I) and the following specific compounds are optically active, the use of individual enantiomers, diastereoisomers or mixtures thereof, including racemates, is also considered to be within the scope of the present invention.
(R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid, particularly in the form of its disodium salt;
(R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid, dimethyl ester;
(R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid, diethyl ester;
(R,R)-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid, diisopropyl ester;
(R,S)-5-(2-((2-(3-chlorophenyl)-2hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid;
(R,R)-(2-((2-(3-chlorophenyl)-2hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid, bis((1-methylethyl)ester hydrochloride.
In a further aspect, the present invention provides a therapeutic agent which comprises an effective amount of a compound which acts as an agonist at β 3 -adrenoceptors for use in medicine. The β 3 agonists of Formula (I) have little or no β 1 or β 2 agonist activity and thus are substantially free of β 1 or β 2 agonist activity. For example (R,R) -5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid, particularly in the form of its disodium salt has been shown to have no binding to human β 1 or β 2 receptors expressed in chinese hamster ovary cells.
Also according to the present invention there is provided a method of treating glaucoma and ocular hypertension in humans or other mammals which comprises administering to a human or other mammal an antiglaucoma or ocular antihypertensive effective amount of a β 3 compound of the present invention.
Further, according to the present invention there are provided pharmaceutical compositions of matter comprising an effective amount of a β 3 compound of the present invention in combination with a pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1: Pre and post-drug intraocular pressure (mean±sem n=7) measured in glaucomatous eyes of glaucomatous monkeys indicating a decrease in intraocular pressure following intravenous injection of (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid, disodium salt.
FIG. 2: The difference in intraocular pressure (mean±sem n=7)comparing intraocular pressure on day 2 following intravenous injection of (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid, disodium salt to that on day 1 with no drug administration.
FIG. 3: The intraocular pressure lowering effect of topical ocular administration of 50 μl of 0.5% (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid disodium salt to 8 glaucomatons cynomolgus monkey eyes (mean±sem).
FIG. 4: The intraocular pressure lowering effect of topical administration of 50 μl of 1% (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid disodium salt to 8 glaucomatous cynomolgus monkey eyes (mean±sem).
FIG. 5: The intraocular pressure lowering effect of topical administration of 50 μl of 1% (R,R)-(5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid bis(1-methylethyl)ester hydrochloride to 8 glaucomatous cynomolgus monkey eyes (mean±sem).
DETAILED DESCRIPTION OF THE INVENTION
This invention provides a method of treating glaucoma or ocular hypertension. The method comprises either topical ocular or oral dosing with a composition comprising an effective intraocular pressure reducing amount of β 3 -adrenergic agonist chosen from 5-(2-((2-aryl-2-hydroxyethyl)amino)propyl)-1,3-benzodioxoles.
In a series of experiments in a glaucomatous monkey model, compositions according to the invention are administered either intravenously or topically to an animal eye and the intraocular pressure in the experimental eye is compared to controls. The results of the comparative tests are presented in FIG. 1 to FIG. 5. The compound (R,R)-(5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2dicarboxylic acid disodium salt is found to lower intraocular pressure in glaucomatous monkeys following both intravenous and topical ocular administration.
The effect of (R,R)-(5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid disodium salt on intraocular pressure is shown in Table I in which seven cynomolgus monkeys with laser induced glaucoma are treated. The procedures for the laser induced glaucoma are published in the following articles: Gaasterland D. and Kupfer C, Invest. Ophthalmol 13: 455-457(1974) and Lee P. Y., Podos S. M., Howard-Williams J. R., Severin C. H., Rose A. D., Siegel M. J., Curr Eye Res 4: 775-781(1985). The intraocular pressure is measured over 2 days during the same 6 hour interval. On day 1, a baseline diurnal intraocular pressure time course is measured. On day 2, three baseline intraocular pressure measurements are made over 2 hours, after which the drug is injected intravenously as a 0.1% aqueous solution of 1 mg/kg in normal saline. The intraocular pressure is subsequently measured at 0.5, 1, 2, 3 and 4 hours post-injection. The mean value of the first 3 intraocular pressure measurements on each day is used as the control intraocular pressure. There is no statistically significant difference (ρ>0.1) between the control intraocular pressure measured on Day 1 (35.2±1.8 mm Hg) and the baseline intraocular pressure measured on Day 2 (36.5±2.5 mm Hg).
TABLE I______________________________________ CHANGE IN IOP FROM Percent IOP BASELINE ρ value* Change______________________________________Day 1baseline 35.2control30 minutes 37.1 2.0 0.031 +61 hour 38.3 3.1 0.023 +92 hours 37.4 2.2 0.022 +63 hours 38.4 3.2 0.043 +94 hours 36.1 1.0 0.644 +3Day 2baseline 36.5control30 minutes 33.9 -2.7 0.124 -81 hour 33.6 -3.0 0.024 -92 hours 34.3 -2.3 0.079 -73 hours 35.9 -0.7 0.602 -24 hours 34.1 -2.4 0.155 -6______________________________________ *paired ttest, 2sided
The intraocular pressure on day 1 tends to increase slightly over the course of the day (TABLE 1). Whereas on day 2, intraocular pressure decreased after the injection of (R,R)-(5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid disodium salt, (FIG. 2). The statistically significant difference in intraocular pressure on day 2 following drug administration compared to day 1 in which no drug is administered (intraocular pressure day 2 minus intraocular pressure day 1) indicates a decrease in intraocular pressure following intravenous injection of the test compound (FIG. 2, TABLE 1). Following topical ocular administration of 0.5% and 1% (R,R)-(5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid disodium salt to glaucomatous monkeys, the intraocular pressure is found to decrease (FIG. 3 and FIG. 4). Topical ocular administration of 1% (R,R)-(5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid bis(1-methylethyl) ester hydrochloride to glaucomatous monkeys is found to cause a statistically significant reduction in intraocular pressure compared to the vehicle control intraocular pressure at 30 minutes, 1 hour and 2 hours after administration (FIG. 5).
The pharmaceutical compositions of the invention are administered in the form of ophthalmic pharmaceutical compositions adapted for topical administration to the eye, such as solutions, suspensions, ointments and solid inserts or standard pharmaceutical compositions for systemic administration, in the form of tablets, capsules or intravenous injections for both instantaneous and controlled release. Topical ophthalmic formulations of the invention may contain β 3 agonists in an amount from about 0.001 to about 15% (w/v %) and especially about 0.05 to about 5% of medicament. As a unit dosage form, an amount of β 3 agonist from between about 500 ng to 7.5 mg, preferably 0.05 mg to 2.5 mg of the active substance applied topically to the human eye. These doses can be administered as a single daily dose or on a 2 to 4 dose per day regimen. Systemically administered formulations may contain β 3 agonists in an amount from about 1 mg to about 2000 mg and especially about 5 mg to 1500 mg. as a single daily dose or on a 2 to 4 dose per day regimen.
Where utilized herein, the term "controlling the elevated intraocular pressure" means the regulation, attenuation and modulation of increased intraocular tension e.g., the primary diagnostic symptom of the disease glaucoma. The term also means that the diminution, in the otherwise elevated intraocular pressure, obtained by the practice of the invention is maintained for a significant period of time as, for example, between consecutive doses of the composition of the invention.
The β 3 agonists may be employed in the composition and methods of the invention as the sole IOP lowering ingredient or may be used in combination with other mechanistically distinct IOP lowering ingredients such as beta adrenergic blocking agents, (e.g., timolol), carbonic anhydrase inhibitors, miotic agents (e.g., pilocarpine), epinephrine and dipivalylepinephrine, α 2 adrenergic agonists prostaglandins or prostaglandin analogs. For the purposes of the present invention, the term beta-adrenergic blocker means a compound which by binding to β-1 or β-2 adrenergic receptors reduces or eliminates sympathetic activity or blocks the effects of exogenously administered catecholamines or adrenergic drugs mediated via these receptors. See, for example, Weiner, N., Drugs That Inhibit Adrenergic Nerves and Block Adrenergic Receptors, in The Pharmaceutical Basis of Therapeutics (ed. A. G. Goodman, L. S. Goodman, A. Gilman), Macmillan Publishing, New York, 1980, 6th ed., pp. 188-197.
The present invention therefore also provides a pharmaceutical formulation suitable for use in reducing intraocular pressure or for treating glaucoma which formulation comprises a novel compound of formula (I) and a pharmaceutically acceptable carrier.
It will be understood that any formulation may further comprise another active ingredient such as another antiglaucoma agent for example a topical carbonic anhydrase inhibitor or a topical β-adrenergic blocking agent.
The active drugs of this invention are most suitably administered in the form of tablets or capsules for oral administration or in the form of ophthalmic pharmaceutical compositions adapted for topical administration to the eye such as a solution, suspension, ointment, or as a solid insert. For oral administration, the drug can be employed in any of the usual dosage forms either in a comtemporaneous delivery system or sustained release form. Any number of the usual excipients or tableting aids can likewise be included. A preferred composition for topical ophthalmic administration is eye drops. Formulations of these compounds may contain from 0.001 to 15% and especially 0.05% to 5% of medicament, which corresponds to dosages from between 500 ng to 7.5 mg, preferably 0.05 to 2.5 mg, generically applied to the human eye, generally on a daily basis in single or divided doses so long as the condition being treated exists. Higher dosages as, for example, about 10% or lower dosages can be employed provided the dose is effective in reducing or controlling elevated intraocular pressure.
This invention therefore further provides a sterile pharmaceutical formulation adapted for topical administration to the eye which formulation comprises a compounds of formula (I) and a carrier suitable for topical administration. These herein before described dosage values are believed accurate for human patients and are based on the known and presently understood pharmacology of the compounds, and the action of other similar entities in the human eye. As with all medications, dosage requirements are variable and must be individualized on the basis of the disease and the response of the patient.
For topical administration, pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or arylalkanols, conventional phosphate buffer vehicle systems, isotonic boric acid vehicles, isotonic sodium chloride vehicles, isotonic sodium citrate vehicles, isotonic sodium acetate vehicles, vegetable oils, polyalkylene glycols, petroleum based jelly, as well as aqueous solutions containing ethyl cellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carbopol, polyvinyl alcohol, polyvinylpyrrolidone, isopropyl myristate and other conventionally-employed non-toxic, pharmaceutically acceptable orqanic and inorganic carriers. The pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying agents, wetting agents, bodying agents and the like, as for example, polyethylene glycols 30, 200, 300, 400 and 600, carbowaxes 1,000,1,500, 4,000, 6,000 and 10,000, and polysorbate 80. Antibacterial and preservative components can also be employed in the topical ophthalmic formulation, as for example, benzalkonium chloride, and other quaternary ammonium preservative agents, phenylmercuric salts, sorbic acid, chlorobutanol, disodium edetate, thimerosal, methyl and propyl paraben, benzyl alcohol, and phenyl ethanol. Osmotic agents and buffering ingredients which may be employed in the topical ophthalmic formulation include sodium chloride, mannitol, sodium borate, sodium acetates, sodium phosphates, gluconate buffers, sodium hydroxide and hydrochloric acid. Other conventional ingredients can be employed such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan 35 monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediamine tetraacetic acid, and the like.
Pharmaceutically suitable salts include both the metallic (inorganic) salts and organic salts; a list of which is given in Remington's Pharmaceutical Sciences, 17th Edition, pg. 1418 (1985). It is well known to one skilled in the art that an appropriate salt form is chosen based on physical and chemical stability, flowability, hygroscopicity and solubility. Preferred salts of this invention for the reasons cited above include potassium, sodium, calcium, magnesium and ammonium salts.
The pharmaceutical formulation may also be in the form of a solid insert such as one which after dispensing the drug remains essentially intact, or a bio-erodible insert that is soluble in lacrimal fluids or otherwise disintegrates.
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Substituted 5-2-((2-aryl-2-hydroxyethyl)amino)propyl)-1,3-benzodioxoles having the structural formula: ##STR1## wherein R4, R5, R6, R7, and R8 are as hereinafter defined, are β3-adrenergic agonists useful in the treatment of elevated intraocular pressure and glaucoma.
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BACKGROUND OF THE INVENTION
The use of intumescent material in cable ducts, for the purpose of preventing the duct from, in effect, becoming a flue for the transmission of smoke, heat and flame from one area to another, is known. Thus, for example, in non-ventilated cable raceways, such as in the so-called under-floor duct commonly used to house cables, telephone lines, electrical wires, etc., in office and apartment buildings, where it is desired to help prevent transmission of damaging effects of fire within the raceway from one section of the building to another, intumescent materials are known to have been utilized.
By an intumescent material is meant one which enlarges, swells or bubbles upon exposure to heat above pre-determined levels. Thus, for example, so-called "FLAMAREST 1600," as marketed by Avco Systems Division of Lowell, Mass., is an intumescent, epoxy coating, containing an intumescent component designed for both interior and exterior use and many industrial applications. It is a two-component, catalyzed, epoxy resin which fuses into a porcelain-like shield to protect the substrate while providing a highly efficient barrier against flame and heat.
Typically, such coatings may be applied in a thickness of 20 to 25 mils. As the coating is exposed to heat at a preselected level, for example, 500° F., the resin softens and the intumescent material begins to change state and evolves from a high density film to a low density "intumescent char," wherein a multiplicity of air cells in the char act as insulators and keep the substrate cool. As an intumescent mechanism, the foregoing phenomenon may be completed in a matter of seconds, for example, 30 seconds or so, after the coating is exposed to heat and/or fire. By positioning such material in a confined passageway, such as the interior of a cable raceway, it is possible to have the intumescent char traverse the cross-section of the passageway such that, upon completion of the heat exposure cycle of the intumescent material, the passageway becomes effectively blocked. This concept has been adopted in the design of enclosed under-floor ducts, for example, as hereinbefore described.
In addressing the question of utilizing intumescent material in generally open, ventilated devices such as cable trays, it must be kept in mind that the problems involved are significantly different than those in generally non-ventilated structures, such as cable raceways and the like.
Typically, one form of cable tray is made as a flat, hung-support member, having a multiplicity of holes for the liberal convection of air therethrough, so that heat generated in the cables in the normal course of use may be easily and adequately dissipated. However, this very feature of enhancement of convection in normal circumstances becomes undesirable in extreme cases such as fire in the ambient region in which the trays are located because, inherently, it tends to enhance the passage of heat and flame into, through and around the areas in which the cables are positioned. In the past, where the consequences of destruction of cables due to these phenomena were mainly mere power losses, concern was somewhat less than now, when the destruction of cables can have the effect of rendering inoperative control, servo, and other mechanisms and devices, which may be critical to health or safety, as, for example, reaction control devices, in nuclear-reactor installations. It might be thought that to address this problem by coating the inside of the holes in such cable trays with intumescent material, would suffice, with the idea that upon exposure to heat, the material would expand and shut off the convective paths. However, the heat from a fire in an ambient region can be so intense, and the consequent "flue effect" through the ventilating holes in a direction normal to the tray can be so pronounced, that by the time a sufficient amount of time has passed for the intumescent material to begin to react to the sudden heat rise, the rate of convection through the holes, coupled with the relatively fragile "char" state of the intumescent material as it approaches its fully expanded condition, can cause the blocking to be inhibited, or even totally precluded.
Accordingly, it is an object of this invention to provide a means for selectively and automatically restricting the flow of heated air through structures, which are intended to encourage free ventilation under usual circumstances.
Another object of this invention is to provide such means in a fashion most likely to achieve effective restriction of the flow of heated air under extraordinary conditions.
Yet another object of this invention is to provide means to satisfy the foregoing objectives, which is structurally sound from an engineering standpoint for its intended functional use, such as supporting cables, and, at the same time, is structurally simple and comparatively inexpensive to produce.
Still another object of this invention is to provide means to satisfy the foregoing objectives using materials and structures which are reliable and effective.
SUMMARY OF THE INVENTION
Desired objectives may be achieved through practice of the present invention, one embodiment of which comprises a structure having walls secured in spaced-apart relationship with respect to each other, in which air and/or gasses may pass between convection holes in one of the walls and convection holes in the other of the walls, the holes in one wall not being aligned with the holes in the other of the walls. Intumescent material is positioned in the passageway between the holes in each of the walls for obstructing the flow of air therebetween upon thermal activation. Another embodiment of this invention comprises such a structure wherein the walls defining the passageway are the double floor members of the cable tray device, and further embodiments in which one or both of the floor members are of the so-called "corrugated" construction. Unperforated portions of the structure are positioned substantially opposite the convection holes in at least one of the walls such that intumescent material may form a char between the hole and the unperforated portion.
DESCRIPTION OF DRAWINGS
This invention will be clear from the description which follows and from the accompanying drawings in which
FIG. 1 is a plan view of an embodiment of this invention;
FIG. 2 is a cross-section of the embodiment of this invention as shown in FIG. 1 taken along section line 2--2;
FIG. 3 is a cross-section of the embodiment of this invention shown in FIG. 1 taken along section line 3--3;
FIG. 4 is a cross-section view of another embodiment of this invention;
FIG. 5 is a cross-sectional view of yet another embodiment of this invention;
FIG. 6 is a cross-sectional view of yet another embodiment of this invention;
FIG. 7 is a cross-sectional view of still another embodiment of this invention;
FIG. 8 is a cross-sectional view of still another embodiment of this invention; and
FIG. 9 is a cross-sectional view of still another embodiment of this invention; while
FIG. 10 illustrates an installation application for an embodiment of this invention.
DESCRIPTION OF PREFERRED EMBODIMENTS
Referring first to FIGS. 1 through 3, there is depicted an embodiment of this invention useful for use as a cable tray support device comprising a floor section having two component layers 12, 14. As may be seen particularly in FIG. 1, the upper floor member 12 includes rows of convection holes 30, 30a, 30b, . . . 30n; 32, 32a, 32b, . . . 32n; . . . (etc.) oriented substantially normal to the long axis of the structure. Similarly, the lower floor member 14 has rows of holes 20, 20a, 20b . . . , 20n; 22, 22a, 22b, . . . 22n; . . . (etc.), which also are oriented substantially normal to the long axis of the device. It will be noted particularly from FIG. 2 that the upper floor member 12 is "corrugated." As there illustrated, these corrugations are substantially "U" shaped in cross-section, since this is a usual structural feature of cable tray devices. It should be understood, however, that although such U-shaped corrugations are shown here for purposes of illustration, corrugations of other configurations, such as triangles, elipses, sinusoids, etc., may be also or alternatively be utilized without departing from the spirit or scope of this invention.
Referring to FIG. 2, it will be seen that the top member 12 is made in a corrugated configuration with lands or peaks 15 and grooves 16, and that in this particular configuration, the grooves 16 have holes 30 positioned therein. Correspondingly, the lower floor member 14 has peaks or lands 18 and grooves 19, the latter of which have holes 20 therethrough. It will be noted further, particularly from FIG. 2, that the corrugations of one of the layers are substantially parallel to the corrugations of the other layers, with the peaks of each positioned substantially opposite the peaks of the other, and with the valleys of each positioned substantially opposite the valleys of the other. By such juxtapositioning of such floor members, it will be further seen, particularly from FIG. 2, that as between floor members the hole sequence alternates; that is, proceeding from left to right substantially at right angles to the axial lines of the corrugations, one comes first to a hole in the lower floor member, and then to a hole in the upper floor member, and so forth. Thus, it will be clear that, as between the two floor members, the holes in them respectively form convection passageways which are tortuous; that is, tend not to be straight but instead, are along devious paths, since the holes in one of the members are out of alignment (i.e. not positioned opposite) the holes in the other of the members.
FIG. 3 further illustrates this embodiment of the present invention, showing, in addition, hangars 24, by which the double floored structure may be suspended, as, for example, from supporting trusses or other known per se support members (not shown).
Turning now to FIG. 4, there is illustrated in greater detail a cross-section of the embodiment shown in FIG. 2. In addition to the structural features shown in FIG. 2, FIG. 4 illustrates the further application of an intumescent material 7 on the upper side of the lower floor member, i.e. on the inside of the passageways between the holes 30 of the upper floor member and the holes 20 of the lower floor member. By this means, the normal convective flow path (A) of air through the cable tray device which, as is known, has a beneficial cooling effect on the cables 5 being supported on the top of peaks 15 of the upper floor member 12, may, upon the application of heat, be caused to become closed when the intumescent material 17, reacting to the heat, turns into intumescent char 9. This phenomena may be seen to have effectively closed off the passageway between the groove hole 30 in the upper floor members 12 and the convection hole 20 in the lower floor member 14. This phenomena, repeated along a substantial portion of the entire tray length will, of course, have the effect of reducing the thermal exposure of the cables, therefore causing them at least to remain operative for a substantially longer period of time, and perhaps even to survive totally an exposure that might otherwise cause them to fail. It should be noted in particular that in the embodiment shown in FIG. 4, assuming that the most immediate exposure to fire in the ambient environment is at the underside of the under-floor member 14, the intumescent material 7, particularly in the area above the valley 18 of the lower floor member 14, may be expected to react quickly to the exposure to flames on the tray floor member 14 of heat transmitted conductively to the region where the intumescent material is positioned immediately below the hole 30 in the bottom of the valley of the upper floor member 12. Thus, this relatively rapid time response, as well as the structural feature of having the intumescent material, as it changes towards becoming intumescent char 9, firmly positioned and supported on the upper side of the valley 18 in the lower floor member 14, as a support base, tends to minimize the "flue effect" which might otherwise occur. For applications such as are discussed here, the space between the two floor members may be typically from, say 1/8" to 1". Preferably the space will be selected to permit adequate ventilation air flow under normal circumstances bur will permit the intumescent char to obstruct air and gas passage under extreme cases when the char is formed.
FIG. 5 illustrates another embodiment of this invention. It will be seen that the upper floor member 12 in this embodiment corresponds to the upper floor member 12 shown in FIG. 4. However in the embodiment shown in FIG. 5, the lower floor member 50 has peaks 52 and grooves 54, in the bottom of which grooves are positioned holes 56. Thus, passageways for the flow of air along path (A) are effectively defined between the holes 56 in the valleys of the lower member 50 and the holes 30 in the valleys of the upper member 12. As is the case with the embodiment shown in FIG. 4, the reaction time of the intumescent material to heat applied to the underside of the lower floor member 50 should be expected to be relatively rapid because of the ability of the material of the lower floor member 50 to transmit heat and thereby cause the generation of intumescent char 9 to block the passageways between holes. However, it will also be noted that in this embodiment, the width and alignment of the upper side of the valleys 54 of the lower floor member 50 are such that they do not provide as broad a structural support member for the generated intumescent char 9 as is the case with an embodiment like that shown in FIG. 4. Turning now to FIG. 6, there is illustrated an embodiment of the present invention having a lower floor member substantially corresponding to that shown in FIG. 5. However, in the embodiment shown in FIG. 6, the upper floor member 60 has valleys 64, and peaks 62 in which are positioned the holes 66. Thus, in this embodiment, the effective convective passageway for air is illustrated as being along the flow path (A) from holes 56 in the grooves of the lower floor member 50 to holes 66 in the peaks of the upper floor member 60. It will also be apparent that although, in this embodiment, the upper side of the grooves 54 in the lower floor member 50 provide a better structural support for the generated intumescent char 9 than that shown in FIG. 5 and can be expected to exhibit similar thermal conductivity and therefore intumescent char actuation characteristics as the embodiment shown in FIG. 5, the structural support characteristics for the intumescent char are better than those shown in FIG. 4.
FIG. 7 illustrates an embodiment of this invention having an upper floor member 60 with elements substantially corresponding to the upper floor member illustrated in FIG. 6, along with a lower floor member 14 having structural characteristics substantially corresponding to the lower floor member shown in FIG. 4. It will be apparent that in the embodiment of this invention shown in FIG. 7, although the thermal actuation through conduction may be expected to be substantially as fast as that which can be expected to be experienced with the embodiment shown in FIG. 4, the structural support for the generated intumescent char 9 is not as broad or well positioned as that shown in FIG. 4.
Thus, from the foregoing, although it will be understood that the embodiments shown in FIGS. 4, 5, 6 and 7 all fall within the contemplation of this invention, it is believed that the embodiment shown in FIG. 4 may be expected to prove to be the most significant technically as well as commercially because of the comparative speed with which its intumescent material will be actuated and the structural features it provides by way of char support and passageway configuration, with consequent attenuation of "flue effect."
Further, from the foregoing, it will be apparent that the principles of this invention may find application in a wide variety of structural embodiments other than cable trays of the configuration hereinbefore described. Thus, for example, a relatively simple panel insert, not necessarily designed to be a cable tray per se or to be used only with cable trays, may be made of parallel, separated wall members with non-aligned holes, to act as an intumescent barrier to an otherwise fluid transmissive structure, or as a flame gas, and the like barrier for other structures as shown in FIG. 10. Thus, it may be used as a vertical wall panel, or as a slab-like floor member to dropped in the bottom of a cable tray or other normally convective permissive structure. Similarly, although the protected device, such as the cables hereinbefore described, may be positioned in the convective top-most position (e.g., atop the top member of a cable tray), they may also be positioned between the upper and lower floor members, even though the exposure to conductive heating may be somewhat greater, since in such an intermediate posture, ultimate surrounding by char can have substantially similar heating inhibiting effect, with consequent preservation benefits. Further, it will be apparent that the desired effect of providing a good foundation base for the intumescent char so as to inhibit "flue effect" to a desired degree, may also be achieved by erecting intermediate baffles between otherwise aligned holes so as to produce the desired tortuous flow path with an adequate support base for generated char. Such a structure is illustrated in FIG. 8, wherein an upper plate 100 with holes 106 and a lower plate 102 with holes 104 have a baffle 108 positioned between the otherwise aligned holes 104, 106. As a result, this flow path (A) is rendered tortuous, whereby intumescent material positioned atop the baffle 108 will be adequately supported structurally to effect blocking of the hole 106 and cessation of convective flow along path (A) upon actuation. Thus, it will be clear that as used in this specification and the accompanying claims, the term "non-aligned holes," or its equivalent, should be taken to mean, in effect, holes between which flow is effected along a path such that the convectively egress hole substantially entirely faces an intumescent material bearing surface, such that upon actuation, the resulting intumescent char is provided with an adequate structural foundation to block the hole or otherwise cut off the normal flow path in the face of "flue effect" which might otherwise tend to keep it open.
FIG. 9 illustrates a specific embodiment of this invention in which a ventilated structure designated generally 200 comprises a perforated wall element 201 which is spaced from another wall 202 which is defined by a plurality of spaced-apart members 203 wherein the spaces 204 between adjacent members 203 define openings which are out of alignment with openings 205 in the planar element 201. The element 201 although shown to be generally planar in shape may assume any of the corrugated forms previously discussed. Elements 201 and the members 203 are held in spaced-apart relationship by conventional side rails 206 having a lower flange 207 if desired.
FIG. 10 illustrates an installation application in which a conventional cable support tray or the like 10', is protected from fire beneath by a ventilated barrier structure 300 suspended beneath it on any conventional suspension or hanger means 301. The barrier 300 in such an installation may correspond to any of the structures herein described or their equivalents.
Although any of a number of intumescent materials may be utilized in the practice of the present invention, it has been found advantageous in connection with embodiments of the invention, particularly of the type herein described, to utilize one which is a catalyzed, epoxy coating containing particulate, intumescent salts and an oxidative resistance additive, since the latter has the beneficial effect of inhibiting oxidation of the intumescent char to the point where it becomes relatively embrittled and therefore structurally less resistant to the adverse effects of the application of further heat and convective currents. The epoxy binder system used in such a coating may be a mixture of an epoxide and a flexibilizing agent to provide a durable, tough, weatherproof overall coating system. Pigmentation of the material may be adjusted also to improve high temperature performance. It is to be regarded as known to make such modifications of commercial materials as are necessary to achieve these ends. This description however, is by no means meant to be exclusionary but is detailed here merely to demonstrate that any of a range of modifications may be made in accordance with accepted technical practices and still be within the contemplation of this invention.
Accordingly it is to be understood that the embodiments of this invention herein disclosed, described and shown, are by way of illustration and not of limitation, and that this invention may be practiced in a wide variety of embodiments by those skilled in the cognizant arts without departing materially from the spirit or scope of this invention.
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This invention relates to structural devices which include intumescent material for the purpose of inhibiting the flow of heated air, smoke, and other products of extraordinary heat conditions, as in the case of a fire, from flowing therethrough. In one embodiment, useful as a tray for supporting insulated electrical conductors, a structure with double floor members spaced apart from each other, has convection holes in both of the floor members. The holes in one of the members are out of alignment with the holes in the other, and the top surface of the lower floor member has intumescent material positioned thereon. Thereby, upon exposure of the lower floor member to the heat of a fire for example, the intumescent material will expand, causing either or both the holes and the passageways that are described by the space between the holes of one floor member and those of the other floor member, to become blocked, thereby preventing the passage of heat, smoke and flame therethrough, to localize the fire, and deter consequent damage to the cables being held in the tray.
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LATIN NAME OF THE GENUS AND SPECIES
[0001] The avocado cultivar of this invention is botanically identified as Persea Americana Mill.
VARIETY DENOMINATION
[0002] The variety denomination is ‘Zentmyer’
BACKGROUND OF THE INVENTION
[0003] Avocado root rot is the limiting factor for the growth of avocados throughout the world. Avocado root rot is caused by the fungus Phytophthora cinnamomi, which attacks and kills the feeder roots of avocado trees. The resultant lack of roots causes the tree to eventually die from water stress. There are a number of varieties of rootstocks that have some tolerance to the disease. These varieties included ‘Duke 7’ (unpatented), the most commonly planted tolerant rootstock in the world; and ‘Thomas’ (U.S. Plant Pat. No. 6,628), another root rot tolerant rootstock. However, even with these rootstocks, growers must still use a variety of methods, including mounding, mulching and the applications of chemical fungicides, to keep the tress from dying in many soils. More resistant rootstocks are necessary to eliminate avocado root rot as a major disease threat.
[0000] Screening and greenhouse evaluation of rootstocks
[0004] ‘Zentmyer’ was identified and characterized using the following screening protocol. As it is difficult to breed avocados because only one in approximately one thousand flowers actually set fruit, plant breeding blocks of avocados were isolated to prevent out crossing with susceptible rootstocks. The breeding blocks were made up of various combinations of selected rootstocks including, ‘Thomas’ (U.S. Plant Pat. No. 6,628), ‘Barr Duke’ (U.S. Plant Pat. No. 6,627), ‘G6’, ‘Duke 7’, ‘Duke 9’, ‘UC 2001’, ‘UC 2011’, ‘Toro Canyon’ (U.S. Plant Pat. No. 5,642), ‘Spencer’, ‘CR1-71’, ‘G 810’, ‘G 875’, ‘G 755A’, ‘VC 256’, and ‘Steyemarkii’. In order to synchronize blooming, attempts were made to girdle late-blooming varieties and spray early-blooming varieties with the pesticide Unicona-zole-P.
[0005] Initial screening was carried out by germinating seeds, which were harvested from the breeding blocks, in flats of vermiculite in the greenhouse. Phytophthora cinnamomi -infested millet was placed in rows along with the young roots of the test seedlings. After 8-10 weeks roots were evaluated and those with a high percentage of surviving roots were transplanted to soil mix incorporated with P. cinnamomi -infested millet. Rootstocks that survived this test were planted and grown in P. cinnamomi -infested soils. Survivors were examined more carefully for various types of resistance using clonally propagated material.
a. Root survival—Rootstocks were grown in typical California avocado soils, inoculated with P. cinnamomi and evaluated for growth, root length and percent healthy roots. b. Root regeneration—Rootstocks were grown in soil inoculated with P. cinnamomi, treated with Aliette to halt Phytophthora root rot and evaluated for root regeneration. c. Attraction to P. cinnamomi —Roots of the rootstocks were placed in water baths with motile zoospores of P. cinnamomi. The numbers of spores attracted to the roots were evaluated.
[0009] Rootstocks that performed well in the screening and greenhouse evaluations were further tested under field conditions.
Selection of ‘Zentmyer’
[0010] ‘Zentmyer’ was developed at Riverside, Calif. The maternal parent is ‘Thomas’ (U.S. Plant Pat. No. 6,628) avocado variety. The pollen parent is unknown. Specifically, the ‘Zentmyer’ rootstock variety was selected in 1993 from an agricultural operations land located Riverside, Calif. The fruit were collected from the avocado breeding blocks, the seed removed, and planted in vermiculite. The seeds were grown in a greenhouse. The plants were inoculated with the fungus Phytophthora cinnamomi. After showing tolerance to the disease, ‘Zentmyer’ was selected as a single plant for further testing. Budwood was collected from the plants and grafted to the stumps of adult avocado trees that had been cut down at Irvine, Calif. The new varieties grew into trees which provided budwood for further testing. At least two ‘mother’ trees of the variety are growing in Irvine Calif., along with the germplasm. During screening and evaluation, ‘Zentmyer’, which was selected and originally designated ‘PP4’, distinguished itself from other varieties by having a high tolerance against Phytophthora root rot. The properties of ‘Zentmyer’ were found to be true to type and transmissible by asexual reproduction.
BRIEF SUMMARY OF THE INVENTION
[0011] This invention relates to a new and distinct avocado variety. ‘Zentmyer’ is an avocado tree having a rootstock that has a high tolerance against Phytophthora root rot under most conditions. However, it is severely damaged by salt and is not recommended for locations where salt is a problem. This variety also does not yield well under non-root rot conditions in comparison to similar varieties. For these reasons it may be an excellent choice for replant situations where root rot infested soils are a problem.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 illustrates a nine-year-old top-worked tree of the ‘Zentmyer’ variety while growing in Irvine, Calif.
[0013] FIG. 2 illustrates typical mature foliage of the ‘Zentmyer’ variety with dimensions in centimeters shown at the right.
[0014] FIG. 3 illustrates typical flush foliage of the ‘Zentmyer’ variety with dimensions in centimeters shown at the bottom.
[0015] FIG. 4 a illustrates typical inflorescence with dimensions in centimeters shown at the right and FIG. 4 b illustrates typical inflorescence by itself.
[0016] FIG. 5 illustrates a typical external view of the fruit of the ‘Zentmyer’ variety, with dimensions in centimeters shown at the bottom.
[0017] FIG. 6 illustrates typical internal views of the fruit of the ‘Zentmyer’ variety, with and without the seed. Dimensions in centimeters are shown at the bottom.
DETAILED DESCRIPTION OF THE INVENTION
[0018] The following is a detailed description of the new ‘Zentmyer’ variety, which was taken from an approximately nine-year-old mature tree, with the exception as a rootstock for a specific scion when reference is made to root rot resistance and salinity tolerance. The tree is located in a experimental orchard in Irvine, Calif. and is grafted on a Persea americana seedling used as a rootstock.
[0019] The Royal Horticulture Society (R.H.S.) color numbering system is used herein for the color description of the rind, seed, bark, leaf, flower, flesh color and other interest of the ‘Zentmyer’ avocado tree.
Trees, foliage, and flowers: Tree:
Growth habit.— vigorous, upright and spreading when compared to the rootstock ‘Thomas’. Vigor.— below are data on the vigor of ‘Hass’ grafted onto the rootstock of ‘Zentmyer’, as determined by trunk diameter measurements from trees planted in an orchard with Phytophthora cinnamomi in Escondido Calif.
[0000]
TABLE 1
Trunk diameter (cm)
Rootstock
year 1
year 2
year 3
year 4
year 5
PP#4 Zent.
2.40
4.39
7.12
9.20
11.25
Thomas
2.44
4.29
6.75
8.40
10.84
* Malone ranch, Escondido Ca., with Hass scion
[0000]
TABLE 2
Canopy volume (cubic feet)
Rootstock
year 1
year 2
year 3
year 4
year 5
PP#4 Zent.
14.81
77.27
397.4
410.
1573
Thomas
13.56
84.48
388.5
367.
1076
*Malone ranch, Escondido Ca., with Hass scion
Size.— medium. The typical canopy size of a three year old top-worked ‘Thomas’ is 388 cu. ft. By comparison the canopy size of a three year old top-worked ‘Zentmyer’ is 397 cu. ft.
Branch:
Color.— the color of the one year old branch is green (RHS 144D). Smoothness.— the bark of a one year old branch is smooth. Lenticels.— the lenticles of a one year old branch are conspicuous.
Main stem:
Color.— grayed-green (RHS 197A and RHS 197D). Texture of bark.— corky.
Young shoot (flush):
Intensity of anthocyanin coloration.— weak. Color.— grayed-orange (RHS 166A). Conspicuousness of lenticles.— medium. Color of lenticels.— purple (RHS 185B). Size of lenticels.— 1.0 mm long. Concentration of lenticels.— +/−26 lenticels per square cm. Color of upper side.— grayed-orange (RHS 174A). Glossiness of upper side.— medium. Color of lower surface.— grayed-orange (RHS 177A).
Mature leaf:
Length.— 15.0 cm. Width.— 6.0 cm. Ratio length/width.— 2.5. Shape.— lanceolate. Color of upper side.— green (RHS 137A). Color of lower side.— green (RHS 138B). Glossiness of upper side.— medium. Prominence of veins on lower side.— prominent and in relief. Color of veins.— yellow-green (RHS 151A). General shape and cross-section.— concave. Reflexing of apex.— absent. Color of petiole.— yellow-green (RHS 144A). Anise aroma.— absent. Margin.— leaf margin is very weak. Leaf apex shape.— acuminate. Leaf base shape.— lanceolate. Length of leaf petiole.— approximately 3.0 cm. Leaf arrangement.— upright.
Flower:
Bud size.— approximately 5 mm in length and approximately 4 mm in diameter. Bud shape.— ovoid. Bud color.— yellow-green (RHS 153A). Opening.— belongs to group “A”, male opening (i.e. with mature stamens) occurs in the afternoon, the flower closes over night, and female opening (i.e. with mature pistil) occurs the next morning; the flower's opening cycle lasts 20-24 hours. Petals.— borne in two whorls of three perianth lobes. The petals possess entire margins and petal coloration is near yellow-green (RHS N144B). Stamen.— there are commonly nine fertile stamens with each having two basal orange nectar glands and three staminodia. The anthers are tetrathecal. Pistil.— the single pistil with a slender style and small stigmatic surface has one carpel with one ovule. The ovary is superior. Pedicel.— commonly approximately 7 mm in length and approximately 1.9 mm in diameter. The coloration is near yellow-green (RHS N144A). Number of flowers on inflorescence.— approximately 170-200 flowers per inflorescence. Fragrance.— absent. Bloom.— bloom period at Riverside, Calif. experiment station varies with cultural conditions. On average ‘Zentmyer’ has been found to bloom from 1st of February through 20th of March.
Fruit, fruit and production characteristics:
Fruit:
Length.— 9.5 cm. Width.— 5.5 cm. Ratio length/width.— 1.7. Shape.— oblong. Color of skin ( when ripe ).—yellow-green (RHS 144A) with some patches of purple (RHS N79). Texture of skin.— smooth. Presence of longitudinal ridges.— absent. Thickness of skin.— thin. Adherence of skin to flesh.— strong. Main color of flesh.— yellow-green (RHS 154C). Color of intensely colored area of flesh next to skin.— green (RHS 140A). Width of intensely colored area next to skin.— 3.0 mm. Conspicuousness of fibers in flesh.— inconspicuous.
Seed:
Length.— 5.6 cm. Width.— 3.4 cm. Shape ( in longitudinal section ).—elliptical. Shape ( in cross section ).—circular. Color of seed coat ( fresh ).—grayed-orange (RHS 166B). Time of harvesting.— ‘Zentmyer’ fruit ripen in September (in Riverside Calif.). Resistance to pests.— strong resistance to Phytophthora cinnamomi. Tolerance to salinity.— sensitive to salinity. Market use.— the fruit of ‘Zentmyer’ are not intended for market use, but rather the variety is used as a rootstock onto which commercial varieties, such as ‘Hass’ are grafted.
[0000]
TABLE 3
Rootstock rating at San Ron Ranch,
Santana, Ventura County, August 2001 1
Tree rating
Canopy
Trunk
No.
(0-5;
volume
diameter
trees
Rootstock
5 = dead)
(cu ft)
(cm)
dead
Steddom
0.80
a
13.89
a
1.92
a
1
Merensky II
0.90
a
15.10
a
1.48
a
1
Uzi
0.90
a
16.92
a
2.02
a
0
Zentmyer
1.05
a
16.48
a
2.05
a
1
G755A (Brokaw)
1.65
a
5.55
a
1.62
a
1
Medina
1.90
a
12.66
a
1.70
a
2
Berg
2.20
a
13.80
a
1.29
a
4
McKee
2.35
a
9.05
a
1.52
a
1
Duke 7
2.50
a
11.40
a
1.24
a
4
Thomas
2.65
a
10.22
a
1.15
a
4
G755 A (C&M)
2.75
a
11.66
a
1.49
a
2
UC 2023
3.00
a
6.21
a
1.25
a
3
1 Mean values in each column followed by identical letters are not statistically different according to Waller's k-ratio t test.
[0000]
TABLE 4
Rootstock rating at San Ron Ranch, Santana, Ventura County, November 2002.
Two-year trial to-date.
Tree rating
Canopy
Trunk
Fruit rating
Tip burn
Canker
No.
(0-5;
volume
diameter
(0-5;
rating
rating
trees
Rootstock
5 = dead)
(cu ft)
(cm)
5 = heavy)
(0-5)
(0-5)
dead
Merensky II
0.17
d
72.27
abc
3.49
ab
0.78
bcd
0.00
a
0.33
a
0/9
Uzi
0.50
cd
69.64
abcd
3.64
a
2.50
a
0.33
a
0.00
a
1/10
Steddom
1.00
bcd
67.95
abcd
2.94
abc
1.70
abc
0.25
a
0.00
a
2/10
Medina
1.06
bcd
79.89
ab
3.26
ab
0.00
d
0.75
a
0.00
a
1/9
Zentmyer
1.50
bcd
81.44
a
3.19
ab
0.60
bcd
0.38
a
0.63
a
1/10
Duke 7
1.67
bcd
32.48
abcde
2.31
abcd
1.11
abcd
0.38
a
0.38
a
3/9
Berg
1.72
bcd
46.57
abcde
2.21
abcd
2.00
ab
0.17
a
0.83
a
3/9
McKee
1.78
abcd
30.92
bcde
2.24
abcd
0.22
cd
0.43
a
0.29
a
2/10
G755A (Brokaw)
2.30
abcd
19.98
de
1.90
bcd
0.10
d
0.29
a
0.14
a
3/10
Thomas
2.60
abc
31.50
bcde
2.02
abcd
0.30
cd
0.17
a
1.00
a
4/10
UC 2023
2.95
ab
25.50
cde
1.41
cd
0.20
d
0.00
a
0.00
a
5/10
G755A (C&M)
4.00
a
15.71
e
0.82
d
0.00
d.
—
—
8/10
[0000]
TABLE 5
Tajiquas Ranch {Leo Curillo) rootstock rating, December 2003.
Three-year trial to-date.
Tree rating
Canopy
Trunk
Fruit rating
Salt rating
Canker
No.
(0-5;
vol
diam
(0-5;
(0-5;
rating (0-5;
trees
Rootstocks
5 = dead)
(cu ft)
(cm)
5-heavy)
5 = severe)
5-severe)
dead (%)
Zentmyer
0.313
d
48.0
ab
6.45
a
1.75
abc
0.00
a
0.00
a
0
Merensky II
0.556
cd
71.6
a
6.49
a
2.67
a
0.00
a
0.00
a
0
Steddom
0.677
bcd
47.2
ab
5.18
ab
2.00
ab
0.00
a
0.06
a
6
Parida
1.147
abcd
50.6
ab
4.91
ab
1.53
abcd
0.00
a
0.07
a
18
Evstro
1.353
abcd
49.6
ab
5.55
ab
2.29
ab
0.00
a
0.06
a
0
Merensky I
1.441
abcd
48.6
ab
5.01
ab
1.41
bcd
0.00
a
0.06
a
18
Guillemet
1.588
abc
39.6
b
4.58
b
0.41
d
0.00
a
0.08
a
22
Thomas
1.875
ab
43.4
ab
4.45
b
0.72
cd
0.00
a
0.08
a
29
UC 2023
2.188
a
27.2
b
4.07
b
0.31
d
0.08
a
0.00
a
19
VC 207
2.382
a
32.4
b
3.79
b
1.12
bcd
0.00
a
0.00
a
35
Mean values in each column followed by identical letters are not statistically different according to Waller's k-ratio t test.
[0000]
TABLE 6
Rootstock ratings of avocado trees planted in root
rot soil at Malone Ranch Plot 1, Escondido, July 2002
Tree
Fruit set
rating
Canopy
Trunk
rating
Tip
0-5;
volume
diameter
0-5;
Burn
Cankers
Dead
Rootstocks
5 = dead
Cu ft
Cm
5 = heavy
Number trees affected
Zentmyer
0.00
c
397.4
abc
7.12
bcd
1.53
cd
0
0
0/15
Rio Frio
0.00
c
313.5
cdef
6.33
cdef
2.13
bcd
0
0
0/16
Merens I
0.00
c
543.6
a
8.74
a
3.50
a
0
0
0/14
Merensk II
0.02
c
409.0
abc
7.81
abc
2.84
ab
0
1
0/17
VC 241
0.06
c
238.4
defg
6.19
defg
1.41
cd
0
0
0/16
Uzi
0.29
bc
504.3
ab
8.57
ab
2.76
ab
2
0
1/17
Steddom
0.36
bc
376.1
bcde
7.07
bcd
2.43
bc
0
0
1/14
Thomas
0.44
bc
388.5
bcd
6.75
cde
1.12
de
0
0
1/17
Guillemet
0.59
bc
192.0
fgh
4.90
fgh
1.12
de
3
1.
2/17
Spencer sdlg
0.63
bc
225.8
efg
5.24
efgh
1.56
cd
0
0
2/16
Leo
0.67
bc
288.2
cdef
5.89
defgh
1.60
cd
0
0
2/15
Spencer clonal
0.69
bc
163.8
fgh
4.65
gh
1.54
cd
0
0
5/16
Duke 7
1.00
b
129.3
gh
4.38
h
1.47
cd
0
0
3/15
G755A
0.16
b
294.1
cdef
5.86
defgh
1.56
cd
2
1
3/16
PolyN
4.12
a
65.6
h
1.26
i
0.24
e
0
0
14/17
[0000]
TABLE 7
Malone Field 1 rootstock trial tree ratio
April 2003 1 . Four-year trial to-date
Tree rating
Canopy
Trunk
Canker
Dead
(0-5;
volume
diam.
(0-5;
Fruit
trees
Rootstock
5 = dead)
(cu ft)
(cm)
Salt
5 = heavy)
rating 2
(%)
MerenI
0.00
d
551
ab
10.7
a
0.08
cd
0
a
2.97
abc
0
VC241
0.06
d
281
efgh
8.0
abc
0.03
cd
0
a
3.41
ab
0
Rio Frio
0.07
d
362
efcd
8.7
abc
0.00
d
0
a
3.73
a
0
Zentmyer
0.07
d
410
bcde
9.2
ab
0.32
bc
0
a
3.71
a
0
MerenII
0.18
d
532
abc
9.4
ab
0.21
dc
0.1
a
2.97
abc
0
Spen sdlg
0.36
d
263
efgh
6.9
bc
0.00
d
0
a
3.57
ab
7
Uzi
0.38
d
669
a
10.6
a
0.68
a
0
a
3.47
ab
6
Steddom
0.39
d
478
bcd
8.6
abc
0.32
bc
0
a
3.75
a
7
Thomas
0.47
cd
367
cdef
8.4
abc
0.62
ab
0
a
3.53
ab
6
Leo
0.77
cbd
274
efgh
7.3
abc
0.13
cd
0
a
3.29
ab
13
Guillemet
0.83
cbd
190
ghi
6.2
bc
0.13
cd
0
a
2.90
abc
13
Duke7
1.34
cb
127
hi
8.8
abc
0.16
cd
0
a
1.53
de
19
Spen cl
1.44
b
211
fghi
5.3
c
0.12
cd
0
a
2.35
bcd
23
G755A
1.69
b
322
defg
7.0
bc
0.25
cd
0
a
1.78
cd
25
PolyN
4.15
a
77
i
1.5
d
0.06
cd
0
a
0.29
e
82
1 Mean values in each column followed by identical letters are not statistically different according to Waller's k-ratio t test.
2 Fruit was rated in November 2003.
[0000]
TABLE 8
Malone Ranch Plot 1, Temecula,
yield 2003 1;2 . Four year trial to-date.
Fruit weight/
Number
Fruit
Rootstock
tree (kg)
fruit/tree
weight (kg)
Zentmyer
15.89
a
68.64
a
0.219
a
Uzi
13.99
ab
59.24
ab
0.19 5
ab
Spencer seedling
12.52
ab
56.27
ab
0.181
ab
Merensky II
11.83
ab
51.12
ab
0.185
ab
Rio Frio
10.87
abc
51.33
ab
0.187
ab
Steddom
10.01
abc
46.20
abc
0.175
abc
Thomas
8.50
abcd
40.12
abcd
0.154
abc
G755A
8.08
abcd
34.56
abcd
0.116
bc
VC241
7.44
bcd
31.75
bcd
0.202
ab
Guillemet
7.42
bcd
30.00
bcd
0.196
ab
Spencer clonal
6.99
bcd
32.00
bcd
0.136
abc
Merensky I
6.95
bcd
32.08
bcd
0.148
abc
Leo
6.53
bcd
28.14
bcd
0.140
abc
Duke 7
3.33
cd
14.81
cd
0.138
abc
PolyN
1.72
d
5.71
d
0.076
c
1 Mean values in each column followed by identical letters are not statistically different according to Waller's k-ratio t test.
2 Only fruit which were grade size were picked; remaining fruit on trees to be picked later.
[0000]
TABLE 9
Malone II, Escondido, Tree ratings, July 2002
Tree rating
Canopy vol.
Trunk
No. trees
No. trees
No. trees
Rootstock
(0-5; 5 = dead)
(cu ft)
diam (cm)
Dead
w/tip burn
w/canker
Uzi
0.039 b
34.69 a
2.43 a
0
6
0
Guillemet
0.042 b
22.86 a
2.06 a
0
4
0
Zentmyer
0.077 b
22.40 a
2.25 a
0
2
0
Spencer sdlg
0.536 b
27.81 a
2.01 a
0
2
1
Steddom
0.615 b
18.93 a
1.99 a
1
0
0
Berg
0.714 b
21.42 a
1.98 a
0
1
2
Merensky II
0.750 b
32.07 a
2.10 a
2
0
1
Elinor
0.786 b
29.44 a
2.03 a
1
0
2
Thomas
0.846 b
23.07 a
1.85 a
1
2
0
Pond
1.00 ab
30.55 a
2.15 a
1
0
2
Crowley
1.083 ab
23.78 a
1.86 a
2
1
0
G755A
1.231 ab
22.64 a
1.85 a
2
0
0
Duke 9
2.270 a
9.40 a
1.07 b
5
0
0
There were significant differences at P = 0.01 between blocks for all tree parameters analyzed.
[0000]
TABLE 10
Malone H, tree ratings, April 2003. Two-year trial to-date.
Tree rating
Canopy
Trunk
Fruit rating
Salt rating
Canker rating
(0-
vol
diam
(0-5;
(0-5;
(0-5;5 =
No. trees
Rootstock
5;5 = dead)
(cu ft)
(cm)
5 = heavy)
5 = severe)
severe)
Dead (%)
Uzi
0.267 c
88.76 a
4.193 a
0.0 a
0.933 ab
0.000 a
0
Berg
0.531 c
44.16 a
2.956 bc
0.0 a
0.633 abcd
0.000 a
6
Zentmyer
0.600 c
54.37 a
3.393 ab
0.0 a
1.000 a
0.000 a
7
Merensky II
0.833 bc
68.49 a
3.333 ab
0.0 a
0.154 cd
0.308 a
13
Steddom
0.867 bc
56.42 a
3.127 ab
0.0 a
0.321 bcd
0.286 a
7
Pond
0.906 bc
55.05 a
3.188 ab
0.0 a
0.767 abc
0.200 a
6
Spenser sdlg
0.906 bc
51.45 a
2.988 bc
0.0 a
0.300 bcd
0.200 a
6
Crowley
0.964 bc
42.05 a
3.021 bc
0.0 a
0.083 d
0.000 a
14
Thomas
1.071 bc
49.99 a
2.900 bc
0.0 a
0.731 abc
0.000 a
0
Guillemet
0.167 abc
43.64 a
2.960 bc
0.1 a
0.615 abcd
0.133 a
13
Elinor
1.393 abc
58.40 a
2.864 bc
0.0 a
0.333 bcd
0.167 a
14
G755A
2.156 ab
44.21 a
2.819 bc
0.0 a
0.846 ab
0.077 a
13
Duke 9
2.577 a
32.16 a
1.885 c
0.0 a
0.313 bcd
0.500 a
38
[0000]
TABLE 11
Smith Ranch, Santa Paula, rootstock rating, December 2002
Tree rating
Salt burn
(0-5;5 =
Canopy
Trunk
(0-5;
Trees
Rootstock
dead)
vol (cu ft)
diam (cm)
Fruit set
5-heavy)
Cankers
dead (%)
McKee
0.00 b
51.41 a
3.45 bc
0.00 a
0
0
0
Merensky II
0.00 b
53.45 a
3.66 ab
0.00 a
0
0
0
Pond
0.00 b
55.08 a
3.69 a
0.00 a
0
0
0
Guillemet
0.00 b
37.98 b
2.71 f
0.00 a
0
0
0
Zentmyer
0.00 b
51.92 a
3.38 cd
0.00 a
0
0
0
Thomas
0.00 b
36.66 b
3.15 de
0.00 a
0
0
0
Crowley
0.03 b
34.91 b
3.17 d
0.05 a
0
0
0
Duke 9
0.05 b
31.93 b
2.93 ef
0.00 a
0
0
0
Steddom
0.27 a
37.14 b
2.75 f
0.00 a
0
0
0
Mean values in each column followed by identical letters are not statistically different according to Waller's k-ratio.
[0000]
TABLE 12
Smith Ranch, Santa Paula, rootstock rating, December 2003. Two-year trial
to-date.
Trunk
Salt burn
Tree rating
Canopy vol
diam
Fruit
(0-5;
Trees dead
Rootstock
(0-5;5 = dead)
(cu ft)
(cm)
set
5-heavy)
Cankers
(%)
McKee
0.025b
184.1b
5.88bc
1.90ab
0
0
0
Merensky II
0.000b
246.8a
6.18abc
2.60a
0
0
0
Pond
0.000b
192.0b
6.24ab
0.00d
0
0
0
Guillemet
0.000b
118.8cd
5.38de
0.00d
0
0
0
Zentmyer
0.026b
182.8b
6.41a
1.32bc
0
0
0
Thomas
0.237a
174.9b
5.72cd
0.47cd
0
0
0
Crowley
0.150ab
124.7c
5.42de
2.15ab
0
0
0
Duke 9
0.053ab
132.6c
5.19e
1.89ab
0
0
0
Steddom
0.083ab
86.3d
5.00e
2.00ab
0
0
0
Mean values in each column followed by identical letters are not statistically different according to Waller's k-ratio t test . . .
[0000]
TABLE 13
Weaver Ranch, Temecula rootstock ratings, Sept 2002
Tree rating
Canopy
Trunk
Fruit rating
Salt
Cankers
(0-5;
vol.
diam
(0-5;
damage (0-
(0-5;
No. trees
Rootstock
5 = dead)
(cu ft)
(cm)
5 = heavy)
5; 5 = heavy)
5 = heavy)
dead
Zentmyer
0.400 c
40.70 ab
2.79 a
0.00 b
1.50 ab
0.00 a
0/15
Crowley
0.618 c
40.38 ab
2.86 a
0.00 b
1.34 b
0.00 a
1/17
Elinor
0.824 c
40.52 ab
2.54 a
0.00 b
1.59 ab
0.00 a
1/17
Guillemet
0.882 bc
39.13 ab
2.42 a
0.00 b
1.41 b
0.00 a
2/17
Steddom
0.969 bc
29.20 bc
2.13 ab
1.16 a
1.54 ab
0.50 a
2/16
Thomas
0.969 bc
31.46 bc
2.13 ab
0.00 b
1.50 ab
0.00 a
3/16
Pond
1.088 bc
54.08 a
2.78 a
0.00 b
1.40 b
0.00 a
2/17
Uzi
1.188 bc
35.08 ab
2.56 a
0.00 b
1.64 ab
0.00 a
2/16
G755A
2.088 ab
37.85 ab
2.41 a
0.00 b
2.50 ab
0.36 a
4/17
Spencer sdlg
2.906 a
11.96 c
1.39 b
0.00 b
2.63 a
0.00 a
4/16
[0000]
TABLE 14
Weaver Ranch, Temecula, rootstock ratings, December 2003. Two-year trial
to-date.
Tree rating
Canopy
Trunk
Fruit rating
Salt damage
Cankers
Trees
(0-5;
vol
diam
(0-5;
(0-5;
(0-5;
dead
Rootstock
5 = dead)
(cu ft)
(cm)
5 = heavy)
5 = heavy)
5 = heavy)
(%)
Zentmyer
0.313c
207.27a
6.23a
2.063a
1.188ab
0.000a
0
Pond
0.906c
307.04a
5.75a
1.813a
0.321cd
0.000a
13
Elinor
0.912c
170.37a
4.80a.
1.059a
0.469cd
0.000a
6
Guillemet
1.059c
199.37a
5.73a
0.882a
0.893abc
0.000a
18
Uzi
1.094bc
206.04a
4.35a
0.813a
0.769abcd
0.000a
19
Crowley
1.250bc
144.14a
5.04a
1.438a
0.731abcd
0.000a
19
Steddom
1.281bc
254.94a
4.89a
1.188a
0.167d
0.000a
25
Thomas
1.313bc
226.39a
5.16a
1.375a
1.308a
0.000a
19
G755A
2.438ab
175.55a
5.23a
0.625a
1.167ab
0.000a
25
Spencer sdlg
2.813a
42.12a
2.26a
0.519a
0.500bcd
0.000a
44
|
A new and distinct variety of Persea americana tree having a high tolerance under most conditions to Phytophthora cinnamomi when used as a rootstock. However, it is severely damaged by salt and is not recommended for locations where salt is a problem. This variety does not yield well under non-root rot conditions in comparison to similar varieties, making it desirable for replant situations where root rot infested soils are a problem.
| 0 |
This is a divisional application of Ser. No. 07/677,024, filed on Mar. 28, 1991, now U.S. Pat. No. 5,148,185, issued on Sep. 15, 1992, which is a continuation of application Ser. No. 07/499,233, filed on Mar. 26, 1990, now abandoned, which is a continuation of application Ser. No. 07/060,206, filed on Jun. 10, 1987, now U.S. Pat. No. 4,914,562, issued on Apr. 3, 1990.
BACKGROUND OF THE INVENTION
This invention relates generally to an ink jet recording apparatus which ejects ink through a plurality of nozzles supplied by an ink reservoir, and especially to a thermal ink jet recording apparatus which ejects ink through a plurality of nozzles without the need for separators between nozzles and an improved ink composition for use in the apparatus.
Thermal ink jet recording apparatus are well known in the art and provide high speed and high density ink jet printing having a relatively simple construction. Conventional ink jet recording apparatus and methods are described in the May, 1985 issue of the Journal of the U.S. Hewlett-Packard Company, hereinafter referred to as the Hewlett-Packard Journal, as well as in U.S. Pat. Nos. 4,359,079; 4,463,359; 4,528,577; 4,568,593 and 4,587,534.
The recording speed and density at which such conventional ink jet recording apparatus operate is limited. In order to protect the pressure of the heated ink underneath any one particular nozzle from affecting the pressure of ink under an adjacent nozzle, a barrier is placed between adjacent nozzles to prevent pressure interference. These barriers must be very thin in order to accommodate a plurality of nozzles on one recording head. Nevertheless, the pitch (i.e., spacing) between adjacent nozzles is still limited because of the need to place a barrier, no matter how thin, between each adjacent nozzle.
Additionally, thin film circuitry is covered by a protective layer of a hard insulated inorganic matter for protecting the heating elements and electrodes which are used to heat the ink from electrical, chemical, thermal and/or acoustic damage. This protective layer acts as a heat sink requiring more heat than would otherwise be required in order to reheat the ink to an appropriate temperature for ejection of the ink through the nozzles. This requires a longer period of time to heat the ink thereby reducing the speed at which the apparatus records. Further, small structural defects such as minute cracks in the protective layer can leave the thin film circuitry unprotected. Since it is difficult to produce protective layers without such small structural defects, the reliability of conventional thermal ink jet apparatus can be quite low.
It is also difficult to control the thickness of the protective layer during its manufacture. The thicker the protective layer, the less responsive the protective layer is to changes in the temperature of the heating element which it covers. Consequently, the heating element cools off much more quickly than the protective layer resulting in the ink adhering to the protective layer. As ink begins to build up heat conduction from the heating element to the ink is adversely affected and can eventually result in the inability to cause the ejection of ink through the nozzles.
The ink jet recording apparatus described in the Hewlett-Packard Journal includes a nozzle plate which covers a substrate on which the electrodes and heating elements are disposed. This nozzle plate, which is made by Ni electroforming, includes minute projecting portions provided on the interior surface thereof for ensuring that a gap of a predetermined height exists between the nozzle plate and substrate. The height of the gap is important to the operation of the ink jet recording apparatus since the amount of ink to be heated depends on the ink trapped within the gap. These minute projecting portions also must be of uniform height to ensure that the ink ejected through each nozzle inpinges the recording medium with the same desired inpact. In view of the foregoing it is essential to provide these minute projecting portions which makes manufacture of the nozzle plate difficult. The substrate and nozzle plate are adhesively bonded. The adhesive bonding material which deteriorates when contacted by ink and deposits can clog the nozzles of the nozzle plate adversely affecting the operation of the apparatus.
In addition to the above problems, the recording paper used for prior art ink jet recording apparatus varies significantly in the pulp, filler or other materials which are contained therein and in its manufacturing process (e.g., wire part, size press). Wood free paper such as described in the Hewlett-Packard Journal is widely used for ink jet recording apparatus. Other wood free paper applicable for use as a recording medium for thermal ink jet recording apparatus include, Japanese Industrial Standards for print A, drawing paper (such as document and Kent paper) and coated paper. Unfortunately, conventional ink has a tendency to significantly blot/spatter wood free paper and thus hinders achieving high quality printing.
Accordingly, it is desirable to provide an ink jet printer having a simplified construction which eliminates the need for barriers between adjacent nozzles. It is also desirable to provide an ink composition suitable for use in the ink jet printer which avoids the blotting problem on wood free paper generally associated with conventional ink compositions.
SUMMARY OF THE INVENTION
In accordance with the invention, a recording apparatus for ejecting ink through nozzles of the apparatus onto a recording medium including a substrate having a front and a back surface, at least two ink supply portions passing from the back surface to the front surface, a plurality of heating elements disposed in rows on the front surface in at least two groups, each group consisting of two rows of heating elements, one row being arranged on each side of the ink supply portion. Each of the groups of the heating elements is associated with a single color ink. This placement of the heating elements in at least two rows on either side of the ink supply portion insures a smooth and uniform ink supply to the area above the heating elements.
In order to allow for printing in at least two colors of ink, each group of nozzles and associated ink supply portion are aligned with an independent space between the nozzle plate and the substrate. Each independent space and its corresponding group of nozzles and ink supply portion is associated with a single color ink and group of heating elements.
The substrate contains means for independently delivering ink of one color from one of a at least two ink reservoirs to each of the spaces containing an ink supply portion and a group of heating elements associated with a single color. In this way, through delivery of colored ink from any particular ink reservoir to a group of heating elements associated with the color of the particular ink reservoir, printing can be independently effected in at least two colors of ink.
Accordingly, it is an object of this invention to provide a thermal ink jet recording apparatus for printing in at least two colors of ink.
It is another object of the invention to provide a thermal ink jet recording apparatus for printing in at least two colors of ink whereby a smooth and uniform ink supply is insured.
It is another object of the invention to provide a thermal ink jet recording apparatus whereby at least two colors of ink are independently delivered to each individual heating element and nozzle associated with a particular color of ink.
Still other objects and advantages of the invention will in part be obvious and will in part be apparent from the specification.
The invention accordingly comprises several steps and the relation of one or more of such steps with respect to each of the others, and the device embodying features of construction, combination of elements and arrangements of parts which are adapted to effect such steps, all is exemplified in the following detailed disclosure, and the scope of the invention will be indicated in the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
For a fuller understanding of the invention, reference is made to the following description taken in connection with the accompanying drawings, in which:
FIG. 1 is a fragmentary perspective view partially in cross-section of a conventional thermal ink jet recording head;
FIG. 2 is a fragmentary cross-sectional view of another conventional thermal ink jet recording head;
FIG. 3 is a fragmentary perspective view of a thermal ink jet recording apparatus in accordance with one embodiment of the invention;
FIG. 4 is a perspective view partially in cross-section of a thermal ink jet recording head shown in FIG. 3;
FIG. 5 is a cross-section view of the head taken along lines 5--5 of FIG. 4;
FIG. 6 is an exploded perspective view of the substrate, film circuit formed thereon and base of the recording head of FIG. 4;
FIG. 7 is a fragmentary perspective view of the substrate and base of FIG. 6 joined together with the substrate being cut to form two separate substrates;
FIG. 8 is an exploded perspective view of the substrates and base of FIG. 7, a nozzle plate, base plate, filter and ink supply line;
FIG. 9 is a perspective view similar to FIG. 4 of the assembled recording head of FIG. 8;
FIG. 10 is a block diagram of a time-sharing drive circuit CPU and other circuitry of the apparatus;
FIG. 11 is an electrical schematic of the time-sharing drive circuit of FIG. 10;
FIG. 12 is a timing diagram illustrating the operation of the time-sharing drive circuit of FIG. 11;
FIGS. 13(a), (b) and (c) and FIGS. 14(a) and (b) are fragmentary perspective views partially in cross-section of thin film circuits in accordance with alternative embodiments of the invention;
FIGS. 15(a) and (b) are fragmentary top plan views of a damaged heating element;
FIGS. 16 (a), (b), (c), (d) and (e) are fragmentary, side elevational views in cross-section of heating elements underneath nozzles during expansion and contraction of air bubbles;
FIGS. 17(a), (b), (c) and (d) and FIGS. 18(a), (b) and (c) are fragmentary top plan views of heating elements in accordance with additional alternative embodiments of the invention;
FIGS. 19(a), (b), (c) , (d) and (e) are fragmentary top plan views of heating elements in accordance with other alternative embodiments of the invention and FIGS. 19(f), (g) and (h) are fragmentary side elevantional views in cross-section of thin film circuitry illustrating the heating element of FIGS. 19(a), (b) and (e);
FIGS. 20(a) and (b) are side elevational views in cross-section of a recording head in accordance with alternative embodiments of the invention;
FIG. 21 is a fragmentary side elevational view in cross-section of the recording head taken along lines 21--21 of FIG. 4;
FIG. 22 is a timing diagram illustrating the voltages applied to the heating elements of FIG. 21;
FIG. 23 is a graph of the ejecting speed of ink droplets versus time interval of Tint of FIG. 22;
FIG. 24(a) is a diagrammatic top plan view of two nozzles of the recording head shown in FIG. 4 and FIG. 24(b) is a timing diagram of the voltages applied to the two nozzles of FIG. 24(a);
FIG. 25 is a perspective view partially in cross-section of a multicolored recording head in accordance with another alternative embodiment of the invention;
FIGS. 26 and 27 are perspective views partially in cross-section of additional alternative embodiments in accordance with the invention;
FIG. 28 is a fragmentary perspective view of a thermal ink jet recording apparatus in accordance with yet another alternative embodiment of the invention; and
FIG. 29 is a side elevational view partially in cross-section taken along lines 29--29 of FIG. 28.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
FIGS. 1 and 2 illustrate conventional recording heads 50 and 80 of thermal ink jet recording apparatus manufactured by Canon Kabushiki Kaisha and Hewlett-Packard Company, respectively. As shown between FIGS. 1 and 2, an ink supply conduit 51 provides ink 53 to a reservoir 61. Heating elements 52 are in electrical contact with electrodes 57 through which current flows to heat elements 52. Ink 53 within reservoir 61 is heated by heating elements 52 to raise the pressure of ink 53 directly underneath nozzle 59 for ejecting ink 53 through nozzles 59 and onto a recording medium. As shown in FIG. 1, heating elements 52 and electrodes 57 are covered by an antioxidizing layer 64 on top of which is an absorbing layer 63. Layer 63 is covered by a layer 62 for preventing corrosion of a photo-sensitive resin 69 (shown only in FIG. 2). Windows 66 directly above heating elements 52 and below nozzles 59 provide openings through which heated ink 53 expands. A plurality of barriers 71 are placed between adjacent nozzles 59 to transform reservoir 61 into a plurality of separated ink wells with one well dedicated to each nozzle 59. Barriers 71 thereby eliminate inadvertent ejection of ink due to pressure interference between adjacent nozzles (hereinafter refered to as cross talk). A thin film 75, shown in FIG. 2, typically made of an inorganic material covers and is next adjacent to heating elements 52 and electrodes 57 to protect the latter from electrical chemical, thermal and acoustic damage.
As mentioned heretofore, barriers 71 must be made minutely and even then limit the pitch/spacing between adjacent nozzles 59. Furthermore, and as previously noted, film layer 75 due to acting as a heat sink dissipates the heat generated by heating element 52 more quickly than may be desired. Consequently, more heat may need to be generated by heating element 52 then would otherwise be necessary if layer 75 were not present. Inasmuch as the protection afforded by film layer 75 is significantly negated in the event of a structural defect therein, it is necessary to provide a fairly thick film layer which, of course, accentuates the heat sink affect of film layer 75. Film layer 75 also exhibits thermal hysteresis, that is, when the voltage applied to electrodes 57 has a high frequency, the temperature of layer 75 lags behind the temperature of heating element 52. Consequently, as the temperature of heating element 52 is reduced by lowering the current flowing through electrodes 57, ink 53 begins to stick to the hotter surface of protective layer 75. Accordingly, heat conduction from heating element 52 to ink 53 deteriorates and can eventually prevent ejection of ink 53 through nozzles 59. The foregoing drawbacks in the prior art are overcome by device 100 as will now be discussed.
Referring now to FIG. 3, a portion of an ink jet recording apparatus 100 includes a recording head 105 which is supplied with an ink 250 (not shown) from an ink source 109 through a pipe 108. Head 105 is coupled to a carriage guide 110. Information is recorded onto a recording medium 111 by head 105. Recording paper 111 is advanced (in a direction denoted by arrow C) by traveling between a guide roller 114 and a platen 117; the latter of which is driven by a paper feed motor 121 via a gear 124 and shaft 125 in a direction denoted by an arrow D. Advancement of paper 111 in a direction C is synchronized with a reciprocating motion denoted by an arrow B of recording head 105. A carriage motor 127 having a carriage belt 131 travels in a reciprocating motion denoted by arrow A. Recording head 105 is operably coupled to carriage belt 131 to provide the reciprocating motion denoted by arrow B.
Head 105 which is shown in greater detail in FIGS. 4 and 5, includes a plate 151 having an opening 153 to which pipe 108 is connected. A base 161 made of resin or metal is integrally connected and disposed above plate 151 and has an opening therein which serves as a reservoir 167. Reservoir 167 is centered about opening 153. A filter 171 is disposed on the top surface of plate 151 covering opening 153. A pair of substrates 174 and 177 are separated from each other to form a gap 211 therebetween and connected to base 161 with a portion of each substrate extending over reservoir 167. The distance separating substrates 174 and 177, that is, the distance of gap 211, is denoted by distance W shown in FIG. 5 and is preferably between 100-500 μm. A plurality of electrodes 181 and heating elements 184, which hereinafter are referred to as thin film circuitry, are disposed on substrates 174 and 177. Electrodes 181 are electrically serially connected to heating elements 184. A voltage source 187 is electrically serially connected to electrodes 181 and heating elements 184 through a corresponding plurality of switches 191. A stepped nozzle plate 194 is disposed on top of and connected to substrates 174 and 177. Nozzle plate 194 has a lower step portion 197 and an upper step portion 201. The outer perimeter of lower step 197 is substantially rectangular, is connected to and covers most of the top surface of substrates 174 and 177 except near the edges of substrates 174 and 177. Upper step portion 201 includes a plurality of air vent holes 204 and a plurality of openings which serve as and form rows of nozzles 207. Each nozzle 207 is substantially directly above a heating element 184 such that their center lines are coincident. The pitch P between adjacent nozzles and between adjacent heating elements is preferably about 100 μm or greater. Nozzles 207 preferably have diameters of about 10-100 μm and desirably of about 30-60 μm based on recording densities and solid-state properties of ink. These solid-state properties include viscosity, surface tension and mixing ratio of coloring materials. The straight line distance between the center line of gap 211 which extends in a direction perpendicular to the plane formed by upper step portion 201, and the center of nozzle 207 is represented by H. Distance H is preferably about 100-800 μm. The centers of nozzle 207 and the nearest air vent hole 204 is separated by a straight line distance I which is preferably about 100-700 μm. A perpendicular distance G between the bottom surface of upper step portion 201 of nozzle plate 194 and electrode 181 is preferably about 15-80 μm and desirably about 25-40 μm. Plate 151 and base 161 have substantially rectangular block shapes. Gap 211 has a length L as measured in the direction in which the rows of heating elements 184 and nozzles 207 extend. A sealant 215 such as a thermoset sealing compound is used to provide a seal to fill that portion of gap 211 existing at the entrance to nozzle plate 194 so as to prevent leakage of ink therethrough.
Head 105, as shown in FIGS. 4 and 5, can be viewed as including three different cross-sectional areas, which together promote capillary action in ejecting droplets of ink through the plurality of nozzles. The first cross-sectional area is formed by perpendicular distance G (between the bottom surface of upper step portion 201 of nozzle plate 194 and electrode 181) and length L. The second cross-sectional area is formed by distance W of gap 211 and length L. The third cross-sectional area is formed within reservoir 167 between the interior sidewalls of base 161 represented by a width R and length L. As can be readily appreciated, since distance G is less than distance W which is less than width R, the first cross-sectional area is less than the second cross-sectional area which is less than the third cross-sectional area thereby promoting capillary action in ejecting droplets of ink through the plurality of nozzles.
Construction of recording head 105 is as follows. A substrate 173 having a substantially flat rectangular block shape with a thin film circuit of electrodes 181 and heating elements 184 formed thereon is adhesively bonded to base 161. A registration mark 219 is located near each of the four corners of substrate 173 with an apex of each registration mark 220 located at a predetermined distance of about 1-3 μm from the nearest row of heating elements 184. Registration marks 219 are formed during manufacture of the thin film circuitry. A cutting element such as, but not limited to, a dicing saw 225 is then used to cut substrate 173 into substrates 174 and 177 with gap 211 therebetween as shown in FIG. 7.
After the swarfs produced in cutting substrate 173 are removed by, for example, ultrasonic cleaning, nozzle plate 194 is adhesively bonded to substrates 174 and 177 as shown in FIG. 8. Prior to bonding, nozzle plate 194 is positioned on substrates 174 and 177 such that apexes 220 of registration marks 219 coincide with a plurality of apexes 229 of registration marks 228 on nozzle plate 194. Registration marks 228 are formed during manufacture of nozzle plate 194 by electroforming and press-etching and the like. Furthermore, apexes 229 of registration marks 228 are located at a predetermined distance of about 2-6 μm from nozzles 207. Consequently, heating elements 184 are substantially directly (i.e., within a tolerance of 3-9 μm underneath nozzles 207. As can be readily appreciated, it is preferable to provide registration marks on lower step portion 197 of nozzle plate 194 rather than on upper step portion 201 to avoid any error due to parallax. Of course, the position of registration marks 219 and 228 shown near the corners of substrate 173 and lower step portion 197 of nozzle plate 194, respectively, have been set forth for explanatory purposes only. These registration marks can be repositioned in other suitable locations provided the necessary alignment of heating elements 184 with nozzles 207 can be obtained. Nozzle plate 194 and substrates 174 and 177 are bonded together with an adhesive 231 (shown in FIG. 4) near the edge of lower step portion 197 such that ink 250 cannot contact adhesive 231 during operation of recording head 105. Thereafter, plate 151 with filter 171 already positioned thereon is attached to base 161. Finally, sealant 215 is provided to seal gap 211 between substrates 174 and 177 at the entrance to nozzle plate 194 to prevent ink leakage therethrough. The assembled recording head 105 is shown in FIG. 9.
Referring once again to FIG. 5, operation of recording head 105 is as follows. Ink 250 is provided by source 109 through pipe 108 past filter 171 to reservoir 167 as well as all other areas under upper step portion 201 of nozzle plate 194. Any air which may be within reservoir 167 or otherwise under upper step portion 201 escapes through air vents 204. When a particular nozzle 207 is required to eject ink therethrough, the corresponding heating element 184 is heated by closing a corresponding switch 191. Ink 250 begins to expand due to the heat generated by element 184 raising the temperature of ink 250 next to heating element 184 to hear its boiling point resulting in the ejection of ink through the desired nozzle 207 as represented by dots of ink 253 in a direction shown by arrow E. The area heated by each heating element 184 preferably is between about three to twenty times the aperture area of each nozzle 207. Based on the foregoing, recording head 105 having 24 or 32 nozzles can eject 180 or 240 dots per inch (dpi), respectively.
Current is intermittently supplied to each heating element 184 through a corresponding switch 191 and electrode 181. A time-sharing driving circuit 290 which provides this intermittent flow of current to each heating element 184 is shown in block diagram form in FIG. 10. A central processing unit (CPU) 281 tied to a host computer 283 controls the operation of circuit 290 as well as other circuitry within apparatus 100 such as the circuitry associated with paper feed motor 121 and carriage motor 127. Recording data for selecting which of switches 191 are to be closed (that is, electrically turned on) is called sequentially from a character generator 287 in accordance with instructions from host computer 283. This recording data is then outputted to a plurality of latches 291 which store the recording data upon receiving a trigger signal TRG which is also outputted from CPU 281. A flip-flop 294 upon receiving trigger signal TRG enables an oscillator 297. The oscillating signal provided by oscillator 297 serves as a clock signal for a shift register 301. The output of flip-flop 294 is also connected to a flip-flop which serves as a single pulse generator 305 and to one of the two inputs of shift register 302. A single pulse provided by generator 305 based on the output of flip-flop 294 is supplied to the other input of shift register 301. These two inputs of shift register 301 are logically ANDED together. The recording data which is stored in latches 291 is connected to a plurality of heating element drivers 309. Each of the plurality of heating element drivers 309 includes one of the plurality of switches 191. The sequence and timing of which heating element driver is to be activated for closing one of the plurality of switches 191 is dependent upon the outputs of shift register 301. Therefore, by controlling the frequency of the oscillating signal produced by oscillator 297 and the recording data inputted into latches 291, current flow-through each heating element 184 can be delayed for a desired time interval to prevent inadvertently heating ink under adjacent nozzles resulting in cross-talk.
Time-sharing drive circuit 290 is schematically illustrated in FIG. 11 as follows. Latch 291 comprises three 8 bit registers 292, 293 and 294. A suitable register for each latch 292, 293 and 294 is part no. LS273. Flip-flop 294 is a dual flip-flop latch such as but not limited to a quarter package from a part no. LS08. Single pulse generator 305 includes a resistor R5 and a dual flip-flop latch such as, but not limited to, a half package from part no. LS74. Shift register 301 comprises three shift registers 302, 303 and 304 each having a serial input and eight parallel outputs such as part no. LS164. Each heat element driver 309 comprises an open collector transistor which serves as switch 191, an AND gate 310 and a resistor R1. AND gate 310 includes inputs 312 and 313. A suitable AND gate 310 includes a quarter package from a part no. 7409. Oscillator 297 includes a resistor R2, capacitor C1, a Schmidtt trigger NAND gate 320 (such as a quarter package from part no. HC132) and inverters 325 and 328 (such as from two of a six package part no. HC04). NAND gate 320 includes inputs 321 and 322. Additionally, although not specifically identified in FIG. 10, circuit 290 includes a flip-flop 335 similar to flip-flop 294, a NOR gate 341 have inverted inputs 342 and 343 and an inverter 339 similar to the inverters in oscillator 297. A suitable NOR gate is a quarter package from part no. LS08.
Time-sharing driving circuit 290-is electrically connected as follows. The clear input of latches 292, 293 and 294, inverted input 343 of NOR gate 341, and the inverted clear inputs of shift registers 302, 303 and 304 are connected to a Reset terminal. The clock inputs of flip-flop 295 and latches 292, 293 and 294 are connected to a trigger signal TRG terminal. The D input and inverted preset PR inputs of flip-flop 295 are connected to a positive d.c. voltage source through resistors R3 and R4, respectively. Single pulse generator 305 has its D input and inverted preset PR input connected to the positive d.c. voltage source through resistors R5 and R6, respectively. The inverted clear input of single pulse generator 305 is connected to the Q output of flip-flop 295. The Q output of flip-flop 295 is also connected to the B input of shift register 302 and to input 322 of NAND gate 320. The Q output of single pulse generator 305 is connected to the A input of shift register 302. The output of NAND gate 320 is connected to one end of resistor R2 and to the input of inverter 325. The other end of resistor R2 is connected to one end of a capacitor C1 and to input 321 of NAND gate 320. The other end of capacitor C1 is grounded. The output of inverter 325 is connected to the input of inverter 328. The output of inverter 328, which serves as the output for oscillator 297, is connected to each of the clock inputs of shift registers 302, 303 and 304. The Q A output of shift register 302 is connected to the clock input of single pulse generator 305. The Q H output of shift register 302 is connected to the B input of shift register 303. Similarly, the Q H of shift register 303 is connected to the B input of shift register 304. The Q H output of shift register 304 is connected to the input of inverter 339. The A inputs of shift registers 303 and 304 are connected to the positive d.c. voltage source through resistors R7 and R8, respectively. The output of inverter 339 is connected to the clock input of flip-flop 335. The D input and inverted preset PR input of flip-flop 335 are connected to the positive d.c. voltage source through resistors R9 and R10, respectively. The inverted clear input of flip-flop 335 is connected to the Q output of flip-flop 295. The Q output of flip-flop 335 is connected to inverted input 342 of NOR gate 341. The output of NOR gate 341 is connected to the inverted clock input of flip-flop 295. For each heating element driver 309, the output of AND gate 310 is connected to one end of a pull-up resistor R1 and to the base of transistor 191. The other end of pull-up resistor R1 is connected to a positive d.c. voltage source. The emitter of transistor 191 is grounded and the collector of transistor 191 is connected through one electrode 181 to one end of a corresponding heating element 184. The other end of heating element 184 is connected through one electrode 181 to voltage source 187. For illustrative purposes, only four of the twenty-four heating element drivers 309 corresponding to data lines DATA 1, DATA 9, DATA 17 and DATA 24 are shown in FIG. 11. The twenty-four outputs of shift register 301 (that is, outputs QA-QH of shift register 302, outputs QA-QH of shift register 303 and outputs QA-QH of shift register 304) are connected to corresponding inputs 313 of the twenty-four AND gates 310. Similarly, the twenty-four outputs of latch 291 (that is, Q 1 -Q 8 of latch 292, Q 1 -Q 8 of latch 293 and Q 1 -Q 8 of latch 294 are connected to corresponding inputs 312 of the twenty-four AND gates 310.
Referring now to FIGS. 11 and 12, operation of time-sharing driving circuit 290 with all recorded data on lines DATA 1-DATA 24 assumed at a high logic level for exemplary purposes only is as follows. Initially, no current flows through any heating elements 184 since the base of each transistor 191 is grounded due to the output of each AND gate 310 being at a low logic level. CPU 281 provides a RESET signal having a low logic level to the inverted clear inputs of latches 292, 293 and 294, inverted input 343 of NOR gate 341 and inverted clear inputs of shift registers 302, 303 and 304. Accordingly, the outputs of latches 292, 293 and 294 and shift registers 302, 303 and 304 are reset to a low logic level. Additionally, inasmuch as the Q output of flip-flop 335 is already at a high logic level, the output of NOR gate 341 is at a low logic level resulting in the inverted clear input of flip-flop 295 resetting the Q output thereof to a logic level of zero. Prior to applying a trigger signal TRG to clock inputs of flip-flop 295 and latches 292, 293 and 294, the Q, Q and Q outputs of flip-flop 295, single pulse generator 305 and flip-flop 335 are at low, high and high logic levels, respectively. A rectangular pulse trigger signal TRG is then provided to the clock inputs of flip-flop 295 and latches 292, 293 and 294. At the same time, the recording data on lines DATA 1-DATA 24 is provided to inputs D 1 -D 8 of latches 292, 293 and 294. These twenty-four data signals represent which of the twenty-four heating elements are to be heated. As previously stated, all twenty-four data signals will be assumed to be at a high logic level. Trigger signal TRG allows each of the data signals to be clocked to the outputs of latches 292, 293 and 294. Additionally, trigger signal TRG clocks the high logic level supplied to D input of flip-flop 295 by the positive voltage source to its Q output represented as signal FF1. With FF1 at a high logic level the clock and preset inputs of single pulse generator 305 are at low logic levels. Thus the Q output single pulse generator 305 (hereinafter referred to as FF2) remains at a high logic level which is supplied to input A of shift register 302. Oscillator 297 provides a high logic level until signal FF1 assumes a high logic level. Oscillator 297 then begins to produce an oscillating output represented hereinafter as CK. Signal CK is supplied to each of the clock inputs of shift registers 302, 303 and 304. With both signals FF1 and FF2 at high logic levels which are inputted to the B and A inputs of shift register 302, a high logic level is produced at Q A output of shift register 302 (which is hereinafter referred to as signal S1). Signal S1 is provided to both the clock input of single pulse generator 305 and input 313 of AND gate 310. Consequently, signal FF2 of single pulse generator 305 assumes a low logic level Signal S1 and Q1 of latch 292 which are now both at high logic levels result in the output of AND gate 310 assuming a high logic level thereby turning transistor 191 to its conductive state. Accordingly, a current il flows through the corresponding heating element 184 and will continue to flow until signal S1 assumes a low logic level which occurs upon the generation of the next signal CK. More specifically, since the A input of shift register 302 is now at a low logic level, the Q A output of shift register 302 will assume a low logic level upon seeing the leading edge of the next signal CK. Similarly, as other outputs of shift registers 302, 303 and 304 assume a high logic level, AND gates 310 which are tied to these outputs will assume high logic levels. Corresponding transistors 191 will then be switched to their conductive states resulting in current flow through corresponding heating elements 184. As can be readily appreciated, each of the plurality of heating elements 184 are turned on and turned off based on the frequency of signal CK produced by oscillator 297. Upon the Q H output of shift register 304 assuming a high logic level, the clock input of flip-flop 335 assumes a low logic level until the next signal CK. At this point in time, Q H of shift register 304 once again assumes a low logic level resulting in the clock input of flip-flop 335 seeing a leading edge. Therefore, Q output of flip-flop 335 (represented as signal FF3 ) changes to a low logic level. The output of NOR gate 341 then assumes a low logic level causing flip-flop 295 to be reset (that is, signal FF1 reverts to a low logic level ). Time-sharing driving circuit 290 is then ready to repeat the foregoing operation.
Referring now to FIGS. 13(a), (b) and (c) and FIGS. 14(a) and (b), alternative embodiments in the construction of the thin film circuit comprising electrodes 181 and heating elements 184 on substrates 174 and 177 are illustrated. Substrates 174 and 177 are preferably made from silicon plate, alumina plate and glass plate. In order to provide desirable chemical and thermal resistances, heat generating and heat dissipating properties surrounding the thin film circuitry, a heat regenerating layer 351 made of SiO 2 is deposited on substrates 174 and 177 employing a sputtering process. Suitable materials for heating elements 184 include Ta-SiO or Ta-N-SiO 2 . Additionally, inasmuch as Ta and Ta-N have a high thermal resistance, a low chemical resistance and oxidize easily it is also desirable to add a layer of SiO 2 to heating elements 184.
In producing heating elements 184 made of Ta-N-SiO 2 , Ta particle coated by SiO 2 is precalcined and is then sputtered in Ar or in Ar-N 2 gas. The ratio between the composition of Ta and SiO 2 varies based on the amount of SiO 2 which is used for coating Ta. By changing the mixing ratio of N 2 to Ar, a thin film having a more stable composition can be obtained.
For purposes of providing a suitable adhesive bond for electrode 181, as shown in FIG. 13(a) an adhesive film 355 such as Ti, Cr, Ni-Cr and the like are then disposed on heating element 184 except for that portion of heating element 184 which is to be in contact with ink 250. Electrode 181 is formed from materials such as Au, Pt, Pd, Al Cu or the like and has a step portion near heating element 184 for connection to the latter. An adhesive film 335 is disposed on electrode 181 by sputtering. The sputtered material is then selectively etched on electrode 181 to form the predetermined shape. The selective etching typically employs a general photolithography process which is suited for both dry-etching and wet-etching. Inasmuch as film 355 improves the adhesion between electrode 181 and heating element 184, it is not necessary for film 355 to be made of aluminum and the like.
An auxiliary electrode 359 made of Ti is sputtered onto electrode 181 and then selectively etched using photolitography so as to cover electrode 181. Consequently, auxiliary electrode 359 prevents both electrode 181 and film 355 from being eluted electrochemically, serves as a backup electrode and decreases the electrical resistivity of electrode 181 and film 355. Since the conductivity of Ti is low, however, auxiliary electrodes 359 are not a very effective backup for electrodes 181. The foregoing construction is then plasma etched using CF 4 gas.
FIGS. 13(b) and 13(c) are constructed in a fashion similar to FIG. 13(a) with the following exceptions. In FIG. 13(b) electrode 181, which has a step portion similar to FIG. 13(a), is disposed directly on top of regenerating layer 351. Additionally, heating element 184 is disposed directly on top of electrode 181 without using an adhesive layer such as film 355. Furthermore, there is no auxiliary electrode 359. In FIG. 13(c) a groove (not shown) is provided on substrates 174 and 177 by photolitography (e.g., dry-etching) with electrode 181 formed thereon. Additionally, regenerating layer 351 rather than having a flat surface as in FIGS. 13(a) and 13(b), has alternating plateaus 371 and flat troughs 367. Furthermore, film 355 is sandwiched between electrodes 181 and regenerating layer 351 as well as between heating element 184 and electrode 181. The additional layer of film 355 between electrode 181 and regenerating layer 351 improves the adhesion therebetween. Still further, and similar to FIG. 13(b), heating element 184 is on top rather than underneath electrode 181. Unlike FIGS. 13(a) and 13(b), however, no cover is provided over electrode 181. This is quite advantageous since from a manufacturing standpoint it is difficult to cover a step portion.
As shown in FIGS. 14(a) and 14(b) in the event that nozzle plate 194 is made from a metallic material, an insulating layer 363 is provided between nozzle plate 194 and the thin film circuitry of heating elements 184 and electrodes 181 to prevent stray current flow through nozzle plate 194. For example, as shown in FIG. 14(a), substrates 174 or 177 are covered by regenerating layer 351 which in turn has disposed thereon heating elements 184. Electrode 181 is sandwiched between film 355. Film 355 is disposed on heating element 184 except for those portions of the latter which are to come into contact with ink 250. Finally, insulating layer 363 is disposed on film 355 so as to cover the latter. As shown in FIG. 14(b), the thin film circuit of FIG. 13(c) is covered by insulating layer 363 having openings 367 to expose those portions of heating element 184 which are to come into contact with ink 250.
Insulating layer 363 is made from a photosensitive resin or other suitable material. In FIGS. 13(a), (b) and (c) and FIGS. 14(a) and (b), heat regenerating layer 351 is about 2-5 μm in thickness, film 355 is about 0.05-0.5 μm in thickness, electrode 181 is about 0.4-2.0 μm in thickness and auxiliary electrode 359 is about 0.05-1.0 μm in thickness.
As shown in Table 1 below, thirteen samples of heating elements 184 having different compositions and sputtering conditions were made. Each of these samples had adhesive film 355 made of Cr with a thickness of about 0.4 μm, electrodes 181 made of Au with a thickness of 1.5 μm, and auxiliary electrode 359 made of Ti with a thickness of 0.5 μm. The samples were made using radio frequency (RF) magnetic sputtering apparatus having two polarities and a power of two watts/cm 2 . The sputtering target was rotated at 10 rpm under a temperature of approximately 250° C. The resistivity of each sample was substantially the same by controlling the sputtering time. Heating element 184 was approximately 86 μm in width and 172 μm in length.
TABLE 1______________________________________Ta/SiO.sub.2 composition Sputtering PressureNo. (weight/mole percent (%)) Ar(mTor) N(mTor)______________________________________1 50/50 5 02 55/45 5 03 58/42 10 04 60/40 5 05 65/35 5 06 67/33 15 07 70/30 5 08 60/40 5 0.39 60/40 5 0.0710 70/30 5 0.311 70/30 5 0.112 80/20 5 0.213 85/15 5 0.2______________________________________
These thirteen samples of different thin film circuits (heating element 184, electrodes 181 and auxiliary electrodes 359) were then used to construct thirteen recording heads 105 as shown in FIG. 4 with recording head 105 having twenty-four nozzles 207. Each of the thirteen heating elements 184 generated 4.0×10 8 w/m 2 based on a driving pulse width of 6 μsec and a driving frequency of 2 KHz applied to electrodes 181. Ink 250 had the following composition:
______________________________________Solvent - Diethlene glycol 55 wt %Water 40 wt %Dye - C.I. Direct Black 154 5 wt %______________________________________
The corresponding test results are shown in Table 2 wherein the "resistivity" of heating element 184 is based on a resistance of approximately 50Ω and wherein "life" is defined as the total number of dots/droplets of ink which are produced by recording head 105 until the resistance of heating element 184 changes by at least 20%.
TABLE 2______________________________________ resistivity thickness lifeNo. (μΩ/cm) (μm) (Dot)______________________________________1 6400 2.6 ˜3 × 10.sup.62 4400 1.8 ˜8 × 10.sup.73 2900 1.1 ˜8 × 10.sup.84 2100 0.84 ˜7 × 10.sup.85 1200 0.50 ˜6 × 10.sup.86 930 0.38 ˜3 × 10.sup.87 700 0.28 ˜9 × 10.sup.78 7800 3.1 ˜2 × 10.sup.69 1900 0.78 >1 × 10.sup.910 4500 1.8 >1 × 10.sup.911 1200 0.51 >1 × 10.sup.912 2900 1.2 ˜8 × 10.sup.813 2000 0.81 ˜6 × 10.sup.6______________________________________
As can be appreciated by the results found in Tables 1 and 2, when a mole percent of Ta in the Ta-SiO 2 is between 58-65%, a life of at least 5×10 8 can be expected. Additionally, when a mole percent of Ta in Ta-N-SiO 2 is between 60-80%, a life of at least 7×10 8 dots can be expected. Consequently, a thickness of approximately 0.5-1.8 μm for heating element 184 is desirable. Still further, no scorching of the thin film circuit comprising electrodes 181, auxiliary electrodes 359 and heating elements 184 was found. There was also no erosion nor elution of electrodes 181. It has been further found that the life of the thin film circuits described in connection with FIGS. 13(a), (b) and (c) did not vary significantly from each other. All the foregoing was obtained without the use of a conventional protective layer as required in the prior art. Another significant advantage over the prior art was that the energy needed for heating heating elements 184 for each life set forth in Table 2 was reduced by 30% due, in part, to no longer needing a conventional protective layer covering the thin film circuitry.
By not providing a protective layer covering that portion of heating element 184 which comes into contact with ink 250, however, cavitation damage to heating element 184 can occur. More particularly, cavitation damage which refers to the cracking of heating element 184 is shown in its initial stages in FIG. 15(a) and in its advanced stages in FIG. 15(b) and is denoted by reference numeral 371. As shown in FIGS. 16(a)-(e), cavitation damage occurs due to the expansion and then rapid contraction of one or more air bubbles 375. As shown in FIG. 16(a), approximately 10 μsec after current begins to flow through heating element 184, air bubble 375 begins to expand resulting in the ejection of ink through nozzle 207 as shown in FIG. 16(b). Thereafter, current flow through heating element 184 ceases due to switch 191 opening, that is, due to the corresponding output of shift register 301 assuming a low logic level. Accordingly, air bubble 375 begins to contract as shown in FIG. 16(c). Air bubble 375 continues to rapidly contract as shown in FIG. 16(d) and substantially collapses within 10-20 μsec after contraction begins. As shown in FIG. 16(e), such sudden and rapid contraction of air bubble 375 results in the generation of concentrated shock waves represented by arrows K which are directed toward and strike the center of heating element 184. The repeated expansion and contraction of air bubbles 375 over a period of time results in the cavitation damage shown in FIG. 15(b). In the thirteen samples of recording head 105 shown in Table 2, a life of 7×10 8 dots or greater was achieved even with such cavitation damage.
Nevertheless, in order to improve the life of recording head 105, four different methods for substantially reducing, if not eliminating, cavitation damage can be employed as follows.
Since air bubbles 375 collapse toward the center of heating element 184, the first method, as shown in FIGS. 17(a)-(d) provides an opening in the center of heating element 184. This opening allows the collapsing air bubbles and associated concentrated shock waves K to pass through heating element 184 without affecting the life of heating element 184 as quickly. For example, as shown in FIG. 17(a) a somewhat elongated donut-shape heating element 184 is employed. In FIG. 17(b) a zigzag S-shaped heating element 184 having no portion thereof at its geometric center. FIG. 17(c) employs a C-shaped heating element 184. As shown in FIG. 17(d) a somewhat elongated donut-shaped heating element 184 similar to FIG. 17(a) is used; the only difference being that one of the distal ends of auxiliary electrode 359 has a C-shaped tail surrounding heating element 184.
Testing of heating elements 184 as shown in FIGS. 17(a)-(d), which were formed based on Sample No. 4 of Tables 1 and 2, resulted in increasing the life of heating element 184 from 7×10 8 dots to 1×10 9 dots. Furthermore, such increase in life was repeated whether or not the ink ejecting direction was varied by an angle ±30° relative to the top surface of upper step portion 201 of nozzle plate 194.
A second method for improving life by minimizing cavitation damage to heating element 184 is shown in FIGS. 18(a)-(c). In the second method, heating element 184 was partially or completely subdivided so that current flow through heating element 184 travelled along parallel paths. In FIG. 18(a), heating element 184 was divided into five strips 376 extending between auxiliary electrodes 359. Each of strips 376 has substantially the same surface area so that the current flow through each strip is about the same. In FIG. 18(b) four slivers 379 of heating element 184 are removed creating five strips 377 for current to flow through. In order for the surface area of each strip 377 to be about the same, the central portion of 184 bulges outwardly slightly thereby ensuring that the current flow through each strip 377 is about the same. In FIG. 18(c), four substantially V-shaped strips 378 of heating element 184 were formed between auxiliary electrodes 359. Each strip 378 also has substantially the same surface area. Tests performed using heating elements 184 as shown in FIGS. 18(a)-(c) similar to the tests performed using heating elements shown in FIGS. 17(a)-(d) resulted in the same increase in life expectancy of at least approximately 1×10 9 dots. By providing such parallel paths for current to flow through heating element 184, cavitation damage was substantially limited to those strips 376, 377 or 378 near the geometric center of heating element 184. Consequently, advanced stages of cracking as shown in FIG. 15(b) were substantially eliminated resulting in a more reliable and durable recording head 105.
A third method of substantially eliminating cavitation damage of heating element 184 is shown in FIGS. 19(a)-(h). In this third method, a film 383 having a thickness (represented by D shown in FIG. 19(f)) of at least 5 μm was disposed about the center of heating element 184 so that any collapsing air bubbles 375 and corresponding concentrated shock waves would impinge upon film 383. Film 383 can be formed from such materials as Ta, Ti, Au, Pt, Cr and the like or insulating materials such as SiO 2 , Ta 2 O 5 , photosensitive resin and the like. For purposes of durability, however, Ti, Au and SiO 2 are best suited to be used to form film 383. Preferably, film 383 is made by a plating or photolithography method at the time that electrodes 181 and heating element 184 are formed on substrates 174 and 177.
In FIG. 19(a), film 383 is substantially a rectangular block rising above heating element 184. FIG. 19(b) illustrates film 383 as a substantially oval block rising above heating element 184. FIG. 19(c) shows film 383 as a substantially oval block similar to FIG. 19(b) but with heating element 184 following first a U-shaped and then inverted U-shaped path between auxiliary electrodes 359. In FIG. 19(d), film 383 has a substantially cylindrical shape rising above heating element 184 wherein heating element 184 has a substantially Z-shaped configuration. In FIG. 19(e), film 383 has a substantially rectangular block shape similar to FIG. 19(a) with heating element 184 divided into strips similar to FIG. 18(a). FIG. 19(f) is a fragmentary side elevational view in cross-section of that portion of recording head 105 centered about film 383 in accordance with the embodiments of FIGS. 19(a), (b) and (e). As shown in FIG. 19(g) when thickness D of film 383 is less than 5 μm, air bubbles normally collapse on heating element 184 rather than film 383 and therefore do not increase the life/durability of the heating element 184. In other words, when thickness D of film 383 is less than 5 μm, the extent of cavitation damage to heating element 184 is not lessened. In contrast thereto, as shown in FIG. 19(h) when thickness D of film 383 is 5 μm or greater, air bubble 375 generally collapses on film 383 thus significantly improving the life of recording head 105. In tests conducted similar to those previously described for FIGS. 17(a)-(d), a life of at least 1×10 9 dots was obtained by using the various embodiments shown in FIGS. 19(a)-(e).
A fourth method for substantially reducing cavitation damage to heating element 184 is shown in FIGS. 20(a) and (b). More particularly, by maintaining the ink temperature at approximately 70° C. or greater while air bubble 375 is collapsing, the time for air bubble 375 to collapse is significantly increased by a factor of approximately two times compared to the time taken for air bubble 375 to collapse when ink 250 is exposed to ambient/room temperature. By extending the time for air bubble 375 to collapse, the shock waves K produced by the sudden and rapid contraction of air bubbles 375 are significantly lessened. Consequently, the life/durability of recording head 105 can be significantly increased. A recording head 105' incorporating this fourth method as shown in FIG. 20(a). Recording head 105' includes a heating apparatus 387 disposed below plate 151 and on lower step portion 197. A temperature sensor 391 is disposed in base 164 so as to be in contact with that portion of ink 250 within reservoir 167. Alternatively, as shown in FIG. 20(b), heating apparatus 387 may be within base 164 with temperature sensor 371 extending through nozzle plate 194 near air vent 204. There are, of course, a number of other positions for heating apparatus 387 and temperature sensor 391 about recording head 105.
Referring once again to FIG. 10, operation of a temperature control circuit 386 embracing this fourth method is shown. More particularly, temperature sensor 391 continuously monitors the temperature of ink 250 and provides an output signal to a non-inverting input of a comparator 395. An inverting input of comparator 395 is connected between a variable resistance Vr and a fixed resistence R13. The end of resistor Vr not connected to resistor R13 is connected to a positive d.c. voltage source. The end of resistor R13 not connected to resistor Vr is connected to ground. Accordingly, the voltage applied to the inverting input of comparator 395 can be varied to correspond with a desired threshold temperature which will turn on heating apparatus 387. The output of comparator 395 is supplied to a buffer Buf whose output is connected to the base of a transistor Tr. The emitter of Tr is grounded and the collector of Tr is connected to heating apparatus 387. Heating apparatus 387 is powered by the positive d.c.voltage source. Accordingly, when the signal produced by temperature sensor 391 is greater than the voltage supplied to the inverting input of comparator 395, an output signal will be produced by comparator 395 and stored in buffer BUF which will switch transistor Tr to its conductive state and thus turn on heating apparatus 387. When the temperature of ink 250 is at or above the predetermined level, however, the signal produced by temperature sensor 391 will no longer be greater than the voltage applied to the inverting input of comparator 395. Consequently, the output signal from comparator 395 will be insufficient to maintain transistor Tr in its conductive state. Accordingly, heating apparatus 387 will be turned off and will not be turned on again until the temperature of ink 250 is sufficient to cause temperature sensor 391 to produce a voltage greater than the voltage supplied to the inverting input of comparator 395. A general thermistor can be used for temperature sensor 391 and a sheathed heater or a positive temperature coefficient (PTC) thermistor can be used for heating apparatus 387. Inasmuch as a PTC thermistor includes a self-temperature control unit which is particularly applicable when a particular temperature is to be maintained, temperature control circuit 386 can be reduced to simply a PTC thermistor as heating apparatus 387.
A recording head 105' prepared in accordance with sample 4 of Tables 1 and 2 using for temperature sensor 391 a general thermistor and for heating apparatus 387 a PTC thermistor-having a resistence of 80Ω at ambient temperature and a Curie point of 100° C. was tested maintaining temperatures varying from room temperature through 90° C. The results of these tests are shown in Table 3.
TABLE 3______________________________________Ink temperature Life (Dots)______________________________________room temperature ˜7 × 10.sup.840° C. ˜7 × 10.sup.850 ˜7 × 10.sup.860 ˜7.8 × 10.sup.870 ˜1 × 10.sup.980 ˜1.2 × 10.sup.990 ˜1.6 × 10.sup.9______________________________________
As can be readily appreciated, when an ink temperature of 70° C. or greater was maintained, a life of at least 1×10 9 dots was obtained. Furthermore, when the ink temperature was maintained at at least 80° C. no observable cavitation damage was observed and very little cavitation damage was observed by maintaining the ink temperature at at least 70° C.
The foregoing four methods of minimizing cavitation damage to heating element 184 also can be used to increase the life, durability and reliability for conventional thermal ink jet recording heads such as those shown in FIGS. 1 and 2.
In accordance with an object of the invention, no barriers 71 as in FIGS. 1 and 2 to prevent cross-talk have been employed. Instead, each of the plurality of heating elements 184 is intermittently energized with a sufficient time delay between energization of adjacent heating elements 184 to prevent cross-talk. These timing delays are described with reference to FIGS. 21, 22 and 23 in which adjacent heating elements are represented by reference numerals 399, 403 and 407. A rectangular pulse from voltage source 187 having an amplitude V 1 and a pulse width of T 1 is applied to heating elements 399, 403 and 407 sequentially. The firing of each of these voltage pulses V 1 is delayed relative to adjacent heating elements 399, 403 and 407 as indicated by time interval Tint in FIG. 22. Time interval Tint is defined as either the time interval between the leading edge of the rectangular pulse applied to heating element 399 and the leading edge of the rectangular pulse applied to heating element 403 or as the time interval between the leading edge of the rectangular pulse applied to heating element 403 and the leading edge of the rectangular pulse applied to heating element 407.
Three recording heads 105 prepared in accordance with Sample 9 of Table 1 had a pitch P between adjacent nozzles of 106 μm, 202 μm, and 317 μm, respectively. The heating area of heating element 105 had a width of 80 μm and a length of 160 μm. The power/surface area under which heating element 105 was operated was 4.0×10 8 W/m 2 . The applied voltage produced by voltage source 187 had a frequency of approximately 2 KHz with rectangular pulse width T 1 of 6 μsec. Results of testing these three recording heads in accordance with the above conditions is shown in FIG. 23 wherein the ejection speed of the ink droplets through nozzle plate 194 was affected by only time interval Tint and not by pitch P. As shown in FIG. 23, when the time interval of Tint was less than Tab, represented by region S, the ejecting speed of the ink droplets was high and relatively stable, however, the ink droplets were swollen due to cross-talk from adjacent nozzles 207. Time interval Tab is about 4-8 μs. When the time interval of Tint was between Tab and Tbc, represented by region M, the ink droplets were not ejected stably and the ejection speed of the ink droplets was reduced compared to region S. Time interval Tbc is about 30-40 μsec. When the time interval of Tint, however, was greater than Tbc, represented as region L, the ink droplets were ejected stably and had a high ejecting speed with no cross-talk occurring. More particularly, the ejecting speed of the ink droplets in region L was approximately 10 m/sec with time interval Tbc equal to approximately 40 μs. The invention is also far superior to a Japanese Laid-Open Patent No. 59-71869 in that the invention is not dependent upon pitch P between heating elements 184 which as disclosed in this Japanese patent requires a pitch P of approximately 130 μm and exhibited the characteristics of region 5. Furthermore, the invention in contrast to this Japanese patent with a time interval Tint of 40 μsec or greater provides a higher density and a higher picture quality ink jet recording.
FIGS. 24 (a) and (b) address the potential problem of slippage, that is, of recording information on a recording medium beyond the point where the information is supposed to be printed. More particularly, in order to compensate for potential slippage due to time interval Tint, adjacent nozzles such as nozzles 413 and 417 of FIG. 24(a) are separated by a distance Xab. Distance Xab is measured from the center line of nozzle 413 to the center line of nozzle 417 in the direction B (i.e., the direction that recording head 105 travels). Each of the center lines is normal to direction B. Distance Xab can be calculated as follows:
Xab=DP (Tint/T+J)
wherein J is an integer and DP represents the distance that recording head 105 travels in a direction B during a minimum driving period T. The parameters Tint, T and T 1 (which is the pulse width of the rectangular pulse applied to nozzles 413 and 417) are illustrated in FIG. 24(b). Xab is preferably less than 1/5 of DP and desirably less than 1/10 of DP to result in no observable slippage.
FIG. 25 illustrates an alternative embodiment of the invention providing a multicolored ink jet recording head 105" in which all colors, namely, yellow, magenta, cyan and black are provided on a plate 151. In contrast thereto, prior art color ink jet recording heads have had great difficulty in regulating a high density of colored inks. Recording head 105" employs the same basic methods of construction as defined heretofore for each colored ink. Additionally, rather than employing one nozzle plate 194 a plurality of nozzle plates for each of the different colors can be used.
In two other alternate embodiments, as shown in FIGS. 26 and 27, respectively, a recording head 425 and 435 each contain two rows of heating elements 184' and 184" and corresponding rows of nozzles 207' and 207" on each of the substrates 174 and 177. These two rows of heating elements and nozzles on each substrate provide for an even higher density and higher quality recording. For example, if one row of nozzles corresponds to 90 dpi, recording heads 425 and 435 will each produce 360 dpi. Furthermore, as shown in FIG. 27, nozzle plate 194 is mechanically secured to substrates 174 and 177 by a push plate 450. Consequently, recording head 435 is more reliable and durable than recording heads which have their substrates and nozzle plates bonded together merely by adhesive. Still further, a packing material 453 disposed on the interior surface of push plate 450 and spacially located between nozzle plate 194 and substrates 174 and 177 provides an absorption medium for any ink which may escape between nozzle plate 194 and substrates 174 and 177.
High quality ink jet recording on commonly used recording paper such as wood-free paper can be achieved by addition of an ionic or non-ionic surface active agent to an aqueous ink composition containing at least one wetting agent, at least one dye or pigment and water. Appropriate amounts of antiseptic, mold inhibitors, pH adjustors and chelating agents can also be added.
The surface active agent functions to increase permeability of the ink to the recording paper. Typical surface active agents are shown in Table 4.
TABLE 4
Ionic surface active agents
dioctyl sulfosuccinate sodium salt.
sodium oleate
dodecylbenzenesulfonic acid
Non-ionic surface active agents
diethylene glycol mono-n-butyl ether
triethylene glycol mono-n-butyl ether
In the case of an ionic surface active agent, sufficient permeability is achieved when the ionic agent is added to the ink at the critical micelle concentration. The properties of the ink become unstable and nozzles in which the ink is used become clogged due to formation of surface active agent deposits when the concentration is greater than the critical micelle concentration. The preferred amount of ionic surface active agent is between about 0.5 and 3% by weight of the ink composition. Dioctyl sulfosuccinate sodium salt is a particularly suitable ionic surface active agent because it has a low kraft point or critical micelle concentration and deposits are not readily formed.
Non-ionic surface active agents having high molecular weights cause the solubility to be lowered and the ink viscosity to be increased. Non-ionic surface active agents having low molecular weights vaporize the ink as a result of their high vapor pressure and produce an offensive odor. The components of the ink using low molecular weight non-ionic surface active agents tend to change over time and increased nozzle clogging results. However, the non-ionic surface active agents shown in Table 4 can be used in a preferred amount of between about 5 and 50% by weight which is sufficient to permit the ink to permeate into the recording paper. A more preferred range is between about 10 and 30% by weight.
Conventional dyes and pigments can be used as coloring agents. In general, azo dyes, indigo dyes and phthalocyanine dyes including any of the following can be used:
C.I. Direct Black 19
C.I. Direct Black 22
C.I. Direct Black 38
C.I. Direct Black 154
C.I. Direct Yellow 12
C.I. Direct Yellow 26
C.I. Direct Red 13
C.I. Direct Red 17
C.I. Direct Blue 78
C.I. Direct Blue 90
C.I. Acid Black 52
C.I. Acid Yellow 25
C.I. Acid Red 37
C.I. Acid Red 52
C.I. Acid Red 254
C.I. Acid Blue 9
Any inorganic or organic pigment having a particle diameter between about 0.01 and 3 μm can be used and is preferably diffused in the ink using a dispersant. Two or more coloring agents can be added in order to achieve a desired color.
Inks containing surface active agents permeate recording paper and disperse rapidly when the paper is contacted. Desirable amounts of coloring agent or pigment are between about 3 and 10% by weight. The optimum amount is between about 5 and 7% by weight.
A wetting agent or solvent can be used to prevent clogging of the nozzles in which the ink is used. The wetting agent can be one or more of glycerine, diethylene glycol, triethylene glycol, polyethylene glycol #200, polyethylene glycol #300 and polyethylene glycol #400. The wetting agent is used in an amount between about 9 and 70% by weight.
In addition to the surface active agent, pigment and wetting agent, appropriate amounts of antiseptic, mold inhibitors, pH adjusters and chelating agents can be added. The remainder of the ink is water.
The following ink compositions were prepared in accordance with the invention. These exemplary compositions are presented for purposes of illustration only and are not intended to be construed in a limiting sense.
______________________________________Ink BWetting Agents - Glycerin 15.0 wt %Polyethylene glycol #300 15.0 wt %Dioctyl sulfosuccinate 1.0 wt %sodium saltWater 61.8 wt %Proxel (a mold inhibitor manufac- 0.2 wt %tured by ICI Corporation, England)Dye - C.I. Direct Black 154 7.0 wt %Ink CWetting Agents - Triethylene glycol 20.0 wt %Triethanolamine 0.01-0.05 wt %Diethylene glycol 40.0 wt %mono-n-butyl etherWater 34.75-34.79 wt %Proxel 0.2 wt %Dye - C.I. Direct Black 154 5.0 wt %Ink DWetting Agents - Triethylene glycol 20.0 wt %Triethanolamine 0.01-0.05 wt %Diethylene glycol 30.0 wt %mono-n-butyl etherWater 44.75-44.79 wt %Proxel 0.2 wt %Dye - C.I. Direct Black 22 5.0 wt %______________________________________
Each of ink mixtures B, C and D was placed into a container and heated to a temperature between 60° and 80° C. with agitation. Each mixture was filtered under pressure using a membrane filter having a 1 μm mesh. The resulting solutions were useful as printing inks.
Ink jet printing onto the wood-free papers shown in Table 5 was carried out using these inks in the ink jet recording apparatus of the invention. The printing conditions were a recording density of 360 dpi, 48 nozzles and a driving frequency of 4 KHz.
TABLE 5______________________________________Manufacturer Product______________________________________Oji-Seishi Wood-free paper (ream weight 70 kg)Kishu-Seishi Fine PPCDaishowa-Seishi BM paperJujo-Seishi Hakuba (wood-free paper)Fuji-Xerox PXerox (U.S.A.) 10 series Smooth 3R54Xerox (U.S.A.) 4024 Supply net 3R721Kimberley Clark (U.S.A.) Neenah bond paper______________________________________
Each of Inks B, C and D was fixed onto each of the papers shown in Table 5 and high quality printing was obtained in each case.
An alternative method for achieving high quality ink jet printing on recording paper is to preheat the recording paper prior to attaching the ink droplets and postheat the recording paper after attaching the ink droplets. In addition, the ink droplets are attached in a swollen condition. This causes the ink to dry and fix on the recording paper quickly.
FIGS. 28 and 29 show an apparatus constructed and arranged in accordance with the invention in which the method of preheating and postheating the recording paper can be utilized. The basic construction of apparatus 500 is the same as that of FIG. 3. A heating element 511, however, is used to heat recording paper 111 and is provided inside platen 117. Recording paper 111 is preheated and postheated while printing is performed at a temperature between about 100° and 140° C. A curl straightening roller 505 is provided in order to straighten the curl caused by the preheating and postheating of recording paper 111. A paper press 519 presses paper 111 against platens 117. A paper feed roller 515 and guide rollers 114 advance paper 111 past recording head 105. Ink droplets ejected from nozzles 207 are attached to preheated recording paper 111. The water in the ink has a higher vapor pressure than the remainder of the ink and vaporizes first, leaving the remaining components such as solvents and coloring agents fixed on recording paper 30.
PTC thermistors or sheathed heaters can be used to heat element 511 as shown in FIG. 29. In a preferred embodiment, heating element 511 includes 5 PTC thermistors, each of which has a diameter of 17 mm, a thickness of 2.5 mm, an average resistance of 20Ω at room temperature and a Curie point of 150° C. The thermistors are coupled in parallel and are provided on the inside surface of platen which is constructed of aluminum having an average thickness of 2 mm. The surface of platen 117 does not contact recording paper 111. Platen 117 has a self-controlled temperature due to the Curie point of the PTC thermistors. The heat loss due to dissipation by platen 117 and transfer resistance from heating element 511 can be compensated when the Curie point is greater than the preheating and postheating temperature of recording paper 111. The limits of the preheating and postheating regions change as a function of the components of the ink, the number of ink droplets, the recording speed and the recording density desired. In a preferred embodiment, the preheated region corresponds to 4 lines and the postheated region corresponds to 8 lines.
Suitable inks for use in this type of preheating and postheating system have a surface tension of solvent and coloring agent remaining on the recording paper at 100° C. of greater than about 35 mN/m. Such inks can have a coloring agent, wetting agent, solvent and water. Appropriate amounts of antiseptic, mold inhibitors, pH adjustors and chelating agents can also be used.
The coloring agents discussed above can be used in ink compositions prepared for use with the preheating and postheating method. The amount of coloring agent is generally between about 0.5 and 10% by weight. A more preferred amount of coloring agent is between about 0.5 and 5% by weight and is optimally between about 1 and 3% by weight.
A wetting agent is also used. Any of glycerine, diethylene glycol, triethylene glycol, polyethylene glycol #200, polyethylene glycol #300, polyethylene glycol #400, thiodiglycol, diethylene glycol monomethyl ether and diethylene glycol diethyl ether can be used alone or in combination. The amount of wetting agent is between about 5 and 20% by weight of the ink composition. The nozzles in which the ink is used become clogged when less than about 5% by weight of wetting agent is used. On the other hand, the ink droplets formed on the recording paper are not easily dried when the amount of wetting agent is greater than about 20%.
Appropriate amounts of antiseptic, mold inhibitors, pH adjustors and chelating agents are also used in the ink composition, with the remainder of the composition being water.
A solvent such as a primary alcohol can be added to the ink in order to improve drying characteristics. The solvent can be selected from methyl alcohol, ethyl alcohol, isopropanol and the like and mixtures thereof. The solvent can be used in an amount between about 3 and 30% by weight of the composition and can be added in place of an equivalent amount of water.
After extensive testing, it became clear that the surface tension of the solvent and the coloring agent contained in the ink remained on the recording paper during printing and affected the print quality. Specifically, inks wherein the surface tension of the solvent and coloring agent remaining on the recording paper was 35 mN/m or greater at 100° C. were suitable for high quality ink jet printing.
The following inks were prepared in accordance with the invention and are presented for purposes of illustration only.
______________________________________Ink EWetting Agent - Glycerin 10.0 wt %Water 88.4 wt %Proxel 0.1 wt %Dye - C.I. Direct Black 154 1.5 wt %Ink FWetting Agent - Thiodiglycol 10.0 wt %Water 88.9 wt %Proxel 0.1 wt %Dye - C.I. Acid Red 37 1.0 wt %Ink GWetting Agents - Glycerin 5.0 wt %Diethylene glycol 3.0 wt %Thiodiglycol 2.0 wt %Water 87.8 wt %Proxel 0.2 wt %Dye - C.I. Direct Black 22 2.0 wt %Ink HWetting Agent - Thiodiglycol 5.0 wt %Solvents - Methyl alcohol 10.0 wt %Ethyl alcohol 10.0 wt %Isopropanol 10.0 wt %Water 63.8 wt %Proxel 0.2 wt %Dye - C.I. Acid Yellow 25 1.0 wt %Ink IWetting Agent - Propylene glycol 10.0 wt %Water 88.4 wt %Proxel 0.1 wt %Dye - C.I. Direct Black 154 1.5 wt %Ink JSolvent - Dimethyl sulfoxide 10.0 wt %Water 88.4 wt %Proxel 0.1 wt %Dye - C.I. Direct Black 154 1.5 wt %______________________________________
Each ink mixture was placed in a separate container and heated to between about 60° and 80° C. with sufficient agitation. The mixtures were then filtered under pressure using a membrane filter having an aperture diameter of 1 μm to obtain printing inks.
Ink jet printing was carried out on the wood-free papers shown in Table 5 using each of these inks in an ink jet recording apparatus of the invention. The printing conditions were a recording density of 360 dpi, 48 nozzles and a driving frequency of 4 KHz.
10 grams of each ink was placed on the scale and maintained in a thermostatic chamber at 80° C. It was confirmed that water had vaporized by measuring the weight a second time. The surface tension of the components remaining at 100° C. and the print quality obtained are shown in Table 6.
TABLE 6______________________________________Ink Surface Tension at 100° C. Printing Quality*______________________________________E 54 mN/m 5F 46 5G 39 4-3H 37 4-3I 28 1J 33 2______________________________________ *Note the higher the number, the better the print quality.
As can be seen in Table 6, good print quality was obtained when inks E, F, G and H were used. Furthermore, after extensive testing, it became clear that the ink compositions were not limited to those of inks E, F, G and H. Excellent quality printing was achieved by inks having between about 0.5 and 10% by weight of a coloring agent, between about 5 and 20% by weight of a polyhydric alcohol such as one or more of glycerin, diethylene glycol, triethylene glycol, polyethylene glycol #200, polyethylene glycol #300, polyethylene glycol #400, thiodiglycol, diethylene glycol monomethyl ether, and dietheylene glycol dimethyl ether and the remainder water with a small amount of antiseptic, molding inhibitor, pH adjustor and chelating agent. Alternatively, between about 3 and 30% by weight of methyl alcohol, ethyl alcohol or isopropanol can be used in place of an equivalent amount of water. When each ink was heated to 100° C., the surface tension of the mixture of solvent and coloring agent that remained on the recording paper was greater than about 35 nM/m.
The life of the recording head was the same as that of the life of a recording head using ink A when any of inks B, C, D, E, F, G or H was used. These inks can be used in conventional thermal ink jet recording heads as well as in recording heads constructed and arranged in accordance with the invention and high quality printing on commonly used recording paper such as wood-free paper can be achieved. These inks can be quickly fixed on recording paper so that high quality pictures can be obtained without wrinkling or blotting of the paper.
As now can be readily appreciated, the invention provides an ink jet recording apparatus having high speed, high print density and high reliability. The invention provides a recording head which is simply and easily constructed and does not require a protective layer covering the heating element or a barrier to prevent crosstalk. The invention provides high picture quality using the inks described above and multicolor recordings of high density and picture quality.
It will thus be seen that the objects set forth above, among those made apparent from the preceding description, are efficiently attained and, since certain changes may be made in carrying out the above process, in the described product, and in the construction set forth without departing from the spirit and scope of the invention, it is intended that all matter contained in the above description and shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense.
It is also to be understood that the following claims are intended to cover all of the generic and specific features of the invention herein described and all statements of the scope of the invention which, as a matter of language, might be said to fall therebetween.
Particularly it is to be understood that in said claims, ingredients or compounds recited in the singular are intended to include compatible mixtures of such ingredients wherever the sense permits.
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A thermal ink jet recording apparatus includes at least a substrate having at least a plurality of heating elements disposed in rows in at least two groups. Each group consists of two rows of heating elements, one row arranged on either side of the ink supply portion, each of the groups of the heating elements being associated with a single color ink. At least one nozzle plate has a plurality of nozzles disposed on the substrate where at least one nozzle plate and the substrate define a space between the nozzle plate and the substrate in registration with each group of heating elements and corresponding group of nozzles associated with a single color ink. Means are provided for independently delivering ink of one color from the ink reservoir to each of the spaces, whereby printing can be independently effected in at least two colors of ink.
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CONTRACTUAL ORIGIN OF THE INVENTION
The United States Government has rights in this invention pursuant to Contract No. W-31-109-ENG-38 between the U.S. Department of Energy and The University of Chicago representing Argonne National Laboratory.
BACKGROUND OF THE INVENTION
This invention relates to reference electrodes for use in high temperature environments which may involve high thermal shock conditions and more particularly to reference electrodes with protective structures over the electrode membranes. Specifically, the invention relates to reference electrodes useful in mixed halide salts as high temperature electrolytes in electrolytic cells for the electrorefining of spent reactor fuels.
In the electrorefining of two or more metals involving the selective deposition of at least one of the metals, a reference electrode is useful as a standard potential in the study of the process and to control the cathode potential without dependence on changing anode potentials. Control of the cathode potential is important in determining which metal of the metal mixture is being deposited on the cathode at a particular stage of the process. One new reactor system under development and evaluation by the U.S. Department of Energy involves the use of a metal fuel of U-Pu-Zr. Processing of spent fuel is carried out electrolytically during which U and Pu may be separately deposited on the cathode. The cell electrolyte is a mixed halide salt and the cell operating temperature is in the order of about 500° C. The anode is a pool of liquid cadmium with the spent fuel below the electrolyte in the cell. The cell is operated in an inert atmosphere of argon with less than 2 ppm of water vapor and less than 2 ppm of oxygen. An earlier version of the cell is disclosed in U.S. Pat. No. 4,596,647 which is hereby incorporated herein by reference.
The reference electrode previously utilized and tested in the experimental electrolytic cell has been an alumina tube with a small hole drilled in the bottom for ionic access between the cell electrolyte and the electrolyte of the reference electrode. The reference electrode was based on a Ag/AgCl electrode with added electrolyte usually having the same composition as the nonreactive components of the main salt electrolyte of the electrolytic cell. The silver electrode was a wire with a lower end formed into a small coil or helix and was primarily retained in the tube except for an exposed upper end section for electrical connection. In general, this reference electrode had a large drift rate and required frequent regeneration by an anodizing step. These problems appeared to be due to a diffusive transport of silver chloride through the small opening (although packed with yttria fiber) at the lower end of the reference electrode.
Accordingly, one object of the invention is an electrolytic cell with a reference electrode operable for an extendable period of time at temperatures in the order of 500° C. A second object of the invention is an electrolytic cell with a reference electrode operable in the cell containing a molten chloride salt electrolyte and a liquid metal anode pool containing uranium, plutonium, zirconium, sodium and other metals. Another object of the invention is a reference electrode with a glass electrode which is usable in a high thermal shock environment. These and other objects will be readily apparent from the following description.
SUMMARY OF THE INVENTION
Briefly, the invention is directed to a reference electrode device for mounting in a housing of an electrolytic cell and extending into an electrolyte layer in the interior of the cell, the device comprising an elongated glass tube extending from the housing into the interior of the cell and having a lower closed-ended section with ionic conductivity for exposure to the cell electrolyte, a metal electrode supported in the glass tube and in separated juxtaposition with the closed end, an electrolyte in the lower section in contact with the electrode, and an electrical insulator separating the electrode and glass tube. The reference electrode device of the invention further includes an elongated metal tube extending from the housing over the glass tube as a protective shield or cover and basket with the metal tube having a perforated side wall in contact with the cell electrolyte and means are provided for supporting the glass tube within the metal tube, and for supporting the metal tube in the cell housing. The one-piece glass tube provides physical isolation of the electrode and inner electrolyte from the cell electrolyte while serving as a membrane while the metal tube provides a shield and basket over the glass tube. Under the conditions of high temperature, motion of the rotating stirrer in the cell electrolyte and other operating conditions in the cell, the elongated glass membrane may be subject to breakage. If glass from a broken membrane is allowed to come in contact with a uranium-containing anode pool, the amount of uranium available for transfer to the cathode will become depleted by the formation of uranium dioxide. Accordingly, the metal tube is designed to provide protection to the glass tube while also serving as a basket to collect separate glass sections of the tube before they would fall into the cell electrolyte and subsequently into a lower anode pool. Perforations in the side wall of the metal tube permit access between the glass membrane and cell components.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings,
FIG. 1 is a top view of an electrolytic cell with various cell components including a reference electrode.
FIG. 2 is a side sectional view of the cell of FIG. 1 taken along line 2--2' showing a reference electrode.
FIG. 3 is a sectional side view of a reference electrode as one embodiment of the invention.
FIG. 4 is a side view of the protective metal tube showing perforations in the side walls.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The reference electrode of the invention is particularly useful in high temperature electrolytic cells where glass membrane sections may be broken during removal or replacement operations in the top cover or lid of the cell housing or by thermal shock at the high temperatures. These cells usually include a cell housing of a rigid metal construction containing a salt electrolyte and a pair of electrodes. In one experimental cell for the recovery of uranium from a mixture of metals where the reference electrode has been tested, the cell interior includes a mixed halide salt as the electrolyte over a cadmium pool as the anode with the cathode being a solid metal rod suspended into the electrolyte. The design further includes a motor for rotating the cathode and devices for separately stirring the electrolyte and anode pool. The operating temperature for the cell is usually in the order of about 500° C. The cell and reference electrode of the invention operate in an inert atmosphere of argon with less than 2 ppm of water vapor and less than 2 ppm of oxygen.
A top and sectional side view of a cell 8 of this type is illustrated in FIGS. 1 and 2. The cell housing 10 includes circular side wall 12, bottom 14 and upper cover 16 which serves to support drives for cathode rotation, electrolyte stirring and anode stirring. As illustrated, the cathode 18 of low carbon steel is rotated by drive 20 while the electrolyte 22 is stirred by drive 24. Electrolyte 22 is composed of a mixture of alkali and/or alkaline earth metal chlorides such as Li, K, Ba and the like and preferably is a mixture of LiCl and KCl in a mole ratio of about 3:2. Stirring of the cadmium pool 26 is provided by motor drive 28. In general the drives are operated at speeds in the order of 100-200 rpm. The construction of housing 10 is low carbon steel. An iron insert 30 and plug inserts 32 and 34 are provided to adjust the cadmium to the desired level in the housing while permitting some excess capacity to the extent desired.
FIGS. 1 and 2 also include reference electrode 40 mounted in cover 16 and extending down into electrolyte 22. Advantageously, reference electrode 40 is positioned near cathode 18 but separated a distance to avoid being struck by the rotating metal deposition 44 on the cathode. As illustrated, reference electrode 40 includes an upper cover 41 to prevent contaminants from falling into the electrode. The cell temperature is in the order of about 500° C. which is provided by an electric furnace (not shown).
The reference electrode of the invention is useful for mounting in a housing of an electrolytic cell and extending into an electrolyte layer in the interior of the cell, the device comprising an elongated glass tube of one-piece construction extending from the housing into the interior of the cell and having a lower closed-ended section with ionic conductivity for exposure to the cell electrolyte, a metal electrode supported in the glass tube and in separated juxtaposition with the closed end, an electrolyte in the lower section in contact with the electrode, and an electrical insulator separating the electrode and glass tube. The device further includes an elongated metal tube extending from the housing over the glass tube as a protective cover and basket with the metal tube having a perforated side wall in contact with the cell electrolyte, and means are provided for supporting the glass tube within the metal tube and for supporting the metal tube in the cell housing.
Advantageously, the metal tube is electrically isolated from the cell housing to reduce the adverse effect of cell voltages and currents on the operation of the reference electrode. It is also important that means are provided for supporting and electrically insulating the electrode from the glass tube and an alumina tube may be advantageously used for that purpose. A further feature of advantage is a removable cover over the upper open end of the glass tube to prevent contamination of the contents of the tube.
FIG. 3 represents a sectional side view of a reference electrode 50 enlarged to provide additional detail. As illustrated, reference electrode 50 includes an inner electrode of silver wire 52 supported in an alumina tube 54 which isolates electrode 50 from glass tube 56. Retention of electrode 52 in the alumina tube is provided by slot 60 in the lower end 58 of tube 54 which serves to capture a looped bent portion 62 of the electrode. The upper end 64 of the electrode is also bent to prevent the electrode from moving downward in the tube. An electrolyte 66 composed of AgCl plus a mixture advantageously of the cell electrolyte such as LiCl and KCl is also in the tube.
Advantageously, glass tube 56 is constructed of a high strength glass having a high silica content which will include a small alkali metal content for ionic conductivity or have the property of absorbing sufficient salt from the electrolyte for the desired conductivity. Suitably, the glass has a silica content above about 90 wt. % and preferably a content in the order of 96 wt. %. Advantageously, the glass may be a type identified by the trademark "Vycor" from Corning Glass Works of Corning, N.Y. having a silica content of about 96 wt. % with the remaining percentage consisting essentially of B 2 O 3 , Al 2 O 3 and compounds of Na and Fe. Quartz glass may also be used. Tube 68 is constructed of low carbon steel and is designed to extend over glass tube 56 as a shield and basket. An insulating sleeve 70 of alumina is positioned over a portion 71 of tube 68 to electrically isolate tube 68 from the cell housing 10. Nut 72 is bonded to the alumina sleeve 70 and threaded to mount the device in the cover 17 of a cell housing. A cover 74 is also provided over the reference electrode 50 to prevent contamination of the electrode and electrolyte in the glass tube 56.
As illustrated in FIGS. 3 and 4, metal tube 68 includes a lower section 76 with small perforations 78 in the order of about 1/8 inch in diameter along lower wall 80. Slot 84 at curved end 82 is provided for ease of fabrication from open-ended tube material, although the spring fingers 85 also provide some resiliency and support glass tube 56. Slot 84 is a limited opening of about 1/16th inch and effectively prevents the loss of the usual large glass sections from a damaged glass tube. As illustrated, glass tube 56 is of one-piece construction and extends into the interior of the housing with a lower end section 59 being supported by curved end 82 of metal tube 68 to provide a slight compression on the glass. The upper section 61 of glass tube 56 may rest against metal tube 68 since clearance (i.e., about 1/16") is small or may be positioned upright in metal tube 68.
An additional detail of a metal tube 86 is provided in FIG. 4 which includes upper section 88 with nut 90 and upper and lower rings 91 and 92 for support of the alumina tube. In addition, metal tube 86 includes lower section 94 with perforations 96 and lower slot 98.
The foregoing description of embodiments of the invention has been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching.
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A reference electrode device is provided for a high temperature electrolytic cell used to electrolytically recover uranium from spent reactor fuel dissolved in an anode pool, the device having a glass tube to enclose the electrode and electrolyte and serve as a conductive membrane with the cell electrolyte, and an outer metal tube about the glass tube to serve as a shield and basket for any glass sections broken by handling of the tube to prevent their contact with the anode pool, the metal tube having perforations to provide access between the bulk of the cell electrolyte and glass membrane.
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This application is a continuation of U.S. Non-Provisional patent application Ser. No. 10/970,365, filed Oct. 21, 2004 now U.S. Pat. No. 7,288,165, which claims priority to U.S. Provisional Patent Application Ser. No. 60/514,458, filed Oct. 24, 2003, both of which are hereby incorporated by reference herein in their entirety.
FIELD OF THE INVENTION
The present invention relates to semiconductor manufacturing, and more particularly to an apparatus for conditioning a polishing surface of a pad used for chemical mechanical polishing/planararization.
BACKGROUND OF THE INVENTION
Semiconductor device manufacturing often includes one or more polishing or planarization steps following material deposition on the device side of a substrate. For example, polishing pads are often used to polish and/or abrade a layer of deposited material in a process known as chemical mechanical polishing/planarization or CMP. The polishing surface of a polishing pad must occasionally be conditioned or ‘roughened’ in order to maintain the efficiency with which it polishes or removes deposited material from a substrate. For this purpose, apparatus have been developed and utilized which abrade the polishing surfaces of polishing pads with coarse conditioning material. For example, apparatus exist which condition polishing pads in the presence of an abrasive polishing fluid such as a microabrasive slurry (used to facilitate substrate polishing) on the polishing surface while causing a conditioning surface of a conditioning disk to press against and rotate relative to the polishing surface in a process also known as in situ pad rejuvenation or pad dressing.
Such conditioning apparatuses often employ conditioning heads comprising end effectors adapted to receive and retain conditioning disks. The conditioning head may be adapted to generate or at least transmit a torque to the end effector so as to rotate the end effector and the conditioning disk during pad conditioning. In addition, a down force may be generated, e.g. local to the conditioning head via pneumatic actuation, or remotely (e.g., via a mounting arm), so as to produce the desired degree of frictional interaction between the conditioning head and the polishing pad. The microabrasive slurry, however, has been known to invade such conditioning heads, e.g., in one or both of a liquid and a vapor form, doing damage to internal components such as bearings. Also, some apparatus, carefully designed to generate a desired degree of down force and/or material removal, nevertheless create manufacturing problems, such as imprecise conditioning brought about by poor rigidity, and/or scoring damage to the polishing pad's processing surface as a result of end effectors designed to reciprocate relative to their conditioning heads becoming frozen or locked-up, sometimes in cockeyed orientations not apparent until after the damage has been done.
Semiconductor manufacturing processes are more and more often demanding quicker pad conditioning, lower down forces, and higher rotation speeds for conditioning pads. As a result, effective methods and apparatus for reliably conditioning polishing surfaces of polishing pads, especially methods and apparatus offering good controllability and reliability, as well as high precision, are both desirable and necessary.
SUMMARY OF THE INVENTION
In a first aspect of the invention, a first apparatus is provided for a chemical mechanical polishing (CMP) process. The first apparatus includes (1) a rotatable member; (2) an end effector adapted to receive and retain a conditioning disk; and (3) an elastic device disposed between the rotatable member and the end effector. The elastic device is (a) adapted to rotate the end effector via a torque from the rotatable member, and (b) flexibly extensible so as to impart a force to the end effector while permitting the end effector to deviate from a perpendicular alignment with the rotatable member in order for a conditioning surface of the conditioning disk to conform to an irregular polishing surface of a pad being conditioned.
In a second aspect of the invention, a second apparatus is provided for a chemical mechanical polishing (CMP) process. The second apparatus includes (1) a rotatable member; and (2) a sealing element comprising a flexible lip disposed around the rotatable member. The flexible lip is adapted to (a) seal against the rotatable member when the rotatable member is not rotating, and (b) retract, in response to a pressure force from a gaseous media, away from the rotatable member, when the rotatable member is rotating so as to permit the gaseous media to flow past the flexible lip, along the rotatable member.
In a third aspect of the invention, a third apparatus is provided for a chemical mechanical polishing (CMP) process. The third apparatus includes (1) a rotatable member; and (2) a sealing element disposed around the rotatable member. The sealing element is adapted to (a) seal against the rotatable member when the rotatable member is not rotating; and (b) retract away from the rotatable member when the rotatable member is rotating.
In a fourth aspect of the invention, a fourth apparatus is provided for a chemical mechanical polishing (CMP) process. The fourth apparatus includes (1) a rotatable member; and (2) a sealing element comprising a flexible lip disposed around the rotatable member. The flexible lip is adapted to (a) seal against the rotatable member when the rotatable member is not rotating; and (b) retract away from the rotatable member when the rotatable member is rotating.
In a fifth aspect of the invention, a fifth apparatus is provided. The fifth apparatus includes (1) a housing; and (2) an end effector coupled to the housing. The end effector is adapted to (a) receive and retain a conditioning disk; (b) move away from the housing so as to position the conditioning disk in contact with a polishing pad; (c) urge a conditioning disk against a polishing pad and rotate relative to the housing for polishing pad conditioning; and (d) pivot relative to the housing during polishing pad conditioning so as to conform to an irregular polishing surface of a polishing pad.
In a sixth aspect of the invention, a sixth apparatus is provided. The sixth apparatus includes (1) a housing; (2) a rotatable member rotatably disposed within the housing, the housing and the rotatable member together defining a gap susceptible to exposure of migrating polishing slurry during pad conditioning; and (3) a duct within the housing adapted to selectively direct a flow of cleaning fluid to the gap so that the cleaning fluid flow passes along the gap, carrying polishing slurry therefrom.
In a seventh aspect of the invention, a first method is provided for chemical mechanical polishing (CMP). The first method includes the steps of (1) providing a pad conditioning head for a CMP process, having (a) a rotatable member; and (b) an end effector coupled to the rotatable member and adapted to receive and retain a conditioning disk; (2) imparting a force to the end effector; and (3) permitting the end effector to deviate from a perpendicular alignment with the rotatable member, and conform to an irregular polishing surface of a pad being conditioned. Numerous other inventive methods are provided, including methods of using liquid or gas to deter polishing slurry or debris from entering the conditioning head.
Other features and aspects of the present invention will become more fully apparent from the following detailed description, the appended claims and the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a side cross-sectional view of a conditioning head in accordance with the present invention.
FIG. 2 is a side cross-sectional view of the conditioning head of FIG. 1 wherein an elastic device of the head causes the head's end effector to assume a non-perpendicular orientation while being utilized to condition a polishing surface of a CMP polishing pad.
FIG. 3 is a side cross-sectional view of the conditioning head of FIG. 1 in a cleaning mode.
FIG. 4 is a partial side cross-sectional view of a shaft, an end effector, and an elastic device of a conditioning head in accordance with the present invention.
FIG. 5 is a partial side cross-sectional view of a conditioning head including a sealing element for sealing against a shaft portion of a rotating member in accordance with the present invention.
FIG. 6 is a partial side cross-sectional view of a conditioning head including a sealing element adapted to retract away from a shaft portion of a rotating member in accordance with the present invention.
DETAILED DESCRIPTION
Multiple inventive pad conditioning heads are disclosed. According to some head embodiments, close conformance of conditioning disks to irregular polishing surfaces of a polishing pad is permitted via deviation of the head's end effector from a perpendicular orientation (e.g., vertical rotation relative to a housing of the head) via an elastic device such as a bellows, as will be explained further below. According to some other head embodiments, also described below, cleaning fluid is introduced within the conditioning head so as to rinse from the conditioning head such polishing slurry as may have migrated into the conditioning head during pad conditioning. According to still other head embodiments, a pressurized gaseous media is introduced within the conditioning head during pad conditioning so as to form a slurry-purging flow of gaseous media outward of the conditioning head, e.g. via a retracting sealing element.
FIG. 1 is a side cross-sectional view of a conditioning head 101 in accordance with the present invention. The conditioning head 101 may be generally circular in shape as viewed from above (not shown), and may include a pulley 103 adapted to be rotatably driven by an external source of torque, a housing 105 adapted to be secured to a means (not shown)(e.g., a rigid mounting arm) for moving the conditioning head relative to (e.g., laterally across) the polishing surface of a polishing pad ( FIG. 3 ), and an end effector 107 adapted to receive a conditioning pad 109 and to be rotated relative to the housing 105 (e.g., when the conditioning pad 109 is in contact with the polishing surface of a polishing pad during polishing pad conditioning). Applicants have observed that providing a mounting arm (not shown) having improved rigidity over arms of certain known conditioning apparatus, e.g., providing an arm comprising aluminum alloy, a width about 100 mm, and a thickness about 90 mm, improves controllability of the conditioning head 101 e.g., by increasing a positioning precision of the end effector 107 relative to a polishing surface of a polishing pad, and by decreasing a tendency of the mounting arm to flex during application of a down-force to the polishing surface by the conditioning head 101 during polishing pad conditioning.
The conditioning head 101 may also include a rotatable member 111 which may comprise an axis 113 about which the rotatable member 111 may be rotated, and which may be fixedly coupled to the pulley 103 so as to permit a torque from the pulley 103 to rotate the rotatable member 111 relative to the housing 105 . The rotatable member 111 may comprise an extended cylindrical portion 114 , which may be in the form of a torque-transmitting shaft, coupled to the pulley 103 and spanning a distance from the pulley 103 , into the housing 105 , and to and/or beyond a lower portion of the housing 105 , where the rotatable member 111 may terminate in a flanged portion 115 of the rotatable member 111 . The flanged portion 115 may be attached to the extended cylindrical portion 114 , e.g., fixedly attached, or the rotatable member 111 comprising the extended cylindrical portion 114 and the flanged portion 115 may be of unitary construction, e.g., a machined piece of stainless steel. The flanged portion 115 may be adapted to participate in an interface between the rotatable member 111 and the end effector 107 , as described further below, or an additional assembly component, e.g., another flange-type component (not shown), specifically designed for the purpose and/or comprising a different material, may be attached to the flanged portion 115 for that purpose.
The conditioning head 101 may also include a bearing 117 disposed within the housing 105 and around the extended cylindrical portion 114 of the rotatable member 111 . The bearing 117 may be any one of a number of conventional bearing types. For example, a sealed and lubricated double row angular-contact ball bearing has been observed to provide a good result and to have wide applicability, in particular with respect to future pad conditioning applications expected to require rotation speeds of 200 RPM or more. The bearing 117 may be adapted to essentially fix a lateral position of the axis 113 of the rotatable member 111 within and relative to the housing 105 (e.g., so as to provide a rigid vertical orientation within the housing 105 ), while permitting the rotatable member 111 to freely rotate about its axis 113 within and relative to the housing 105 .
Movement of the End Effector 107 Relative to the Flanged Portion 115 of the Rotatable Member 111
The conditioning head 101 may also comprise an elastic device 119 coupled between the flanged portion 115 of the rotatable member 111 and the end effector 107 and having important features and functions adapted to provide improved pad conditioning. For example, and as shown in the side cross-sectional view of the conditioning head 101 illustrated in FIG. 2 , in operation, the elastic device 119 may be adapted via elastic extension to permit the end effector 107 to move relative to the flanged portion 115 of the rotatable member 111 in a direction aligned with the axis 113 of the rotatable member 111 , e.g., so as to extend away from the flanged portion 115 of the rotatable member 111 and establish contact between the conditioning pad 109 and the polishing surface of a polishing pad P, and/or to retract away from the polishing pad P and toward the flanged portion 115 of the rotatable member 111 (e.g., to enable the conditioning head 101 and/or a polishing pad to be moved toward or away from a conditioning position). The elastic device 119 may also be adapted to generate and/or apply a force (e.g., a down force) to the end effector 107 , e.g., a down force sufficient for pad conditioning. The elastic device 119 may be further adapted to permit torque to be transmitted from the rotatable member 111 to the end effector 107 for rotation of the end effector 107 , e.g., while the conditioning pad 109 is in contact with the polishing surface of the polishing pad P, so as to condition the polishing pad P in combination with the down force.
During polishing pad conditioning, and as also shown in FIG. 2 , the elastic device 119 may be adapted to permit the end effector 107 to deviate from a perpendicular orientation with respect to the axis 113 of the rotatable member 111 (e.g., as necessary in response to irregular pad surfaces). Also, where the elastic device 119 may be adapted to permit non-perpendicular positions of the end effector 107 during pad conditioning, the elastic device 119 may also be adapted to prevent the end effector 107 from becoming stuck in non-perpendicular and extended positions during or after pad conditioning, e.g., so as to protect the conditioning head 101 and/or the polishing surface of the polishing pad from the risk of damage associated with the end effector 107 being frozen in an extended and/or cockeyed position/orientation.
Protection of the Bearing 117 from Polishing Slurry During Pad Conditioning
Applicants have observed that sensitive and/or precision components disposed within the housings of conditioning heads may be prematurely degraded (e.g., wherein a period of useful life is shortened) and/or entirely disabled by the invasion of polishing slurry, e.g., via the effects of corrosion and/or abrasion. For example, and as shown in FIG. 2 , while the rotatable member 111 and the end effector 107 are rotating, and while the conditioning pad 109 is being used to condition the polishing surface of a polishing pad P in the presence of a polishing slurry (not shown), a risk exists that polishing slurry, such as liquid or particulate polishing slurry, or polishing slurry in vapor form, will migrate into the conditioning head 101 , e.g., via a gap 121 between the housing 105 and the flanged portion 115 of the rotatable member 111 , and ultimately enter a cavity 123 within the housing 105 containing sensitive and/or precision components, such as the bearing 117 .
In accordance with the present invention, the conditioning head 101 is adapted to block the polishing slurry, whether in liquid, particulate, or vapor form, from entering the cavity 123 , e.g., while the conditioning head 101 is in use conditioning a polishing pad, and to do so without requiring frictional sealing contact (e.g., which may tend be a source of contamination via particle generation) with the rotatable member 111 . For example, and as shown in FIG. 2 , during polishing pad conditioning (e.g., while the rotatable member 111 and the end effector 107 are being rotated), the conditioning head 101 may be adapted to direct a flow 125 of pressurized gas away from the cavity 123 , along the gap 121 , and outward of the housing 105 of the conditioning head 101 . Applicants have observed that positive pressure gas applied in this way will reduce and/or minimize, if not essentially prevent, the problem of polishing slurry entering the housing 105 and invading the cavity 123 via the gap 121 in liquid, particle, or vapor form. In addition, and as also shown in FIG. 2 , where the conditioning head 101 comprises a sealing element 127 adapted to achieve sealing contact (see FIG. 1 ) against the rotatable member 111 (e.g., for sealing the cavity 123 (e.g., during periods when the rotatable member 111 is not rotating relative to the housing 105 of the conditioning head 101 ), the sealing element 127 may be further adapted to break and/or extend away from such sealing contact (see FIG. 2 ) during rotation of the rotatable member 111 so as to reduce and/or preclude potentially particle-generating friction, and to permit the slurry-purging flow 125 of pressurized gas away from the cavity 123 and outward of the conditioning head 101 .
Preventing Polishing Slurry from Accumulating within the Conditioning Head 101
The conditioning head 101 is further adapted to prevent any potentially damaging polishing slurry which may (e.g., despite the action of the flow 125 ( FIG. 2 ) of pressurized gas) enter the conditioning head 101 via the gap 121 during polishing pad conditioning from accumulating therein over time and/or as a result of repeated use of the conditioning head 101 for conditioning multiple pads. For example, and as shown in the side cross section view of the conditioning head 101 illustrated in FIG. 3 , the conditioning head 101 may be adapted (e.g., between pad conditioning sessions) to direct a flow 129 of cleaning fluid, e.g., an aqueous cleaning fluid adapted to dissolve a buildup of polishing slurry, outward along the gap 121 from within the conditioning head 101 , e.g., so as to rinse the affected surfaces of the flanged portion 115 of the rotatable member 111 and of the housing 105 .
Applicants have observed that given a sufficient time and volume of flow of the cleaning/rinsing fluid, an operator may be assured that any polishing slurry which may have accumulated in the gap 121 during polishing pad conditioning will have been rinsed off the affected surfaces and subsequently flushed out of the conditioning head 101 , and that the next polishing session may be commenced, e.g., without risk of the gap 121 remaining clogged with a residue of polishing slurry such as may inhibit a relative rotation of the rotatable member 111 relative to the housing 105 or as may partially or completely block a flow 125 ( FIG. 2 ) of slurry-purging pressurized gas from within the conditioning head 101 .
Exemplary Embodiment of an Inventive Elastic Device 119
FIG. 4 is a partial side cross-sectional view of a subset of the components of a conditioning head 101 a , similar to the conditioning head 101 of FIGS. 1-3 but including specific embodiments of the above-discussed components, including a shaft 111 a , an end effector 107 a , and an elastic device 119 a . The rotatable member 111 a , the end effector 107 a and the elastic device 119 a may be similar to the rotatable member 111 , the end effector 107 , and the elastic device 119 discussed above, and may include additional features and aspects as discussed below.
The elastic device 119 a may include an elastic element adapted to be selectively extended (e.g. via inflation/pressurization) and/or retracted (e.g., via deflation/depressurization), and which may provide a reciprocating motion of the end effector 107 . For example, based on a predetermined degree of inflation and/or internal pressure, the elastic device 119 a may be adapted to produce a desired position of the end effector 107 relative to the flanged portion 115 of the rotatable member 111 and/or relative to a polishing surface of a polishing pad (see the polishing pad P of FIG. 2 ). Also, the same element of the elastic device 119 a may permit a desired and/or predetermined amount of force (e.g., down force) to be applied to the end effector 107 while the conditioning pad 109 contacts a polishing surface of a polishing pad ( FIG. 2 ), and may be further adapted to transmit torque from the rotatable member 111 a to the end effector 107 a so as to provide pad conditioning.
For example, and as shown in the particular embodiment of the elastic device 119 a shown in FIG. 4 , the elastic device 119 a may comprise a bellows 131 (shown in a cutaway view) which may be caused to flexibly span a selectively adjustable distance between an downward-facing surface of the flanged portion 115 of the rotatable member 111 a and an upward-facing surface of the end effector 107 a . For example, applicants observe that providing a bellows 131 that may extend, e.g., from a free length of 0.2 inches to an extended length of 0.4 inches provides a good result. The bellows 131 may further be of such a construction and be comprised of any suitable materials so that it may further be adapted to perform reliably during and after numerous reciprocation cycles, e.g., one million reciprocation cycles, wherein a reciprocation cycle may consist of a pressurized inflation followed by a deflation in which pressure is relaxed. For example, the bellows 131 may comprised of INCo 625, 0.004 inches thick in a two-ply construction, welded so as to comprise 5 convolutions, reaching an extended length via a 3 PSID internal pressure, and exerting an additional 7 pounds of load with each additional 1 PSID of internal pressure.
The bellows 131 may also be suitably flexible in an extended state (e.g., during pad conditioning) to permit various non-perpendicular positions of the end effector 107 as described above with reference to FIG. 2 . For example, the above-described embodiment of the bellows 131 readily permits the end effector 107 to diverge on the order of from 0 to 5 degrees or more from a perpendicular orientation with respect to the flanged portion 115 of the rotatable member 111 , e.g., for close conformance to a polishing surface during polishing pad conditioning. Also, the extended bellows 131 may comprise a suitably strong spring force so as to promptly retrieve the end effector 107 from such positions when the cause of the misaligned condition is removed, e.g., such as when the conditioning head 101 is moved during pad conditioning from an irregular (e.g., angled, bumpy, curved) region of the polishing surface to a region that is relatively horizontal and/or flat, and/or when being employed to retract the end effector 107 from the polishing surface and toward the flanged portion 115 of the rotatable member 111 a.
The bellows 131 may comprise an internal volume 133 that may be caused to increase, e.g., via inflation from an external source (not shown) of elevated pressure and/or caused to decrease, e.g., via deflation as determined by the same source of elevated pressure (e.g., such that the source of pressure is adapted to vary the pressure applied) and/or by an external source of vacuum pressure. For example, Applicants have observed that at least briefly applying subatmospheric levels of pressure to the internal volume 133 of the bellows 131 for purposes of deflation may afford a greater range and/or a more precise degree of control over the motion of the end effector 107 a and/or the position of the end effector 107 a relative to the flanged portion 115 of the rotatable member 111 a at any given time.
Where an external source of pressure and/or vacuum is desired to inflate and/or deflate the bellows 131 , the rotatable member 111 a may comprise a pressure duct 135 , e.g., leading from the internal volume 133 , through the flanged portion 115 and the extended cylindrical portion 114 of the rotatable member 111 a , to an upper end of the rotatable member 111 a . The pressure duct 135 may be aligned with the axis 113 ( FIG. 1 ) of the rotatable member 111 a , and a rotary pressure fitting 137 may be coupled to the rotatable member 111 where the pressure duct 135 emerges from the upper end of the rotatable member 111 , such that pressure and/or vacuum may be applied to the bellows 131 while the rotatable member 111 a is rotating during pad conditioning.
It may also be desired to shield the bellows 131 of the elastic device 119 from exposure to polishing slurry. For example, where a particular construction and/or material composition of the bellows 131 may be preferable from a mechanical/functional standpoint, the same bellows 131 (e.g., which may comprise a metal or a metal alloy) may be somewhat or particularly susceptible to damage and/or deterioration from effects of exposure to polishing slurry, e.g., corrosion and/or abrasion. As such, the elastic device 119 a may further comprise a boot 139 adapted to be disposed around the bellows 131 and coupled between the flanged portion 115 of the rotatable member 111 a and the end effector 107 a , e.g., via retaining rings 141 , so as to seal outward-facing surfaces of the bellows 131 and substantially prevent polishing slurry in any form from contacting the same. For example, the boot 139 may be of a flexible length so as to be adapted to extend and retract to the same extent as bellows 131 while remaining firmly affixed to the flanged portion 115 of the rotatable member 111 a and the end effector 107 a , e.g. so as to maintain an airtight seal against the same. As such, the boot 139 may comprise any inert material of suitable toughness, flexibility (e.g., EPDM Rubber).
Where the seals formed between the boot 139 and the flanged portion 115 of the rotatable member 111 a and between the boot 139 and the end effector 107 a are intended to be, and to remain, air tight, it may be desirable to prevent the creation of, and or minimize the potential for, a pressure cycle within a volume 142 between the boot 139 and an outward-facing surface of the bellows 131 . For example, as the bellows 131 undergoes an inflation/deflation cycle via regulation of an internal pressure such that the internal volume 133 increases or decreases, and if there is no provision for introducing and/or removing air from the volume 142 , the volume 142 may be subject to cyclical increases and/or decreases in pressure. Such pressure cycles may, e.g., break integrity of the seal between the boot 139 and the end effector 107 a and infuse the surrounding slurry into the volume 142 , which may in turn reduce a useful life of the bellows 131 and/or the elastic device 119 a.
The conditioning head 101 a may be adapted to prevent and/or minimize the potential for such undesired pressure cycles in the volume 142 between the boot 139 and the bellows 131 . For example, and as shown in FIG. 4 , the end effector 107 a may comprise a pressure relief duct 143 leading inward from the volume 142 . The rotatable member 111 a may also comprise a pressure relief duct 145 which, similar to the pressure duct 135 , may lead from the internal volume 133 , through the flanged portion 115 and the extended cylindrical portion 114 of the rotatable member 111 a , to an upper end of the rotatable member 111 a , and which (as opposed to the pressure duct 135 ) may be permitted to communicate with the atmosphere. A coupling apparatus 146 may be provided within the end effector 107 a and/or within the internal volume 133 of the bellows 131 so as to connect the pressure relief duct 143 of the end effector 107 a and the pressure relief duct 145 of the rotatable member 111 a and to form a ventilation path from the volume 142 to atmosphere. A rotationally symmetrical arrangement of such ducts and connection apparatus, or of other (e.g., similar) ducts and connection apparatus adapted to perform the same function, may be provided such that any resulting imbalance in the rotating portions of the conditioning head 101 a may be substantially eliminated, or at least substantially reduced and/or minimized. For example, such an arrangement may be of particular importance as pad rotation speeds in the multiple hundreds of RPM become common.
Exemplary Embodiments of Apparatus and Methods for Preventing Polishing Slurry from Damaging Internal Components of a Conditioning Head
Embodiments of the present invention provide methods and apparatus for preventing (and/or reducing an amount of) polishing slurry from migrating into a conditioning head and risking damage to precise and/or sensitive components disposed therein. For example, FIG. 5 is a partial side cross sectional view of a conditioning head 101 b similar to the conditioning head 101 shown in FIG. 1 and having additional features and functions as described below.
Referring to FIG. 5 , the conditioning head 101 b may comprise a sealing element sealing element 127 a similar to the sealing element 127 described above and having additional features and functions as described below. The sealing element 127 a may be adapted to assume a fixed non-rotating position within the housing 105 above the gap 121 (e.g., the conditioning head 101 may comprise an insert (not shown) adapted to provide a receptacle for receipt of the sealing element 127 a ) and may comprise one or more circular lips 147 adapted to form a water-tight seal about a circumference of the extended cylindrical portion 114 of the rotatable member 111 . For example, a lower lip 147 a of a relatively thin gage may be provided which extends from a main seal body 149 inward and downward toward the extended cylindrical portion 114 of the rotatable member 111 , so that the integrity of the seal formed between the lower lip 147 a and the extended cylindrical portion 114 of the rotatable member 111 is adapted to generally increase (e.g., the seal will become tighter) should the lower lip 147 a be acted on by forces tending to urge the lower lip 147 a upward. As discussed generally with regard to FIG. 3 , and as more specifically described here with regard to FIG. 5 , should the conditioning head 101 be subjected to irrigation by a flow 129 of cleaning fluid directed into the housing 105 for subsequent diversion outward of the housing 105 along the gap 121 , the lower lip 147 a of the sealing element 127 a may provide a water-tight seal against the extended cylindrical portion 114 of the rotatable member 111 that may prevent cleaning fluid from entering the cavity 123 of the housing 105 that contains the bearing 117 . Moreover, the lower lip 147 a may form a surface adapted to absorb pressure forces associated with the flow 129 of cleaning fluid in a manner which increases seal integrity and diverts the flow 129 of cleaning fluid into the gap 121 so as to rinse a build-up of polishing slurry from the adjacent surfaces of the housing 105 and of the flanged portion 115 of the rotatable member 111 .
As also shown in FIG. 5 , the housing 105 may comprise a utility interface surface 151 , which may be parametrically disposed about the housing 105 , and which may feature one or more apertures. For example, the utility interface surface 151 may comprise a cleaning fluid inlet 153 , and the housing 105 may include a cleaning fluid duct 155 adapted to direct the flow 129 of cleaning fluid into a space 157 beneath the sealing element 127 a and near the lower lip 147 a . The space 157 may be the deepest and highest location within the housing 105 at which polishing slurry may be expected to accumulate, and so to direct the flow 129 of cleaning fluid toward such a location may be the most effective method of ensuring that it and all downstream locations are rinsed clean of polishing slurry deposits.
In operation, the end effector 107 ( FIG. 2 ) of the conditioning head 101 b may be retracted from a polishing surface of a polishing pad P ( FIG. 2 ) and the conditioning head 101 b may be moved to a stand-by position, e.g., separate from a pad conditioning station, where an internal rinse may be performed to eliminate polishing slurry deposits. The rotatable member 111 may be caused to cease rotation, and the sealing element 127 a may be caused to seal against the extended cylindrical portion 114 of the rotatable member 111 . Specifically, the lower lip 147 a of the sealing element 127 a may be caused to press against the extended cylindrical portion 114 of the rotatable member 111 for sealing the cavity 123 against entry of cleaning fluid and/or polishing slurry as a result of the rinse. Once the necessary seal is achieved, the flow 129 of cleaning fluid may be introduced to the housing 105 via an appropriate fitting (not shown) attached to the utility interface surface 151 at the cleaning fluid inlet 153 , and the flow 129 may be allowed to flow along the cleaning fluid duct 155 and into the space 157 for rinsing and/or cleaning of polishing slurry deposits as described above. A time and volume of the flow 129 may be predetermined and may be adapted to permit the rinse to be accomplished during the time necessary to swap a conditioned polishing pad for a polishing pad requiring conditioning.
FIG. 6 is a partial side cross sectional view of a conditioning head 101 c similar to the conditioning head 101 shown in FIG. 1 and having additional features and functions as described as follows. Referring to FIG. 6 , the conditioning head 101 c may comprise the sealing element 127 a described above with reference to FIG. 5 , and the sealing element 127 a may be adapted to break or retract away from sealing contact with the extended cylindrical portion 114 of the rotatable member 111 (see FIG. 2 and relevant description above) during rotation of the rotatable member 111 and the flow 125 of pressurized gas used to block polishing slurry from entering the cavity 123 of the housing 105 that contains the bearing 117 . The sealing element 127 a may comprise both a lower lip 147 a and an upper lip 147 b , with the upper lip 147 b having structure and function that may be similar to the lower lip 147 a except in that the upper lip 147 a is adapted to extend inward and upward (i.e., from the main seal body 149 ) toward the extended cylindrical portion 114 of the rotatable member 111 . As discussed generally with regard to FIG. 2 , and as more specifically described here with regard to FIG. 6 , just prior to the conditioning head 101 c being employed to condition a polishing surface of a polishing pad (e.g., before the rotatable member 111 of the conditioning head 101 c has begun rotating), the conditioning head 101 c may direct the flow 125 of pressurized gas to the main seal body 149 of the sealing element 127 a , and the main seal body 149 of the sealing element 127 a may direct the flow 125 into a gap 159 between the upper and lower lips 147 a , 147 b . Pressure within the gap 159 caused by the flow 125 of pressurized gas may cause the lower lip 147 a to break sealing contact with the extended cylindrical portion 114 of the rotatable member 111 and/or flex away from the extended cylindrical portion 114 , permitting at least a portion of the flow 125 of pressurized gas to flow (e.g., downward) along the extended cylindrical portion 114 of the rotatable member 111 (e.g., away from the cavity 123 and the bearing 117 ) and outward of the housing 105 along the gap 121 . Once such a flow of slurry-purging pressurized gas has been established, and the lower lip 147 a (along with the upper lip 147 b as described below) has retracted away from the extended cylindrical portion 114 of the rotatable member 111 , the rotatable member 111 may begin rotating and pad conditioning may begin, and the flow 125 of pressurized gas may act to protect sensitive components of the conditioning head 101 c (e.g., the bearing 117 ) from damage from migrating polishing slurry.
As also shown in FIG. 6 , the utility interface surface 151 of the housing 105 may comprise a pressurized gas inlet 161 , and the housing 105 may include a pressurized gas duct 163 adapted to direct the flow 125 of pressurized gas to the main seal body 149 of the sealing element 127 a , after which the flow 125 of pressurized gas will flow to the gap 159 between the lips 147 a , 147 b as described above. The gap 159 may be an advantageous location at which to apply the flow 125 of pressurized gas since it is below the bearing 117 and immediately upstream of the space 157 ( FIG. 5 ) at which the flow 129 ( FIG. 5 ) of the cleaning fluid is applied and redirected downstream along the gap 121 .
As is also shown in FIG. 6 , the housing 105 may also comprise a pressurized gas ventilation duct 165 , and pressure from the flow 125 of pressurized gas within the gap 159 between the lips 147 may also force the upper lip 147 a to break sealing contact with the extended cylindrical portion 114 of the rotatable member 111 and/or flex outward, permitting a portion of the flow 125 of pressurized gas to flow into the cavity 123 , past the bearing 117 , and outward of the housing 105 through the pressurized gas ventilation duct 165 . Such an arrangement may be utilized so as to exhaust any contamination which may have accumulated in the cavity 123 of the housing 105 (e.g., by expelling particles generated by operation of the bearing 117 and/or any slurry particles or other types contamination which may have entered the cavity 123 from below despite the combined cleaning action of the flow 125 of the pressurized gas and the flow 129 of cleaning fluid. It should be noted that the upper lip 147 b may be of the same rigidity as the lower lip 147 a for the creation of an air bearing between said lips 147 a - b and the shaft 114 . Such an arrangement would both eliminate the possibility of seal abrasion and reduce the operating torque.
In operation, the flow 125 of pressurized gas may be introduced to the housing 105 via an appropriate fitting (not shown) attached to the utility interface surface 151 at the pressurized gas inlet 161 , the flow 125 may be allowed to flow along the pressurized gas duct 163 and into the gap 159 , the sealing element 127 a may be caused to retract (e.g., via the pressure from the flow 125 of pressurized gas) from the extended cylindrical portion 114 of the rotatable member 111 , and the flow 125 of pressurized gas may then be used to purge, e.g., in the manner described above, any polishing slurry, e.g., slurry in particulate, liquid, or vapor form, that may tend to migrate into the housing 105 along the gap 121 during upcoming pad conditioning. As also described above, a portion of the flow 125 of pressurized gas may be directed through the cavity 123 of the housing 105 so as to exhaust contamination from the cavity 123 and eject the same from the housing 105 through the pressurized gas ventilation duct 165 . Once the purging flow 125 of pressurized gas has been established and is flowing, the end effector 107 ( FIG. 1 ) of the conditioning head 101 c may be extended away from the flanged portion 115 of the rotatable member 111 and into contact with a polishing surface of a polishing pad P ( FIG. 2 ) so as to rotate relative to the same in the presence of polishing slurry during pad conditioning. A continuous flow 129 of pressurized gas may be maintained throughout the period of pad conditioning so as to provide continuous protection against slurry migration into the housing 105 of the conditioning head 101 c.
Testing of an Embodiment of an Inventive Conditioning Head
A conditioning head 101 ( FIG. 1 ) comprising a sealing element 127 a ( FIG. 5 ) as described above, a flow 125 of pressurized gas applied throughout pad conditioning, a rotatable member 111 having a extended cylindrical portion 114 of 20 mm, and a bearing 117 comprising a 20 mm ID ball bearing manufactured by Koyo Corporation (part number 5204), was placed in contact with polishing pads and operated in a pad conditioning mode. The rotatable member 111 of the conditioning head 101 was rotated at 1600 RPM for 10 hours during testing in pad polishing conditions (e.g., in the presence of polishing slurry). Applicants observed no signs of degradation of the bearing 117 or the sealing element 127 a . Since conventional conditioning pad rotation speeds typically range from 90-120 RPM, and with new pad conditioning applications being predicted to require rotation speeds of 400-500 RPM, conditioning heads in accordance with the present invention would appear well suited for use either in any compatible pad conditioning apparatus which are either presently available or are being developed for such future applications.
The foregoing description discloses only particular embodiments of the invention; modifications of the above disclosed methods and apparatus which fall within the scope of the invention will be readily apparent to those of ordinary skill in the art. For instance, although specific embodiments of the inventive conditioning heads described herein are configured for use with an aqueous cleaning fluid for dissolving/removing deposits of polishing slurry, non-aqueous cleaning fluids, or even a flow of deposit-purging gas may be substituted for the aqueous cleaning fluid in certain applications, if desired. Further, it will be understood that the specific configuration of the rotating member, bearing, housing, sealing element, elastic device, and end effector, etc., may vary and still fall within the scope of the invention. The housing may include multiple cleaning fluid ducts and/or pressurized gas ducts, e.g., radially-arrayed around the head, and/or one or more annular ducts (i.e., passing into the paper of FIG. 5 or 6 and concentric with the axis of rotation of the rotating member) as desired, e.g., so as to provide a plurality of parametrically-spaced locations from which to direct a pressurized gas purge or a flow of irrigating/cleaning fluid outward from the center of the head. The rotating member need not comprise a shaft portion of a smaller diameter than a flange portion. The seal need not necessarily include an upper lip, whether flexible or not, and an additional duct for gas purging near the bearing may be omitted. The elastic device may comprise any manner of device which, like the bellows disclosed herein, provides torque and down-force transmission while permitting various non-perpendicular orientations of the end effector and conditioning pad. Accordingly, while the present invention has been disclosed in connection with specific embodiments thereof, it should be understood that other embodiments may fall within the spirit and scope of the invention, as defined by the following claims.
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In a first aspect, a first apparatus is provided for a chemical mechanical polishing (CMP) process. The first apparatus includes (1) a rotatable member; (2) an end effector adapted to receive and retain a conditioning disk; and (3) an elastic device disposed between the rotatable member and the end effector. The elastic device is (a) adapted to rotate the end effector via a torque from the rotatable member, and (b) flexibly extensible so as to impart a force to the end effector while permitting the end effector to deviate from a perpendicular alignment with the rotatable member in order for a conditioning surface of the conditioning disk to conform to an irregular polishing surface of a pad being conditioned. Numerous other aspects are provided, including methods and apparatus for using liquid or gas to deter polishing slurry or debris from entering the conditioning head.
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FIELD OF THE INVENTION
[0001] The present invention relates to the field radiation detection and more particularly to single crystal scintillation detectors for gamma rays, x-rays and like radiation.
BACKGROUND OF THE INVENTION
[0002] Transparent single crystal scintillators are well known in the art for use as detectors of gamma rays, x-rays, cosmic rays, other types of high energy radiation and energetic particles of approximately 1 KeV or above. When radiation is incident on the scintillator secondary photons are generated within the crystal. These secondary photons result from the interaction of the incident radiation and an activation ion contained within the crystal. Once produced, the secondary photons can be optically coupled to a photodetector so as to produce a voltage signal that is directly related to the number and amplitude of the secondary photons. Such crystal scintillators are typically employed for medical imaging such as Positron Emission Tomography (PET), digital radiography, mineral and petroleum exploration.
[0003] An ideal detector for the detection of the above radiation and particles employs a single crystal scintillator characterised in that it exhibits:
[0004] A high density so as to provide a high stopping power on the aforesaid radiation or particles;
[0005] A high light output, this results in the production of bright visible light, typically in the blue/UV region of the electromagnetic spectrum, in response to the absorption of the aforesaid radiation or particles;
[0006] A good energy resolution, which is an important characteristic as it allows good event identification, for example in PET applications;
[0007] A short decay time, associated with the ions excited by the aforesaid radiation or particles, so as to provide detectors with a fast response time; and
[0008] A rugged structure so as to reduce the opportunity of accidental damage.
[0009] The Prior Art teaches of various single crystal scintillator materials that have been employed in an attempt to satisfy the above criteria. One of the earliest types of scintillator employed was Thallium doped Sodium Iodide (NaI:Tl). Although capable of producing very high light outputs and being relatively inexpensive to produce NaI:Tl exhibits an inherently low density and so has a low incident radiation absorption efficiency. In addition, NaI:Tl is hygroscopic, has a slow scintillation decay time and produces a large persistent afterglow that acts to impair the counting rate performance of the material.
[0010] Table 1 provides a summary of some of the main characteristics of NaI:Tl as well as other known scintillator materials. The data within this table are taken from papers and Patents that teach of the relevant crystals, as discussed below. It should be noted that:
[0011] The light output values are relative values measured relative to the light output of NaI:Tl;
[0012] The decay times are measured in nanoseconds and refer to the time it takes for a particular activation ion of a crystal scintillator to luminesce from the excited electronic state;
[0013] The density values are measured in g/cc;
[0014] The emission peak wavelengths are measured in nanometers; and
[0015] The melting point values are measured in ° C.
[0016] Inorganic metal oxides provide alternative single crystal scintillators devised for gamma ray detection and the like. For example a commonly employed inorganic metal oxide crystal is Bismuth Germanate (BGO). As well as being denser than NaI:Tl, BGO does not suffer from being hygroscopic. However, BGO scintillators have even slower scintillation decay times, exhibit lower light output levels that drop further with increasing temperatures and exhibit poor energy resolution values, as compared to NaI:Tl. In addition the refractive index values for BGO scintillators are relatively high so resulting in significant levels of light being lost through internal reflection processes within the crystal.
[0017] Attempts have been made to develop alternative single crystal scintillators that improve on the inherent characteristics of the aforementioned crystals. For example, Cerium activated Yttrium Orthosilicate (YSO) crystals have been developed while European Patent Application No. EP 0,231,693 teaches of a Cerium activated Gadolinium Orthosilicate (GSO) scintillator. The characteristic properties for both of these crystals are summarised in Table 1. Although exhibiting significantly faster scintillation decay times than NaI:Tl or BGO, both YSO and GSO have low densities. The light output and energy resolution values exhibited by YSO are generally good, however the inherent low density makes it a poor candidate for applications such as PET. GSO exhibits a lower light output than YSO but does have a higher density. However, the inherent poor mechanical properties of GSO make such crystals expensive to produce.
[0018] Another material that has been the subject of much development over the last few years is Cerium activated Lutetium Silicate (LSO) as taught in U.S. Pat. No. 4,958,080 and the equivalent European Patent No. 0,373,976. In particular LSO has become one of the most common crystals presently employed as a single crystal scintillator in PET as these crystals have good properties for such applications (see Table 1). LSO exhibits a fast scintillation decay time, has a fairly high density, high light output values and an average energy resolution. However, one main drawback of employing LSO as a single crystal scintillator is again the fact that it is an extremely expensive crystal to produce. This is due mainly to the fact that the melting point is very high (typically ˜2100° C.) as compared to other standard oxide crystals.
[0019] Further single crystal scintillators have been developed in attempts to improve on the working characteristics of LSO while reducing the production costs. Such attempts concentrate exclusively on introducing a substitute ion at the site of the Lutetium ions within the original LSO structure. In particular U.S. Pat. No. 6,278,832 and the equivalent European Patent Application No. EP 1,004,899 teach of mixed Lutetium Orthosilicate crystals, commonly referred to as MLS crystals. Alternatively, U.S. Pat. No. 6,323,489 teaches of a single crystal of Cerium activated Lutetium Yttrium Oxyorthosilicate (LYSO). Both MLS crystals and LYSO crystals exhibit similar physical properties to LSO but are still expensive to produce since their melting point is only slightly lower that that of LSO.
[0020] A further restricting factor that is common to LSO, LYSO and MLS crystals is the fact that they all exhibit only average levels of energy resolution, compared to GSO or NaI:Tl.
[0021] U.S. Pat. No. 5,864,141 teaches of a high resolution gamma ray imaging device that employs a Yttrium Aluminium Perovskite (YAP) crystal scintillator while U.S. Pat. No. 5,864,141 teaches of a gamma ray detector based on a Yttrium Aluminium Perovskite (YAP) crystal. A YAP single crystal scintillator is found to exhibit very fast scintillation decay times and provide very good energy resolution and light output levels. However, YAP exhibits low density levels and is again an expensive crystal to produce. The fact that YAP has superior energy resolution than LSO is due to the fact that LSO exhibits a strong non-linearity of energy response which YAP does not suffer from. The superior energy resolution has been attributed to the perovskite structure.
[0022] An alternative single crystal scintillator to YAP that is also based on the Aluminium Perovskite structure, is LuAP, which has also been known to those skilled in the art for over a decade. For example, U.S. Pat. No. 5,961,714 teaches of a method of growing Cerium activated Lutetium Aluminium Perovskite (LuAP). LuAP crystal has a significant advantage over YAP in that it exhibits a much higher density and hence a higher stopping power. This characteristic makes LuAP extremely attractive as a gamma-ray scintillator and in particular for employment within PET applications.
[0023] The main drawback with LuAP is that it is extremely difficult to manufacture due to the fact that it is metastable at high temperature, which causes decomposition of the perovskite phase at high temperature. Therefore, to date attempts to manufacture LuAP have yielded only small size samples.
[0024] Research work has also been conducted on mixed Lutetium Yttrium Aluminium Perovskite crystals e.g. Cerium activated LuYAP, which is basically a mixed crystal of LuAP and YAP. Several references, such as:
[0025] “Growth and Light Yield Performance of Dense Ce 3+ doped (Lu,Y)AlO 3 Solid Solution Crystals”, by Petrosyan et al, JCG 211 (2000) 252-256;
[0026] “Development of New Mixed Lu (RE 3+ ) AP:Ce Scintillator: Comparison With Other Ce Doped or Intrinsic Scintillating Crystals”, by Cheval et al, Nuclear Inst. And methods in Phys. Res. A443 (2000) 331-341;
[0027] “Intrinsic Energy Resolution and Light Output of the Lu0.7Y0.3AP:Ce Scintillator”, by Kuntner et al, Nuclear Inst; and
[0028] Methods in Phys. Res. A 493 (2002) 131-136.
[0029] describe the physical properties of a LuYAP crystal that comprises 30% Yttrium and 70% Lutetium. This LuYAP crystal requires such a high level of Yttrium in order for it not to decompose at high temperatures. However, this results in a crystal that exhibits a density and stopping power that is significantly lower than LuAP. For example in the case of LuYAP with a 30% Yttrium level the crystal density becomes comparable with LSO, namely 7.468 g/cc. The decay time of such LuYAP crystals is about 25 ns but there also exists a significant long decay time component that is detrimental to applications where a fast crystal scintillator is preferred.
SUMMARY OF THE INVENTION
[0030] It is clearly desirable to be able to provide an affordable single crystal scintillator having as many of the aforementioned desirable properties as possible. Therefore, it is an object of at least one aspect of the present invention to provide a single crystal scintillator capable of detecting gamma rays, x-rays, cosmic rays and similar high energy radiation as well as energetic particles.
[0031] It is a further object of at least one aspect of the present invention to provide a single crystal scintillator that exhibits good working characteristics while remaining cost effective to produce.
[0032] According to a first aspect of the present invention there is provided a crystal scintillator comprising a transparent single crystal of a Cerium activated mixed Perovskite having a general formula
Ce x Lu (1−x−z) A z Al (1−y) B y O 3 , wherein
[0033] x is within the range of from approximately 0.00005 to approximately 0.2,
[0034] y is within the range of from 0.00005 to approximately 1.0,
[0035] z is within the range of from 0 to approximately (1−x), where A comprises one or more of the following cations: Y, Sc, La, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, In, Ga and B comprises one or both of the following cations: Sc and Ga.
[0036] According to a second aspect of the present invention there is provided a crystal scintillator comprising a transparent single crystal of a Cerium activated mixed Perovskite having a general formula
Ce x Lu (1−x−z) A z Al (1−y) B y O 3 , wherein
[0037] x is within the range of from approximately 0.00005 to approximately 0.2,
[0038] y is within the range of from 0.0 to approximately 1.0,
[0039] z is within the range of from 0.00005 to approximately (1−x),
[0040] where A comprises one or more of the following cations: Sc, La, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, In and B comprises one or both of the following cations: Sc and Ga.
[0041] Most preferably A further comprises one or both of the following cations: Y and Ga.
[0042] Preferably x is within the range of from approximately 0.0005 to approximately 0.005, y is within the range of from 0.005 to approximately 0.05 and z is within the range of from 0.0005 to approximately 0.05.
[0043] Preferably the crystal scintillator has a luminescence decay time within the range of from approximately 15 ns to approximately 45 ns.
[0044] Preferably the crystal scintillator has a density of more than 7.5 g/cc.
[0045] Preferably the crystal scintillator generates a luminescence wavelength within the range of from approximately 330 nm to approximately 440 nm.
[0046] Preferably the crystal scintillator generates a luminescence wavelength of approximately 365 nm.
[0047] According to a third aspect of the present invention there is provided a scintillation detector comprising a crystal scintillator in accordance with the first or second aspect of the present invention and a photodetector optically coupled to said crystal scintillator for detecting light emitted from the crystal scintillator.
[0048] According to a fourth aspect of the present invention there is provided a scintillation detector comprising two or more a crystal scintillators and a photodetector optically coupled to said crystal scintillators for detecting light emitted from the crystal scintillators wherein at least one of the crystal scintillators comprises a crystal scintillator in accordance with the first or second aspect of the present invention.
[0049] Preferably the photodetector comprises a detector selected from the group comprising a photo-multiplier, a photo-diode and a charge-coupled device.
DETAILED DESCRIPTION OF THE INVENTION
[0050] Embodiments of the present invention will now be described, by way of example only and with reference to the accompanying Tables, in which:
[0051] Table 1 presents a summary of characterising properties for crystal scintillators taught in the Prior Art as compared with typical characteristics of a crystal scintillator in accordance with aspects of the present invention; and
[0052] Table 2 presents a summary of chemical formulae and starting melts for crystal scintillators produced in accordance with aspects of the present invention.
TABLE 1 Light 100 20 40 20 40 50 25 25 40 Output Energy 7 19 7 11 6 14 7 7 7 Resolution Decay 230 300 40 30 28 40 18 25 20 Time (ns) Density 3.67 7.15 4.45 67 5.5 7A 8.3 7.4 8.2- (g/cc) 8.3 Emission 415 480 420 440 380 428 365 365 365 Peak (nm) Melting 650 1050 1980 1900 1900 2100 1950 1950 1900 Point (° C.) Rugged No Yes Yes No Yes Yes Yes Yes Yes
[0053] [0053] TABLE 2 Ce 0.006 Lu 0.894 Gd 0.1 LuAlO 3 —GdScO 3 8.202 Al 0.9 Sc 0.1 O 3 (Ce 0.006 )Lu (0.984) Gd 0.01 LuAlO 3 —GdScO 3 8.395 Al 0.99 Sc 0.01 O 3 (Ce 0.006 )Lu (0.994 )La (0.05 ) LuAlO 3 —LaGaO 3 8.317 Al (0.95) Ga(0.05) O 3 (Ce 0.006 )Lu (0.964) La (0.03) LuAlO 3 —LaScO 3 8.295 Al (0.97) Ga (0.03) O 3 (Ce 0.006 )Lu (0.894) La( (0.10) LuAlO 3 —LaAlO 3 8.258 Al (0.9) Ga (0.1) O 3 (Ce 0.006 )Lu (0.914) La 0.08 LuAlO 3 —LaAlO 3 8.229 AlO 3 (Ce 0.006 )Lu (0.974) Y 0.02 LuAlO 3 —YGaO 3 8.307 Al 0.98 Ga 0.02 O 3 (Ce 0.006 )Lu (0.974) Y 0.02 LuAlO 3 —YScO 3 8.307 Al 0.98 Sc 0.02 O 3
[0054] In order to produce a commercially viable crystal scintillator it is necessary to develop a material that can be produced by a standard growth process. The following embodiments of the present invention employ the Czochralski growth method to produce the crystal scintillators, although any other growth method may be employed. The Czochralski growth method is described in detail by C. D. Brandle in a paper entitled “ Czochralski Growth of Rare-Earth Orthosilicates ( Ln 2 SiO 5 )” published in the Journal of Crystal Growth, Volume 79, Page 308-315, (1986).
[0055] A further criterion for a commercially viable crystal scintillator is that it should be physically stable at high temperature, a criterion that is currently lacking in LuAP. By substituting a critical amount of Lu or Al by different trivalent cations, the Perovskite structure can be stabilised so as to prevent metastability of the material at high temperature.
[0056] The lack of stability in LuAP can be related to the Goldschmidt tolerance factor that is a measure of the geometric fit of the various atoms based on a hard sphere model and is defined by:
t =( R A +R o )/({square root}{square root over (2)}( R B +R o )) (1)
[0057] where R A =radius of the larger cation, e.g. Lu
[0058] R B =radius of the smaller cation, e.g. Al
[0059] R o =radius of the oxygen anion, i.e. 1.4 Å
[0060] As t becomes larger, i.e. approaches unity, the tendency for stability of the Perovskite structure increases. For a given B cation, e.g. Al, the increase in the tolerance factor is also reflected in the unit cell volume. The condition for better stability at high temperature is to have an approximate value for the critical unit cell volume ranging from about 198.7 Å 3 to 201.3 Å 3 .
Example Lutetium Mixed Perovskite Crystal Scintillators
[0061] In a particular example (a solid solution of LuAlO 3 and GdScO 3 ) is employed to produce a transparent single crystal scintillator, grown by the Czochralski growth method, having a formula:
Ce 0.006 Lu 0.894 Gd 0.1 Al 0.9 SC 0.1 O 3
[0062] Initially the following chemical substances (with respective weights): Lu 2 O 3 (711.5 g), Gd 2 O 3 (72.5 g), Al 2 O 3 (183.9 g), Sc 2 O 3 (27.6 g) and CeO 2 (4.12 g) are loaded into an iridium crucible. The crucible is then loaded into a growth furnace composed of Zirconia insulation and heated by an induction coil under an inert atmosphere containing a small amount of oxygen, typically less than 2%, to prevent evaporation of the various components. The crystal is then pulled from the melt at a slow rate, typically 1 mm/h to 2 mm/h, and using a rotation rate from 10 to 30 rpm. This method provides a crystal scintillator having a density of 8.202 g/cc (see Table 2), the other characterising parameters are as shown in Table 1.
[0063] Further examples of physically stable crystal scintillators grown by the aforementioned Czochralski growth method are presented in Table 2. The starting melt compositions shown were employed since these melts are found to be stable at high temperatures.
[0064] It should also be pointed out that for each of the solid solutions, the “dopant perovskite” e.g. GdScO 3 , LaAlO 3 and YScO 3 is in itself a congruent melting compound and hence a stable compound.
[0065] Seven of the Lutetium Mixed Perovskite crystals described in Table 2 produce Cerium activated Lutetium Mixed Perovskite scintillators where cation substitution has taken place at the Aluminium host sites. In all of the scintillators described in Table 2 a second cation, in addition to the Cerium cations, have been substituted at the Lutetium ions host sites. This has been carried out so as to provide an alternative activation ion and to aid in the chemical stability of the Lutetium Mixed Perovskite crystals.
[0066] The described Lutetium Mixed Perovskite crystals provide a number of clear advantages when compared to other materials described in the Prior Art such as LSO, LuAP or YAP (see Table 1), both from a growth process point of view and a performance point of view.
[0067] Compared with LuAP, the multiple ionic substitutions employed to modify the physical structure improve the thermal stability of the material. This improved thermal stability renders the growth process scalable to commercial levels since it permits improved yields. Such yields are not readily feasible for LuAP due to the inherent metastability of this material at high temperatures.
[0068] The decay time of the described Lutetium Mixed Perovskite crystals, like other perovskite materials (LuAP, YAP), are shorter than LSO. In addition the energy resolution values of these crystals are also of a more advantageous value for use as a scintillator material when compared with those for LSO.
[0069] It should also be noted that the higher density and stopping power of the described Lutetium Mixed Perovskite crystals provide these materials with a significant advantage in their use as a crystal scintillator when compared to the typical values associated with both YAP and LuYAP.
[0070] The aforementioned crystal scintillators can be readily modified to form a scintillator detector. This is achieved by simply optically coupling one or more of the crystal scintillators to a photodetector. The photodetector then provides an output electrical voltage in response to the secondary photons produced within the crystal scintillators themselves created in response to the absorption of the incident gamma rays, x-rays or high energy particles. A wide variety of photodetectors may be employed and a variety of coupling methods used, as is well known in the art.
[0071] In an alternative embodiment the scintillator detector may comprise one or more crystal scintillators, as described above, and one or more crystal scintillators as taught in the Prior Art. All of these crystal scintillators are then coupled to one or more photodetectors, as described previously.
[0072] The foregoing description of the invention has been presented for purposes of illustration and description and is not intended to be exhaustive or to limit the invention to the precise form disclosed. The described embodiments were chosen and described in order to best explain the principles of the invention and its practical application to thereby enable others skilled in the art to best utilise the invention in various embodiments and with various modifications as are suited to the particular use contemplated. Therefore, further modifications or improvements may be incorporated without departing from the scope of the invention herein intended.
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A single crystal scintillator with perovskite structure is described. The crystal is formed by crystallisation from the liquid and has the composition
Ce x Lu (1−x−z) A z Al (1−y) B y O 3
where A is one or more of the elements selected from the group comprising Y, Sc, La, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, In, and Ga; and B is one or more of the following elements selected from the group comprising: Sc and Ga. The crystal scintillator exhibits a high density and a good scintillation response to gamma radiation.
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RELATED APPLICATION DATA
[0001] This application is related to Provisional Patent Application Ser. No. 61/679,533 filed on Aug. 3, 2012 entitled “Storage and Retrieval Device of Clasping Mechanisms.” Priority is claimed for these earlier filings under 35 U.S.C. §119(e), and the Provisional patent application is also incorporated by reference into this utility patent application.
TECHNICAL FIELD
[0002] The invention relates to a storage and retrieval device for paper clasping and binding mechanisms.
BACKGROUND OF THE INVENTION
[0003] Currently there are a number of different clipping and clasping devices of various sizes, shapes and uses available to the public, such as binder clips, magnetic clips, workbench clamps, hemostats, wire clamps, lapel clamps for name tags, clothes pins, and many others. Binder clips and paper clips are normally transported in small boxes or plastic containers, like many other office supplies. Clip holders have included circular vessels made from stamped metal or wire mesh, and these clip holders can be stacked on top of each other to conserve space on an office desk.
[0004] Magnetic binder and paper clip holders have also been produced that possess an aperture surrounded by magnetic elements. These types of holders may be shaped in a box, tray or cylinder design, and apertures can be placed in a circular, triangular or rectangular shapes on the holder body. Magnetic elements can surround the opening or an aperture on the container, which assists in keeping the clips organized and more accessible to the office worker.
[0005] Many of these containers are composed of multiple parts, including a body structure and a lid or top portion of the container. These multiple part containers are cumbersome, and sometimes these multiple parts of the container come apart when paper and binder clips are accessed in the container. What is needed is a single body modular clip holder than does not possess multiple parts or the need for expensive magnetic elements.
[0006] The existing containers often present the paper and binder clips in an unorganized fashion grouped all together in a mass of intertwined clips, which makes it difficult to access a single clip when it is needed by the user. Binder clips generally have a gripping end and handle or lever means for causing the gripping end to grasp or release a work piece. The user actuates gripping of the binder clip by exerting pressure on handles or levers to cause either a clasping or releasing reaction of the gripping end.
[0007] When binder and paper clips are massed together in an unorganized fashion, they often get tangled together. Storage of binder clip mechanisms in a neat and convenient manner can be challenging due to the size and shape of said mechanisms, and there is a need to present paper and binder clips to the user in an organized and segregated fashion with the grasping portions of the binder clips being easily accessible.
SUMMARY OF THE INVENTION
[0008] In the present invention, the storage and retrieval device holds paper and binder clip devices and comprises a cluster of extended plastic posts protruding outwardly from a base surface in such a manner to allow a binder clip to grip one or more of the extended plastic posts quickly and easily, without the necessity of the user selecting any particular post or position on the container. Moreover, the storage and retrieval device has a reservoir or well that holds paper clips, clips, or other assorted items (e.g. coins, tokens, etc.).
[0009] The cluster format for the extended plastic posts may include any number of extended posts spaced relatively equidistant from one another. Moreover, the number of extended plastic posts should be sufficient to allow for storage of a sufficient number of the binder clips such that the storage device will prove efficient in the context of use.
[0010] The extended plastic posts may include a two stage structure where the lower portion of the post has a predetermined diameter, and the upper portion of the post has a diameter much less than the predetermined diameter. The post is topped with a semi-circular end for ease of use, and the shape of the extended post may be circular, rectangular, square, octagonal, or any other geometric shape so long as the thickness of the post and shape allow it to stand upright under normal conditions, and to withstand the stress of being gripped by the binder clip mechanism without breaking. The extended plastic posts should be long enough to permit easy gripping by the binder clip mechanism.
[0011] Generally, the extended plastic posts are made of flexible material, but the need for, or degree of; flexibility will depend upon the type of binder clip mechanism for which the particular storage device is designed. In a preferred embodiment, the base surface from which the extended plastic posts protrude is planar, but the surface could have a nonplanar contour such as hemispherical, pyramidical, or with other geometric shapes or designs that permit the extended plastic posts to protrude upward and/or outward for access by the user. The surface may also be circular, spherical, egg shaped, cylindrical or otherwise designed to employ a 360 degree user field that would turn on an axis so that all 360 degrees could be accessed by the user.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] For a more complete understanding of the present invention, and for further details and advantages thereof, reference is now made to the following Detailed Description taken in conjunction with the accompanying drawings, in which:
[0013] FIG. 1 is a perspective view of a storage and retrieval device according to one embodiment of the present invention;
[0014] FIG. 2A is a top view of the storage and retrieval device shown in FIG. 1 ;
[0015] FIG. 2B is a right side view of the storage and retrieval device shown in FIG. 1 ;
[0016] FIG. 2C is a left side view of the storage and retrieval device shown in FIG. 1 ;
[0017] FIG. 2D is a front view of the storage and retrieval device shown in FIG. 1 ;
[0018] FIG. 2E is a rear view of the storage and retrieval device shown in FIG. 1 ;
[0019] FIG. 3 is a partial side view illustrating the posts of an embodiment of the storage and retrieval device;
[0020] FIG. 4A is a perspective view of an alternate embodiment of a storage and retrieval device;
[0021] FIG. 4B is a perspective view of an alternate embodiment of a storage and retrieval device;
[0022] FIG. 5A is a perspective view of an alternate embodiment of a storage and retrieval device;
[0023] FIG. 5B is a perspective view of an alternate embodiment of a storage and retrieval device;
[0024] FIG. 6A is a perspective view of an alternate embodiment of a storage and retrieval device;
[0025] FIG. 6B is a perspective view of an alternate embodiment of a storage and retrieval device;
[0026] FIG. 7A is a perspective view of an alternate embodiment of a storage and retrieval device;
[0027] FIG. 7B is a perspective view of an alternate embodiment of a storage and retrieval device.
DETAILED DESCRIPTION
[0028] The present invention is directed to a system and method of making a storage and retrieval device for various binder and paper clip devices, as well as other items. These clip devices range from binder clips, magnetic clips, work bench clamps, hemostats, wire clamps, lapel clamps for name tags, close pin clamps and the like. The present invention is fabricated with a high-density plastic composition. In order to make the present invention, the manufacturer will need high density liquid plastic, a heat source and heating vessel, a thermometer, coloring, a mold configured to imitate the shape and size of the storage and retrieval device.
[0029] Referring to FIG. 1 , the storage and retrieval device comprises a base 120 , having an upper base surface 122 and a bottom base surface on the opposing side of base 120 from the upper base surface 122 . The upper base surface 122 has a post portion 105 and a recess portion 107 . Base 120 is a planar shape. Post portion 105 has a plurality of extended plastic posts 124 that are integrally formed or attached to the upper base surface 122 and extend perpendicularly outward from upper base surface 122 .
[0030] To provide additional strength, a fillet 132 may be integral with the device at the junction between the post base 126 and the base 120 (as best shown in FIG. 3 ). Extended plastic posts 124 are positioned in a cluster format on base 120 and may be placed in rows and columns spaced such that the separation between rows and column are of relatively equal distance. This orientation is best viewed in the top view illustrated in FIG. 2A .
[0031] With regard to the dimensions of the present invention, in one form of the invention, the base has a dimension of 106 mm by 152 mm. The extended plastic posts are positioned in a matrix of ten extended plastic posts by sixteen extended plastic posts with a spacing between extended plastic posts of 7.5 mm. Post spacing may be adjusted as necessary. Each post is 17 mm in length from the base connection to the hemispherical tip and is filleted at the base for additional strength. The fillet has a radius of 1.4 mm. The diameter of the pin just above the fillet is 7.6 mm and gradually tapers to 6 mm as it transitions into the hemispherical tip. There is a step reduction in the diameter of the base. The thickness of base is 6.5 mm and may be honeycombed to reduce the material required for construction.
[0032] Although a preferred embodiment provides for the equal distance spacing of extended plastic posts 124 , equal distance positioning of the extended plastic posts is not essential to the proper operation of the present invention. Moreover, the number of extended plastic posts may be increased or decreased to provide for sufficient storage of an appropriate number of binder clip mechanisms such that the storage device proves sufficient for the use intended. No specific number or orientation of extended plastic posts is essential to the operation of the present invention.
[0033] Recess portion 107 of the storage and retrieval device is located laterally of post portion 105 , and is configured in a unitary single molded construction for both the recess portion 107 and the post portion 105 . Recess portion 107 comprises a large recess, reservoir or indentation 130 extending down into base 120 from upper base surface 122 . Recess 130 is preferably deep enough to hold paper clips, coins, tokens, while still allowing sufficient thickness of the base 120 under the recess 130 .
[0034] The surface of the recess 130 may be dimpled or textured to allow for easier pick up of small and/or flat items placed within recess 130 . Additionally, a fillet may be integral with the recess 130 edges to also allow for easier pick up of small and/or flat items within recess 130 as the fillets would help push the items up when the items are slid towards and make contact with the fillets. Optionally, the storage and retrieval device may comprise lettering, symbols, or designs imprinted, embossed, debossed, or etched preferably along an outer edge of base 120 or along the lower surface of recess 130 .
[0035] For illustrative purposes, FIG. 1 shows a paper clip resting in recess 130 to demonstrate the reservoir 130 on the device in use. The bottom base surface of the storage and retrieval device may have a magnetic or adhesive strip secured thereto, but magnetic or adhesive strips are not required for the use of the present invention. The magnetic and adhesive strip would allow the storage and retrieval device to be temporarily secured to a placement surface (surface upon which the storage and retrieval device is placed).
[0036] In one form of the invention, the material used for the extended plastic posts has a durometer between Shore A 45 and Shore A 60. A durometer of Shore A 60 has been found to be appropriate for the present invention. A high tear resistance is also preferred. Use of materials having a tear resistance over 100 P.l. is preferred. Having such a high tear resistance assists in providing a product wherein the extended plastic posts will not be torn or otherwise separated from the base when binder clip mechanisms, such as binder clips, are removed from the extended plastic posts.
[0037] The material used also should have a minimal compression set. A low compression set assures that the binder clip mechanisms do not leave compression indentions or marks on the extended plastic posts when binder clips are removed. Also, use of materials having a minimal compression set will provide extended plastic posts having resilience to retain their original shape even after being crimped or bent for long periods of time.
[0038] Although many materials will meet the requirements necessary to implementation of the present invention, plastic such as flexible thermoplastic polyurethane or polyvinyl chloride (PVC) as well as many rubbers will provide an appropriate material.
[0039] The steps in the manufacturing process include several steps. As Step 1, the plastic composition used to make the single molded unit should be mixed and combined thoroughly. The plastic composition must be thoroughly blended into a homogeneous mixture without separations of the material by settling or other means. This plastic composition is heated in a vessel over a low heat from 250-350° F. with frequent stirring or agitation. The plastic composition is a thermoplastic composition which changes its solidity characteristics with heat, but thermosetting plastic could also be used to set once upon heating and cooling. The plastic composition will become clear as it heats. Remove the vessel from the heat source with the plastic composition reaches 325-350° F.
[0040] The heat source can be a gas burner, electric heating element, or even a microwave oven. If the plastic composition is heated using a stove top or a melting pot, the mixture should be stirred constantly to prevent burning. Some heating pots may have an integrated heating element.
[0041] One can also use a microwave, but a safety measuring cup or safety glass/porcelain ware to heat the plastic composition. If you use a microwave, fill your measuring cup with about ½ cup of mixed liquid plastic. Heat for approximately 1 minute, and then stir the heated mixture. Apply another cycle of heat, and then stir again. Repeat until plastic becomes clear and thick (like syrup) Microwaves vary in power, we have found 1-3 minutes is average for this amount of soft plastic.
[0042] In step 2, the mixture should have coloring added to the base plastic mix. Coloring can be added into the hot plastic composition until the plastic has reached your desired color and shade. Coloring should be highly concentrated pigment and can color up to ½ gallon of plastic when mixed to a proper concentration. Coloring can be added with a dropper at this stage in the processing.
[0043] In Step 3, the colored plastic composition is injected or otherwise placed in the mold body. The plastic mixture can be placed in a glass measuring cup or fill container beforehand, if needed. Molds can be made of metal or clay, which are fabricated separately, and an impression of the storage and retrieval device is placed in the mold material. Storage and retrieval device molds can be one piece injection molds or two piece molds that produce three dimensional fully formed storage and retrieval devices. The molds are virtually unbreakable and feature built-in alignment pins for easy assembly.
[0044] An injector of the plastic material is used to force the hot plastic into the mold. Its reservoir is large enough to make several baits from one filling. Place the mold on the injector with the nozzle in the smaller injection gate of the mold. Holding the mold firmly with both hands, apply slow downward pressure until the soft plastic fills the mold and the overflow reservoir at the top of the mold. Two cavity molds need a short cooling period before filling the second cavity. Set the mold aside for a few seconds and fill another mold while you wait for the first cavity to cool.
[0045] You should have enough plastic to make approximately 20-30 storage and retrieval devices. The plastic composition will shrink as it cools, so one needs to make sure the overflow and fill reservoirs of the mold are full to the top when you inject the mold. Underfilling the mold can causes hollow devices, which is not desired. The liquid plastic composition is scorch resistant hot-melt plastic thermoplastic compositions that can be reheated, allowing you to reuse plastic scraps. A hardener can be added to make harder, tougher devices.
[0046] In the final step, one should remove the devices from the molds and place them in cool water until they have cooled completely. The devices in the molds are allowed to cool, and one can remove the mold from the injector and stand the mold upright. The soft plastic should be allowed to cool to a solid consistency. The amount of cooling time will vary based on the size of the device and number of mold cavities. After removal from the mold, one should allow the storage and retrieval devices to cool for three to five minutes.
[0047] Referring to FIG. 2A , different views of the embodiment in FIG. 1 is illustrated. Looking at FIG. 2A , the storage and retrieval device comprises a base 220 , having an upper base surface 222 and a bottom base surface adjacent a placement surface (surface upon which the storage and retrieval device is placed), a post portion 205 and a recess portion 207 . Base 220 is a planar shape. Post portion 205 has a plurality of extended plastic posts 224 that are integrally formed or attached to the upper base surface 222 and extend perpendicularly outward from upper base surface 222 .
[0048] To provide additional strength, a fillet 232 may be integral with the device at the junction between the post base 226 and the base 220 . Extended plastic posts 224 are positioned in a cluster format on base 220 and may be placed in rows and columns spaced such that the separation between rows and column are of relatively equal distance. This orientation is best viewed in the top view illustrated in FIG. 2A .
[0049] Although a preferred embodiment provides for the equal distance spacing of extended plastic posts 224 , equal distance positioning of the extended plastic posts is not essential to the proper operation of the present invention. Moreover, the number of extended plastic posts may be increased or decreased to provide for sufficient storage of an appropriate number of binder clip mechanisms such that the storage device proves sufficient for the use intended. No specific number or orientation of extended plastic posts is essential to the operation of the present invention.
[0050] Recess portion 207 of the storage and retrieval device is located laterally of post portion 205 , and is constructed from a single molded unitary structure that is used to produce the post portion 205 and recess portion 207 . Recess portion 207 comprises a large reservoir, recess or indentation 203 extending down into base 220 from upper base surface 222 . Recess 203 is preferably deep enough to keep paper clips, coins and tokens while still allowing for sufficient thickness of base 220 under the recess 203 .
[0051] For illustrative purposes, FIGS. 2B and 2E show a binder clip attached to the extended plastic posts 224 to demonstrate the device in use. FIG. 2A is a top view of the storage and retrieval device shown in FIG. 1 , FIG. 2B is a left side view of the storage and retrieval device shown in FIG. 1 , FIG. 2C is an upside down view of side of the storage and retrieval device shown in FIG. 1 , FIG. 2D is a front view of the storage and retrieval device shown in FIG. 1 , and FIG. 2E is a rear view of the storage and retrieval device shown in FIG. 1 .
[0052] For each of FIGS. 2B to 2E , the storage and retrieval device comprises a base 220 , having an upper base surface 222 and a bottom base surface adjacent a placement surface (surface upon which the storage and retrieval device is placed), a post portion 205 and a recess portion 207 . Base 220 is a planar shape. Post portion 205 has a plurality of extended plastic posts 224 that are integrally formed or attached to the upper base surface 222 and extend perpendicularly outward from upper base surface 222 .
[0053] To provide additional strength, a fillet 232 may be integral with the device at the junction between the post base 226 and the base 220 . Extended plastic posts 224 are positioned in a cluster format on base 220 and may be placed in rows and columns spaced such that the separation between rows and column are of relatively equal distance. This orientation is best viewed in the top view illustrated in FIG. 2A .
[0054] Although a preferred embodiment provides for the equal distance spacing of extended plastic posts 224 , equal distance positioning of the extended plastic posts is not essential to the proper operation of the present invention. Moreover, the number of extended plastic posts may be increased or decreased to provide for sufficient storage of an appropriate number of binder clip mechanisms such that the storage device proves sufficient for the use intended. No specific number or orientation of extended plastic posts is essential to the operation of the present invention.
[0055] Recess portion 207 of the storage and retrieval device is located laterally of post portion 205 , and is constructed from a single molded unitary structure that is used to produce the post portion 205 and recess portion 207 . Recess portion 207 comprises a large reservoir, recess or indentation 203 extending down into base 220 from upper base surface 222 . Recess 203 is preferably deep enough to keep paper clips, coins and tokens while still allowing for sufficient thickness of base 220 under the recess 203 .
[0056] FIG. 3 shows a side view illustrating the extended plastic posts of an embodiment of the storage and retrieval device. Post portion 305 has a plurality of extended plastic posts 324 that are integrally formed or attached to the upper base surface 322 and extend perpendicularly outward from upper base surface 322 . Extended plastic posts 324 are illustrated with a cylindrical post base 326 , a slightly tapered post leg portion 328 extending from the base and terminating at the end opposite the base in a hemispherical post tip 329 .
[0057] Support reinforcing ledge 334 is formed of the transition between post base 326 and post leg portion 328 . Support reinforcing ledge 334 would be more commonly found when extended plastic posts 324 are attached to the upper base surface 322 . Alternatively, especially when integrally formed, post base 326 and post leg portion 328 provide a continuous surface that does not have step 334 .
[0058] To provide additional strength, a fillet 332 may be integral with the device at the junction between the post base 326 and the base 320 . Extended plastic posts 324 are positioned in a cluster format on base 320 and may be placed in rows and columns spaced such that the separation between rows and column are of relatively equal distance.
[0059] Although a preferred embodiment provides for the equal distance spacing of extended plastic posts 324 , equal distance positioning of the extended plastic posts is not essential to the proper operation of the present invention. Moreover, the number of extended plastic posts may be increased or decreased to provide for sufficient storage of an appropriate number of binder clip mechanisms such that the storage device proves sufficient for the use intended. No specific number or orientation of extended plastic posts is essential to the operation of the present invention.
[0060] Referring to FIGS. 4A and 4B , an alternative layout of the storage and retrieval device is shown. The storage and retrieval device comprises a base 420 A coupled to an outer base surface 422 and a post portion 405 . Post portion 405 is formed in a cylindrical shape with a plurality of extended plastic posts 424 that are integrally formed or attached to the outer base surface 422 and extend outwardly from outer base surface 422 .
[0061] To provide additional strength, a fillet 432 may be integral with the device at the junction between the post base 426 and the base 420 . Extended plastic posts 424 are positioned in a cluster format on base 420 and may be placed in rows and columns spaced such that the separation between rows and column are of relatively equal distance.
[0062] Although a preferred embodiment provides for the equal distance spacing of extended plastic posts 424 , equal distance positioning of the extended plastic posts is not essential to the proper operation of the present invention. Moreover, the number of extended plastic posts may be increased or decreased to provide for sufficient storage of an appropriate number of binder clip mechanisms such that the storage device proves sufficient for the use intended. No specific number or orientation of extended plastic posts is essential to the operation of the present invention.
[0063] Alternatively, post portion 405 may have a square, triangle, octagon, or other polygonal shape instead of a circular shape. As illustrated in FIGS. 4A and 4B , post portion 405 can also be a tube shape. The tube shape would allow for objects such as pens, pencils, markers, scissors, and the like to be maintained in the storage and retrieval device. For illustrative purposes, FIG. 4B shows a pencil resting inside post portion 405 and a binder clip clipped onto extended plastic posts 424 to demonstrate the tube-shaped embodiment of the device in use.
[0064] With post portion 405 in an upright position, recess portion 407 of the storage and retrieval device is located at a base 420 A and 420 b coupled to the bottom edge of the post portion 405 . Recess portion 407 is integrally formed from or secured to this bottom edge and extends radially outward to an outer border forming recess portion base 420 b . Recess portion base 420 A and 420 b has an upper base surface 422 b and a bottom base surface adjacent a placement surface (surface upon which the storage and retrieval device is placed). This outer border as illustrated is circular, but may also be other shapes such as a square, triangle, octagon, or other polygonal shapes.
[0065] Recess portion 407 comprises a large recess or indentation 430 in FIGS. 4A and 130 in FIG. 4B extending down into recess portion base 420 b from outer base surface 422 . Recess 430 in 4 A and 130 in FIG. 4B is preferably deep enough to keep paper clips, coins or tokens, while still being thick enough to allow for stability of base 420 A and 420 b under recess 430 in 4 A and 130 in FIG. 4B . Preferably the outer border of the recess portion 407 is wide enough to provide stability to post portion 405 , thus preventing post portion 405 from falling over.
[0066] Recess portion 407 may additionally comprise an attachment secured to the bottom base surface of the recess portion 407 that acts like a lazy Susan or any similar structure, as a shelf or tabletop, designed to revolve so that all the objects held within recess 430 in 4 A and 130 in FIG. 4B or clipped to extended plastic posts 424 can be seen or reached easily.
[0067] Referring to FIGS. 5A and 5B , an alternative layout of the storage and retrieval device is shown, which is most preferable for the edge of a table or desk. The storage and retrieval device comprises a base 520 , having an outer base surface 522 , an inner base surface adjacent a placement surface (surface upon which the storage and retrieval device is placed), and a post portion 505 . Post portion 505 is a planar shape with a plurality of extended plastic posts 524 that are integrally formed or attached to the outer base surface 522 and extend outwardly from outer base surface 522 .
[0068] To provide additional strength, a fillet 532 may be integral with the device at the junction between the post base 526 and the base 520 . Extended plastic posts 524 are positioned in a cluster format on base 520 and may be placed in rows and columns spaced such that the separation between rows and column are of relatively equal distance.
[0069] Although a preferred embodiment provides for the equal distance spacing of extended plastic posts 524 , equal distance positioning of the extended plastic posts is not essential to the proper operation of the present invention. Moreover, the number of extended plastic posts may be increased or decreased to provide for sufficient storage of an appropriate number of binder clip mechanisms such that the storage device proves sufficient for the use intended. No specific number or orientation of extended plastic posts is essential to the operation of the present invention.
[0070] Referring to FIG. 5B , the storage and retrieval device as described in FIG. 5A further comprises a recess portion 507 . Recess portion 507 is integrally formed from or secured to an edge of post portion 505 in a single unitary molded construction and extends horizontally from the post portion 505 thereby forming recess portion base 520 b . Recess portion base 520 b has an upper base surface 522 b and a bottom base surface adjacent a placement surface (surface upon which the storage and retrieval device is placed). Preferably recess portion base 520 b is oriented with its bottom base surface downward. This outward border is illustrated in FIG. 5B as rectangular, but may be other shapes such as a circular, square, triangle, octagon, or other polygonal shapes.
[0071] Recess portion 507 comprises a large recess or indentation 530 extending down into recess portion base 520 b from upper base surface 522 b . Recess 530 is preferably deep enough to keep paper clips, coins and tokens, while allowing the base 520 b to retain sufficient stability and thickness under recess 530 . Recess portion 507 may also have a magnetic or adhesive strip secured to the bottom base surface of recess portion 507 . For illustrative purposes, FIG. 5B shows a paper clip resting in recess 530 and a binder clip clipped onto extended plastic posts 524 to demonstrate the device in use.
[0072] Referring to FIGS. 6A and 6B , the storage and retrieval device comprises a base 620 , which takes on the shape similar to a hedgehog. Other animal or object shapes may also be used, for example, but not limited to, a porcupine, a cactus, a head. The device shown in FIGS. 6A and 6B have an outer surface 622 , a bottom surface adjacent a placement surface (surface upon which the storage and retrieval device is placed), a post portion 605 and an optional recess portion 607 (shown in FIG. 6B ). Base 620 shows the post portion 605 that has a plurality of extended plastic posts 624 that are integrally formed or attached to the upper base surface 622 and extend perpendicularly outward from upper base surface 622 .
[0073] To provide additional strength, a fillet 632 may be integral with the device at the junction between the post base 626 and the base 620 . Extended plastic posts 624 are positioned in a cluster format on base 620 and may be placed in rows and columns spaced such that the separation between rows and column are of relatively equal distance. Although a preferred embodiment provides for the equal distance spacing of extended plastic posts 624 , equal distance positioning of the extended plastic posts is not essential to the proper operation of the present invention. Moreover, the number of extended plastic posts may be increased or decreased to provide for sufficient storage of an appropriate number of binder clip mechanisms such that the storage device proves sufficient for the use intended. No specific number or orientation of extended plastic posts is essential to the operation of the present invention.
[0074] Referring to FIG. 6B , the storage and retrieval device as described in FIG. 6A further comprises a recess portion 607 . The optional recess portion 607 of the storage and retrieval device is located laterally of post portion 605 and formed of a unitary single molded construction with the recess portion 607 . The recess portion 607 has an upper surface 622 b and a bottom surface. As illustrated in FIG. 6B , recess portion 607 extends laterally from post portion 605 from the “feet” of the hedgehog creating recess portion base 620 b.
[0075] Preferably recess portion 607 is adjacent to a placement surface (surface upon which the storage and retrieval device is placed) as that placement surface provides additional stability to the recess portion 607 . The recess portion 607 may extend laterally to the side of base 626 . The recess portion 607 may require a more rigid material or reinforcements applied to the recess portion 607 , and recess portion 607 may also extend forward or rearward instead of laterally.
[0076] Alternatively, recess portion 607 may be integrated into a part of post portion 605 as illustrated in FIG. 6B . Although the recess portion 607 is integrated into the “head area” of the hedgehog, it may also be integrated into other areas of the post portion 605 , for example the “back” or “rear” of the hedgehog.
[0077] Recess portion 607 comprises a large recess or indentation 630 extending down into base recess portion base 620 b from upper surface 622 b . Recess 630 is preferably deep enough to maintain paper clips, coins and tokens while still sufficiently thick to maintain stability of the base 620 b under recess 630 .
[0078] Referring again to FIGS. 6A and 6B , secured to the bottom surface of base 620 and/or the bottom surface of recess portion base 620 b may be a magnetic or adhesive strip. This strip allows post portion 605 and/or recess portion 607 the ability to be temporarily attached to the placement surface.
[0079] Referring to FIGS. 7A and 7B , another alternative layout of the storage and retrieval device is shown with a post portion 705 aligned vertically for placement along a vertical wall. The storage and retrieval device comprises a base 720 , having an outer base surface 722 , an inner base surface adjacent a placement surface (surface upon which the storage and retrieval device is placed), and a post portion 705 . Post portion 705 is a planar shape with a plurality of extended plastic posts 724 that are integrally formed or attached to the outer base surface 722 and extending outwardly from outer base surface 722 .
[0080] To provide additional strength, a fillet 732 may be integral with the device at the junction between the post base 726 and the base 720 . Extended plastic posts 724 are positioned in a cluster format on base 720 and may be placed in rows and columns spaced such that the separation between rows and column are of relatively equal distance.
[0081] Although a preferred embodiment provides for the equal distance spacing of extended plastic posts 724 , equal distance positioning of the extended plastic posts is not essential to the proper operation of the present invention. Moreover, the number of extended plastic posts may be increased or decreased to provide for sufficient storage of an appropriate number of binder clip mechanisms such that the storage device proves sufficient for the use intended. No specific number or orientation of extended plastic posts is essential to the operation of the present invention.
[0082] Referring to FIG. 7B , the storage and retrieval device as described in FIG. 7A further comprises a recess portion 707 . Recess portion 707 is integrally formed from or secured to an edge of post portion 705 using a single unitary molded construction with the recess portion 707 . The recess portion 707 extends outwardly to an outer border forming recess portion base 720 b . Recess portion base 720 b has an upper base surface 722 b and a bottom base surface adjacent a placement surface (surface upon which the storage and retrieval device is placed). Preferably recess portion base 720 b is oriented with its bottom base surface downward. This outward border is illustrated in FIG. 7B as rectangular, but may be other shapes such as a square, circular, triangle, octagon, or other polygonal shapes.
[0083] Recess portion 707 comprises a large recess or indentation 730 extending down into recess portion base 720 b from upper base surface 722 b . Recess 730 is preferably deep enough to keep binder clip mechanisms and allow their retrieval from the device. The recess thickness will still allow for stability within the thickness of base 720 b along recess 730 . Recess portion 707 may also have a magnetic or adhesive strip secured to the bottom base surface of recess portion 707 .
[0084] For illustrative purposes, FIG. 7B shows a paper clip resting in recess 730 and a binder clip clipped onto extended plastic posts 724 to demonstrate the device in use. Referring to FIGS. 7A and 7B , secured to the inner base surface of base 720 or the bottom base surface of recess portion base 720 b may be a magnetic or adhesive strip. This strip allows post portion 705 and/or recess portion 707 the ability to be temporarily attached to the placement surface. Alternatively, connectors may be secured to the inner base surface of base 720 that engage other connectors on the placement surface, for example loops secured to the inner base surface of base 720 that engage screws or hooks secured to a wall.
[0085] Optionally, the storage and retrieval device may comprise lettering, symbols, or designs imprinted, embossed, debossed, or etched on the device. This allows for personalization of the device or even advertisement.
[0086] The horizontal cross section of the extended plastic posts used may be circular as shown in the Figures, but alternative geometries may also be employed. For example, the horizontal cross section of the extended plastic posts may also be rectangular, square, octagonal, or any other geometric shape, so long as the thickness of the extended plastic posts and shape allow it to stand upright under normal conditions and to withstand the stress of being gripped by the binder clip mechanism without breaking, and so long as the extended plastic posts are of a sufficient length to permit easy gripping by the binder clip mechanism. Generally, the extended plastic posts are made of flexible material, but the need for, or degree of flexibility will depend upon the type of binder clip mechanism for which the particular storage device is designed.
[0087] Although preferred embodiments of the invention have been described in the foregoing Detailed Description and illustrated in the accompanying drawings, it will be understood that the invention is not limited to the embodiments disclosed, or the specific dimensions or materials discussed, but is capable of numerous arrangements, modifications and substitutions of parts and elements without departing from the spirit of the invention. Accordingly, the present invention is intended to encompass such rearrangements, modifications and substitutions as fall within the spirit and scope of the invention.
[0088] While preferred embodiments of the invention have been shown and described, modifications thereof can be made by one skilled in the art without departing from the spirit and teachings of the invention. The embodiments described herein are exemplary only, and are not intended to be limiting. Many variations and modifications of the invention disclosed herein are possible and are within the scope of the invention.
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The present invention is a storage and retrieval device for binder clip mechanisms and comprises a cluster of extended plastic posts protruding outward from a surface in such a manner to allow a binder clip mechanism to easily grip one or more of the extended plastic posts quickly and easily and without the necessity of the user selecting any particular post.
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REFERENCE TO RELATED APPLICATIONS
[0001] This is a Continuation-In-Part of co-pending application Ser. No. 10/828,435, filed Apr. 20, 2004.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to covalently-tethered polyhedral oligomeric silsesquioxane/polyimide nanocomposites and the synthesis process thereof. Polyhedral oligomeric silsesquioxane in the composites has nanoporous inorganic architecture, polyimide has high-temperature resistance and good mechanical properties; as both are synthesized through specific process, the composites with low dielectric constant while maintaining certain mechanical properties is obtained; in the synthesis process, the polyhedral oligomeric silsesquioxane having one or multiple reactive groups, for example, amino, is used as a monomer for reacting with dihydride or is directly reacted with polyimide having complementary reactive functional groups, to form nanocomposites.
[0004] The applications of the present nanocomposites, according to the properties (for example, dielectric properties) of the materials, are not limited to the needs of traditional high-temperature insulting materials, including in industrial fields of microelectronics, aerospace technologies, semiconductor elements, nano technologies and the like; further, due to the consistent nanopore features, are expandable to some other fields, for example, the utilities in the ultra-micro filtration technologies.
[0005] 2. Description of the Prior Art
[0006] In recent years, due to the miniaturization of electronic elements and increase of integral density, the quantity of conductor connection in the circuits is continuously increased, and the parasitic effect between resistances (R) and capacitances (C) in the conductor connection architecture is created, which results serious RC-delay and also becomes the primary factor to limit the signal transmission speed. D. D. Denton et al., J. Master Res., 1991, 6, 2747, B. S. Lim et al., J. Polymer Sci., Part B: Polym. Phys., 1993, 31, 545, and S. Z. Li et al., J. Polymer Sci., Part B: Polym. Phys., 1995, 33, 403, all disclose the finding of the above. Therefore, in order to effectively elevate the operating speed of the chips, it is necessary to introduce leads having low resistivity and inter-lead insulting films having low parasitic capacitance during the production processes of multilayer conductor connection. With this technical background of development, it becomes an interesting objective in this field to search for better, more reliable dielectric materials, in which polyimide is preferably used as the dielectric intermediate layer material through simple spin coat technology, since it has heat resistance (above 500° C.), chemical resistance, high mechanical strength, and high electrical resistance due to its aromatic chemical structure, high symmetry, and rigid chain structure; however, it is necessary to further reduce the not-low-enough dielectric constant (usually between 3.1 and 3.5) of the general pure polyimide, particularly for the possibility of interlacing of conductor leads after the elements and line width are constricted during the miniaturization.
[0007] One of the methods to reduce the dielectric constant of polyimide is to modify its physical or chemical architecture, for example, as disclosed in Eashoo, M. et al., J. Polym. Sci., Part B: Polym. Phys., 1997, 35, 173, which synthesizes fluorine containing polyimide materials, utilizes high electronegative fluorine elements, blends them into polyimide to reduce the polarization of electrons and ions in the films, then obtains polyimide with dielectric constant at 2.5 to 2.8; however, the mechanical strength of this fluorine containing polyimide material is largely reduced and the prices of said polymerization monomers are high, so that there are difficulties in applying this material; next, the method disclosed by Carter, K. R. et al (see related documents published by Carter, K. R. et al., for example, Adv. Mater., 1998, 10, 1049 ; Chem. Mater. 1997, 9, 105; 1998, 10(1), 39; 2001, 13, 213) uses a small molecular material which is cracked at specific temperature, and goes into polyimide by mixing or reacting; this small molecular material creates pores inside polyimide material when the proceeding heat treatment reaches its thermal crack temperature (i.e., about 250-300° C.). These pores reduce the dielectric constant of polyimide because the dielectric constant of air is close to 1, i.e., κ=1. These porous type materials are produced, and the dielectric constant of said materials are reduced to between 2.3 and 2.5; however, the problems associated with this technology include the difficulties to homogeneously distribute the small molecules into polyimide material and to form closed pores, to eliminate the inconsistency of the pore size, and to remove the organic residues after the crack; further, the mechanical properties of porous type polyimide are less preferable and too weak to be determined, and also the flattening effect is not good.
[0008] As to the synthesis of polyimide, the finding of polyimide began in 1908 when Bogert and Renshaw conducted intra-fusion polycondensation of intramolecules with 4-amino phthalic anhydride or dimethyl-4-aminophthalate; however, it was not further studied (refer to M. T Bogert and R. R. Renshaw, J. Am. Chem. Sci., 1908, 30, 1135) until Dupont took out patents for aromatic polyimide in 1950, and it was commercially applied to high temperature insulting materials in 1960. The synthesis of polyimide is a typical polycondensation, as disclosed in related documents as T. L. Porter et al., J. Polymer Sci., Part B. Polym. Phys., 1998, 36, 673, and A. Okada et al., Mater. Sci. Eng., 1995, 3, 109; the producing process is divided into two stages, first diamine and dianhydride monomers are solubilized in polar solvents to form the precursor of polyimide, poly(amic acid) (PAA), and then imidization is carried out at high temperature (300˜400° C.), so that the precursor is closed-ring dehydrated into polyimide products.
SUMMARY OF THE INVENTION
[0009] The primary object of the present invention is to provide nanocomposites which is formed by molecular architectures of polyimide presenting multiple side-chain-tethered caged polyhedral oligomeric silsesquioxanes (POSSes), wherein every caged POSS is bonded to polyimide chain through a spacer that attaches one end of POSS and such that each caged POSS is bonded to the middle of polyimide chains and has rotation freedom to interact with other caged POSSes bonded in the same manner to form self-assembled nanostructures and therefore have low dielectric constant. Further, a self free-standing film can be formed with said materials, i.e., said insulting film is of given mechanical strength to be peeled off from conductors and substrates without being supported by substrates while maintaining the integrity.
[0010] Another object of the present invention is to provide a process for synthesizing polyhedral oligomeric silsesquioxane/polyimide nanocomposites, in which porous type inorganic oxide oligomers are formed first and then are reacted with dianhydride, or directly through reacting with synthesized polyimide.
[0011] The inventor has completed extensive studies in order to have inorganic substances with nanopores regularly distributed inside polyimide to reduce dielectric constant without impairing mechanical strength of said polyimide. In various applications for foming organic-inorganic nanocomposites, polyhedral oligomeric silsesquioxane is easily bonded to form polymers due to having functional groups, such as single functional groups or graftable monomers, difunctional comonomers, surface modifying agents, or multifunctional crosslinking agents. For example, a member of polyhedral oligomeric silsesquioxane, octamer (RSiO 1.5 ) 8 , which has pores of 0.3 to 0.4 nanometer, exhibits cage shape and is composed of a central silicon atom and cube peripheral oxygen atoms; wherein R groups are capable of reacting with linear or thermosetting polymers and incorporating with some polymers, for example, acrylics, styrenics, epoxide derivatives, and polyethylenes, to have enhanced thermal stability and mechanical strength.
[0012] The inventor has proved in researches that POSS covalently tethering nanopores connects to end groups of polyimide to obtain low dielectric constant and controllable mechanical properties. However, the maximum amount of POSS in polyimide is no more than 2.5 mole %, since the amount of end groups available for tethering POSS is limited. If the dielectric constant of polyimide is to be further reduced, then it is very critical to increase the amount of covalently bonded POSS; therefore, copolymerization is implanted alternatively in the present invention to form porous films, that is, molecules tethering POSS containing defined architecture are directed onto side chains of polyimide. As the amount of side chains for tethering POSS is greater than that of end groups, the advantage of producing materials with variable dielectric constant by changing the proportion of POSS in polyimide is obtained.
[0013] Typically, the polyimide usable in the present invention has polymerization units represented by following formula:
wherein R is
wherein A is —O—, —S—, —CH 2 —, C(CH 3 ) 2 , or C(CF 3 ) 2 and the like; B is —H, —OH, or —NH 2 .
[0014] Typically, the polyhedral oligomeric silsesquioxane usable in the present invention is represented by chemical formula (SiO 1.5 ) n R n-1 R′, wherein n=6, 8, 10, 12, R is alkyl having 1 to 6 carbon atoms or phenyl, R′ is —R 1 —B; R 1 is alkyl having 1 to 6 carbon atoms or phenyl, and B is selected from group at least consisting —NH 2 , —OH, —Cl, —Br, —I, or other derivatives having diamine group (2NH 2 ), for example, reactive functional groups as —R 1 —N(—Ar—NH 2 ) 2 , —R 1 —O—Ar—CH(—Ar—NH 2 ) 2 and the like.
[0015] Comparing to conventional technology used for reducing dielectric constant of polyimide mentioned above, the present composites are modified reactive inorganic oligomers, which are formed through bonding to polyimide substrate by way of covalent bonds regularly and homogeneously; the advantages of the present composites at least include effectively improving the distribution of polyhedral oligomeric silsesquioxane in polyimide through the covalent bonding of modified polyhedral oligomeric silsesquioxane and polyimide; and the consistency of pores of polyhedral oligomeric silsesquioxane, with pore size ranging between 0.3 and 0.4 nanometer. As to the synthesis of said material, the starting materials of polyhedral oligomeric silsesquioxane usable in the present invention are readily available, which can be substituted by commercial grade products available from Hybrid Plastic Corp.; in addition, the present invention utilizes traditional polyimide synthesis process to directly react polyhedral oligomeric silsesquioxane, which has 2NH 2 -reactive functional groups on the surface, with dianhydride to form said nanocomposites, therefore, the synthesis technology is well known.
[0016] Another object of the present invention is to provide a process to improve the distribution of inorganic molecular cluster in polyimide. Polyhedral oligomeric silsesquioxane/polyimide nanocomposites are a self-assembled system, in which polyhedral oligomeric silsesquioxane is distributed inside polyimide regularly, and POSS tethering onto different chains based on polyimide is automatically assembled by the van der Waals interactions between the alkyl or aromatic group such as but not limited to cyclopentyl group of POSS molecules; therefore, the self-assembled system formed by covalent bonding is capable of controlling the distribution of polyhedral oligomeric silsesquioxane inside polyimide effectively and homogeneously.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1 is an X-ray diffractogram from the polyhedral oligomeric silsesquioxane and polyhedral oligomeric silsesquioxane/polyimide nanocomposite film of Examples 3; wherein (a) 6FDA-HAB, (b) 10 mole % Cl-POSS/6FDA-HAB, (c) 22 mole % Cl-POSS/6FDA-HAB, (d) 35 mole % Cl-POSS/6FDA-HAB, and (e) Cl-POSS.
[0018] FIG. 2 is an X-ray diffractogram from the polyhedral oligomeric silsesquioxane and polyhedral oligomeric silsesquioxane/polyimide nanocomposite film of Examples 4; wherein (a) PMDA-ODA, (b) 5 mole % 2NH 2 -POSS/PMDA-ODA, (c) 10 mole % 2NH 2 -POSS/PMDA-ODA, (d) 16 mole % 2NH 2 -POSS/PMDA-ODA, and (e) 2NH 2 -POSS.
[0019] FIG. 3 is a diagram showing tethering cage shape POSS on polyimide main chains and exhibiting self-assembled architecture; wherein the size of pores contained in cage shape POSS is 0.3 to 0.4 nanometer.
[0020] FIGS. 4 and 5 are sectional field emission scanning electronic microscopy and transmission electronic microscopy images from Example 3.
[0021] FIG. 6 is a transmission electronic microscopy image of Example 4.
DETAILED DESCRIPTION OF THE INVENTION
[0022] The dielectric constant of the present polyhedral oligomeric silsesquioxane/polyimide (PMDA-ODA) nanocomposites is lower than that of general pure polyimide (PMDA-ODA) (for example, as the testing results shown in Examples and Control Examples of the present invention, in which a best result is obtained reducing from 3.26 to 2.32). The reasons to reduce dielectric constant include factors as: the nanopores contained in polyhedral oligomeric silsesquioxane are homogeneously distributed in polyimide; when polyhedral oligomeric silsesquioxane connects to ends or side chains of polyimide and forms self-assembled architecture, the distance between polyimide molecular chains is largely increased so that free volume is increased; and the polarization degree of polyhedral oligomeric silsesquioxane is lower than that of polyimide.
[0023] The structure of nanocomposites as shown in Examples 2, 3, and 4 can be divided into main chain such as anhydride, a spacer and a side-chain-tethered POSS; wherein the spacer is between the main chain and caged POSS and is flexible, that is, it increases the flexibility freedom of tethered POSSes so that tethered POSSes can form a large aggregates and provide free volume and lowered dielectric constant. The side-chain-tethered POSS can interact with several other side-chain-tethered POSSes and form large POSS aggregates or self-assembled structures.
[0024] As mentioned herein, “self-assembled” acts like what hydrophilicity and hydrophobicity do in synthesizing cell membranes with proteins and molecules in biochemistry; it is necessary for said molecules to have hydrophilic and hydrophobic areas, and these molecules utilize said hydrophilic and hydrophobic areas to automatically form more complicated and biologically useful architecture after being put into water; while this process is called “self-assembled”, a difference is that the synthesis of the present composites utilizes non-polar area in the cage architecture of polyhedral oligomeric silsesquioxane.
[0025] An opposite term is “positional assembly”, in contrast to “self-assembled”, which highly requires engineers to dispose to control the assembly of each independent atom or molecule; relative to “self-assembled”, it is a passive but less complicated chemical synthesis process.
[0026] In one embodiment of the present invention, when a small amount of polyhedral oligomeric silsesquioxane is added, Young's modulus and maximum stress of the nanocomposite film are almost the same as pure polyimide; however, as the added amount of polyhedral oligomeric silsesquioxane is increased, Young's modulus, maximum stress, and maximum elongation of the nanocomposite film reduce to a certain degree, which is caused by that the interaction between molecular chains of the nanocomposite film are weakened by the effects from polyhedral oligomeric silsesquioxane (as its free volume increases). As to other similar low dielectric materials, for example, the pore type siloxane (HSSQ, MSSQ) prepared by sol-gel process, the dielectric constant is lowered by the presence of other low dielectric materials, so that the low dielectric property derives from the loose structure; however, most portion of said loose structure is not capable of forming self-standing free film, and it is not able to be measured mechanically (mechanical properties are very weak).
[0027] Further, in the present composites, elastic modulus, E 1 , decreases as the added amount of polyhedral oligomeric silsesquioxane is increased, which is similar to Young's modulus in the mechanical stretching test results; however, hardness, H, of the nanocomposites is not significantly correlated to the addition of polyhedral oligomeric silsesquioxane, which is different from the case of general low dielectric materials in which hardness is lowered because of loose structure, for example, the hardness value of porous silica dioxide is about 1/7 of that of general silica dioxide; it may be due to the covalent bonding between polyhedral oligomeric silsesquioxane and polyimide, and the nanometer dimensional distribution inside polyimide, so that the hardness value of the materials is not effected.
[0028] As to the thermal properties and hydroscopicity of the present nanocomposites, the thermal properties are reduced with the increased added amount of polyhedral oligomeric silsesquioxane, which is due to the inferior thermal properties of the cyclopentyl groups attached to the vertices of polyhedral oligomeric silsesquioxane comparing to polyimide. In addition, when polyhedral oligomeric silsesquioxane is added to low content, the hydroscopicity is higher than pure polyimide (PMDA-ODA), and while added to high content, the hydroscopicity is lower than pure polyimide (PMDA-ODA); it may be effected generally by two factors, the addition of polyhedral oligomeric silsesquioxane makes loose polyimide molecular chains to enable moisture to be easily adsorbed into materials, and the hydroscopicity of polyhedral oligomeric silsesquioxane is lower than that of polyimide.
[0029] Another object of the present invention is to provide a reactive polyhedral oligomeric silsesquioxane and the synthesis thereof. Typically, the polyhedral oligomeric silsesquioxane usable in the present invention is represented by chemical formula (SiO 1.5 ) n R n-1 R′, wherein n=6, 8, 10, 12, R is alkyl having 1 to 6 carbon atoms or phenyl, R′ is —R 1 —B; R 1 is alkyl having 1 to 6 carbon atoms or phenyl, and B is selected from group at least consisting —NH 2 , —OH, —Cl, —Br, —I, or other derivatives having diamine group (2NH 2 ), for example, reactive functional groups as —R 1 —N(—Ar—NH 2 ) 2 , —R 1 —O—Ar—CH(—Ar—NH 2 ) 2 and the like. By example of Cl as reactive functional groups, the preparation process includes: trichloro(4-(choloromethyl)-phenyl)silane, cyclohexyltrisilanol-POSS, and triethylamine are put into a bottle containing dry THF solvent; thereafter, the content is agitated under the condition of flowing nitrogen to react about 2 hours, and then filtered to remove HNEt 3 Cl. Finally, the filtrate is dropped into acetonitrile solution to give precipitate, and polyhedral oligomeric silsesquioxane with Cl on surface as reactive functional groups is obtained after filtering and drying said precipitate. If NH 2 group is used as reactive functional group, then distinct from Cl, NH 2 group is selective for more reactive species than Cl, especially for anhydrides.
DESCRIPTION OF PREFERRED EMBODIMENTS
[0030] The present invention discloses the following examples but should not be limited thereto.
Example 1
The Preparation of Polyhedral Oligomeric Silsesquioxane with Cl Reactive Functional Groups on Surface
[0031]
1. Trichloro(4-(choloromethyl)-phenyl)silane (1.00 ml; 5.61 mmol), cyclohexyltrisilanol-POSS (5.00 g; 2.11 mmol), and triethylamine (2.2 ml; 15.41 mmol) were put into a three-necked bottle containing 30.0 ml dry THF solvent.
2. Thereafter, the content was agitated under the condition of flowing nitrogen to react about 2 hours, and then filtered to remove HNEt 3 Cl.
3. The filtrate was dropped into acetonitrile solution to give precipitate, and 4.61 g (solid content is 80%) of polyhedral oligomeric silsesquioxane with Cl reactive functional groups on surface was obtained after filtering and drying said precipitate.
Example 2
The Preparation of Polyhedral Oligomeric Silsesquioxane with 2NH 2 Reactive Functional Groups on Surface
[0035]
1. 4-Hydroxybenzaldehyde (0.14 g; 1.06 mmol) and K 2 CO 3 (0.32 g; 0.98 mmol) were put into a three-necked bottle containing dry DMF (10.0 ml) solvent.
2. Thereafter, the content was heated to 80° C. under the condition of flowing nitrogen and agitated to react about 1 hour, and then Cl-POSS (1.00 g; 0.80 mmol) and NaI (0.14 g; 0.98 mmol) solubilized in 10 ml dry THF were added into the three-necked bottle to react 4 hours.
3. The reaction solution was dropped into water, extracted 3 times with dichloromethane (3×15.0 ml), then the pale yellow powder resulting from concentration of organic layer was dried.
4. Aniline (3.14 g; 34.5 mmol), aniline hydrochloride (0.08 g; 0.59 mmol), and the yellow powder from step 3 (1.22 g; 10.0 mmol) were added into the three-necked bottle to solubilize with heat.
5. After the mixed solution was heated to 150° C. to react 1 hour, aniline was removed by distillation under reduced pressure.
6. Polyhedral oligomeric silsesquioxane with 2NH 2 reactive functional groups on surface (solid content is 50%) was separated by column chromatography.
Comparative Example 1
The Synthesis of Polyamic Acid
[0000]
1. 0.0147 mole of 4,4′-oxydianiliane (ODA) was solubilized into 32.94 g of N,N-dimethylacetamide (DMAC) in a three-necked bottle with flowing nitrogen at room temperature, after ODA was solubilized completely, 0.015 mole of pyromellitic dianhydride (PMDA) was added in portions until PMDA was solubilized completely, the agitation was continued for 1 hour, and a viscous polyamide acid solution (solid content is 11˜16%) was formed.
2. By way of doctor blade coating, the polyamide acid solution mentioned above was applied on a glass plate to form a film, which was heated with an elevation rate of 2° C./min and was maintained 1 hour at 100, 150, 200, and 250° C., and 30 minutes at 300° C., respectively, so that the polyamide acid solution was closed-ring dehydrated, and a polyimide (PMDA-ODA) film was formed.
Example 3
The Reaction Between Polyimide with OH Groups and Polyhedral Oligomeric Silsesquioxane with Cl Functional Groups (Cl-POSS) to Synthesize Nanocomposites
[0044]
1. 18.50 mmoles of 3,3′-dihydroxy-4,4′-diaininobyphenyl (HAB) was solubilized into 90.83 g of N,N-dimethylacetamide (DMAc) in a three-necked bottle with flowing nitrogen at room temperature, after HAB was solubilized completely, 18.88 mmoles of 2,2′-bis(3,4-dicarboxyphenyl)hexafluoropropane dianhydride (6FDA) was added in portions until 6FDA was solubilized completely, the agitation was continued for 1 hour, and a viscous polyamide acid solution (solid content is 11˜16%) was formed.
2. Dry xylene (30 ml) was added into the three-necked bottle heated to 160° C. to proceed imidization for 3 hours.
3. The reaction solution was dropped into water to precipitate polyimide, and the polyimide was dried in vacuum oven for about 12 hours.
4. The polyimide (6FDA-HAB) was solubilized into DMAc/THF, various NaH ratios were added to react 0.5 hour at room temperature, and the polyhedral oligomeric silsesquioxane with Cl functional groups (Cl-POSS) of the same mole as NaH was added to react 2 hours at 70° C.
5. The reaction solution was dropped into water, and the precipitate was dried in vacuum oven.
6. By way of doctor blade coating, the polyhedral oligomeric silsesquioxane/polyamide acid nanocomposites mentioned above were applied on a glass plate to form a film, which was heated gradually and was maintained 1 hour at 100, 200, and 250° C., respectively, so that polyhedral oligomeric silsesquioxane/polyimide (6FDA-HAB) nanocomposite film was formed.
Example 4
The Synthesis of Polyhedral Oligomeric Silsesquioxane with 2NH 2 Reactive Functional Groups on Surface (2NH 2 -POSS)/Polyimide Nanocomposites
[0051]
x
y
100
0
95
5
90
10
84
16
1. Various molar ratios of ODA and 2NH 2 -POSS (95/5, 90/10, 84/16) in a total amount of 0.0147 mole were added to NMP/THF (2/1) respectively in a three-necked bottle with flowing nitrogen at room temperature, after ODA was solubilized completely, 0.015 mole of PMDA was added in portions until PMDA was solubilized completely, the agitation was continued for 8 hour, and a viscous polyamide acid solution (solid content is 11%) was formed.
2. By way of doctor blade coating, the polyhedral oligomeric silsesquioxane/polyamide acid nanocomposites mentioned above was applied on a glass plate to form a film, which was heated with an elevation rate of 2° C./min and was maintained 1 hour at 100, 150, 200, and 250° C., and 30 minutes at 300° C., respectively, so that the polyhedral oligomeric silsesquioxane/polyamide acid mixture was closed-ring dehydrated, and a polyhedral oligomeric silsesquioxane/polyimide (PMDA-ODA) nanocomposite film was formed.
Results
[0054] FIGS. 1 and 2 show X-ray diffractograms from the polyhedral oligomeric silsesquioxane and polyhedral oligomeric silsesquioxane/polyimide nanocomposite film of Examples 3 and 4. As can be seen from the figures, the polyhedral oligomeric silsesquioxane is of molecule size of about 1.2 nm, and exhibits crystalline structure. In addition, the polyhedral oligomeric silsesquioxane in polyhedral oligomeric silsesquioxane/polyimide nanocomposite film still exhibits crystalline structure, and this structure has pores with size of 0.3-0.4 nm.
[0055] FIG. 3 shows the architecture diagram of Examples 3 and 4, which exhibits self-assembled architecture, contains cage shape POSS with pore size of about 0.3 to 0.4 nanometer, and cage shape POSS on different polyimide main chains with crystalline structure formed of polar areas.
[0056] FIGS. 4 and 5 are sectional field emission scanning electronic microscopy and transmission electronic microscopy images from Example 3; as can be found in FIG. 4 , particles with size of 10 nm are homogeneously distributed in polyimide with a little regularity, and as can be found in FIG. 5 , in the whole distribution of polyhedral oligomeric silsesquioxane, the darker part of the image in the figure is caused by polyhedral oligomeric silsesquioxane; and from the figure it can be known that the polyhedral oligomeric silsesquioxane/polyimide nanocomposites are a self-assembled system, however, due to synthesis process, it is necessary to precipitate nanocomposites after formed to remove by-products, and it is also necessary to solubilize and form a film again, so that the focusing particles are larger (about 10 nm).
[0057] FIG. 6 is a transmission electronic microscopy image of Example 4; as can be found in the figure, in the whole distribution of polyhedral oligomeric silsesquioxane, the black lines (with width of 2 nm) of the image in the figure are caused by polyhedral oligomeric silsesquioxane, and are distributed in polyimide regularly and homogeneously. Polyhedral oligomeric silsesquioxane/polyimide (PMDA-ODA) nanocomposites are a self-assembled system, so that nanocomposites formed by covalent bonding can be distributed in polyimide in a way of effectively controlling polyhedral oligomeric silsesquioxane.
[0058] Table 1 is a list of dielectric constants for Comparative Example 1, and Examples 3 and 4. In Example 3, the dielectric constant of nanocomposites decreases as the molar amount of polyhedral oligomeric silsesquioxane increases. In Example 4, the dielectric constants of polyhedral oligomeric silsesquioxane/polyimide (PMDA-ODA) nanocomposites with different composition are lower than that of pure polyimide (PMDA-ODA) from Comparative Example 1.
[0059] Table 2 is the analytical data of mechanical stretching properties from polyimide (PMDA-ODA) of Comparative Example 1 and polyhedral oligomeric silsesquioxane/polyimide nanocomposites of Example 3 and 4; when a small amount of polyhedral oligomeric silsesquioxane is added, Young's modulus and maximum stress of the nanocomposite film are almost the same as pure polyimide; however, as the added proportion of polyhedral oligomeric silsesquioxane is increased, Young's modulus, maximum stress, and maximum elongation of the nanocomposite film reduce to a certain degree, which is caused by that the interaction between molecular chains of the nanocomposite film are weakened by the effects from polyhedral oligomeric silsesquioxane (as its free volume increases). Further, comparing to other low dielectric materials, for example, the pore type siloxane (HSSQ, MSSQ) prepared by sol-gel process, which use loose structure in order to reduce the dielectric constant, most of them are not capable of completing the measurement of mechanical stretching properties.
[0060] Table 3 is the analytical result of surface recess hardness test from polyhedral oligomeric silsesquioxane/polyimide (PMDA-ODA) nanocomposites of Example 3 and 4. The equivalent reduced elastic modulus, E 1 , decreases as the added amount of polyhedral oligomeric silsesquioxane is increased, which is similar to Young's modulus in the mechanical stretching test results; however, hardness, H, of the nanocomposites is not significantly changed due to the addition of polyhedral oligomeric silsesquioxane, which is different from the case of general low dielectric materials in which hardness is lowered because of loose structure, for example, the hardness value of porous silica dioxide is about 1/7 of that of general silica dioxide; it may be due to the covalent bonding between polyhedral oligomeric silsesquioxane and polyimide, and the nanometer dimensional distribution inside polyimide, so that the hardness value of the materials is not effected.
[0061] Table 4 is thermal properties and hydroscopicity measurement from polyhedral oligomeric silsesquioxane/polyimide (PMDA-ODA) nanocomposites of Example 3 and 4, the thermal properties decrease as the added amount of polyhedral oligomeric silsesquioxane is increased, which is due to the inferior thermal properties of cyclopentyl groups attached to the vertices of polyhedral oligomeric silsesquioxane comparing to polyimide. In addition, it can be found from the table, when polyhedral oligomeric silsesquioxane is added to low content, the hydroscopicity is higher than polyimide (PMDA-ODA), and while added to high content, the hydroscopicity is lower than polyimide (PMDA-ODA); it may be effected generally by two factors: first, the addition of polyhedral oligomeric silsesquioxane makes loose polyimide molecular chains to enable moisture to be easily adsorbed into materials; second, the hydroscopicity of polyhedral oligomeric silsesquioxane is lower than that of polyimide. Since low added amount greatly effects the activity of polyimide molecular chains (as can be known from the difference between glass transition temperatures (Tg) of nanocomposites), the hydroscopicity increases when the first factor effects more significantly than the second does, and the hydroscopicity decreases when the added amount is increased and the second factor effects more significantly than the first does.
TABLE 1 Dielectric constants of polyhedral oligomeric silsesquioxane/polyimide (PMDA-ODA) nanocomposites Mol % of POSS in polyimide Dielectric constant Example 3 0 3.35 ± 0.16 Example 3 10 2.83 ± 0.04 Example 3 22 2.67 ± 0.07 Example 3 35 2.40 ± 0.04 mol % of POSS in polyimide Dielectric constant Comparative 0 3.26 ± 0.09 Example 1 Example 4 5 2.86 ± 0.04 Example 4 10 2.57 ± 0.08 Example 4 16 2.32 ± 0.05
[0062]
TABLE 2
Analysis of Mechenical properties of polyhedral oligomeric
silsesquioxane/polyimide (PMDA-ODA) nanocomposites
wt % of
mol % of
POSS in
Young's
Elongation
Maximum
POSS in
polyimide
modulus
at break
stress
polyimide
(%)
(GPa)
(%)
(MPa)
Compar-
0
0
1.86 ± 0.08
5 ± 1
59.2 ± 7.7
ative
Example 3
Example 3
10
14.3
1.85 ± 0.09
4 ± 1
45.1 ± 5.1
Example 3
22
26.5
1.20 ± 0.02
3 ± 1
22.3 ± 4.9
Example 3
35
36.7
0.61 ± 0.07
2 ± 1
11.2 ± 3.9
Compar-
0
0
1.60 ± 0.07
6 ± 1
50.9 ± 1.2
ative
Example 1
Example 4
5
14.2
1.58 ± 0.08
5 ± 1
48.9 ± 5.1
Example 4
10
26.6
1.43 ± 0.07
4 ± 1
46.4 ± 7.9
Example 4
16
39.4
1.25 ± 0.04
2 ± 1
20.4 ± 1.1
[0063]
TABLE 3
Surface recess hardness test analysis of polyhedral oligomeric
silsesquioxane/polyimide (PMDA-ODA) nanocomposites
Equivalent
mol % of
elastic
Surface
Maximum
POSS in
modulus
hardness
dislocation
polyimide
(GPa)
(GPa)
(nm)
Comparative
0
1.86 ± 0.08
0.15 ± 0.01
—
Example 1
Example 3
10
1.85 ± 0.09
0.11 ± 0.02
—
Example 3
22
1.20 ± 0.02
0.07 ± 0.01
—
Example 3
35
0.61 ± 0.07
0.06 ± 0.02
—
Comparative
0
4.4 ± 0.1
0.23 ± 0.01
361.3 ± 4.3
Example 1
Example 3
5
4.3 ± 0.1
0.23 ± 0.02
363.4 ± 3.5
Example 3
10
4.2 ± 0.1
0.22 ± 0.01
370.0 ± 5.4
Example 3
16
4.0 ± 0.1
0.21 ± 0.02
378.9 ± 3.9
[0064]
TABLE 4
Thermal properties and hydroscopicity of polyhedral oligomeric
silsesquioxane/polyimide (PMDA-ODA) nanocomposites
mol % of
Td (° C.)
POSS in
at 5
Tg
Hydroscopicity
polyimide
wt % loss
(° C.)
(%)
Comparative
0
430.2
359.3
—
Example 1
Example 3
10
415.1
355.1
—
Example 3
22
407.9
350.5
—
Example 3
35
405.7
337.6
—
Comparative
0
604.6
350.7
1.8
Example 1
Example 4
5
583.7
316.6
2.0
Example 4
10
552.4
308.1
2.3
Example 4
16
534.5
303.9
1.4
|
Polyhedral oligomeric silsesquioxane/polyimide nanocomposites with certain mechanical properties and low dielectric constant is synthesized by covalently tethering functionalized polyhedral oligomeric silsesquioxane molecules to polyimide. These nanocomposites appear to be self-assembled systems. A process for synthesizing said polyhedral oligomeric silsesquioxane/polyimide nanocomposites also is provided, comprising a step of forming porous type polyhedral oligomeric silsesquioxane, and a subsequent step of reacting with dianhydride or directly reacting with synthesized polyimide.
| 2 |
CROSS REFERENCE TO RELATED APPLICATION
This application claims priority to French patent application No. FR 13 02877 filed on Dec. 10, 2013, the disclosure of which is incorporated in its entirety by reference herein.
BACKGROUND OF THE INVENTION
(1) Field of the Invention
The present invention relates to a method for tending to optimize both the noise emitted by an auxiliary rotor of a rotorcraft and also the performance of the rotorcraft, and it also relates to a rotorcraft applying the method.
The invention thus lies in the narrow technical field of tail fins for aircraft, and more particularly for rotorcraft.
(2) Description of Related Art
For example, a helicopter type rotorcraft may have a single main rotor that is driven mechanically by at least one engine. The main rotor then provides the helicopter with lift and propulsion.
The helicopter is also provided with an auxiliary tail rotor that performs an anti-torque function by exerting transverse thrust in order to compensate the yaw thrust created by rotating the main rotor. This torque is referred to below as “rotor torque” for convenience.
Furthermore, the auxiliary rotor enables the pilot to control the yaw movements of the helicopter by exerting transverse thrust that is positive or negative.
The auxiliary rotor may then for example be arranged on a tail fin carried by a tail boom of the aircraft. The term “fin” designates a streamlined body extending in elevation and that is substantially contained in a vertical plane. Nevertheless, the fin may be inclined relative to this vertical anteroposterior plane of symmetry. The term “vertical fin” is sometimes used.
An unducted auxiliary rotor is known, and for convenience is referred to below as a “conventional” auxiliary rotor. Conventionally, an unducted auxiliary rotor is mounted laterally at a top end of the tail fin.
Such an unducted auxiliary rotor is in widespread use. Nevertheless, it is possible to implement an auxiliary rotor that is ducted, as known under the trademark Fenestron®, for example.
A ducted auxiliary rotor comprises a rotor arranged in a duct provided through the tail fin of a helicopter. The axis of symmetry of the duct is substantially perpendicular to the vertical anteroposterior plane of symmetry of the helicopter.
Consequently, the streamlined shape of the vertical fin of the helicopter surrounds said duct and thus the auxiliary rotor. It should be observed that the streamlined structure is commonly referred to by the person skilled in the art as a fairing. Such a rotor is referred to for convenience below as a “ducted” rotor.
Independently of the ducted or unducted nature of the auxiliary rotor, the tail fin participates in controlling yaw movements. The fin generates transverse lift while the helicopter is in forward flight. The greater the forward speed of the helicopter, the greater this transverse lift.
A ducted or unducted auxiliary rotor thus makes it possible to control yaw movements of a rotorcraft. Nevertheless, an auxiliary rotor can generate a greater or smaller amount of noise depending on the stage of flight of the rotorcraft.
Document FR 2 338 845 refers to a helicopter having a rotor driven by an engine.
Document FR 2 338 845 then provides for controlling the helicopter in yaw by means of a fixed-pitch ducted propeller driven by the engine, with the thrust of that propeller being modulated by variable-pitch vanes situated in a duct of the propeller and upstream therefrom. The auxiliary rotor is thus a ducted rotor provided with a propeller and with vanes arranged in the duct of the ducted rotor.
Document EP 0 867 364 suggests reducing the noise emitted by a rotorcraft by reducing the speed of rotation of a main rotor, and by controlling accordingly an auxiliary rotor and a movable fin element. The pitch of the blades of the auxiliary rotor and the angle of attack of the movable fin element are determined on the basis of an air speed and of the torque exerted by the main rotor.
Document U.S. Pat. No. 6,290,171 provides for a device for controlling a hybrid anti-torque system for opposing the torque generated by a main rotor for providing a helicopter with lift and propulsion, and comprising:
an anti-torque auxiliary rotor that is controllable and that exerts anti-torque lateral thrust; and
at least one steering airfoil that is controllable and that generates anti-torque transverse thrust.
That device includes control means:
for controlling as a priority said airfoil so that it generates lift that is representative of at least a portion of a first control order, which portion is suitable for being executed by said airfoil; and
for controlling said auxiliary rotor so that the combined action of said airfoil and of said auxiliary rotor is representative of a yaw control order for the helicopter.
Document EP 1 547 919 describes a method and a device for reducing the vibration generated by the structure of a helicopter. That vibration results from the flow of air coming from a main rotor that provides the aircraft with lift and propulsion, and from the flow of air running along the fuselage. The method and the device then make use of a measurement of vibration in order to determine the angle of incidence of a tail fin in order to generate a force in opposition to the measured vibration.
Document EP 0 566 452 describes a helicopter having a single main lift and propulsion rotor, together with an anti-torque system. The anti-torque system comprises:
an anti-torque auxiliary rotor driven in rotation from engine means for said main rotor and exerting controllable anti-torque lateral thrust; and
at least one steering airfoil of controllable deflection for generating anti-torque transverse lift.
Under such circumstances, the helicopter includes means for automatically controlling the deflection angle of said steering airfoil as a function of the collective pitch angle of said main rotor and as a function of the forward speed of said helicopter.
Finally, Document DE 1 144 116 describes a fin carrying an auxiliary rotor and a control surface capable of being pivoted.
Also known is Document US 2012/104156.
BRIEF SUMMARY OF THE INVENTION
An object of the present invention is thus to propose a method for tending to optimize the noise emitted by an auxiliary rotor of a rotorcraft.
The invention thus provides a method for tending to minimize the noise emitted by an auxiliary rotor of a rotorcraft. The rotorcraft extends longitudinally along a first anteroposterior plane between a first side and a second side of the rotorcraft. The rotorcraft thus extends laterally from the first side to the second side.
In addition, the rotorcraft is provided with at least one main rotor, the rotorcraft also having an auxiliary rotor exerting controllable lateral thrust for controlling movement of the rotorcraft in yaw. The thrust is then directed towards the second side in order to counter torque generated by said main rotor on the fuselage of the rotorcraft. The term “thrust directed towards the second side” is used to mean thrust acting in a direction going from the auxiliary rotor towards the second side.
The rotorcraft also has a power plant for driving the main rotor and the auxiliary rotor in rotation.
The rotorcraft also has a tail fin provided at least in part with a steerable airfoil extending in elevation and generating transverse thrust, the airfoil presenting a deflection angle of zero when the airfoil is present in a reference plane referred to as the “second” plane, the airfoil having a trailing edge. The airfoil thus comprises a body that is defined in a chord direction between a leading edge and a trailing edge.
The airfoil thus extends vertically from a low portion towards a high portion, and longitudinally from a leading edge towards a trailing edge. The term “when said airfoil is present in a reference plane referred to as a “second” plane” is used to designate the position in which the airfoil is to be found when a reference chord of the airfoil is present in the second plane.
In this method, the deflection angle of the airfoil is controlled so as to direct its trailing edge towards said second side so that the airfoil presents a deflection angle that is negative relative to the second plane, or to direct its trailing edge towards said first side so that the airfoil presents a deflection angle that is positive relative to the second plane, the airfoil having the function of causing the auxiliary rotor to tend towards at least one predetermined operating point seeking to optimize the performance of the rotorcraft and to minimize the noise generated by the auxiliary rotor, the deflection of said airfoil being controlled at least as a function of a current value of a speed parameter of the rotorcraft and of a current value of a power parameter of said power plant.
By convention, the deflection angle is considered as being:
zero when the airfoil is situated in the second plane;
positive when the airfoil is offset angularly relative to the second plane by being turned towards the first side; and
negative when the airfoil is offset angularly relative to the second plane by being turned towards the second side.
Furthermore, by convention it is considered that a positive deflection angle is greater than a negative deflection angle.
Consequently, the airfoil may perform pivoting movements to present a deflection angle lying between a minimum negative deflection angle and a maximum positive deflection angle.
In the method, this deflection angle is controlled so as to cause the auxiliary rotor to tend towards at least one operating point that minimizes the noise generated by the auxiliary rotor. The airfoil thus enables the auxiliary rotor to be put under conditions seeking to reduce the sound nuisance and to improve the performance of the aircraft.
The deflection angle is controlled to optimize the thrust generated by the auxiliary rotor from the point of view of acoustic comfort, while nevertheless conserving performance for the rotorcraft that is acceptable.
As a result, the thrust from the auxiliary rotor is adapted as a function of the angular position of the airfoil. This adaptation seeks to cause the auxiliary rotor to tend towards optimum operating points. The airfoil thus enables the thrust generated by the auxiliary rotor to be increased or reduced in order to satisfy as well as possible both a performance target for the rotorcraft and also an acoustic target.
In order to control the deflection angle of the airfoil, the method makes use of the current value of a speed parameter of the rotorcraft and of the current value of a power parameter of said power plant.
The method applies equally well to a ducted auxiliary rotor and to an unducted auxiliary rotor.
The method may include one or more of the following characteristics.
Thus, by way of example, said speed parameter is selected from a list comprising at least: an air speed and a ground speed.
These air and ground speeds are measured using a conventional first measurement system. For example, the air speed may be determined with the help of a Pitot tube. Furthermore, the ground speed may be obtained with a positioning system known under the acronym GPS, or indeed by using Doppler radar, for example.
By way of example, the power plant includes at least one engine and a main gearbox interposed between each engine and the main rotor, and the power parameter may be selected from a list comprising at least: total power developed by said at least one engine; total torque generated by said at least one engine; power transmitted to the main gearbox; torque transmitted to the main gearbox; and torque exerted on a mast driving said main rotor.
These power parameters of the power plant may be measured with the help of a conventional second measurement system. This second measurement system may be a conventional system having the function of determining either power as such, or else torque as a function of the nature of the parameter.
The second measurement system may thus comprise a first device for measuring torque transmitted by a rotating shaft. For example, the first device may be a torque meter having phonic wheels.
When the power parameter is power as such, the second measurement system may also include a second device measuring a speed of rotation of said shaft, e.g. a device such as a phonic wheel.
The second measurement system may also include a calculation unit. The calculation unit then determines the power by multiplying said torque by said speed of rotation.
Furthermore, the rotorcraft may have arranged thereon a tail fin constituted entirely by said airfoil, or by a stationary tail fin provided with at least one movable control surface representing said airfoil, or indeed by a movable tail fin provided with at least one movable control surface, together representing said airfoil. In other words, the airfoil may be a steerable tail fin, possibly also having a steerable control surface, or indeed a steerable control surface arranged on a stationary tail fin.
In addition, in the invention it is possible:
to position said airfoil at a small negative deflection angle during a stage of descending flight at a low speed for the rotorcraft, e.g. an angle lying in the range −15 degrees to 0 degrees;
to position said airfoil at a large negative deflection angle during a descending stage of flight at a high speed of the rotorcraft or when it is in auto-rotation, e.g. an angle of −15 degrees; and
to position said airfoil at a positive deflection angle during a climbing stage of flight, e.g. at an angle of 35 degrees.
When the airfoil presents a negative deflection angle, the lateral lift from the tail fin is reduced in order to reduce the torque that adds to the torque exerted on the fuselage by the main rotor. In order to compensate for this reduction in torque, it is appropriate to increase the thrust generated by the auxiliary rotor in order to keep the yaw angle of the aircraft constant.
Conversely, when the airfoil presents a positive deflection angle, the lateral lift from the tail fin is increased. In order to compensate for this increase in torque, it is appropriate to reduce the thrust generated by the auxiliary rotor.
Under such conditions, the method tends to optimize the performance of a rotorcraft and the noise emitted by the rotorcraft during multiple stages of flight.
During a cruising stage of flight, a tail fin of a rotorcraft may generate lateral thrust capable of creating torque suitable for compensating the torque exerted by the main rotor on the fuselage.
The auxiliary rotor may then optionally be stopped. Nevertheless, a ducted auxiliary rotor may then give rise to a noisy phenomenon of fluid recirculating within the duct of the ducted auxiliary rotor.
The invention then proposes placing the airfoil at a negative deflection angle in order to reduce the lateral thrust from the tail fin while requesting operation of the auxiliary rotor. The phenomenon of fluid recirculation is then at least reduced.
This method appears to be surprising insofar as it leads to the auxiliary rotor being operated even though that appears to be penalizing. Nevertheless, a small negative angle serves to minimize the power required from operation of the auxiliary rotor, thereby conserving acceptable performance.
Furthermore, the method makes it possible to use a tail fin of large dimensions, by minimizing the impact of the fin on the noise that is emitted during a cruising stage of flight. Such a tail fin is advantageous. The tail fin contributes to the anti-torque action of the auxiliary rotor and may thus optionally enable an auxiliary rotor to be installed that requires less power than in certain prior art embodiments. The power saving that results therefrom can lead to an increase in the payload of the rotorcraft.
Fuel consumption can also be optimized.
During a descending stage of flight, a tail fin of large dimensions can generate a large amount of lateral thrust that is substantially equivalent to the lateral thrust developed during cruising flight. Nevertheless, the torque from the rotor tends to diminish. Under such circumstances, this lateral thrust may generate torque on the fuselage that is greater than the rotor torque exerted on the fuselage by the main rotor. This results in a yaw movement of the rotorcraft that needs to be countered by generating negative thrust using the auxiliary rotor in order to maintain a constant yaw angle for the aircraft.
Such negative thrust generates noise, and may degrade the performance of the rotorcraft, in particular by making it more difficult for a pilot to control.
The invention thus proposes positioning the airfoil at a deflection angle that is large and negative so as to avoid creating torque greater than the rotor torque.
The airfoil may also be used for this purpose during a stage of flight in auto-rotation.
The rotor torque exerted by the main rotor on the fuselage is then low. Under such circumstances, the airfoil may be positioned at a large negative deflection angle in order to induce lateral thrust from the tail fin that is small or even zero.
In auto-rotation, and also during a rapid descent, the auxiliary rotor is used mainly for controlling the yaw movement of the aircraft and not for countering any lateral thrust generated by a tail fin. The invention thus provides an optimized margin for controlling yaw by using the auxiliary rotor. Furthermore, the noise emitted by the auxiliary rotor can then be reduced, in particular by avoiding operation with negative thrust.
During a climbing stage of flight, the main rotor is heavily stressed so it induces a large amount of rotor torque on the fuselage. This rotor torque is conventionally countered by generating a large amount of thrust from the auxiliary rotor. This high level of thrust generates noise.
In addition, operating the auxiliary rotor then requires a large amount of power. The power available for the main rotor is then reduced, thereby reducing the performance of the rotorcraft, and in particular reducing its rate of climb.
Conversely, the invention proposes positioning the airfoil at a positive deflection angle during a climbing stage of flight. The auxiliary rotor then needs to generate a smaller amount of thrust compared with certain prior art embodiments, thereby enabling the above-mentioned drawbacks to be reduced.
In addition, the airfoil may also be positioned at a positive deflection angle in the event of a failure of the auxiliary rotor. The torque generated by the airfoil on the fuselage enables a greater amount of rotor torque to be compensated. The invention thus makes it possible to reduce the speed of descent of the aircraft. Specifically, the invention makes it possible to reduce the forward speed of the aircraft during a running landing as needs to be performed after descending in the event of a failure of the auxiliary rotor.
Furthermore, it is possible to incline the second plane relative to the first anteroposterior plane so that the second plane presents a positive angle relative to the first anteroposterior plane, the trailing edge of the airfoil being directed towards the first side when the airfoil is present in the second plane.
This characteristic makes it possible to impart a positive angle to the airfoil relative to incident air during forward flight when the airfoil has a zero deflection angle.
Likewise, it is also possible to impart positive camber to the airfoil, the airfoil presenting a cambered face directed towards the second side.
Furthermore, it is possible to control the orientation of the airfoil with the help of a relationship providing a target angle for the airfoil as a function of said speed parameter of the rotorcraft and of said power parameter of the power plant.
This relationship optionally includes the following equations:
δ 1 = { V < V 1 -> δ ma x V 1 ≤ V < V 2 -> [ sw ] · ( A · V + B ) + [ δ ma x - [ sw ] · ( A · V + B ) ] · { 1 - [ sin ( π 2 · V - V 1 V 2 - V 1 ) ] 2 } V 2 ≤ V -> [ sw ] · ( A · V + B )
δ 2 = { W < W 1 -> δ m i n W 1 ≤ W < W 2 -> δ 1 - [ δ 1 - δ m i n ] · { [ sin ( π 2 · W - W 2 W 2 - W 1 ) ] 2 } W 2 ≤ W -> δ 1
δ = { V > V 4 -> δ 2 V 3 < V ≤ V 4 -> δ ma x - [ δ ma x - δ 2 ] · { [ sin ( π 2 · V - V 3 V 4 - V 3 ) ] 2 } V ≤ V 3 -> δ ma x
where:
“δ” represents the target angle;
“δ1” and “δ2” represent calculation parameters;
“δmax” and “δmin” represent respectively the predetermined maximum positive threshold angle and minimum negative threshold angle;
“V1” represents the first speed threshold, “V2” represents the second speed threshold, “V3” represents the third speed threshold, and “V4” represents the fourth speed threshold;
“V” represents the current value of the speed parameter;
“W1” represents the first power threshold and “W2” represents the second power threshold;
“W” represents the current value of the power parameter;
“sw” represents a predetermined adjustment parameter; and
“A” and “B” represent variables that are functions of said adjustment parameter.
Where, by way of example, “δmax”, “δmin”, “V1”, “V2”, “V3”, “V4”, and “W1”, “W2” are determined by the manufacturer performing tests and/or simulations so as to match them to a particular rotorcraft and/or to a particular mission.
The variables “A” and “B” are determined by the manufacturer by tests or by simulation in order to induce the predetermined threshold angle. For example, these variables “A” and “B” may be determined using the following formulas:
A= 0.1×[ sw ] and B=− 21×[ sw]
In a first implementation, the adjustment parameter is equal to a predetermined value. The deflection angle applied to the airfoil is then equal to the target angle.
By way of example, the predetermined angle may be zero.
The relationship makes it possible to define a single sheet for determining the deflection angle as a function of the current speed parameter and of the current power parameter.
This sheet may in particular have four distinct operating zones that are interconnected by transition zones, namely:
a first zone Z1 for which the deflection angle is at a maximum, reaching a positive threshold angle, the first zone being reached at a low forward speed;
a second zone Z2 for which the deflection angle is at a maximum reaching a positive threshold angle, the second zone being reached at an intermediate forward speed and at high power developed by the power plant;
a third zone Z3 for which the deflection angle is positioned at a medium deflection, e.g. close to zero or equal to zero, the third zone being reached at a high forward speed and at high power developed by the power plant; and
a fourth zone for which the deflection angle is small, reaching the negative threshold value, the fourth zone being reached at a high forward speed and at low power developed by the power plant.
The medium deflection lies between the positive threshold angle δmax and a negative threshold value δmin.
In a second implementation the following steps are performed:
determining a maximum angle for the target angle in application of said relationship and imparting a first value to the adjustment parameter, e.g. a first value equal to −1;
determining a minimum angle for the target angle in application of said relationship and imparting a second value to the adjustment parameter, e.g. a second value equal to +1;
measuring a current collective pitch of the blades of said auxiliary rotor;
increasing said deflection angle of the airfoil by causing it to tend towards said maximum angle so long as said pitch is greater than a predetermined setpoint pitch, the deflection angle being limited to be less than or equal to the maximum angle;
decreasing said deflection angle of the airfoil by causing it to tend towards said minimum angle so long as said pitch is less than the predetermined setpoint pitch, the deflection angle being limited to be greater than or equal to the minimum angle; and
automatically modifying said pitch in parallel with modifying said deflection angle.
The relationship makes it possible to define an upper sheet and a lower sheet serving respectively to determine a maximum angle and a minimum angle. Each sheet may include the four above-described zones.
The deflection angle of the airfoil is then limited by these upper and lower sheets.
Under such circumstances, the deflection angle is determined as a function of the current collective pitch of the blades of the auxiliary rotor, while nevertheless being limited by the upper and lower sheets.
This second implementation seeks to cause the auxiliary rotor to operate at a predetermined operating point. The manufacturer then determines the pitch of the blades that will bring the auxiliary rotor into this operating point.
This operating point can lead to the auxiliary rotor generating positive lateral thrust.
When the collective pitch of the blades is greater than the setpoint pitch, the lateral lift from the tail fin is increased by increasing the deflection angle, i.e. by making it tend towards the maximum angle. In parallel, an autopilot system acts on the auxiliary rotor to reduce the collective pitch of the blades of the auxiliary rotor.
When the collective pitch of the blades is less than the setpoint pitch, the lateral thrust from the tail fin is reduced by reducing the deflection angle, i.e. by making it tend towards the minimum angle. In parallel, an autopilot system acts on the auxiliary rotor to increase the collective pitch of the blades of the auxiliary rotor.
In addition, for an aircraft including manual control means for controlling the pitch of the blades of the auxiliary rotor, it is possible to inhibit any modification to the deflection angle whenever the pilot is operating said control means. The second implementation is then inhibited.
It should be observed that a single rotorcraft may use both of the above-described implementations, with it being possible for a pilot to select the desired mode of operation.
In addition to a method, the invention provides a rotorcraft extending longitudinally along a first anteroposterior plane separating a first side from a second side of the rotorcraft, said rotorcraft being provided with at least one main rotor, said rotorcraft being provided with an auxiliary rotor exerting lateral thrust that is controllable in order to control yaw movement of the rotorcraft, said thrust being directed towards said second side in order to counter torque generated by said main rotor on a fuselage of the rotorcraft, said rotorcraft including a power plant for driving the main rotor and the auxiliary rotor in rotation, said rotorcraft including a tail fin extending in elevation and provided at least in part with a deflectable airfoil of controllable deflection and generating transverse lift, said airfoil presenting a zero deflection angle when said airfoil is present in a second plane, said airfoil having a trailing edge.
The rotorcraft then includes a processor unit connected to mover means for causing the airfoil to pivot, the processor unit being connected to a first measurement system for measuring a current value of a speed parameter of the rotorcraft and to a second measurement system for measuring a current value of a power parameter of said power plant, said processor unit then applying the above-described method.
Consequently, the processor unit may include calculation means such as a processor executing instructions stored in a non-volatile memory in order to perform the method.
The processor unit thus communicates with the mover means for controlling the deflection of the airfoil by directing its leading edge towards the first side so that the airfoil presents a deflection angle that is positive relative to the second plane or by directing its trailing edge towards the second side so that the airfoil presents a deflection angle that is negative relative to the second plane. For this purpose, the processor unit controls the deflection angle of said airfoil at least as a function of a current value of a speed parameter of the rotorcraft and of a current value of a power parameter of said power plant.
The rotorcraft may then include a deflectable tail fin representing said airfoil, or a stationary tail fin provided with at least one movable control surface representing said airfoil, or a movable tail fin having at least one movable control surface together representing said airfoil.
In addition, the second plane may present a positive angle relative to the first anteroposterior plane, said trailing edge being directed towards said first side when said airfoil is present in said second plane.
Furthermore, the airfoil may have positive camber, said airfoil presenting a cambered face directed towards the second side.
In addition, the processor unit may include a non-volatile memory storing a relationship providing a target angle for the airfoil as a function of the speed parameter of the rotorcraft and of the power parameter of the power plant in order to perform the first and/or the second above-described implementation.
The rotorcraft may also include manual control means for controlling the pitch of the blades of the auxiliary rotor, and the control means being in communication with the processor unit directly or indirectly via measurement devices.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
The invention and its advantages appear in greater detail from the following description of embodiments given by way of illustration and with reference to the accompanying figures, in which:
FIG. 1 is a diagram of an aircraft of the invention;
FIG. 2 is a diagram showing a stationary tail fin carrying a movable airfoil;
FIG. 3 is a diagram showing a movable tail fin;
FIG. 4 is a diagram showing a cambered airfoil;
FIG. 5 is a diagram explaining the positioning of a movable airfoil having a positive deflection angle or a negative deflection angle;
FIG. 6 is a diagram showing a first implementation; and
FIG. 7 is a diagram showing a second implementation.
DETAILED DESCRIPTION OF THE INVENTION
Elements present in more than one of the figures are given the same references in each of them.
FIG. 1 shows a rotorcraft 1 having a fuselage 2 . The fuselage 2 extends longitudinally along an anteroposterior plane of symmetry P1 from a nose 3 to a tail 4 . The fuselage 2 also extends transversely from a first side 6 to a second side 7 .
The fuselage 2 also has at least one main rotor 5 providing at least part of the lift and possibly also the propulsion of the rotorcraft 1 .
The main rotor 5 has a plurality of blades performing rotary motion in a first direction S1. During this movement, one blade usually referred to as a “retreating” blade moves from the first side 6 towards the second side 7 . Conversely, a blade usually referred to as the “advancing” blade moves from the second side 7 towards the first side 6 .
This rotary motion of the main rotor gives rise to rotor torque in yaw on the fuselage 2 in a second direction S2 opposite to the first direction S1. The rotor torque then tends to change the yaw angle of the rotorcraft.
Under such conditions, the rotorcraft has at least one auxiliary rotor 10 for controlling the yaw movements of the rotorcraft.
The auxiliary rotor 10 is usually arranged at one of the longitudinal ends of the rotorcraft. Thus, the auxiliary rotor is arranged at the tail 4 of the rotorcraft, and in particular in a tail fin 20 .
The auxiliary rotor may be an unducted rotor as shown in FIG. 1 , or it may be a ducted rotor.
The auxiliary rotor 10 then generates lateral thrust 100 . This lateral thrust 100 may be controlled using conventional control means 50 , such as pedals.
In order to oppose the rotor torque, the lateral thrust is referred to as “positive” thrust 101 , this positive thrust being directed towards the second side 7 . The auxiliary rotor may also exert negative thrust 102 directed towards the first side 6 .
In order to drive the main rotor 5 and the auxiliary rotor 10 , the rotorcraft includes a power plant 90 . The power plant 90 has at least one engine 91 and a main gearbox 92 that is interposed between the main rotor 5 and at least one engine 91 .
The rotorcraft 1 also has a tail fin comprising at least in part a movable airfoil 25 that can be pivoted to generate adjustable transverse thrust 111 , 112 .
This airfoil 25 extends in elevation in a substantially vertical plane that presents an angle relative to the first plane P1.
In the variant of FIGS. 1 and 2 , the rotorcraft 1 presents a stationary tail fin 20 . The airfoil 25 then comprises a control surface 26 hinged to the stationary tail fin in order to represent said airfoil.
In the variant of FIG. 3 , the rotorcraft has an airfoil comprising a movable tail fin. The tail fin is movable as a whole and represents said airfoil.
In a variant that is not shown, the rotorcraft has an airfoil including a movable tail fin, itself carrying a movable control surface.
In addition, and with reference to FIG. 4 , the airfoil 25 may optionally include positive camber, the airfoil 25 presenting a cambered face 29 facing the second side 7 .
Independently of the variant and with reference to FIG. 1 , the airfoil 25 presents a deflection angle 200 that is zero when a reference chord of the airfoil 25 lies in a second plane P2. The airfoil is then in a middle position, and it may be deflected on either side of this middle position.
It can be understood that the manufacturer can perform tests or simulations to determine the appropriate amount of lift to be delivered when the airfoil is in the middle position so as to be located in the second plane P2.
The deflection angle is measured relative to a second plane P2. This second plane P2 may coincide with the first plane P1. Nevertheless, the second plane P2 may present a positive angle 300 relative to the first plane P1, as in the variant shown.
The airfoil may then be moved in order to present a deflection angle relative to the second plane P2.
By convention, the airfoil 25 presents a positive deflection angle when its trailing edge 27 moves away from the second plane P2 so as to be situated on the first side 6 of the rotorcraft, i.e. on the right-hand side of the second plane in FIG. 1 . Conversely, the airfoil 25 presents a negative deflection angle when its trailing edge 27 moves away from the second plane P2 so as to be situated on the second side 7 of the rotorcraft, i.e. on the left-hand side of the second plane in FIG. 1 .
In order to control the deflection angle, the rotorcraft 1 has a processor unit 30 that is connected to mover means 35 for causing the airfoil 25 to pivot.
The mover means 35 may comprise a hydraulic valve 36 communicating with the processor unit, and a hydraulic actuator 37 connected to the hydraulic valve 36 and to the airfoil 25 . Alternatively, and by way of example, the mover means may comprise an electronic controller controlling an electromechanical actuator.
The processor unit 30 may include a processor 31 executing information stored in a non-volatile memory 32 for controlling the mover means.
Consequently, the processor unit 30 is connected to a first measurement system 41 for measuring a current value of a speed parameter V of the rotorcraft 1 and to a second measurement system 42 for measuring a current value of a power parameter W of the power plant 90 .
The speed parameter V is selected from a list comprising at least: an air speed and a ground speed.
Furthermore, the power parameter is selected from a list comprising at least: total power developed by the engines 91 of the power plant; total torque generated by the engines 91 of the power plant; power transmitted to the main gearbox 92 ; torque transmitted to the main gearbox 92 ; and torque exerted on a mast 93 for driving the main rotor.
Depending on the method applied, the deflection angle of the airfoil is controlled with the help of the processor unit 30 and the mover means 35 as a function of a current value of a speed parameter V measured using the first measurement system and of a current value of a power parameter W measured using the second measurement system.
FIG. 5 explains the operation of the rotorcraft and the method that is applied.
According to the invention, the airfoil 25 is placed at a large negative deflection angle, e.g. during a stage of descending flight with the rotorcraft flying at high speed or in auto-rotation. A negative deflection angle is represented by the airfoil drawn in dashed lines.
With a negative deflection angle, the airfoil tends to reduce the lateral lift generated by the tail fin, as represented by vector 111 ″. The vector 111 ″ of this lateral thrust is directed towards the second side 7 and is short in length, and it may potentially be directed towards the first side in the event of thrust becoming negative. Conversely, the airfoil 25 is placed at a positive deflection angle 200 during a climbing stage of flight. A positive deflection angle is represented by the airfoil drawn in continuous lines.
With a positive deflection angle, the airfoil tends to increase the lateral lift generated by the tail fin by directing it towards the second side 7 in order to counter the rotor torque. More precisely, the vector 111 ′ of this lateral thrust is directed towards the second side 7 and presents a length that is considerable. It is also possible to position the airfoil 25 at a small negative deflection angle during a stage of descending flight with the rotorcraft at low speed.
Furthermore, a first adjustment zone Z1 is defined in which the deflection angle is at a maximum and reaches a positive threshold angle δmax. This first zone Z1 is reached at a forward speed less than a speed referred to as a “third” speed V3.
In addition, a second zone Z2 is defined at which the deflection angle 200 is at a maximum and reaches a positive threshold angle δmax. This second zone Z2 is reached when the following two conditions are satisfied:
the forward speed of the rotorcraft is an intermediate forward speed lying between the third speed V3 and a “first” speed V1 that is greater than the third speed V3; and
the power developed by the power plant is high, being greater than a “second” power W2.
The processor unit then positions the airfoil at this positive threshold angle δmax when the rotorcraft is flying in the first zone Z1 or the second zone Z2.
A third zone Z3 is also defined in which the deflection angle 200 is equal to a medium deflection, this third zone Z3 being reached at a high forward speed at high power. This medium deflection is close to zero, e.g. lying in the range minus 5 degrees to plus 5 degrees, and may possibly be equal to zero.
The processor unit then positions the airfoil at a medium orientation close to zero when the following two conditions are satisfied:
the forward speed of the rotorcraft is faster than a second speed V2 that is faster than the first speed V1; and
the power developed by the power plant is greater than the second power W2.
A fourth zone Z4 is also defined in which the deflection angle 200 is small, reaching a negative threshold value δmin. This fourth zone Z4 is reached at a high forward speed and at low power developed by the power plant.
The processor unit then positions, the airfoil at a negative threshold value δmin when the following two conditions are satisfied:
the forward speed of the rotorcraft is faster than a fourth speed V4 lying between the first speed V1 and the third speed V3; and
the power developed by the power plant is less than the first power W1.
By way of example, the processor unit controls the deflection of the airfoil 25 using a relationship L giving a target angle for the airfoil 25 as a function of the speed parameter V of the rotorcraft 1 and of the power parameter W. This relationship L may possibly correspond to the following equations:
δ 1 = { V < V 1 -> δ ma x V 1 ≤ V < V 2 -> [ sw ] · ( A · V + B ) + [ δ ma x - [ sw ] · ( A · V + B ) ] · { 1 - [ sin ( π 2 · V - V 1 V 2 - V 1 ) ] 2 } V 2 ≤ V -> [ sw ] · ( A · V + B )
δ 2 = { W < W 1 -> δ m i n W 1 ≤ W < W 2 -> δ 1 - [ δ 1 - δ m i n ] · { [ sin ( π 2 · W - W 2 W 2 - W 1 ) ] 2 } W 2 ≤ W -> δ 1
δ = { V > V 4 -> δ 2 V 3 < V ≤ V 4 -> δ ma x - [ δ ma x - δ 2 ] · { [ sin ( π 2 · V - V 3 V 4 - V 3 ) ] 2 } V ≤ V 3 -> δ ma x
where:
“δ” represents the target angle;
“δ1” and “δ2” represent calculation parameters;
“δmax” and “δmin” represent respectively the predetermined positive threshold angle and negative threshold angle;
“V1”, “V2”, “V3”, and “V4” respectively represent first, second, third, and fourth speeds predetermined by the manufacturer;
“V” represents the current value of the speed parameter;
“W1” and “W2” respectively represent the first and the second predetermined powers;
“W” represents the current value of the power parameter;
“sw” represents a predetermined adjustment parameter; and
“A” and “B” represent variables that are functions of said adjustment parameter.
In the implementation of FIG. 6 , the adjustment parameter sw is equal to a predetermined value, e.g. 0. The deflection angle 200 is then equal to the target angle δ.
The relationship L then serves to define a sheet presenting the deflection angle plotted along a vertical first axis AX1, the power parameter W plotted along a horizontal second axis AX2, and the speed parameter plotted along a third axis AX3.
This sheet makes it possible to reach the first zone Z1, the second zone Z2, the third zone Z3, and the fourth zone Z4, together with transition areas between these zones.
The processor unit then applies the relationship L directly in order to determine the deflection angle.
FIG. 7 shows a second implementation.
In this second implementation, the processor unit determines a maximum angle 400 equal to the target angle in applying the relationship L while giving a first value to the adjustment parameter sw. The maximum angle 400 is then in the form of an upper sheet in FIG. 7 .
Furthermore, the processor unit determines a minimum angle 500 equal to the target angle by applying the relationship L and giving a second value to the adjustment parameter sw. The minimum angle 500 then gives a sheet having the lower shape in FIG. 7 .
These lower and upper sheets put limits on the deflection angle.
Under such circumstances, the current collective pitch of the blades 11 of the auxiliary rotor 10 is measured using a conventional pitch measurement device that is connected to the processor unit.
Thereafter, the processor unit controls means for modifying the pitch of the blades 11 , such as an autopilot system. The processor unit then requests an increase in the deflection angle 200 of the airfoil 25 so as to cause it to tend towards the maximum angle 400 so long as said pitch is greater than a predetermined setpoint pitch.
Conversely, the processor unit requests a decrease in the deflection angle 200 of the airfoil 25 by causing it to tend towards the minimum angle 500 so long as said pitch is less than the predetermined setpoint pitch.
In parallel, the autopilot system automatically modifies said pitch in parallel with modification to the deflection angle 200 , in order to compensate for the modification in the deflection angle.
The processor unit may optionally inhibit any modification to the deflection angle 200 whenever the pilot is operating the control means 50 .
This implementation enables the airfoil to be controlled in a manner that is transparent for the pilot. Pilot action on the control means 50 then stops this implementation being performed so as to leave full authority to the pilot.
Naturally, the present invention may be subjected to numerous variations as to its implementation. Although several implementations are described, it will readily be understood that it is not conceivable to identify exhaustively all possible implementations. It is naturally possible to envisage replacing any of the means described by equivalent means without going beyond the ambit of the present invention.
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A rotorcraft extends longitudinally along a first anteroposterior plane separating a first side from a second side of the rotorcraft. The rotorcraft includes at least one main rotor, an auxiliary rotor, and at least one steerable airfoil. The rotorcraft further includes a processor unit connected to a first measurement system configured to measure a current value of a speed parameter (V) of the rotorcraft and to a second measurement system configured to measure a current value of a power parameter (W) of a power plant of the rotorcraft. The processor unit is configured to adjust the deflection angle of the airfoil as a function of the current speed and power parameter values (V, W) to cause the auxiliary rotor to move towards at least one predetermined operating point which optimizes performance of the rotorcraft and minimizes noise generated by the auxiliary rotor.
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FIELD OF THE INVENTION
The invention is directed to pharmaceuticals useful in diseases characterized by unwanted matrix metalloproteinase activity.
BACKGROUND OF THE INVENTION
A number of small peptide like compounds which inhibit metalloproteinase have been described. Perhaps the most notable of these are those relating to the angiotensin converting enzyme (ACE) where such agents act to blockade the conversion of the decapeptide angiotensin I to angiotensin II, a potent pressor substance. Compounds of this type are described in EP-A-0012401.
Certain hydroxamic acids have been suggested as collagenase inhibitor as in U.S. Pat. No. 4,599,361; WO-A-9005716 and WO-A-9005719. Other hydroxamic acids have been prepared as ACE inhibitors, for example, in U.S. Pat. No. 4,105,789, while still others have been described as enkephalinase inhibitors as in U.S. Pat. No. 4,495,540.
The hydroxamic and carboxylic acids of the current invention act as inhibitors of mammalian matrix metalloproteinases (MMPs). The MMPs include, for example, collagenase, stromelysin and gelatinase. Since the MMPs are involved in the breakdown of the extracellular matrix of articular cartilage (Arthritis and Rheumatism, 20, 1231-1239, (1977)), potent inhibitors of the MMPs may be useful in the treatment of arthritides, for example, osteoarthritis and rheumatoid arthritis and other diseases which involve the breakdown of extracellular matrix. These diseases include corneal ulceration, osteoporosis, periodontitis, tumor growth and metastasis.
The use of hydroxamic acid derivatives for the effective inhibition of the destruction of articular cartilage as a model of rheumatoid and osteoarthritis has been demonstrated (Int. J. Tiss. Reac., XIII, 237-243 (1991)).
Topical application of hydroxamate inhibitors may be effective against corneal ulceration as demonstrated in the alkali-injured cornea model (Invest. Ophthalmol Vis. Sci., 33, 33256-3331 (1991)).
In periodontitis, the effecticeness of tetracycline has been attributed to its collagenase inhibitory activaty (J. Perio. Res., 28, 379-385 (1993)).
Hydroxamic acid derivatives have also been effective in models of tumor growth (Cancer Research, 53, 2087-2091 (1993)) and tumor invasion (Mol. Cell Biol., 9, 2133-2141 (1989)).
The current invention relates to a series of hydroxamic and carboxylic acids, which act as inhibitors of matrix metalloproteinases, their preparation, pharmaceutical compositions containing them, and the intermediates involved in their preparation.
SUMMARY OF THE INVENTION
This invention provides compounds which are matrix metalloproteinase inhibitors. The compounds have the structure: ##STR1## wherein A is A 1 --A 2 --A 3
A 1 is C 1-10 alkyl, C 2-10 alkene, C 2-10 alkyne having C 1-5 in the backbone or a chemical bond;
A 2 is X--Y--Z; wherein
X is a chemical bond, --O--, --NH--, or --S--;
Y is --CO--, or --CHR 9 ; and
Z is --O--, --NH--, --S--, or a chemical bond;
A 3 is hydrogen, C 1-6 alkyl, substituted C 1-6 alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, aryl C 1-6 alkyl, substituted aryl C 1-6 alkyl, heterocyclic C 1-6 alkyl, heteroaryl C 1-6 alkyl, substituted heteroaryl C 1-6 alkyl, or substituted heterocyclic C 1-6 alkyl;
with the proviso that
(a) at least one of X, Y and Z must contain a heteroatom;
(b) when Y is --CH 2 --, then only one of X and Z can be a heteroatom;
(c) when Y is --CO-- and both X and Z are heteroatoms, then one must be --NH-- and the other --NH-- or --O--;.
(d) when A 1 is alkyl, X is --O-- or --S--, Y is CHR 9 and Z is a chemical bond, then A 3 cannot be H or C 1-6 alkyl;
(e) when A 1 is alkyl, X is a chemical bond, Y is CHR 9 and Z is --O-- or --S--, then A 3 cannot be C 1-6 alkyl;
(f) when A 1 is a chemical bond, X is O or S, Y is CH 2 , and Z is a chemical bond, then A 3 cannot be aryl or aryl C 1-6 alkyl;
(g) when A 1 is a chemical bond, X is a chemical bond, Y is CO, and Z is O, then A 3 cannot be H, alkyl, aryl, aryloxyalkyl, alkanoyloxyalkyl or aroyloxyalkyl; or
(h) when A 1 is a chemical bond, X is a NH, Y is CH 2 , and Z is a chemical bond, then A 3 cannot be alkyl, aryl, arylalkyl, cycloalkyl, or cycloalkyl alkyl;
R 1 is HN(OH)CO--, HCON(OH)--, CH 3 CON(OH)--, HO 2 C--, HS--, or phosphinate;
R 2 is OR 6 or NR 10 R 6
where R 6 is hydrogen, C 6-12 aryl, or (CH 2 ) n R 7 ,
wherein R 7 is hydrogen, phenyl, substituted phenyl, hydroxy, C 1-6 alkoxy, C 2-7 acyloxy, C 1-6 alkylthio, phenylthio, sulfoxide of a thio, sulfone of a thio, carboxyl, (C 1-6 alkyl) carbonyl, (C 1-6 alkoxy) carbonyl, (C 1-6 alkyl)aminocarbonyl, arylaminocarbonyl, amino, substituted acyclic amino, heterocyclic amino, N-oxide of an amine, or C 2-7 acylamino, and n is 1 to 6; or
R 3 and R 6 taken together are a group of the formula --(CH 2 ) m -- where m is from 5 to 12, optionally interrupted by a NR 8 group
where R 8 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, aryl, aralkyl, or aralkyloxycarbonyl, in each of which the aryl moiety is optionally substituted;
R 3 is a characterizing group of an alpha amino acid, C 1-6 alkyl, aryl methylene, substituted aryl methylene, C 3-10 cycloalkyl, C 3-10 cycloalkyl methylene, aryl, substituted aryl, fused bicycloaryl methylene, fused substituted bicycloaryl methylene, conjugated bicycloaryl methylene, or conjugated substituted bicycloaryl methylene;
R 4 is hydrogen or C 1-4 alkyl;
R 5 is hydrogen, phenyl, substituted phenyl, amino, hydroxy, mercapto, C 1-4 alkoxy, C 1-6 alkylamino, C 1-6 alkylthio, C 1-6 alkyl or C 2-6 alkenyl,
optionally substituted by
alkyl, phenyl, substituted phenyl, heterocylic, substituted heterocyclic, amino, acylated amino, protected amino, hydroxy, protected hydroxy, mercapto, protected mercapto, carboxy, protected carboxy, or amidated carboxy;
R 9 is hydrogen or C 1-4 alkyl;
R 10 is hydrogen or C 1-4 alkyl;
and the salts, solvates and hydrates thereof.
Preferred compounds have the structure: ##STR2## wherein A is A 1 --A 2 --A 3
wherein
A 1 is (CH 2 ) n , and n is 3-5,
A 2 is X--Y--Z,
wherein,
X is a chemical bond or --NH--;
Y is --(C═O)--, --CH 2 --, --(CHCH 3 )--,
Z is --O--, --NH--, or a chemical bond; and
A 3 is
hydrogen, methyl, ethyl, propyl, butyl, pentyl, phenyl, methylphenyl, chlorophenyl, methoxyphenyl, phenylmethylene, methoxyphenylmethylene, methylphenylmethylene or phenylethylene;
R 1 is HO 2 C-- or HN(OH);
R 3 is
tertiary butyl, phenylmethylene, cyclohexyl methylene, or 3,5 dimethyl phenylmethylene;
R 4 is hydrogen or methyl;
R 5 is hydrogen, methyl, 2-methylpropyl, or 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl; and
R 6 is
methyl,
2-pyridylethylene,
phenylethylene,
4-sulfamoyl phenylethylene, or
morpholino-N-ethylene;
Even more preferred are compounds wherein A is
--(CH 2 ) 4 --O--H,
--(CH 2 ) 3 --C═O--O--H,
--(CH 2 ) 3 --C═O--NH--(CH 2 ) 2 CH 3 ,
--(CH 2 ) 3 --C═O--NH--(CH 2 ) 2 -phenyl
--(CH 2 ) 3 --CH(CH 3 )--O--H,
--(CH 2 ) 4 --NH--C═O--(CH 2 ) 2 CH 3 ,
--(CH 2 ) 4 --O-phenyl,
--(CH 2 ) 4 --O-(4-chlorophenyl),
--(CH 2 ) 4 --O-(3-methylphenyl),
--(CH 2 ) 4 --O-(4-methoxyphenyl),
--(CH 2 ) 4 --O-(4-methylphenyl),
--(CH 2 ) 5 --O-phenyl,
--(CH 2 ) 4 --O--CH 2 -phenyl,
--(CH 2 ) 5 --O--CH 2 -(4-methylphenyl), or
--(CH 2 ) 3 --O--CH 2 -(4-methylphenyl).
Included in the invention are pharmaceutical compositions comprising an effective amount of at least one of the compounds and methods of promoting an antiarthritic effect in a mammal in need thereof comprising administering thereto a matrix metalloproteinase inhibitory effective amount of at least one compound of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Hereafter in this specification the term "compound" includes salt solvates and hydrates unless the context requires otherwise.
As used herein the term "C 1-6 alkyl" refers to a straight or branched chain alkyl moiety having from one to six carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl and the like.
The term "C 2-6 alkenyl" refers to a straight or branched chain alkyl moiety having two to six carbons and having in addition one double bond, of either E or Z stereochemistry where applicable. This term would include, for example, vinyl, 1-propenyl, 1- and 2-butenyl, 2-methyl-2-propenyl etc.
The term "cycloalkyl" refers to a saturated alicyclic moiety having from 3 to 8 carbon atoms and includes for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
The term "heterocyclic" refers to a saturated or unsaturated ring containing at least one hetero atom such as nitrogen, oxygen or sulphur and includes for example, furan, pyrrole, thiophen, morpholine, pyridine, dioxane, imidazoline, pyrimidine, pyridazine and the like.
The term "substituted", as applied to a phenyl or other aromatic ring, means substituted with up to four substituents each of which independently may be C 1-6 alkyl, C 1-6 alkoxy, hydroxy, thiol, C 1-6 alkylthiol, amino, substituted amino, halo (including fluoro, chloro, bromo and iodo), trifluoromethyl, nitro, --COOH, --CONH 2 or --CONHR A , wherein R A represents a C 1-6 alkyl group or an amino acid such as alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine or histidine.
The term "amino acid" means one of the following R or S alpha-amino acids: glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid and aspartic acid.
Derivatives of amino acids include acid halides, esters and substituted or unsubstituted amides, for example N-methyl amide.
There are several chiral centers in the compounds according to the invention because of the presence of asymmetric carbon atoms.
The presence of several asymmetric carbon atoms gives rise to a number of diastereomers with the appropriate R or S stereochemistry at each chiral center. The invention is understood to include all such diastereomers and mixtures thereof.
Preferred compounds include the following:
a/ N- (2R)-2- 2'-(Hydroxyamino)-2'-(oxo)ethyl!-5-(carboxy)pentanoyl!-L-phenylalanine N-methylamide;
b/ N- (2R)-2- 2'-(Hydroxyamino)-2'-(oxo)ethyl!-6-(phenylmethoxy)hexanoyl!-L-phenylalanine N-methylamide;
c/ N- (2R)-2- 2'-(Hydroxyamino)-2'-(oxo)ethyl!-6-(propylamino)-6-(oxo)hexanoyl!-L-phenylalanine N-methylamide;
d/ N- (2R)-2- 2'-(Hydroxyamino)-2'-(oxo)ethyl!-(6RS)-6-(hydroxy)heptanoyl!-L-phenylalanine N-methylamide;
e/ (2S)-N-2- (2'R)-2'- 2"-(Hydroxyamino)-2"-(oxo)ethyl!-6'-(hydroxy)hexanoyl!amino-3,3-dimethylbutanoic acid N-methylamide;
f/ (2S)-N-2- (2'R)-2'- 2"-(Hydroxyamino)-2"-(oxo)ethyl!-6'-(phenylmethoxy)hexanoyl!amino-3,3-dimethylbutanoic acid N-methylamide;
g/ N- (2'R)-2- 2'-(Hydroxyamino)-2'-(oxo)ethyl!-6-(4'-oxobutylamino)hexanoyl!-L-phenylalanine N-methylamide;
h/ 2(S)-N-2- (2'R)-2'- 2"-(Hydroxyamino)-2"-(oxo)ethyl!-6'-(oxo)-6'-(propylamino)hexanoyl!amino-3,3-dimethylbutanoic acid N-methylamide;
i/ N- (2R)-2- (1'S)-1'-(Methyl)-2'-(hydroxyamino)-2'-(oxo)ethyl!-6-(phenylmethoxy)hexanoyl!-L-phenylalanine N-methylamide;
j/ N- (2R)-2- (1'S)-1'-(Methyl)-2'-(hydroxyamino)-2'-(oxo)ethyl!-6-(oxo)-6-(propylamino)hexanoyl!-L-phenylalanine N-methylamide;
k/ (2S)-N-2 (2'R)- (1"R)-1"-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl-2"-(hydroxyamino)-2"-(oxo)ethyl!-6'-(phenylmethoxy)hexanoyl!amino-3,3-dimethylbutanoic acid N-methylamide;
l/ N- (2R)-2- 2'-(Hydroxyamino)-2'-(oxo)ethyl!-6-(oxo)-6-(propylamino)hexanoyl!-L-phenylalanine N-2-phenylethylamide;
m/ (2S)-N-2- (2'R)-2'- (1"S)-1"-(Methyl)-2"-(hydroxyamino)-2"-(oxo)ethyl!-6-(phenylmethoxy)hexanoyl!amino-3,3-dimethylbutanoic acid N-2-phenylethylamide;
n/ (2S)-N-2- (2'R)-2'- (1"S)-1"-(Methyl)-2"-(hydroxyamino)-2"-(oxo)ethyl!-6'-(oxo)-6'-(propylamino)hexanoyl!amino-3,3-dimethylbutanoic acid N-2-phenylethylamide;
o/ (2S)-N-2- (2'R)-2'- (1"S)-1"-(Methyl)-2"-(hydroxyamino)-2"-(oxo)ethyl!-6'-(oxo)-6'-(propylamino)hexanoyl!amino-3,3-dimethylbutanoic acid N-2-(4'-sulfamoyl) phenylethylamide;
p/ (2S)-N- (2'R)-2'- 2"-(Hydroxyamino)-2"-(oxo)ethyl!-6'-(phenylmethoxy)hexanoyl!amino-3-cyclohexylpropionic acid N-2-(4'-sulfamoyl)phenylethylamide;
q/ N- (2R)-2- 2'-(Hydroxyamino)-2'-(oxo)ethyl!-6'-(phenylmethoxy)hexanol!-L-(3,5-dimethyl)phenylalanine N-2-(4'-sulfamoyl)phenylethylamide;
r/ (2S)-N-2'- (2'R)-2'- 2"-(hydroxyamino)-2"-(oxo)ethyl!-6'- (4-methoxy)phenoxy!hexanoyl!amino-3,3-dimethylbutanoic acid N-2-(4'-sulfamoyl)phenylethylamide;
s/ (2S)-N-2'- (2'R)-2'- 2"-(hydroxyamino)-2"-(oxo)ethyl!-6'- (4-methyl)phenoxy!hexanoyl!amino-3,3-dimethylbutanoic acid N-2-(4'-sulfamoyl)phenylethylamide;
t/ (2S)-N-2'- (2'R)-2'- 2"-(Hydroxyamino)-2"-(oxo)ethyl!-6'- (1-oxo)butylamino!hexanoyl!amino-3-cyclohexylpropionic acid N-2-(4'-sulfamoyl)phenylethylamide;
u/ (2S)-N-2- (2'R)-2'- (1"S)-1"-(Methyl)-2"-(hydroxyamino)-2"-(oxo)ethyl!-6-(phenylmethoxy)hexanoyl!amino-3,3-dimethylbutanoic acid N-methylamide;
v/ (2S)-N-2- (2'R)-2'- (1"S)-1"-(2-Methylpropyl)-2"-(hydroxyamino)-2"-(oxo)ethyl!-6-(phenylmethoxy)hexanoyl!amino-3,3-dimethylbutanoic acid N-methylamide;
w/ N- (2R)-2- 2'-(Hydroxyamino)-2'-(oxo)ethyl!-6-(phenoxy)hexanoyl!-L-phenylalanine N-methylamide;
x/ N- (2R)-2- 2'-(Hydroxyamino)-2'-(oxo)ethyl!-7-(phenoxy)heptanoyl!-L-phenylalanine N-methylamide;
y/ (2S)-N-2'- (2'R)-2'- 2"-(Hydroxyamino)-2"-(oxo)ethyl!-6'-(phenylmethoxy)hexanoyl!amino-3,3-dimethylbutanoic acid N-2-phenylethylamide;
z/ (2S)-N-2'- (2'R)-2'- 2"-(Hydroxyamino)-2"-(oxo)ethyl!-6'-(phenylmethoxy)hexanoyl!amino-3,3-dimethylbutanoic acid N-2-(4'-sulfamoyl)phenylethylamide;
aa/ N- (2R)-2- 2'-(Hydroxyamino)-2'-(oxo)ethyl!-5-(phenylmethoxy)pentanoyl!-L-phenylalanine N-methylamide;
ab/ N- (2R)-2- 2'-(Hydroxyamino)-2'-(oxo)ethyl!-7-(phenylmethoxy)heptanoyl!-L-phenylalanine N-methylamide;
ac/ N- (2R)-2- 2'-(Hydroxyamino)-2'-(oxo)ethyl!-6-(phenyloxy)hexanoyl!-L-phenylalanine N-methylamide;
ad/ N- (2R)-2- 2'-(Hydroxyamino)-2'-(oxo)ethyl!-7- (phenyloxy)heptanoyl!-L-phenylalanine N-methylamide;
ae/ (2S)-N-2'- (2'R)-2'- 2"-(Hydroxyamino)-2"-(oxo)ethyl!-6'- (2-phenethylamino)-6'(oxo)hexanoyl!amino-3,3-dimethylbutanoic acid N-methylamide;
af/ (2S)-N-2'- (2'R)-2'- 2"-(Hydroxyamino)-2"-(oxo)ethyl!-6'- (4-methylphenoxy)hexanoyl!amino-3,3-dimethylbutanoic acid N-methylamide;
ag/ (2S)-N-2'- (2'R)-2'- 2"-(Hydroxyamino)-2"-(oxo)ethyl!-6'- (4-chlorophenoxy)hexanoyl!amino-3,3-dimethylbutanoic acid N-methylamide;
ah/ (2S)-N-2'- (2'R)-2'- 2"-(Hydroxyamino)-2"-(oxo)ethyl!-6'- (3-methylphenoxy)hexanoyl!amino-3,3-dimethylbutanoic acid N-methylamide; and
ai/ (2S)-N-2'- (2'R)-2'-(carboxymethyl)-6'-(3-methylphenoxy)hexanoyl!amino-3,3-dimethylbutanoic acid N-methylamide.
Compounds of the invention may be prepared by any suitable method known in the art and/or by the following process, which itself forms part of the invention.
According to another aspect of the invention, there is provided a process for preparing compounds of the invention as defined above.
The following is a schematic for the preparation of a common intermediate used to prepare compounds of the invention by various routes. ##STR3##
In a further aspect of the invention there is provided the use of a compound of invention in medicine, particularly in a method of treatment of diseases in which collagenolytic activity is important.
In another aspect of the invention there is provided the use of a compound of the invention in the preparation of an agent for the treatment of diseases in which collagenolytic activity is important.
The invention also provides a pharmaceutical composition comprising one or more compounds of the invention in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants. Other active ingredients may also be included in the compositions of the invention.
The compositions of the present invention may be formulated for administration by any route depending on the disease being treated. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parental solutions or suspensions.
Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients. Examples of these are binding agents such as syrup, acacia, gelatin, sorbitol, tragacanth, and polyvinylpyrollidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tableting lubricants, for example, magnesium sterate, talc, polyethylene glycol or silica; disintegrants, for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydrogenated edible fats; emulsifiying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavoring or coloring agents.
The dosage unit involved in oral administration may contain from about 1 to 250 mg, preferably from about 25 to 250 mg. A suitable daily dose for a mammal may vary widely depending on the condition of the patient. However, a dose of about 0.1 to 300 mg/kg body weight, particularly from about 1 to 100 mg/kg body weight may be appropriate.
For topical application to the skin, the drug may be made up into a cream, lotion or ointment. Cream or ointment formulations that may be used for the drug are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics such as the British Pharmacopoeia.
For topical applications to the eye, the drug may be made up into a solution or suspension in a suitable sterile aqueous or nonaqueous vehicle. Additives, for instance buffers such as sodium metabisulphite; preservatives including bactericidal and fungicidal agents, such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorohexidine, and thickening agents such as hydrocellulose may also be included.
The dosage employed for the topical administration will, of course, depend on the size of the area being treated.
The active ingredient may also be administered parenterally in a sterile medium. The drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anaesthetic, preservatives and buffering agents can be dissolved in the vehicle.
For use in the treatment of rheumatoid arthritis, the compounds of this invention can be administered by the oral route or by injection intra-articularly into the affected joint. The daily dosage for a 70 kg mammal will be in the range of 1 mgs to 1 gram.
EXAMPLE 1
PREPARATION OF INTERMEDIATES
1a. Synthesis of 6-Phenylmethoxyhexane-1-ol.
Hexane-1,6-diol 25 g, 0.21 mol! is dissolved in dry/distilled THF (300 mL) under a N 2 atmosphere. 80% NaH 6.3 g, 0.21 mol! is then added with vigorous stirring in small portions over ˜10-20 minutes Evolution of gas (H 2 ) is noted. The reaction is heated to reflux with continued vigorous stirring for 4.5 hours resulting in the formation of a thick gray-colored solid. Benzyl bromide 25 mL, 0.21 mol! is added in one portion, and the reaction is allowed to reflux for ˜22 hours The solid mass is replaced by a white-colored solid (NaBr) which is filtered from the reaction after cooling to room temperature. The solid is washed with THF and the combined filtrates are evaporated, leaving a yellow oil. The oil is taken up in Et 2 O, and washed successively with distilled water until there is no indication of the starting diol (as determined by TLC) and then washed with brine. The organic layer is dried over Na 2 SO 4 and the Et 2 O is evaporated. The resulting oil is a mixture of the di- and mono-benzylated hexanol (approximately a 2:1 ratio of mono to di-benzylated based on 1 H-NMR data, 38.05 g, 60% yield). The mixture is used without further purification in the next step. Isolation of a small amount of mono benzylated product gives the following data; 1 H-NMR (CDCl 3 ): δ1.3-1.7 (m, 9H, --(CH 2 ) 4 and --OH), 3.5 (t, 2H, --CH 2 OCH 2 Ph), 3.64 (t, 2H, --CH 2 OH), 4.5 (s, 2H, --OCH 2 Ph), 7.3 (m, 5H, Ar).
1b. Synthesis of 6-Phenylmethoxyhexanoic acid
A solution of compound obtained in example 1a (38 g, 0.114 mol) in 50 mL of dry DMF is added dropwise to a solution of DMF (300 mL) containing pyridinium dichromate (128 g, 0.342 mol) The reaction is slightly exothermic and so is maintained at 10°-20° C. for the first few hours of the reaction. The reaction is stirred for 9 hours at room temperature. The reaction is diluted with 2.5L H 2 O and extracted 10 times with EtOAc (150 mL) which is in turn washed with H 2 O. Remaining PDC is removed by filtering the EtOAc extractions through anhydrous MgSO 4 . The organic layer is then extracted with 1N NaOH (5 times). The combined basic extractions are washed with several portions of fresh EtOAc. The basic layer is then slowly acidified with concentrated HCl to a pH 2-3 and extracted 5 times with EtOAc. The combined organic layers are dried over Na 2 SO 4 and the solvent is evaporated to afford pure acid (˜75% yield).
1 H-NMR (CDCl 3 ): δ1.45 (m, 2H, --CH 2 ), 1.65 (m, 4H, --(CH 2 ) 2 ), 2.35 (t, 2H, --CH 2 COOH), 3.37 (t, 3H, --CH 2 OCH 2 Ph), 4.5 (s, 2H, --OCH 2 Ph), 7.3 (m, 5H, Ar).
1c. Synthesis of 6-phenylmethoxyhexanoyl chloride
30.52 g of the compound of Example 1b 0.14 mol! is dissolved in dry CH 2 Cl 2 and cooled to 0° C. Oxalyl chloride 13.09 mL, 0.154 mol! is added in one portion. Some minor gas evolution (CO 2 ) is observed. ˜5 drops of dry DMF is added with stirring and the gas evolution is noticeably more vigorous. The reaction is allowed to stir while warming to room temperature until no more bubbling is observed and then stirred ˜30 minutes more. The solvent and remaining oxalyl chloride is removed under vacuum. A yellow oil with some solid dispersed in it remains. The oil is filtered through a dry filter, then is placed on high vacuum suction until used in the next step (29.6 g, 90+% yield).
1 H-NMR (CDCl 3 ): δ1.37 (m, 2H, --CH 2 ), 1.7 (m, 4H, --(CH 2 ) 2 ), 2.9 (t, 2H, --CH 2 COCl), 3.5 (t, 2H, --CH 2 OCH 2 Ph), 4.5 (s, 2H, --OCH 2 Ph), 7.35 (m, 5H, Ar).
1d. Synthesis of (4S)-4-benzyl-3- (6'-phenylmethoxy)hexanoyl!-2-oxazolidone
(S)-(-)-4-benzyl-2-oxazolidinone 21.08 g, 0.12 mol! is dissolved in dry/distilled THF (250 mL) under a N 2 atmosphere and cooled to -78° C. A solution of 1.6M n-butyl lithium in hexane (n-BuLi) 74.77 mL, 0.12 mol! is added dropwise with stirring while maintaining the reaction between -65° C. to -78° C. Near the end of this addition, the reaction is observed to turn a deeper yellow color, indicating benzylic protons being deprotonated and that enough n-BuLi has been added. The reaction is allowed to stir at -78° C. for 25 minutes, then 28.8 g of the compound of example 1c 0.12 mol! in THF (100 mL) is added dropwise, maintaining the reaction near -78° C. The deep yellow color of the reaction lightens with the addition. The reaction is allowed to gradually warm to room temperature and then is quenched with the addition of a saturated solution of NH 4 Cl (150 mL). The THF is evaporated and the residue is extracted into Et 2 O which is washed with 0.5 N NaOH (5 times), H 2 O, and finally brine. It is then dried over Na 2 SO 4 and evaporated to an oil residue which is purified by flash column chromatography to give 46.5 g (85% yield).
1 H-NMR (CDCl 3 ): δ1.5 (m, 2H, --CH 2 ), 1.7 (m, 4H,--CH 2 ) 2 ), 2.77 (dd, 1H, --CHCH 2 Ph), 2.95 (m, 2H, --CH 2 CON), 3.3 (dd, 1H, --CHCH 2 Ph), 3.5 (t, 2H, --CH 2 OCH 2 Ph), 4.17 (m, 2H, ring --CH 2 ), 4.5 (s, 2H, --OCH 2 Ph), 4.67 (m, 1H, ring --CH), 7.3 (m, 10H, Ar).
1e. Synthesis of (4S)-4-benzyl-3- (2'R)-2'-(tert-butoxycarbonylmethyl)-6'- phenylmethoxy)hexanoyl!-2-oxazolidone
Diisopropylamine 1.82 mL, 13 mmol! in dry/distilled THF (10 mL) is cooled to -15° C. under a N 2 atmosphere. A solution of 1.6M n-BuLi in hexane 8.12 mL, 13 mmol! is slowly added dropwise with stirring while maintaining the temperature below 0° C. The reaction is allowed to stir at 0° C. for 30 minutes and then cooled to -78° C. The product of example 1d 4.71 g, 12 mmol! in 50 mL THF is added dropwise with stirring while maintaining the temperature near -78° C. Stirring is continued for 30 minutes. A solution of t-butyl bromoacetate 1.8 mL, 12 mmol! in THF (25 mL) is then added dropwise at -78° C. Following addition, the reaction is allowed to warm to room temperature and then quenched cautiously with H 2 O. The THF is evaporated and the residue extracted into EtOAc. The organic layer is washed with 5% NaHCO 3 , 5% citric acid, and brine, and then dried over Na 2 SO 4 . The solvent is evaporated, and the resulting oil solidified on standing. The solid product is recrystalized with EtOAc/hexane several times, or alternatively, flash chromatography is used. This affords 3.21 g of a white fluffy crystal (55% yield).
1 H-NMR (CDCl 3 ): δ1.4-1.72 (s and m, 15H, t-butyl and --(CH 2 ) 3 ), 2.48 (dd, 1H, --COCH 2 CHCO), 2.75 (overlapping dd, 2H, one --COCH 2 CHCO and one --CHCH 2 Ph), 3.34 (dd, 1H, --CHCH 2 Ph), 3.45 (t, 2H, --CH 2 OCH 2 Ph), 4.15 (m, 3H, ring --CH 2 and --CH 2 CHCO), 4.48 (s, 2H, --OCH 2 Ph), 4.63 (m, 1H, ring --CH), 7.3 (m, 10H, Ar).
1f. Synthesis of (2R)-2-(tert-butoxycarbonylmethyl)-6-(phenylmethoxy) hexanoic acid
0.5 g of the compound of Example 1e is dissolved in 15 mL of a 4:1 THF/H 2 O solution and cooled to about 0° C., but not below, under a N 2 atmosphere. Slowly, dropwise and with stirring, 30% aqueous H 2 O 2 0.5 mL, 4.4 mmol! is added. After stirring 5 minutes, a solution of LiOH•H 2 O 0.07 g, 1.5 mmol! in 2 mL H 2 O is added dropwise. Some gas evolution is observed. The reaction is warmed slowly to room temperature and stirred for 1 hour, then a solution of Na 2 SO 3 0.2 g, 1.7 mmol! in 2 mL H 2 O is added dropwise. Some heat is evolved during this process, so the reaction is cooled with an ice bath. After stirring ˜20 minutes the THF is evaporated (below 30° C.) and the basic, aqueous mixture remaining is extracted with EtOAc (5 times). These combined extracts contain the free benzyl oxazolidinone which can be recrystalized and recycled for further use.
The basic layer is then cooled and acidified with the slow addition of concentrated HCl to a pH 2-3. The cloudy mixture is then extracted 5 times with EtOAc, dried over Na 2 SO 4 and evaporated to give 0.29 g of pure acid (86% yield).
1 H-NMR (CDCL 3 ): δ1.42-1.7 (s and m, 15H, 5-butyl and --(CH 2 ) 3 ), 2.37 (dd, 1H, --COCH 2 CHCO), 2.6 (dd, 1H, --COCH 2 CHCO), 2.8 (m, 1H, --COCH 2 CHCO), 3.45 (t, 2H, --CH 2 OCH 2 Ph), 4.5 (s, 2H, --OCH 2 Ph), 7.3 (m, 5H, Ar).
1g. Synthesis of N- (2R)-2-(tert-butoxycarbonylmethyl)-6-(phenylmethoxy) hexanoyl!-L-phenylalanine N-methylamide
A solution of the product of Example 1f (3.36 g, 0.01 mol) and L-phenylalanine N-methylamide TFA salt (2.9 g, 0.01 mol) in dry dimethylformamide (40 mL) under nitrogen are cooled to -6° C. and treated dropwise with diethylcyanophosphonate (1.63 g, 0.01 mol) followed by triethylamine (3.03 g, 0.03 mol). The reaction mixture is stirred at 0° C. for 1 hour, warmed to room temperature over 1 hour, and then stirred for two additional hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The combined ethyl acetate layers are sequentially washed with 5% citric acid, saturated sodium bicarbonate, water, and brine. The ethyl acetate is separated, dried (Na 2 SO 4 ), and evaporated. The residue is purified by silica gel column chromatography using 50-70% ethyl acetate in hexanes as the eluent. The appropriate fraction yielded 4.21 g of the product (85%).
1 H NMR (CDCl 3 ) δ1.20-180 (m, 15H, CCH 2 CH 2 CH 2 C and t-butyl H), 2.25-2.60 (m, 3H, CH 2 CO and CHCO), 2.65 (d, 3H, NCH 3 ), 3.38 (t, 2H, CCH 2 O), 3.07 (d, 2H, ArCH 2 C), 4.44 (s, 2H, OCH 2 Ar), 4.57 (q, 1H, NCH), 6.34 (q, 1H, NH), 6.52 (d, 1H, NH), 7.20-7.60 (m, 10H, ArH).
EXAMPLE 2
N- (2R)-2- 2'-(Hydroxyamino)-2'(oxo)ethyl!-6-(phenylmethoxy)hexanoyl!-L-phenylalanine N-methylamide
2a. Synthesis of N- (2R)-2-(carboxymethyl)-6-(phenylmethoxy)hexanoyl!-L-phenylalanine N-methylamide
A solution of the compound formed in Example 1g (0.33 g, 0.66 mmol) in trifluoroacetic acid (7 mL) and water (3 mL) is stirred at room temperature for 6 hours. The solvents are removed on a rotary evaporator. The residue is treated with acetonitrile and evaporated (three times) in order to azeotrope water. The crude product is placed on a high vacuum pump for 2 hours to give a gummy material, which is triturated with diethyl ether to produce a colorless solid. The solid was collected by filtration and air dried. (0.227 g, 78% yield).
1 H NMR(MeOH-d 4 ) δ0.80-1.50 (m, 6H, CCH 2 CH 2 CH 2 C), 2.00-2.60 (m, 6H, NCH 3 , CH 2 CO and CHCO), 2.74 (dd) and 2.92 (dd), (2H, CCH 2 Ar), 3.20 (t, 2H, OCH 2 C), 4.25 (m, OCH 2 Ar and NCH), 6.90-7.30 (m, 10H, ArH).
2b. Under nitrogen atmosphere, the carboxylic acid formed in Example 2a (0.44 g, 1.0 mmol) is dissolved in dry tetrahydrofuran (20 mL), and treated with N-methyl morpholine (0.13 g, 1.15 mmol) via syringe. The reaction mixture is cooled to -10° C. and treated with isobutylchloroformate (0.15 mL, 1.15 mmol) via syringe. After stirring the suspension for 20 minutes, O-(trimethylsilyl)hydroxylamine (0.12 mL, 1.15 mmol) is added via syringe and the reaction mixture is stirred in the cold for 3 hours. The ice bath is removed, the reaction mixture is filtered, and the filtrate is evaporated to a colorless solid. The solid is triturated with methylene chloride, collected by filtration, and air dried to give 0.27 g of a colorless solid (59% yield).
1 H NMR(MeOH-d 4 ) δ1.6-1.1 (m, 6H, CCH 2 CH 2 CH 2 C), 2.22 (dd, 1H) and 2.10 (dd, 1H) CH 2 CON, 2.60 (m, 1H, CH 2 CHCO), 2.64 (d, 3H, NHCH 3 ), 3.15 (dd, 1H) and 2.96 (dd, 1H, OCH 2 Ar), 3.40 (t, 2H, CH 2 OCH 2 Ar), 4.46 (s, 2H, ArCH 2 O), 4.49 (M, 1H, NCHCO), 7.35-7.10 (m, 10H), 7.90 (m, 1H), 8.20 (d, 1H).
EXAMPLE 3
N- (2R)-2- 2'-(hydroxyamino)-2'-(oxo)ethyl!-6-(hydroxy)hexanoyl!-L-phenylalanine N-methylamide
3a. Synthesis of N- (2R)-2-(tert-butoxycarbonylmethyl)-6-(hydroxy)hexanoyl!-L-phenylalanine N-methylamide
Under nitrogen atmosphere, a solution of the compound formed in Example 1g (2.5 g, 0.005 mol) in methanol (50 mL) is treated with ammonium formate (2.5 g) and 10% Pd/C (1.0 g). The mixture is heated to reflux for 4 hours at which point 2.5 g of ammonium formate is added and refluxing is continued for 2 hours. The heat is removed and the reaction mixture is allowed to stand overnight at room temperature. After 15 hours, ammonium formate (2.5 g) and 10% Pd/C (0.2 g) are added and the reaction mixture is heated at reflux for 4 hours. The reaction mixture is cooled and the catalyst is collected via filtration. The filtrate is evaporated to dryness and the residue is partitioned between water and ethyl acetate. The ethyl acetate layer is washed with water, then dried (Na 2 SO 4 ), filtered, and evaporated. The product is purified by silica gel column chromatography using 5% methanol in ethyl acetate as the eluent, (1.3 g, 64% yield).
1 H NMR (CDCl 3 ) δ1.00-1.70 (m, 15H, CCH 2 CH 2 CH 2 C and t-butyl H), 2.25-2.60 (m, 3H), 2.69 (d, 3H, NCH 3 ), 3.00-3.20 (m, 2H, CH 2 Ar), 3.50-3.70 (m, 2H, CH 2 O), 4.56 (q, 1H, NCH), 6.15 (m, 1H, NH), 7.13 (d, 1H, NH), 7.15-7.45 (m, 5H, ArH).
3b. Synthesis of N- (2R)-2-(Carboxymethyl)-6-(hydroxy)hexanoyl!-L-phenylalanine N-methylamide
The product formed in Example 3a (0.7 g, 1.72 mmol) is dissolved in 10 mL of a 7:3 trifluoroacetic acid-water mixture and stirred at room temperature for 4.5 hours The solvents are removed on a rotary evaporator and the residue is treated with acetonitrile and evaporated (three times) in order to azeotrope water. The colorless solid is dried on a high vacuum pump for 4 hours, then triturated with diethyl ether. The colorless solid is collected by filtration and dried. (0.6 g, 100% yield).
1 H NMR(MeOH-d 4 ) δ0.88-1.60 (m, 6H, CCH 2 CH 2 CH 2 C), 2.15-2.60 (m, 6H, NCH 3 , CH 2 CO and CHCO), 2.75 (dd) and 2.90 (dd) (2H, CH 2 Ar), 4.10 (t, 2H, CH 2 O), 4.30 (q, 1H, NCH), 6.90-7.30 (m, 5H, ArH), 7.58 (m, 1H, NH), 8.00 (d, 1H, NH).
3c. Under nitrogen atmosphere, the product of example 3b (0.245 g, 0.7 mmol) is dissolved in dry tetrahydrofuran (20 mL), cooled to -15° C. and treated with N-methylmorpholine (0.14 g, 1.33 mmol). After 5 minutes, isobutylchloroformate (0.18 g, 1.33 mmol) is added dropwise and the reaction mixture is stirred for 15 minutes. O-(trimethylsilyl)hydroxylamine (0.42 g, 3.9 mmol) is added dropwise. The reaction mixture is stirred at -15° C. for 1 hour, followed by 1 hour at 0° C., then 30 minutes at room temperature. The reaction mixture is filtered and the filtrate is evaporated to dryness. The residue is triturated first with diethyl ether followed by methylene chloride. The solid is collected by filtration and purified by preparative thin-layer chromatography using 15% methanol in methylene chloride as eluent, giving a colorless solid. (0.12 g, 25% yield).
1 H NMR(MeOH-d 4 ) δ0.80-1.50 (m, 6H, CCH 2 CH 2 CH 2 C), 1.80-2.10 (m, 2H, CH 2 CO), 2.30-2.44 (m, 1H, CHCO), 2.47 (s, 3H, NCH 3 ), 2.95 (dd) and 2.72 (dd) (2H, ArH), 3.25 (t, 2H, CH 2 O), 4.30 (q, 1H, NCH), 6.90-7.30 (m, 5H, ArH). Mass (FAB): 366(MH + )
EXAMPLE 4
N- (2R)-2- 2'-(Hydroxyamino)-2'-(oxo)ethyl!-5-(carboxy)pentanoyl!-L-phenylalanine N-methylamide
4a. Synthesis of N- (2R)-2- 2'-(Phenylmethoxyamino)-2'-(oxo)ethyl!-6-(hydroxy)hexanoyl!-L-phenylalanine N-methylamide
Under nitrogen atmosphere, the carboxylic acid product formed in Example 3b (0.035 g, 0.1 mmol) is dissolved in anhydrous dimethylformamide (1 mL) and treated with N-methylmorpholine (0.017 mL, 0.15 mmol). The reaction is cooled to -10° C. and treated dropwise with isobutylchloroformate (0.02 mL, 0.15 mmol). The reaction is stirred for 20 minutes, then a suspension of O-benzylhydroxylamine hydrochloride (0. 024 g, 0.15 mmol) and N-methylmorpholine (0.017 mL, 0.15 mmol) in dimethylformamide (1.5 mL) is added. After stirring 20 minutes, the ice bath is removed and the reaction mixture is stirred for 3 hours. The dimethylformamide is removed on a rotary evaporator and the residue is dissolved in ethyl acetate. The ethyl acetate is washed with 5% citric acid and 5% sodium bicarbonate, then dried (Na 2 SO 4 ), filtered, and evaporated. The solid is triturated with diethyl ether and collected by filtration to give 10 mg (2% yield) of compound.
1 H NMR (MeOH-d4) δ1.6-1.1 (m, 6H, CCH 2 CH 2 CH 2 C), 2.13 (m, 2H, CH 2 CHCO), 2.67 (m, 1H, CH 2 CHCO), 2.69 (d, 3H, NCH 3 ), 3.15 (dd) and 2.94 (dd), (2H, CH 2 Ar), 3.48 (t, 2H, CH 2 OH), 4.50 (m, 1H, NCHCO), 4.80 (s, 2H, ArCH 2 O), 7.4-7.17 (m, 10H, Ar), 7.94 (m, 1H, NH), 8.24 (d, 1H, NH).
4b. Synthesis of N- (2R)-2- 2'-(Phenylmethoxyamino)-2'-(oxo)ethyl!-5-(carboxy)pentanoyl!-L-phenylalanine N-methylamide
A solution of the compound of Example 4a (0.05 g, 0.11 mmol) in dimethylformamide (1 mL) is treated with pyridinium dichromate (0. 144 g, 0.38 mmol) at room temperature overnight. The reaction mixture is partioned between ethyl acetate and water. The aqueous layer is separated and extracted with ethyl acetate. The ethyl acetate extracts are combined, dried (Na 2 SO 4 ), filtered, and evaporated to a gum. Trituration with diethyl ether produces an off-white solid (0.023 g, 45% yield).
1 H NMR (MeOH-d4) δ1.6-1.1 (m, 6H, CCH 2 CH 2 CH 2 C), 2.27-2.02 (m, 4H, CH 2 CHCO and CH 2 COOH), 2.70 (m, 4H, NCH 3 and CH 2 CHCO), 3.15 (dd) and 2.92 (dd), (2H, CH 2 Ar), 4.55 (m, 1H, NCHCO), 4.80 (s, 2H, ArCH 2 O), 7.43-7.10 (m, 10H, Ar), 7.91 (m, 1H, NH), 8.24 (d, 1H, NH).
4c. A solution of the compound formed in Example 4b (0.023 g, 0.049 mmol) in ethanol (5 mL) is treated with 10% Pd/C (0.010 g) and pyridine (2 drops) under hydrogen atmosphere. After 32 hours, the reaction mixture is filtered to remove catalyst and the filtrate evaporated to a yellow oil and placed under high vacuum to give a gum. Trituration with diethylether produces an off-white solid, which is collected by filtration and dried under a nitrogen flow to give the final compound.
1 H NMR (MeOH-d4) δ1.91-1.35 (m, 6H, CCH 2 CH 2 CH 2 C), 2.30-2.10 (m, 4H, CH 2 CHCO and CH 2 COOH), 2.62 (m, 1H, CH 2 CHCO), 2.70 (s, 3H, NCH 3 ), 3.15 (m) and 2.95 (m), (4H), 4.52 (t, 1H, NCHCO), 7.36-7.15 (m, 5H, Ar).
EXAMPLE 5
N- (2R)-2- 2'-(Hydroxyamino)-2'-(oxo)ethyl!-6-(propylamino)-6-(oxo)hexanoyl!-L-phenylalanine N-methylamide
5a. Synthesis of N- (2R)-2-(tert-Butoxycarbonylmethyl)-5-(carboxy)pentanoyl!-L-phenylalanine N-methylamide
Pyridinium dichromate (0.658 g, 1.7 mmol) is added to a solution of the compound formed in Example 3a (0.203 g, 0.5 mmol) in DMF (2 mL) under a nitrogen atmosphere. The resulting mixture is stirred at room temperature for 16 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The combined ethyl acetate layers are washed with water and brine. The ethyl acetate is separated, dried (Na 2 SO 4 ), and evaporated. The gummy crude product (0.18 g) without any further purification is used in the next step.
1 H NMR (CDCl 3 ) δ1.10-1.80 (m, 13H, CCH 2 CH 2 C, t-butyl H), 2.20-2.80 (m, 8H), 3.00-3.20 (m, 2H), 4.68 (q, 1H, NCH), 6.50 (s, 1H), 7.00-7.60 (m, 5H, ArH).
5b. Synthesis of N- (2R)-2-(tert-Butoxycarbonylmethyl)-6-(propylamino)-6-(oxo)hexanoyl!-L-phenylalanine N-methylamide
A solution of the acid of example 5a (0.18 g, 0.43 mmol) and n-propylamine (0.1 g, 1.7 mmol) in dry DMF (5 mL) under nitrogen is cooled to -5° C. and treated dropwise with diethylcyanophosphonate (0.07 g, 0.43 mmol) followed by triethylamine (0.86 g, 0.85 mmol). The reaction mixture is stirred at 0° C. for 1 hour, then slowly allowed to come to room temperature during 1 hour. The reaction mixture is stirred at room temperature for 3 hours, then diluted with water and extracted with ethyl acetate and ether solvents. The combined organic layers are sequentially washed with 5% citric acid, saturated NaHCO 3 , water, and brine. The organic layer is separated, dried (Na 2 SO 4 ), and evaporated. The residue is triturated with diethyl ether to produce a white solid. The solid is collected by filtration and air dried to give 0.065 g. The overall yield for two steps is 28.3%.
1 H NMR (CDCl 3 ) δ0.91 (t, 2H, CH 2 CH 3 ), 1.30-1.80 (m, 15H, CCH 2 CH 2 C, CH 2 CH 3 , t-butyl H), 2.13 (t, 2H, CH 2 CON), 2.25-2.60 (m, 3H, CH 2 COO and CHCO), 2.71 (d, 3H, NCH 3 ), 3.05-3.30 (m, 4H, NHCH 2 Ar and CH 2 Ar), 4.62 (q, 1H, NCH), 5.98 (br signal, 1H, NH), 6.38 (br signal, 1H, NH), 6.70 (br signal, 1H, NH), 7.10-7.40 (m, 5H, ArH).
5c. Synthesis of N- (2R)-2-(Carboxymethyl)-6-(propylamino)-6-(oxo)hexanoyl!-L-phenylalanine N-methylamide
A solution of the compound formed in example 5b (0.06 g, 0.13 mmol) in trifluoroacetic acid (3.5 mL), and water (1.5 mL) is stirred at room temperature for 4 hours. The solvents are removed on a rotary evaporator. The residue is treated with acetonitrile and evaporated (three times) in order to azeotrope water. The white solid obtained is placed on a high vacuum pump for 1 hour. The product is triturated with diethyl ether. The product is collected by filtration and air dried to give 0.045 g (85.4% yield) of a white solid.
1 H NMR (MeOH-d 4 ) δ0.70 (t, 2H, CH 2 CH 3 ), 1.10-1.5 (m, 6H, CH 2 CH 3 and CCH 2 CH 2 C), 1.91 (t, 2H, CH 2 CON), 2.05-2.60 (m, 6H, CH 2 COO, CHCO and NCH 3 ), 2.70-3.00 (m, 4H, NHCH 2 and CH 2 Ar), 4.30 (q, 1H, NCH), 6.90-7.30 (m, 5H, ArH), 7.60 (m, 1H), 8.00 (d, 1H).
Mass (FAB): 406 (MH + )
5d. Under a nitrogen atmosphere, the carboxylic acid compound formed in example 5c (0.04 g, 0.1 mmol) in dry THF (10 mL) is cooled to -15° C. (solubility of the acid seems to be low in THF, at low temperature some acid precepitated out) and treated with N-methylmorpholine (0.02 g, 0.2 mmol). After five minutes, isobutylchloroformate, (0.027 g, 0.2 mmol) is added dropwise and the reaction mixture is stirred for 35 minutes. O-(trimethylsilyl)hydroxylamine (0.126 g, 1.2 mmol) is added dropwise. The reaction mixture is stirred at -15° C. for 1 hour, followed by 1 hour at 0° C., then 1.5 hours at room temperature. The reaction mixture is filtered and the precipitate washed several times with dichloromethane. The residue is once again taken into dichloromethane and stirred for 2 hours. The white solid is collected by filtration and dried in vacuo to give the final product.
1 H NMR (MeOH-d 4 ) δ0.70 (t, 3H, CH 2 CH 3 ), 1.10-1.50 (m, 6H, CH 2 CH 3 and CCH 2 CH 2 C), 1.80-2.10 (m, 4H, CH 2 COO and CH 2 CON), 2.30-2.60 (m, 4H, CHCO, NCH 3 ), 2.65-3.05 (m, 4H, NHCH 2 and CH 2 Ar), 4.30 (d, 1H, NCH), 6.90-7.30 (m, 5H, ArH).
Mass (FAB): 421 (MH + )
EXAMPLE 6
N- (2R)-2- 2'-(Hydroxyamino)-2'(oxo)ethyl!-(6RS)-6-(hydroxy)heptanoyl!-L-phenylalanine N-methylamide
6a. Synthesis of (4S)-4-Benzyl-3- (2'R)-2'-(tert-butoxycarbonylmethyl)-6'-(hydroxy)hexanoyl!-2-oxazolidone.
The compound of example 1e 1.5g, 3 mmol! is dissolved in absolute ethanol and enough EtOAc to get the material into solution. 1g of 20% Palladium Hydroxide on carbon (Pd(OH) 2 /C) and 0.28 mL 30 mmol! of 1,4-cyclohexadiene are added, and the reaction is warmed slowly to 65° C. while stirring under a N 2 atmosphere. A vigorous frothing occurs shortly after (H 2 generation). The reaction is stirred for 12 hrs. The reaction is cooled and filtered through Celite, and the Celite is washed with EtOAc. The solvent is evaporated, and the residue solidified. The solid is recrystalized from Et 2 O/hexane, which affords 1.04 g of a white fluffy solid product (85% yield).
1 H-NMR (CDCl 3 ): δ1.4-1.8 (s and m, 16H, t-butyl, --OH, and --(CH 2 ) 3 ), 2.54 (dd, 1H, --COCH 2 CHCO), 2.84 (overlapping dd, 2H, one --COCH 2 CHCO and one --CHCH 2 Ph), 3.4 (dd, 1H, --CHCH 2 Ph), 3.68 (t, 2H, --CH 2 OH), 4.22 (m, 3H, oxazol. ring --CH 2 and --CH 2 CHCO), 4.72 (m, 1H, oxazol. ring --CH), 7.35 (m, 5H, Ar).
6b. Synthesis of (4S)-4-Benzyl-3- (2'R)-2'-(tert-butoxycarbonylmethyl)-5'-(formyl)pentanoyl)-2-oxazolidone
Oxalyl chloride 0.231 mL, 2.7 mmol! is dissolved in 10 mL anhyd. CH 2 Cl 2 and cooled to -78° C. under a N 2 atmosphere. 0.192 mL 2.7 mmol! of anhydrous dimethyl sulfoxide (DMSO) in 5 mL CH 2 Cl 2 is added dropwise via syringe; this is accompanied by the evolution of CO 2 and CO bubbles. The reaction is stirred at -78° C. for 30 min. 1.0 g 2.46 mmol! of the compound of example 6a in 10 mL of CH 2 Cl 2 is then added dropwise via syringe, which causes the reaction to become cloudy white. Stirring is continued for 1 hr. at -78° C., then 1.58 mL 11 mmol! of triethylamine (Et 3 N) in 10 mL of CH 2 Cl 2 is added dropwise via syringe and the reaction warmed to room temperature. During this time, the reaction becomes increasingly clearer. The reaction is partitioned between H 2 O and CH 2 Cl 2 and the organic layer washed with 5% NaHCO 3 , 5% citric acid, H 2 O, and brine, then dried over Na 2 SO 4 . The solvent is removed and the residue is flash chromatographed to give 0.81 g of a gummy solid (81%).
1 H-NMR (CDCl 3 ): δ1.4-1.8 (s and m, 13H, t-butyl and --(CH 2 ) 2 ), 2.54 (overlapping t and dd, 3H, --CH 2 CHO and one --COCH 2 CHCO), 2.8 (overlapping dd, 2H, one --COCH 2 CHCO and one --CHCH 2 Ph), 3.36 (dd, 1H, one --CHCH 2 Ph), 4.2 (m, 3H, oxazol. ring --CH 2 and --CH 2 CHCO), 4.7 (m, 1H, oxazol. ring --CH), 7.3 (m, 5H, Ar), 9.78 (s, 1H, CHO).
6C. Synthesis of (4S)-4-Benzyl-3- (2'R)-2'-(tert-butoxycarbonylmethyl)-(6'RS)-6'-(hydroxy)heptanoyl!-2-oxazolidone
The compound of example 6b 1.33 g, 33 mmol! is dissolved in dry/distilled THF and cooled to -15° C. under a N 2 atmosphere. A solution of 3M solution of methyl magnesium bromide in ether 1.1 mL, 33 mmol! is added dropwise with stirring. Stirring is continued for 1 hr. at -15° C. then the reaction is warmed to room temperature and quenched with a aqueous NH 4 Cl solution. The THF is evaporated and the reaction is extracted with EtOAc. The combined EtOAc layers are then washed with 5% NaHCO 3 , 5% citric acid, and brine, and then dried over Na 2 SO 4 . Flash chromatography is used to isolate 250 mg of the desired secondary alcohol (18% yield).
1 H-NMR (CDCl 3 ): δ1.23 (d, 3H, CHCH 3 ), 1.4-1.8 (s and m, 16H, t-butyl, --OH, and --(CH 2 ) 3 ), 2.55 (dd, 1H, one --COCH 2 CHCO), 2.82 (overlapping dd, 2H, one --COCH 2 CHCO and one --CHCH 2 Ph), 3.39 (dd, 1H, one --CHCH 2 Ph), 3.84 (m, 1H, CHOH, 4.22 (m, 3H, oxazol. ring --CH 2 and --CH 2 CHCO), 4.72 (m, 1H, oxazol. ring --CH), 7.3-7.45 (m, 5H, Ar). No peak doubling due to the presence of diasteromers was observed.
6d. Synthesis of (2R)-2-(tert-Butoxycarbonyl)methyl-(6RS)-6-(hydroxy)heptanoic acid
The compound of example 6c 0.25g, 0.6 mmol! is dissolved in 2.5 mL of a 4:1 THF/H 2 O solution and cooled to ˜2° C. but no lower, under a N 2 atmosphere. Dropwise and with stirring, 30% aqueous H 2 O 2 , 0.265 mL 0.09 g, 2.6 mmol! is added. After stirring 5 minutes, a solution of LiOH•H 2 O 0.042 g, 1.0 mmol! in 1 mL H 2 O is added slowly. During these additions, the temperature of the reaction is maintained below 3°-4° C. The temperature of the reaction is slowly allowed to come to room temperature (30 min), and stirred for 1 hr. The reaction is cooled and quenched slowly with Na 2 SO 3 0.126 g, 1.0 mmol! in 2.5 mL H 2 O. The THF is evaporated (keeping the temperature low so as not to racemize stereo centers) and the basic, aqueous mixture remaining is extracted with methylene chloride to remove free benzyl oxazolidinone which can be recrystalized and recycled for further use. The basic layer is then cooled and acidified with the slow addition of concentrated HCl (pH 1). The cloudy mixture is then extracted with EtOAc. The EtOAc extracts are dried over Na 2 SO 4 and evaporated to give 0.15 g of pure acid (96% yield).
1 H-NMR (CDCl 3 ): δ1.25-1.85 (m, 16H, OH, CCH 2 CH 2 CH 2 C, t-butyl H), 2.25-2.68 (two dd, s, COCH 2 ), 2.73-2.85 (m, 1H, CHCOO), 3.70-3.90 (m, 1H, CHOH).
6e. Synthesis of N- (2R)-2-(tert-Butoxycarbonylmethyl)-(6RS)-6-hydroxy-heptanoyl!-L-phenylalanine N-methylamide
A solution of the compound of example 6d 0.10 g, 0. 384 mmol! and L-phenylalanine N-methylamide TFA salt (0.136 g, 0.768 mmol) in dry dimethylformamide (2 mL) under nitrogen is cooled to -6° C. and treated dropwise with diethylcyanophosphonate 0.062 g, 0.384 mmol! followed by triethylamine 0.116 g, 1.15 mmol!. The reaction mixture is stirred at 0° C. for 1 hr, allowed to warm to room temperature over 1 hr, then stirred for two additional hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The combined ethyl acetate layers are sequentially washed with 5% citric acid, saturated sodium bicarbonate, water, and brine. The ethyl acetate is separated, dried (Na 2 SO 4 ), and evaporated. The residue is purified by silica gel column chromatography using 10% methanol in ethyl acetate as the eluent. The appropriate fraction yields 0.15 g (93% yield) of product.
1 H-NMR (CDCl 3 ): δ1.14 (d, 3H, --CHCH 3 ), 1.14-1.7 (m and s, 15H, t-butyl and --(CH 2 ) 3 ), 2.27-2.6 (m, 3H, --COCH 2 CHCO, --COCH 2 CHCO), 2.68 (d, 3H, NCH 3 ), 3.07 (d, 2H, --CHCH 2 Ph), 3.82 (m, 1H, CHOH), 4.68 (q, 1H, NHCHCO), 6.32 (d, 1H, --NHCH 3 ), 6.63 (d, 1H, --NHCH), 7.24 (m, 5H, Ar). Peak doubling due to diastereomers was observed for --CHCH 3 and --NHCH 3 peaks.
6f. Synthesis of N- (2R)-2-(Carboxylmethyl)-(6RS)-6-(hydroxy)heptanoyl!-L-phenylalanine N-methylamide
The compound of example 6e 0.13 g, 0.39 mmol! is dissolved in 7 mL of trifluoroacetic acid (TFA) and 3 mL H 2 O and stirred at room temperature until the t-butyl ester is consumed (followed by TLC). The TFA/H 2 O is then evaporated and the residue triturated in Et 2 O until a white solid is formed. The solid is filtered, washed with fresh Et 2 O, and dried in vacuo. 0.05 g of the acid as a white powder is obtained (44% yield).
1 H-NMR (CD 3 OD): δ1.1 (d, 3H, --CHCH 3 ), 1.15-1.6 (m, 6H, --(CH 2 ) 3 ), 2.25 (2 dd, 2H, --CH 2 COOH), 2.63 (overlapping m and s, 4H, --COCH 2 CHCO and --NCH 3 ), 2.9 and 3.17 (2 dd, 2H, --CH 2 Ph), 3.61 (m, 1H, CHOH), 4.49 (q, 1H, NHCHCO), 7.3 (m, 5H, Ar).
6g. The compound of example 6f 0.025 g, 0.07 mmol! is dissolved in 5 mL dry/distilled THF and cooled to -15° C. under a N 2 atmosphere. N-methyl morpholine 8.6 μL, 0.077 mmol! is added via syringe with stirring, followed by 10 μL 0.077 mmol! of isobutylchloroformate. The solution becames slightly cloudy. The reaction is stirred for 30 min. at -15° C., then 17 μL 0.14 mmol! of O-trimethylsilyl hydroxyl amine is added. After stirring for 1.5 hrs. the reaction is poured onto 5 mL of 5% NaHCO 3 then extracted with EtOAc. The organic layer is separated and washed with 5% citric acid, H 2 O, and brine, then dried over Na 2 SO 4 . The solvent is evaporated to give 0.01 g of hydroxamate (37% yield).
1 H-NMR (CD 3 OD): δ1.1 (d, 3H, --CHCH 3 ), 1.15-1.6 (m, 6H, --(CH 2 ) 3 ), 2.15 (2 dd, 2H, --CH 2 COOH), 2.63 (overlapping m and s, 4H, --COCH 2 CHCO and NCH 3 ), 2.9 and 3.17 (2 dd, 2H, --CH 2 Ph), 3.61 (m, 1H, CHOH), 4.49 (q, 1H, NHCHCO), 7.3 (m, 5H, Ar).
EXAMPLE 7
Alternative route to N- (2R)-2-(tert-Butoxycarbonylmethyl)-(6RS)-6-hydroxy-heptanoyl!-L-phenylalanine N-methylamide
7a. Synthesis of N- (2R)-2-(tert-Butoxycarbonylmethyl)-6-(hydroxy)hexanoyl!-L-phenylalanine N-methylamide
The compound obtained in example 1 g 2.0 g, 4 mmol! in 20 mL absolute EtOH is treated with 0.75 g 20% Pd(OH) 2 /C and 3.8 mL 40 mmol! of 1,4-cyclohexadiene. The reaction is heated slowly to 65° C. and stirred as such for ˜20 hrs. The reaction is cooled and filtered through Celite. The Celite is washed with EtOAc, and the combined filtrates evaporated. The residue is flash chromatographed, resulting in a white solid 1.14 g, 70% yield!.
1 H-NMR (CDCl 3 ): δ1.3-1.7 (m and s, 15H, t-butyl and --(CH 2 ) 3 ), 2.35-2.8 (m, 3H, --COCH 2 CHCO and --COCH 2 CHCO), 2.74 (d, 3H, NCH 3 ), 3.14 (2 d, 2H, --CHCH 2 Ph), 3.64 (m, 2H, --CH 2 OH), 4.62 (q, 1H, NHCHCO), 6.35 (d, 1H, --NHCH 3 ), 6.71 (d, 1H, --NHCH), 7.3 (m, 5H, Ar).
7b. Synthesis of N- (2R)-2-(tert-Butoxycarbonylmethyl)-5-(formyl)pentanoyl!-L-phenylalanine N-methylamide
The compound of example 7a 0.05 g, 0.12 mmol! and 0.06 g, 0.24 mmol! of pyridinium chlorochromate (PCC) are dissolved in 10 mL of anhydrous CH 2 Cl 2 under a N 2 atmosphere and stirred at room temperature. The reaction is followed by TLC until the alcohol is consumed. EtOAc is then added to precipitate PCC salts, and the reaction is filtered through Celite several times. The solvent is evaporated and the residue flash chromatographed to afford 0.07 g (47%) of the aldehyde as a gummy solid.
1 H-NMR (CDCl 3 ): δ1.4-1.75 (m and s, 13H, t-butyl and --(CH 2 ) 2 ), 2.4-2.75 (m, 5H, --COCH 2 CHCO, --COCH 2 CHCO, --CH 2 CHO), 2.8 (d, 3H, NCH 3 ), 3.2 (2 dd, 2H, --CHCH 2 Ph), 4.66 (q, 1H, NHCHCO), 6.18 (d, 1H, --NHCH 3 ), 6.63 (d, 1H, --NHCH), 7.3 (m, 5H, Ar), 9.8 (s, 1H, CHO).
7c. Synthesis of N- (2R)-2-(tert-Butoxycarbonylmethyl)-(6RS)-6-hydroxy-heptanoyl!-L-phenylalanine N-methylamide
Titanium isopropoxide 0.211 g, 0.74 mmol! is dissolved in 5 mL dry/distilled THF and cooled to -10° C. under a N 2 atmosphere. A solution of 1.0M titanium (IV) chloride in CH 2 Cl 2 0.25 mL, 0.25 mmol! is then added dropwise via syringe. The reaction is then warmed to room temperature and stirred 1.5 hours. The reaction is cooled to -78° C. and 0.71 mL 0.98 mmol! of 1.4M methyl lithium in Et 2 O is added via syringe. The reaction becomes red in color, and upon warming slowly to room temperature, lithium chloride (LiCl) precipitates from the reaction, causing it to also be cloudy. After 1 hour, stirring is stopped and the LiCl is allowed to settle. The solution of triispropoxymethyl titanium is again cooled to -78° C. then transfered slowly via syringe to a dry/distilled THF solution (7 mL) of 0.1 g 0.25 mmol! of the compound formed in example 7b cooled to -78° C. under a N 2 atmosphere. The reaction is warmed slowly to 0° C., stirred for 1 hour, then quenched with dilute aqueous HCl. The THF is evaporated and the aqueous layer extracted with EtOAc. The organic layer is washed with H 2 O and brine, and then dried over Na 2 SO 4 . Flash chromatography is used to isolate 0.01 g of the desired secondary alcohol (10% yield).
1 H-NMR (CDCl 3 ): δ1.14 (d, 3H, --CHCH 3 ), 1.14-1.7 (m and s, 15H, t-butyl and --(CH 2 ) 3 ), 2.27-2.6 (m, 3H, --COCH 2 CHCO, --COCH 2 CHCO), 2.68 (d, 3H, NCH 3 ), 3.07 (d, 2H, --CHCH 2 Ph), 3.82 (m, 1H, CHOH), 4.68 (q, 1H, NHCHCO), 6.32 (d, 1H, --NHCH 3 ), 6.63 (d, 1H, --NHCH), 7.24 (m, 5H, Ar). Peak doubling due to diastereomers was observed for --CHCH 3 and --NHCH peaks.
EXAMPLE 8
(2S)-N-2- (2'R)-2'- 2"-(Hydroxyamino)-2"-(oxo)ethyl!-6'-(phenylmethoxy)hexanoyl!amino-3,3-dimethylbutanoic acid N-methylamide
8a. Synthesis of (2S)-N-2- (2'R)-2'-(tert-Butoxycarbonylmethyl)-6'-(phenylmethoxy)hexanoyl!amino-3,3-dimethylbutanoic acid N-methylamide
A stirred solution of the compound of example 1f (0.3 g, 0.9 mmol) and (2S)-2-Amino-3,3-dimethylbutanoic acid N-methyl amide hydrochloride (0.187 g, 1 mmol) in 3 mL DMF under nitrogen is cooled to -5° C., and is treated with diethylcyanophosphonate (0.19 mL, 1.2 mmol), followed by dropwise addition of triethylamine (0.4 mL, 2.8 mmol). The reaction mixture is stirred cold for 2.5 hours, then at ambient temperature for 2.5 hours longer. The reaction mixture is then diluted with 30 mL of ethyl acetate, and washed sequentially with 5% citric acid solution, 5% sodium bicarbonate solution, and brine. The ethyl acetate is separated, dried over anhydrous sodium sulfate, filtered, and evaporated to 424 mg (91%) of a colorless oil, which can be used in the following step without further purification.
1 H NMR (CDCL 3 ): δ1.00 (s, 9H, (CH 3 ) 3 ), 1.2-1.75 (m, 15H), 2.30-2.70 (m, 3H, COCH 2 CHCO), 2.80 (d, 2H, NHCH 3 ), 3.45 (t, 2H, CH 2 O), 4.25 (d, 1H, NCHCO), 4.50 (s, 2H, PhCH 2 O), 6.15 (bs, 1H, NH), 6.55 (d, 1H, NH), 7.2-7.5 (m, 5H, Ar).
8b. Synthesis of (2S)-N-2- (2'R)-2'-(carboxymethyl)-6'-(phenylmethoxy)hexanoyl!amino-3,3-dimethylbutanoic acid N-methylamide
The compound of example 8a (424 mg, 0.9 mmol) is dissolved in a mixture of trifluoroacetic acid (3 mL) and water (1 mL), and stirred at ambient temperature for 3 hours. The solvents are evaporated, and the residue placed under high vacuum for 2 hours. The oily residue is purified by flash silica gel chromatography (2% methanol in CH 2 Cl 2 ). Product containing fractions is evaporated to yield 295 mg (81%) of a white foam.
1 H NMR (CDCL 3 ): δ0.95 (s, 9H, (CH 3 ) 3 ), 1.20-1.70 (m, 6H), 2.40-2.75 (m, 3H, COCH 2 CHCO), 2.80 (d, 2H, NCH 3 ), 3.40 (t, 2H, CH 2 ), 4.40 (d, 1H, NCHCO), 4.50 (s, 2H ArCH 2 O), 6.70 (bs, 1H, NH), 7.23-7.6 (m, 6H, Ar & NH).
8c. To a -10° C. stirred solution of the compound of example 8b (295 mg, 0.73 mmol) in 3 mL of dry distilled THF under nitrogen is added in one portion N-methylmorpholine (0.09 mL, 0.8 mmol). After stirring 5 minutes, the reaction mixture is treated dropwise with isobutylchloroformate (0.1 mL, 0.8 mmol), and the resultant suspension is stirred for 15 to 20 minutes. The reaction mixture is then treated with O-(trimethylsilyl)hydroxylamine (84 mg, 0.8 mmol), and the stirring continued for 2 hours at ice bath temperature, followed by 2 hours at ambient temperature. The reaction mixture is filtered, and the filtrate evaporated to a white foam. The foam is stirred overnight in 10 mL of diethyl ether, which produces the desired hydroxamate as a white solid (220 mg, 71%).
1 H NMR (DMSO d 6 ): δ0.90 (s, 9H, (CH 3 ) 3), 1.10-1.60 (m, 6H), 1.95-2.20 (m, 2H), 2.50 (d, 3H, NCH 3 ), 2.79 (m, 1H), 4.15 (d, 1H, COCHN), 4.40 (s, 2H, ArCH 2 O), 7.20-7.40 (m, 5H, Ar), 7.67 (d, 1H, NH), 7.85 (bs, 1H, NH), 8.65 (s, 1H, OH).
EXAMPLE 9
(2S)-N-2- (2'R)-2'- 2"-(Hydroxyamino)-2"-(oxo)ethyl!-6'-(hydroxy)hexanoyl!amino-3,3-dimethylbutanoic acid N-methylamide
9a. Synthesis of (2S)-N-2- (2'R)-2'-(tert-Butoxycarbonylmethyl)-6'-(hydroxy)hexanoyl!-amino-3,3-dimethylbutanoic acid N-methylamide
Under a nitrogen atmosphere, a solution of the compound formed in example 8a (1.5 g, 3.2 mmol) in ethanol (25 mL) is treated with 20% Pd(OH) 2 on C (0.6 g) and 1,4-cyclohexadiene (10 mL). The mixture is heated at 65° C. for 16 hours at which point 0.5 g of 20% Pd(OH) 2 on C and 1,4-cyclohexadiene (4 mL) is added and heating is continued for another 5 hours. The reaction mixture is cooled and the catalyst is collected via filtration. The filtrate is evaporated to dryness and the residue is purified by silica gel column chromatography using 5% methanol in ethyl acetate as the eluent to give the desired product (0.85 g, 71% yield).
1 H NMR(CDCl 3 ) δ0.95 (s, 9H, t-butyl H), 1.15-1.80 (m, 15H, CCH 2 CH 2 CH 2 C and t-butyl H), 2.40 (dd, 1H, COCH 2 CHCO), 2.50-2.90 (m, 5H, NCH 3 , COCH 2 CHCO), 3.45-3.75 (m, 2H, CH 2 O), 4.40 (d, 1H, NCH), 6.70 (m, 1H, NH), 7.26 (m, 1H, NH).
9b. Synthesis of (2S)-N-2- (2'R)-2'-(Carbonylmethyl)-6'-(hydroxy)hexanoyl!amino-3,3-dimethylbutanoic acid N-methylamide
The compound of example 9a (0.6 g, 1.6 mmol) is dissolved in 10 mL of a 7:3 trifluoroacetic acid-water mixture and stirred at room temperature for 4.0 hours. The solvents are removed on a rotary evaporator and the residue is treated with acetonitrile and evaporated (three times) in order to azeotrope water. The colorless gummy product (0.635 g) is dried on a high vacuum pump. The product does not solidify, perhaps due to remaining impurities and trifluoroacetic acid. The compound without any further purification is used in next reaction.
1 H NMR (MeOH-d 4 ) δ0.95 (s, 9H, t-butyl H), 1.20-1.85 (m, 6H, CCH 2 CH 2 CH 2 C), 2.35-3.00 (m, 6H, NCH 3 , COCH 2 CHCO), 3.64 (m, 2H, CH 2 O), 4.45 (d, 1H, NCH).
9c. Under a nitrogen atmosphere, the compound of example 9b (0.143 g, 0.4 mmol), dissolved in dry tetrahydrofuran (10 mL), is cooled to -15° C. and treated with N-methylmorpholine (0. 081 g, 0.8 mmol). After 5 min, isobutylchloroformate (0.109 g, 0.8 mmol) is added dropwise and the reaction mixture is stirred for 15 min. O-(trimethylsilyl)hydroxylamine (0.25 g, 2.4 mmol) is added dropwise. The reaction mixture is stirred at -15° C. for 1 hour, followed by 1 hour at 0° C., then 30 minutes at room temperature. The reaction mixture is filtered and the filtrate is evaporated to dryness. The crude product is purified by preparative thin layer chromatography using 25% methanol in ethyl acetate as eluent, giving a colorless solid product (0.068 g, 45% yield).
1 H NMR(MeOH-d 4 ) δ0.77 (s, 9H, t-butyl H), 0.90-1.50 (m, 6H, CCH 2 CH 2 CH 2 C), 1.90-2.25 (two dd's, 2H, CH 2 CO), 2.50 (s, 3H, NCH 3 ), 2.56-2.78 (m, 1H, CHCO), 3.30 (t, 2H, CH 2 O), 3.98 (s, 1H, NCH).
EXAMPLE 10
N- (2R)-2- 2'-(Hydroxyamino)-2'-(oxo)ethyl!-5-(phenylmethoxy)pentanoyl!-L-phenylalanine N-methylamide
Synthesis using a procedure analogous to that of Example 2 results in a compound having the following analysis:
1 H-NMR (CD 3 OD): δ1.24-1.36 (m, 4H, --(CH 2 ) 2 ), 1.95 (2 dd, 2H, --CH 2 CONHOH), 2.5 (overlapping s and m, 4H, --NCH 3 and --CHCH 2 CONHOH), 2.75 and 2.98 (2 dd, 2H, --CCH 2 Ph), 3.27 (t, 2H, --CH 2 OCH 2 Ph), 4.33 (overlapping s and q, 3H, --OCH 2 Ph and --NCHCO), 7.06-7.33 (m, 10H, Ar).
EXAMPLE 11
N- (2R)-2- 2'-(Hydroxyamino)-2'-(oxo)ethyl!-7-(phenylmethoxy)heptanoyl!-L-phenylalanine N-methylamide)
Synthesis using a procedure analogous to Example 2 results in a compound which is produces the following analysis:
1 H-NMR (CD 3 OD): δ1.01-1.5 (m, 8H, --(CH 2 ) 4 ), 1.98-2.21 (2 dd, 2H, --CH 2 CONHOH), 2.52 (m, 1H, --CHCH 2 CONHOH), 2.59 (s, 3H, --NCH 3 ), 2.86 and 3.09 (2 dd, 2H, --CHCH 2 Ph), 3.38 (t, 2H, --CH 2 OCH 2 Ph), 4.41 (overlapping s and q, 3H, --OCH 2 Ph and --NCHCO), 7.05-7.28 (m, 10H, Ar).
EXAMPLE 12
N- (2'R)-2- 2'-(Hydroxyamino)-2'-(oxo)ethyl!-6-(4'-oxobutylamino)hexanoyl!-L-phenylalanine N-methylamide
12a. Synthesis of (4S)-4-Benzyl-3- (2'R)-2'-(tert-butoxy-carbonylmethyl)-6'-(methanesulfonyloxy)hexanoyl!-2-oxazolidone
0.5 g 1.23 mmol! of the product formed in example 6a, 0.24 mL 1.72 mmol! of Et 3 N, and 0.03 g of 4-dimethylamino pyridine 0.24 6 mmol! are dissolved in 10 mL dry CH 2 Cl 2 and cooled to 0° C. under N 2 . Methanesulfonyl chloride 0.105 mL, 1.35 mmol! is then added dropwise via syringe with stirring. The reaction is stirred at 0° C. for 2 hrs. then warmed to room temperature and quenched with H 2 O. The layers were separated and the organic layer was washed with 5% NaHCO3, 5% citric acid, H 2 O, and brine, then dried over Na 2 SO 4 . Evaporation of the solvent affords 0.57 g of the desired product (96%) as a colorless oil. No further purification is done.
1 H-NMR (CDCl 3 ): δ1.41-1.84 (m and s, 15H, -t-Bu and --(CH 2 ) 3 ), 2.48 (dd, 1H, --CH 2 COOtBu), 2.84 (2 overlapping dd, 2H, one --CH 2 COOtBu and one --CHCH 2 Ph), 3.02 (s, 3H, --SO 2 CH 3 ), 3.34 (dd, 1H, --CHCH 2 Ph), 4.13-4.28 (m, 5H, --CH 2 OSO 2 , oxazol. ring --CH 2 , and --CHCH 2 COOtBu), 4.69 (m, 1H, oxazol. ring --CH), 7.23-7.39 (m, 5H, Ar).
12b. Synthesis of (4S)-4-Benzyl-3- (2'R)-2'-(tert-butoxy-carbonylmethyl)-6'-(azido)-hexanoyl!-2-oxazolidone
The compound of example 12a 2.1 g, 4.34 mmol! and tetrabutylammonium iodide 1.6 g, 4.34 mmol! are dissolved in 20 mL toluene. A sodium azide solution 2.8 g, 43 mmol! in 20 mL H 2 O is then added and the two-phase reaction stirred vigorously at 70° C. for 17 hours under N 2 . The reaction is cooled, the layers separated, and the aqueous layer extracted with EtOAc. The EtOAC and toluene layers are combined and washed with 5% NaHCO 3 , 5% citric acid, H 2 O, and brine, then dried over Na 2 SO 4 . The solvent is evaporated, leaving an oil residue which solidifies. The solid is recrystalized from Et 2 O/hexane which yields 1.5 g of the desired azide (80%) as white crystals.
1 H-NMR (CDCl 3 ): δ1.45-1.75 (m and s, 15H, -t-Bu and --(CH 2 ) 3 ), 2.47 (dd, 1H, --CH 2 COOtBu), 2.78 (2 overlapping dd, 2H, one --CH 2 COOtBu and one --CHCH 2 Ph), 3.28 (t, 2H, --CH 2 N 3 ), 3.34 (dd, 1H, --CHCH 2 Ph), 4.17 (m, 3H, oxazol. ring --CH 2 , and --CHCH 2 COOtBu), 4.67 (m, 1H, oxazol. ring --CH), 7.23-7.37 (m, 5H, Ar).
12c. Synthesis of (2R)-2-(tert-Butoxycarbonylmethyl)-6-(azido)hexanoic acid
The compound of example 12c 0.3 g, 0.7 mmol! is dissolved in 15 mL of a 4:1 THF/H 2 O solution and cooled to ˜2° C. but not below, under a N 2 atmosphere. A solution of 30% aqueous H 2 O 2 0.285 mL, 2.8 mmol! is then added via syringe while maintaining the temperature below 5° C. After stirring 5 minutes, a solution of LiOH•H 2 O 0.046 g, 1.12 mmol! in 2 mL H 2 O is added slowly via syringe. Some gas evolution is observed. The reaction is stirred for 10 minutes, then warmed to room temperature and stirred 1 hour. A solution of Na 2 SO 3 0.35 g, 2.8 mmol! in 2 mL H 2 O is then added dropwise; some heat is evolved during this process, so the reaction is cooled. After stirring ˜20 minutes, the THF is evaporated (below 30° C.) and the remaining basic layer is extracted with EtOAc. These EtOAc extracts contain free (S)-(-)-4-benzyl-2-oxazolidone which is recrystalized and recycled for further use. The basic layer is cooled and acidified with the slow addition of concentrated aqueous HCl to a pH 2-3. The cloudy mixture is extracted with EtOAc, and the EtOAc dried over Na 2 SO 4 and evaporated to give 0.17 g of pure acid (90% yield).
1 H-NMR (CDCl 3 ): δ1.39-1.7 (m and s, 15H, -t-Bu and --(CH 2 ) 3 ), 2.4 (dd, 1H, --CH 2 COOtBu), 2.65 (dd, 2H, --CH 2 COOtBu), 2.82 (m, 1H, --CHCH 2 COOtBu), 3.29 (t, 2H, --CH 2 N 3 ).
12d. Synthesis of N- (2R)-2-(tert-Butoxycarbonylmethyl)-6-(azido)hexanoyl!-L-phenylalanine N-methylamide
The compound of example 12c 0.17 g, 0.64 mmol! and L-phenylalanine methyl amide TFA salt 0.182 g, 0.7 mmol! are dissolved in 10 mL dry DMF and cooled to -10° C. under a N 2 atmosphere. Diethylcyanophosphonate 0.101 mL, 0.67 mmol!, followed by Et 3 N 0.264 mL, 1.9 mmol!, are added dropwise via syringe. The reaction is stirred for 1 hour at -10° C. then at room temperature for 2 hours. The reaction is diluted with 30 mL H 2 O and extracted with EtOAc. The combined EtOAc layers are then washed with 5% NaHCO 3 , 5% citric acid, H 2 O, and brine, then dried over Na 2 SO 4 . The solvent is evaporated, and the residue flash chromatographed, affording 1.05 g of the coupled product (74% yield).
1 H-NMR (CDCl 3 ): δ1.4-1.68 (m and s, 15H, -t-Bu and --(CH 2 ) 3 ), 2.3-2.58 (m, 3H, --CHCH 2 COOtBu), 2.7 (d, 3H, --NCH 3 ), 3.09 (2 dd, 2H, --CHCH 2 Ph), 3.21 (t, 2H, --CH 2 N 3 ) 4.51 (q, 1H, NCHCO), 5.81 (d, 1H, --NH), 6.35 (d, 1H, NH), 7.19-7.33 (m, 5H, Ar).
12e. Synthesis of N- (2R)-2-(tert-Butoxycarbonylmethyl)-6-(amino)hexanoyl!-L-phenylalanine N-methylamide
The compound of example 12d 0.083 g, 0.19 mmol! in 15 mL dry/distilled THF is hydrogenated (0.1 g 10% Pd/C, 30 psi, 25° C. 1.2 hours ) on a Parr shaker apparatus After this time, the reaction is filtered through Celite and the Celite washed with EtOH. The combined filtrates are evaporated, leaving 0.084 g of a gummy solid. No further purification is done (>90% yield).
1 H-NMR (CD 3 OD): δ1.1-1.5 (m and s, 15H, -t-Bu and --(CH 2 ) 3 ), 2.15-2.41 (m, 3H, --CHCH 2 COOtBu), 2.47-2.61 (overlapping s and t, 5H, --CH 2 NH 2 and --NCH 3 ), 2.9 and 3.05 (2 dd, 2H, --CHCH 2 Ph), 4.41 (t, 1H, --NCHCO), 7.07-7.26 (m, 5H, Ar).
12f. Synthesis of N- (2R)-2-(tert-Butoxycarbonylmethyl)-6-(4'-oxobutylamino)-hexanoyl-L-phenylalanine N-methylamide
The compound of example 12e 0.394 g, 0.97 mmol! is dissolved in 15 mL dry DMF and cooled to -10° C. under a N 2 atmosphere. Triethylamine 0.203 mL, 1.46 mmol!, followed by butyroyl chloride 0. 111 mL, 1.07 mmol! are added dropwise via syringe. The reaction becomes slightly cloudy white. The reaction is stirred 20 minutes at -10° C. then warmed to room temperature and stirred 1.5 hours. The reaction mixture was treated with 40 mL H 2 O and then extracted with EtOAc. The combined extracts were washed with 5% NaHCO 3 , 5% citric acid, H 2 O, and brine, then dried over Na 2 SO 4 . The solvent is evaporated, leaving a fluffy white solid which is recystalized from CH 3 CN/Et 2 O and washed with cold Et 2 O. This affords 0.29 g of the desired acyl amine (63% yield).
1 H-NMR (CDCl 3 ): δ0.95 (t, 3H, --CH 2 CH 3 ), 1.2-1.71 (m and s, 17H, -t-Bu and --(CH 2 ) 4 ), 2.15 (t, 2H, --NCOCH 2 ), 2.27-2.59 (m, 3H, --CHCH 2 COOtBu), 2.7 (d, 3H, --NCH 3 ), 3.09 (2 dd, 2H, --CHCH 2 Ph), 3.21 (m, 2H, --CH 2 NH), 4.51 (q, 1H, --NCHCO), 5.81 (broad s, 1H, --NH), 5.89 (broad s, 1H, --NH), 6.35 (d, 1H, --NH), 7.14-7.34 (m, 5H, Ar).
12g. Synthesis of N- (2R)-2-(Carboxymethyl)-6-(4'-oxobutyl-amino)hexanoyl!-L-phenylalanine N-methylamide
The compound of example 12f 0.15 g, 0.31 mmol! was dissolved in 10 mL of a 7:3 TFA/H 2 O solution and stirred at room temperature until the t-butyl ester is consumed (followed by TLC). The TFA/H 2 O is then evaporated, and the residue triturated in Et 2 O, producing a white solid. The solid is filtered, washed with CH 3 CN several times, and dried in vacuo. 0.125 g of the acid as a white powder are obtained (94% yield).
1 H-NMR (CD 3 OD): δ0.87 (t, 3H, --CH 2 CH 3 ), 1.02-1.63 (m, 8H, --(CH 2 ) 4 ), 2.08 (t, 2H, --NCOCH 2 ), 2.2-2.48 (2 dd, 2H, --CH 2 COOH), 2.56 (overlapping s and m, 4H, --NCH 3 and --CHCH 2 COOH), 2.84-3.1 (overlapping t and 2 dd, 4H, --CH 2 NH and--CHCH 2 Ph), 4.41 (t, 1H, NCHCO), 7.02-7.27 (m, 5H, Ar).
12h. The compound of example 12g 0.08 g, 0.19 mmol! is dissolved in ˜5 mL dry DMF and cooled to -10° C. under a N 2 atmosphere. The reaction mixture is treated with N-methylmorpholine 0.026 mL, 0.23 mmol!, followed by isobutylchloroformate 0.030 mL, 0.23 mmol! via syringe with stirring. The solution becomes slightly cloudy. The reaction is stirred for 30 min. at -10° C., then 0.058 mL 0.48 mmol! of O-trimethylsilyl hydroxylamine is added via syringe and stirred another 1.5 hours at -10° C. The reaction is warmed to room temperature and the solvent evaporated. The gummy residue is triturated in Et 2 O, causing it to solidify. The solid is triturated (CH 3 CN) and recrystalized (MeOH/CH 3 CN) several times to give 0.065 g of hydroxamate as a white powder (78% yield).
1 H-NMR (CD 3 OD): δ0.85 (t, 2H, --CH 2 CH 3 ), 0.99-1.61 (m, 8H, --(CH 2 ) 4 ), 1.98-2.2 (overlapping t and 2 dd, 4H, --CH 2 NHCOCH 2 and --CH 2 CONHOH), 2.48-2.63 (overlapping s and m, 4H, --CHCH 2 CONHOH and --NCH 3 ), 2.81-3.11 (overlapping t and 2 dd, 4H, --CH 2 NH and--CHCH 2 Ph), 4.41 (q, 1H, NCHCO), 7.13-7.25 (m, 5H, Ar).
EXAMPLE 13
N- (2R)-2- 2'-(Hydroxyamino)-2'(oxo)ethyl)-6-(phenoxy)-hexanoyl!-L-phenylalanine N-methylamide
13a Synthesis of N- (2R)-2-(tert-butoxycarbonylmethyl)-6-(phenoxy)hexanoyl!-L-phenylalanine N-methylamide
Diethyl azodicarboxylate DEAD! (0.145 g, 0. 837 mmol) is added to a solution of triphenylphosphine (0.218 g, 0.837 mmol) in 20 mL of dry THF under a nitrogen atmosphere. The mixture is stirred at room temperature for 15 minutes. Phenol (0.078 g, 0.837 mmol), followed by the compound of example 3a (0.340 g, 0.837 mmol), is added and the resulting mixture stirred at room temperature for 18 hours. The solvent is evaporated to dryness and the residue is partitioned between water and methylene chloride. The methylene chloride layer is washed with water and brine, then purified by preparative thin-layer chromatography using 60% ethyl acetate in hexanes as eluent (0.255 g, 63.2% yield).
1 H NMR (CDCl 3 ) δ1.25-1.85 (m, 15H, CCH 2 CH 2 CH 2 C and t-butyl H), 2.28-2.78 (m, 6H, NCH 3 , CH 2 CO and CHCO), 3.00-3.20 (m, 2H, OCH 2 Ph), 3.88 (t, 2H, OCH 2 C), 4.54 (dd, 1H, NCH), 5.95 (m, 1H, NH), 6.45 (,d, 1H, NH), 6.75-7.40 (m, 10H, ArH).
13b Synthesis of N- (2R)-2-(carboxymethyl)-6-(phenoxy)hexanoyl!-L-phenylalanine N-methylamide
A solution of the compound of example 13a (0. 213 g, 0. 442 mmol) in trifluoroacetic acid (4 mL) and methylene chloride (6 mL) is stirred at room temperature for 5 hours. The solvents are removed on a rotary evaporator. The residue is placed on a high vacuum pump for 2 hours, then triturated with diethyl ether and hexanes to produce a colorless solid. The solid was collected by filtration and air dried (0.165 g, 87.7% yield).
1 H NMR (CD 3 OD) δ1.00-1.60 (m, 6H, CCH 2 CH 2 CH 2 C), 2.05-2.60 (m, 6H, NCH3, CH2CO and CHCO), 2.69-3.00 (two dd, 2H, CCH2Ph), 3.66 (t, 2H, OCH2C), 4.30 (dd, 1H, NCH), 6.60-7.20 (m, 10H, ArH).
13c Under a nitrogen atmosphere, the compound of example 13b (0.106 g, 0.25 mmol) is dissolved in dry THF (10 mL), and treated with N-methylmorpholine (0. 076 g, 0.75 mmol) via syringe. The reaction mixture is cooled to -15° C. and treated with isobutylchloroformate (0.051 mL, 0.37 mmol) via syringe. After stirring the suspension for 15 minutes, O-(trimethylsilyl)hydroxylamine (0.105 mL, 1 mmol) is added and the reaction mixture is stirred at -15° C. for 1 hour, followed by 1 hour at 0° C., then 30 minutes at room temperature. The reaction mixture is filtered and the filtrate is evaporated to dryness. The crude product is purified by preparative thin-layer chromatography using 15% methanol in ethyl acetate as eluent (0.063 g, 57.4% yield).
1 H NMR (CD 3 OD) δ0.90-1.60 (m, 6H, CCH 2 CH 2 CH 2 C), 1.80-2.14 (two dd, 2H, CH 2 CO), 2.32-2.54 (m, 4H, NCH 3 , CHCO), 2.54 (dd) and 2.94 (dd) (2H CH 2 Ph), 3.68 (t, 2H, OCH 2 ), 4.32 (dd, 1H, NCH), 6.6-7.7 (m, 10H, ArH).
EXAMPLE 14
N- (2R)-2- 2'-(Hydroxyamino)-2'(oxo)ethyl!-7-(phenoxy)heptanoyl!-L-phenylalanine N-methylamide
Synthesis using a procedure analogous to that of example 13 results in a compound having the following analysis.
1H NMR (CD 3 OD) δ0.8-1.60 (m, 8H, CCH 2 CH 2 CH 2 CH 2 C), 1.84-2.10 (m, 2H, CH 2 CO), 2.40-2.60 (m, 4H, NCH 3 , CHCO), 2.72 (dd) and 2.94 (dd) (2H, CH 2 Ph), 3.72 (t, 2H, OCH 2 ), 4.30 (dd, 1H, CNH), 6.59-6.75 (m, 2H, ArH), 6.90-7.20 (m, 8H, ArH).
EXAMPLE 15
(2S)-N-2'- (2'R)-2'- 2"-(Hydroxyamino)-2"-(oxo)ethyl!-6'-(2-phenethylamino)-6'(oxo)hexanoyl!amino-3,3-dimethylbutanoic acid N-methylamide
Synthesis using a procedure analogous to that of example 5 results in a compound having the following analysis.
1 H NMR (CD 3 OD) δ0.98 (s, 9H, t-butyl H), 1.30-1.7 (m, 6H), 2.10 (t, 2H, CH 2 CO), 2.38 (dd, 1H), 2.50-2.65 (m, 2H), 2.76 (s,3H, NCH 3 ), 2.80 (t, 2H, NHCH 2 ), 3.40 (t, 2H, CH 2 Ph), 4.20 (d, 1H, NCH), 7.10-7.30 (m, 5H, ArH), 7.80 (d, 1H, NH).
EXAMPLE 16
(2S)-N-2'- (2'R)-2'- 2"-(Hydroxyamino)-2"-(oxo)ethyl!-6'-(4-methylphenoxy)hexanoyl!amino-3,3-dimethylbutanoic acid N-methylamide
Synthesis using a procedure analogous to that of example 13 results in a compound having the following analysis.
1 H NMR (CD 3 OD) δ0.91 (s, 9H, t-butyl), 1.28-1.7 (m, 6H, (CH 2 ) 3 ), 2.1-2.32 (overlapping s and dd, 5H, PhCH 3 and CH 2 CONHOH), 2.61 (s, 3H, NCH 3 ), 2.8 (m, 1H, CHCH 2 CONHOH), 3.81 (t, 2H, CH 2 OPh), 4.12 (d, 1H, NCH), 6.69 (d, 2H, ArH), 6.97 (d, 2H, ArH).
EXAMPLE 17
(2S)-N-2'- (2'R)-2'- 2"-(Hydroxyamino)-2"-(oxo)ethyl!-6'-(4-chlorophenoxy)hexanoyl!amino-3,3-dimethylbutanoic acid N-methylamide
Synthesis using a procedure analogous to that of example 13 results in a compound having the following analysis.
1 H NMR (CD 3 OD) δ0.91 (s, 9H, t-butyl), 1.25-1.74 (m, 6H, (CH 2 ) 3 ), 2.1-2.32 (dd, 2H, CH 2 CONHOH), 2.59 (s, 3H, NCH 3 ), 2.8 (m, 1H, CHCH 2 CONHOH), 3.83 (t, 2H, CH 2 OPh), 4.12 (d, 1H, NCH), 6.78 (d, 2H, ArH), 7.13 (d, 2H, ArH)
EXAMPLE 18
(2S)-N-2'-!(2'R)-2'-!2"-(Hydroxyamino)-2"-(oxo)ethyl!-6'-(3-methylphenoxy)hexanoyl!amino-3,3-dimethylbutanoic acid N-methylamide
Synthesis using a procedure analogous to that of example 13 results in a compound having the following analysis.
1 H NMR (CD 3 OD) δ0.98 (s, 9H, t-butyl), 1.32-1.77 (m, 6H, (CH 2 ) 3 ), 2.16-2.4 (overlapping s and dd, 5H, PhCH 3 and CH 2 CONHOH), 2.65 (s, 3H, NCH 3 ), 2.85 (m, 1H, CHCH 2 CONHOH), 3.85 (t, 2H, CH 2 OPh), 4.2 (d, 1H, NCH), 6.6 (overlapping t and s, 3H, ArH), 7.09 (t, 1H, ArH)
EXAMPLE 19
(2S)-N-2'- (2'R)-2'-(carboxymethyl)-6'-(3-methylphenoxy)hexanoyl!amino-3,3-dimethylbutanoic acid N-methylamide
Synthesis using a procedure analogous to that of example 13 results in a compound having the following analysis.
1 H NMR (CD 3 OD) δ0.97 (s, 9H, t-butyl), 1.36-1.8 (m, 6H, (CH 2 ) 3 ), 2.25 (s, 3H, PhCH 3 ), 2.4-2.59 (dd, 2H, CH 2 COOH), 2.64 (s, 3H, NCH 3 ), 2.84 (m, 1H, CHCH 2 CONHOH), 3.9 (t, 2H, CH 2 OPh), 4.2 (d, 1H, NCH), 6.68 (overlapping t and s, 3H, ArH), 7.09 (t, 1H, ArH)
The potency of compounds of the present invention to act as inhibitors of the MMPs is determined by using recombinant MMPs as follows.
Human cDNA for fibroblast collagenase and fibroblast stromelysin is obtained (Goldberg, G. I., Wilhelm, S. M., Kronberger, A., Bauer, E. A., Grant, G. A., and Eisen, A. Z. (1986) J. Biol. Chem. 262, 5886-9). Human cDNA for neutrophil collagenase is obtained (Devarajan, P., Mookhtiar, K., Van Wart, H. E. and Berliner, N. (1991) Blood 77, 2731-2738). The MMPs are expressed in E. coli as inclusion bodies with the expression vector pET11a (Studier, F. W., Rosenberg, A. H. Dunn, J. J., and Dubendorff, J. W. (1990) Methods in Enzymology 185, 60-89). Fibroblast stromelysin and neutrophil collagenase are expressed as mature enzymes with C-terminal truncations, Phe83-Thr260 and Met100-Gly262, respectively. Fibroblast collagenase is expressed as a proenzyme with a C-terminal truncation, Met1-Pro250. Inclusion bodies are solubilized in 6M urea, purified by ion exchange, and folded into their native conformation by removal of urea. Fibroblast collagenase is activated by incubation with p-aminophenylmercury. All active MMPs are purified by gel filtration.
MMPs are assayed with peptide substrates based on R-Pro-Leu-Ala-Leu-X-NH-R 2 , where R=H or benzoyl, X=Trp or O-methyl-Tyr, R 2 =Me or butyldimethylamino. The product is determined by fluorescence after reaction with fluorescamine with overall conditions and procedures similar to those of Fields, G. B., Van Wart, H. E., and Birkedal-Hansen, H. (1987) J. Biol. Chem. 262, 6221.
In the following table K i values are micromolar and are calculated from the measured percent inhibition using the K m value, and assuming competitive inhibition. HFS is Human Fibroblast Stromelysin. HFC is Human Fibroblast Collagenase. HNC is Human Neutrophil Collagenase.
______________________________________Compound ofExample HFS HFC HNC______________________________________ 2 0.015 1.45 <0.002 3 2.19 0.03 0.007 4 14.56 3.35 0.270 5 0.378 5.10 <0.002 6 1.50 0.15 0.020 8 0.057 1.4 0.005 9 5.00 0.027 0.01710 0.044 2.27 0.2111 0.019 0.92 0.00412 0.70 1.6 0.12013 0.028 0.008 --14 0.014 0.026 --15 0.026 0.035 0.01616 0.017 0.014 --17 0.009 0.021 --19 0.22 1.8 --______________________________________
Although this invention has been described with respect to specific modification, the details thereof are not to be construed as limitations, for it will be apparent that various equivalents, changes and modifications may be restored and modification may be resorted to without departing from the spirit and scope thereof and it is understood that such equivalent embodiments are intended to be included therein.
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This disclosure relates to a novel class of hydroxamic and carboxylic acid based matrix metalloproteinase inhibitor derivatives. The disclosure further relates to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in the treatment of matrix metalloproteinase induced diseases.
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RELATED APPLICATION
[0001] This application is a continuation-in-part application of U.S. patent application Ser. No. 11/122,472, filed May 5, 2005, which is a continuation application of U.S. patent application Ser. No. 10/824,214, filed Apr. 14, 2004, and claims the benefit of prior provisional application 60/513,396, filed on Oct. 21, 2003 under 35 U.S.C. 119(e). This application claims the benefit of these prior applications and these applications are incorporated by reference herein as though set forth in full.
BACKGROUND
[0002] 1. Field of the Invention
[0003] The present invention generally relates to mobile medical diagnostic measurement devices and more particularly relates to a media card authorization apparatus and its method of use.
[0004] 2. Related Art
[0005] Diabetes remains one of the most serious and under-treated diseases facing the worldwide healthcare system. Diabetes is a chronic disease where the body fails to maintain normal levels of glucose in the bloodstream. It is now the fifth leading cause of death from disease in the U.S. today and accounts for about 15% of the entire healthcare budget. People with diabetes are classified into two groups: Type 1 (formerly known as “juvenile onset” or “insulin dependent” diabetes, that are required to take insulin to maintain life) and Type 2 (formerly known as “adult onset” or “non-insulin dependent,” that may require insulin but may sometimes be treated by diet and oral hypoglycemic drugs). In both cases, without dedicated and regular blood glucose measurement, all patients face the possibility of the complications of diabetes that include cardiovascular disease, kidney failure, blindness, amputation of limbs and premature death.
[0006] The number of cases of diabetes in the U.S. has jumped 40% in the last decade. This high rate of growth is believed to be due to a combination of genetic and lifestyle origins that appear to be a long-term trend, including obesity and poor diet. The American Diabetes Association (“ADA”) and others estimate that about 17 million Americans and over 150 million people worldwide have diabetes, and it is estimated that up to 40% of these people are currently undiagnosed [Diabetes Association, “Facts & Figures”].
[0007] Diabetes must be “controlled” in order to delay the onset of the disease complications. Therefore, it is essential for people with diabetes to measure their blood glucose levels several times per day in an attempt to keep their glucose levels within the normal range (80 to 126 mg/dL). These glucose measurements are used to determine the amount of insulin or alternative treatments necessary to bring the glucose level to within target limits. Self-Monitoring of Blood Glucose (“SMBG”) is an ongoing process repeated multiple times per day for the rest of the patient's lifetime.
[0008] All currently Food and Drug Administration (“FDA”) approved invasive or “less-invasive” (blood taken from the arm or other non-fingertip site) glucose monitoring products currently on the market require the drawing of blood in order to make a quantitative measurement of blood glucose. The ongoing and frequent measurement requirements (1 to possibly 10 times per day) presents all diabetic patients with pain, skin trauma, inconvenience, and infection risk resulting in a general reluctance to frequently perform the critical measurements necessary for selecting the appropriate insulin dose or other therapy.
[0009] These current product drawbacks have led to a poor rate of patient compliance. Among Type 1 diabetics, 39% measure their glucose levels less than once per day and 21% do not monitor their glucose at all. Among Type 2 diabetics who take insulin, only 26% monitor at least once per day and 47% do not monitor at all. Over 75% of non-insulin-taking Type 2 diabetics never monitor their glucose levels [Roper Starch Worldwide Survey]. Of 1,186 diabetics surveyed, 91% showed interest in a non-invasive glucose monitor. As such, there is both a tremendous interest and clinical need for a non-invasive glucose measurement device. A further need exists for systems and methods to track glucose measurements from a non-invasive glucose measurement device to ensure timely use and for monitoring the use of such a device to ensure compliance.
SUMMARY
[0010] Accordingly, the present invention provides systems and methods for enabling the use of a non-invasive analyte measurement (“NAM”) device through a refillable media card that allows the non-invasive analyte measurement device to operate regardless of location. The NAM device is configured to measure one or more analyte levels of a user (e.g., the concentration, presence, and/or absence of one or more analytes). The ability to operate the NAM device may be governed by a media card that tracks a predetermined number of authorized uses. In addition to tracking the number of authorized uses of the NAM device, the media card may also store the results of the measurements for tracking by a tracking server. When the number of authorized uses on the media card is depleted, the media card may be refilled by completing a refill transaction over a wired or wireless communication network. Alternatively, the media card may be refilled at a kiosk station or a new media card may be obtained.
[0011] Other features and advantages of the present invention will become more readily apparent to those of ordinary skill in the art after reviewing the following detailed description and accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] The details of the present invention, both as to its structure and operation, may be gleaned in part by study of the accompanying drawings, in which like reference numerals refer to like parts, and in which:
[0013] FIG. 1 is a block diagram illustrating an example non-invasive analyte measurement device in operation according to an embodiment of the present invention;
[0014] FIG. 2 is a block diagram illustrating an non-invasive analyte measurement device and an example media card for use with the non-invasive analyte measurement device according to an embodiment of the present invention;
[0015] FIG. 3 is a network diagram illustrating an example system for refilling a media card for use with a non-invasive analyte measurement device according to an embodiment of the present invention;
[0016] FIG. 4 is a block diagram illustrating an example media card for use with a non-invasive analyte measurement device according to an embodiment of the present invention;
[0017] FIG. 5 is a flow diagram illustrating an example process for use of a media card with a predetermined number of authorized uses for a non-invasive analyte measurement device according to an embodiment of the present invention;
[0018] FIG. 6 is a block diagram illustrating an example wireless communication device that may be used in connection with various embodiments described herein; and
[0019] FIG. 7 is a block diagram illustrating an example computer system that may be used in connection with various embodiments described herein.
DETAILED DESCRIPTION
[0020] Certain embodiments as disclosed herein provide for a media card for use with a non-invasive analyte measurement (“NAM”) device. In one embodiment, the media card contains a certain number of pre-authorized uses of the NAM device and authenticates the continued use of the NAM device. When the number of pre-authorized uses is depleted or near depleted, the media card can be refilled or replaced to allow continued pre-authorized operation of the NAM device. For example, a network or kiosk transaction can replenish the number of pre-authorized uses on the media card or a new card can be purchased at a pharmacy or other convenient location.
[0021] After reading this description it will become apparent to one skilled in the art how to implement the invention in various alternative embodiments and alternative applications. However, although various embodiments of the present invention will be described herein, it is understood that these embodiments are presented by way of example only, and not limitation. As such, this detailed description of various alternative embodiments should not be construed to limit the scope or breadth of the present invention as set forth in the appended claims.
[0022] Additionally, in the context of this application, the term “analyte” as used herein describes any particular substance or chemical constituent to be measured. Analyte may also include any substance in the tissue of a subject, in a biological fluid (for example, blood, interstitial fluid, cerebral spinal fluid, lymph fluid or urine), or is present in air that was in contact with or exhaled by a subject, which demonstrates an electromagnetic radiation signature, for example, infrared. Analyte may also include any substance which is foreign to or not normally present in the body of the subject. Analytes can include naturally occurring substances, artificial substances, metabolites, and/or reaction products. In some embodiments, the analyte for measurement by the devices and methods described herein is glucose. However, other analytes are contemplated as well, including, but not limited to, metabolic compounds or substances, carbohydrates such as sugars including glucose, proteins, glycated proteins, fructosamine, hemoglobin Alc, peptides, amino acids, fats, fatty acids, triglycerides, polysaccharides, alcohols including ethanol, toxins, hormones, vitamins, bacteria-related substances, fungus-related substances, virus-related substances, parasite-related substances, pharmaceutical or non-pharmaceutical compounds, substances, pro-drugs or drugs, and any precursor, metabolite, degradation product or surrogate marker of any of the foregoing. Other analytes are contemplated as well, including, but not limited, to acarboxyprothrombin; acylcarnitine; adenine phosphoribosyl transferase; adenosine deaminase; albumin; alpha-fetoprotein; amino acid profiles (arginine (Krebs cycle), histidine/urocanic acid, homocysteine, phenylalanine/tyrosine, tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers; arginase; benzoylecgonine (cocaine); biotinidase; biopterin; c-reactive protein; carnitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase; conjugated 1-hydroxy-cholic acid; cortisol; creatine kinase; creatine kinase MM isoenzyme; cyclosporin A; d-penicillamine; de-ethylchloroquine; dehydroepiandrosterone sulfate; nucleic acids (deoxyribonucleic acids and ribonucleic acids including native and variant sequences related to acetylator polymorphism, alcohol dehydrogenase, alpha 1-antitrypsin, cystic fibrosis, Down's syndrome, Duchenne/Becker muscular dystrophy, glucose-6-phosphate dehydrogenase, hemoglobin A, hemoglobin S, hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F, D-Punjab, beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1, Leber hereditary optic neuropathy, MCAD, PKU, Plasmodium vivax, sexual differentiation, 21-hydroxylase); 21-deoxycortisol; desbutylhalofantrine; dihydropteridine reductase; diptheria/tetanus antitoxin; erythrocyte arginase; erythrocyte protoporphyrin; esterase D; fatty acids/acylglycines; free -human chorionic gonadotropin; free erythrocyte porphyrin; free thyroxine (FT4); free tri-iodothyronine (FT3); fumarylacetoacetase; galactose/gal-1-phosphate; galactose-1-phosphate uridyltransferase; gentamicin; glucose-6-phosphate dehydrogenase; glutathione; glutathione perioxidase; glycocholic acid; glycosylated hemoglobin; halofantrine; hemoglobin variants; hexosaminidase A; human erythrocyte carbonic anhydrase I; 17-alpha-hydroxyprogesterone; hypoxanthine phosphoribosyl transferase; immunoreactive trypsin; lactate; lead; lipoproteins ((a), B/A-1, ); lysozyme; mefloquine; netilmicin; phenobarbitone; phenytoin; phytanic/pristanic acid; progesterone; prolactin; prolidase; purine nucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3); selenium; serum pancreatic lipase; sissomicin; somatomedin C; specific antibodies (adenovirus, anti-nuclear antibody, anti-zeta antibody, arbovirus, Aujeszky's disease virus, dengue virus, Dracunculus medinensis, Echinococcus granulosus, Entamoeba histolytica, enterovirus, Giardia duodenalisa, Helicobacter pylori, hepatitis B virus, herpes virus, HIV-1, IgE (atopic disease), influenza virus, Leishmania donovani, leptospira, measles/mumps/rubella, Mycobacterium leprae, Mycoplasma pneumoniae, Myoglobin, Onchocerca volvulus, parainfluenza virus, Plasmodium falciparum, poliovirus, Pseudomonas aeruginosa, respiratory syncytial virus, rickettsia (scrub typhus), Schistosoma mansoni, Toxoplasma gondii, Trepenoma pallidium, Trypanosoma cruzi/rangeli, vesicular stomatis virus, Wuchereria bancrofti, yellow fever virus); specific antigens (hepatitis B virus, HIV-1); neurotransmitters (such as glutamate, GABA, dopamine, serotonin), opioid neurotransmitters (such as endorphins, and dynorphins), neurokinins (such as substance P); succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH); thyroxine (T4); thyroxine-binding globulin; trace elements; transferrin; UDP-galactose-4-epimerase; urea; prokaryotic and eukaryotic cell-surface antigens; peptidoglycans; lipopolysaccharide; uroporphyrinogen I synthase; vitamin A; white blood cells; and zinc protoporphyrin. Salts naturally occurring in blood or interstitial fluids can also constitute analytes in certain embodiments. The analyte can be naturally present in the biological fluid, for example, a metabolic product, an antigen, an antibody, and the like. Alternatively, the analyte can be introduced into the body, for example, a contrast agent for imaging, a radioisotope, a chemical agent, a fluorocarbon-based synthetic blood, or pharmaceutical composition, including but not limited to insulin; ethanol; cannabis (marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide, amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine (crack cocaine); stimulants (amphetamines, methamphetamines, Ritalin, Cylert, Preludin, Didrex, PreState, Voranil, Sandrex, Plegine); depressants (barbiturates, methaqualone, tranquilizers such as Valium, Librium, Miltown, Serax, Equanil, Tranxene); tricyclic antidepressants, benzodiazepines, acetaminophen (paracetamol, APAP), aspirin, methadone, hallucinogens (phencyclidine, lysergic acid, mescaline, peyote, psilocybin); narcotics (heroin, codeine, morphine, opium, meperidine, Percocet, Percodan, Tussionex, Fentanyl, Darvon, Talwin, Lomotil); designer drugs (analogs of fentanyl, meperidine, amphetamines, methamphetamines, and phencyclidine, for example, Ecstasy); anabolic steroids; and nicotine. The metabolic products of drugs and pharmaceutical compositions are also contemplated analytes. Analytes such as neurochemicals and other chemicals generated within the body can also be analyzed, such as, for example, ascorbic acid, uric acid, dopamine, noradrenaline, 3-methoxytyramine (3MT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5HT), and 5-hydroxyindoleacetic acid (5HIAA).
[0023] FIG. 1 is a block diagram illustrating an example wireless NAM device 20 in operation according to an embodiment of the present invention. In the illustrated embodiment, the NAM device 20 interrogates a body surface of the subject, for example the eye 40 . Advantageously, the interrogation can be accomplished using electrogmagnetic signals, and more advantageously, infrared (“IR”) signals, such that the measurement is taken non-invasively. As a result of the interrogation, the NAM device 20 measures one or more analyte levels (e.g., the concentration, presence, and/or absence of one or more analytes) for the subject and the measured concentrations can be stored in the data storage area 25 . An example non-invasive analyte measurement device is described in U.S. patent application Ser. No. 11/122,472, which is incorporated by reference herein as though set forth in full. Measurements can be taken periodically by the NAM device 20 such that the data for multiple interrogations can be stored in the data storage area 25 .
[0024] The NAM device 20 is a non-invasive analyte measurement device and can be integrated into any of a variety of types of wired or wireless communication devices including a personal digital assistant (“PDA”), cellular telephone, handheld gaming device, personal computer, laptop computer, specific purpose device, general purpose device, or other device that is capable of use as or modification for use as a non-invasive measurement device. A general purpose wireless communication device is described later with respect to FIG. 6 and a general purpose computer device is described later with respect to FIG. 7 . As will be understood by those having skill in the art, each of these types of devices are suitable for modification and use as the NAM device 20 .
[0025] The data storage area 25 can be any sort of internal or external, fixed or removable memory device and may include both persistent and volatile memories. The function of the data storage area 35 is to maintain data for long term storage and also to provide efficient and fast access to instructions for applications or modules that are executed by the NAM device 20 .
[0026] FIG. 2 is a block diagram illustrating an example media card 100 for use with a NAM device 20 according to an embodiment of the present invention. In one or more embodiments, the media card 100 is any of a variety of types of media cards, for example, but not by way of limitation, compact flash, memory stick, micro drive, multimedia card, smart media card, picture card, card disk, hyper drive, spy disk, walk key, jump drive, or the like. The function of the media card 100 is to store data and information related to the use of the NAM 20 and any sort of media device capable of achieving this function may be employed.
[0027] As shown in the illustrated embodiment, the card 100 is inserted into the NAM 20 for integrated use, for example by inserting the card 100 into a media slot 50 that is configured to receive a media card 100 or other memory storage device. Advantageously, the card 100 contains a certain number of pre-authorized uses for the NAM device 20 and is also configured in combination with the NAM device 20 to store information related to the various measurements taken by the NAM device 20 .
[0028] FIG. 3 is a network diagram illustrating an example system 200 for refilling a media card 100 for use with a NAM device 20 according to an embodiment of the present invention. In the illustrated embodiment, the system 200 comprises NAM device 20 and refill device 210 . These devices are communicatively coupled with a refill server 220 and a tracking server 230 over a network 240 . In one or more embodiments, the system 200 includes more or fewer NAM devices 20 , refill devices 210 , refill servers 220 , and/or tracking servers 230 .
[0029] In one embodiment, the NAM device 20 is configured for network communication and can therefore communication directly with the refill server 220 to replenish the number of authorized uses stored on a media card 100 being used with the NAM device 20 . Such communication may be a simple authorization from the NAM device 20 to charge an account associated with the particular NAM device 20 and in return replenishes the number of authorized uses on the media card 100 . Alternatively, such a communication is an interactive session that walks through a refill transaction that also results in replenishing the number of authorized uses on the media card 100 .
[0030] The network 240 is any of a variety of network types and topologies and any combination of such types and topologies. Network 240 is one or more of a telephone network, a data network, a wired network, a wireless network or any combination of these. For example, in one or more embodiments, the network 240 comprises a plurality of networks including private, public, circuit switched, packet switched, personal area networks (“PAN”), local area networks (“LAN”), wide area networks (“WAN”), metropolitan area networks (“MAN”), or any combination of the these. In one or more embodiments, network 240 includes the particular combination of networks ubiquitously known as the Internet.
[0031] The refill device 210 is any of a variety of computing devices and platforms that are capable of communication with NAM device 20 and/or the refill server 220 and/or the tracking server 230 over the network 240 . In one embodiment, the refill device 210 is resident at a public kiosk and includes a media card reader capable of reading from and writing to a media card 100 being used with the NAM device 20 . The refill device 210 is also configured to communicate with the refill server 220 over the network 240 and to facilitate a transaction that provides the media card 100 with additional pre-authorized uses. In one or more embodiments, the refill device 210 is a dongle that attaches to a general purpose computer or the refill device 210 is integrated with a kiosk device. Advantageously, the refill device 210 may be located in a convenient place such as a local pharmacy, Internet cafe, integrated with a public telephone, ATM machine, or other location/device.
[0032] The refill server 220 is any of a variety of computing devices and platforms that are capable of communication with NAM device 20 or refill device 210 over the network 240 . The refill server 220 is configured to process a transaction with a remote device (e.g., NAM device 20 or refill device 210 ) and replenish the number of pre-authorized uses stored on a memory card. Advantageously, this may be accomplished over network 240 such that a single refill server 220 may contemporaneously process requests for a significant number of NAM devices 20 and refill devices 210 .
[0033] The tracking server 230 can be any of a variety of computing devices and platforms that are capable of communication with NAM device 20 or refill device 210 over the network 240 . In one embodiment, the tracking server 230 is integrated with the refill server 220 . The tracking server 230 is configured to track information related to the use of a NAM device 20 , for example information including the measurements taken by the NAM device 20 and the number of measurements taken by the NAM device 20 . The tracking server 230 is optional but advantageous in that it can help users of the NAM devices 20 to spot trends over time as related to an individual's analyte measurements (e.g., the concentration, presence, and/or absence of one or more analytes) at different times of day and other beneficial metrics may also be tracked and reported by the tracking server 230 .
[0034] FIG. 4 is a block diagram illustrating an example media card 100 for use with a NAM device 20 according to an embodiment of the present invention. In the illustrated embodiment, the media card 100 is provided in a packaging 140 that advantageously allows for distribution of the media card 100 through retail outlets and vending machines. For example, in one or more embodiments, media card 100 is sold at a local pharmacy. In one or more embodiments, the media card 100 is sold with a predetermined number of authorized uses such as, but not limited to 100 uses, 200 uses, 500 uses, and 1000 uses. In one or more embodiments, different media cards 100 come with various numbers of authorized uses, depending on the need of the individual user. In one embodiment, a NAM device 20 is integrated with a kiosk device that allows any person from the general public to use the device to measure the individual's analyte levels (e.g., the concentration, presence, and/or absence of one or more analytes). In such an embodiment, the purveyor of the kiosk device may purchase a media card 100 with 1000 authorized uses so that the kiosk needs infrequent servicing to replenish the number of authorized uses.
[0035] FIG. 5 is a flow diagram illustrating an example process for use of a media card 100 with a predetermined number of authorized uses for a NAM device 20 according to an embodiment of the present invention. The illustrated process may be carried out by a NAM device 20 such as that previously described with respect to FIGS. 1 and 3 . Initially, in step 300 the NAM device 20 receives a request for use. The request can come from a user of the NAM device 20 by depressing a button or speaking a command or by some other means. For example, in an exemplary embodiment, the user holds the device in proximity to a body surface such as the eye and press a button for one or more analyte measurements to be taken (e.g., the concentration, presence, and/or absence of one or more analytes).
[0036] In step 310 , the NAM device 20 determines if the NAM device 20 is authorized for use. For example, in one embodiment, the NAM device 20 is leased with a certain number of pre-authorized uses. Advantageously, the number of pre-authorized uses is identified on a media card device and updated by the NAM device 20 after each use of the NAM device 20 . Accordingly, in step 310 the NAM device 20 determines if there are additional authorized uses remaining and if there are, the NAM device 20 proceeds to normal use in step 320 .
[0037] If, however, there are no remaining authorized uses, the NAM device 20 next determines if the user wants to refill the number of authorized uses, as shown in step 330 . In one embodiment, the NAM device 20 is configured so that additional authorized uses are automatically obtained without intervention by the user. Advantageously, the NAM device 20 is configured to obtain the additional authorized uses prior to the number of uses being completely depleted so that there is no inconvenience to the user with respect to the need for obtaining additional authorized uses.
[0038] In step 330 if the NAM device 20 determines that the user does not wish to obtain more authorized uses, in the step 340 the NAM device 20 disables the measurement functionality until such authorized uses are obtained. Advantageously, other functions of the NAM device 20 are still usable, for example if the NAM device 20 is combined with a cell phone or PDA or the like.
[0039] In step 330 if the NAM device 20 determines that the user does wish to obtain more authorized uses, in step 350 the NAM device 20 determines if it is able to replenish the authorized uses via an available network connection. If a network connection is available, the NAM device 20 contacts a refill server 220 , as shown in step 360 . Advantageously, as part of the network communication, the NAM device 20 provides additional measurement related information to the refill server 220 or a tracking server 230 .
[0040] If no network connection is available, as determined in step 350 , then the user manually replenishes the authorized uses at a kiosk or other refill device, as shown in step 370 . Alternatively, the user provides the NAM device 20 with a new or different media card 100 that includes additional authorized uses. Thus, it can be advantageous for a user to carry an additional media card 100 with authorized uses stored on it so that the user is able to take a measurement, for example, when the primary media card 100 is depleted and the user is out of range of any network that would provide the NAM device 20 with access to a refill server 220 .
[0041] FIG. 6 is a block diagram illustrating an example wireless communication device 450 used in connection with one or more embodiments described herein. For example, in one or more embodiments, the wireless communication device 450 is used in conjunction with the NAM device 20 or the refill device 210 previously described with respect to FIG. 3 . However, in alternative embodiments, other wireless communication devices and/or architectures are used, as will be clear to those skilled in the art.
[0042] In the illustrated embodiment, wireless communication device 450 comprises an antenna system 455 , a radio system 460 , a baseband system 465 , a speaker 470 , a microphone 480 , a central processing unit (“CPU”) 485 , a data storage area 490 , and a hardware interface 495 . In the wireless communication device 450 , radio frequency (“RF”) signals are transmitted and received over the air by the antenna system 455 under the management of the radio system 460 .
[0043] In one embodiment, the antenna system 455 comprises one or more antennae and one or more multiplexors (not shown) that perform a switching function to provide the antenna system 455 with transmit and receive signal paths. In the receive path, received RF signals can be coupled from a multiplexor to a low noise amplifier (not shown) that amplifies the received RF signal and sends the amplified signal to the radio system 460 .
[0044] In alternative embodiments, the radio system 460 comprises one or more radios that are configured to communication over various frequencies. In one embodiment, the radio system 460 combines a demodulator (not shown) and modulator (not shown) in one integrated circuit (“IC”). Alternatively, the demodulator and modulator are separate components. In the incoming path, the demodulator strips away the RF carrier signal leaving a baseband receive audio signal, which is sent from the radio system 460 to the baseband system 465 .
[0045] If the received signal contains audio information, then baseband system 465 decodes the signal and converts it to an analog signal. Then the signal is amplified and sent to the speaker 470 . The baseband system 465 also receives analog audio signals from the microphone 480 . These analog audio signals are converted to digital signals and encoded by the baseband system 465 . The baseband system 465 also codes the digital signals for transmission and generates a baseband transmit audio signal that is routed to the modulator portion of the radio system 460 . The modulator mixes the baseband transmit audio signal with an RF carrier signal generating an RF transmit signal that is routed to the antenna system and may pass through a power amplifier (not shown). The power amplifier amplifies the RF transmit signal and routes it to the antenna system 455 where the signal is switched to the antenna port for transmission.
[0046] The baseband system 465 is also communicatively coupled with the central processing unit 485 . The central processing unit 485 has access to a data storage area 490 . The central processing unit 485 is preferably configured to execute instructions (i.e., computer programs or software) that can be stored in the data storage area 490 . Computer programs can also be received from the baseband processor 465 and stored in the data storage area 490 or executed upon receipt. Such computer programs, when executed, enable the wireless communication device 450 to perform the various functions of the present invention as previously described. For example, data storage area 490 includes various software modules (not shown) that facilitate the operation of the various functions of the invention.
[0047] In this description, the term “computer readable medium” is used to refer to any media used to provide executable instructions (e.g., software and computer programs) to the wireless communication device 450 for execution by the central processing unit 485 . Examples of these media include the data storage area 490 , microphone 470 (via the baseband system 465 ), antenna system 455 (also via the baseband system 465 ), and hardware interface 495 . These computer readable mediums are means for providing executable code, programming instructions, and software to the wireless communication device 450 . The executable code, programming instructions, and software, when executed by the central processing unit 485 , preferably cause the central processing unit 485 to perform the inventive features and functions previously described herein.
[0048] The central processing unit 485 is also preferably configured to receive notifications from the hardware interface 495 when new devices are detected by the hardware interface. Hardware interface 495 can be a combination electromechanical detector with controlling software that communicates with the CPU 485 and interacts with new devices. The hardware interface 495 may be a firewire port, a USB port, a Bluetooth or infrared wireless unit, or any of a variety of wired or wireless access mechanisms. Examples of hardware linkable with the device 450 include data storage devices, computing devices, headphones, microphones, and the like.
[0049] FIG. 7 is a block diagram illustrating an exemplary computer system 550 used in connection with one or more embodiments described herein. For example, in one embodiment, the computer system 550 is used in conjunction with the refill server 220 and/or the tracking server 230 previously described with respect to FIG. 3 . However, in alternative embodiments, other computer systems and/or architectures are used, as will be clear to those skilled in the art.
[0050] The computer system 550 preferably includes one or more processors, such as processor 552 . Additional processors may be provided, such as an auxiliary processor to manage input/output, an auxiliary processor to perform floating point mathematical operations, a special-purpose microprocessor having an architecture suitable for fast execution of signal processing algorithms (e.g., digital signal processor), a slave processor subordinate to the main processing system (e.g., back-end processor), an additional microprocessor or controller for dual or multiple processor systems, or a coprocessor. Such auxiliary processors are discrete processors or integrated with the processor 552 .
[0051] The processor 552 is preferably connected to a communication bus 554 . The communication bus 554 includes a data channel for facilitating information transfer between storage and other peripheral components of the computer system 550 . The communication bus 554 provides a set of signals used for communication with the processor 552 , including a data bus, address bus, and control bus (not shown). The communication bus 554 comprises any standard or non-standard bus architecture such as, for example, bus architectures compliant with industry standard architecture (“ISA”), extended industry standard architecture (“EISA”), Micro Channel Architecture (“MCA”), peripheral component interconnect (“PCI”) local bus, or standards promulgated by the Institute of Electrical and Electronics Engineers (“IEEE”) including IEEE 488 general-purpose interface bus (“GPIB”), IEEE 696/S-100, and the like.
[0052] Computer system 550 preferably includes a main memory 556 and, in one or more embodiments, includes a secondary memory 558 . The main memory 556 provides storage of instructions and data for programs executing on the processor 552 . The main memory 556 is typically semiconductor-based memory such as dynamic random access memory (“DRAM”) and/or static random access memory (“SRAM”). Other semiconductor-based memory types include, for example, synchronous dynamic random access memory (“SDRAM”), Rambus dynamic random access memory (“RDRAM”), ferroelectric random access memory (“FRAM”), and the like, including read only memory (“ROM”).
[0053] In one or more embodiments, the secondary memory 558 includes a hard disk drive 560 and/or a removable storage drive 562 , for example a floppy disk drive, a magnetic tape drive, a compact disc (“CD”) drive, a digital versatile disc (“DVD”) drive, etc. The removable storage drive 562 reads from and/or writes to a removable storage medium 564 in a well-known manner. Removable storage medium 564 may be, for example, a floppy disk, magnetic tape, CD, DVD, etc.
[0054] The removable storage medium 564 is preferably a computer readable medium having stored thereon computer executable code (i.e., software) and/or data. The computer software or data stored on the removable storage medium 564 is read into the computer system 550 as electrical communication signals 578 .
[0055] In alternative embodiments, secondary memory 558 includes other similar means for allowing computer programs or other data or instructions to be loaded into the computer system 550 . Such means include, for example, an external storage medium 572 and an interface 570 . Examples of external storage medium 572 include an external hard disk drive or an external optical drive, or and external magneto-optical drive.
[0056] Other examples of secondary memory 558 include semiconductor-based memory such as programmable read-only memory (“PROM”), erasable programmable read-only memory (“EPROM”), electrically erasable read-only memory (“EEPROM”), or flash memory (block oriented memory similar to EEPROM). Also included are any other removable storage units 572 and interfaces 570 , which allow software and data to be transferred from the removable storage unit 572 to the computer system 550 .
[0057] In one or more embodiments, computer system 550 includes a communication interface 574 . The communication interface 574 allows software and data to be transferred between computer system 550 and external devices (e.g. printers), networks, or information sources. For example, computer software or executable code are transferred to computer system 550 from a network server via communication interface 574 . Examples of communication interface 574 include a modem, a network interface card (“NIC”), a communications port, a PCMCIA slot and card, an infrared interface, and an IEEE 1394 fire-wire, just to name a few.
[0058] Communication interface 574 preferably implements industry promulgated protocol standards, such as Ethernet IEEE 802 standards, Fiber Channel, digital subscriber line (“DSL”), asynchronous digital subscriber line (“ADSL”), frame relay, asynchronous transfer mode (“ATM”), integrated digital services network (“ISDN”), personal communications services (“PCS”), transmission control protocol/Internet protocol (“TCP/IP”), serial line Internet protocol/point to point protocol (“SLIP/PPP”), and so on, but may also implement customized or non-standard interface protocols as well.
[0059] Software and data transferred via communication interface 574 are generally in the form of electrical communication signals 578 . These signals 578 are preferably provided to communication interface 574 via a communication channel 576 . Communication channel 576 carries signals 578 and can be implemented using a variety of wired or wireless communication means including wire or cable, fiber optics, conventional phone line, cellular phone link, wireless data communication link, radio frequency (RF) link, or infrared link, just to name a few.
[0060] Computer executable code (i.e., computer programs or software) is stored in the main memory 556 and/or the secondary memory 558 . In one or more embodiments, computer programs are received via communication interface 574 and stored in the main memory 556 and/or the secondary memory 558 . Such computer programs, when executed, enable the computer system 550 to perform the various functions of the present invention as previously described.
[0061] In this description, the term “computer readable medium” is used to refer to any media used to provide computer executable code (e.g., software and computer programs) to the computer system 550 . Examples of these media include main memory 556 , secondary memory 558 (including hard disk drive 560 , removable storage medium 564 , and external storage medium 572 ), and any peripheral device communicatively coupled with communication interface 574 (including a network information server or other network device). These computer readable mediums are means for providing executable code, programming instructions, and software to the computer system 550 .
[0062] In an embodiment that is implemented using software, the software is stored on a computer readable medium and loaded into computer system 550 by way of removable storage drive 562 , interface 570 , or communication interface 574 . In such an embodiment, the software is loaded into the computer system 550 in the form of electrical communication signals 578 . The software, when executed by the processor 552 , preferably causes the processor 552 to perform the inventive features and functions previously described herein.
[0063] Another embodiment is implemented primarily in hardware using, for example, components such as application specific integrated circuits (“ASICs”), or field programmable gate arrays (“FPGAs”). Implementation of a hardware state machine capable of performing the functions described herein will also be apparent to those skilled in the relevant art. One or more further embodiments are implemented using a combination of both hardware and software.
[0064] Furthermore, in one or more embodiments, the various illustrative logical blocks, modules, circuits, and method steps described in connection with the above described figures and the embodiments disclosed herein are implemented as electronic hardware, computer software, or combinations of both. To clearly illustrate this interchangeability of hardware and software, various illustrative components, blocks, modules, circuits, and steps have been described above generally in terms of their functionality. Whether such functionality is implemented as hardware or software depends upon the particular application and design constraints imposed on the overall system. Skilled persons can implement the described functionality in varying ways for each particular application, but such implementation decisions should not be interpreted as causing a departure from the scope of the invention. In addition, the grouping of functions within a module, block, circuit or step is for ease of description. Specific functions or steps are movable from one module, block or circuit to another without departing from the invention.
[0065] Moreover, in one or more embodiments, the various illustrative logical blocks, modules, and methods described herein are implemented or performed with a general purpose processor, a digital signal processor (“DSP”), an ASIC, FPGA or other programmable logic device, discrete gate or transistor logic, discrete hardware components, or any combination thereof designed to perform the functions described herein. In one or more embodiments, a general-purpose processor is a microprocessor. Alternatively, the processor is any processor, controller, microcontroller, or state machine. In one or more embodiments, a processor is implemented as a combination of computing devices, for example, a combination of a DSP and a microprocessor, a plurality of microprocessors, one or more microprocessors in conjunction with a DSP core, or any other such configuration.
[0066] Additionally, in one or more embodiments, the steps of a method or algorithm described in connection with the embodiments disclosed herein are embodied directly in hardware, in a software module executed by a processor, or in a combination of the two. A software module resides in RAM memory, flash memory, ROM memory, EPROM memory, EEPROM memory, registers, hard disk, a removable disk, a CD-ROM, or any other form of storage medium including a network storage medium. An exemplary storage medium is coupled to the processor such the processor reads information from, and writes information to, the storage medium. In the alternative, the storage medium is integral to the processor. In one or more embodiments, the processor and the storage medium reside in an ASIC.
[0067] The above description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles described herein can be applied to other embodiments without departing from the spirit or scope of the invention. Thus, it is to be understood that the description and drawings presented herein represent a presently preferred embodiment of the invention and are therefore representative of the subject matter which is broadly contemplated by the present invention. It is further understood that the scope of the present invention fully encompasses other embodiments that may become obvious to those skilled in the art and that the scope of the present invention is accordingly limited by nothing other than the appended claims.
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An apparatus and method of use for enabling a NAM device are provided. The NAM device is configured to authenticate its use each time a measurement is requested. The operation of the NAM device is governed by a refillable media card that tracks a predetermined number of authorized uses. The NAM device confirms that remaining authorized uses are available on the refillable media card. In addition to tracking the number of authorized uses of the NAM device, the media card may also store the results of the measurements for tracking by a tracking server. When the number of authorized uses on the media card is depleted, the media card may be refilled by completing a refill transaction over a wired or wireless communication network. Alternatively, the media card may be refilled at a kiosk station or a new media card may be obtained for use with the NAM device.
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FIELD OF THE INVENTION
[0001] The present invention is generally related to a herbal extract, and more particularly to a herbal extract for inhibiting growth of tumor.
BACKGROUND OF THE INVENTION
[0002] There is one new cancer patient in Taiwan for every 5 minutes and 48 seconds in 2010, according to the Department of Health (DOH) of Taiwan. The DOH also reports that there are 90,649 new cancer patients in total in 2010 to reach the highest all-time record, and the disease of cancer has been the top cause of death in Taiwan for the past 31 years.
[0003] The disease of cancer is occurred because of uncontrollably growing of human's cells that are not to be dead but become immortalized. Normal cells in the body follow an orderly path of growth, division, and death. A programmed death of cell is called apoptosis, and when this process breaks down, cancer begins to form. Accordingly, the immortalized cells growing beyond their normal limit will invade adjacent tissues and the malignant cells may also metastasize to spread to other locations in the body via the bloodstream or lymphatic system. Therefore, cancer cells often form a mass tissue known as a tumor.
[0004] There are many different causes of cancer including; carcinogens, age, genetic mutations, immune system problems, diet, weight, lifestyle, andenvironmental factors such as pollutants. Some viruses such as a human papilloma virus (HPV) that is implicated in cervical cancer and some bacterial infections are also known to cause cancers.
[0005] There are many well-know cancer treating methods that are being implemented today. Some of them include the standard methods of cancer treatments such as surgery, chemotherapy and radiation therapy. The choice of therapy depends upon the location and grade of the tumor, the situation of the disease, and the general condition of a person's health as well. Surgery is used for removing the visible tumor and is effective when the cancer is small and confined. However, the metastasis situation that cancers already invade the adjacent tissue or spread to distant sites often limits effectiveness of surgery. Chemotherapy, using drugs to kill cancer cells, can be used for destroying cancer cells that are hard to detect and that have been spreading. The effectiveness of chemotherapy is often limited by toxicity to tissues of the body. Radiation, designed to kill cancer cells, can be applied externally or internally of the body, but also can cause damage to normal tissue.
[0006] There are other alternative methods available for cancer treatment that are applied by integrating traditional treating manners to help the cancer patient, and sometimes to be recommended for alleviating some side effects of treatments caused in chemotherapy and radiation. In these alternative treatments, it includes a treatment by use of traditional medical herb. In theory and practice, the traditional medical herb is completely different from the modern western medical treatment in that the traditional medical herb is applied by considering the way that the tissues of human body work with each other, the way that the human body falls illness, and that processes to treat the illness. The treating theory of the traditional medical herb is for treating a whole human body rather than a specific portion of the human body. The traditional medical herb is used for treating (I) the vitality of human body by tonic herbs, (II) the cancer by anti-cancer herbs and (III) the side effects caused by radiation therapy and chemotherapy.
[0007] Therefore, the formula of the traditional medical herb usually comprises components extracting from raw herbs with a very small quantity. The theory pursues the goal of achieving synergism among these different components. One advantage of this kind of synergism theory is that it avoids the chance of excessive toxicity that is happened when any one in these components is given in large quantity. This is in sharp contrast to the modern western medical treatment where a pharmacologically active molecule is given in a large dose, which is a maximally tolerated dose, to target one physiologic endpoint.
SUMMARY OF THE INVENTION
[0008] It becomes an important issue regarding how to provide a herb for inhibiting a growth of tumor and a herbal extracts that can be taken by a user conveniently.
[0009] A castor plant ( Ricinus communis ) belongs to a Euphorbia Family ( Euphorbiaceae ), where there are diverse species as a kind of economically-important flowering plants. It is the only member of the genus Ricinus, and it has no immediate relatives. It is a robust annual that may grow 2 to 5 meters in one season with full sunlight, heat and adequate moisture. In areas with mild, frost-free winters, it may live for many years and become quite woody and tree-like. The large, palmately lobed leaves may be over 50 cm. The stalked leaves usually consist of eight radiating, pointed leaflets with slightly serrated edges and prominent central veins. Flowers occur most of the year in dense terminal clusters (inflorescences), with female flowers just above the male flowers. This species is clearly monoecious, with separate male and female flowers on the same individual. There are no petals and each female flower consists of a little spiny ovary (which develops into the fruit or seed capsule), and a bright red structure with feathery branches (stigma lobes) that receives pollen from male flowers. Each male flower consists of a cluster of many stamens which literally smoke as they shed pollen in a gust of wind. The spiny seed pod or capsule is composed of three sections or carpels which split apart at maturity. Each section (carpel) contains a single seed. When the carpel dries and splits open, the seed is often ejected with considerable force. The seeds (and to a much lesser extent the leaves) contain ricin, a protein, which is highly toxic in small quantities.
[0010] Ricin can be targeted to specific unwanted cells, such as cancer cells, by conjugating the Ricin toxin A-chain (RTA subunit) to antibodies or growth factors that preferentially bind the unwanted cells. These immunotoxins have worked very well for vitro applications, e.g. bone marrow transplants.
[0011] In bone marrow transplant procedures, RTA-immunotoxins have been used successfully to destroy T lymphocytes in bone marrow taken from histocompatible donors. This reduces rejection of the donor bone marrow, a problem called “graft-vs-host disease” (GVHD). With regard to steroid-resistance, in an acute GVDH situation, it is found RTA-immunotoxins can help to alleviate the condition. Also, for a patient in autologous bone marrow transplantation, the patient's own bone marrow is treated anti-T cell immunotoxins to destroy malignant T-cells existing in T cell leukemias and lymphomas.
[0012] Formosanum Elderberry ( Sambucus formosanum Nakai ), belonging to Caprifoliaceae , has been used in Taiwan as a folk remedy for men's health although it smells really bad. Another name of Formosanum Elderberry is said as Sambucus Chinensis . Their roots and leaves can be used for remedying twist, sprain and strain, and reduce swelling and asepticize. They also can be used for dissolving phlegm, dispelling stasis, relaxing muscles and joints and stimulating blood circulation as well. By the way, the leaves can treat gonorrhea. With leaves covered on the bodies for external treatment, they can sterilize wound, reduce swelling, and waist sprain. The roots, stems, and leaves have the function of removing heat, detoxifying, and treating carbuncle-abscess and swelling.
[0013] Furthermore, Formosanum Elderberry can endure blaze and semi-shade. It can grow in subtropical regions and warm temperate zones. It prefers growing and sowing in moist soil. Its flowering phase is from late spring to summer (May. to Sep.) and its florescence is from May to July. The fruits are bacciform, spherical, and gamboge when they are ripe. The mature period of fruits is from September to December.
[0014] Therefore, an object of the present invention is to provide a herbal extract for inhibiting a growth of tumor. The herbal extracts comprise a combination of herbal extracts derived from plants of Formosanum Elderberry and white castor. The herbal extracts provided herein can be administered to an individual patient who suffers from cancerous conditions to improve a situation of symptoms associated with these diseases.
[0015] According to the present invention, a herbal extract for inhibiting tumor growth is obtained by extracting a mixture of white castor and Formosanum elderberry by use of water and/or alcohol under a heating condition, in which a weight ratio of white castor is 1 to 99% and a weight ratio of Formosanum elderberry is 99 to 1%.
[0016] According to the present invention, in the heating condition of extracting the mixture of white castor and Formosanum elderberry by use of water, the weight ratio of white castor to Formosanum elderberry is within the range of 1:1 to 1:2.
[0017] According to the present invention, in the heating condition of extracting the mixture of white castor and Formosanum elderberry by use of water, the weight ratio of white castor to Formosanum elderberry is within the range of 2:1 to 1:1.
[0018] According to the present invention, the heating condition of extracting the mixture of white castor and Formosanum elderberry by use of water is processed at a temperature above 70° C.
[0019] According to the present invention, the heating condition of extracting the mixture of white castor and Formosanum elderberry by use of water is processed at a temperature above 70° C. for over 60 minutes.
[0020] According to the present invention, a cancer is the one selected from a group consisting of leukemia, lymphoma, Hodgkin lymphomas, non-Hodgkin lymphomas, colorectal cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, thyroid cancer, renal cell carcinoma, hepatoma, bile duct carcinoma, esophageal cancer, nasopharyngeal carcinoma, lung carcinoma, and any combination thereof.
[0021] According to the present invention, the herbal extract is used for reducing a size of a tumor.
[0022] According to the present invention, the herbal extract is in a form of a oral dosage.
[0023] According to the present invention, the oral dosage is in a form of a liquid, a powder, a tablet, a capsule or a multiparticulate dosage form.
[0024] According to the present invention, the herbal extract is obtained by extracting a mixture of white castor, Formosanum elderberry and pig bone by use of water and/or alcohol under a heating condition, in which a weight ratio of white castor is 1 to 99%, a weight ratio of Formosanum elderberry is 99 to 1%, and a weight ratio of pig bone is 99 to 1%.
[0025] The extracts of the present invention possess the effect of reducing the size of the tumor, inhibiting tumor metastasis, inhibiting to some extent of tumor growth, abating to some extent for one or more symptoms associated with cancer, stabilizing the growth of the tumor, extending the time to disease progression, improving overall survival, and increasing the quality of life.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0026] The foregoing and other aspects of the present invention will now be described in more detail with respect to the description and methodologies provided herein. It should be appreciated that the invention can be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
[0027] The terminology used in the description of the invention herein is for the purpose of describing embodiments only but is not intended to limit the invention.
[0028] In one embodiment the herbal composition is an aqueous solution of herbal extracts. In another embodiment the herbal composition is a mixture of the herbal extracts in powdered form. The extracts may be aqueous or organic solvent extracts of the herbs. The extracts may be in liquid or powdered form.
[0029] An extract refers to the residue of soluble solids obtained after an herb, or selected part thereof is for example chopped, crushed, pulverized, minced, or otherwise treated to expose its maximum surface area and to be placed in intimate contact with a liquid, usually but not necessarily, under conditions of agitation and elevated temperature. Then, after a period of time under these conditions, the mixture is filtered to remove solids to obtain the liquid material. In other embodiment, the liquid obtained is further processed by, for example but not limitation, evaporation or freeze drying. The liquid for the extracting process may be water or an organic solvent, for example but not for limitation, an alcohol.
Embodiment 1
[0030] White castor and Formosanum elderberry are picked and washed with cold water, and then the water is drained off from the two herbs, in which the white castor, preferably the root of the white castor, and the Formosanum elderberry are mixed in a weight ratio 1:1 before are put in a pot. In a preferable embodiment, a weight of the white castor and the Formosanum elderberry is 210 gram respectively. And then add an amount of pig bone in a way such as 30 gram into the pot. Add about five bowls of water, which is approximately 1200 mL to thus the water level is high enough to cover all of the herbs materials. Stewing them at above 70° C. over at least 60 minutes by a small fire to evaporate out most of the water. The concentrated herbal extract provided herein can be administered to individuals.
Example 1
[0031] Chang, female patients, complained her loss of appetite for over three months. Her chest X-ray showed mediastinal nodules for examination in the hospital. The mediastinal nodules was diagnosed as diffuse large cell lymphoma by pathological examination. She accepted CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy in the Division of Hematology-Oncology of the hospital. After Chang received six times chemotherapy, she had symptoms including a poor appetite, abdominal distension, dry skin, and hair loss. The assessment of positron emission tomography scanning indicated that there was still residual tumors existing. According to the available blood test data, Chang before chemotherapy was RBC:5.1×10 6 /μl, WBC:5450/μl, PLT:223×10 3 /μl, Hb:15.5 g/dl, Hct:43.9%, MCH:30.4 pg. The data of Chang in chemotherapy final stage was WBC:995/μl, PLT:53×10 3 /μl, Hb:13.3 g/dl. Chang discharged from hospital then she took the herbal extracts as described in the first embodiment. She then went back to the hospital for a blood test a few weeks later, and her data is showed as WBC:7040μl, PLT:570×10 3 /μl, Hb:13.5 g/dl. Before the first beginning of the treatment of chemotherapy, the patient had a normal amount of blood cells (WBC:5450/μl). By the process of chemotherapy that the patient received a variety of combinative chemotherapy drugs in the hospital, therefore she showed side effects of bone marrow suppression, while the number of her white blood cells (WBC:995/μl) was downed in the chemotherapy final stage. However, after she left the hospital and started to administer the herbal composition of the first embodiment, the data of WBC as 1230μl in the beginning is increased 7040/μl. Her health is recovered fast, and her tumor is changed to be smaller. This shows the herbal extract in the first embodiment of the present invention has a significant role in preventing bone marrows suppression.
Embodiment 2
[0032] White castor and Formosanum elderberry are washed with cold water and then the water is drained from the two herbs. The white castor and the Formosanum elderberry are mixed in a weight ratio 1:2 into a pot. And then add an amount of pig bone into the pot. Add about five bowls of water to cover all over the herbs and materials. Stewing them with at above 70° C. over at least 60 minutes by a small fire until most of the water is evaporated out. The concentrated herbal extract provided herein can be administered to individuals.
Example 2
[0033] Patient Chao is a 63-year-old man who firstly developed vague abdominal discomfort. When the pain persisted, his physician referred him for a CT scan, which revealed enlarged lymph nodes in neck, groin, abdominal and aorta. The pathology report described the enlarged lymph nodes was consistent with non-Hodgkin's lymphoma. Chao then completed four cycles of chemotherapy, but the chemotherapy revealed poor treatment efficacy for him. Then Chao discharged from hospital, and he took the herbal extracts in the second embodiment of the present invention. A few weeks later, his fever is stopped. He then goes back to the hospital by lymphatic Photography (Lymphangiogram), and his right cervical and inguinal lymph nodes were clear. His spirits become sparkled and his physical situation is improved to even allow him for outdoors activities. Before he received chemotherapy, his white blood cell count of 5900/μl was normal, but the count values were reduced to degree of 950/μl during a course of treatment. However, after he took herbal extracts in the second embodiment of the present invention continuously after he left the hospital, his white blood cell count is raised to 6540/μl. That indicates the herbal extract in the second embodiment of the present invention has a significant role in preventing bone marrows suppression.
Embodiment 3
[0034] White castor and Formosanum elderberry are washed with cold water and then the water is drained from the two herbs. The white castor and the Formosanum elderberry are mixed in a weight ratio 2:1 into a pot. And then add an amount of pig bone into the pot. Add about five bowls of water to cover all over the herbs and materials. Stewing them at above 70° C. over at least 60 minutes by a small fire to evaporate most of the water out. The concentrated herbal extract provided herein can be administered to individuals.
Example 3
[0035] Patient Chan is a 54-year-old man with a syndrome of recurrent cold and persistent fever. One day, he found there was a lump just above his left clavicle bone suddenly. He went for a biopsy and it was clearly indicated Hodgkin lymphomas. Then Chen went to the hospital through one more surgery to remove multiple lymph nodes near the spinal cord and the spleen. Furthermore, he accepted an entire course of chemotherapy following the surgery, and he started to experience significant chemotherapy-related side effects. Chan tried the medical herbal extracts of the third embodiment following the end of chemotherapy. The herbal extract improves his symptoms of a dry mouth (xerostomia), upset stomach, constipation, diarrhoea and other side effects of chemotherapy. He claims feeling good and stronger and more powerful than ever. No abnormal abdominal lymph node enlargements of his abdomen is presently checked by ultrasonography and positron emission tomography. Before he received chemotherapy, his white blood cell count of 5750/μl was normal. After a course of treatment, his white blood cell count values were reduced at 1050/μl. His white blood cell count is raised to 6650/μl, while he starts to take the herbal extracts in the third embodiment of the present invention continuously following the end of chemotherapy. That also indicates the herbal extract has a significant role in preventing bone marrows suppression and bone marrow stem cells enhanced proliferation.
[0036] Furthermore, a pharmaceutical composition as defined in the specification refers to a mixture of the herbal composition with other chemical components, such as physiologically acceptable carriers and excipients. The purpose of a pharmacological composition is to facilitate administration of an extract or extracts of this invention to patients, e.g. the herbal extract said above is in a form of a oral dosage.
[0037] A physiologically acceptable carrier as defined in the specification refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered composition.
[0038] An excipient as defined in the specification refers to an inert substance added to a pharmaceutical composition to further facilitate administration of the herbal composition. Examples, but not for limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
[0039] When the herbal composition is administered without combination with any other substances, the composition may be encased in a suitable capsule, such as a gelatin capsule. When administered in admixture with other excipients, adjuvants, binders, diluents, disintegrants, etc., the herbal composition may be compressed into a capsule, a tablet, a multiparticulate or a caplet in a conventional manner that is well-known in the art.
[0040] The above description should be considered as only the discussion of the preferred embodiments of the present invention. However, a person with an ordinary skill in the art may make various modifications to the present invention. Those modifications may be considered as still being fallen within the spirit and scope defined by the appended claims.
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A herbal extract for inhibiting the growth of tumor described herein and the herbal extract is obtained by extracting a mixture of white castor and Formosanum elderberry with water and/or alcohol under a heating condition, in which a weight ratio of white castor is 1 to 99% and a weight ratio of Formosanum elderberry is 99 to 1%. The herbal extract is useful in preventing, treating, relieving, and improving the quality-of-life of patients suffering from cancer.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to US Patent Application Ser. No. 61/386,718, the disclosure of which is incorporated herein by reference in its entirety.
BACKGROUND
[0002] 1. Field of Technology
[0003] The present disclosure relates generally to arthroscopic surgery and, specifically to a device and methods for use during arthroscopic surgery.
[0004] 2. Related Art
[0005] During hip arthroscopy, it is often necessary for a surgeon to use an arthroscopy knife to make incisions that will allow the surgeon to gain access to areas near the hip joint. For example, the knife may be used to detach the labrum from the acetabular rim. During the same procedure, the knife may be used to make an incision in the hip capsule. Using the knife to detach the labrum from the acetabulum has its drawbacks because the point at which the knife will exit the labrum is not known prior to making the cut. Therefore, a knife and specifically, methods of use that allow for more precision control of the knife are needed.
SUMMARY
[0006] In one aspect, the present disclosure relates to a method of use during arthroscopic surgery. The method includes inserting a cannulated needle into a joint area of the body, inserting a guidewire through the needle, removing the needle, and inserting an arthroscopy knife into the joint area via the use of the guidewire.
[0007] In an embodiment, the method further includes using the knife to detach a portion of the soft tissue from the bone, performing surgery on the bone, and reattaching the detached portion of the soft tissue to the bone. In another embodiment, the knife includes a proximal end and a distal end. In yet another embodiment, the distal end includes a blade and a guidewire component. In a further embodiment, the soft tissue is a labrum and the bone is an acetabulum. In yet a further embodiment, the step of inserting an arthroscopy knife into the joint area via use of the guidewire includes coupling the arthroscopy knife to the guidewire and inserting the knife into the joint area such that a blade of the knife is inserted between the soft tissue and bone. In yet an even further embodiment, coupling the arthroscopy knife to the guidewire includes inserting the guidewire through the component. In an embodiment, the method further comprises using the knife to make an incision in the hip.
[0008] In another aspect, the present disclosure relates to an arthroscopy knife. The knife includes a proximal end and a distal end, the distal end including a blade and a guidewire component.
[0009] In an embodiment, the distal end is curved. In another embodiment, the guidewire component includes a through hole.
[0010] In yet another aspect, the present disclosure relates to a method of use during arthroscopic surgery. The method includes inserting a cannulated needle through a first passage into a joint area of the body; inserting a guidewire through the needle; inserting an arthroscopy knife into the joint area via the use of the guidewire; and creating an incision in a capsule surrounding the joint, the incision located between the first passage and a second passage.
[0011] In an embodiment, the method further includes removing the needle after inserting the guidewire. In another embodiment, the method further includes using the knife to detach a portion of soft tissue from bone, performing surgery on the bone, and reattaching the detached portion of the soft tissue to the bone. In yet another embodiment, the knife includes a proximal end and a distal end. In a further embodiment, the distal end includes a blade and a guidewire component. In yet a further embodiment, the soft tissue is a labrum and the bone is an acetabulum. In yet a further embodiment, the step of inserting an arthroscopy knife into the joint area via use of the guidewire includes coupling the arthroscopy knife to the guidewire and inserting the knife into the joint area such that a blade of the knife is inserted between the soft tissue and bone. In an embodiment, coupling the arthroscopy knife to the guidewire includes inserting the guidewire through the component.
[0012] Further areas of applicability of the present disclosure will become apparent from the detailed description provided hereinafter. It should be understood that the detailed description and specific examples, while indicating the preferred embodiment of the disclosure, are intended for purposes of illustration only and are not intended to limit the scope of the disclosure.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] The accompanying drawings, which are incorporated in and form a part of the specification, illustrate the embodiments of the present disclosure and together with the written description serve to explain the principles, characteristics, and features of the disclosure. In the drawings:
[0014] FIG. 1 shows a perspective view of the arthroscopy knife of the present disclosure.
[0015] FIG. 1A shows an exploded view a distal end of the knife of FIG. 1 .
[0016] FIGS. 2A-2E show a method of detaching a soft tissue from bone during arthroscopic surgery.
[0017] FIG. 3 shows a cross-sectional view of the hip joint while an incision is being made in the hip capsule.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0018] The following description of the preferred embodiment(s) is merely exemplary in nature and is in no way intended to limit the disclosure, its application, or uses.
[0019] As shown in FIGS. 1 and 1A , the knife 10 includes a proximal end 11 and a distal end 12 . The proximal end 11 is configured for being held by a user, such as a surgeon. The distal end 12 includes a blade 12 a and a guidewire component 12 b, the purpose of which will be further described below. The distal end 12 , especially the blade 12 a, may be curved, as shown in FIGS. 1 and 1A . Having a curved distal end 12 biases the blade 12 a against a guidewire when the blade 12 a is coupled to a guidewire, as is further shown in FIGS. 2A-2E and described below, which minimizes the amount of divergence between the blade 12 a and the guidewire. However, a knife 10 having a non-curved distal end may also be used.
[0020] As mentioned above, one of the uses for the knife 10 is detaching soft tissue from bone. Specifically, the knife 10 is used in surgery on the hip joint 20 to detach a labrum 40 from an acetabulum 30 , as shown in FIGS. 2A-2E . A cannulated needle 50 is disposed Within the joint 20 along one of the trajectories A,B, as shown in FIGS. 2A-2B . Other trajectories may be used. A guidewire 60 is then disposed through the cannulation of the needle 50 and the needle 50 is removed from the joint, as shown in FIGS. 2C and 2D . Subsequently, the knife 10 is inserted into the joint 20 via use of the guidewire 60 . Specifically, the knife 10 is coupled to the guidewire 60 by inserting the guidewire 60 through the through hole 12 b ′ of the component 12 b and sliding the knife 10 along the guidewire 60 and into the joint 20 , such that the blade 12 a is located between the acetabulum 30 and the labrum 40 , as shown in FIG. 2E . The surgeon operates the knife 10 to cut at least a portion of the labrum 40 away from the acetabulum 30 , the purpose of which is to allow access to a portion or portions of the acetabulum 30 where surgery is needed. Subsequently, the knife 10 is removed and surgery on the acetabulum 30 is performed. Once surgery is completed, the detached portion of the labrum 40 is reattached to the acetabulum 30 via the use of soft tissue anchors or other fixation devices known to those of skill in the art.
[0021] FIG. 3 shows the use of the knife 10 in creating an incision in the hip capsule 70 . The capsule 70 is a thick layer of soft tissue surrounding the joint 80 , ie the area where the head 91 of the femur 90 is inserted into the acetabulum 30 . This thick layer makes changing the trajectory of instruments placed into the joint 80 difficult. For instance, a first instrument (not shown), such as an endoscope, and a second instrument, such as the knife 10 , may both be inserted through the capsule 70 and into the joint 80 via the use of separate portals or passages. In order to make the use of these instruments less difficult, an incision or slit may be made in the capsule 70 that would connect the portals and allow for less restricted movement of the instruments. This method of creating an incision in the hip capsule 70 may be used in conjunction with the above-described method of detaching soft tissue from bone. For instance, prior to cutting a portion of the labrum 40 away from the acetabulum 30 , the knife 10 may be inserted into the joint area 80 , as described above, and then used to create the incision between the knife portal 100 and the endoscope portal.
[0022] For purposes of clarity, FIG. 3 only shows a cross-sectional view of the hip joint 80 and the knife passage 100 . While the endoscope passage is usually placed within close proximity to the knife passage 100 , the endoscope passage may be created anywhere along the capsule 70 that would allow the surgeon to view the surgical area. The passage 100 may also be used for other instruments, such as an anchor delivery device, or other devices used in surgery on the hip joint 80 .
[0023] For the purposes of this disclosure, the arthroscopy knife 10 is made from a metal material. However, other materials could be used. The knife 10 is made via a process known to one of skill in the art. Additionally, the knife may be used in either manner described above in a joint area other than the hip joint. Furthermore, the incision made in the capsule may be made in other manners. For example, the incision does not have to connect the portals.
[0024] As various modifications could be made to the exemplary embodiments, as described above with reference to the corresponding illustrations, without departing from the scope of the disclosure, it is intended that all matter contained in the foregoing description and shown in the accompanying drawings shall be interpreted as illustrative rather than limiting. Thus, the breadth and scope of the present disclosure should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims appended hereto and their equivalents.
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The present disclosure relates to a method of use during arthroscopic surgery. The method includes inserting a cannulated needle into a joint area of the body, inserting a guidewire through the needle, removing the needle, and inserting an arthroscopy knife into the joint area via the use of the guidewire. An arthroscopy knife and another method of its use is also disclosed.
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BACKGROUND OF THE INVENTION
Field of the Invention
The invention relates to reactive chlorine compounds such as dichloric acids, the intermediate product peroxochloric acid as well as peroxochlorous acid and their individual derivatives, anions, and/or salts. It further relates to processes for manufacturing these compounds and their use in the pharmaceutical field, here in particular, in medical treatment as drugs and disinfectants, in the fields of cosmetics and medicinal care as histocompatible deodorants, in the field of foodstuff treatment and technology, in particular in the preservation of foods and beverages, as a bleaching agent and for drinking water disinfection, in the antimicrobial treatment of plants and fruits in agriculture, and as an oxidizing agent in technical chemistry and for cleaning waste gas.
Oxidizing agents have a very wide range of applications in technical chemistry, in hygiene and in food preservation, in cosmetics and also in pharmaceutical uses.
According to Polly Matzinger (Polly Matzinger: “Tolerance, Danger, and the Extended Family” in Annu. Rev. Immunol. 1994, 12) cells dying due to violence, i.e. through massive radiation effects, toxic substances, parasitic, bacterial or viral infective agents, lytic, non-apoptotic effects, emit danger signals. These must persist so that the body's own defences, which as well as the actual antigen signal require a non-specific co-stimulation from antigen-presenting cells (e.g. macrophages), can have an optimum clinical effect.
During a violent, non-apoptotic cell death, phagocytes (so-called micro and macrophages) are responsible for cellular debris disposal. In this debris disposal process oxidatively effective oxygen metabolites are released. Hydrogen peroxide (H 2 O 2 ) is the most well-known of these substances. In-vitro-trials show that, in the micromolar range, H 2 O 2 can lead to an immune modulation of lymphocytes via the activation of the transcription factor HF-kappa B (R. Schreck et al., The EMBO Journal 10(8), 2247-58 (1991); M. Los et al., Eur. J. Immunol. 25, 159-65 (1995). The working group of Avraham Novogrodsky was the first to demonstrate in vitro that certain oxidizing agents (Bowers W. E.: “Stimulation of Lymphocytes with Periodate or Neuraminidase plus Galactose Oxidase—NAGO” p. 105-109, Review in Immunochemical Techniques Part K Methods in Enzymology Vol. 150, 1987), among other effects, also increase the H 2 O 2 formed in the body itself co-mitogenically by lymphocyte proliferation due to antigen stimulation, if macrophages are simultaneously present in the lymphocyte culture (Stenzel K. H., Rubin A. L., Novogrodsky A.: “Mitogenic and Comitogenic Properties of Hemin.” J. Immunol. 127, 6: 2469-2473 et ibid. cit. ref.). An immune response will be incomplete or not even take place at all if the oxidatively effective oxygen metabolites are not formed in sufficient quantities in the body. Thus a tolerance or pathological anergy results. If the metabolites are produced excessively or for a disproportionately long period, then chronic inflammation and tissue scars will form.
As a result of these findings, one can assume that oxidatively effective oxygen compounds will have a therapeutic effect, particularly in such clinical situations where their endogenous formation is insufficient or deteriorates before the body injuries have completely healed and the infective agents have been totally removed. A treatment success is expected especially in those cases where the cells are indeed affected by the infection but not destroyed and therefore do not emit “danger signals”. Exemplary here are infections with leprosy and tuberculosis bacilli as well as infections caused by herpes and AIDS (HIV) viruses.
A report was published as early as 1906 on the successful clinical use of potassium bichromate in the healing of ichorous chronic wounds (Fenwick, J.: “ The Treatment of Cancer by the Use of Potassium Bichromate ”, British Medical Journal, Mar. 6, 1909, 589-591).
Further numerous publications, which have appeared in the meantime, show that hydrogen peroxide formed physiologically within the body—as well as the in vivo even more short-lived peroxonitrite which can also form from the equally physiological nitroxide and hydrogen peroxide—also demonstrates wound healing effects, whereby a positive immunomodulation plays an essential role. For example, the EPA-0390829 describes a method for increasing the syngenic intradermal cell proliferation through human growth factors using hydrogen peroxide injections. Such a comitogenic increase in the growth factor effects of interleukin-2 was also described for periodate in 1987 (Wang J. et al., The American Journal of Medicine 1987, 83: 1016-1023).
It is known that (co)mitogenic oxidants have intolerable side effects, such as e.g. for bichromate:—the now recognized carcinogenic effect of chromium oxide: For periodate:—iodine hypersensitivity and toxic effects. Therefore, their clinical use has to take place laboriously as an “adoptive transfer”, i.e. the blood cells are taken out, treated in vitro and then returned in vivo—as described in the previously quoted study by J. Wang et al. 1987. For NAGO side effects are:—the foreign protein sensitisation: For H 2 O 2 :—the formation of toxic oxygen radicals. Here too, there are also technical problems concerning their use as drugs, e.g. for H 2 O 2 :—short storage life in diluted aqueous solution; the catalase lability with massive oxygen gas release. For oxidized ubichinon derivatives problems are:—pharmaceutical manufacturing problems and limited bioavailability.
Therefore, it was not possible up to now to transfer the experimentally demonstrated immunopharmacological action of (co)mitogenic oxidants in clinical practice into tissue regeneration/wound healing, infection resistance and the strengthening of the immune response. In clinical practice, as well as a local application, a systemic treatment, usually in the form of an intravenous administration, is also desirable.
Theo Gilbert Hinze (US 20030133878, “American Composition for the treatment of legionella pneumophila and a method for such treatment”) processed aqueous solutions of NaCl or KCl 2 (presumably the latter chemical formula here is a printing error) with electrochemical oxidation at pH 6.5-7.5. It was conjectured that, as well as other ions, only the Cl 2 O 6 2− ion could be present which at that time had been described only in the preceding invention. This dimer contains the chlorine atoms in the +3 and +5 valence states.
The patent literature contains descriptions of a few further chlorine-oxygen preparations which are particularly used in such technical fields where they serve as oxidants not only in industrial technology as bleaching agents and deodorants, but also where they are recommended for paramedical applications such as in cosmetics for skin and hair care, for household cleaning, in the sanitary sector for hygiene and/or as disinfectants for surfaces (U.S. Pat. Nos. 2,701,781; 3,123,521) and/or wounds (U.S. Pat. No. 4,084,747; EP-A-0 744 895), as preservation agents for cheese (U.S. Pat. No. 3,147,124) and for the conditioning of drinking and bathing water (U.S. Pat. No. 4,296,103; DE-A-44 05 800, DE-A-19 518 464; WO 96/33947; WO 97/06098). The U.S. Pat. No. 4,296,103, EP-A-0 136 309, U.S. Pat. No. 4,507,285 and EP-A-0255145 describe the medical application of chlorine-oxygen preparations.
WO 00/48940 contains a description of the preparation of a chlorohydroperoxide with the formula HOOClO 2 where the chlorine has valence of 5. This hydroperoxide behaves as an acid which supplies the anion O 2 ClOO − in an aqueous environment. Therefore, it was called peroxochloric acid and its anion is called peroxochlorate. It is reported that the combination of two peroxochlorate ions, under separation of an oxygen molecule, can lead to derivatives of peroxochlorate with one peroxo group and two chlorine atoms with different valences. This ion is allocated the empirical formula (Cl 2 O 6 ) 2− .
It is disclosed that it would be possible to manufacture stable peroxochloric acid and stable salts or anions thereof in solution. For example, these compounds are obtained in aqueous solution by the reaction of chlorine dioxide with hydrogen peroxide if the work is carried out at pH values which are equal to, or greater than, the pKs value of peroxochloric acid (HOOClO 2 ). pH values of 6.5 and more are preferable, and the pH range of 10-12 is especially preferable.
Thus, in WO 00/48940 peroxochloric acid or its salts, peroxochloric acid and its salts or anions in aqueous solution, oligomeric derivatives of the peroxochlorate with mixed-valent chlorine atoms and their salts or anions in aqueous solution as well as the carbon dioxide adduct as an acid, an anion in solution or as a salt are disclosed.
In the meantime, it has been proved that an isolation of a crystalline metallic salt of peroxochlorate, according to the specifications given in WO 00/48940, is unsuccessful.
Due to the low concentrations of peroxochlorate in the preparations manufactured according to the specifications of WO 00/48940, it is only possible to prepare the deoxo dimers to a limited degree.
Svensson und Nelander published the preparation of HOOClO 2 at low temperatures of 17K (−256, 15° C.) in J. Phys. Chem. A 1999, 103, 4432-4437.
Therefore, all the published chlorine-oxygen preparations do not fulfil the requirement criteria of modem drug approval. These state that the pharmacodynamics of the preparation must be allocatable to a chemically defined compound as the so-called active substance which is to be standardized as the pharmaceutical product. This is also necessary in order to guarantee homogeneous drug quality.
The intrinsically good chlorine-oxygen compounds of WO 00/48940, and in particular the deoxo dimer defined there, can, up to now, only be manufactured to a limited degree. Therefore, a commercial exploitation appears to be impossible.
GENERAL DESCRIPTION OF THE INVENTION
It is therefore one object of the invention to prepare an oxidant without the disadvantages described above. As well as the usual technical, medicinal and disinfectant fields of application, such an oxidant should also offer the possibility of formulation as a medicament for both local and systemic treatment, e.g. for intravenous application as, for example, a drug for tissue regeneration, for wound healing and against infections or for enhancing the immune response. Furthermore, it should fulfill the requirements of modern new drug approval procedures.
Particularly, therefore, it was one object of the invention to prepare a further improved oxidant and an improved process for its manufacture and application.
This object, as well as further objects which are not specifically named but which are evident from the initially described status of technology, is achieved by the embodiments of the invention defined in the claims.
Surprisingly, it has become evident that this object can be solved through the preparation of reactive chlorine compounds such as dichloric acids, the intermediate product peroxochloric acid as well as peroxochlorous acid, as well as their individual derivatives, anions and/or salts.
The novel dichloric acids, according to the invention, are shown in the following Table 1. Among these dichloric acids, the acids numbered No 1 to No. 3 are particularly preferred embodiments of this invention.
TABLE 1
Formal
oxidation
numbers of
Structural formula of the
No.
chlorine
Structural formula of the acid
dianion
1
+5, +5
2
+6, +4
3
+5, +5
4
+5, +3
As well as the valence pairs already described previously +3/+5 (WO 00/48940) and +4/+4 (Bogdanchikov et al.), the dichloric acids according to the invention No. 1 to No. 3 with valences of +6/+4 and +5/+5 for chlorine were manufactured for the first time according to the process of the invention. The anion of the acid of No. 4 is described in WO 00/48940. The manufacturing process described there, however, does not work.
In WO 00/48940 the postulation was made that the deoxo dimer is formed from two molecules of a reactive chlorine-oxygen species (peroxochlorate) via the reaction
2 − OOClO 2 →Cl 2 O 6 2− +O 2 ,
whereby the chlorine atoms are present in the oxidation numbers +3 and +5. However, the manufacture of a stable compound according to example 6 of WO 00/48940, which is desirable under pharmaceutical law aspects, is not successful.
The formation of the dimeric derivative from 2 molecules of peroxochlorate according to the formula
2−OOClO 2 →Cl 2 O 6 2− +O 2
can namely only be expected at very high concentrations of peroxochlorate (roughly from 2 to 3 mol/L). Such high concentrations, however, are impossible in practice due to the high instability of the compound.
However, the examinations which led to the invention show that the reaction of peroxochlorate ions O 2 ClOO − with chlorite ions (ClO 2 − ) leads surprisingly directly to the palette of “dimeric” Cl 2 O 6 2− species:
O 2 ClOO − +ClO 2 − →Cl 2 O 6 2− ->->and isomers
Furthermore, surprisingly, with the help of the process according to the invention, the preparation of the previously unknown peroxochlorite ion, O═ClOO − and the peroxochlorous acid O═ClOOH derived from it is successful—in particular in the solutions containing chlorite according to the invention.
These chlorine compounds have not been described previously.
Especially round about the point of neutrality, the dissociation of the dichlorine species Cl 2 O 6 2− into chlorate ions ClO 3 − and peroxochlorite ions OClOO − is a clearly competitative reaction to the described intramolecular redox reactions of the dichlorine species which lead to the compounds 1-4 in the above table.
Insofar as reference is made to anions in the disclosure, the presence of the necessary counterions (particularly in solution) is included as well. The term “anions” is used in particular to stress that, in solution, the dichlorate is the more stable form compared with the protonated acid. However, the term “anion” can, according to the invention, and depending on the context, also be used in place of acid. The term “acid” can equally be used in place of “anion”.
The invention also relates to the process of manufacturing preparations which contain the dichloric acids and their derivatives, anions and/or salts, and/or the peroxochlorous acid according to the invention and its derivatives, anions and/or salts.
If one carries out the following steps, one can, in an amazingly simple way, manufacture the dichloric acids and the peroxochlorite ion according to the present invention.
Chlorine dioxide reacts with an aqueous solution or water-containing solution of hydrogen peroxide or another hydroperoxide or peroxide at a pH value of ≧6.5,
the pH value is lowered by adding an acid,
the gaseous free reactive chlorine compound, preferably the protonated peroxochlorine compound, is expelled with a cooled gas and collected in an alkaline solution,
the collected free reactive chlorine compound, preferably the peroxochlorine compound, is incubated at a pH between 6 and 8, preferably about 7 with an up to 100-fold excess, preferably up to a 10-fold chlorite excess.
The dichloric and peroxochlorous acids of the invention, and also the ions which are present at physiological pH values can therefore, according to the invention, also be present as a mixture with peroxochlorate and chlorite in solution. Such a solution containing dichloric acids, peroxochlorous acid, peroxochlorate and chlorite according to the invention, therefore counts among the particularly preferable experimental practice examples of the invention.
In WO 00/48940, in contrast, chlorite-free solutions were produced in which the dichloric acids and the peroxochlorous acid of the invention are not contained, or, chlorite-containing preparations were produced which contained practically only chlorite so that they are unsuitable for pharmaceutical applications.
Because large amounts of chlorite are detrimental to the use of dichloric acids according to the invention in the pharmaceutical sector, it is especially advantageous if the end-product of the solutions, according to the invention, do not contain chlorite in more than 20-fold excess, preferably in not more than 5-fold excess and even more preferably in not more than a 3-fold excess in percentage by weight related to the total weight of the solution.
In particular, the dichloric acids and peroxochlorous acid according to the invention are present in this solution in volumes of about 0.1-20 weight %, preferably 3-5 weight %, related to the percentage by weight of the ClO 2 employed. The qualitative detection is successful using Raman spectroscopy. The performance of this type of spectroscopy is a matter of course for an expert in this field. The spectrograms which are obtained clearly differ from those which are obtained with the process described in WO 00/48940. The determination of the quantitative share can be carried out using titration.
A further qualitative detection is possible using the reaction with the heme iron. In the presence of the dichloric acids of the invention, the temporal course of the change in intensity of the Soret bands is clearly different to the results of the solutions which were obtained with the process described in WO 00/48940.
The process according to the invention consists of a reaction of chlorine dioxide with an aqueous or water-containing hydrogen peroxide (or another hydroperoxide or peroxide known to an expert, such as e.g. peroxocarbonate, or perborate, or the urea adduct of the hydrogen peroxide) at a pH value of 6.5 or greater, preferably pH 10-12. Preferably, the pH value should be kept at a constant level.
Moreover, surprisingly, it has been shown that peroxochloric acid, which occurs as an intermediate product, as well as its anions and derivatives, can also be obtained by the reaction of chlorine dioxide with other oxidants which contain the peroxo group.
The reaction can be carried out in an aqueous environment or a water-containing environment. For example, as well as water, solvents can be present which are miscible with water such as alcohols or alkanols such as methanol, ethanol or mixtures of these.
Alternatively, other chlorine oxides can be used initially. For example, chlorine monoxide, preferably in its dimeric form (Cl 2 O 2 ), can also be converted with a hydroperoxide (preferably hydrogen peroxide) to the desired product. The reaction is successful in the same pH range as stated for chlorine dioxide.
The reaction temperature can be increased for example up to about 50° C.; in purely aqueous systems, the lowest temperature should be preferably about 0° C. One should not work with chlorine dioxide under +10° C. however, because the chlorine dioxide gas liquefies below this temperature and deflagration can occur. If additional organic solvents and/or high concentrations of the active reagents are present, then lower temperatures, i.e. below the freezing temperature of water, can be used. Preferably, work takes place at room temperature.
The chlorine dioxide required for the reaction is available to experts and can be manufactured in the usual way. For example, it can be manufactured by the reaction of a chlorite with an acid (e.g. sodium chlorite with sulphuric acid) or by the reduction of chlorate—for example with sulphurous acid.
The chlorine dioxide thus obtained can be liberated in the usual manner—if necessary after removal of traces of chlorine (Granstrom, Marvin L.; and Lee, G. Fred, J. Amer. Water Works Assoc. 50, 1453-1466 (1958)).
If the chlorite used to make ClO 2 is contaminated with carbonate, the ClO 2 will be contaminated with CO 2 and/or the carbonic acid adducts described in WO 00/48940. In order to absorb the carbon dioxide, the gas stream containing chlorine dioxide and carbon dioxide should be directed through a washing bottle filled with a lye. During short contact times, the CO 2 but not the ClO 2 will be absorbed by the lye. It is preferable, however, to remove the carbonate contamination by fractioned crystallisation of the sodium chlorite which is used. A contamination of the peroxochlorate with carbonate can be easily recognized on the Raman spectrum. Instead of sharp bands at 1051 cm −1 , one obtains a double band 1069 cm −1 (wide) and the important bands, within the scope of the invention, at 1051 cm −1 (sharp).
The chlorine dioxide can be transported with an inert gas such as nitrogen or with a rare gas such as argon, however, air or oxygen for the reaction with the peroxo compound or the hydroperoxide such as hydrogen peroxide or perborate can also be used. For example, it is possible to make the chlorine dioxide in a first reaction vessel and then to introduce it with the above mentioned gases or mixtures of them into a second reaction vessel which contains the peroxo compound (peroxide or hydroperoxide) in an aqueous or water-containing solution.
The pH value of the reaction mixture is kept equal to, or above, 6.5 by adding a base. It is preferable to keep the pH value constant. This can be carried out either manually or by using a “pH stat”.
The usual organic or inorganic bases can be used such as bases, for example caustic soda solution or caustic potash solution or alkaline-earth hydroxides as well as ammonia; or organic bases such as nitrogenous bases. Furthermore, the hydroxides from of quaternary ammonium salts in particular alkyl, trialkyl or tetraalkyl ammonium hydroxide, or zinc hydroxide can also be used.
The content of hydroperoxide in the reaction mixture can, for example, be determined using potentiometric titration with an acid such as hydrochloric acid.
The solutions obtained according to the procedures described above can be used in both the form in which they were made or in variations of this. For example, superfluous hydrogen peroxide can be removed in the usual way, e.g. with a heavy metal compound such as manganese dioxide. Surpluses of the other oxidants can be removed with similar means.
Surpluses of chlorine dioxide (ClO 2 ) can be removed with H 2 O 2 . This should take place as soon as possible, otherwise via
2ClO 2 +2OH − ->ClO 2 − +ClO 3 − +H 2 O
disturbing ClO 3 − with pentavalent chlorine (chlorate) will be formed. A product containing chlorate is however undesirable.
In order to improve the storage life of the reaction product, storage at a high pH value is suitable, for example, pH 10 and above. The adjustment of this pH value can be carried out with a suitable base—as described previously in the manufacturing procedure.
In the manufacture of solutions which contain the dichloric acids and/or the salts of these acids, surprisingly, it is possible to expel and collect the free acid HOOClO, the dichloric acids or the peroxochloric acid out of the mixture containing chlorite ions with an inert gas such as a noble gas, e.g. argon, or with nitrogen or with the gases oxygen or air, while lowering the pH to below 6, e.g. pH 5, or less. Surprisingly, it has been demonstrated that the yield can be enormously increased if the gas stream distance is kept very short and the stream is cooled.
The mixture which forms after the start of step (a) in the manufacturing procedure described above contains, at first, very high concentrations of chlorite ions (ClO 2 − ). The chlorite content, however, can be considerably reduced by the “passing over” in a gas stream in a basic solution. In this process, all types of chloric acids are expelled as volatile compounds in protonated (neutral) form. These are however very instable. A base is present in the receiving vessel through which the chloric acids are deprotonated and the anions are formed. After the solution has been adjusted to pH 6-8, and after defined volumes of chlorite—for example, in the form of sodium chloride—have been added, the anions of the dichloric acids are formed.
Collection can be carried out, for example, in a base, such as an alkaline metal base, alkaline-earth metal base or a zinc base or nitrogenous base such as ammonia or an organic amine. It is also possible to freeze out the gaseous acids in a cold trap (e.g. at −100 to −190° C.).
Counterions can be all metal cations and organic cations such as those from nitrogenous bases, in particular quaternary ammonium salts. The choice of the most suitable cations can be determined from the individual purpose of use. For pharmaceutical applications, alkaline earth or alkaline metals, preferably Na + or K + , or Zn 2+ are most suitable. In technical applications, organic cations, such as cations from nitrogenous bases, in particular alkyl ammonium cations such as trialkyl ammonium cations or especially quaternary ammonium cations can be used.
It is appropriate and preferable to store the acid and the salts, according to the invention, in the dark and to make aqueous solutions with high pH values out of them, e.g. with pH values of 10, 11 or 12 and above, in particular the range of pH 10 to pH 13, in order to ensure a long storage life. Depending on the need, the free acid can be regained from such solutions in the manner described previously and, if necessary, can be converted to solutions with the desired pH value or into salts.
The dichloric acids according to the invention, their derivatives or anions and salts of these, can be used as they are, but particularly also in aqueous or water-containing solutions, as oxidants for very different medical, cosmetic, technical and agricultural purposes.
Examples for possible test systems are included in the initially named publications and patent documents, which are included herein in this respect by reference.
An application possibility exists in the use as pharmaceutical preparations (medicaments), or for the manufacture of medicaments, which can be administered in all possible methods, in particular topically but also parentally. The medicament can be formulated in the usual way with the usual pharmaceutically well-tolerated vehicles and diluting agents.
The invention also relates to pharmaceutical preparations which incorporate the dichloric acids or peroxochlorous acid, respectively, according to the invention, their anions, derivatives or salts as the active substance and which can be used in particular to treat the illnesses mentioned in the introduction. Especially preferential, are preparations for enteral administration such as nasal, buccal, rectal and especially oral administration (preferably avoiding the acid of the stomach, e.g. gastric juice-resistant preparations such as capsules or coated tablets), as well as particularly for local or parenteral treatment, such as intravenous, intramuscular or subcutaneous administration to homothermal animals—in particular humans. The preparations contain the active substance alone or preferably together with one or more pharmaceutically applicable vehicle materials. The dosing of the active substance depends on the illness being treated as well as the species being treated, its age, weight and individual condition, individual pharmacokinetic circumstances as well as the method of application. Preferably, the dosage for the enteral or particularly the parental administration (for example by infusion or injection) (most favourably in humans) lies in the range of 0.01 to 100 pmol/kg, in particular between 0.1 and 100 pmol. Therefore, for example, a person with a bodyweight of 70 kg should receive 1 mg to 1 g/day, in particular between 8.5 mg and 850 mg/day, administered in one dose or split up into several smaller doses. For local application, the preferable dosage range lies between 0.1 and 10, in particular between 0.5 and 5 mL/100 cm 2 of a 0.1 to 10 millimolar solution (correspondingly more or less for larger or smaller surfaces—either applied directly or using, for example, bandages out of impregnated gauze).
Thus the invention also relates to a method—for the prophylactic and/or therapeutic treatment of the pathological conditions described here, in particular for the prophylactic and/or therapeutic treatment of diseases where a strengthening of tissue regeneration, an immunomodulation, an improvement of vaccination reaction or a radiation sensitisation is indicated and successful, or one or more of these effects, in particular in the treatment of wounds in warm blooded animals—incorporating the administration of the dichloric acids or peroxochlorous acid, respectively, its anions, derivatives or salts, according to the invention, in an effective dosage against the aforementioned diseases to a warm blooded animal, e.g. a human being who requires such a treatment.
The invention also relates to a pharmaceutical composition—for the prophylactic, and in particular, for the therapeutic treatment of the disease conditions described here, preferably for the prophylactic and/or therapeutic treatment of diseases where a strengthening of tissue regeneration, an immunomodulation, an improvement of vaccination reaction or a radiation sensitisation is indicated and successful, or for one or more of these effects, in particular in the treatment of wounds, preferably of a warm blooded animal who is suffering from such a condition—which contains dichloric acids or peroxochlorous acid, respectively, its anions, derivatives or salts, according to the invention, in a prophylactically, or in particular, therapeutically effective dosage against the aforementioned diseases and one or more pharmaceutically applicable vehicle materials.
The invention also relates to a procedure—for the treatment of pathological conditions preferably for the prophylactic and/or therapeutic treatment, in particular of a warm blooded animal, especially a human being, where a strengthening of tissue regeneration, an immunomodulation, an improvement of vaccination reaction or a radiation sensitisation is indicated and successful, in particular in the treatment of wounds in warm blooded animals—which incorporates the administration of the dichloric acids, or peroxochlorous acid, respectively, its anions, derivatives or salts, according to the invention, in an effective dosage against the aforementioned diseases to a warm blooded animal, e.g. a human being who requires such a treatment.
The invention also relates to the use of the dichloric acids and/or the peroxochlorous acid and their derivatives, anions or salts, according to the invention, in a procedure for the treatment of an animal or human body.
Therefore, the invention also relates to the use of the dichloric acids and/or the peroxochlorous acid and their derivatives, anions or salts, according to the invention, preferably for prophylactic and/or therapeutic treatment of diseases, in particular of a warm blooded animal, especially a human being, where a strengthening of tissue regeneration, an immunomodulation, an improvement of vaccination reaction or a radiation sensitisation is indicated and successful, in particular in the treatment of wounds.
The invention also relates to the use or a method for the use of the dichloric acids and/or the peroxochlorous acid and their derivatives, anions or salts, according to the invention, for the (cosmetic) care of the skin, for example when a person has a tendency to develop spots and pimples (e.g. acne) or if pimples are present.
Dosage unit forms are e.g. dragées, tablets, ampoules, vials, suppositories or capsules. Further administration forms, in particular for solutions of the dichloric acids and/or the peroxochlorous acid and their derivatives, anions or salts, according to the invention, are e.g. ointments, creams, pastes, gels, foams, mouthwash, drops, sprays and similar. The dosage unit forms, e.g. ampoules, tablets or capsules, contain preferably between about 0.05 g to about 1.0 g, in particular from 8.5 mg to 850 mg, of a salt of the dichloric acids their anions or derivatives according to the invention with the usual pharmaceutical vehicle materials.
The pharmaceutical preparations of the invention were essentially manufactured in the known manner, e.g. using conventional mixing, granulating, coating, dissolving or lyophilising methods.
In a preferential experimental procedure, a 0.05 to 1 M solution of a dichloric acid salt or the peroxochlorous acid and/or a salt of its derivatives can be dissolved in bidistilled water at a pH equal to or >10, preferably 10 to 13, in particular 12.5. Immediately before administration, this solution is diluted with common salt, sodium or potassium bicarbonate and bidistilled water to isotonie in concentrations of about 1-5 mM approaching the physiological pH. This solution is suitable for parental, preferably intravenous application.
In order to make a preferential formulation of a drug for topical use, the method of choice is to dissolve the dichloric acids and/or the peroxochlorous acid or their derivatives, according to the invention, as salts in bidistilled water with concentrations in the lower millimolar or in the upper micromolar range—preferably in the concentration range of 0.5-5 mM with the pH equal to or >10, in particular 10 to 13, most preferably e.g. pH 11.5 and adjust the solution to isotonie with glycerine or common salt or another suitable well-tolerated, preferably physiological agent. Before application, a physiological pH is set with HCl. Further additives are possible. In particular, in connection with the filling of the medicament into plastic containers, such additives are suitable which can neutralise traces of transition-metals, because, during storage, transition-metals in the walls can be dissolved and can catalyse a degradation of the active substance. Examples of such additives are oligo and polyalcohols, such as ethylene glycol, desferrioxamine or EDTA (e.g. as disodium EDTA). The solution which is obtained in the above manner can also be applied directly to wounds.
The anions of the dichloric acids or peroxochlorous acid according to the invention are stable, the acids themselves decompose relatively quickly. Therefore, an active substance stabilisation can be carried out using the pH. In order to improve tolerance, the active substance solution can be lowered to an almost physiological pH by buffer dilution immediately before use. This is adequate for a deployment of the pharmacological action throughout the body, because this action does not rely on the receptor-ligand interaction of a conventional drug, but it is, as previously stated, related to a fast and irreversible oxidation reaction. The pharmacological action remains in effect as long as the cell and/or its chemically changed structures are present, i.e. it is not terminated after diffusion of an active substance from a receptor.
Examples for indication fields in which an enhancement of tissue regeneration is successful, either prophylactically or in particular therapeutically, for the treatment of a pathological condition are the regeneration after physical damage (e.g. traumatic contusions or lacerations, short-wave rays, radioactive radiation) and after chemical damage (e.g. through tissue poisons, such as Lost, chemotherapeutic agents). A further application area in this field is the improvement of wound healing—in particular stubborn so-called “spontaneous” wounds—which occur as a result of a primary disease (e.g. Diabetes mellitus, vascular disorders, immunosuppression or the result of old age) and which will not heal. Outstanding examples of such disorders are bedsores and chronic varicose ulcers. Here, wound treatment is to be understood as treatment of wounds of the skin, mucous membranes and other tissues such as e.g. liver, myocardium or bone marrow.
Because the dichloric acids or peroxochlorous acid according to the invention are defined compounds, there are no related difficulties in new drug approval.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the results of the cell culture experiments (stimulation of growth of fibroblasts) as shown in Example 3. These were obtained with active substance concentrations in the culture medium of 100 μM chlorite and 50 μM of reactive chlorine (RC=sum of the anions of all dichloric acids and the peroxochlorous acid).
Here, a growth stimulating effect of 20-25% of the trial solution 1, which includes both dichloric acids according to the invention and also chlorite, is clearly recognisable in the cell culture which, in relation to the controls, is significantly higher.
The application of the solutions containing only RC or chlorite shows exactly how the controls have no effect whatsoever on the growth behaviour of the fibroblasts.
FIG. 2 shows the titration of the anions of the peroxo acids (dichloric acid, peroxochlorous acid) present in the solution to determine the concentration of the acid ions.
In FIG. 3 , the titration curve derived from FIG. 2 is shown which provides exact concentration determination.
FIGS. 4 and 5 are examples of UV spectra. The UV absorption measurements permit the determination of the chlorite concentration and show any dissolved free chlorine dioxide which may be present.
FIG. 6 shows a mass spectrum of the product solution whereby the peroxochlorite (mass 83.2) and the anion of the dichloric acid (mass 189) were identified.
In FIG. 7 , the results of an ion chromatography are shown. The retention times of reference substances are provided in Example 4 part 5. The dichloric acid is detected at 19.77 min, whereby no chlorate (ClO 3 − ) is determined which excludes chlorate as the cause of the peak in the mass spectrum at 82.3 in FIG. 6 .
FIG. 8 shows decay rate kinetics with three bacteria strains, E. coli, S. aureus and P. aeruginosa. In all three strains, a bactericidal action according to DIN 58940 was obtained with the product solution.
DETAILED DESCRIPTION
The following examples provide more details about the invention, these should however by no means be understood in a limiting sense.
EXAMPLES
Example 1
Preparation of the Dichloric Acids
Carefully, drop for drop, sulphuric acid (96%) is stirred into a solution of 100 g anhydrous sodium chlorite in 200 mL water. The chlorine dioxide which forms is expelled using a strong gas stream (Ar, N 2 or O 2 or CO 2 -free air). The gas stream must be so strong that the content of ClO 2 does not exceed 5% (danger of explosion). In order to trap elemental chlorine, the gas stream containing ClO 2 is introduced into three washing bottles attached to each other which are each filled with 30 mL of a 2 M NaClO 2 solution at pH 11, in a solution of 15 mL of 30% hydrogen peroxide in 35 mL of water, which had previously been adjusted to pH 12 by adding 4M caustic soda solution. A solution of sodium perborate or sodium percarbonate or another peroxo compound, such as e.g. the H 2 O 2 adduct of urea can be used instead of hydrogen peroxide. During the introduction of the gas, the pH value is controlled with a glass electrode. By adding 4M NaOH, the pH value during the reaction can be kept at 12. The hydroperoxide or peroxo compound are exhausted when the inflow of gas leads to a permanent yellow coloring. A drop of the solution of the oxidant (e.g. H 2 O 2 ) will subsequently decolorize the yellow solution again.
While stirring, the solution containing reactive chlorine is dripped into a solution of 500 g citric acid in 3 liters of water which has previously been adjusted to pH 4.5 with 2 M caustic soda solution. During this addition, the reactive chlorine compound which forms is expelled with a strong gas stream (N 2 or O 2 ). Preferably, the gas stream should be cooled. The tube connections should be as short as possible. The gas is collected, for example in three washing bottles which are attached behind each other and which are each filled with 50 mL 0.1 M NaOH.
The contents of the three washing bottles are combined and kept at pH >10.
In order to form the dichloric acids according to the invention, the pH is adjusted to 7—for example with hydrochloric acid—and a 10-fold molar excess of sodium chlorite is added. For storage, preferably, the pH should be adjusted to about more than 10 up to about 13.
The total content of reactive chlorine anions is determined by potentiometric titration with 0.1 M HCl with the usual method known to the man skilled in the art.
The dichloric acids which are formed are present in solution in a mixture with a defined volume of chlorite as well as further reactive chlorine compounds.
The presence of the dichloric acids is detected with Raman spectroscopy.
Example 2
Cultivation of MRC 5 Fibroblasts
Solutions:
Culture medium for MRC 5:
89 mL IF basal medium 10 mL FCS (foetal calf serum) 1 mL L-glutamine stock solution
IF basal medium
The IF basal medium is a 1:1 mixture of IMDM (Iscove's Modified Dulbecco's Medium) and Ham's F12 medium
L-glutamine stock solution
200 mM L-glutamine are dissolved in IF basal medium and sterilized by filtration.
Cultivation:
The MRC 5 cell line used is seeded in non-gelatine coated cell culture dishes. The subsequent cultivation is carried out in an incubator at 37° C. and 5 vol % CO 2 in a water vapour saturated atmosphere. Every second to third day, the culture medium is changed and after confluence is reached the cells are passaged with a separation rate of 1:5 to 1:10.
Example 3
Cell Biological Test of Active Substance
Solutions:
culture medium for MRC 5:
89 mL IF basal medium 10 mL FCS (Foetal Calf Serum) 1 mL L-glutamine stock solution
serum-reduced culture medium for MRC-5:
98 mL IF basal medium 1 mL FCS (Foetal Calf Serum) 1 mL L-glutamine stock solution
PBS (Phosphate Buffered Saline):
140 mM NaCl, 3 mM KCl, 8 mM Na 2 HPO 4 and 1.5 mM KH 2 PO 4 are dissolved in water, whereby a pH value of 7.2-7.4 is set. The solution thus obtained is sterilized by autoclaving.
Cell lysis buffer
0.04% SDS (stock solution 10% SDS) 2×SSC (stock solution 20×SSC) to obtain 25 mL of finished cell lysis buffer, 5.0 mL 20×SSC and 100 μL 10% SDS are filled up to 25 mL with PBS.
DAPI solution
2 μM DAPI in PBS
Cultivation:
The MRC 5 cells are seeded at 400 cells/cm 2 in a 24 well cell culture plate. The subsequent cultivation is carried out in an incubator 37° C. and 5 vol. % CO 2 in a water vapour saturated atmosphere. After 24 hours of precultivation, the culture medium is suctioned off and the cells are washed with PBS. The culture medium is then changed to serum-reduced culture medium and the active substances to be tested (the following table shows an overview) are added.
After 24, 48 and 72 hours, the proliferation of the cells is determined by quantification of the cellular DNA in a fluorometer (Novostar—Company: BMG Labtechnologies) after DAPI staining. Here, the increased fluorescence in the samples is equal to a proliferation of the cells.
The plate to be measured is washed once per well with 500 μl PBS and then 250 μl PBS is placed in each well. 250 μl lysis buffer are added and the cells are lysed in a shaker at the lowest setting for 30 min at RT. Subsequently, 500 μl DAPI solution is added and the plate is left to stand for a further 10 min at RT.
The plate is measured at 355 nm ex. and 460 nm em. in the Novostar. Normally, work is carried out with a gain adjustment of 1400-1600.
The multiple determinations are averaged and the error values are calculated. The data obtained is evaluated graphically.
The following stock solutions are used:
TABLE 2
Combination of the active substances used
[Concentration of the stock solutions]
Content of
Content of chlorite
Designation
[mM]
[mM]
Comment
Control
—
—
Serum-reduced
culture medium
Sample 1
40
6
in serum-reduced
culture medium
Sample 2
40
—
in serum-reduced
culture medium
Sample 3
—
6
in serum-reduced
culture medium
Observed Growth Stimulation of Fibroblasts:
For use in the cell culture, the solutions are first diluted in the given culture medium. The results shown in FIG. 1 were obtained with active substance concentrations of 100 μM chlorite and 50 μM of the RC (=mixture of the dichloric acid and the peroxochlorous acid, according to the invention, or the anions thereof).
Here, a growth-stimulating effect of 20-25% of the sample solution 1, which contains both RC and also chlorite, is clearly recognisable and this is also significantly higher in relation to the control.
Example 4
Analytical Determination of the Solution Obtained from Example 1
1) pH measurement:
The pH measurement is made with a single-rod glass electrode. The product content and the position of the equilibrium is dependent on the pH value.
2) Titration with 0.1 M HCl:
The titration serves for example for the quantitative determination of the dichloric acid content or also the content of peroxochlorous acid or the peroxochlorate.
1 mL each of the product solution are titrated potentiometrically with 0.1 M hydrochloric acid. The titration curves are recorded (pH vs. mL 0.1 M HCl). From the acid consumption measured in the derivation of the titration curve between pH 8.5 and 4.5, the anion content from the corresponding acids is determined as a sum.
In a typical result, 1 mL product solution results in a consumption 0.72 mL 0.1 M HCl and thus a concentration of 0.072 M.
FIG. 2 shows a recorded titration curve:
The derivation of the titration curve and the determination of the concentration are shown in FIG. 3 .
3) UV-Vis absorption spectrum:
The measurement of the UV spectrum serves the quantification of the chlorite content in the product solution. For comparison, FIGS. 1 and 5 show spectra of a chlorite-containing and a chlorite-free product solution. The chlorite signal is seen at 260 nm; chlorine dioxide, which originates from the process, shows a signal at 360 nm.
The absorption values are determined at 260 nm and 500 nm in 1 cm quartz cuvettes. The CIO 2 − ion content is determined from the difference A260-A500 and with the help of the extinction coefficient for chlorite of ε260 nm=140 M −1 cm −1 at 260 nm.
An absorption at 360 nm suggests free chlorine dioxide (ε360 nm=1260 M −1 cm −1 ).
4) Mass spectroscopy
The ESI mass spectrometry was carried out with a Bruker Esquire-LC spectrometer in the standard MS mode. The sample was an aqueous product solution which had been diluted with methanol before the measurement. The scan range used lay between 30 m/z and 400 m/z with capillary exit −65, voltage and skim −15 V; the spectrum represented an average value from 50 measurements.
The arrow on the right in FIG. 6 points to the signal of the dichloric acid (sum formula: Cl 2 O 6 2− ), the arrow on the left shows the previously unknown peroxochlorite species (sum formula: ClO 3 − ).
5) Ion chromatography
All analyses were carried out with a modular ion chromatography system from the Metrohm company.
Pump: Metrohm IC 709 Pump
Detector: Metrohm 732 IC Detector
Suppressor: Metrohm 753 Suppressor Module
Column: Metrosep A 250
Flow rate: 1 ml/min
Injection volume: 20 μL
Eluent: 1 mM NaOH
Immediately before each measurement, known concentrations of the reference substances were freshly prepared. These were then measured with the method described above and with the eluents stated.
Retention times of the reference substances:
Substance
Retention time [min]
NaCl
13.21
NaClO 2
12.30
NaClO 3
16.26
NaClO 4
4.36
NaOH
17.32
Na 2 CO 3
21.98
Na 2 Cl 2 O 6
19.77
FIG. 7 : In the ion chromatography, the dichloric acid shows a typical peak as a retention time of 19.77 min. None of the known reference substances could be detected. The ion chromatography confirmed the findings of the mass spectroscopy. A chlorate-typical peak (NaClO 3 , retention time 16.26 min) cannot be detected in the solution prepared according to Example 1. Therefore, the peak with the sum formula ClO 3 − in the mass spectroscopy ( FIG. 6 , mass 83.2) can only be the new peroxochlorous acid or anions thereof.
Example 5
Bactericidal Action of the Solution Obtained from Example 1
Decay kinetics according to DIN 58940
Solution according to Example 1 was used in a 1:10 dilution.
Test organisms: Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 29213
Nutrient medium: Casein peptone—Soya peptone (Ph. Eur. 2.6.12)
Bacteria incubation time: 18 h+/−1 h
The result is shown in the following Table 3 as well as in FIG. 8 . Thus, the bactericidal action of the solution used has been proved according to DIN 58940.
TABLE 3
E. coli Na
P. aeruginosa NaCl
S. aureus NaCl
Time
log
log
log
(h)
cfu/ml
cfu/ml
cfu/ml
cfu/ml
cfu/ml
cfu/ml
0
1.04E+06
6.02
6.02
1.58E+05
5.20
5.20
1.98E+06
6.30
6.30
2
5.60E+05
5.75
5.75
8.60E+05
5.93
5.93
9.00E+05
5.95
5.95
4
5.00E+05
5.70
5.70
6.00E+05
5.78
5.78
1.12E+05
5.05
5.05
6
8.60E+05
5.93
5.93
5.40E+05
5.73
5.73
9.80E+05
5.99
5.99
24
1.04E+06
6.02
6.02
7.60E+05
5.88
5.88
8.00E+05
5.90
5.90
Trials with 300 μg/ml
DPOLC
E. coli DPOLC
P. aeruginosa DPOLC
S. aureus DPOLC
Time
log
log
log
(h)
cfu/ml
cfu/ml
cfu/ml
cfu/ml
cfu/ml
cfu/ml
0
4.60E+05
5.66
5.66
1.04E+06
6.02
6.02
1.22E+05
5.09
5.09
2
<20
<1.30
1.30
<20
<1.30
1.30
2.20E+02
2.34
2.34
4
<20
<1.30
1.30
<20
<1.30
1.30
<20
<1.30
1.30
6
<20
<1.30
1.30
<20
<1.30
1.30
<20
<1.30
1.30
24
<20
<1.30
1.30
<20
<1.30
1.30
<20
<1.30
1.30
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This invention relates to aqueous solutions of reactive chlorine compounds having the empirical formulae H 2 Cl 2 O 6 or ClO 3 H, for example, and the derivatives, anions or salts thereof. The invention further relates to methods for the production of said compounds and the use thereof in the pharmaceutical and particularly in the medical field, in cosmetics, medicinal care and in the domains of food technology and technology.
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CROSS REFERENCE TO RELATED APPLICATION
This application is a continuation of International Application Serial No. PCT/US2011/036,622 filed on May 16, 2011, which claims the benefit of U.S. Provisional Application No. 61/346,556 filed on May 20, 2010.
FIELD OF INVENTION
The present invention relates to a composition containing a particulate solid, a non-polar organic medium, and a compound obtained/obtainable by reacting an aromatic amine with hydrocarbyl-substituted acylating agent. The invention further provides compositions for coatings, inks, toners, plastic materials (such as thermoplastics), plasticisers, plastisols, crude grinding and flush.
BACKGROUND OF THE INVENTION
Many formulations such as inks, paints, mill-bases and plastics materials require effective dispersants for uniformly distributing a particulate solid in a non-polar organic medium.
Numerous publications disclose polyester amine dispersants derived from a poly(C 2-4 -alkylene imine) such as polyethylene imine to which is attached a polyester chain. The polyester chain may be derived from 12-hydroxy stearic acid, as disclosed in U.S. Pat. No. 4,224,212, or it may be derived from two or more different hydroxy carboxylic acids. GB 1 373 660 discloses polyester amine dispersants obtainable by reaction of a polyester from hydroxycarboxylic acid with diamine, especially alkylene diamines and salts thereof.
SUMMARY OF THE INVENTION
One objective of the present invention is to provide compounds that are capable of at least one of improving colour strength, increasing a particulate solid load, forming improved dispersions, having improved brightness, and producing a composition with reduced viscosity.
In one embodiment, the invention provides a composition comprising a particulate solid, a non-polar organic medium, and a compound obtained/obtainable by reacting an aromatic amine with a hydrocarbyl-substituted acylating agent, wherein the hydrocarbyl-substituted acylating agent is selected from the group consisting of an oligomer or polymer from condensation polymerization of a hydroxy-substituted C 10-30 carboxylic acid into a polyester, an optionally hydroxy-substituted C 10-30 carboxylic acid, a C 10-30 -hydrocarbyl substituted acylating agent, and a polyolefin-substituted acylating agent (typically succinic anhydride).
The compound may have a number average molecular weight of 500 to 20,000, or 600 to 15,000, or 700 to 5000.
The aromatic amine may be mono-functional when reacting with the hydrocarbyl-substituted acylating agent but typically di- or poly-functional.
In one embodiment, the aromatic amine to hydrocarbyl-substituted acylating agent mole ratio may be in the range of 2:1 to 1:10, or 2:1 to 1:4, or 1:1 to 1:3, or 1:1 to 1:2, or 1:2.
The hydrocarbyl-substituted acylating agent may be at least 50 mol %, or at least 75 mol %, or at least 90 mol % mono-functional or di-functional (when in the form of an anhydride) when reacted with the aromatic amine.
The particulate solid may be a pigment or a filler.
The non-polar organic medium may, for instance, include a mineral oil, an aliphatic hydrocarbon, an aromatic hydrocarbon, a plastic material (typically a thermoplastic resin), or a plasticiser.
The present invention also provides a composition comprising a particulate solid (typically a pigment or filler), a non-polar organic medium and a compound of the invention described above.
In one embodiment, the invention provides a paint or ink comprising a particulate solid, a non-polar organic medium, a film-forming resin and a compound of the invention disclosed herein.
The ink may be an ink-jet ink, a gravure ink, or an offset ink.
In one embodiment, the invention provides a composition comprising a compound of the present invention, a particulate solid (typically a pigment or filler), and a non-polar organic medium, wherein the organic medium may be a plastics material. The plastic material may be a thermoplastic resin.
In one embodiment, the invention provides for the use of the compound described herein as a dispersant in a composition disclosed herein.
In one embodiment, the invention provides a compound obtained/obtainable by reacting an aromatic amine with a hydrocarbyl-substituted acylating agent, wherein the hydrocarbyl-substituted acylating agent is selected from the group consisting of an oligomer or polymer from condensation polymerisation of a hydroxy-substituted C 10-30 carboxylic acid into a polyester, and an optionally hydroxy-substituted C 10-30 carboxylic acid, or mixtures thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a composition and use disclosed herein above.
Aromatic Amine
The aromatic amine includes aniline, nitroaniline, aminocarbazole, 4-aminodiphenylamine (ADPA), and coupling products of ADPA. In one embodiment, the amine may be 4-aminodiphenylamine (ADPA), or coupling products of ADPA. In one embodiment, the amine may be coupling products of ADPA. In one embodiment, the aromatic amine may not be a heterocycle.
Coupled products of ADPA may be represented by the formula (1):
wherein independently each variable,
R 1 may be hydrogen or a C 1-5 alkyl group (typically hydrogen); R 2 may be hydrogen or a C 1-5 alkyl group (typically hydrogen); U may be an aliphatic, alicyclic or aromatic group, with the proviso that when U is aliphatic, the aliphatic group may be linear or branched alkylene group containing 1 to 5, or 1 to 2 carbon atoms; and w may be 1 to 10, or 1 to 4, or 1 to 2 (typically 1).
In one embodiment, the coupled ADPA of Formula (1) may be represented by Formula (1a):
wherein independently each variable,
R 1 may be hydrogen or a C 1-5 alkyl group (typically hydrogen); R 2 may be hydrogen or a C 1-5 alkyl group (typically hydrogen); U may be an aliphatic, alicyclic or aromatic group, with the proviso that when U is aliphatic, the aliphatic group may be linear or branched alkylene group containing 1 to 5, or 1 to 2 carbon atoms; and w may be 1 to 10, or 1 to 4, or 1 to 2 (typically 1).
Alternatively, the compound of Formula (1a) may also be represented by:
wherein each variable U, R 1 , and R 2 are the same as described above and w is 0 to 9 or 0 to 3 or 0 to 1 (typically 0).
Examples of an amine having at least 3 aromatic groups may be represented by any of the following Formulae (2) and/or (3):
A person skilled in the art will appreciate that compounds of Formulae (2) and (3) may also react with the aldehyde described below to form acridine derivatives. Acridine derivatives that may be formed include compounds represented by Formula (2a) or (3a) below. In addition to these compounds representing these formulae, a person skilled in the art will also appreciate that other acridine structures may be possible where the aldehyde reacts with other benzyl groups bridged with the >NH group. Examples of acridine structures include those represented by Formulae (2a) and (3a):
Any or all of the N-bridged aromatic rings are capable of such further condensation and perhaps aromatisation. One other of many possible structures is shown in Formula (3b):
Examples of the coupled ADPA include bis[p-(p-aminoanilino)phenyl]-methane, 2-(7-amino-acridin-2-ylmethyl)-N-4-{4-[4-(4-amino-phenylamino)-benzyl]-phenyl}-benzene-1,4-diamine, N 4 -{4-[4-(4-amino-phenylamino)-benzyl]-phenyl}-2-[4-(4-amino-phenylamino)-cyclohexa-1,5-dienylmethyl]-benzene-1,4-diamine, N-[4-(7-amino-acridin-2-ylmethyl)-phenyl]-benzene-1,4-diamine, or mixtures thereof.
The coupled ADPA may be prepared by a process comprising reacting the aromatic amine with an aldehyde. The aldehyde may be aliphatic, alicyclic or aromatic. The aliphatic aldehyde may be linear or branched. Examples of a suitable aromatic aldehyde include benzaldehyde or o-vanillin. Examples of an aliphatic aldehyde include formaldehyde (or a reactive equivalent thereof such as formalin or paraformaldehyde), ethanal or propanal. Typically, the aldehyde may be formaldehyde or benzaldehyde.
The acylating agent, from which the compound of the invention may be derivable, may have one or more acid functional groups, such as a carboxylic acid or anhydride thereof. Examples of an acylating agent include an alpha, beta-unsaturated mono- or polycarboxylic acid, anhydride ester or derivative thereof. Examples of an acylating agent include (meth)acrylic acid, methyl(meth)acrylate, maleic acid or anhydride, fumaric acid, itaconic acid or anhydride, or mixtures thereof. In one embodiment, the acylating agent, from which the compound of the invention may be derivable may, be maleic anhydride, or mixtures thereof.
In one embodiment, the compound of the invention may be obtained/obtainable by reacting an aromatic amine with a hydroxy-substituted C 10-30 carboxylic acid, or mixtures thereof.
The hydroxy-substituted C 10-30 carboxylic acid may typically be polymerised to form a polyester. The polyester may be a polymerisation product of a hydroxy-substituted carboxylic acid of general formula HO—X—COOH, wherein X is a divalent saturated or unsaturated aliphatic radical containing at least 4 carbon atoms between the hydroxyl and carboxylic acid groups. The hydroxy-substituted C 10-30 carboxylic acid may also be in a mixture with a C 10-30 carboxylic acid that is free from hydroxyl groups.
X may contain 12-20 carbon atoms; and that there are between 3 and 14, or 8 and 14 carbon atoms between the carboxylic acid and hydroxy groups.
Examples of the hydroxy-substituted C 10-30 carboxylic acid may include ricinoleic acid, 12-hydroxystearic acid, a mixture of 9- and 10-hydroxystearic acids, 10-hydroxyundecanoic acid, 12-hydroxydodecanoic acid, 4-hydroxydecanoic acid, 5-hydroxydecanoic acid (or delta-decanolactone), or 5-hydroxydodecanoic acid (or delta dodecanolactone). In different embodiments, the hydroxy-substituted C 10-30 carboxylic acid may be ricinoleic acid, 12-hydroxystearic acid, or a mixture of 9- and 10-hydroxystearic acids. In one embodiment, the hydroxy-substituted C 10-30 carboxylic acid may be a mixture of ricinoleic acid and either 12-hydroxystearic acid or 9- and 10-hydroxystearic acids.
The polyester may have 4 to 20 repeat units of the hydroxy-substituted C 10-30 carboxylic acid.
The polyester may be a homopolymer or a copolymer. The copolymer may be either a random or block copolymer.
In one embodiment, the compound of the invention may be obtained/obtainable by reacting an aromatic amine with an optionally hydroxy-substituted C 10-30 carboxylic acid (typically a C 10-30 carboxylic acid), or mixtures thereof.
The optionally hydroxy-substituted C 10-30 carboxylic acid may include ricinoleic acid, 12-hydroxystearic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, or mixtures thereof. In one embodiment, the C 10-30 carboxylic acid may include lauric acid or stearic acid. In one embodiment, the optionally hydroxy-substituted C 10-30 carboxylic acid may include a mixture of (i) at least one of ricinoleic acid, or 12-hydroxystearic acid, and (ii) at least one of C 10-30 carboxylic acid such as lauric acid or stearic acid.
In one embodiment, the compound of the invention may be obtained/obtainable by reacting one mole of an aromatic amine with a one to two moles of a C 10-30 carboxylic acid, or mixtures thereof. The compound may be particularly useful in a composition including a plastic material.
In one embodiment, the compound of the invention may be obtained/obtainable by reacting an aromatic amine with a mixture of (i) C 10-30 -hydrocarbyl substituted acylating agent (as described above), and (ii) a hydroxy-substituted C 10-30 carboxylic acid (as described above). In one embodiment, the mixture includes (i) stearic acid, and (ii) a polyester of hydroxystearic acid or a polyester of ricinoleic acid.
In one embodiment, the compound of the invention may be obtained/obtainable by reacting an aromatic amine with a C 10-30 -hydrocarbyl substituted acylating agent, or mixtures thereof.
The C 10-30 -hydrocarbyl substituted acylating agent may be an alk(en)yl-substituted succinic acid, anhydride, or partial esters thereof. Examples of suitable succinic anhydrides include dodecyl succinic anhydride, hexadecyl succinic anhydride, octadecyl succinic anhydride, eicosyl succinic anhydride, C 24-28 -alkyl succinic anhydride, dodecenyl succinic anhydride, hexadecenyl succinic anhydride, octadecenyl succinic anhydride, eicosenyl succinic anhydride, C 24-28 -alkenyl succinic anhydride, or mixtures thereof. In one embodiment, the C 10-30 -hydrocarbyl substituted acylating agent may be hexadecyl succinic anhydride, octadecyl succinic anhydride, or mixtures thereof.
In one embodiment, the compound of the invention may be obtained/obtainable by reacting an aromatic amine with a polyolefin-substituted succinic anhydride, or mixtures thereof.
The polyolefin-substituted succinic anhydride may be a polyisobutylene succinic anhydride. The polyisobutylene from which the polyisobutylene succinic anhydride is derivable may have a number average molecular weight of 300 to 5000, 450 to 4000, 500 to 3000 or 550 to 2500. Particular ranges of the number average molecular weight may include 550 to 1000, or 750 to 1000, or 950 to 1000, or 1600 to about 2300.
The polyolefin may have a vinylidene group. The vinylidene group may be present on at least 2 wt. %, or at least 40%, or at least 50%, or at least 60%, or at least 70% of the polyolefin molecules. Often, the amount of vinylidene group present is about 75%, about 80% or about 85%.
When the polyolefin is a polyisobutylene the polyolefin may be obtained commercially under the tradenames of Glissopal®1000 or Glissopal®2300 (commercially available from BASF), TPC®555, TPC®575 or TPC®595 (commercially available from Texas Petrochemicals).
The polyolefin-substituted succinic anhydride may be obtained by reacting a polyolefin (typically polyisobutylene) with maleic anhydride by Diels Alder or by an “ene” reaction. Both reactions are known in the art. In one embodiment, the polyolefin-substituted succinic anhydride may be obtained by reacting a polyolefin (typically polyisobutylene) with maleic anhydride by an “ene” reaction.
The compound of the invention may be prepared by reacting an aromatic amine with a hydrocarbyl-substituted acylating agent at a reaction temperature in the range of 80° C. to 220° C., or 100° C. to 200° C.
In one embodiment, the aromatic amine to hydrocarbyl-substituted acylating agent mole ratio may be in the range of 2:1 to 1:10, or 2:1 to 1:4, or 1:1 to 1:3, or 1:1 to 1:2, or 1:2. In one embodiment, the aromatic amine to hydrocarbyl-substituted acylating agent mole ratio may be 1:1 to 1:2, or 1:2.
The reaction may be carried out in an inert atmosphere, for example, under nitrogen or argon, typically nitrogen.
The reaction may be a one-step process or a two-step process.
A two-step process may be employed if the hydrocarbyl-substituted acylating agent is a polyester. The first step comprises forming a polyester by copolymerising a hydroxy-substituted C 10-30 carboxylic acid as described above. The reaction may also optionally be carried out in the presence of a catalyst such as zirconium butoxide. The polymerisation step is known and is described for instance in U.S. Pat. No. 3,996,059. The second step comprises reacting the polyester with the aromatic amine.
Processes to prepare the compound of the invention when the hydrocarbyl-substituted acylating agent is a polyolefin-substituted acylating agent is described in International Application U.S. Ser. No. 09/065,452 (filed 23 Nov. 2009), also provisionally filed with U.S. Patent Application No. 61/118,012 (on 26 Nov. 2008). A process to prepare a compound of this type is shown below in EX1 and EX2.
Preparative Example 1 (EX1) is a coupled aromatic amine head group synthesis. 500 mL of 2M hydrochloric acid is added to a one-liter 4-neck flask equipped with an overhead stirrer, thermowell, addition funnel with nitrogen line, and condenser. 184.2 g of 4-aminodiphenylamine is added, and the flask is heated to 75° C. The addition funnel is then charged with 40.5 g of a 37% formaldehyde solution and the solution is added drop-wise to the flask over a period of 30 minutes. The flask is maintained at 100° C. for 4 hours. The flask is then cooled to ambient temperature. 80 g of a 50/50 wt./wt. solution of sodium hydroxide in water is added over 30 minutes. At the end of the reaction, a solid product is obtained via filtration. The resultant solid product is believed to primarily be the compound of Formula (2) as described above. In addition, the resultant product may contain a small percentage of product based on Formula (3) as described above.
Preparative Example 2 (EX2) is a reaction product of polyisobutylene succinic anhydride with the product of EX1. A three-liter, 4-neck flask equipped with an overhead stirrer, thermowell, subsurface inlet with nitrogen line, and Dean-Stark trap with condenser is charged with polyisobutylene succinic anhydride (1270.0 g) (where the polyisobutylene from which it is derived has a number average molecular weight of 2000) and diluent oil (1400.1 g). The flask is heated to 90° C. The product of EX1 (442.0 g) is added slowly. The temperature is then raised to 110° C. and held until the water from reaction with the product of EX1 is removed. The temperature is then raised to 160° C. and held for 10 hours. To the flask is added a portion of a diatomaceous earth filter aid, and then flask contents are filtered through a second portion of the diatomaceous earth filter aid. The resultant product is a dark oil with a nitrogen content of 0.65 wt. %.
INDUSTRIAL APPLICATION
In one embodiment, the compound of the invention disclosed herein may be a dispersant, typically used for dispersing particulate solid materials.
The compound of the invention disclosed herein in different embodiments may be present in the composition of the invention in a range selected from 0.1 to 50 wt. %, or 0.25 to 35 wt. %, and 0.5 to 30 wt. %.
The particulate solid present in the composition may be any inorganic or organic solid material which is substantially insoluble in the non-polar organic medium at the temperature concerned and which it is desired to stabilize in a finely divided form therein. The particulate solids may be in the form of a granular material, a fibre, a platelet or in the form of a powder, often a blown powder. In one embodiment, the particulate solid is a pigment of a filler. The pigment may be a organic or inorganic pigment, typically an organic pigment.
Examples of suitable particulate solids include pigments for solvent inks; pigments, extenders, fillers, blowing agents and flame retardants for paints and plastics materials; dyes, especially disperse dyes; optical brightening agents and textile auxiliaries for solvent dyebaths, inks and other solvent application systems; solids for oil-based and inverse-emulsion drilling muds; metals; particulate ceramic materials and magnetic materials for ceramics, piezoceramic printing, refactories, abrasives, foundry, capacitors, fuel cells, ferrofluids, conductive inks, magnetic recording media, water treatment and hydrocarbon soil remediation; organic and inorganic nanodisperse solids, such as metal, metal oxides and carbon for electrodes in batteries; fibres such as carbon and boron for composite materials; and biocides, agrochemicals and pharmaceuticals which are applied as dispersions in organic media.
In one embodiment, the particulate solid may be an organic pigment from any of the recognised classes of pigments described, for example, in the Third Edition of the Colour Index (1971) and subsequent revisions of, and supplements thereto, under the chapter headed “Pigments”. Examples of organic pigments are those from the azo, disazo, trisazo, condensed azo, azo lakes, naphthol pigments, anthanthrone, anthrapyrimidine, anthraquinone, benzimidazolone, carbazole, diketopyrrolopyrrole, flavanthrone, indigoid pigments, indanthrone, isodibenzanthrone, isoindanthrone, isoindolinone, isoindoline, isoviolanthrone, metal complex pigments, oxazine, perylene, perinone, pyranthrone, pyrazoloquinazolone, quinacridone, quinophthalone, thioindigo, triarylcarbonium pigments, triphendioxazine, xanthene and phthalocyanine series, especially copper phthalocyanine and its nuclear halogenated derivatives, and also lakes of acid, basic and mordant dyes. Carbon black, although strictly inorganic, behaves more like an organic pigment in its dispersing properties. In one embodiment, the organic pigments are phthalocyanines, especially copper phthalocyanines, monoazos, disazos, indanthrones, anthranthrones, quinacridones, diketopyrrolopyrroles, perylenes and carbon black including single- and multi-walled carbon nanotubes, reinforcing and non-reinforcing carbon black, graphite, Buckminster fullerenes, asphaltene, and graphene.
In one embodiment, the solid particulate is not carbon black, or has less than 80, 50, or 10 wt. % carbon and metal wear byproducts as a component of the particulate solid, based on the total weight of the solid particulate.
Other useful particulate solids include flame retardants such as pentabromodiphenyl ether, octabromodiphenyl ether, decabromodiphenyl ether, hexabromocyclododecane, ammonium polyphosphate, melamine, melamine cyanurate, antimony oxide and borates; biocides or industrial microbial agents such as those mentioned in Tables 2, 3, 4, 5, 6, 7, 8 and 9 of the chapter entitled “Industrial Microbial Agents” in Kirk-Othmer's Encyclopedia of Chemical Technology, Volume 13, 1981, 3 rd Edition, and agrochemicals such as the fungicides flutriafen, carbendazim, chlorothalonil and mancozeb.
The non-polar organic medium present in the composition of the invention in one embodiment may be a plastics material and in another embodiment an organic liquid.
In one embodiment, non-polar organic liquids are compounds containing aliphatic groups, aromatic groups or mixtures thereof. The non-polar organic liquids include non-halogenated aromatic hydrocarbons (e.g., toluene and xylene), halogenated aromatic hydrocarbons (e.g., chlorobenzene, dichlorobenzene, chlorotoluene), non-halogenated aliphatic hydrocarbons (e.g., linear and branched aliphatic hydrocarbons containing six or more carbon atoms both fully and partially saturated), halogenated aliphatic hydrocarbons (e.g., dichloromethane, carbon tetrachloride, chloroform, trichloroethane) and natural non-polar organics (e.g., vegetable oil, sunflower oil, linseed oil, terpenes and glycerides).
In one embodiment, the non-polar organic medium includes at least 0.1% by weight, or 1% by weight or more of a polar organic liquid based on the total organic liquid, with the proviso that the composition remains substantially non-polar. The non-polar medium may contain up to 5 wt. % or up to 10 wt. % of a polar organic liquid. Typically, the non-polar organic medium is substantially free of, to free of a polar organic liquid. In one embodiment, the non-polar medium is substantially free of, to free of water.
Examples of suitable polar organic liquids include amines, ethers, especially lower alkyl ethers, organic acids, esters, ketones, glycols, alcohols and amides. Numerous specific examples of such moderately strongly hydrogen bonding liquids are given in the book entitled “Compatibility and Solubility” by Ibert Mellan (published in 1968 by Noyes Development Corporation) in Table 2.14 on pages 39-40, and these liquids all fall within the scope of the term polar organic liquid as used herein.
In one embodiment, polar organic liquids include dialkyl ketones, alkyl esters of alkane carboxylic acids and alkanols, especially such liquids containing up to, and including, a total of 6 or 8 carbon atoms. As examples of the polar organic liquids include dialkyl and cycloalkyl ketones, such as acetone, methyl ethyl ketone, diethyl ketone, di-isopropyl ketone, methyl isobutyl ketone, di-isobutyl ketone, methyl isoamyl ketone, methyl n-amyl ketone and cyclohexanone; alkyl esters such as methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, ethyl formate, methyl propionate, methoxy propylacetate and ethyl butyrate; glycols and glycol esters and ethers, such as ethylene glycol, 2-ethoxyethanol, 3-methoxypropylpropanol, 3-ethoxypropylpropanol, 2-butoxyethyl acetate, 3-methoxypropyl acetate, 3-ethoxypropyl acetate and 2-ethoxyethyl acetate; alkanols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and isobutanol and dialkyl and cyclic ethers such as diethyl ether and tetrahydrofuran. In one embodiment, solvents are alkanols, alkane carboxylic acids and esters of alkane carboxylic acids.
Examples of organic liquids, which may be used as polar organic liquids are film-forming resins. Examples of such film-forming resins include polyamides, such as Versamid™ and Wolfamid™, and cellulose ethers, such as ethyl cellulose and ethyl hydroxyethyl cellulose, nitrocellulose and cellulose acetate butyrate resins, including mixtures thereof. Examples of resins include short oil alkyd/melamine-formaldehyde, polyester/melamine-formaldehyde, thermosetting acrylic/melamine-formaldehyde, long oil alkyd, polyether polyols and multi-media resins, such as acrylic and urea/aldehyde.
The organic liquid may be a polyol, that is to say, an organic liquid with two or more hydroxy groups. In one embodiment, polyols include alpha-omega diols or alpha-omega diol ethoxylates.
If desired, the compositions containing a non-polar organic medium may contain other ingredients, for example, resins (where these do not already constitute the organic medium), binders, co-solvents, cross-linking agents, fluidising agents, wetting agents, anti-sedimentation agents, plasticisers, surfactants, dispersants other than the compound of the present invention, humectants, anti-foamers, anti-cratering agents, rheology modifiers, heat stabilizers, light stabilizers, UV absorbers, antioxidants, levelling agents, gloss modifiers, biocides and preservatives.
The plastics material may be a thermosetting resin or a thermoplastic resin. The thermosetting resins useful in this invention include resins which undergo a chemical reaction when heated, catalysed, or subject to ultra-violet, laser light, infra-red, cationic, electron beam, or microwave radiation and become relatively infusible. Typical reactions in thermosetting resins include oxidation of unsaturated double bonds, reactions involving epoxy/amine, epoxy/carbonyl, epoxy/hydroxyl, reaction of epoxy with a Lewis acid or Lewis base, polyisocyanate/hydroxy, amino resin/hydroxy moieties, free radical reactions or polyacrylate, cationic polymerization of epoxy resins and vinyl ether and condensation of silanol. Examples of unsaturated resins include polyester resins made by the reaction of one or more diacids or anhydrides with one or more diols. Such resins are commonly supplied as a mixture with a reactive monomer such as styrene or vinyltoluene and are often referred to as orthophthalic resins and isophthalic resins. Further examples include resins using dicyclopentadiene (DCPD) as a co-reactant in the polyester chain. Further examples also include the reaction products of bisphenol A diglycidyl ether with unsaturated carboxylic acids such as methacrylic acid, subsequently supplied as a solution in styrene, commonly referred to as vinyl ester resins.
Polymers with hydroxy functionality (frequently polyols) are widely used in thermosetting systems to crosslink with amino resins or polyisocyanates. The polyols include acrylic polyols, alkyd polyols, polyester polyols, polyether polyols and polyurethane polyols. Typical amino resins include melamine formaldehyde resins, benzoguanamine formaldehyde resins, urea formaldehyde resins and glycoluril formaldehyde resins. Polyisocyanates are resins with two or more isocyanate groups, including both monomeric aliphatic diisocyanates, monomeric aromatic diisocyanates and their polymers. Typical aliphatic diisocyanates include hexamethylene diisocyanate, isophorone diisocyanate and hydrogenated diphenylmethane diisocyanate. Typical aromatic isocyanates include toluene diisocyanates and biphenylmethane diisocyanates.
The plastics material such as a thermoset resin may be useful for parts in boat hulls, baths, shower trays, seats, conduits and bulkheads for trains, trams, ships aircraft, body panels for automotive vehicles and truck beds.
In one embodiment, thermoplastic resins include polyolefins, polyesters, polyamides, polycarbonates, polyurethanes, polystyrenics, poly(meth)acrylates, celluloses and cellulose derivatives. Said compositions may be prepared in a number of ways but melt mixing and dry solid blending are typical methods. Examples of a suitable thermoplastic include (low density, or linear low density or high density) polyethylene, polypropylene, polystyrene, polyethylene terephthalate (PET), polybutylene terephthalate (PBT), nylon 6, nylon 6/6, nylon 4/6, nylon 6/12, nylon and nylon 12, polymethylmethacrylate, polyethersulphone, polysulphones, polycarbonate, polyvinyl chloride (PVC), thermoplastic polyurethane, ethylene vinyl acetate (EVA), Victrex PEEK™ polymers (such as oxy-1,4-phenylenoeoxy-1,4-phenylene-carbonyl-1,4-phenylene polymers) and acrylonitrile butadiene styrene polymers (ABS); and various other polymeric blends or alloys.
If desired, the compositions containing plastic material may contain other ingredients, for example, dispersants other than the compound of the present invention, antifogging agents, nucleators, blowing agents, flame retardants, process aids, surfactants, plasticisers, heat stabilizers, UV absorbers, anti-oxidants, fragrances, mould release aids, anti-static agents, anti-microbial agents, biocides, coupling agents, lubricants (external and internal), impact modifiers, slip agents, air release agents and viscosity depressants.
The compositions typically contain from 1 to 95% by weight of the particulate solid, the precise quantity depending on the nature of the solid and the quantity depending on the nature of the solid and the relative densities of the solid and the polar organic liquid. For example, a composition in which the solid is an organic material, such as an organic pigment, in one embodiment contains from 15 to 60% by weight of the solid whereas a composition in which the solid is an inorganic material, such as an inorganic pigment, filler or extender, in one embodiment contains from 40 to 90% by weight of the solid based on the total weight of composition.
The composition may be prepared by any of the conventional methods known for preparing dispersions. Thus, the solid, the organic medium and the dispersant may be mixed in any order, the mixture then being subjected to a mechanical treatment to reduce the particles of the solid to an appropriate size, for example, by ball milling, bead milling, gravel milling, high shear mixing or plastic milling until the dispersion is formed. Alternatively, the solid may be treated to reduce its particle size independently or in admixture with either, the organic medium or the dispersant, the other ingredient or ingredients then being added and the mixture being agitated to provide the composition.
In one embodiment, the composition of the present invention is suited to liquid dispersions. In one embodiment, such dispersion compositions comprise: (a) 0.5 to 40 parts of a particulate solid, (b) 0.5 to 30 parts of a composition as disclosed herein above, and (c) 30 to 99 parts of an organic medium; wherein all parts are by weight and the amounts (a)+(b)+(c)=100.
In one embodiment, component a) includes 0.5 to 40 parts of a pigment and such dispersions are useful as mill-bases, coatings, paints, toners, or inks.
If a composition is required including a particulate solid and a composition as disclosed herein above in dry form, the organic liquid is typically volatile so that it may be readily removed from the particulate solid by a simple separation means such as evaporation. In one embodiment, the composition includes the organic liquid.
If the dry composition consists essentially of the composition as disclosed herein above and the particulate solid, it typically contains at least 0.2%, at least 0.5% or at least 1.0% the composition as disclosed herein above based on weight of the particulate solid. In one embodiment, the dry composition contains not greater than 100%, not greater than 50%, not greater than 20%, or not greater than 10% by weight of the composition as disclosed herein above based on the weight of the particulate solid. In one embodiment, the composition, as disclosed herein above, is present at 0.6 wt. % to 8 wt. %.
As disclosed hereinbefore, the compositions of the invention are suitable for preparing mill-bases wherein the particulate solid is milled in an organic liquid in the presence of a composition, as disclosed herein above, or salts thereof.
Thus, according to a still further embodiment of the invention, there is provided a mill-base including a particulate solid, an organic liquid and a composition as disclosed herein above, or salts thereof.
Typically, the mill-base contains from 20 to 70% by weight particulate solid based on the total weight of the mill-base. In one embodiment, the particulate solid is not less than 10 or not less than 20% by weight of the mill-base. Such mill-bases may optionally contain a binder added either before or after milling. The binder is a polymeric material capable of binding the composition on volatilisation of the organic liquid.
Binders are polymeric materials including natural and synthetic materials. In one embodiment, binders include poly(meth)acrylates, polystyrenics, polyesters, polyurethanes, alkyds, polysaccharides such as cellulose, and natural proteins such as casein. In one embodiment, the binder is present in the composition at more than 100% based on the amount of particulate solid, more than 200%, more than 300% or more than 400%.
The amount of optional binder in the mill-base can vary over wide limits but is typically not less than 10%, and often not less than 20% by weight of the continuous/liquid phase of the mill-base. In one embodiment, the amount of binder is not greater than 50% or not greater than 40% by weight of the continuous/liquid phase of the mill-base.
The amount of dispersant in the mill-base is dependent on the amount of particulate solid, but is typically from 0.5 to 5% by weight of the mill-base. Continuous/liquid phase includes all of the liquid materials (e.g., solvent, liquid binder, dispersants, etc.) and any solid material that dissolves in the liquid materials after a short mixing period, e.g., it specifically excludes solid particulates that are dispersed in the continuous liquid phase.
Dispersions and mill-bases made from the composition of the invention are particularly suitable for use in aqueous, non-aqueous and solvent free formulations in which energy curable systems (ultra-violet, laser light, infra-red, cationic, electron beam, microwave) are employed with monomers, oligomers, etc., or a combination present in the formulation. They are particularly suitable for use in coatings such as paints, varnishes, inks, other coating materials and plastics. Suitable examples include their use in low, medium and high solids paints, general industrial paints including baking, 2 component and metal coating paints such as coil and can coatings, powder coatings, UV-curable coatings, wood varnishes; inks, such as flexographic, gravure, offset, lithographic, letterpress or relief, screen printing and printing inks for packaging printing, non impact inks such as ink jet inks, inks for ink jet printers and print varnishes such as overprint varnishes; polyol and plastisol dispersions; non-aqueous ceramic processes, especially tape-casting, gel-casting, doctor-blade, extrusion and injection moulding type processes, a further example would be in the preparation of dry ceramic powders for isostatic pressing; composites such as sheet moulding and bulk moulding compounds, resin transfer moulding, pultrusion, hand-lay-up and spray-lay-up processes, matched die moulding; construction materials like casting resins, cosmetics, personal care like nail coatings, sunscreens, adhesives, toners, plastics materials and electronic materials, such as coating formulations for colour filter systems in displays including OLED devices, liquid crystal displays and electrophoretic displays, glass coatings including optical fibre coatings, reflective coatings or anti-reflective coatings, conductive and magnetic inks and coatings. They are useful in the surface modification of pigments and fillers to improve the dispersibility of dry powders used in the above applications. Further examples of coating materials are given in Bodo Muller, Ulrich Poth, Lackformulierung und Lackrezeptur, Lehrbuch fr Ausbildung und Praxis, Vincentz Verlag, Hanover (2003) and in P. G. Garrat, Strahlenhartung, Vincentz Verlag, Hanover (1996). Examples of printing ink formulations are given in E. W. Flick, Printing Ink and Overprint Varnish Formulations—Recent Developments, Noyes Publications, Park Ridge N.J., (1990) and subsequent editions.
In one embodiment, the composition of the invention further includes one or more additional known dispersants.
The following examples provide illustrations of the invention. These examples are non exhaustive and are not intended to limit the scope of the invention.
EXAMPLES
Inventive Compound 1 (IC1): 12-hydroxystearic acid (404.3 g) is placed postionwise in a 1 L flask with heating until the acid melted. The flask is attached to a Dean Stark apparatus with a stirrer. The mixture is then heated to 110° C. under N 2 with stirring (at 230 rpm). The product of EX1 (as described above) (44.7 g) is then added portion wise through a powder funnel over 5 minutes. The reaction is then heated to 150° C. and held for 4 hours. 4.7 g of water is collected. The flask is cooled to 100° C. and the zirconium butoxide (80% solution) (2.6 g) is added via a pipette. A subsurface nitrogen sparge was added and set to 471.94 cm 3 /min (or 1 scfh). The reaction is heated to 195° C. and held for 22 hours. Water (8.3 g) is collected. The reaction is cooled and diluent oil is added (150.3 g). The resultant mixture is stirred for 1 hour. A further 147.2 g of diluent oil is added to homogenise for a further 30 minutes at 100° C. The product is then filtered through Fax-5 diatomaceous filter. A further 200 g of diluent oil is added to homogenise for a further 30 minutes at 100° C. to give the final product.
Inventive Compound 2 (IC2): 12-hydroxystearic acid (400.9 g) is placed postionwise in a 1 L flask with heating until the acid melted. The flask is attached to a Dean Stark apparatus with a stirrer. The mixture is then heated to 110° C. under N 2 with stirring (at 240 rpm). 40.6 g of 4-aminodiphenylamine is then added portion wise through a powder funnel over 5 minutes. The reaction is then heated to 150° C. and held for 4 hours. The flask is cooled to 100° C. and the zirconium butoxide (80% solution) (2.5 g) is added via a pippette. A subsurface nitrogen sparge was added and set to 471.94 cm 3 /min (or 1 scfh). The reaction is heated to 195° C. and held for 22 hours. The reaction is cooled to 100° C. and diluent oil is added (133.5 g). The resultant mixture is stirred for 1 hour at 100° C. The product is then filtered through Fax-5 diatomaceous filter to give the final product.
Inventive Compound 3 (IC3): Ricinoleic acid (631.5 g) is placed postionwise in a 1 L flask with heating until the acid melted. The flask is attached to a Dean Stark apparatus with a stirrer. The mixture is then heated to 110° C. under N 2 with stirring (at 200 rpm). 69.1 g of the product of EX1 described above is then added portion wise through a powder funnel over 10 minutes. The reaction is then heated to 150° C. and held for 4 hours. 14 g of water is collected. The flask is cooled to 100° C. and the zirconium butoxide (80% solution) (4.0 g) is added via a pippette. A subsurface nitrogen sparge was added and set to 471.94 cm 3 /min (or 1 scfh). The reaction is heated to 195° C. and held for 19 hours. Water (23.3 g) is collected. The reaction is cooled to 100° C. and diluent oil is added (220.3 g). The resultant mixture is stirred for 1 hour at 100° C. The product is then filtered through Fax-5 diatomaceous filter to give the final product.
Inventive Compound 4 (IC4): Ricinoleic acid (406 g; 1.362 moles) and the product of EX1 (89.6 g; 0.2357 moles) are charged to a 1 liter flask, under a nitrogen sparge. The flask is attached to a Dean Stark apparatus with a stirrer. The flask is heated to 150° C. and maintained at this temperature for 5 hours. Zirconium butoxide (2.5 g) is then charged and the batch heated to 195° C. for 20 hours. The product is then cooled.
Inventive Compound 5 (IC5): Ricinoleic acid (516.6 g; 1.734 moles) and the product of EX1 (44.7 g; 0.1176 moles) are charged to a 1 liter flask, under a nitrogen sparge. The flask is attached to a Dean Stark apparatus with a stirrer. The flask is heated to 150° C. and maintained at this temperature for 5 hours. Zirconium butoxide (2.5 g) is then charged and the batch heated to 195° C. for 20 hours. The product is then cooled.
Inventive Compound 6 (IC6): 12-Hydroxystearic acid (405.6 g; 1.352 moles) is melted out at 100° C. in a 1 liter flask, under a nitrogen sparge. The flask is attached to a Dean Stark apparatus with a stirrer. Once the 12-hydroxystearic acid, the flask is charged with melted the product of EX1 (89.6 g; 0.2379 moles). The flask is heated to 150° C. and maintained at this temperature for 5 hours. Zirconium butoxide (2.5 g) is then charged and the batch heated to 195° C. for 20 hours. The product is then cooled.
Inventive Compound 7 (IC7): 12-Hydroxystearic acid (515.6 g; 1.719 moles) is melted out at 100° C. in a 1 liter flask, under a nitrogen sparge. The flask is attached to a Dean Stark apparatus with a stirrer. Once the 12-hydroxystearic acid, the flask is charged with melted the product of EX1 (44.7 g; 0.2379 moles). The flask is heated to 150° C. and maintained at this temperature for 5 hours. Zirconium butoxide (2.5 g) is then charged and the batch heated to 195° C. for 20 hours. The product is then cooled.
Inventive Compound 8 (IC8): Polyisobutylenesuccinic anhydride (250.5 g; 0.2386 moles) and the product of EX1 (89.6 g; 0.2357 moles) are charged to a 1 liter flask, under a nitrogen sparge. The flask is attached to a Dean Stark apparatus with a stirrer. The flask is heated to 160° C. and maintained at this temperature for 8 hours. The flask is then heated to 180° C. and held at for 5 hours. The product is then cooled.
Comparative Example 1
(CE1) is a dispersant as described in Example 2 of GB 1 373 660.
Comparative Example 2
(CE2) is a dispersant as described in Example 5 of U.S. Pat. No. 4,224,212.
0.38 g of each of the compounds of the invention and comparative examples are each dissolved in toluene (6.47 g) by warming as necessary and added to a trident vial. 0.15 g of Solsperse®5000 (ex., The Lubrizol Corporation) is added. 17 g of 3 mm diameter glass beads and 3 g of copper phthalocyanine pigment (Monastral Blue BG, ex Heubach) is added. The vial is capped and sealed. A control vial is also prepared that does not contain a dispersant. The pigment is milled by shaking on a horizontal shaker for 16 hours. The viscosity of the resulting dispersion is assessed using an arbitrary scale of A to E (good to poor) based on stability of dispersion upon standing. The results obtained are as follows:
Compound
Rating
IC1
A
IC2
B
IC3
A
IC4
A
IC5
A
IC6
A
IC7
A
IC8
B
CE1
B/C
CE2
C
Control
E
The results indicate that the compounds of the invention provide superior fluidity of pigment dispersions in a non-polar organic medium.
Each of the documents referred to above is incorporated herein by reference. Except in the Examples, or where otherwise explicitly indicated, all numerical quantities in this description specifying amounts of materials, reaction conditions, molecular weights, number of carbon atoms, and the like, are to be understood as modified by the word “about.” Unless otherwise indicated, each chemical or composition referred to herein should be interpreted as being a commercial grade material which may contain the isomers, by-products, derivatives, and other such materials which are normally understood to be present in the commercial grade. However, the amount of each chemical component is presented exclusive of any solvent or diluent oil, which may be customarily present in the commercial material, unless otherwise indicated. It is to be understood that the upper and lower amount, range, and ratio limits, set forth herein, may be independently combined. Similarly, the ranges and amounts for each element of the invention may be used together with ranges or amounts for any of the other elements.
While the invention has been explained in relation to its preferred embodiments, it is to be understood that various modifications thereof will become apparent to those skilled in the art upon reading the specification. Therefore, it is to be understood that the invention disclosed herein is intended to cover such modifications as fall within the scope of the appended claims.
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The present invention relates to a composition containing a particulate solid, a non-polar organic medium, and a compound obtained/obtainable by reacting an aromatic amine with hydrocarbyl-substituted acylating agent, wherein the hydrocarbyl-substituted acylating agent is selected from the group consisting of an oligomer or polymer from condensation polymerization of a hydroxy-substituted C 10-30 carboxylic acid into a polyester, an optionally hydroxy-substituted C 10-30 carboxylic acid, a C 10-30 -hydrocarbyl substituted acylating agent, and a polyolefin-substituted maleic anhydride. The invention further provides compositions for inks, thermoplastics, plasticizers, plastisols, crude grinding and flush.
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CROSS-REFERENCE TO RELATED APPLICATIONS
The present application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application Ser. Nos. 60/771,627, filed Feb. 9, 2006, and 60/746,097 filed May 1, 2006, both of which are incorporated by reference herein in their entirety, and also claims priority under 35 U.S.C. §120 to co-pending U.S. non-provisional application Ser. No. 11/427,233, filed Jun. 28, 2006, which is also incorporated herein by reference.
BACKGROUND OF THE INVENTION
1. Field of Invention
The present invention relates generally to the field of oilfield exploration, production, and testing, and more specifically to deflector apparatus commonly known as whipstocks comprising degradable compositions, and methods of using same.
2. Related Art
Existing structural compositions, that is materials and combinations of materials, have been developed to sustain elevated loads (forces, stresses, and pressures) at useful ranges of temperatures, and also not to react, and thus degrade by dissolving, disintegrating, or both in the presence of common fluids such as water, or moist air. Note, for a better understanding of the invention, that a composition is here defined as a tangible element created by arranging several components, or sub-compositions, to form a unified whole; the definition of composition is therefore expanded well beyond material chemical composition and includes all combinations of materials that are used smartly to achieve the purposes of the invention.
Structural compositions found in everyday applications (mainly metals and alloys) are required to be durable over intended element lifetimes; i.e. they must be chemically inert, or not reactive, even though many rust or corrode over the intended element lifetimes. In generic terms, a reactive metal may be defined as one that readily combines with oxygen to form very stable oxides, one that also interacts with water and produces diatomic hydrogen, and/or one that becomes easily embrittled by interstitial absorption of oxygen, hydrogen, nitrogen, or other non-metallic elements. There are clearly various levels of reactivity between metals, alloys, or in general compositions, or simply any element listed on the periodic table. For instance, compared to iron or steels (i.e. alloys of iron), aluminum, magnesium, calcium and lithium are reactive; lithium being the most reactive, or least inert of all four. Reactive metals are properly grouped in the first two columns of the Periodic Table of the Elements (sometimes referred to as Column I and II elements); i.e., among the alkaline and alkaline-earth elements. Of the alkaline metals, namely lithium (Li), sodium (Na), potassium (K), rubidium (Rb), cesium (Cs), francium (Fr), and alkaline-earth metals, namely beryllium (Be), magnesium (Mg), calcium (Ca), strontium (Sr), barium (Ba), radium (Ra), few may be directly utilized for the excellent reasons that they are either 1) far too reactive to be handled safely and thus be readily procurable to be useful for any commercial applications, or 2) not sufficiently reactive as they for instance passivate in aqueous environments and thus form stable protective barriers (e.g. adherent oxides and hydroxide films), or 3) their rate of reaction or transformation, and thus degradation, is too slow, as it is for instance seen when magnesium, aluminum and their commercial alloys are immersed in cold and neutral water (i.e. neither acidic nor basic; pH=7). Though profoundly less reactive than the alkaline and alkaline-earth metals, aluminum may be also included among the reactive metals. Yet, aluminum does not react, or degrade with water nearly to the same extents as the Columns I and II elements since aluminum is a typical material used in durable elements for applications as diverse as automotive, aerospace, appliances, electrical, decoration, and the like. To quantify reactivity of an element, galvanic corrosion potentials may be used, or if unavailable measured, as for instance for any novel composition compared to a reference, for instance the hydrogen reaction; for instance the higher the potential of a composition with respect to hydrogen the lesser its reactivity and its likelihood to degrade noticeably, or rapidly. Because reactivity of an element is linked to the ease chemical reactions proceed with non-metallic elements (e.g. oxygen, nitrogen), for periodic table elements electronegativity constitutes an excellent measure of reactivity. Electronegativity, and especially corrosion potential of aluminum are sufficiently low compared to the other elements of the periodic table to categorize aluminum as a reactive metal rather than a non-reactive, inert or noble metal or element.
In the oilfield environment, it would be advantageous to be able to utilize a whipstock or deflector component comprised of a reactive composition comprising alkaline, alkaline-earth elements, or other metal (e.g. aluminum) having either an enhanced reactivity (e.g. compositions comprising aluminum) or reduced reactivity (e.g. compositions comprising calcium) relative to that of the (pure or unalloyed) alkaline or alkaline-earth elements in the composition. Whipstocks and deflectors are currently used as a means to deflect assemblies and tools into a lateral section of a multilateral wellbore. They are currently made using non-degradable components. These devices must be retrieved with a separate trip in the well, which is added cost. So in some cases, the deflector or whipstock is left in the hole (to save cost) and production is brought online. However, the presence of the devices in the main bore means reduced flow area. It would also be of great benefit to controllably enhance or delay the interaction or degradation of the whipstock or deflector with its fluidic environment; an environment that may comprise water, completion fluids, and the like and will therefore be corrosive to the whipstock or deflector. The compositions of interest are those that degrade by either dissolving or disintegrating, or both when demanded by the application or the user. The degradation may proceed within minutes, hours, days or weeks depending upon the application requirements; in oilfield environments typical time for degradation may range from minutes to days, occasionally weeks.
In many well operations it is thus desirable to possess and use whipstock and deflectors that controllably degrade either in rate, location of the element, or both (or include a portion that predictably degrades) in the wellbore environment, without having to resort to highly acid conditions, high temperatures, mechanical milling, or a combination of these. Since none of the known diverters and whipstocks have the ability to degrade in a controlled user defined fashion, such degradable elements could potentially be in high demand in both the oilfield.
SUMMARY OF THE INVENTION
In accordance with the present invention, whipstock and deflector apparatus comprising a user-controlled degradable composition, and methods of using same are described that reduce or overcome limitations of previously known whipstock and deflector apparatus and methods. By combining reactive metals and their properties with other relatively reactive or non-reactive supplemental components, including in certain embodiments alloying elements, the inventive apparatus (for example, but not limited to alloys, composites, and smart combinations of materials) are formed and may be utilized to advantage in oilfield operations. Deflectors and whipstocks of the invention may be applied to a multitude of oilfield operations, including, but not limited to, deflecting drill bits and other equipment from a first wellbore to a lateral wellbore. As one example of an apparatus and method of use of the invention, a whipstock comprising a highly reactive composition consisting essentially of a degradable component, for example dissolving within minutes, may be protected by a coating that specifically becomes dysfunctional at or about reservoir temperature. Such whipstock and deflector embodiments of the invention, though simplistically described in this example, offer new advantages to temporarily deflect equipment into separate laterals and zones of a reservoir. The whipstock or deflector apparatus, once allowed to warm up for instance to the reservoir temperature, first fails for instance by the melting or fracture of its coating, among other mechanisms, before fully degrading by dissolution, disintegration, or both. When the element becomes dysfunctional, the element may not yet be entirely degraded and therefore may either fall or float to a new position but without obstructing well operation. In this and other embodiments of the invention, no intervention is therefore required to remove the element after its useful life of diverting equipment is completed.
A first aspect of the invention is a whipstock or deflector having a body, the body comprising a degradable composition as described more fully herein, the body having a first body portion for connection to a securing component for securing the whipstock in a primary wellbore, and a second body portion for deflecting a tool into a lateral wellbore intersecting the primary wellbore, the second body portion comprising a surface positioned at an oblique angle to the longitudinal axis of the primary wellbore. The oblique angle may be substantially equal to a “lateral angle”, that is, the angle that a lateral makes with the primary wellbore, although exact identity of the two angles is not critical. The difference in angles can be as much as 10, 12, 14, 16, 18, or 20 degrees in some embodiments.
The degradable composition may consist essentially of one or more reactive metals in major proportion, and one or more alloying elements in minor proportion, with the provisos that the composition is high-strength, controllably reactive, and degradable under defined conditions. These compositions are fully described in assignee's co-pending parent application Ser. No. 11/427,233, filed Jun. 28, 2006, previously incorporated herein by reference. Exemplary compositions useful in the invention may exist in a variety of morphologies (i.e., physical forms on the atomic scale), including 1) a reactive metal or alloy of crystalline, amorphous or mixed crystalline and amorphous structure, and the features characterizing the composition (e.g. grains, phases, inclusions, and the like) may be of micron or submicron scale, for instance nanoscale; 2) powder-metallurgy like structures (e.g. pressed, compacted, sintered) including a degradable composition including at least one relatively reactive metal or alloy combined with other metals, alloys or compositions that preferentially develop large galvanic couples with the reactive metal or elements in the non-intra-galvanic degradable alloy; and 3) composite and hybrid structures comprising one or more reactive metals or alloys as a metal matrix, imbedded with one or more relatively non-reactive materials of macro-to-nanoscopic sizes (e.g. powders, particulates, platelets, flakes, fibers, compounds, and the like) or made for instance from stacks of layers of dissimilar metals, alloys and compositions with the provisos that certain layers are reactive.
Compositions useful in the invention include certain alloy compositions comprising a reactive metal selected from elements in columns I and II of the Periodic Table combined with at least one element (alloying element) that, in combination with the reactive metal, produces a high-strength, controllably reactive and degradable metallic composition having utility as, or as a component of, apparatus of the invention. Exemplary compositions usable in the invention include compositions wherein the reactive metal is selected from calcium, magnesium, aluminum, and wherein the at least one alloying element is selected from lithium, gallium, indium, zinc, bismuth, calcium, magnesium, and aluminum if not already selected as the reactive metal, and optionally a metallic solvent to the alloying element. Another class of compositions useful in apparatus and methods of the invention is a class of aluminum alloys wherein aluminum is made considerably more reactive than commercially available aluminum and aluminum alloys. To enhance reactivity of aluminum, aluminum is essentially alloyed with gallium, indium, among other elements such as bismuth or tin for example. For commercial applications, including in the oilfield, aluminum is particularly attractive because of its availability worldwide, relatively low cost, high processability (e.g. aluminum can be cast, welded, forged, extruded, machined, and the like), and non-toxicity; thus aluminum and its alloys may be safely handled during fabrication, transportation, and final use of the degradable whipstock and deflector apparatus of the invention. Other suitable compositions are composite or hybrid structures, for instance made from those novel aluminum alloys. A non-restrictive example of these innovative compositions is a metal-matrix composite of these degradable aluminum alloys reinforced by ceramic particulates or fibers, itself coated with one or several other compositions, possibly metallic, ceramic, polymeric.
Whipstocks and deflectors of the invention may be formed or processed into shaped articles of manufacture, solid parts as well as hollow parts, or partially hollow parts with one or more coatings on all or only selected surfaces. The coatings may also vary from one surface to the other, and a surface may be coated with one or multiple layers (thus generating a functionally graded composite composition) depending upon the applications needs. Consequently certain compositions usable in the inventive apparatus may serve as coatings on substrates, such as metal, plastic, and ceramics making up the body of the whipstock or deflector wherein the compositions may be applied by processes such as co-extrusion, adhesive bonding, dipping, among other processes. In certain whipstock and deflector embodiments of the invention the shape of the whipstock or deflector may further contribute to the controllably reactive and degradable nature of the apparatus.
The controllability of the reactivity and thus degradability may in certain embodiments depend on the physical form, or morphology of the composition making up the whipstock pr deflector. The morphology of the composition may be selected from pure metals, alloys purposely formulated to be reactive, for example pressed, compacted, sintered, or metallic-based composites and hybrid metallic compositions or combinations, for example, but not limited to metal matrix embedded with relatively inert ingredients, metallic mesh compositions, coated metallic compositions, multilayered and functionally graded metallic compositions, that degrade either partially or totally, immediately or after well-controlled and predictable time once exposed to a fluid (liquid and/or gaseous), either fully or partially aqueous (water and water-based fluids), organic, metallic (e.g. liquid metals), organometallic compounds of the formula RM, wherein R is a carbon (and in certain cases, silicon, or phosphorous) directly attached to a metal M, and combinations thereof. Compositions usable in the invention include those that are highly sensitive to the presence of water, including water vapor, or humidity. The fluid environment, that is either a liquid or gas is corrosive (moderately to highly) to compositions of the invention. Nanomaterials, either carbon-based (e.g. carbon nanotubes—single wall or multi-wall, buckyballs, nanofibers, nanoplatelets, and derivatized versions of these) or non-carbon-based of all types of morphologies, may be used to further develop new compositions and further alter the strength or the reactivity of the inventive compositions, when added to compositions usable in the invention, like alloys for instance.
The inventive whipstock and deflector apparatus are degradable, and may be categorized as biodegradable when formulated to be safe or friendly to the environment. Use of regulated compositions, including those comprising hazardous elements has been restricted; for instance lead (Pb) and cadmium (Cd) that are both technically desirable for alloy formulation are avoided in apparatus of the invention, whenever possible.
As used herein the term “high-strength” means the whipstock and deflector apparatus of the invention possess intrinsic mechanical strengths, including quasi-static uniaxial strengths and hardness values at least equal to and typically greater than that of pure metals. Their strength is such that they can withstand thousands of pounds-per-square-inch pressures for extended periods of time, depending upon needs of the applications or users. High-strength also refers to non-metallic compositions, in particular plastics for which strength at room temperatures or higher temperatures is typically considerably smaller than that of metals or alloys. It is implied here that strength of apparatus of the invention at room-temperature and downhole temperatures may be defined as high relative to that of the plastics. As used herein the term “controllably reactive” refers to compositions that “react” in the presence of fluids typically considered non-reactive or weakly reactive to oil and gas engineering compositions. Compositions usable in whipstocks and deflectors of the invention are engineered smartly to either exhibit enhanced reactivity relative to the pure reactive metals, or delay the interaction of the reactive metals with the corrosive fluid. Compositions usable in apparatus of the invention also include those that degrade under conditions controlled by oilfield personnel. Whipstock and deflector apparatus of the invention that disintegrate are those that loose structural integrity and eventually break down in pieces or countless small debris. As used herein the term “degradable” refers to apparatus made from compositions that are partially or wholly consumed because of their relatively high reactivity. Whipstocks and deflectors of the invention may comprise compositions that are considered reactive and degradable and include those that are partially or wholly dissolvable (soluble) in the designated fluid environment, as well as those that disintegrate but do not necessarily dissolve. Also, the reaction byproducts of a degradable apparatus of the invention may not be soluble, since debris may precipitate out of the fluid environment. “Hybrid”, as used herein to characterize an inventive apparatus, refers to combinations of distinct compositions used together as a part of a new and therefore more complex apparatus because of their dissimilar reactivities, strengths, among other properties. Included are composites, functionally-graded compositions and other multi-layered compositions regardless of scale. In order of increasing reactivity are macro-, meso-, micro- and nanoscale compositions. These scales may be used in compositions usable in apparatus of the invention to further control reactivity, thus rate of degradation of apparatus of the invention.
In use, introduction of an alloying element or elements may function to either restrict or on the contrary enhance degradation of whipstocks and deflectors of the invention by limiting either the rate and/or location (i.e., front, back, center or some other location of the whipstock or deflector), as in the example of a non-uniform material. The alloying element or component may also serve to distribute loads at high stress areas, such as at the angled surface of the whipstock or deflector which actually contacts the equipment being displaced into a lateral wellbore, and may function to moderate the temperature characteristic of the reactive metal such that it is not subject to excessive degradation at extreme temperature by comparison.
Whipstock and deflectors of the invention function to deflect equipment into lateral wellbores, and then controllably react to therefore degrade when exposed to conditions in a controlled fashion, i.e., at a rate and location controlled by the user of the application. In this way, zones in a wellbore, or the wellbore itself or lateral branches of the wellbore, may be blocked or accessed for periods of time uniquely defined by the user.
Whipstocks and deflectors of the invention may be of a number of shapes, and may be of any shape provided it can traverse at least a portion of a wellbore and function to direct another tool, piping, or apparatus into a lateral wellbore. Suitable shapes include a main body that may be cylindrical, round, bar shaped, dart shaped, and the like, axis-symmetrical and non-axis-symmetrical shapes, and which includes the angled surface as described for actually contacting and deflecting the equipment in to the lateral. A dart shape means that the bottom has a tapered end, in some embodiments pointed, in other embodiments truncated, flat or rounded, and the like. Certain embodiments may have one or more passages to allow well fluids or injected fluids to contact inner portions of the whipstock or deflector. Since the diameter, length, and shape of the passages through the apparatus are controllable, the rate of degradation of the apparatus may be controlled solely by mechanical manipulation of the passages, if desired. The one or more passages may extend into the apparatus a variable distance, diameter, and/or shape as desired to control the rate of degradation of the whipstock or deflector. The rate of degradation may be controllable chemically by choice of supplementary components. Whipstocks and deflectors of the invention may comprise a structure wherein a composition consisting essentially of reactive metal and alloying elements is fashioned into a plurality of strips embedded in an outer surface of a relatively inert component, or some other relatively inert shaped element, such as a collet may be embedded in the composition. In other whipstocks and deflectors of the invention, the degradable composition may comprise a plurality of strips or other shapes adhered to an outer surface of a relatively inert component. In all embodiments, the whipstock or deflector angled surface is sufficiently hard to deflect equipment into a lateral.
Another aspect of the invention includes methods of using a whipstock or deflector of the invention in performing a defined task, one method comprising:
(a) deploying a degradable whipstock or deflector in a primary wellbore just below a point of intersection of the primary wellbore with a lateral wellbore; (b) deploying a tool into the primary wellbore until it contacts the degradable whipstock or deflector; (c) directing the tool into the lateral wellbore using the degradable whipstock or deflector; and (c) degrading the degradable whipstock or deflector or a portion thereof prior to or during production from the lateral wellbore.
Methods of the invention may include, but are not limited to, those wherein the high-strength, controllably reactive and degradable whipstock or deflector comprises an aluminum alloy, or composition such as an aluminum-alloy composite or an aluminum alloy coated with a variety of coatings. Other methods of the invention include those wherein the degrading of the degradable whipstock or deflector or portion thereof includes application of acid, heat, or some other degradation trigger in a user defined, controlled fashion. Degradable deflectors and whipstocks of the invention may be used as a means to deflect assemblies and tools into a lateral section of a multilateral well, as illustrated further herein. Deflectors and whipstocks of the invention may be run on slick line, coiled tubing, or jointed pipe. The deflectors and whipstocks of the invention may have one or more holes or other passages running through the entire length of the part to permit flow from the main bore for a time, which may also help degrade the element.
The various aspects of the invention will become more apparent upon review of the brief description of the drawings, the detailed description of the invention, and the claims that follow.
BRIEF DESCRIPTION OF THE DRAWINGS
The manner in which the objectives of the invention and other desirable characteristics can be obtained is explained in the following description and attached drawings in which:
FIGS. 1 , 2 , and 3 are schematic diagrammatical cross-sectional views of an exemplary apparatus of the invention;
FIG. 4 is a photograph of an experiment illustrating utility of a composition and apparatus within the invention;
FIG. 5A is a perspective view of an apparatus of the invention, and FIG. 5B a graphical rendition of test data for the apparatus illustrated in FIG. 5A ; and
FIGS. 6 , 7 , and 8 are scanning electron micrographs of compositions usable in the invention, illustrating regions able to form galvanic cells.
It is to be noted, however, that the appended drawings are highly schematic, not necessarily to scale, and illustrate only typical embodiments of this invention, and are therefore not to be considered limiting of its scope, for the invention may admit to other equally effective embodiments.
DETAILED DESCRIPTION
In the following description, numerous details are set forth to provide an understanding of the present invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these details and that numerous variations or modifications from the described embodiments may be possible.
All phrases, derivations, collocations and multiword expressions used herein, in particular in the claims that follow, are expressly not limited to nouns and verbs. It is apparent that meanings are not just expressed by nouns and verbs or single words. Languages use a variety of ways to express content. The existence of inventive concepts and the ways in which these are expressed varies in language-cultures. For example, many lexicalized compounds in Germanic languages are often expressed as adjective-noun combinations, noun-preposition-noun combinations or derivations in Romantic languages. The possibility to include phrases, derivations and collocations in the claims is essential for high-quality patents, making it possible to reduce expressions to their conceptual content, and all possible conceptual combinations of words that are compatible with such content (either within a language or across languages) are intended to be included in the used phrases.
The invention describes compositions, shaped articles of manufacture (apparatus) employing the compositions, and methods of using the apparatus, particularly as oilfield elements, such as well operating elements, although the invention is not so limited. For example, compositions and apparatus of the invention may be employed in applications not strictly considered to be oilfield applications, for instance coalbed methane production; hydrogen generation; power plants; as components of electrical and thermal apparatus; medical instruments and implants (such as stents, catheters, prosthetics, and the like); and automotive and aerospace (transportation) components (such as engine and motor components) to name a few. When applied to oilfield applications, these may include exploration, drilling, and production activities including producing water wherein oil or gaseous hydrocarbons are or were expected. As used herein the term “oilfield” includes land based (surface and sub-surface) and sub-seabed applications, and in certain instances seawater applications, such as when exploration, drilling, or production equipment is deployed through a water column. The term “oilfield” as used herein includes oil and gas reservoirs, and formations or portions of formations where oil and gas are expected but may ultimately only contain water, brine, or some other composition.
An “oilfield element” is an apparatus that is strictly intended for oilfield applications, which may include above-ground (surface) and below-ground applications, and a “well operating element” is an oilfield element that is utilized in a well operation. Well operations include, but are not limited to, well stimulation operations, such as hydraulic fracturing, acidizing, acid fracturing, fracture acidizing, fluid diversion, equipment diversion, or any other well treatment, whether or not performed to restore or enhance the productivity of a well.
A whipstock is an inclined wedge placed in a wellbore to force a drill bit to start drilling in a direction away from the wellbore axis. They may also be used as a means to deflect assemblies and tools into a lateral of a multilateral well, as illustrated schematically in embodiment 1 of FIG. 1 . Referring to the drawing figures, which admittedly are not to scale, and wherein the same reference numerals are used throughout except where noted, FIG. 1 illustrates schematically an embodiment 1, with parts broken away, illustrating a main wellbore 2 , a cemented lateral or open hole lateral 4 , a liner 6 , and a deflector or whipstock 8 mounted to a packer or cement plug 10 , itself mounted to a bottom hole assembly 11 in this embodiment. Deflectors and whipstocks ordinarily must be retrieved with a separate trip in the well, which is added cost. So in some cases, the deflector or whipstock is left in the hole (to save cost) and production is brought online. However, the presence of the device in the main bore means reduced flow area. Ordinarily, whipstocks must have hard steel surfaces so that the bit will preferentially drill through casing or rock rather than the whipstock itself. Whipstocks may be oriented in a particular direction if needed, or placed into a wellbore blind, with no regard to the direction they face. Most whipstocks are set on the bottom of the hole or on top of a high-strength cement plug, but some are set in the openhole.
In accordance with another embodiment of the present invention, we have developed degradable deflectors and whipstocks 8 that are reactive and/or dissolvable using degradable compositions disclosed in assignee's parent application Ser. No. 11/427,233, filed Jun. 28, 2006, previously incorporated herein by reference. These new devices may be manufactured using a composition consisting essentially of one or more reactive metals in major proportion, and one or more alloying elements in minor proportion, with the provisos that the composition is high-strength, controllably reactive, and degradable under defined conditions. The mechanism triggering the controlled reaction and/or degradation may be any of the mechanisms mentioned herein, including, but not limited to a combination of fluids, pressure triggers, and the like. A deflector or whipstock 8 made from the described compositions is run downhole as usual. After the device(s) have served its purpose of deflecting lateral assemblies, one or more triggering mechanism may be activated, resulting in dissolving of or reacting of the deflector or whipstock over a controlled period of time thereby providing full bore access in the main wellbore.
Whipstock 8 is secured in primary wellbore 2 just below the intersection of primary wellbore 2 with lateral wellbore 4 by a packer 10 or other support, which is in turn connected to a bottom hole assembly 11 in this embodiment. Whipstock 8 comprises a degradable composition as described herein, and includes a surface 9 angled to the axis of primary wellbore 2 by an angle α, which may range from about 5 to about 75 degrees, or from about 10 to about 60 degrees, or from about 15 to about 50 degrees, or from about 20 to about 45 degrees, or from about 25 to about 35 degrees. Also illustrated is an angle β which is the angle that lateral 4 makes with primary wellbore 2 . Angles α and β may be identical or substantially the same, where substantially the same implies that angles α and β may differ by as much as 5 degrees, or even as much as 20 degrees in certain embodiments.
FIGS. 2 and 3 illustrate less detailed schematic views of embodiment 1 of FIG. 1 , but illustrating further features of apparatus and methods of the invention. Lateral wellbore 4 is illustrated intersecting a reservoir 16 potentially or actually containing hydrocarbon deposits. The earth's surface is illustrated at 12 , as are a wellhead 14 and a pump 18 . FIG. 2 illustrates a tubular 6 in position to deliver a stimulation treatment fluid or other composition to reservoir 16 . FIG. 3 illustrates the situation after tubular 6 has been removed from lateral wellbore 4 and primary wellbore 2 . Ordinarily at this stage, a non-degradable whipstock would have to be removed to allow full production cross-sectional area through wellbores 2 , 4 , or left in place sacrificing some of the production cross-sectional area. However, in accordance with embodiments of the present invention, a corrosive fluid, such as water or acid, may be contacted with degradable whipstock 8 by pumping such fluid through pump 18 , or otherwise flowing such fluid so that it contacts degradable whipstock 8 . After a time, which may be engineered to the desires of the operator, as the composition making up whipstock 8 degrades for instance by dissolving, a result such as illustrated in FIG. 3 , where the whipstock 8 is at least partially degraded, may allow full production area to be obtained without actually retrieving the whipstock.
Specific oilfield applications of the inventive apparatus include stimulation treatments. Stimulation treatments fall into two main groups, hydraulic fracturing treatments and matrix treatments. Fracturing treatments are performed above the fracture pressure of the reservoir formation and create a highly conductive flow path between the reservoir and the wellbore. Matrix treatments are performed below the reservoir fracture pressure and generally are designed to restore the natural permeability of the reservoir following damage to the near-wellbore area. One matrix treatment may be acidizing. Acidizing means the pumping of acid into the wellbore to remove near-well formation damage and other damaging substances. Acidizing commonly enhances production by increasing the effective well radius. When performed at pressures above the pressure required to fracture the formation, the procedure is often referred to as acid fracturing. Fracture acidizing is a procedure for production enhancement, in which acid, usually hydrochloric (HCl), is injected into a carbonate formation at a pressure above the formation-fracturing pressure.
In the oilfield context, a “wellbore” may be any type of well, including, but not limited to, a producing well, a non-producing well, an injection well, a fluid disposal well, an experimental well, an exploratory well, and the like. Wellbores may be vertical, horizontal, deviated some angle between vertical and horizontal, and combinations thereof, for example a vertical well with a non-vertical component. Wellbores may be multilateral in nature, having one or more laterals branching off of a primary wellbore, such as illustrated schematically in FIGS. 1-3 .
Reactive Metals, Alloying Elements, and Alloys
Compositions usable in the invention should have both high-strength (as defined herein) and have controllable and thus predictable degradation rate. One of the following morphologies, broadly speaking, may be appropriate, depending on the end use; the boundaries between these categories are somewhat arbitrary, and are provided for the purpose of discussion only and are not considered limiting:
1. A reactive, degradable metal or alloy formed into a solidified (cast) or extruded (wrought) composition of crystalline, amorphous or mixed structure (e.g. partially crystalline, partially amorphous), and the features characterizing the resulting compositions (e.g. grains, phases, inclusions, and like features) may be of macroscopic, micron or submicron scale, for instance nanoscale so as to measurably influence mechanical properties and reactivity. In the context of the invention, the term “reactive metal” includes any element (with the provisos that follow) that satisfies the definition of “reactivity” given earlier herein, and includes any element that tends to form positive ions when its compounds are dissolved in liquid solution and whose oxides form hydroxides rather than acids with water. In the context of the invention, also included among reactive metals (and compositions) are metals (and compositions) that simply disintegrate and in fact may be practically insoluble in the fluid environment; examples of these compositions include alloys that lose structural integrity and become dysfunctional for instance due to grain-boundary embrittlement or dissolution of one of its elements. The byproduct of this degradation from the grain boundaries may not be an ionic compound such as a hydroxide but a metallic powder residue, as appears to be the case of severely embrittled aluminum alloys of gallium and indium. Unless oxidized or corroded at their surfaces, that is superficially degraded, most of these composition are electrically conductive solids with metallic luster; many also possess high mechanical strength in tension, shear and especially compression and therefore exhibit high hardness. Many reactive metals useful in the invention also readily form limited solid solutions with other metals, thus forming alloys, novel alloys and increasingly more complex compositions such as composite and hybrid structures of these novel alloys. Regarding alloying elements in these alloys, very low percentages are often enough to affect to the greatest extent the properties of many metals or, e.g., carbon (C) in iron (Fe) to produce steel. Lithium (Li), magnesium (Mg), calcium (Ca), and aluminum (Al) are considered to be important reactive metals in the inventive compositions. These metals or elements may function as metallic solvents, like iron in steels, or alloying elements, in dilute or high concentrations, like carbon in steels or chromium in stainless steels. Many compositions usable in the invention may be termed “degradable alloys”, wherein “degradable” may comprise any number of environmental conditions, temperatures, and pressures (including loads and forces). Degradable alloy compositions useful in the invention include alloy compositions that degrade largely due to the formation of internal galvanic cells between structural heterogeneities (e.g. phases, internal defects, inclusions, and in general internal compositions) and resist or entirely prevent passivation or the formation of stable protective layers. In degradable alloys useful in the invention, the presence of alloying elements trapped in solid solution, for instance in aluminum, is therefore critical to impede the aluminum from passivating or building a resilient protective layer. In compositions useful in the invention, concentrations of solute elements, trapped in interstitial and especially in substitutional solid solutions may be controlled through chemical composition and processing; for instance rapid cooling from a high temperature where solubility is higher than at ambient temperature or temperature of use. Other degradable compositions of the invention include elements, or phases that liquate (melt) once elevated beyond a certain critical temperature or pressure, which for alloys may be predictable from phase diagrams, or if phase diagrams are unavailable, from thermodynamic calculations as in the CALPHAD method. In these embodiments, compositions useful in the invention may intentionally fail by liquid-metal embrittlement, as in some alloys containing gallium and/or indium for instance. Other degradable compositions, including alloys within the invention possess phases that are susceptible to creep (superplastic) deformation under intended forces (and pressures), or possess phases that are brittle and thus rapidly rupture under impact. Examples of degradable compositions, in particular alloys that fall under this first category are calcium alloys; e.g. calcium-lithium (Ca—Li), calcium-magnesium (Ca—Mg), calcium-aluminum (Ca—Al), calcium-zinc (Ca—Zn), and the like, including more complex compositions like calcium-lithium-zinc (Ca—Li—Zn) alloys without citing their composites and hybrid structures. In calcium-based alloys, alloying addition of lithium in concentrations between 0 up to about 10 weight percent is beneficial to enhance reactivity; greater concentrations of lithium in equilibrium calcium-lithium (Ca—Li) alloys form an intermetallic phase, still appropriate to enhance mechanical properties, but often degrades reactivity slightly. In addition to lithium, in concentrations ranging from 0 up to about 10 weight percent, aluminum, zinc, magnesium, and/or silver in up to about 1 weight percent are also favorable to improve mechanical strengths. Other useful degradable composition embodiments include magnesium-lithium (Mg—Li) alloys enriched with tin, bismuth or other low-solubility alloying elements, as well as special alloys of aluminum, such as aluminum-gallium (Al—Ga) or aluminum-indium (Al—In), as well as more complex alloying compositions; e.g. aluminum-gallium-indium (Al—Ga—In), aluminum-gallium-bismuth-tin (Al—Ga—Bi—Sn) alloys, and more complex compositions of these alloys. A non-exhaustive list of degradable alloys is provided in Table 2 in the Examples section. Note that all the compositions of Table 2 are more reactive than aluminum, as proven by their lower galvanic corrosion potentials, consistently 0.5 to 1 Volts below that of aluminum in the selected test conditions. Though galvanic corrosion potentials of compositions usable in the invention are substantially lower than that of aluminum, magnesium, and even calcium that dissolves at impressive rates, several of the compositions of the invention dissolve, or more generally degrade far slower than calcium despite lower galvanic corrosion potentials, as indicated by the last column of Table 2. For a number of oilfield applications, the degradation rate exhibited by calcium in neutral water is appropriate, as are those of the alloys of Table 2, or more complex compositions like composites made from these alloys. In practical situations, the applications, the users, or both will dictate the needed combination of degradation rate, mechanical properties (particularly strength), and they will both depend upon the environmental conditions (i.e. temperature, pressure, fluid environments) that may also be affected by the user. Even though the degradation rates of many compositions of Table 2 may be low, substantially greater rates may be anticipated in downhole environments, where the fluids are sour and thus more corrosive than the water used in testing the compositions of Table 2.
2. A powder-metallurgy like structure (i.e. a composition with a structure developed by pressing, compacting, sintering, and the like, formed by various schedules of pressure and temperature) including a relatively reactive metal or alloy (e.g. an alloy of magnesium, aluminum) combined with other compositions (e.g. an alloy of copper, iron, nickel, among a few transition-metal elements) that with the first and relatively reactive composition develops galvanic couples, preferentially strong for a rapid degradation. The result from the combination of these metals, alloys or compositions is a degradable composition that may be also characterized as a composite composition. However, because of the powder-metallurgy like structure, voids or pores may be intentionally left in order to promote the rapid absorption of corrosive fluid and thus rapid degradation of the formed compositions. Such compositions usable in the invention may include one or more of fine-grain materials, ultra-fine-grain materials, nanostructured materials as well as nanoparticles for enhanced reactivity (i.e. rates of degradation) as well as low temperature processing or manufacturing. The percentage of voids in such powder-metallurgy composition may be controlled by the powder size, the composition-making process, and the process conditions such that the mechanical properties and the rates of degradation become predictable and within the requirements of the applications or end users. These compositions may be a pressed, compacted, or sintered composition that has been fabricated from different powders. Examples of such compositions may include sintered end products of ultrafine powders of magnesium and copper; an example where magnesium and aluminum will develop a galvanic cell and where magnesium is due to its lower galvanic corrosion potential anodic whereas aluminum is necessarily cathodic. Selecting from the galvanic series elements that are as different as possible in galvanic potential is one way of manufacturing these compositions.
3. Composite and hybrid structures comprising one or more reactive or degradable metals or alloys as a matrix, imbedded with one or more relatively non-reactive compositions of micro-to-nanoscopic sizes (e.g. powders, particulates, platelets, whiskers, fibers, compounds, and the like) or made from the juxtaposition of layers, bands and the like, as for instance in functionally-graded materials. In contrast with compositions in category 2 , these compositions are closer to conventional metal-matrix composites in which the matrix is degradable and the imbedded materials are inert and ultra-hard so as to purposely raise the mechanical strength of the formed composition. Also in contrast with compositions in category 2 , voids, pores and other spaces where the corrosive fluid could rapidly infiltrate the composition are not particularly desirable as the matrix is already degradable, and primarily needs reinforcement. Metal matrix may be comprised of any reactive metal (e.g. pure calcium, Ca) or degradable alloy from previous categories (e.g. aluminum-gallium based alloy, Al—Ga), while relatively non-reactive compositions useful in the invention include particles, particulates, powders, platelets, whiskers, fibers, and the like that are expected to be inert under the environmental conditions expected during use. Examples of these composite structures include aluminum-gallium (Al—Ga) based alloys (including complex alloys of aluminum-gallium (Al—Ga), aluminum-gallium-indium (Al—Ga—In), aluminum-gallium-indium-bismuth (Al—Ga—In—Bi) as examples) reinforced with, for example, silicon carbide (SiC), boron carbide (BC) particulates (silicon carbide and boron carbide are appropriate for casting because of their densities, which are comparable to that of aluminum-gallium based alloys). Mechanical strength and its related properties, hardness, for these composite structures wherein one composition is blend to another, or several others may be estimated by a lever rule or rule of mixture, where strength or hardness of the metal-matrix composite is typically proportional to volume fraction of the material strength (hardness) of both matrix and reinforcement materials. Consequently, strength and hardness of these compositions lie anywhere between that of the materials comprising the composite (e.g. from low-metallic fractions to extremely high, and correspondingly from high to low silicon carbide or boron carbide reinforcement fractions).
For many compositions usable in the invention, enhanced mechanical properties (e.g. strength, toughness) may be achieved from highly-reactive metals (e.g. calcium) or moderately reactive metals (aluminum, magnesium) by means of alloying or additions of other, relatively inert compositions, imbedded in the reactive metal or degradable alloy (thus forming a metal-matrix composite). For alloys, the strengthening mechanisms are those by solid-solution (interstitial and substitutional), phase formation (e.g. intermetallic phases), grain refinement (Hall-Petch type strengthening), substructure formation, cold-working (dislocation generation), and combination of these. In degradable alloys useful in the invention developed from calcium-magnesium (Ca—Mg), calcium-aluminum (Ca—Al), calcium-zinc (Ca—Zn), calcium-lithium (Ca—Li) for instance the formation of calcium intermetallic phases or compounds results in a significant strengthening; a strengthening that adds to the solid-solution strengthening of the calcium lattice provided by the elements trapped within. In magnesium-lithium (Mg—Li), calcium-lithium based alloys (Ca—Li) usable in the invention, strengthening by precipitation after ageing heat treatment may occur and, when combined with the other strengthening mechanisms, generate even greater strengthening. In aluminum-based degradable alloys, solid-solution strengthening and grain refinement are important to reach suitable strength levels. Precipitation is also possible after appropriate heat-treatment such as solutionizing, quench and aging to further strengthen certain alloys of the invention.
Degradable alloy compositions usable in the invention for whipstocks and deflectors have relatively low fabrication costs. Of the degradable alloys, aluminum-based alloys may be regarded as more suitable than calcium-based alloys because of their non-UN rating and ease of procurement, as well as their relatively good strengths compared to other compositions.
Degradable whipstocks and deflectors of the invention may be coated so that the apparatus no longer presents substantial risks to handling, shipping and other personnel, and in general its environment, unless this environment is the environment where this coating and its coated composition (substrate) is designed to degrade; i.e. dissolve, disintegrate, or both. Coatings may be characterized as thin or thick, and may range in thickness from millimeters to centimeters in scale. Usable coatings may comprise one coating or several layered coatings, and different regions of substrate may comprise different compositions as coatings. Coatings may comprise wrapping the whipstock or deflector with a wrapping material, and this is herein considered as a coating. The coating may, when required, provide a temporary barrier against the degradation of the whipstock or deflector. Coatings may include compositions of the invention as discussed herein. To be specific, a coating when selected to be metallic may be made of:
1. Less reactive compositions than the whipstock or deflector body; e.g. a magnesium or aluminum alloy layer covering a calcium or lithium alloy.
2. Low-melting compositions, as found in solder eutectic alloys (e.g. bismuth-tin, Bi—Sn, bismuth-tin-indium, Bi—Sn—In, and the like) combined or not with other compositions to create new composites or hybrid structures. These compositions, though relatively inert, may creep (i.e. superplastically deform over time at low stress levels) and thus fail when stressed or pressured, or melt in the presence of a heat flux or elevated pressures and expose the more reactive substrate that is temporarily protected by these coatings. Several examples of commercially available low-melting alloys are given in Table 1.
3. Other metallic compositions that form either low-melting point phases (e.g. intermetallic phases or compounds with melting temperatures lower than that of the main phases of the composition) or brittle phases; i.e. phases that have low toughness and therefore do not plastically deform and are especially susceptible to fracture under impact loading conditions (e.g. intermetallic phases with limited active slip systems, amorphous phases, ceramic-type phases such as oxides, etc).
4. Composite and hybrid structures including for instance hygroscopic materials (e.g. metallic compositions combined with hygroscopic additives), layered materials (i.e. multiple layers of distinct compositions), and the like.
TABLE 1
List of low-melting alloy coatings - ranked in order of increasing
melting temperature, with compositions in weight percent
Bi
Sn
Pb
Cd
In
Sb
Liquid (° C./° F.)
44.0
11.3
22.6
5.3
16.1
—
52/126
30.8
—
—
7.5
61.7
—
61.5/143
50.5
12.4
27.8
9.3
—
—
73/163
48.5
—
—
10.0
41.5
—
77.5/172
54.0
16.3
—
—
29.7
—
81/178
52.0
15.3
31.7
1.0
—
—
92/198
15.5
32.0
—
—
—
—
95/203
54.0
26.0
—
20.0
—
—
103/217
67.0
—
—
—
33.0
—
109/228
53.7
3.2
43.1
—
—
—
119/246
32.0
34.0
34.0
—
—
—
133/271
55.1
39.9
5.0
—
—
—
136/277
60.0
—
—
40.0
—
—
144/291
21.0
37.0
42.0
—
—
—
152/306
10.0
50.0
40.0
—
—
—
167/333
25.5
60.0
14.5
—
—
—
180/356
3.5
86.5
—
—
4.5
—
186/367
48.0
14.5
28.5
—
—
—
227/441
100.0
—
—
—
—
—
271/520
Suitable coatings may also be non-metallic or semi-metallic, or a composite of metallic and non- or semi-metallic compositions, including one of more of the following:
1. Any natural or synthetic polymeric material, including thermoplastics, thermosets, elastomers (including thermoplastic elastomers), regardless of permeability for water in the liquid or gaseous form (vapor); examples include epoxy, polyurethane, and rubber coatings. These coating compositions may be formulated from a number of fillers and additives as the end use and cost dictate.
2. Dissolvable polymers and their composites, which by absorbing a corrosive fluid from its environment enable this corrosive fluid to contact with the degradable body of the whipstock or deflector and fully degrade this substrate.
3. Swellable polymers and their composites, which through time swell in a fluid environment and enable corrosive fluid from the environment to eventually degrade the body of the whipstock or deflector.
4. Porous ceramics and composites thereof, wherein the transport of corrosive fluid through pores (voids) or other microchannels enable the corrosive fluid to reach the degradable body of the whipstock or deflector.
5. Oriented and randomly-oriented micro and nanofibers, nanoplatelets, mesoporous nanomaterials and the like, making a more or less tortuous path for the liquid to diffuse through and contact with the degradable body of the whipstock or deflector.
Coatings useful in the invention include those wherein the coating, if not sufficiently reactive and therefore too inert, may either be damaged or removed to allow the underlying high-strength, degradable, controllably reactive composition making up the body or portions of the body of the inventive whipstocks and deflectors to react and degrade by dissolution, disintegration, or both. The dissolution or disintegration of the body if the whipstock or deflector may be activated by one or both of a) temperature, as in applications involving one or more of relatively-hot fluids, electrical discharges and Joule heating, magnetic discharges and induced Joule heating, and an optically-induced heating; and b) pressure, as for a composition that may become semi-liquid (semi-solid) or fully liquid at elevated (downhole) pressure, as described by the Clausius-Clapeyron equation; in this example, the greater the pressure, the closer this composition is to becoming liquid and thus weaken and fail, for instance by creep). In this invention, changes in both temperature and pressure may be continuous, discontinuous, cyclic (repeated) or non-cyclic (e.g. random), lengthy (durable) or short-lived (transient) as in the cases of thermal or mechanical shocks or impacts.
Relatively Inert Components
As mentioned in the Summary of the Invention, apparatus of the invention may comprise a relatively inert component (i.e. not significantly reactive), including a relatively inert shaped element, such as a collet. The relatively inert component functions to limit the degradation of the degradable body of the whipstock or deflector by limiting either the rate, location (i.e., front, back, center or some other location of the whipstock or deflector), or both rate and location of degradation. The relatively inert component may also function to distribute the sustained mechanical loads at highly-stressed sections, such as at the angled surface of the whipstock or deflector; as a result it may contribute to expand the temperature ranges of the more reactive component or components of the invention such that the relatively inert component is not subject to premature degradation. The relatively inert component may provide structural integrity to the apparatus, both during its use, as well as for pumping out if desired. Compositions useful in the invention as the relatively inert component are clearly selected to be not water-soluble and resistant to weak acid, hydrocarbons, brine, and other produced or injected well fluids. The relatively inert component may be selected from relatively-inert metals (e.g. iron, titanium, nickel), their alloys, polymeric compositions, compositions soluble over time in strongly acidic compositions, frangible ceramic compositions, and composites of these. Regarding acid resistance, the relatively inert component compositions may be resistant to weak acidic compositions (pH ranging from about 5 to 7) for lengthy time periods, for example days, weeks, months, and even years, but resistant to strongly acidic compositions having pH ranging from about 2 to about 5, for relatively shorter time periods, for example weeks, days, or even hours, depending on operator preference and the particular oilfield operation to be carried out. The relatively inert component may include fillers and other ingredients as long as those ingredients are degradable by similar mechanisms, or if non-degradable, are able to be removed from the wellbore, or left in the wellbore if relatively inert to the environment.
Suitable polymeric compositions for the relatively inert component include natural polymers, synthetic polymers, blends of natural and synthetic polymers, and layered versions of polymers, wherein individual layers may be the same or different in composition and thickness. The term “polymeric composition” includes composite polymeric compositions, such as, but not limited to, polymeric compositions having fillers, plasticizers, and fibers therein. Suitable synthetic polymeric compositions include those selected from thermoset polymers and non-thermoset polymers. Examples of suitable non-thermoset polymers include thermoplastic polymers, such as polyolefins, polytetrafluoroethylene, polychlorotrifluoroethylene, and thermoplastic elastomers. The term “polymeric composition” includes composite polymeric compositions, such as, but not limited to, polymeric compositions having fillers, plasticizers, and fibers therein.
One class of useful compositions for the relatively inert component are the elastomers. “Elastomer” as used herein is a generic term for substances emulating natural rubber in that they stretch under tension, have a high tensile strength, retract rapidly, and substantially recover their original dimensions. The term includes natural and man-made elastomers, and the elastomer may be a thermoplastic elastomer or a non-thermoplastic elastomer. The term includes blends (physical mixtures) of elastomers, as well as copolymers, terpolymers, and multi-polymers. Useful elastomers may also include one or more additives, fillers, plasticizers, and the like.
Examples of thermoplastic compositions suitable for use in relatively inert components according to the present invention include polycarbonates, polyetherimides, polyesters, polysulfones, polystyrenes, acrylonitrile-butadiene-styrene block copolymers, acetal polymers, polyamides, or combinations thereof.
Suitable thermoset (thermally cured) polymers for use in relatively inert components in the present invention include those known in the thermoset molding art. Thermoset molding compositions are generally thermosetting resins containing inorganic fillers and/or fibers. Upon heating, thermoset monomers initially exhibit viscosities low enough to allow for melt processing and molding of an article from the filled monomer composition. Upon further heating, the thermosetting monomers react and cure to form hard resins with high stiffness. Thermoset polymeric substrates useful in the invention may be manufactured by any method known in the art.
Compositions susceptible to chemical attacks by strongly acidic environments may be valuable compositions in the relatively inert component, as long as they can be used in the intended environment for at least the time required to perform their intended function(s). Ionomers, polyamides, polyolefins, and polycarbonates, for example, may be attacked by strong oxidizing acids, but are relatively inert to weak acids. Depending on the chemical composition and shape of the degradable composition of the body of the whipstock, its thickness, the expected temperature in intended application, for example a local wellbore temperature, the expected composition of the well and injected fluids, including the pH, the rate of decomposition of the relatively inert component may be controlled.
Frangible ceramic compositions useful as relatively inert component compositions include chemically strengthened ceramics of the type known as “Pyroceram” marketed by Corning Glass Works of Corning, N.Y. and used for ceramic stove tops. This is made by replacing lighter sodium ions with heavier potassium ions in a hardening bath, resulting in pre-stressed compression on the surface (up to about 0.010 inch or 0.0254 cm) thickness) and tension on the inner part. One example of how this is done is set forth in U.S. Pat. No. 2,779,136, assigned to Corning Glass Works. As explained in U.S. Pat No. 3,938,764, assigned to McDonnell Douglas Corporation, such composition normally had been used for anti-chipping purposes such as in coating surfaces of appliances, however, it was discovered that upon impact of a highly concentrated load at any point with a force sufficient to penetrate the surface compression layer, the frangible ceramic will break instantaneously and completely into small pieces over the entire part. If a frangible ceramic is used for the relatively inert component, a coating or coatings such as described in U.S. Pat. No. 6,346,315 might be employed to protect the frangible ceramic during transport or handling of the inventive well operating elements. The '615 patent describes house wares, including frangible ceramic dishes and drinking glasses coated with a protective plastic coating, usually including an initial adhesion-promoting silane, and a coating of urethane, such as a high temperature urethane to give protection to the underlying layers, and to the article, including protection within a commercial dishwasher. The silane combines with glass, and couples strongly with urethane. The urethane is highly receptive to decoration, which may be transferred or printed onto the urethane surface, and this may be useful to apply bar coding, patent numbers, trademarks, or other identifying information to the inventive well operating elements and other apparatus of the invention.
Regardless of the composition of the relatively inert component, a protective coating may be applied, as mentioned with respect to frangible ceramic relatively inert components. The coating, if used, is also generally responsible for adhering itself to the degradable components, however the invention is not so limited. The coating may be conformal (i.e., the coating conforms to the surfaces of the polymeric substrate), although this may not be necessary in all applications, or on all surfaces of the relatively inert component or any exposed portions of the reactive metal or degradable alloy component. Conformal coatings based on urethane, acrylic, silicone, and epoxy chemistries are known, primarily in the electronics and computer industries (printed circuit boards, for example). Another useful conformal coating includes those formed by vaporization or sublimation of, and subsequent pyrolization and condensation of monomers or dimers and polymerized to form a continuous polymer film, such as the class of polymeric coatings based on p-xylylene and its derivatives, commonly known as Parylene. Parylene coatings may be formed by vaporization or sublimation of a dimer of p-xylylene or a substituted version (for example chloro- or dichloro-p-xylylene), and subsequent pyrolization and condensation of the formed divalent radicals to form a Parylene polymer, although the vaporization is not strictly necessary.
Another class of useful coatings are addition polymerizable resins, wherein the addition polymerizable resins are derived from a polymer precursor which polymerizes upon exposure to a non-thermal energy source which aids in the initiation of the polymerization or curing process. Examples of energy sources that are normally considered non-thermal include electron beam, ultraviolet light (UV), and visible light. Addition polymerizable resins are readily cured by exposure to radiation energy. Addition polymerizable resins can polymerize through a cationic mechanism or a free radical mechanism. Depending upon the energy source that is utilized and the polymer precursor chemistry, a curing agent, initiator, or catalyst may be used to help initiate the polymerization.
Soluble, and Particularly Water-Soluble Coatings
The relatively inert component, if somewhat water-soluble, may be used to deliver controlled amounts of chemicals useful in particular industries, such as wellbore acid fracturing fluids, in similar fashion to controlled release pharmaceuticals. Compositions useful in this sense include water-soluble compositions selected from water-soluble inorganic compositions, water-soluble organic compositions, and combinations thereof. Suitable water-soluble organic compositions may be water-soluble natural or synthetic polymers or gels. The water-soluble polymer may be derived from a water-insoluble polymer made soluble by main chain hydrolysis, side chain hydrolysis, or combination thereof, when exposed to a weakly acidic environment. Furthermore, the term “water-soluble” may have a pH characteristic, depending upon the particular polymer used.
Suitable water-insoluble polymers which may be made water-soluble by acid hydrolysis of side chains include those selected from polyacrylates, polyacetates, and the like and combinations thereof.
Suitable water-soluble polymers or gels include those selected from polyvinyls, polyacrylics, polyhydroxyacids, and the like, and combinations thereof.
Suitable polyvinyls include polyvinyl alcohol, polyvinyl butyral, polyvinyl formal, and the like, and combinations thereof. Polyvinyl alcohol is available from Celanese Chemicals, Dallas, Tex., under the trade designation Celvol. Individual Celvol polyvinyl alcohol grades vary in molecular weight and degree of hydrolysis. Molecular weight is generally expressed in terms of solution viscosity. The viscosities are classified as ultra low, low, medium and high, while degree of hydrolysis is commonly denoted as super, fully, intermediate and partially hydrolyzed. A wide range of standard grades is available, as well as several specialty grades, including polyvinyl alcohol for emulsion polymerization, fine particle size and tackified grades.
Suitable polyacrylics include polyacrylamides and the like and combinations thereof, such as N,N-disubstituted polyacrylamides, and N,N-disubstituted polymethacrylamides. A detailed description of physico-chemical properties of some of these polymers are given in, “Water-Soluble Synthetic Polymers: Properties and Behavior”, Philip Molyneux, Vol. I, CRC Press, (1983) incorporated herein by reference.
Suitable polyhydroxyacids may be selected from polyacrylic acid, polyalkylacrylic acids, interpolymers of acrylamide/acrylic acid/methacrylic acid, combinations thereof, and the like.
Adhesion promoters, coupling agents and other optional ingredients may be used wherein a better bond between the degradable body or portion thereof of the whipstocks and deflectors of the invention and a protective layer or coating is desired. Mechanical and/or chemical adhesion promotion (priming) techniques may used. The term “primer” as used in this context is meant to include mechanical, electrical and chemical type primers or priming processes. Examples of mechanical priming processes include, but are not limited to, corona treatment and scuffing, both of which increase the surface area of the degradable body. An example of a preferred chemical primer is a colloidal dispersion of, for example, polyurethane, acetone, isopropanol, water, and a colloidal oxide of silicon, as taught by U.S. Pat. No. 4,906,523, which is incorporated herein by reference.
Relatively inert components of the invention that are polymeric may include, in addition to the polymeric composition, an effective amount of a fibrous reinforcing composition. Herein, an “effective amount” of a fibrous reinforcing composition is a sufficient amount to impart at least improvement in the physical characteristics, i.e., hydrocarbon resistance, toughness, flexibility, stiffness, shape control, adhesion, etc., but not so much fibrous reinforcing composition as to give rise to any significant number of voids and detrimentally affect the structural integrity during use. The amount of the fibrous reinforcing composition in the substrate may be within a range of about 1-40 percent, or within a range of about 5-35 percent, or within a range of about 15-30 percent, based upon the weight of the inert component.
The fibrous reinforcing composition may be in the form of individual fibers or fibrous strands, or in the form of a fiber mat or web (e.g. mesh, cloth). The mat or web can be either in a woven or nonwoven matrix form. Examples of useful reinforcing fibers in applications of the present invention include metallic fibers or nonmetallic fibers. The nonmetallic fibers include glass fibers, carbon fibers, mineral fibers, synthetic or natural fibers formed of heat resistant organic compositions, or fibers made from ceramic compositions.
Other compositions that may be added to polymeric relatively inert components (and metallic components) for certain applications of the present invention include inorganic or organic fillers. Inorganic fillers are also known as mineral fillers. A filler is defined as a particulate composition, typically having a particle size less than about 100 micrometers, preferably less than about 50 micrometers. Examples of useful fillers for applications of the present invention include carbon black, calcium carbonate, silica, calcium metasilicate, cryolite, phenolic fillers, or polyvinyl alcohol fillers. Typically, a filler would not be used in an amount greater than about 20 percent, based on the weight of its matrix. At least an effective amount of filler may be used. Herein, the term “effective amount” in this context refers to an amount sufficient to fill but not significantly reduce the tensile strength of the matrix.
Whipstocks and deflectors of the invention may include many optional items. One optional feature may be one or more sensors located in the degradable or inert components to detect the presence of hydrocarbons (or other chemicals of interest) in the zone of interest. The chemical indicator may communicate its signal to the surface over a fiber optic line, wire line, wireless transmission, and the like. When a certain chemical or hydrocarbon is detected that would present a safety hazard or possibly damage a downhole tool if allowed to reach the tool, the element may act or be commanded to close a valve before the chemical creates a problem.
EXAMPLES AND EXPERIMENTAL RESULTS
FIG. 4 is a photograph of a simple experiment on a sub-sized laboratory sample to first demonstrate the validity of the claims. In FIG. 4 is pictured a extruded calcium rod that was simplistically cast inside a 54Bi-30In-16Sn eutectic alloy for coating purposes, and fully immersed in distilled (neutral-pH) water while subjected to a slow heating from ambient temperature. Once the water temperature exceeded the melting temperature of the coating (i.e. of the eutectic alloy), the coating melted away, exposing the calcium metal to the corrosive fluid (distilled water) and thus triggering its rapid degradation by dissolution. In FIG. 4 , the bubbling that may seen in the liquid above the composition is evidence of the release of diatomic hydrogen; i.e. the only gas that may be produced from a simple metallic composition like calcium in water. As demonstrated, a reactive metal such as calcium and a temporary protective coating made for instance of a low-melting alloy may constitute as a useful apparatus of the invention. The reactive material dissolves once the coating fails, either because of a phase transformation such as melting, as in the example of FIG. 4 , or simply because its properties are degraded by temperature or pressure, or both, as in the case where the coating is subjected to high stresses (loads), strains (displacements) and is cracked in downhole environments for instance. In the simple experiments shown in FIG. 4 , melting was the sole mechanism of failure or apparatus trigger because no external force, or pressure was applied to the apparatus.
FIGS. 5A and 5B demonstrate that a sizeable calcium plug of the invention offers some minimal mechanical properties that are satisfactory for basic downhole applications. This sizeable calcium well plug of FIG. 5A was one of a first full-scale prototype of an entirely degradable composition for the so-called Schlumberger treat and produce (TAP) well operations. FIG. 5B illustrates pressure and temperature testing of the well plug prototype of FIG. 5A . Over a ten hour period, the prototype was first held for thirty minutes at a pressure of about 6000 psi (about 40 mPa) and ambient temperature (about 70° F. or 21° C.); then pressure was reduced to ambient and the temperature raised over a period of about one hour to about 200° F. (about 93° C.). The plug was then held at 200° F. (93° C.) and the pressure rose to about 6000 psi (about 40 mPa) again, and held at this pressure and temperature for two hours. The pressure was then suddenly dropped to about 4000 psi (about 28 mPa) and temperature raised over the course of about 30 minutes to about 250° F. (about 121° C.) and again held for two hours at these conditions. Results from these initial prototype tests demonstrated that pure calcium possessed the minimal properties needed for many TAP applications, and that compositions of the invention with greater strengths than pure calcium would offer improvements over calcium.
Table 2 illustrates a list of pure metals, with certain metals like calcium and magnesium technically commercially available but in reality extremely difficult to procure, and alloy compositions of the invention that were specifically designed to degrade in moist and wet environments. Except for the pure metals, these alloys were all cast at Schlumberger (Rosharon, Tex.) using a regular permanent die-casting method. The alloys were fabricated from blends of pellets and powders of the pure ingredients, cast at 1600° F. (870° C.) for at least 3 hours, stirred, poured into permanent (graphite) molds and air cooled at room temperature (about 25° C.) with no subsequent thermal or thermomechanical treatments. In Table 2 are summarized important results for 16 compositions; 3 pure metals acquired from commercial chemical suppliers followed by 13 cast alloys. In Table 2 are shown the chemical composition in the first row, results of Vickers microhardness indentations from six measurements in columns 2 to 7, average mechanical strength in columns 9 and 11 (estimated from average hardness using a well-known strength-hardness correlation), qualitative results to describe the degradation of the compositions in columns 12 and 13, galvanic corrosion potentials for the various compositions with respect to pure copper in column 14, and in the last column description of test results when the compositions were immersed in distilled and neutral-pH water. Note that the alloys in Table 2 were all aluminum alloys and the alloying elements were selected with the a-priori that they would resist mixing by promoting eutectic transformations, prevent the formation of inert intermetallic phases or compounds, promote liquid-metal embrittlement (though liquid metal embrittlement is perhaps not the main mechanism of failure), and eliminate alloy passivation (i.e. the formation of a protective film) by making aluminum more reactive. The alloy compositions were kept simple; i.e. typically 5 percent or an integral fraction of 5 percent, although the invention is not so limited. The compositions of Table 2 were therefore not intended to be optimal compositions, but exemplary compositions to display the benefits of these novel aluminum alloys; alloys that may be either used directly as alloys or as ingredients to more advanced compositions, for instance composites and hybrid structures. The results of Table 2 reveal in particular that calcium possesses the least strength of all tabulated compositions and that certain compositions comprising aluminum and gallium degraded at rates that are comparable to (and seemingly greater than) that of calcium. Regardless the degradation rates, note that all the alloys were more anodic than calcium itself, as indicated by the corrosion potentials of Column 14 and that alone demonstrates their remarkable reactivity compared to the pure metals. Nonetheless note that a number of the compositions of Table 2, namely compositions 4, 5, 7 to 11, 13 and 16 were not observed to degrade in distilled (neutral-pH) water, and consequently they are for practical purposes not degradable enough in neutral water alone. A lack of degradation in neutral water was observed in alloys that either did not contain gallium with alloying elements such as indium or bismuth and tin for instance or contained excessive concentrations of magnesium, copper or silicon for instance. Based upon these results in distilled water, corrosion potential alone may be insufficient to identify the appropriate compositions for the foreseen oilfield applications, and the lack of degradation observed in certain alloy indicates that passivation is equally important to consider in designing new compositions. In other words, reactivity, as defined by galvanic corrosion potential, is not incomplete to make the composition degradable, and the absence of a strong protective layer on the composition is crucial to guarantee, unless the fluid environment is made more corrosive, as done by acidizing for instance. To prevent the formation of a protective layer in the composition, alloying elements, even in minor concentrations, are clearly crucial; e.g. gallium and indium promotes degradation whereas magnesium, silicone, copper reduces degradation (however certain elements such as magnesium may be tolerated, as revealed by composition 14). From the results of Table 2, several compositions, namely aluminum-gallium-indium (Al—Ga—In) and aluminum-gallium-zinc-bismuth-tin (Al—Ga—Zn—Bi—Sn) and their derivatives (e.g. metal-matrix composites) demonstrate a potential to outperform pure calcium because of their superior strength as well as degradation rates that are often comparable to that of pure calcium in neutral water (e.g. compositions 6, 12, 14, and 15).
TABLE 2
List of exemplary pure metals and degradable alloys specially developed to degrade
in moist and wet environments and results in distilled water at the exception of
corrosion potential measured in 5 wt. % sodium chloride (NaCl) distilled water.
Vickers microhardness (500 g)
Estimated strength
Composition
#1
#2
#3
#4
#5
#6
Average
(MPa)
(ksi)
(1)
23.1
23.0
23.3
22.7
23.2
23.1
23.1
69.2
10.3
Pure calcium
(2)
32.5
34.0
33.6
34.3
33.0
31.4
33.1
99.4
14.9
Pure Aluminum
(3)
33.7
31.4
32.1
33.1
33.8
31.3
32.6
97.7
14.6
Pure Magnesium
(4)
30.7
31.0
31.6
29.8
31.6
31.2
31.0
93.0
13.9
80Al—20Ga
(5)
28.5
31.8
35.1
34.7
35.6
35.7
33.6
100.7
15.1
80Al—10Ga—10Bi
(6)
31.9
33.8
33.5
30.4
35.2
35.6
33.4
100.2
15.0
80Al—10Ga—10In
(7)
42.0
41.7
40.6
39.1
46.5
41.0
41.8
125.5
18.8
80Al—10Ga—10Zn
(8)
116.6
118.3
104.0
93.1
89.6
125.8
107.9
323.7
48.4
80Al—10Ga—10Mg
(9)
45.6
45.7
43.0
50.6
50.1
46.3
46.9
140.7
21.0
85Al—5Ga—5Zn—5Mg
(10)
46.1
41.0
47.0
50.7
44.4
45.9
45.9
137.6
20.6
85Al—5Ga—5Zn—5Cu
(11)
31.8
32.4
33.3
32.8
31.9
32.6
32.5
97.4
14.6
80Al—5Zn—5Bi—5Sn
(12)
34.6
34.6
34.3
32.4
32.4
33.6
33.7
101.0
15.1
80Al—5Ga—5Zn—5Bi—5Sn
(13)
37.8
34.4
31.5
32.7
27.5
31.2
32.5
97.6
14.6
90Al—2.5Ga—2.5Zn—2.5Bi—2.5Sn
(14)
43.2
36.7
33.5
38.9
44.6
43.5
40.1
120.2
18.0
75Al—5Ga—5Zn—5Bi—5Sn—5Mg
(15)
41.0
38.7
42.2
41.6
35.6
35.8
39.2
117.5
17.6
65Al—10Ga—10Zn—5Bi—5Sn—5Mg
(16)
43.76
44.2
49.4
52.6
52.8
50.2
48.8
146.5
21.9
80Al—5Ga—5Zn—15Si
Degradation in water*
Degradation in air*
Potential
Degradation rate in distilled
Composition
(Normalized)
in V**
Water at 25° C.
(1)
1.00
3
4
−1.12
0.1 g/min
Pure calcium
(2)
1.44
0
0
−0.60
Does not dissolve***
Pure Aluminum
(3)
0.98
0
0
Does not dissolve***
Pure Magnesium
(4)
1.34
1
1
−1.02
Initially reacts and pits
80Al—20Ga
over time but does not
dissolve***
(5)
1.46
3
1
−1.28
Reacts slowly but does
80Al—10Ga—10Bi
not dissolve
(6)
1.45
3
4
−1.48
~1 g/min degraded;
80Al—10Ga—10In
granular residue***
(7)
1.81
1
1
−1.15
Reacts slowly but does not
80Al—10Ga—10Zn
dissolve***
(8)
4.68
0
1
−1.30
Reacts slightly, does not
80Al—10Ga—10Mg
dissolve***
(9)
2.03
0
0
−1.28
Does not dissolve, even
85Al—5Ga—5Zn—5Mg
after 1 week in water***
(10)
1.99
0
0
−1.29
Reacts slowly but does not
85Al—5Ga—5Zn—5Cu
dissolve after days***
(11)
1.41
0
0
−1.15
Does not react with
80Al—5Zn—5Bi—5Sn
water***
(12)
1.46
4
−1.28
~1-2 g/min degraded
80Al—5Ga—5Zn—5Bi—5Sn
(13)
1.41
1
−1.36
Does not dissolve even
90Al—2.5Ga—2.5Zn—2.5Bi—2.5Sn
after 3 days in water***
(14)
1.74
2
−1.38
~1 g/min degraded
75Al—5Ga—5Zn—5Bi—5Sn—5Mg
(15)
1.70
2
−1.25
~2 g/min degraded
65Al—10Ga—10Zn—5Bi—5Sn—5Mg
(16)
2.12
0
0
−1.20
Slightly reactive, but does
80Al—5Ga—5Zn—15Si
not dissolve even after 3
days***
*Degradation in air was assessed by the rate of darkening after sample polishing; reactivity in water was assessed from the rate of degradation (0- least; 4 most reactive)
**Potential (Volts) measured in 5 wt. % sodium chloride (NaCl) distilled water at 25° C. with reference to a pure copper electrode (error in measurement estimated to 10%).
***Does not dissolve, or is not observed to dissolve after 1-week unless galvanically coupled, immersed in a more corrosive aqueous environment, or both.
In FIGS. 6 to 8 are examples of alloy microstructures to illustrate and better identify the microstructural characteristics that make certain compositions not only reactive but also highly degradable. FIG. 6 illustrates IXRF-EDS compositional maps of composition 12 (Table 2), consisting of a 80Al-5Ga-5Zn-5Sn-5Bi alloy in its as-cast condition. The non-uniform distribution of the composition, revealed by the various maps of FIG. 6 reveals that certain alloying elements such as tin and bismuth have most noticeably exceeded their solubility limit in solid aluminum. Due to solid solubility limits, these alloying elements have segregated during the slow air-cooling of the cast process to internal surfaces (boundaries) such as the interdendritic spacings. The non-homogeneity of the composition at the microscopic level is well quantified in Table 3 with IXRF-EDS spot analyses of the chemical compositions at selected locations of the microstructure; e.g. aluminum grains or phases along grain boundaries. For the alloy of FIG. 6 , gallium is quite uniformly distributed even at the microscopic level and that is in contrast with tin and bismuth that are nearly-exclusively encountered along the internal boundaries. Based upon the results for this alloy in Table 2, the fact that tin and bismuth did essentially not mix with aluminum, as they are segregated to boundaries, promoted the formation of micro-galvanic cells, in particular between aluminum, tin, and bismuth. Also the fact that approximately 5 to 8 percent gallium remained in solid solution in the aluminum (Table 3) appears to be a factor to prevent passivation, or the formation of a protective layer at the surface of the composition. Gallium in solid solution, trapped in the aluminum lattice, also reduces the galvanic corrosion potential, as proven by the results of Table 2 for the binary aluminum-gallium alloy (Al—Ga). In addition to 5 to 8 percent gallium, approximately 2 percent zinc and 2 to 4 percent bismuth was also found trapped in the aluminum. The contribution of 2 percent zinc in the aluminum is well-known to strengthen the lattice by solid solution. The contribution of bismuth on strength is unclear, and the fact that bismuth was repeatedly detected within grains remains also surprising since bismuth is normally insoluble in solid aluminum, as depicted by the aluminum-bismuth (Al—Bi) equilibrium phase diagram (though to be confirmed, the preliminary measurements suggest that the other alloying elements, in particular gallium, increases bismuth solid solubility).
TABLE 3
EDS composition measured at dendrite/grain boundaries
and centers of randomly-selected grains in the
Al—5Ga—5Zn—5Sn—5Bi alloy.
Composition in wt. %
Al
Zn
Ga
Sn
Bi
Total
Location
1.81
0.77
2.49
81.66
13.27
100.00
Grain boundary phase
26.52
2.36
22.57
38.21
10.34
100.00
Grain boundary phase
14.11
1.03
4.73
64.58
15.55
100.00
Grain boundary phase
2.70
0.70
2.17
90.61
3.82
100.00
Grain boundary phase
0.44
0.39
4.88
87.04
7.25
100.00
Grain boundary phase
81.15
3.62
5.97
5.97
3.29
100.00
Center of grain
86.13
2.13
6.77
0.89
4.08
100.00
Center of grain
89.13
2.18
5.39
0.74
2.57
100.00
Center of grain
86.63
2.35
7.21
1.26
2.55
100.00
Center of grain
84.18
2.03
8.11
1.65
4.03
100.00
Center of grain
FIG. 7 presents another set of IXRF-EDS compositional maps for composition 6 (Table 2), representing a ternary aluminum alloy having 10-weight percent gallium and 10-weight percent indium. This alloy, 80A1-10Ga-10In, was the most reactive of all alloys of Table 2, as it degraded in cold water seemingly even faster than pure calcium. In this alloy composition (not like for composition 12, FIG. 6 ), gallium clearly exceeded its solubility limit since it was encountered along the grain boundaries, more specifically over the surfaces of the aluminum dendrite arms. Like in the alloy composition of FIG. 6 , gallium also promoted the formation of a galvanic cell with the gallium and indium saturated aluminum. Based upon FIG. 7 , the exact same remark is also applicable to indium that is seen to be more heavily concentrated at grain boundaries, or dendrite arms. It is therefore suspected that indium, like gallium did not allow the aluminum to passivate which resulted in a rapid degradation from the grain boundaries ( FIGS. 8 , 8 A, 8 B, 8 C, and 8 D) even in direct contact with ambient humidity ( FIG. 8 ). As ,indicated in Table 2, the composition of FIG. 7 was observed to immediately tarnish in air, as attributed to ambient humidity, and in water it was found to degrade at astonishing rates. FIG. 8 shows a high-magnification scanning electron micrograph of the surface of composition 6 about 1 minute after its surface had been polished. As can be seen from FIG. 8 , the surface was at least in certain locations already severely degraded. As already mentioned, FIG. 8A to 8D shows that the composition was degraded from the grain boundaries. The degradation byproduct, due to its non-metallic appearance ( FIG. 8 ) and the presence of oxygen ( FIG. 8D ) is typical of a non-adherent hydroxide. Like gallium, indium is proven to increase dramatically the reactivity and degradability of aluminum alloys, and when combined with gallium, the effects on reactivity and degradability are considerable, as proven by composition 6. Both aluminum and indium, in addition to creating microgalvanic cells, prevent aluminum from building up a protective scale, or film.
Well operating elements of the invention may include many optional items. One optional feature may be one or more sensors located in the first or metallic component to detect the presence of hydrocarbons (or other chemicals of interest) in the zone of interest. The chemical indicator may communicate its signal to the surface over a fiber optic line, wire line, wireless transmission, and the like. When a certain chemical or hydrocarbon is detected, then alerting that a safety hazard is imminent or a downhole tool is for instance damaged, the element may act or be commanded to shut a valve before the chemical creates more problems.
In summary, generally, this invention pertains to degradable whipstocks and deflectors and methods of use. Apparatus of the invention may comprise a relatively inert component and a component of a degradable composition as described herein, and optionally a relatively inert protective coating, which may be conformal, on the outside surface of the either or both components. One useful protective coating embodiment is a Parylene coating. Parylene forms an almost imperceptible plastic conformal coating that protects compositions from many types of environmental conditions. Any process and monomer (or combination of monomers, or pre-polymer or polymer particulate or solution) that forms a polymeric coating may be utilized. Examples of other methods include spraying processes (e.g. electrospraying of reactive monomers, or non-reactive resins); sublimation and condensation; and fluidized-bed coating, wherein, a single powder or mixture of powders which react when heated may be coated onto a heated substrate, and the powder may be a thermoplastic resin or a thermoset resin.
Although only a few exemplary embodiments of this invention have been described in detail above, those skilled in the art will readily appreciate that many modifications are possible in the exemplary embodiments without materially departing from the novel teachings and advantages of this invention. Accordingly, all such modifications are intended to be included within the scope of this invention as defined in the following claims. In the claims, no clauses are intended to be in the means-plus-function format allowed by 35 U.S.C. §112, paragraph 6 unless “means for” is explicitly recited together with an associated function. “Means for” clauses are intended to cover the structures described herein as performing the recited function and not only structural equivalents, but also equivalent structures.
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Whipstocks and deflectors comprising a degradable composition, and methods of using same are described. A degradable composition may consist essentially of one or more reactive metals in major proportion, and one or more alloying elements in minor proportion, with the provisos that the composition is high-strength, controllably reactive, and degradable under defined conditions. Methods of using degradable whipstocks in oilfield operations are also described. This abstract allows a searcher or other reader to quickly ascertain the subject matter of the disclosure. It will not be used to interpret or limit the scope or meaning of the claims. 37 C.F.R. 1.72( b ).
| 2 |
RELATED CASES
This is a continuation of U.S. application Ser. No. 07/849,847, filed Mar. 12, 1992, now abandoned.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to fed-batch fermentation, and more particularly to computer automated feed-back control of the nutrient level of a broth in fed-batch fermentation.
2. Description of the Prior Art
During fermentation processes, the bacteria or yeasts growing in a fermentation broth consume nutrient at a variable rate related to, among other things, the microorganism density and rate of growth. In the case of fed-batch fermentation of bacteria, for example, the rate of consumption of nutrient, typically, glucose, can increase exponentially with time until affected by the limitations of the environment or alteration of the conditions, such as varying the rate of agitation and aeration. Another process interference results from the introduction of chemical agents for inducing the bacteria to produce recombinant DNA products. Accordingly, the yield or productivity of a fermentation process is increased when nutrient is added during the fermentation to compensate for that depleted through consumption by the bacteria.
It is desirable to maintain a constant nutrient concentration throughout the fermentation process despite the variable rate at which the nutrient is depleted. When nutrient concentration, usually glucose, is very high, undesirable waste by-products, usually acetic acid, lactic acid or ethanol are produced. The economic implications of inefficient nutrient utilization are very important because of the high cost of glucose. When the nutrient concentration is too low, or absent, the growth of the microorganisms is restricted usually resulting in reduced productivity of the process. Thus, significant efforts have been expended in attempting to develop methods for maintaining the nutrient concentration relatively constant during the fermentation process. Nevertheless, completely satisfactory techniques have not been found to maintain the concentration within a sufficiently desirable narrow range, especially in the situations in which the standard exponential consumption rate is disrupted.
Generally, manual techniques have been employed for controlling the nutrient concentration by measuring the nutrient level of the medium and replenishing the nutrient to compensate for depletion. Recent reports have described the development of at least partially automated techniques. For example, in G. Luli et al., "An Automatic, On-Line Glucose Analyzer for Feed-Back Control of Fed-Batch Growth of Escherichia coli", Biotechnology Techniques, Vol. 1, No. 4, pp. 225-230 (1987), a process control technique for maintenance of glucose concentration is described in which the glucose level is monitored periodically and matched against archived profiles of glucose consumption rate versus time as determined by earlier experimentation. The amount of glucose to be introduced during the next interval is then determined according to the archived curve. This process also required the separation of cells from the broth by membrane filtration prior to analysis of the cell-free medium for nutrient concentration. Glucose concentrations were maintained between 1.0 and 2.0 grams per liter with this method.
In a later paper, G. Lull et al., "Comparison of Growth, Acetate Production and Acetate Inhibition of Escherichia coli Strains in Batch and Fed-Batch Fermentations", Applied and Environmental Microbiology, April 1990, pp. 1004-1011, a similar technique with a higher sampling rate is discussed. The article reports that archived data for glucose consumption rates were required for computer-controlled glucose addition. The glucose concentration is reported to have been maintained at about 1.0+/-0.2 g/l.
G. Kleman et al., "A Predictive and Feedback Control Algorithm Maintains a Constant Glucose Concentration in Fed-Batch Fermentations", Applied and Environmental Microbiology, April 1991, pp. 910-917, describes a method which requires linear regression analysis of nutrient concentrations to feed-forward control the addition of nutrient to match consumption rate (glucose demand, GD). The method assumes that the theoretical glucose demand is based on a constant yield of biomass from glucose. The method requires cell-free broth for analysis of nutrient concentration requiring frequent broth sampling at two minute intervals and has a response time between sample analysis and nutrient pump response.
However, such techniques suffer from several drawbacks. The technique of Luli et al. requires that numerous trials of the particular strain of microorganism under various conditions and desired nutrients and nutrient concentrations be conducted to prepare an archive of nutrient consumption rate curves for comparison purposes. In addition, because the nutrient feed rate is dependent on the archived curve, a curve for the same strain being cultivated under the same conditions must be located in order to predict the rate of consumption of the nutrient during the next time interval. Further, if the fermentation conditions change, for example, if the agitation rate is varied or if a chemical agent is introduced to induce the microorganism to produce recombinant DNA products, archived curves cannot be relied on. The requirement for cell-free broth for nutrient analysis adds another level of complexity to the method. Although the second Luli et al., article makes reference to control of glucose concentration at 1.0 gram per liter +/-0.2 grams per liter, it appears that such control is maintained only for undisturbed fermentation conditions with standardized strains of Escherichia coli. Again the major limitations of this method is that this system does not adapt to variances from the conditions under which the archived consumption rate curves were derived, and cell-free broth is required for nutrient analysis. Kleman et al., requires a linear regression analysis in the algorithm and is therefore a major limitation to the method. When glucose consumption rates are very high the method significantly underpredicts glucose demand. Further, linear regression analysis for determining glucose demand during metabolic shifts creates errors in response to matching glucose demands and feed rates.
SUMMARY OF THE INVENTION
Briefly, therefore, the present invention is directed to a novel method for controlling nutrient concentration at a desired level in a broth undergoing fermentation by microorganisms in the broth. A method for controlling nutrient concentration levels in a broth under the control of a computer, comprising the steps of:
a. fermenting a broth containing microorganisms and a nutrient;
b. withdrawing a series of samples of the broth, the samples being withdrawn at periodic intervals;
c. measuring the nutrient concentrations of samples in the series;
d. comparing the nutrient concentration of a designated sample with the nutrient concentration of a preceding sample withdrawn before the designated sample;
e. determining the nutrient utilization rate in real-time by comparing the nutrient concentration of the designated sample with that of the preceding sample, the calculated rate at which the nutrient concentration of the broth decreased during a designated interval extending from the time which the preceding sample was withdrawn to the time at which the designated sample was withdrawn;
f. comparing the calculated rate at which the nutrient concentration of the broth decreased during the designated interval to the rate at which the nutrient concentration of the broth decreased during at least one interval preceding the designated interval;
g. predicting from comparing such rates an estimated rate at which the nutrient concentration of the broth is expected to decrease in an interval succeeding the designated interval; and
h. adding fresh nutrient to the broth at a rate and quantity based on the estimated rate.
The present invention is also directed to a method for culturing microorganisms in a medium containing glucose, wherein the glucose concentration is regulated at a selected level in the range of from about 0.2 g/l to about 1 g/l.
It is an objective of the present invention to provide an improved method for controlling nutrient concentration at a desired level in a broth undergoing fermentation by microorganisms in a broth.
It is an advantage of the present invention to provide control of the nutrient concentration of a broth at a desired level without the need for comparative test runs and despite disturbances to the fermentation processes.
It is another advantage of the present invention to better predict nutrient demand of a broth undergoing fermentation, when consumption rates are elevated.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic representation of a single control system for glucose control.
FIG. 2 is a schematic representation of a multiple control broth glucose control.
FIG. 3a, 3b are terms and equations used in the invention.
FIG. 4a, 4b, 4c is a program flow chart for the method of the present invention.
FIG. 5 is a typical glucose control profile.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In accordance with the present invention, it has been discovered that improved control of nutrient concentration in a fermentation broth may be achieved by periodically sampling a fermentation broth for nutrient concentration, calculating the nutrient consumption rate by comparing the nutrient concentration of the sample to a concentration determined from an earlier sample, and then comparing that consumption rate to those calculated from earlier samples to predict the consumption rate over the next time period and introducing fresh nutrient accordingly. It is intended that the present invention is capable of controlling the concentration of any nutrient which can be measured. It is envisioned that a computer is the optimal device for this method. This process, which may be conducted automatically, has been found to provide many advantages over conventional techniques. For example, it obviates the necessity for creating an archive of nutrient consumption rate profiles. In addition, it permits maintenance of nutrient level within a narrow range. Not only that, but good control of nutrient level has been found to be possible even for nonstandard fermentation broths (even involving recombinant strains), for fermentations under varying conditions and for fermentation processes that are disturbed by the introduction of agents for inducing protein production.
Moreover, because of the great precision afforded by this method, nutrient concentration has been regulated at lower levels than previously employed and it has been found that such lower levels surprisingly result in improved expression of recombinant protein. In other words, a method has been discovered by which yield of recombinant protein can be increased. And because the improved yield is achieved with a lower glucose concentration, it can be achieved at lower cost. Preferable E. Coli is fermented at a nutrient setpoint of 0.20 grams per liter for optimum glucose conversion and for optimum production of rDNA proteins. All prepared proteins in this method is bovine prolactin (BPRL) and bovine placental lactogen (BPL).
The method of the present invention is shown schematically in FIG. 1. In short, samples of a fermentation broth (2) are periodically withdrawn from a fermentor (4) in which agitation means (6) maintains a generally consistent concentration throughout the broth, by a sampling device (8) by the periodically opening of a pinch or solenoid valve (10) via a solenoid swithching box (12) and are submitted to a nutrient concentration analyzer (14) to determine the nutrient concentration of the sample. The concentration data are fed to a computer(16) preferably an "IBM XT, AT®" or compatible with "DOS version 2.0"® or higher, with at least one RS 232 port and a minimum of 350K RAM memory, via a multiplexor (18) preferably being an "Omega"® multiplexor which compares the concentration to that measured of an earlier sample, preferably the immediately preceding sample, to calculate the rate at which the nutrient was consumed over the period of time from the earlier sample to the most recent sample. This consumption rate is compared to earlier consumption rates determined in the same way. From this comparison, a consumption rate over the next time period (extending from the most recent sampling to the next sampling) is predicted by the computer (16) and a signal is sent from the computer (16) to a pump (20) preferably a "Masterflex"® computerized drive pump capable of communicating to the computer via the multiplexor (18) and to deliver the determined volume of nutrient stock (22) to the fermentation broth (2) to compensate for the predicted nutrient consumption and maintain the nutrient concentration at the desired level. The sampling frequency may also be controlled by the computer (16), which may further be programmed to catch errors by directing solenoid valve (10) to resample the fermentation broth (2) if the nutrient concentration of the sample differs too significantly from that expected or that of an earlier sample. The error ranges may be arbitrarily set depending upon the microorganism and the nutrient setpoint to be used during the fermentation.
Generally, the fermentation broth (whole broth) comprises microorganisms and a nutrient medium. The microorganisms typically are bacteria or yeast. Preferably the bacteria are Escherichia coli, Bacillus subtilis or Serratia marcescens. The yeast is preferably Saccharomyces cerevisiae.
The fermentation broth is agitated by means (6) to maintain access to the nutrient by the microorganisms. Sufficient agitation is also particularly important in the present invention to maintain generally uniform concentrations through the broth so that samples withdrawn therefrom fairly represent the entire broth.
It has been found that a superior technique for withdrawing broth (2) from the fermentor (4) is through a sampling valve (8), preferably being a "VANASYL SAMPLING VALVE"®, Vanasyl Valves, Ltd., Sheffield England. This sampling valve is an in-place sterilizable, aseptic spindle valve which is attached, through a small orifice to thin silicone tubing (24) preferably being "Masterflex"® to withdraw a small sample (about 1-3 ml) of the broth for analysis. The sample may be withdrawn by opening a solenoid valve (10) set on the thin tubing (24) of the sampling device. Because back-pressure is maintained on the fermentation broth in the sparged fermentor (4), when the solenoid valve (10) is opened, broth (2) is forced through the orifice, into the tubing (24) and to a nutrient concentration analyzer (14) to which the sampling device is also attached. Alternatively or additionally, the nutrient concentration analyzer (14) can apply a vacuum to pull broth to the analyzer.
Upon opening of the valve (10) of the sampling device, flow from the thin tubing (24) is first directed away from or outwardly from the analyzer (14), thus flushing the tubing of the stagnant broth remaining in the tubing to a waste container located in the analyzer (14). Then, flow is redirected to introduce a sample of fresh broth (2) to the analyzer after which the solenoid valve (10) is dosed. The intervals between samples may be selected as desired, with shorted intervals generally being associated with greater precision in maintaining the nutrient concentration level. All of these functions may be controlled by computer.
This on and off sampling technique has been found to permit the withdrawal and sampling of such minor volumes of broth (1-3 ml samples have been found to be possible and sufficient), that frequent sampling can be achieved without depleting the broth. For example, samples may be taken two minutes or five minutes apart, as desired, without the volume withdrawn exceeding the volume of nutrient being added.
When the nutrient is glucose, it has been found that a "YSI Model 2000 Glucose and L-Lactate Analyzers"® is particularly well suited for use as the nutrient concentration analyzer (14) for a number of reasons: 1) "The YSI Model 2000 analyzer"® is a microprocessor based analyzer which is computer compatible with an RS-232 interface; 2) it is capable of sample aspiration and it can accurately measure glucose concentrations in a small volume (0.5 mls ) of whole broth without the need for separating cells from the broth; 3) glucose measurements can be made over a wide range of glucose concentrations (0 to 20 grams per liter); 4) it is self-calibrating which improves the precision of measurements to within +/-2.0% or 0.04 grams per liter; 5) the sample response time required for the measurement is 60 seconds, an advantage for fast control response; 6) it is capable of using two glucose oxidase membranes to enzymatically determine glucose concentration, but one membrane is sufficient for control purposes.
There are several methods for calculating the glucose consumption rate which known in the art but the preferred method and formulas are shown in FIG. 3a and 3b. The computer performs these functions as shown in FIG. 4a, 4b, and 4c.: 1) it compares the glucose concentration of the sample (Y2) to that of an earlier sample, preferably the next previous sample (Y1), 2) it calculates the amount of glucose added over the time interval and 3) calculates the rate at which the nutrient was consumed over that time interval.
A further error-check method requires the computer to compare that rate to rates determined in like fashion for preceding intervals, preferably the rate is compared to the average of the four immediately preceding intervals to develop a profile of the change in consumption rate over time.
From this comparison, the consumption rate over that next interval is predicted and glucose setpoint control is achieved with the formulas shown in FIGS. 3a and 3b. First, setpoint correction is calculated by comparing the measured concentration (Y2) to the predetermined setpoint. Second, the amount of glucose required to adjust the glucose concentration (Y2) to the predetermined setpoint is calculated and the desired amount of glucose is delivered via the new pump rate. Further, an error compensation factor, calculated by using a gain constant (K), modifies the newly corrected flow rate either positively or negatively, depending upon whether the measured glucose concentration is higher or lower than the setpoint.
The computer may further be programmed to recognize sampling or measurement errors. If the measured nutrient concentration falls outside a preselected range from the predicted nutrient concentration or the nutrient concentration measured for the previous sample, the computer discounts that sample and directs a new sample to be withdrawn. The error ranges will probably differ depending on the organism being grown in the fermentor and by the vessel size since the mixing characteristics of the fermentors vary with size. The computer (16) may also be programmed to maintain high analyzer precision by instructing the analyzer to recalibrates periodically, such as after every fifth sample or every fifteen minutes. The program may further enable the computer to recognize inappropriate shutdowns of the analyzer, at which point it would instruct the analyzer to restart.
The method of the present invention also includes the ability to control more than one fermentation process simultaneously, shown schematically in FIG. 2. When two or more fermentation processes are controlled by the invention, one additional hardware modification is made. The nutrient pumps (20, 21) which contain RS232 ports are serially connected, allowing the computer (16) to communicate with nutrient pump (21) and nutrient pump (20) via the multiplexor (18). Upon completion of a control action from the current process, additional processes are accommodated and prioritized on a timed, sequential basis. While additional processes are waiting for updated control actions by the computer (16), nutrient feed rates continue at the previously calculated
The control process of this invention has been found to allow greater control sensitivity than has been achieved with conventional manual control techniques, and this superior sensitivity has been accomplished with much faster response to deviations of nutrient concentration from desired levels. Moreover, because of the automated nature of the process of the present invention, substantial labor savings are provided over the manual methods.
Highly sensitive control is afforded without the need for comparative tests or an archive of nutrient consumption rate profiles. Accordingly, as compared to other techniques known in the art, the method of the present invention provides a highly flexible control system applicable to fermentations even of untested strains of microorganisms, regardless of the fermentation conditions or disturbances or changes in conditions. When the broth is disturbed, causing a discontinuity in the consumption rate profile, a sudden change in nutrient concentration or some other nonstandard consumption rate profile, the control technique of this invention quickly adapts and reins in or controls the nutrient concentration to yield desired level.
The method of the present invention is far more flexible than that known in the art and is applicable even to unusual bacterial strains (including recombinant strains) or other microorganisms under unusual or varying conditions, and is particularly suitable for production of proteins--a prime reason for carrying out fermentation. In protein production, two fermentations are effectively carried out. The first fermentation increases bacterial density. Then, when protein production is induced, a discontinuity in nutrient consumption results, followed by commencement of what is effectively a second fermentation. The present invention can adapt to this nonstandard consumption rate profile--it is not limited to the comparison to standard profiles.
The following examples describe preferred embodiments of the invention. Other embodiments within the scope of the claims herein will be apparent to one skilled in the art from consideration of the specification or practice of the invention as disclosed herein. It is intended that the specification, together with the examples, be considered exemplary only, with the scope and spirit of the invention being indicated by the claims which follow the examples. In the examples all percentages are given on a weight basis unless otherwise indicated.
EXAMPLE 1
A typical glucose control profile resulting from the invention is shown in FIG. 5. The example shown was a profile generated from an E. coli fermentation producing the rDNA protein Porcine Somatotropin (PST). Glucose was initially batched in the fermentation at 3.4 g/l and allowed to be depleted until it reached the glucose control setpoint of 0.5 g/l. Glucose concentration was maintained at 0.5 g/l+/-0.20 g/l throughout the fermentation. Glucose uptake rate (mls of 50% glucose feed solution/min) is also plotted in this profile. It can be seen that even when glucose utilization changed dramatically during induction (age=10 hrs.) glucose control was unaffected. Final Dry Cell Weight was 31.5 g/l.
EXAMPLE 2
E. coli strains containing plasmids for the production of three rDNA proteins were run under identical fermentation conditions except for glucose setpoint control as shown in Table 1. The rDNA proteins were porcine somatotropin (PST), bovine placental lactogen (BPL) and bovine prolactin (BPRL). Glucose setpoints were controlled at 0.2 grams/liter (g/l), 1.0 g/l, 2.5 g/l, 5.0 g/l and 10.0 g/l. Samplings were made at 5 minute intervals, and the pans were carried out for 18 hours. The concentration of glucose in the feed stream was 0.50 g/l and the starting concentration of bacteria in each culture was 0.3-0.5 g/l. At the end of the runs, the glucose conversion efficiency, i.e., grams of biomass produced per gram of glucose consumed (g. DCW/g. Glucose) were measured by reference. The experimental results (Table 1) show that glucose conversion efficiency is 1) highest when glucose concentration is controlled at very low concentrations, and 2) is independent of the heterologous protein being produced.
TABLE 1______________________________________ Glucose ConversionGlucose Efficiency (g. DCW/g.Glucose)Setpoint(g/l) PST BPL BPRL______________________________________0.2 0.321 0.43 0.651.0 0.277 0.32 0.552.5 0.252 0.31 0.525.0 0.250 0.29 0.5010.0 0.247 0.26 0.48______________________________________
EXAMPLE 3
In the case of the BPL and BPRL fermentations it was discovered that the glucose setpoint was a critical parameter in optimizing production of these rDNA proteins. The yield of BPL is expressed as the percentage of total cellular protein made as BPL (%TCP) and was determined by spectrophotometric scanning of an SDS-PAGE gel. The yield of BPRL is expressed in grams per liter (g/l) and was determined by high performance liquid chromatography (HPLC). Results are shown in Table 2.
TABLE 2______________________________________Glucose Setpoint % TCP g/l(g/l) BPL BPRL______________________________________0.0 (starvation) 4.5 1.140.2 20.0 1.461.0 9.0 1.542.5 8.0 1.275.0 8.0 1.1010.0 7.0 0.65______________________________________
EXAMPLE 4
To further demonstrate generic capability of the method to perform equally well with other industrially important microorganisms, fermentations were run with the bacteria Bacillus subtilis and Serratia marcescens, and the yeast Saccharomyces cerevisiae. The Bacillus subtilis fermentation media or nutrient was Luria Broth, a complex medium which generated high glucose conversion efficiencies because of its high nitrogen source content. The Serratia marcescens fermentation media consisted of M9 and 2% casamino acids, and the Saccharomyces cerevisiae fermentation media consisted of yeast extract-peptone-dextrose (YEPD). All three microorganisms were grown in fermentations where the glucose setpoints were 0.5 g/l, 5.0 g/l and 10.0 g/l. These results shown in Table 3 demonstrate that the invention can be used to optimize glucose conversion efficiency for a variety of microorganisms.
TABLE 3______________________________________ Glucose ConversionGlucose Efficiency (g. DCW/g.Glucose)Setpoint(g/l) Bacillus s. Serratia m. Saccharomyces c.______________________________________0.5 1.250 0.220 0.0745.0 0.898 0.217 0.06010.0 0.437 0.271 0.069______________________________________
In view of the above, it will be seen that the several advantages of the invention are achieved and other advantageous results attained. As various changes could be made in the above methods and compositions without departing from the scope of the invention, it is intended that all matter contained in the above description and shown in the accompanying drawing shall be interpreted as illustrative and not in a limiting sense.
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A method for controlling nutrient concentration levels in a fermentation broth containing bacteria or a yeast and a nutrient is disclosed. A computer calculates the nutrient consumption rate of the broth for selected intervals of time between successive samples in real time by comparing the nutrient concentrations of the samples. Thus, the computer having the capability to predict an estimated rate at which the nutrient concentration is expected to decrease at selected sample intervals. Further, adding fresh nutrient to the fermentation broth at a rate and quantity based on the estimated rate to control nutrient concentration levels. Furthermore, a means for obtaining a series of samples and measuring nutrient concentrations is also disclosed.
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BACKGROUND OF THE INVENTION
(1) Field of the Invention
The present invention relates to a new pharmaceutical use for cinnamamide derivatives and more particularly to use of cinnamamide derivatives for centrally relaxing muscle tone.
(2) Prior Art
The cinnamamide derivatives of the present invention have not been reported except that (E)-N-cyclopropyl-3-(3-chlorophenyl)-2-butenamide has disclosed as showing sedative or taming action in J. Med. Chem., vol. 9 (No. 5), page 675-681 (1966). The drugs showing the sedative or taming action lower the abnormally high psychic state of the upper central nervous system or depress the hyperemotion. On the contrary, the muscle relaxant normalizes the disorder of motor nervous system. Therefore, these two pharmacological actions are different apparently each other. Accordingly, it has heretofore been realized that the muscle relaxant is different from the sedative agent in the object of the use.
Furthermore, there are known other cinnamamide derivatives having the muscle relaxing activity, of which a typical compound is cinflumide that has the most preferred effect (Japanese Patent Publication No. 60-56700).
As a result of the earnest researches, the present inventors have found some cinnamamide derivatives to have much stronger and prolonged centrally-acting muscle relaxation activity, and have accomplished the present invention.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a method for relaxing muscle tone which comprises administering to a patient a pharmaceutically effective amount of a cinnamamide derivative represented by the formula ##STR2## where X is a halogen atom.
In one aspect of the present invention, there is provided use of a cinnamamide derivative of Formula I for the manufacture of a pharmaceutical composition for relaxing muscle tone.
In further another aspect of the present invention, there is provided a pharmaceutical composition for relaxing muscle tone which comprises a cinnamamide derivative represented by Formula I as active ingredient and a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION OF THE INVENTION
In Formula I, the halogen atom refers to a fluorine, chlorine, bromine or iodide atom, and preferably a fluorine or chlorine atom.
The compound of Formula I can be prepared, for example, as follows: a (E)-3-(3-halogenophenyl)-2-butenoic acid well-known is first reacted with an ordinary halogenating agent (e.g., thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride, thionyl bromide or phosphorus tribromide) to give an acid halide of the formula ##STR3## wherein X is as defined above, and X' is a halogen atom. Although the halogenating agent itself in this reaction can be a solvent, the reaction is also achieved in an inert-solvent (e.g., benzene, toluene, tetrahydrofuran, ether, methylene chloride or chloroform) with stirring at room temperature to the reflux temperature of the solvent for 30 minutes to 5 hours. A catalyst is not necessarily used, but acceleration of the reaction can be achieved by the addition of a catalystic amount to an equimolar amount of a catalyst such as pyridine, triethylamine or N,N-dimethylformamide.
The compound of Formula II dissolved in the same inert-solvent as described above is then reacted with cyclopropylamine to give the compound of Formula I. In order to eliminate the halogenated hydrogen which forms in the reaction, it is preferable to use more than two molar equivalents of cyclopropylamine, or it is preferable to coexist a tert-amine such as pyridine or triethylamine. The reaction is carried out at from -30° to 50° C., and finished by 1 to 24 hours.
Alternatively, a (E)-3-(3-halogenophenyl)-2-butenoic acid is reacted with an alkyl halogenocarbonate (e.g., methyl chlorocarbonate, ethyl chlorocarbonate and isobutyl chlorocarbonate) in the presence of a base (e.g., triethylamine, diisopropylethylamine and N-methylmorpholine) in the same inert-solvent as described above at -30° to 30° C. for 0.2 to 3 hours to give a mixed acid anhydride represented by the formula ##STR4## wherein X is as defined above and R is an alkyl group having 1 to 7 carbon atoms, which is then in the reaction solution, without isolation, reacted with cyclopropylamine at the same temperature to give the compound of Formula I.
The compounds of Formula I exhibit remarkable muscle relaxant and rigidity mitigation activity. On the other hand, their sedative activity is weak at the dose effective to relax muscle tone. Accordingly, these compounds are useful as the therapeutic agents of the disorder of motor nervous system such as dolorous muscle spasm (e.g., low-back pain and back pain, and herniated disc of the spine) or spastic paralysis such as the cerebral injuries. For these purposes, the compound of Formula I is mixed with suitable pharmaceutically acceptable carriers for solid or liquid form to give the pharmaceutical preparation for oral or parenteral administration. Examples of the pharmaceutical preparation are solid forms such as tablets, pills, capsules and granules, liquid forms such as injectional solutions, syrups and emulsions, and external forms such as ointments and suppositories, all of which can be prepared according to conventional pharmaceutical practices. The carriers in the above-mentioned preparations can include ordinary additives such as auxiliaries, stabilizers, wetting agents and emulsifiers. For example, there can be used solublizers (e.g., injectional distilled water, physiological saline solution and Ringer's solution) and preservers (e.g., methyl p-oxybenzoate and propyl p-oxybenzoate) for injectional solutions; and used sorbitol syrup, methylcellulose, glucose, sucrose syrup, hydroxyethylcellulose, food oil, glycerin, ethanol, water, emulsifers (e.g., gum arabic and lecithin) and detergents (e.g., Tween or Span) for syrups and emulsions. For the solid forms, there can be used excipients (e.g., lactose, corn starch and mannitol), lubricants (calcium phosphate, magnesium stearate and tulc), binders (e.g., sodium carboxymethylcellulose and hydroxypropylcellulose), disintegraters (e.g., crystal cellulose, calcium carboxymethylcellulose) and fluid accelerators (e.g., light silicic anhydride).
The dosage of the compound of Formula I depends on the age of the patient, the kind and conditions of the disease, but usually it is from 5 to 1000 mg in single or several divided doses per adult per day.
Then, the experiments are illustrated below in order to show the effects of the compounds of Formula I.
Experiment 1 [Inhibition test of the mesocephalous decerebrate rididity]
The rigidity animals were prepared according to the method of Ono et al [Gen. Pharm., vol. 18, page 57-59 (1987)].
Four male Wistar rats weighing 250 to 350 g were used for each group. The animals were anesthetized with ethyl ether and fixed on a brain stereotaxic apparatus to break the midbrain bilaterally (APO, V-3, L ±1.5). The advanced rigidity occurred in the hind limb with awaking from the ethyl ether anesthesia. The test drugs [A; (E)-N-cyclopropyl-3-(3-chlorophenyl)-2-butenamide, B; (E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide and C; cinflumide] dissolved in propylene glycol were each administered intravenously in the amount of 5 mg/kg or 10 mg/kg (0.1 ml per 100 g of rat), and these test drugs suspended in 0.4% aqueous carboxymethylcellulose solution were each administered intraduodenally in the amount of 50 mg/kg (0.1 ml per 100 g of rat) to determine the inhibition time of the rigidity.
Results are shown in Table 1.
TABLE 1______________________________________ Dose Dose (mg/kg i.v.) (mg/kg i.d.)Drug 5 10 50______________________________________A 13 37* 36*B 6 12 53C 0 3 0______________________________________ *The values show the length of time (minutes) during which the inhibition action occurs.
Experiment 2[Inhibition of Anemic Decerebrate rigidity]
The rigidity animals were prepared according to the method of Fukuda et al [Japan J. Pharmacol., vol. 24, page 810-813 (1974)].
Four male Wistar rats weighing 250 to 350 g were used for each group.
The animals were anesthetized with ethyl ether and carotid artery was ligated bilaterally. A round hole was digged in the suboccipital skeleton and the basal artery was coagulated using a bipolar electrocoagulator. The advanced rigidity occurred on the fore limb with awaking from the ethyl ether anesthesia. The drugs [A; (E)-N-cyclopropyl-3-(3-chlorophenyl)-2-butenamide, B; (E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide, and C; cinflumide] dissolved in polyethylene glycol 400 were each administered intravenously in the amount of 5 mg/kg or 10 mg/kg (0.1 ml per 100 g of rat) to determine the inhibition time of the rigidity.
Results are shown in Table 2.
TABLE 2______________________________________ Dose (mg/kg i.v.)Drug 5 10______________________________________A 9 13*B 8 12C -- 8______________________________________ *The values show the length of time (minutes) during which the inhibition occurs.
Experiment 3 [Straub tail reaction]
Test was carried out according to the method of Ellis et al [Neuropharmacology, vol. 13, page 211 to (1974)].
Six male ICR mice weighing 20-30 g were used as the animals for each group. The drugs [A; (E)-N-cyclopropyl-3-(3-chlorophenyl)-2-butenamide, and C; cinflumide] suspended in 0.4% aqueous carboxymethylcellulose solution were each administered orally to the animals in the amounts of 50, 70.7, 100 and 140 mg/kg (0.1 ml per 10 g of mouse). After 15 minutes, 15 mg/kg of morphine hydrochloride were administered subcutaneously. After 30 minutes, the tail-raising reaction was determined. The muscle relaxation activity was judged as positive in case where the drug produces the value of less than 45 degrees of the tail-raising's angle, and the inhibition rate was culculated.
Results are shown in Table 3.
TABLE 3______________________________________ Dose (mg/kg i.v.)Drug 50 70.7 100 140______________________________________A 40 40 100 100*C 0 20 80 100______________________________________ *The values show the inhibition rate (%).
Experiment 4 [Spontaneous motor activity test]
Six male ICR mice weighing 20-30 g were used as the test animals for each group. The test drugs [A: (E)-N-cyclopropyl-3-(3 chlorophenyl)-2-butenamide and B: (E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide] suspended in 0.4% aqueous carboxymethylcellulose solution were each administered orally to mice in the amounts of 50, 70.7 and 100 mg/kg (0.1 ml per 10 g of mouse). The control group were administered with 0.4% aqueous carboxymethylcellulose solution only. After 15 minute, mice were placed in ANIMEX apparatus (manufactured by Muromachi Kikai K.K.) to determine the spontaneous moter activity for 30 minutes
Results after 30 minutes of the administration are shown in Table 4.
From the results the group treated with the test drugs was found not to have substantial inhibition activity when compared with the control group.
TABLE 4______________________________________ Dose Spontaneous motor activityDrug (mg/kg p.o.) (Counts/30 minutes)______________________________________A 50 1736.0 ± 366.6 70.7 1570.2 ± 326.9 Control 2116.0 ± 256.6B 70.7 2264.2 ± 506.0 100 1667.8 ± 152.4 Control 2128.7 ± 228.0______________________________________
Experiment 5 [Acute toxicity test]
Ten male ICR mice weighing 25 to 34 g were used. (E)-N-cyclopropyl-3-(3-chlorophenyl)-2-butenamide suspended in 0.4% aqueous carboxymethylcellulose solution was each administered orally to mice in the amount of 0.1 ml per 10 g of mice. The survivals were observed for 7 days after administration, but no death occurred in case of the dose of 1 g/kg. The LD 50 values were more than 1 g/kg p.o.
The present invention is illustrated by the following examples in more detail, and Compounds 1 and 2 in Examples 1 to 5 mean (E)-N-cyclopropyl-3-(3-chlorophenyl)-2-butenamide and (E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide, respectively.
EXAMPLE 1 (Tablets)
______________________________________Compound 1 600 gCrystal cellulose 120 gCorn starch 125 gHydroxypropylcellulose 45 gMagnesium stearate 10 gTotal 900 g______________________________________
The above components were mixed according to an ordinary manner and tableted to give 9 mm diameter tablets weighing 300 mg.
EXAMPLE 2
______________________________________Compound 2 600 gCrystal cellulose 150 gCorn starch 140 gMagnesium stearate 10 gTotal 900 g______________________________________
The above components were mixed according to an ordinary manner, and each 300 mg of the mixture was filled into a No. 1 cupsule.
EXAMPLE 3 (Granules)
______________________________________Compound 1 200 gMannitol 300 gCorn starch 450 gMagnesium stearate 10 gHydroxypropylcellulose 50 gTotal 1010 g______________________________________
Granules were prepared from the above components by a wet granulation method.
EXAMPLE 4 (Powders)
______________________________________ Compound 1 200 g Lactose 800 g Total 1000 g______________________________________
The above components were mixed uniformly according to an ordinary manner to give powders, each 1000 mg of which were filled into a pack.
EXAMPLE 5
Fifty g of Compound 2 was dissolved in 1000 ml of distilled water for injection and filled into 2 ml ampules.
EXAMPLE 6
To a solution of 18.0 g of (E)-3-(3-fluorophenyl)-2-butenoic acid in 200 ml of benzene was added 14.5 ml of thionyl chloride, and the mixture was stirred at reflux under heating. The benzene and the excess amount of thionyl chloride were evaporated under reduced pressure, and the residue was concentrated to give 19 g of the crude acid chloride. To a solution of the crude chloride in 200 ml of toluene was added dropwise a solution of 15.2 ml of cyclopropylamine in 50 ml of toluene under ice-cooling with stirring, and the mixture was stirred at room temperature for 6 hours. The reaction solution was washed, in turn, with water, a saturated aqueous bicarbonate solution, dilute hydrochloride and water, and dried over magnesium sulfate. The toluene was evaporated under reduced pressure, and the residue was recrystallized from n-hexane-acetone to give 12.9 g of (E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide as colorless needles.
m.p. 119.0°-120 5° C.
EXAMPLE 7
To a solution of 18.0 g of (E)-3-(3-fluorophenyl)-2-butenoic acid in 200 ml of toluene was added 13.9 ml of triethylamine under cooling and a nitrogen atmosphere with stirring, followed by the addition of 13.0 ml of isobutyl chlorocarbonate, and then the solution was stirred at room temperature for 30 minutes. To the reaction solution cooled on ice was added dropwise 7.6 ml of cyclopropylamine with stirring, and the mixture was stirred at room temperature for 2 hours. Then, following a procedure similar to that of Example 6 to give 14.0 g of (E)-N-cyclopropyl-3-(3-fluorophenyl)-2-butenamide.
m.p. 119.0°-120.5° C.
Following a procedure similar to that of Example 7, there was obtained (E)-N-cyclopropyl-3-(3-bromopheyl)-2-butenamide.
m.p. 129.0°-131.5° C.
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A cinnamamide derivative represented by the formula ##STR1## wherein X is a halogen atom is useful as a muscle relaxant.
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FIELD OF THE INVENTION
[0001] The invention relates generally to an RFID tag test fixture and method and, more specifically, a testing fixture and method for a RFID tire tag.
BACKGROUND OF THE INVENTION
[0002] RFID tags are incorporated into a range of products for the purpose of allowing an identification of the product by a remote reading device. It is important that tags of variable lengths and configurations be tested in order to verify that they are operating correctly within system specifications for the particular product and application for which they are intended. In addition, it is desirable to determine the minimum read and write power characteristics of the tag so that testing will provide a reliable quality control assessment. Furthermore, it is desirable to test the tags under controlled environmental conditions to improve the reliability and relevance of the test results.
SUMMARY OF THE INVENTION
[0003] According to an aspect of the invention, a test fixture and electronic tag assembly includes an electronic tag comprising an electronic device and a half wave dipole antenna of antenna length L. The antenna is configured as first and second coiled dipole antenna segments connecting with and extending in opposite directions from the electronic device. The assembly further includes a support frame; first and second electrically conductive pads positioned in spaced apart relationship within the support frame; and apparatus for fixedly holding end segments of the first and second coiled dipole antenna segments respectively against the first and second conductive pads in an overlapping relationship.
[0004] Pursuant to another aspect of the invention, a combined length of the first and second coiled dipole antenna segments and the conductive pads define a calculated effective antenna length for operative utility in performance measurement of the electronic tag in air. Verification of the minimum read and write power levels required by tags of varying lengths may be established.
[0005] In a further aspect, the retention apparatus comprises abutting first and second blocks defining a block cavity dimensioned and shaped for receipt of the electronic tag and conductive pads therein. The spacing between the conductive pads may be selectively altered to accommodate testing tags of varying lengths.
BRIEF DESCRIPTION OF THE DRAWINGS
[0006] The invention will be described by way of example and with reference to the accompanying drawings in which:
[0007] FIG. 1A is a perspective view of a tag assembly.
[0008] FIG. 1B is a perspective view of the tag in an encapsulating protective medium.
[0009] FIG. 2 is a perspective view of a support stand sub-assembly of the test fixture apparatus.
[0010] FIG. 3 is a partial exploded perspective view of the test fixture apparatus.
[0011] FIG. 4 is a partial exploded perspective view of an upper portion of the support stand
[0012] FIG. 5 is a partial perspective view of an upper portion of the support stand.
[0013] FIG. 6 is a top plan view of the tag support block component of the apparatus.
[0014] FIGS. 7A , 7 B, and 7 C are plan view of a substrate insert component of the apparatus showing alternative conductive pad schematic configurations.
[0015] FIG. 8A is a top plan view of the tag support block and loaded tag with insert substrate components of the apparatus configured to provide a longer conductive pad extension to the tag antenna.
[0016] FIG. 8B is a top plan view of the tag support block and loaded tag with the insert components of the apparatus configured to provide comparatively shorter conductive pad extension to the tap antenna.
DETAILED DESCRIPTION OF THE INVENTION
[0017] Referring first to FIGS. 1A and 1B , an electronic tire tag 10 is of a conventional commercially configured type and includes an antenna formed by a pair of coiled antenna segments 12 , 14 . An integrated circuit package (IC) 16 is mounted to a carrier substrate 18 and includes interconnection leads 20 , 22 extending from opposite IC package sides respectively. The antenna 12 , 14 is conventionally electrically connected to the IC leads 20 , 22 and is suitably tuned to a predetermined radio frequency “f” substantially within a range of 902 to 928 MHz, for receiving RF signals, referred to herein as interrogation signals, from an external transceiver (not shown).
[0018] Operatively, the interrogation signal is received by the antenna 12 , 14 from a remote transponder (not shown) and transmitted to the integrated circuitry within the package 16 . The integrated circuit within the package 16 processes the RF interrogation signal into a power signal for powering a logic circuit that includes conventional ROM, RAM, or other known types of memory storage devices and circuitry. Data transmission from the storage devices is thereby enabled and stored data is transmitted by the antenna 12 , 14 back to an external reader or transponder (not shown). The tag 10 may be incorporated within various products and utilized to communicate stored data relating to such products to the remote reading device.
[0019] The electronic tire tag 10 may be encapsulated in a rigid or semi-rigid material, such as a urethane, epoxy or polystyrene resin, hard rubber compound or the like in a configuration such as the cylindrical package 24 shown in FIG. 1B . Thereafter, the encapsulated electronic tire tag 10 is preferably wrapped with a suitable green rubber material (not shown) to form a green rubber patch (not shown) that is vulcanized and fixedly secured to a tire (not shown). Alternatively, the tag 10 may be incorporated within the green tire prior to tire cure.
[0020] Accordingly, the RFID tire tag must be tuned to rubber for efficient operation. However, testing (minimum read and minimum write power) the tag 10 within a rubber material is problematic. Placing the tag in close contact to cured rubber does not provide the optimal coupling method and as the cured rubber sample ages, the testing data may become unreliable. Also, in order to test RFID tire tags 10 with different antenna lengths, different sized rubber samples would need to be employed to accommodate the antenna length differences. Testing the tag 10 in air would, ordinarily, not achieve satisfactory and reliable results because the tag 10 is not tuned for air. That is, its length (and impedance) is designed to transmit in rubber and not air.
[0021] The subject invention varies the effective length (and consequently its impedance) of a tag antenna in a testing apparatus and methodology disclosed herein. By so doing, the RFID tag 10 may be tested in air yet yield results analogous to a rubber transmission test environment. The testing apparatus is shown in FIGS. 2-5 . As shown, the apparatus includes a support from assembly 26 formed having a base 28 , vertically extending spaced-apart legs 30 , 32 affixed at one end to the base by suitable means such as bolts 31 . A test fixture assembly 34 includes a cover member or block 36 having a cover cavity 37 within an underside. The block 36 may be formed of any suitably rigid material such as a thermoplastic resin. A holding plate or second block 38 is provided having indented sides 39 A, B. The holding plate or block 38 fits closely within the cover cavity 37 such that a bottom surface of the cover and a top surface 44 of the holding plate are in abutment. The holding plate attaches to vertical slots 42 extending along the upper spans of legs 30 , 32 by suitable means such as bolts 40 whereby the holding plate 38 is vertically adjustable along the support legs 30 , 32 to a preferred height. For example, a testing height for a tag 10 may place the tag at a level simulating a mounting location of the tag within a tire.
[0022] Within the upper plate surface 44 of the holding plate 38 are spaced apart, generally rectangular, cavities 46 , 48 connected by a centrally disposed tag cavity 50 . The tag cavity 50 has a geometric profile for receipt of the IC package 16 of tag 10 as will be explained. A pair of substrate insert bodies 52 , 54 are further provided have a generally rectangular form dimensioned for close receipt within respective holding plate cavities 46 , 48 . Positioned within each substrate body 52 , 54 are a pair of adjustment slots 56 that receive bolts 58 . The bolts 58 extend through sockets 60 within the floor of the cavities 46 , 48 to secure the substrate bodies within the holding plate cavities. Each substrate body 52 , 54 is laterally repositionable within a respective holding plate cavity 46 , 48 to the extent of the slots 56 .
[0023] The substrate bodies 52 , 54 each are preferably although not necessarily multi-level, having a raised shelf region 62 along one side of the body. The raised shelf region 62 of each body 52 , 54 supports a conductive pad 64 that is affixed by appropriate means to a top surface of the shelf region. The conductive pad 64 connected to each substrate body 52 , 54 may comprise a conductive plate member (not shown) of suitably conductive material. In the embodiment shown, the conductive pads 64 are formed by foil tape having a conductive copper metallic surface. The foil tape comprising the conductive pads is affixed by adhesive to the shelf region 62 of each body 52 , 54 . The coverage of the shelf region 62 may be varied as illustrated in the alternatively-sized pads of 7 A, B, and C. The sizing of the pads 64 determines the extent to which the test fixture assembly can accommodate tags of varying sizes.
[0024] To conduct a test on a tag 10 , the tag 10 is positioned over the holding plate 38 and loaded into the cavities 46 , 48 and 50 . So situated, as shown best by FIG. 8B , the coiled antenna segments 12 , 14 of the tag 10 overlap the conductive pads 64 on substrate bodies 52 , 54 . It will be noted that the extent of overlap may differ from tag to tag, depending on the length of the antenna segments 12 , 14 of a given tag and the position of the substrate bodies 52 , 54 within the cavities 46 , 48 . Bodies 52 , 54 may be adjusted laterally within and to the extent of slots 56 to alter the extent of overlap with the antenna segments 12 , 14 . The shape and size of the central cavity 50 is somewhat oversized to accommodate receipt of the IC package 16 of a range of tag devices.
[0025] The cover 36 is thereafter assembled upon the holding plate 38 to enclose the tag 10 within the cavities 46 , 48 , and 50 in a sandwich configuration. The tag 10 is thereby rendered relatively immobile for the testing procedure. The testing procedure includes sweeping the sandwiched tag 10 at varying power levels from a transmitting device (not shown) to determine the minimum read and write power characteristics of the tag. At the conclusion of the test procedure, the cover 36 is removed and tag 10 withdrawn.
[0026] FIG. 8B shows the tag placed in the testing fixture assembly 34 . The number of coils of the tag antenna touching the copper tape foil may be varied. The substrate inserts 52 , 54 are screwed down by the screws 58 so that they do not shift during testing. The tag 10 for incorporation into a tire is designed such that the tag length and impedance are tuned to transmit in rubber. Testing the tag in a rubber medium, however, is difficult for the reasons previously explained. For the tag to be able to transmit in air, its effective length and consequently its impedance requires variation. The copper tape pads 64 on the inserts 52 , 54 facilitate a variation to the length of the antenna of tag 10 , as will be appreciated from the following example.
[0027] Since the antenna is a half-wave dipole antenna, its length can be computed according to the formula:
[0028] Length (L)=468/f (MHz) feet, where f=Frequency of transmission (for the subject example 902-928 MHz). Selecting a mean frequency of, as an example, 915 Hz, the effective length of the antenna was calculated to be 6.13 inches. A tag of approximately 3.1 inches in length was employed. The effective length of antenna represents the combination of conductive pad and tag length. Therefore, the conductive pad length required to total 6.13 inches is approximately 3.0 inches, or, 1.5 inches of conductive pad on either side within the testing fixture assembly. FIGS. 8A and 8B show the apparatus having conductive pads 64 of differing lengths, FIG. 8A pads being comparatively longer than those of FIG. 8B . The effective length of the antenna may be changed by sliding the substrates that carry the conductive pads within respective cavities 46 , 48 . Screws 58 within slots 56 are tightened when the requisite position required for the desired effective length of antenna is established.
[0029] From experimental results, it was concluded that the length of the copper tape affected the test results as the impedance of the tag varied with the length of the copper pad employed. Minimum power requirement at a range of test frequencies verified that the median and the mode nearly coincided and the standard deviation of the data was low, implying that the data obtained was accurate and precise. The testing of the tag in air utilizing the test fixture assembly 34 thus was concluded to be accurate.
[0030] The subject test fixture assembly 34 can accommodate different length tags. The copper foil taped pads 64 are laterally adjustable and may cover more or less of the surface area of the substrate inserts in order to accommodate a range of tag lengths. The pads act to extend the length of the antenna of the tag 10 to a requisite extent necessary to achieve a requisite effective antenna length. The testing assembly 34 eliminates the need for customized apparatus because tags of varying sizes and lengths may be accommodated. In addition, the assembly 34 eliminates the problem of testing an RFID tire tag in a rubber medium. Testing the tag within fixture assembly 34 and in air proved to be an accurate indicator that the tag 10 was performing according to predetermined minimum and maximum power criteria. Issues relating to testing within cured rubber and aging rubber accordingly may be avoided. The apparatus and assembly 34 thus provides a flexible fixture for testing tags having antenna segments of varied lengths by utilizing the conductive pads to extend the antenna length to a required extent. In addition, the sandwich configuration of the fixture assembly 34 acts to render a tag undergoing testing immoveable at a desired height for reliable and repeatable test results.
[0031] Variations in the present invention are possible in light of the description of it provided herein. While certain representative embodiments and details have been shown for the purpose of illustrating the subject invention, it will be apparent to those skilled in this art that various changes and modifications can be made therein without departing from the scope of the subject invention. It is, therefore, to be understood that changes can be made in the particular embodiments described which will be within the full intended scope of the invention as defined by the following appended claims.
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A test fixture and electronic tag assembly includes an electronic tag comprising an electronic device and a half wave dipole antenna of antenna length L. The antenna is configured as first and second coiled dipole antenna segments connecting with and extending in opposite directions from the electronic device. The assembly further includes a support frame; first and second electrically conductive pads positioned in spaced apart relationship within the support frame; and apparatus for fixedly holding end segments of the first and second coiled dipole antenna segments respectively against the first and second conductive pads in an overlapping relationship. A combined length of the first and second coiled dipole antenna segments and the conductive pads less the length of the overlapping end segments define a calculated effective antenna length for operative utility in performance measurement of the electronic tag in air analogous with the performance of the performance of the tag in a non-air medium such as in a tire. The spacing between the conductive pads may be selectively altered to accommodate the testing of tags of varying lengths within the fixture.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention is a method that elates to assaying and collecting biological and other specimens and is especially designed for the collection and determination of the presence of chemical constituents in drugs of abuse, urinalysis, infectious disease, clinical chemistry and other areas of analysis. The present art provides a simple and convenient method for the collection, testing, photocopying, and reading by an instrument or other device of results that the prior art cannot provide.
[0003] Some of the collection devices of the prior art for urine for example were not designed to be used for analysis. These devices were strictly designed to collect urine on the ward of a hospital and then sent to the laboratory for testing. Or, the nurse would collect a urine and take it back to the nurse's station and test the urine commonly with a urine dipstick. There are several drawbacks to this. First the nurse will have to have an open urine container at the nurses station. This presents a biological hazard that the nurse, doctors, patients, and passerby's would be exposed to. The chances are spillage of the urine specimen or any liquid for that matter is high when ever you have an open container present. With this specimen now present at the nurses station after collection the pressure to test and dispose of the specimen is increased for workload, safety and storage area (clutter) reasons alone. The next step for the nurse would be to take the urine specimen and dip a dry chemistry test strip into the urine and analyze for urine analytes of interest (constituents). The constituents that are commonly analyzed in urine specimens are glucose, pH, specific gravity, bilirubin, urobilinogen, nitrite, protein, red blood cells (hemoglobin), ketones, white blood cells (human leukocyte esterase), bladder cancer, human chorionic gonadotropin (HCG) and drugs of abuse. Once the test strip has been removed from the specimen it needs to be compared to a color chart to determine the concentration of the urinary constituents. The nurse will then wait the pre-required time to read each and every color pad and or test line as designated by the package insert for the test strip by the manufacturer. After analysis the nurse does not want to lay this strip on the counter for contamination reasons. The nurse may possibly use a paper towel to lay the strip on. Once the results are recorded the nurse will then properly dispose of the test strip and urine specimen and container. Resulting in an inordinate amount of risk, time, and labor.
[0004] 2. Description of the Related Art
[0005] The present is device that is designed to collect and assay the presence of urinary constituents (analytes of interest) in a biological urine specimen. This specimen could come from humans, animals or other sources submitted for analysis of the analyte of interest. That is to say for example that the present device (invention) is designed to be used for the collection and detection of glucose in the urine specimen or the device is used to collect urine and detect virulent disease causing viruses such as HIV, proteins, viruses, drugs of abuse, drug metabolites, clinical analytes of interest, and therapeutic drugs.
[0006] There is no prior that produces the unexpected results of the present device and the answers to a solution to that was never before even recognized that the present art provides. The prior art teaches away from the present art in that it goes in a completely different direction. That is to say that the collection devices of the past for urine were not designed to be used for analysis but strictly collection. For example these devices were strictly designed to collect urine on the ward of a hospital and then be sent to the laboratory for testing. The collection device was designed to collect urine and test however these devices are cumbersome, expensive, and not designed for the specific purpose of testing biological constituents. There are some devices that are designed to perform analysis of certain constituents but in a cumbersome and messy manner and these devices were not designed to collect urine for any period time and have numerous drawbacks and limitations when related to the advance that the present device brings to the art.
[0007] A thorough search of patents, publications, and research revealed no relative art (i.e., prior art) showing any direct correlation to this novel invention. The search included the USPTO (United States Patent Office) data base with no patents issued for a device designed specifically for biological specimen or other fluid collection and testing that is unique this device. However, the following art will be mentioned to further illustrate the novelty of the present art and the obvious advancement to the current art. The following patents, without exception do not mention the use of a cup for collection and analysis of biological specimens for detecting specific analytes of interest with the additional ability to photocopy each side of the device for recording and/or analysis of the results.
[0008] It is known in the art that the urine matrix is very complex and consists of many urinary constituents which create strong buffering and interference problems (e.g. cannibal-like enzymes such as protease) that have to be overcome to provide a method that can be used for the general population with precision and accuracy. Simply because a technique can accommodate a liquid sample does not imply that it can be successfully used with any liquid test matrix. Such successful adaptation of test techniques to accurately deal with specific sample matrices aren't often “obvious” to any scientist. The same can be said of certain types of techniques used to analyze urine. For instance, the art is replete with examples of devices that provide dry chemistry dipsticks for dipping into a urine container and reading the result. However these dipsticks devices have crossover contamination problems from reaction pad to reaction pad because the dipstick is covered with urine and the urine from back and forth from reaction pad to reaction pad. However, the present art will demonstrate in detail the techniques developed that will overcome these type of interferences and issues with the prior art.
[0009] The number of collections of biological specimens is very large in the United States and worldwide. The numbers are in the hundreds of thousands of specimens per day collected in urine containers for drugs of abuse screening, adulteration testing, urinalysis, infectious disease testing, clinical chemistry and other testing. Since very large numbers collected are involved it is very important to the art for a device designed to answer the problems of the current art that will be effective, safe, simple, and cost effective. No current device in the art solves these problems until this invention which can provide millions in savings with regards to rising health care cost.
[0010] Specimens collected for drugs of abuse testing sometimes require that the specimen integrity and chain of custody be validated. The adulteration of samples submitted for drug testing is unacceptable. The assay(s) run on any specimen submitted for any analysis is only as good as the specimen collected.
[0011] Also with the onset of HIV (human immunodeficiency virus), STD's (sexually transmitted diseases), hepatitis and other infectious diseases the health risk associated with the handling of body fluids has increased exponentially over the last few years. Therefore, if a device is invented that can provide added safety it is very likely that it will save lives.
[0012] The multiple steps of specimen collection as required with the prior art are hazardous with regards to infectious diseases. First the sample is collected in a container then the specimen is transferred to another container for testing in a device, test tube, or instrument. In the case of drugs of abuse testing the sample has to be split to another container before it is tested so that the original container is not contaminated with the test device (in case of cross contamination from the test device). These multiple steps procedures of potentially infectious material have required the manual use of test tubes, pipettes, syringes, or other devices used in the transfer of specimens from collection device to the final container use for analysis. Then of course after the assay is completed the assay container and/or the specimen has to be discarded.
[0013] Another issue with the prior art is the possible misidentification or mislabeling of the specimen collected anytime the specimen has to be removed from the original container. This could in an erroneous result for the original specimen. Imagine a urine submitted for an HIV test and it was mix up with another specimen because of mislabeling and as erroneous result was reported. The implications are grave.
[0014] Different attempts at providing an effective collection device have been attempted but all have failed for multiple reasons. U.S. Pat. No. 5,403,551 to Galloway, describes a cup for collecting and analyzing a specimen but this device has multiple drawbacks. The device requires that the user to invert the container prior to analysis. When the container is inverted it leaks quite profusely. Which does not answer the contamination problem. The device is assay part of the device is attached to the collection cup and is not part of the cup and requires a number of chambers, channels, and other means that add to the cost and complexity of the device. In addition, the Galloway device requires the use of a plenum (a space in which a gas, usually air, is contained at a pressure greater than atmospheric pressure. And this device does not have anyway to simply collect and analyze the specimen in a single step while providing a way for the analyst to photocopy and or have the results recorded by an instrument independent of the device thereby removing subjective analysis. In, addition, U.S. Pat. Nos. 5,096,813 and 4,769,215 to Ehrenkranz provides drug testing urine collector type devices that includes perhaps the most complex devices ever designed for urine collection. The complexity of the devices alone would raise the cost of the devices to a level that it would infeasible to market and sell the devices. The devices have almost as many problems as the Galloway device. They actually has adulteration detection reagents in the reservoir. This is a major problem with regard sample contamination. The complexity of manufacturing and the contamination issues from the adulteration detection reagents to name a few are major drawbacks to these devices. And this device does not have anyway to simply collect and analyze the specimen in a single step while providing a way for the analyst to photocopy and or have the results recorded by an instrument independent of the device thereby removing subjective analysis.U.S. Pat. No. 5,096,813 to Krumhar is a device designed specifically to for storage and the detection of oxygen and has no relative bearing on the present invention. It is however, a device used for storage and by no means can be compared to the present device which can analyze a specimen at the point of collection, without tilting the cup, or pouring into another device, etc. And this device does not have anyway to simply collect and analyze the specimen in a single step while providing a way for the analyst to photocopy and or have the results recorded by an instrument independent of the device thereby removing subjective analysis.
[0015] Other patents such as the following have no relative bearing from the present art because there is no semblance in shape of function they are mentioned just to further illustrate the absolute unique properties of the present art.
[0016] For instance, U.S. Pat. No. 2,953,132 discloses a solution bottle with an inwardly projecting tube and a rubber stopper and an associated dispenser bottle, which is adapted to introduce the medication into the solution bottle. And this device does not have anyway to simply collect and analyze the specimen in a single step while providing a way for the analyst to photocopy and or have the results recorded by an instrument independent of the device thereby removing subjective analysis. U.S. Pat. No. 3,066,671 discloses a disposable additive container provided with a cover formed with a shaft-guiding sleeve. The shaft-guiding sleeve receives an infusion holder and an additive container. And this device does not have anyway to simply collect and analyze the specimen in a single step while providing a way for the analyst to photocopy and or have the results recorded by an instrument independent of the device thereby removing subjective analysis.
[0017] Another patent, U.S. Pat. No. 3,608,550 discloses a transfer needle assembly for transferring fluid from a fluid source to a fluid collection container. The needle assembly includes a first cannula mounted on a support means, which engages the collection container and is adapted to be connected at its forward end to the fluid source and at its rear end to the collection container. A second cannula is mounted on the support means and is adapted to be connected at its forward end to the fluid source and at its rear end to the atmosphere allowing fluid to be transferred from a fluid source to a collection container by atmospheric pressure when the volume within the collection container is sufficiently increased. And this device does not have anyway to simply collect and analyze the specimen in a single step while providing a way for the analyst to photocopy and or have the results recorded by an instrument independent of the device thereby removing subjective analysis.
[0018] Another patent, U.S. Pat. No. 3,904,482 discloses an apparatus and method for the collection, cultivation and identification of microorganisms obtained from body fluids. The apparatus includes an evacuated tube containing a culture medium, an inert gaseous atmosphere and a vent-cap assembly. The tube containing the culture medium is fitted with a stopper for introduction of body fluid by means of a cannula and, after growth of the organisms, transfer of the cultured medium is completed for subculturing or identification procedures. And this device does not have anyway to simply collect and analyze the specimen in a single step while providing a way for the analyst to photocopy and or have the results recorded by an instrument independent of the device thereby removing subjective analysis.
[0019] Another patent, U.S. Pat. No. 4,024,857 discloses a micro device for collecting blood from an individual or other blood source into a blood sampler cup. The cup has a removable vented truncated cone shaped top with a capillary tube passing through a well formed in the top proximate to the inside wall of the cup to deliver blood directly from the blood source to the cup. And this device does not have anyway to simply collect and analyze the specimen in a single step while providing a way for the analyst to photocopy and or have the results recorded by an instrument independent of the device thereby removing subjective analysis.
[0020] Another patent, U.S. Pat. No. 4,116,066 discloses a device for the collection of a liquid, such as urine comprising an open-ended urine collection container provided with a hollow cannula attached to its bottom. The cannula is slotted near its base, and serves as the conduit through which liquid may be transferred from the container to an evacuated tube. When the stopper of the evacuated tube is punctured by the cannula, the pressure difference causes liquid deposited in the container to be drawn through the slot into the hollow cannula and into the tube. And this device does not have anyway to simply collect and analyze the specimen in a single step while providing a way for the analyst to photocopy and or have the results recorded by an instrument independent of the device thereby removing subjective analysis.
[0021] And yet another attempt to solve this problem is seen in U.S. Pat. No. 4,300,404, in which a container is developed having a liquid container with a snap fit lid. The lid is provided with a cannula which extends into the lower end of the container and which projects through the lid at its upper end so as to be able to pierce the stopper of an air-evacuated tubular container. The container is also provided with a depressed bottom to assure the maximum collection of fluids and the lid is provided with a recess to accommodate the air-evacuated tube. And this device does not have anyway to simply collect and analyze the specimen in a single step while providing a way for the analyst to photocopy and or have the results recorded by an instrument independent of the device thereby removing subjective analysis.
[0022] None of the afore mentioned devices teach, illustrate or have anything in common with the present art, in fact all of the afore mentioned devices could be combined and still not produce the present device. Therefore, there is no chance that these devices could used as prior teachings of the present art.
[0023] While the prior art provides certain devices for the collection of fluids or other types of samples the prior art however suffers from a certain number of drawbacks.
[0024] The inflation, insertion, and closure of the prior art devices all require multiple steps and are not simple efficient method to collect and analyzed urine without the risk or contamination, spillage, or other problems. All of the prior art requires tedious and complex methods for use. For instance, the one prior requires that certain the cup be tilted prior to analysis increasing the risk of leakage and contamination as the specimen leaks out of the container. Another device requires the use of a plunger (syringe) for use and yet another requires the use of tilting and a plenum. These are just some, not all, of the limitations of the prior art.
[0025] The present device is designed for the analysis of biological specimens on site. That is to say the device can be used for the collection and analysis of the specimen within the container without removal of the specimen and without have to adjust the lid of the container, use a plunger, a plenum, or other multiple steps as required by the prior art. The specimen can be analyzed immediately at the point of collection or sent to the lab and tested the next day. The device can be used for long storage of a specimen before testing and/or for immediate analysis. This removes the risk of contamination, mislabeling, chain of custody, and cross over contamination and offers the added ability to copy results from any side of the collection device for recording of test results or the device can be easily read by an instrument providing a means of removing subjective analysis that is inherent the novel and inventive design of the present device.
SUMMARY OF THE INVENTION
[0026] The present invention is designed to advance the art of urine collection and on site (at the point of collection) analysis past the prior arts drawbacks and provide a collection and analyzing cup that is simple to use, requires minimal instruction, has the minimum number of parts, and is cost effective. Another object of the present invention is to provide a method that allows for an easily automated process and readable. This is to say that the device is designed to be copied from any of the three sides that the test device can be read from.
[0027] Correspondingly, another advantage of the present art is to provide a collection and analyzing device that will allow the user to collect the specimen in the cup, place the lid on the cup to prevent any biohazard accidents or contamination, analyze the specimen without having to further manipulate the cup like tilting, using a plunger, a plenum, etc. This is truly a one step process which is not currently known in the art.
[0028] It has been found that the foregoing objects of the present art are accomplished in accordance with this invention by providing a collection and analyzing cup that is designed to collect the specimen and immediately have the lid secured onto the top of the cup. The cup is designed for long term storage if necessary before and after analysis.
[0029] The present invention provides a method of specimen collection and analysis as defined above, and the method being characterized by the following steps:
a) collecting the specimen in the cup; b) placing the lid on the cup and closing; c) and recording the results of the analysis without the use of a plunger or the requirement of tilting the specimen by direct observation or photocopying the results.
[0033] Other aspects and advantages of the present invention appear more clearly from reading the following detailed description of the preferred embodiment of the invention, given by way of example and made with reference to the accompanying drawings. Such as the determination of exactly how the device works. A thorough search of the literature reveals no relative art resembling this technology; therefore, this invention is clearly a novel in creation, and is not obvious to anyone skilled in the art, in fact the prior art devices teaches away from the present art in that the prior art requires that the cup be tilted in order for the device to be used (this is not a requirement of the present device in fact the present device is a teaching of simplicity with no manipulation of the cup as a requirement) and the prior art devices teach away from the present device in that some prior art require that the lid be off the container to activate, and the prior art teaches away from the present device in that the prior teaches the use and requirement of a plenum which is a pressurized space, etc. The present device teaches the use of a chamber that does not require pressure and a stable pressure to a vacuum would actually be preferred. There are certain aspects of the present art that can be found in the prior art (e.g. the use of a cup) but no prior has advanced the art of specimen collection and analysis as much as the present art. This art solves an unrecognized problem that was never before even recognized. Specifically this allows for the user the unexpected results of using a device that is simple, efficient and cost effective that only utilizes a cup and activation device without the use of plungers, plenums, tilting, etc., for a much more effective and safe method of collection and analysis of a specimen which can be read and photocopied and analyzed by instruments which is inherently made possible by the novel design of the device.
[0034] The collection and assaying device, in accordance with the present device, for both collecting and analyzing specimens, includes a container (cup) having an opening for collection of the specimen and a chamber for storing the collected specimen. A cap provides a means for sealing the container opening and an assay means which, is not attached but integrated into the container providing for chemically analyzing the specimen. In addition, after a sample has been introduced into the device the results can be recorded by a photocopier or other means made possible by the unique design of the device.
[0035] The specimen can be a biological sample (urine, etc.) or other type of fluid.
[0036] It important that the means are provided for introducing a portion of the collected specimen within the chamber into the assay means when the cap is not on the container. However, this device and testing means does not require that the cap be in place. By placing the cap into position there is no requirement for removing the sample from the assaying device in order to conduct chemical analysis.
[0037] Therefore, the apparatus of the present device (invention) totally removes the need to transfer the collected sample from the device in order to conduct a chemical analysis as is the case with prior art devices. As mentioned this has a significant importance with regard to safety, biohazard, time, accuracy, ease of use and savings.
[0038] Additionally, one embodiment of the present device is particularly suitable for Infectious disease, Drugs of Abuse, Pregnancy, Urinalysis Testing of biological fluids which includes a convenient method for the photocopying of result. And, since the fluid specimen never leaves the device, if a positive test for HIV (infectious disease), or drug, etc., is indicated, the entire device may be removed or shipped to the laboratory or other facility for further or confirmation testing.
[0039] Additionally, the present device, the assay means may include chromatograph, thin layer chromatography and dry chemistry hybrid, dry chemistry test pads attached to lateral flow device or other material assay means integrated in the container for enabling direct visual observation of the assay results. Therefore, no additional steps are necessary for effecting an analysis of a biological specimen.
[0040] As mentioned above, the assaying means of the device in accordance with the present invention includes a means for preventing biological fluid from entering the assay means during the collection of the body as is the case with all prior art (as discussed with the plenum and the tilting as required by one particular art (note: this could happen with the prior art during collection the cup could be tilted while the specimen is entering the cup and the specimen goes directly into the plenum).
[0041] A wicking means may be provided but is not required for enabling the biological fluid to enter the assaying means or aid the assaying means in the movement of fluid from one end of the assaying means to the other.
[0042] The assaying means is integrated into the container sidewall (not bottom or top), and no activation means is required by the present art and is a limitation of the prior art.
[0043] The assaying means may contain a plurality of separated thin layer chromatograph strips with each strip comprising means for chemically analyzing the biological fluid for a different analyte, or chromatograph, or thin layer chromatography and dry chemistry hybrid, or dry chemistry test pads attached to lateral flow device or other material assay means.
[0044] And the assaying means may include a wick for evenly distributing the biological fluid to each of the assay means if more than one is present. The wick can be at both ends of the assaying means or at just one end of the assay means, or not present at all.
BRIEF DESCRIPTION OF THE DRAWINGS
[0045] Other objects, features and advantages of the invention will become obvious from the following detailed description of the invention when taken in conjunction with the accompanying drawings, in which:
[0046] FIG. 1 is a plan view of one embodiment of the Delta Cup made in accordance with this invention generally showing the container, activation device, and assaying means;
[0047] FIG. 1A-1E are plan view and cross section views of the assay means which are inserted into the slots in the Delta Cup in accordance with this invention generally showing the container, assay device, and assaying means;
[0048] FIG. 2 is a cross section view of FIG. 1 prior to placing the lid onto the container generally looking down into the container from the top;
[0049] FIG. 3 is a plan view of the Delta Cups lid which can be placed and snapped onto the top of the container;
[0050] FIGS. 4 and 4 A is a plan view of the Delta Cup with at least one flat side and cross section view of the lid for the single side cup which can be placed and snapped onto the top of the container.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0051] The present invention will now be described more fully with reference to the accompanying drawings, in which the preferred embodiments of the present art invention are shown. It is understood from the embodiments that a person skilled in the art may make variations and modifications without departing from the spirit and scope of the invention. Such as changing the size or shape of a Delta Cup, the optional addition of a wick, or the addition of a magnifying side wall to allow for easier reading and automation of the assaying mean results, the addition of more than one slot on one side of the Delta Cup. In such that the present arts cup is capable of having as many 15 to 20 slots for analysis of multiple assays simultaneously or the device could have just one slot for analysis on a single wall.
[0052] Referring now to the drawings and in particular FIGS. 1 , 1 A- 1 E, 2 , and 3 , there is shown an collection and assaying device which includes a container 10 , in accordance with the present invention. The device generally includes an opening 17 which provides a means for collecting the biological fluid and a chamber 32 which provides a means for storing the collected fluid.
[0053] The container 10 and assaying means as illustrated by FIG. 's 1 A- 1 E may be formed, or molded, from any suitable material such as plastic, polymers, etc., and may include a snap on lid 11 as illustrated in FIG. 3 at the top of the container 17 formed into the top 17 of the side walls 20 of the container and would be sized for accepting the lid 11 . The lid 11 when snapped onto the container 10 opening 16 . For typical biological collection to include urinalysis (UA), drug screening, clinical chemistry, pregnancy testing, etc., the typical container 10 capacity of about 100 to 150 mLs of liquid to accommodate split specimen requirement and additional testing.
[0054] The assaying means which may contain a plurality of separated thin layer chromatograph strips with each strip comprising means for chemically analyzing the biological fluid for a different analyte, or chromatograph, or thin layer chromatography and dry chemistry hybrid, or dry chemistry test pads attached to lateral flow device or other material assay means, as once such possible means is illustrated by FIGS. 1A-1E which can be inserted into the slots 13 of the Delta Cup.
[0055] The lateral flow device(s) hybrid (LFDH) that can be used in the Delta Cup takes the form of dry chemistry test pads that make up lateral flow hybrid devices that can be inserted into the Delta Cup slots 13 . The hybrid is composed of some or all of the following compounds: test pad (usually filter paper) impregnated with buffers, and reaction components that can include indicators, surfactants or other ingredients needed for the test pad to be reactive to a specific target analyte of interest, hereinafter referred to as the test pad. The lateral flow material can be composed of any form of absorbent, solid phase carrier that is capable of transporting a fluid and in some cases can be used as a support material. The LFDH in its simplest terms is a dry chemistry test pad chemically impregnated identically to the current art for dipsticks. The test pad is then placed in (direct) contact with lateral flow paper (such as nitrocellulose) or other suitable wicking material. This device is then exposed to a fluid (urine for example). The urine (or other fluid) then migrates to the location of the test pad, saturates the test pad, and the reaction takes place. In the case of the Delta Cup the devices are exposed to fluid from the bottom of the cup. Therefore the direction of the drops and arrows for illustrative purposes are from the bottom of the cup 18 towards the top 17 of the Delta Cup.
[0056] Referring now to FIG. 1A of the drawing, the liquid sample 1 is introduced from the bottom 18 of the Delta Cup illustrated as drops exposing in some manner to the sample introduction area 2 of the lateral flow material 3 . The sample 1 then migrates (as illustrated by the arrows) from the sample introduction area 2 to opposite end of the lateral flow material 4 to the top of the cup 17 . While the sample 1 is flowing from the sample introduction area 2 to the opposite end 4 of the lateral flow material 3 the chemically impregnated dipstick test pad 5 (which is in direct (fluid) contact 6 with the lateral flow material 3 ) will become saturated (acting as a wick) with the sample 1 . The chemical reaction will occur between the test pad 5 and the sample 1 producing a detectable response. FIG. 1B -E all function in relatively the same manner as FIG. 1A . The only functional difference in these illustrations from the device of FIG. 1A is that the lateral flow material 4 is placed onto the top edge of the chemically impregnated dipstick test pad 5 as shown in FIG. 1D or in fluid contact such as illustrated in FIG. 1E . Thus, when the fluid sample 1 reaches the edge of the dipstick test pad 5 , the test pad 5 becomes saturated with the sample 1 in the same manner as FIG. 1A and the chemical reaction takes place and a detectable response occurs. FIG. 1E again, also functions in the same manner as FIG. 1A-1D . The only functional difference in this device from that of FIG. 1A and FIG. 1E is that the lateral flow material 4 is placed next to the chemically impregnated dipstick test pad 5 (but, still in direct (fluid) contact 6 with the lateral flow material 3 ). All of the FIG. 's as shown function in the same novel and inventive manner. For instance, as shown in FIG. 1C multiple test pads 5 are in direct contact 6 with the lateral material 4 . As the fluid migrates from one pad to the next, no cross over from one test pad 5 to the next occurs, thus, preventing cross contamination. This has never been available, taught or eluded to in the prior art. This method also allows for a specific and constant amount of fluid to reach each pad, enhancing precision, accuracy, and specificity. As shown in detail in FIGS. 1 and 2 the slots 13 for inserting the assay means can be six to ten or more per side or there can simply be one slot 13 . It can be readily understood from the illustrations of the device that photocopying the device or reading the device using an instrument is made simple by the inherent design advantage of the present device. FIG. 3 illustrates the triangular shaped lid 11 that can be placed on the Delta Cup but is not required.
[0057] This detailed description as provided allows for a marked advance in the art of specimen collection, analysis and recording of results by photocopying. The present invention provides a method of specimen collection and analysis as defined above, and the method being characterized by the following steps:
a) collecting the specimen in the cup; b) placing the lid on the cup and closing; c) reading the result by direct observation, recording the results by photocopying the side(s) of the cup, or reading the results using an instrument.
[0061] The simplicity and novelty of the invention is unmatched in the art. This device could be easily automated and include a magnifying plastic lens that would increase visibility of the assay means results. An automation example would be to have an instrument reads the side of the container automatically and download the result to a computer. This invention is going to save the clinical diagnostic, drug of abuse testing, and other industries millions of dollars in analysis time, safety prevention and accident control, time (labor), and cost through the novel simplicity of the present invention.
[0062] To further explain the assaying device for collecting a fluid specimen and analyzing a portion of the sample, said device comprises a container means, having an opening, for collecting a specimen, and a chamber with flat side(s) (e.g. that is to say that the cup has at least one flat side), for storing said specimen. A cap means for sealing the container means opening and assay means, integrated into the said container means, for chemically analyzing said specimen, said assay means being positioned in the outside wall of the container means for enabling direct visual observation or photocopying thereof of the assay results. This device does not require the use of a plunger, tilting, pumping or other means. In other words the following is not required of the present art and can be excluded in the claims if necessary for instance the present art does not require the inflation, insertion, and closure of the device or require multiple steps as required by the prior art and the prior art are not simple efficient methods to collect and analyzed urine without the risk or contamination, spillage, or other problems. All of the prior art requires tedious and complex methods for use. For instance, the one prior requires that certain the cup be tilted prior to analysis increasing the risk of leakage and contamination as the specimen leaks out of the container. Another device requires the use of a plunger (syringe) for use and yet another requires the use of tilting and a plenum. These are just some, not all, of the limitations of the prior art.
[0063] The present device is designed for the analysis of biological specimens on site. That is to say the device can be used for the collection and analysis of the specimen within the container without removal of the specimen and without have to adjust the lid of the container, use a plunger, a plenum, or other multiple steps as required by the prior art. The specimen can be analyzed immediately at the point of collection or sent to the lab and tested the next day. The device can be used for long storage of a specimen before testing and/or for immediate analysis. This removes the risk of contamination, mislabeling, chain of custody, and cross over contamination and offers the added ability to copy results from any side of the collection device for recording of test results or the device can be easily read by an instrument providing a means of removing subjective analysis that is inherent the novel and inventive design of the present device. The assaying device of the present are wherein said device comprises a lateral flow means the allows fluid contact between the assay means and liquid introduced into the device. In addition the assaying device incorporates a means (e.g. such as a slot) that is integrated into the outside wall of the assay device that allows the assay means to be inserted into during manufacture of the device. Therefore this device is for collecting and analyzing a fluid specimen, assaying a portion of the fluid specimen comprising; containing means for collecting the said specimen; placing said specimen into said containing means; placing cap means for sealing onto the said container means; observing the assay means by direct observation, photocopying or analysis by instrumentation.
[0064] The invention has been described in detail with particular reference to a preferred embodiment and the operation thereof and it is understood that variations, modifications, and substitution of equivalent means can be effected and still remain within the spirit and scope of the invention. And all such modifications and variations are to be included within the scope of the invention as defined in the appended claims.
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The present invention is a device for assaying and collection of biological and other specimens and is especially designed for the collection and determination of the presence of chemical constituents in clinical chemistry, pregnancy, drugs of abuse testing, infectious disease testing, and other fields of analysis of fluids.
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BACKGROUND
Back pain is among the most common conditions for which patients seek medical care. More than 70 percent of adults suffer back pain or neck pain at some time in their lives. In the United States, medical treatment of back pain is estimated to cost $25 billion dollars annually. Workers compensation costs and time lost from work add another $25 billion.
Medical management is the first treatment choice. If there is no improvement in the patient's condition, surgery is often the next treatment of choice. Despite the uncertainty about how effective surgery is for patients, the number of fusion surgeries rose 127% from 1997 to 2004, to more than 303,000. Recent research demonstrates that even after two years patients treated conservatively are as well off as those treated surgically. Surgical costs are continuing to rise, as patients receive ever more aggressive treatments.
Recently, vertebral axial decompression therapy for the spine and discs has emerged as a frontline treatment for back pain. This is a non-surgical treatment for herniated discs, degenerative disc disease, posterior facet syndrome and failed back surgery. With traditional traction therapy, forces are applied in a linear fashion and the resultant muscle guarding prevents the discs from being decompressed. Paraspinal muscles are conditioned to oppose abrupt and linear changes in tension, but will relax if the force is applied in a smooth gradual manner whereby the rate is slowed progressively according to a logarithmic time scale.
It has been shown that tension forces to the spine applied in a ‘logarithmic’ time/force curve will decompress the discs and spine. Vertebral axial decompression is the only treatment that has been shown in clinical study to decrease the intervertebral disc pressure to negative levels and to decompress the lateral nerve roots that supply the legs.
While this known vertebral axial decompression therapy is advantageous, an improved vertebral decompression therapy would be desirable.
SUMMARY
A logarithmically increasing decompression force is applied to a spinal column in a progressively changing direction lying in the mid-sagittal plane. This allows the decompression force to be focused on selective vertebrae.
A table to achieve this decompression force has a fixed table section, a moveable table section, a vertically adjustable upstanding support supported by the moveable table section, an attachment point associated with the upstanding support for attachment to a harness; a first drive for extending the moveable table section from the fixed table section and for retracting the moveable table section toward the fixed table section, and a second drive for driving the upstanding support to different vertical positions.
Other features and advantages will be apparent from the following description in conjunction with the drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
In the figures which illustrate example embodiments of the invention,
FIG. 1 is a schematic side view of a vertebral decompression table made in accordance with this invention,
FIGS. 2 and 3 are perspective views of the table of FIG. 1 shown in use,
FIG. 4 is a perspective partial view of the table of FIG. 1 shown in use,
FIG. 5 is an exploded view of the cervical-head harness,
FIG. 6 is a side view of the cervical-head harness shown in FIG. 5 ,
FIG. 7 is an angled view of an integrated cervical-head harness and anchor strap assembly which may be used with the table of FIG. 1 ,
FIG. 8 is a screen shot from a computer display associated with the table of FIG. 1 ,
FIGS. 9 and 10 are schematic side partial view of the table of FIG. 1 illustrating its operation,
FIGS. 11 , 12 , 13 and 14 are force vector diagrams illustrating operation of the table of FIG. 1 ,
FIG. 15 is a schematic side view of a vertebral decompression table made in accordance with another embodiment of this invention, and
FIG. 16 is a schematic side view of a vertebral decompression table made in accordance with a further embodiment of this invention.
DETAILED DESCRIPTION
Turning to FIG. 1 , a vertebral decompression table 10 has a fixed table section 12 and a moveable table section 14 . The fixed table section 12 has a linear actuator 16 which may be activated to push the moveable table section 14 away from the fixed table section 12 or draw the moveable table section 14 toward the fixed table section 12 . The fixed table section also has a pair of handgrips 28 . A motor 29 controls the longitudinal position of these handgrips. The moveable table section has a reciprocating arm 18 which may be extended outwardly from the end 20 of the moveable table section 14 or retracted inwardly toward the end 20 of the moveable table section by a linear actuator 22 housed within the moveable table section. The base 26 of a vertically adjustable support 30 is joined to arm 18 . Base 26 houses a linear actuator 32 which may extend support 30 upwardly or retract support 30 downwardly.
A tensionometer-head 36 is pivotably attached to the vertically adjustable support 30 at horizontal pivot 38 so that the tensionometer-head may pivot up and down. The tensionometer-head 36 houses a tensionometer 40 with a protruding attachment 42 for attachment to a harness. The attachment may be a protruding metal tang with a central opening to connect to a seat-belt like buckle.
Each of linear actuators 16 , 22 , and 32 are operatively connected to a controller 46 . The controller 46 is input by the output of the tensionometer 40 and the output of positional encoders 17 , 23 , and 33 attached to each linear actuator 16 , 22 , and 32 , respectively. The controller is operatively connected to a personal computer 48 which is pivotably mounted to the fixed table section 12 on arm 50 .
Controller 46 , which may be a microprocessor, and computer 48 may be loaded with software from a computer readable media such as CD 84 .
Turning to FIG. 2 , a patient 60 may lie prone on table 10 , with feet facing tensionometer 40 . The patient wears a pelvic harness 62 with straps 64 attached to attachment 42 of the tensionometer. A suitable pelvic harness is described in U.S. Pat. No. 5,115,802 issued May 26, 1992, the contents of which are incorporated herein by reference. The patient's upper body may be restrained by wearing a thoracic restraint 66 attached to handgrips such that the handgrips act as mounts. Alternatively, or additionally, the patient may grip the handgrips 28 . Similarly, as shown in FIG. 3 , a patient 60 may lie in a supine position on table 12 with feet facing the tensionometer. As in the prone position, the patient may wear a pelvic harness attached to attachment 42 and a thoracic restraint 66 attached to handgrips 28 .
With reference to FIG. 4 , as a further alternative, the patient 60 may lie in a supine position on table 10 with their head facing tensionometer 40 . In this instance, the patient may wear a cervical-head harness 70 composed of a support collar 71 and anchor strap assembly attached to attachment 42 of the tensionometer 40 . In this orientation, there is no need to tether the body of the patient to the table because the decompression forces applied by the table to the head and neck are too low to overcome body weight.
The cervical-head harness 70 is detailed in FIGS. 5 , 6 , and 7 . Turning to these figures, collar 71 has a curved dorsal member 74 and a curved ventral member 76 . A strap 78 extends from each side of the dorsal member and is provisioned with hook fasteners. A loop fastener strap 79 is attached to each side of the ventral member. Thus, the dorsal and ventral members may be placed around the neck of a patient and the straps 78 , 79 connected with a hook-and-loop (VELCRO™) attachment. Many alternate arrangements for the cervical collar are possible. For example, a single piece flexible collar could be flexed to allow placement around the neck of a patient and then the free ends joined by straps to complete its attachment to a patient.
As part of the anchor strap assembly, a pair of straps 72 D extend from the dorsal member to a crossbar 80 and a second pair of straps 72 V extend from the ventral member to the crossbar. When the cervical collar is properly positioned, these straps extend on either side of the head of the patient with the dorsal member straps 72 D directly behind the ventral member straps 72 V. Also, with the collar properly positioned on the patient, the attachment connectors 75 V of the ventral straps 72 V lie below the patient's mandible and between the chin and the ear of the patient. The attachment connectors 75 D of the dorsal straps 72 D lie below the patient's occiput on each side. The straps 72 D, 72 V extend upwardly and slightly outward from their attachment points to the crossbar 80 . A main strap 77 M extends from the middle of the crossbar and terminates in a buckle 82 . The straps 72 D and 72 V are adjustable in length, and can be tightened or loosened independently by adjustable connectors 73 V and 73 D. The dorsal straps may be tightened more than the ventral straps in order to apply more force to the occiput of the head. Alternatively, the ventral straps may be tightened more than the dorsal straps in order to direct and apply more force to the patient's mandible. Straps may also be tightened or loosened from left side or right side, to direct the force more to one side.
Returning to FIG. 1 , with the patient tethered to the table 10 , the operator may enter via computer 48 a pre-tension, a maximum tension, a starting and ending height, a cycle time, the time to reach maximum tension (i.e., the time for the decompression phase), and the time to return to the pre-tension (i.e., the time for the retraction phase). Then, once the operator presses a start button, the controller will first control linear actuator 32 to adjust the height of the tensionometer-head 36 to match the entered starting height. Next, the controller 46 will operate linear actuator 22 to extend arm 18 in order to linearly increase the distracting tension on the patient's spine, up to the pre-tension. A tension feedback signal from the tensionometer 40 allows the controller to apply an appropriate drive signal to the linear actuator 22 to achieve this result. With lumbar treatments, when the pre-tension has been achieved, the controller may then activate both linear actuator 16 in order to increase the separation of the table halves and linear actuator 32 in order to move the tensionometer-head 36 vertically. These movements are controlled so that the tensionometer-head moves in an arc toward the specified ending height and so that the tension on the patient's spine logarithmically increases to the specified maximum tension. After reaching the maximum tension, the controller controls linear actuators 16 and 32 to move the tensionometer-head in the same arc back to its initial position in a retraction phase in order to reduce the tension logarithmically to the pre-tension. Indeed, as the head 36 returns to its initial position; the tension may begin to fall below the desired pre-tension and so, the controller controls linear actuator 22 in order to maintain the desired pre-tension at the end of the retraction phase. The controller may then repeat the cycle to maximum force and back to pre-tension. Once a specified number of cycles have been completed, the controller, after a rest phase at the pre-tension, releases the pre-tension.
As the table operates, the computer 48 may display a tension versus time curve as shown in FIG. 8 . Turning to FIG. 8 , curve segment 90 shows the linear increase in the tension to the pre-tension amount. Following a short rest segment 92 at the pre-tension level, segment 94 shows the tension increasing logarithmically to the maximum tension at point 96 . Segment 98 shows the tension thereafter logarithmically decreasing back to the pre-tension amount. After a rest period, a new cycle commences. The computer may also display the current height of the tensionometer-head 36 above the plane of the table with bar 102 .
The tensionometer provides a mechanism for registering the reaction of the spinal column structures as the distraction tension is applied progressively along the spinal column. Reactions such as release of facets, myofascial strictures, and/or compressive lesions register immediately as irregularities or deviations in an otherwise smooth display captured in the displayed time versus tension curve. The controller quickly adjusts so that the reactions register as brief irregularities.
If the starting height is lower than the ending height, the arc followed by the tensionometer-head 36 will be an ascending arc, as shown in FIG. 9 at 110 . If the starting height is higher than the ending height, the arc followed by the tensionometer-head 36 will be a descending arc, as shown in FIG. 10 at 112 . Notably, as seen in FIG. 9 , the tensionometer-head 36 pivots so that the attachment point 42 always aligns with the patient. This ensures that the tensionometer will accurately measure the applied tension. The display of FIG. 8 may also indicate whether the arc is ascending or descending. In particular, FIG. 8 illustrates at 104 a descending arc.
As shown in FIG. 11 , the patient's spine has cervical vertebrae C, thoracic vertebrae T, and a lumbar vertebrae L. With a patient lying prone on table 10 and tethered to the tensionometer-head 36 of the table, with a pelvic harness 62 as shown in FIG. 2 , FIG. 11 shows the ascending force vectors 120 a , 120 b , 120 c , 120 d , 120 e progressively applied to the patient's spine 122 during logarithmic tension increase where the tensionometer-head 36 follows an ascending arc 123 . FIG. 12 shows the descending force vectors 130 a , 130 b , 130 c , 130 d , 130 e progressively applied to the patient's spine during logarithmic tension increase where the tensionometer-head 36 follows a descending arc 131 . It will be apparent that these force vectors lie in the mid-sagittal plane of the patient and, with the table top horizontal, this mid-sagittal plane will be a vertical plane.
The progressively ascending and increasing force illustrated in FIG. 11 (applied to the spine of a person in the prone position) tends to increase the lordotic curvature of the lumbar spine L on an anterior/posterior plane and so the lumbar spine is progressively extended as the direction of the force progressively inclines. Anatomical, physical dynamics tend to apply the force, as its direction progressively ascends, progressively higher along the lumbar spine, i.e., toward the L1 vertebra. This may be seen by recognising that the direction of the force is initially misaligned with the predominant line of the lumbar spine. In consequence, the force is applied more heavily toward the base of the lumbar spine, i.e., toward L5. As the direction of the force ascends, the direction lies progressively closer to the predominant line of the lumbar spine. With the force more aligned with the lumbar spine, the force is applied more evenly to each lumbar vertebra and hence more of the force reaches the upper lumbar vertebrae. This ascending change in vectors targets vertebral segments higher in the lumbar vertebral chain. The extending force will apply more force at the anterior border of the annulus and so may open disc spaces higher in the lumbar chain anteriorly.
FIG. 12 illustrates (the spine of a person in the prone position and) the situation where the direction of the force progressively descends while the magnitude of the force increases. This tends to decrease the lordotic curvature of the lumbar spine; thus the lumbar spine is progressively flexed as the direction of the force descends. Anatomical, physical dynamics (as the force becomes progressively more mis-aligned with the predominant line of the lumbar spine) tend to apply this changing force progressively lower along the lumbar spine, i.e., toward the L5 vertebra. The flexing force will apply more force at the posterior border of the annulus and so may open disc spaces lower in the lumbar chain posteriorly.
If the patient were lying in a supine position on table 10 and tethered to the tensionometer-head 36 of the table 10 with a pelvic harness 62 as shown in FIG. 3 , applying a progressively greater, progressively more upwardly directed forces progressively flexes the lumbar spine. Anatomical, physical dynamics tend to apply this changing force progressively lower along the lumbar spine. On the other hand, with the patient tethered to the table in this manner, applying a progressively greater, progressively more downwardly directed force progressively extends the lumbar spine and anatomical, physical dynamics tend to apply this changing force progressively higher along the lumbar spine.
With a patient lying in a supine position on table 10 and tethered to the tensionometer-head 36 of the table 10 with a cervical-head harness 70 as shown in FIG. 4 , FIG. 13 shows the ascending force vectors 140 a , 140 b , 140 c , 140 d progressively applied to the patient's spine during logarithmic tension increase where the tensionometer-head 36 follows an ascending arc 142 . During cervical spine treatments, the use of a full ascending curve (arc) progressively flexes the cervical spine from C2-C3 to C7-T1 as the tension increases gradually.
FIG. 14 shows the force vectors 150 a , 150 b , 150 c , 150 d progressively applied to the patient's spine during logarithmic tension increase where the tensionometer-head 36 follows a descending arc 152 . These force vectors lie in the mid-sagittal plane of the patient and, with the table top horizontal, this mid-sagittal plane will be a vertical plane.
The progressively directionally ascending and strengthening force illustrated in FIG. 13 progressively pulls and rotates the cervical spine in flexion and so tends to decrease the lordotic curvature of the cervical spine C on an anterior/posterior plane. During application of this force, the thoracic spinal chain is essentially immobile due to the connections of the thoracic spine to the rib cage. Anatomical, physical dynamics tend to apply the force, as its direction progressively ascends (and the cervical vertebrae chain is progressively “straightened out”), progressively lower along the cervical spine, i.e., toward the C7 vertebra.
A downward dynamic curve as shown in FIG. 14 pulls and rotates the cervical spine and patient's head in extension. This will tend to increase the curvature of the cervical spine. Anatomical, physical dynamics tend to apply the force, as its direction progressively descends, progressively higher along the cervical spine.
The logarithmic distraction force decompresses the spinal column and hence is a decompression force. Because changing the direction of the force changes which vertebrae are most exposed to the force, judicious selection of the starting height and ending height of the tensionometer-head 36 (and therefore the final direction of the force) allows a decompressive force to be selectively focused on different vertebral segments of the cervical or lumbar spine. This is in contrast to known tables which linearly apply a distraction force to the spine; with these known tables, the distracting force will be applied more or less evenly along the vertebral chain. In another mode of operation, table 10 may apply a logarithmic or linearly increasing uni-directional force by selecting a fixed vertical height of adjustable support 30 .
A suitable function for time versus tension for the logarithmic decompression phase is described in U.S. Pat. No. 6,039,737 issued Mar. 21, 2000, the contents of which are incorporated herein by reference. The same function may be used for the logarithmic tension retraction phase [0039] Turning to FIG. 15 , where like parts have been given like reference numerals, vertebral decompression table 200 differs from the table 10 of FIG. 1 in that linear actuator 22 and its arm 18 are omitted and the base 26 of vertically adjustable support 30 is joined directly to the moveable table section 14 . With this arrangement, linear actuator 16 is used to separate the table halves to establish and maintain a pre-tension and as well, linear actuator 16 , along with linear actuator 32 , operate, under control of controller 46 , to produce the logarithmic directionally changing forces hereinbefore described.
Turning to FIG. 16 , where like parts have been given like reference numerals, a vertebral decompression table 300 differs from the table 10 of FIG. 1 in two respects: firstly, linear actuator 22 and its arm 18 are omitted and, secondly, linear actuator 16 is provisioned with a reciprocating arm 318 which extends through the moveable table section 14 to join to the base 26 of vertically adjustable support 30 . With this arrangement, the controller 46 controls the linear actuator 16 to apply a pre-tension and then controls both linear actuator 16 and 32 to apply the aforedescribed logarithmic directionally changing forces. In doing so, moveable table section 14 may passively slide with the patient. With this embodiment, it would be possible to provide a table which has no moveable section, but this would have the drawback that the table would then frictionally engage the patient and distort the applied forces.
While the table has been described with linear actuators as drives, obviously any other controllable drive may be substituted as, for example, hydraulic cylinders and/or belt drives and/or pulleys.
While the retraction phase has been described as a logarithmic phase, alternatively, tension could be released linearly rather than logarithmically.
Other modifications will be apparent to those skilled in the art and, therefore, the invention is defined in the claims.
|
A logarithmically increasing decompression force is applied to a spinal column in a progressively changing direction lying in the mid-sagittal plane. This focuses the decompression force as compared with a straight-line pull. A table to achieve this decompression force has a fixed table section, a moveable table section, a reciprocating arm which acts as a movable pre-tension section, a vertically adjustable upstanding support supported by the pre-tension section, an attachment point attached to a tensionometer-head associated with the upstanding support for attachment to a harness, a moveable table section drive for extending the moveable table section from the fixed table section and for retracting the moveable table section toward the fixed table section, a reciprocating arm drive for extending and retracting the reciprocating arm from the movable table section, and an upstanding support drive for driving the upstanding support to different vertical positions.
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STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
This invention was made with government support under Contract Number DE-FG36-05G01 5015 between Air Products and Chemicals, Inc. and the U.S. Department of Energy. The Government has certain rights to this invention.
CROSS REFERENCE TO RELATED APPLICATIONS
This application is related to commonly assigned application having U.S. Ser. No. 10/833,484 and a filing date of Apr. 27, 2004, the subject matter of which is incorporated by reference.
BACKGROUND OF THE INVENTION
Hydrogen fueled vehicles, sometimes referred to as the Freedom Car are receiving considerable interest as part of a plan to reduce the reliance on foreign oil and reduce pollution. There are several current designs of hydrogen cars, with one example being a fuel cell powered vehicle commonly called an FCV. In the FCV, hydrogen is supplied to a fuel cell which produces electricity, which is used to power electric motors that propel the vehicle. Another type of hydrogen car is based upon a hydrogen internal combustion engine (HICE). In both designs, hydrogen is the fuel source with water being generated as the combustion byproduct.
A central issue with respect to both types of hydrogen vehicles, i.e., the FCV and HICE vehicles, is one of fuel supply. Not only is there a large infrastructure required for hydrogen dispensation, if one considers all the service stations, production and distribution equipment that are required, but there are issues with respect to fuel handling and use of the fuel on the vehicle itself. Before there can be a progression to dedicated fuel cell propulsion systems and hydrogen internal combustion engines, one must foresee a fuel infrastructure.
Two sources of hydrogen for use in hydrogen cars include the reforming of natural gas (fossil fuels) or from water using electrolysis. Once hydrogen gas is generated it must be stored for subsequent filling of cars or converted into a liquid fuel. Storage of hydrogen gas requires compression and transfer to a cylinder storage vessel. And, if the gaseous hydrogen is stored on the vehicle, such storage cylinders are expensive and they can represent a possible safety hazard in the case of an accident. Alternatively, hydrogen can be stored under low pressure in metal hydride canisters, but, at present, hydride canisters are a lot more expensive than cylinders.
Liquid methanol and other alcohols have been touted as particularly attractive hydrogen sources because they can be catalytically converted over a catalyst allowing pure hydrogen to be released on demand. On site conversion of liquid fuels to gaseous hydrogen overcomes the disadvantages of gaseous storage. Further, fuels such as methanol, and other alcohols are not overly expensive and there is an infrastructure in place today that allows for handling of liquid fuels. Although methanol and alcohols are suitable as a fuel source, they are consumed in the combustion process. In addition, the byproducts of such catalytic conversion, carbon dioxide and water, cannot easily be converted back to a hydrogen source.
Representative patents illustrating hydrogen storage and use are as follows:
Hydrogen Generation by Methanol Autothermal Reforming In Microchannel Reactors , Chen, G., et al, American Institute of Chemical Engineers, Spring Meeting, Mar. 30-Apr. 3, 2003 pages 1939-1943 disclose the use of a microchannel reactor as a means for conducting the endothermic steam-reforming reaction and exothermic partial oxidation reaction. Both reactions are carried out in the gas phase.
Scherer, G. W. et al, Int. J. Hydrogen Energy,1999, 24,1157 disclose the possibility of storing and transporting hydrogen for energy storage via the catalytic gas phase hydrogenation and the gas phase, high temperature, dehydrogenation of common aromatic molecules, e.g., benzene and toluene.
US 2004/0199039 discloses a method for the gas phase dehydrogenation of hydrocarbons in narrow reaction chambers and integrated reactors. Examples of hydrocarbons for dehydrogenation include propane and isobutane to propylene and isobutene, respectively. Reported in the publication are articles by Jones, et al, and Besser, et al, who describe the gaseous dehydrogenation of cyclohexane in a microreactor. Jones, et al employ a reported feed pressure of 150 kPa and an exit pressure of 1 Pa.
U.S. Pat. No. 6,802,875 discloses a hydrogen supply system for a fuel cell which includes a fuel chamber for storing a fuel such as isopropyl alcohol, methanol, benzene, methylcyclohexane, and cyclohexane, a catalytic dehydrogenation reactor, a gas-liquid separation device wherein byproduct is liquefied and separated from the gaseous dehydrogenation reaction product, and a recovery chamber for the hydrogen and dehydrogenated byproduct.
BRIEF SUMMARY OF THE INVENTION
The present invention provides an improved process for the storage and delivery of hydrogen by the reversible hydrogenation/dehydrogenation of an organic compound wherein the organic compound initially is in its fully or partially hydrogenated state. It is subsequently catalytically dehydrogenated and the reaction product comprised of hydrogen and byproduct dehydrogenated or partially dehydrogenated organic compound is recovered. The improvement in a route to generating hydrogen via dehydrogenation of the organic compound and recovery of the dehydrogenated or partially dehydrogenated organic compound resides in the following steps:
introducing a hydrogenated organic compound, typically a hydrogenated substrate which forms a pi-conjugated substrate on dehydrogenation, to a microchannel reactor incorporating a dehydrogenation catalyst; effecting dehydrogenation of said hydrogenated organic compound under conditions whereby said hydrogenated organic compound is present in a liquid phase; generating a reaction product comprised of a liquid phase dehydrogenated organic compound and gaseous hydrogen; separating the liquid phase dehydrogenated organic compound from gaseous hydrogen; and, recovering the hydrogen and liquid phase dehydrogenated organic compound.
Significant advantages can be achieved by the practice of the invention and these include:
an ability to carry out the dehydrogenation of a liquid organic compound and generate hydrogen at desired delivery pressures; an ability to carry out dehydrogenation under conditions where the liquid organic fuel source and dehydrogenated liquid organic compound remain in the liquid phase, thus eliminating the need to liquefy or quench the reaction byproduct; an ability to employ extended pi-conjugated substrates as a liquid organic fuel of reduced volatility in both the hydrogenated and dehydrogenated state, thus easing the separation of the released hydrogen for subsequent usage; an ability to carry out dehydrogenation under conditions where there is essentially no entrainment of the hydrogenated organic compound such as the hydrogenated pi-conjugated substrate fuel source and dehydrogenated reaction product in the hydrogen product; an ability to carry out dehydrogenation in small-catalytic reactors suited for use in motor vehicles; an ability to generate hydrogen without the need for excessively high temperatures and pressures and thereby reduce safety concerns; and an ability to use waste heat from the fuel cell or an IC engine for liberating the hydrogen.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a flow diagram of a dehydrogenation process for producing hydrogen from a liquid fuel while maintaining the liquid fuel and dehydrogenated byproduct in liquid phase.
DETAILED DESCRIPTION OF THE INVENTION
In the process described herein, the fuel source is an organic compound which can be catalytically dehydrogenated forming carbon-carbon unsaturated bonds under liquid phase conditions at modest temperatures. The fuel source can further be described as one that has a low vapor pressure in order to avoid entrainment and loss of liquid fuel in the hydrogen product. Preferably, the vapor pressure is less than 10 millimeters mercury at 200 ° C.
In copending application U.S. Ser. No. 10/833,484 having a filing date of Apr. 27, 2004 which has been incorporated by reference, Pi-conjugated (often written in the literature using the Greek letter π) several molecules are suggested as fuel sources of hydrogen which are in the form of liquid organic compounds. These Pi-conjugated substrates are characteristically drawn with a sequence of alternating single and double bonds. In molecular orbital theory, the classically written single bond between two atoms is referred to as a σ-bond, and arises from a bonding end-on overlap of two dumbbell shaped “p” electron orbitals. It is symmetrical along the molecular axis and contains the two bonding electrons. In a “double” bond, there is, in addition, a side-on overlap of two “p” orbitals that are perpendicular to the molecular axis and is described as a pi-bond (or “Π-bond”). It also is populated by two electrons but these electrons are usually less strongly held, and more mobile. The consequence of this is that these pi-conjugated molecules have a lower overall energy, i.e., they are more stable than if their pi-electrons were confined to or localized on the double bonds.
The practical consequence of this additional stability isthat hydrogen storage and delivery via catalytic hydrogenation/dehydrogenation processes are less energy intensive and can be carried out at mild temperatures and pressures. This is represented by the following. The most common highly conjugated substrates are the aromatic compounds, benzene and naphthalene. While these can be readily hydrogenated at, e.g., 10-50 atm. at H 2 at ca 150° C. in the presence of appropriate catalysts, extensive catalytic dehydrogenation of cyclohexane and decahydronaphthalene (decalin) at atmospheric pressure is only possible at excessively high temperatures leading to gas phase conditions.
For the purposes of this description regarding suitable organic compounds suitable as hydrogen fuel sources, “extended pi-conjugated substrates” are defined to include extended polycyclic aromatic hydrocarbons, extended pi-conjugated substrates with nitrogen heteroatoms, extended pi-conjugated substrates with heteroatoms other than nitrogen, pi-conjugated organic polymers or oligomers, ionic pi-conjugated substrates, pi-conjugated monocyclic substrates with multiple nitrogen heteroatoms, pi-conjugated substrates with at least one triple bonded group and selected fractions of coal tar or pitch that have as major components the above classes of pi-conjugated substrates, or any combination of two or more of the foregoing.
In one embodiment, the pi-conjugated substrates have a standard enthalpy change of hydrogenation, |ΔH H2 o |, to their corresponding saturated counterparts (e.g., the at least partially hydrogenated extended pi-conjugated substrates) of less than about 20 kcal/mol H 2 and generally less than 15.0 kcal/mol H 2 . This value can be determined by combustion methods or by the ab initio DFT method. For purposes of the hydrogenation/dehydrogenation cycle to store and release hydrogen and to re-hydrogenate the substrate, the extended pi-conjugated substrate may exist and be cycled between different levels of full or partial hydrogenation and dehydrogenation as to either the individual molecules or as to the bulk of the substrate, depending upon the degree of conversion of the hydrogenation and dehydrogenation reactions.
The liquid phase pi-conjugated substrates useful according to this invention may also have various ring substituents, such as -n-alkyl, -branched-chain alkyl, -alkoxy, -nitrile, -ether and -polyether, which may improve some properties such as reducing the melting temperature of the substrate while at the same time not adversely interfering with the hydrogenation/dehydrogenation equilibrium. Preferably, any of such substituent groups would have 12 or less carbons. As discussed below in the section on “Pi-conjugated Substrates with Multiple Nitrogen Heteroatoms” alkyl substituents (and it's expected that also alkoxy substituents) will actually favorably slightly lower the modulus of the heat of hydrogenation, ΔH H2 o .
Extended Pi-Conjugated Substrates
Classes of extended pi-conjugated substrates suitable for the processes of this invention are further and more specifically defined as follows:
Extended Polycyclic Aromatic Hydrocarbons (EPAH). For the purposes herein, “extended polycyclic aromatic hydrocarbons” are defined to be those molecules having either (1) a polycyclic aromatic hydrocarbon comprising a fused ring system having at least four rings wherein all rings of the fused ring system are represented as 6-membered aromatic sextet structures; or (2) a polycyclic aromatic hydrocarbon of more than two rings comprising a six-membered aromatic sextet ring fused with a 5-membered ring.
The EPAH molecules represent a particular class of extended pi-conjugated substrates since their pi electrons are largely delocalized over the molecule. While, on a thermodynamic basis, generally preferred are the larger molecules (i.e., those with considerably more than four rings), the value of the standard enthalpy change of hydrogenation, ΔH H2 o , and thus the ease of reversible hydrogenation can be very dependent on the “external” shape or structure of the EPAH molecule. Fundamentally, the EPAH molecules that have the highest aromatic resonance stabilization energy will have the lowest modulus (absolute value) of the standard enthalpy of hydrogenation, ΔH H2 o . As is taught by E. Clar in “Polycyclic Hydrocarbons” Academic Press, 1964, Chapter 6, it is a general principle that the stability of isomers of fused ring substrates increases with the number of aromatic sextets. For instance anthracene
has one aromatic sextet (conventionally represented by three alternating single and double bonds in a single ring or by an internal circle), as for benzene, while phenanthrene,
has two aromatic sextets, with the result that phenanthrene is more stable by 4.4 kcal/mol (based on the molecules' relative heats of formation).
For an EPAH of a given number of fused-rings the structural isomer that is represented with the largest number of aromatic sextets and yet remain liquid at reaction temperatures will be preferred as a hydrogenation/dehydrogenation extended pi-conjugated substrate. Non-limiting examples of polycyclic aromatic hydrocarbons or derivatives thereof particularly useful as a fuel source include pyrene, perylene, coronene, ovalene, picene and rubicene.
EPAH's comprising 5-membered rings are defined to be those molecules comprising a six-membered aromatic sextet ring fused with a 5-membered ring. Surprisingly, these pi-conjugated substrates comprising 5-membered rings provide effective reversible hydrogen storage substrates since they have a lower modulus of the ΔH o of hydrogenation than the corresponding conjugated system in a 6-membered ring. The calculated (PM3) ΔH o for hydrogenation of three linear, fused 6-membered rings (anthracene) is −17.1 kcal/mol H 2 . Replacing the center 6-membered ring with a 5-membered ring gives a molecule (fluorene, C 13 H 10 )
Non-limiting examples of fused ring structures having a five-membered ring include fluorene, indene and acenanaphthylene.
Extended polycyclic aromatic hydrocarbons can also include structures wherein at least one of such carbon ring structures comprises a ketone group in a ring structure and the ring structure with the ketone group is fused to at least one carbon ring structure which is represented as an aromatic sextet. Introducing a hydrogenable ketone substituent into a polyaromatic substrate with which it is conjugated, acceptable heats and hydrogen storage capacities are achievable. Thus for the pigment pyranthrone,
having a standard calculated enthalpy of hydrogenation is −14.4 kcal/mol H 2 .
Extended Pi-conjugated Substrates with Nitrogen Heteroatoms can also be used as a fuel source. Extended pi-conjugated substrates with nitrogen heteroatoms are defined as those N-heterocyclic molecules having (1) a five-membered cyclic unsaturated hydrocarbon containing a nitrogen atom in the five membered aromatic ring; or (2) a six-membered cyclic aromatic hydrocarbon containing a nitrogen atom in the six membered aromatic ring; wherein the N-heterocyclic molecule is fused to at least one six-membered aromatic sextet structure which may also contain a nitrogen heteroatom.
It has been observed that the overall external “shape” of the molecule can greatly affect the standard enthalpy of hydrogenation, ΔH o . The N heteroatom polycyclic hydrocarbons that contain the greatest number of pyridine-like aromatic sextets will be the most preferred structure and have the lowest modulus of the standard enthalpy of hydrogenation ΔH H2 o structures. The incorporation of two N atoms in a six membered ring (i.e., replacing carbons) provides an even further advantage, the effect on ΔH H2 o depending on the nitrogens' relative positional substitution pattern. A particularly germane example is provided by 1,4,5,8,9,12-hexaazatriphenylene, C 18 H 6 N 6 ,
and its perhydrogenated derivative, C 12 H 24 N 6 system
for which the (DFT calculated) ΔH H2 o of hydrogenation is −11.5 kcal/mol H 2 as compared to the (DFT calculated) ΔH H2 o of hydrogenation of −14.2 kcal/mol H 2 for the corresponding all carbon triphenylene, perhydrotriphenylene system. Another representative example is pyrazine[2,3-b]pyrazine:
where the (DFT calculated) of ΔH H2 o of hydrogenation is −12.5 kcal/mol H 2 .
Pi-conjugated aromatic molecules comprising five membered rings substrate classes identified above and particularly where a nitrogen heteroatom is contained in the five membered ring provide the lowest potential modulus of the ΔH H2 o of hydrogenation of this class of compounds and are therefore effective substrates for dehydrogenation in a microchannel reactor under liquid phase conditions according to this invention. Non-limiting examples of polycyclic aromatic hydrocarbons with a nitrogen heteroatom in the five-membered ring fitting this class include the N-alkylindoles such as N-methylindole, 1-ethyl-2-methylindole; N-alkylcarbazoles such as N-methylcarbazole and N-propylcarbazole; indolocarbazoles such as indolo[2,3-b]carbazole; and indolo[3,2-a]carbazole; and other heterocyclic structure with a nitrogen atom in the 5- and -6-membered rings such as N,N′,N″-trimethyl-6,11-dihydro-5H-diindolo[2,3-a:2′,3′-c]carbazole, 1,7-dihydrobenzo[1,2-b:5,4-b′]dipyrrole, and 4H-benzo[def]carbazole.
Extended pi-conjugated substrates with nitrogen heteroatoms can also comprise structures having a ketone group in the ring structure, wherein the ring structure with the ketone group is fused to at least one carbon ring structure which is represented as an aromatic sextet. An example of such structure is the molecule flavanthrone, a commercial vat dye,
a polycyclic aromatic that contains both nitrogen heteroatoms and keto groups in the ring structure, and has a favorable (PM3 calculated) ΔH o of hydrogenation of −13.8 kcal/mol H 2 for the addition of one hydrogen atom to every site including the oxygen atoms.
Extended Pi-conjugated Substrates with Heteroatoms other than Nitrogen can also be used as a fuel source and for purposes of this description “extended pi-conjugated substrates with heteroatoms other than nitrogen” are defined as those molecules having a polycyclic aromatic hydrocarbon comprising a fused ring system having at least two rings wherein at least two of such rings of the fused ring system are represented as six-membered aromatic sextet structures or a five-membered pentet wherein at least one ring contains a heteroatom other than nitrogen. An example of an extended pi-conjugated substrate with an oxygen heteroatom is dibenzofuran, C 12 H 8 O,
for which the (DFT calculated) ΔH H2 o of hydrogenation is −13.5 kcal/mol H 2 . An example of a extended pi-conjugated substrate with a phosphorous heteroatom is phosphindol-1-ol:
An example of a extended pi-conjugated substrate with a silicon heteroatom is silaindene:
An example of a extended pi-conjugated substrate with a boron heteroatom is borafluorene:
Non-limiting examples of extended pi-conjugated substrates with heteroatoms other than nitrogen include dibenzothiophene, 1-methylphosphindole, 1-methoxyphosphindole, dimethylsilaindene, and methylboraindole.
Pi-conjugated Organic Polymers and Oligomers Containing Heteroatoms can also be used as a fuel source. For the purposes of this description the, “pi-conjugated organic polymers and oligomers containing heteroatoms” are defined as those molecules comprising at least two repeat units and containing at least one ring structure represented as an aromatic sextet of conjugated bonds or a five membered ring structure with two double bonds and a heteroatom selected from the group consisting of boron, nitrogen, oxygen, silicon, phosphorus and sulfur. Oligomers will usually be molecules with 3-12 repeat units. While there are often wide variations in the chemical structure of monomers and, often, the inclusion of heteroatoms (e.g., N, S, O) replacing carbon atoms in the ring structure in the monomer units, all of these pi-conjugated polymers and oligomers have the common structural features of chemical unsaturation and an extended conjugation. Generally, while the molecules with sulfur heteroatoms may possess the relative ease of dehydrogenation, they may be disfavored in fuel cell applications because of the potential affects of the presence of trace sulfur atoms.
The chemical unsaturation and conjugation inherent in this class of polymers and oligomers represents an extended pi-conjugated system, and thus these pi-conjugated polymers and oligomers, particularly those with nitrogen or oxygen heteroatoms replacing carbon atoms in the ring structure, are a potentially suitable substrate for hydrogenation. These pi-conjugated organic polymers and oligomers may comprise repeat units containing at least one aromatic sextet of conjugated bonds or may comprise repeat units containing five membered ring structures. Aromatic rings and small polyaromatic hydrocarbon (e.g., naphthalene) moieties are common in these conducting polymers and oligomers, often in conjugation with heteroatoms and/or olefins. For example, a heteroaromatic ladder polymer or oligomer containing repeat units such as:
which contains a monomer with a naphthalene moiety in conjugation with unsaturated linkages containing nitrogen atoms.
A pi-conjugated polymer or oligomer formed from a derivatised carbazole monomer repeat unit,
can also be used as a fuel source. Other oligomers that contain 5-membered ring structures with nitrogen atoms are also subject of the present invention. For example, oligomers of pyrrole such as:
which has four pyrrole monomers terminated by methyl groups has an ab initio DFT calculated ΔH H2 o of hydrogenation of −12.5 kcal/mol H 2 . Other members of this class of pi-conjugated organic polymers and oligomers which are particularly useful according to this invention as extended pi-conjugated substrates are polyindole, polyaniline, poly(methylcarbazole), and poly(9-vinylcarbazole).
Ionic Pi-conjugated Substrates can also be used as fuel source, i.e., a hydrogen source. These ionic pi-conjugated substrates are defined as those substrates having pi-conjugated cations and/or anions that contain unsaturated ring systems and/or unsaturated linkages between groups. Pi-conjugated systems which contain a secondary amirie function, HNR 2 can be readily deprotonated by reaction with a strong base, such as lithium or potassium hydride, to yield the corresponding lithium amide or potassium amide salt. Examples of such systems include carbazole, imidazole and pyrrole and N-lithium carbazole. Non-limiting examples of ionic pi-conjugated substrates include N-lithiocarbazole, N-lithioindole, and N-lithiodiphenylamine and the corresponding N-sodium, N-potassium and N-tetramethylammonium compounds.
Pi-conjugated monocyclic substrates with multiple nitrogen heteroatoms are another form of hydrogen fuel source. For the purposes of this description “pi-conjugated monocyclic substrates with multiple nitrogen heteroatoms” are defined as those molecules having a five-membered or six-membered aromatic ring having two or more nitrogen atoms in the aromatic ring structure, wherein the aromatic ring is not fused to another aromatic ring. The pi-conjugated monocyclic substrates with multiple nitrogen heteroatoms may have alkyl, N-monoalkylamino and N, N-dialkylamino substituents on the ring. A non-limiting example of a pi-conjugated monocyclic substrates with multiple nitrogen heteroatoms is pyrazine.
Pi-conjugated substrates with triply bonded groups can be used as a fuel source. For the purposes of this description, “pi-conjugated substrates with triply bonded groups” are defined as those molecules having carbon-carbon and carbon-nitrogen triple bonds. The pi-corijugated molecules described thus far comprise atom sequences conventionally written as alternating carbon-carbon single, and carbon-carbon double bonds, i.e., C—C═C—C═C— etc., incorporating, at times, carbon-nitrogen double bonds, i.e., imino groups as in the sequence, C—C═N—C═C—.
An illustration is provided by 1,4-dicyanobenzene:
which can be reversibly hydrogenated to 1,4-aminomethyl cyclohexane:
The enthalpy for this reaction, ΔH H2 o , is −6.4 kcal/mol H 2 . Table 1a. provides representative extended polycyclic aromatic hydrocarbon substrates, some of which can be used as a liquid hydrogen fuel source or converted to a liquid by incorporating substituents groups such as alkyl groups on the substrate and relevant property data therefor. Comparative data for benzene (1), naphthalene (2, 3), anthracene (46) and phenanthrene (47).
TABLE 1a
Substrate
ΔH° H2 (300 K)
ΔH° H2 (298 K)
T 95% ° C.
T 95% ° C.
Number
Substrate Structure
(cal.)
(exp.)
(cal.)
(exp.)
1
−15.6
−16.42
319
318
2 a
−15.1
−15.29
244
262
3 b
−15.8
−15.91
273
280
6
−14.6
226
7
−13.0
169
22
−13.9
206
26
−52.2
27
−17.9
333
28
−14.4
223
31
−14.1
216
34
−14.2
216
46
−15.8
271
47
−14.8
237
a Heat of hydrogenation to form cis/decalin.
b Heat of hydrogenation to form the trans-decalin.
Table 1b shows extended pi-conjugated substrates with nitrogen heteroatoms some of which may be liquids or converted to liquids and thus suited as a hydrogen fuel source. Property data are included.
TABLE 1b
Substrate
ΔH° H2 (300 K)
ΔH° H2 (298 K)
T 95% ° C.
T 95% ° C.
Number
Substrate Structure
(cal.)
(exp.)
(cal.)
(exp.)
4
−13.2
−13.37
248
274
5
−15.2
−14.96
268
262
8
−12.2
153
9
−11.9
164
10
−12.5
182
11
−11.2
117
12
−10.6
96
13
−10.7
87
14
−11.4
131
15
−14.4
225
16
−11.5
124
17
−9.7
66
18
−11.7
132
19
−8.7
27
20
−12.1*
−12.4*
128
128
21
−12.4
164
23
−14.2
220
24
−14.8
239
25
−12.5
168
30
−12.2
139
35
−13.8
201
36
−15.1
245
37
−12.5
163
38
−15.2
413
39
−9.9
82
40
−8.8
70
41
−6.4
42
−9.0
43
−10.5
88.
53
−13.5
54
−7.7
*Calculated and experimental data, both at 150° C.
Table 1c shows extended pi-conjugated substrates with heteroatoms other than nitrogen some of which may be liquids or converted to liquids and thus suited for use as fuels. Property data are included. Comparative data for diphenylsilanes also are shown.
TABLE 1c
Substrate
ΔH° H2 (300 K)
ΔH° H2 (298 K)
T 95% ° C.
T 95% ° C.
Number
Substrate Structure
(cal.)
(exp.)
(cal.)
(exp.)
29
−10.2
52
32
−13.5
197
33
−16.4
285
44
−15.6
275
45
273
55
−17.0
56
−16.4
Table 1d shows pi-conjugated organic polymers and oligomers some of which may be liquids or converted to liquids and thus suited for use as fuels. Property data are included. Comparative data for phenylene oligomers also are shown.
TABLE 1d
Substrate
ΔH° H2 (300 K)
ΔH° H2 (298 K)
T 95% ° C.
T 95% ° C.
Number
Substrate Structure
(cal.)
(exp.)
(cal.)
(exp.)
52
−12.5
57
−15.1
48
−16.0
298
49
−15.7
50
−15.6
51
−15.8
Sometimes one can convert hydrogenated extended pi-conjugated substrates which normally would be solid under reaction conditions to a liquid by utilizing a mixture of two more components. In some cases, mixtures may form a eutectic mixture. For instance chrysene (1,2-benzophenanthrene, m.p. 250° C.) and phenanthrene, (m.p. 99° C.) are reported to form a eutectic melting at 95.5° C. and for the 3-component system consisting of chrysene, anthracene and carbazole (m.p. 243° C.), a eutectic is observed at 192° C. (Pascal, Bull. Soc. Chim. Fr. 1921, 648). The introduction of n-alkyl, alkyl, alkoxy, ether or polyether groups as substituents on the ring structures of the polycyclic aromatic molecules, particularly the use such substituents of varying chain lengths up to about 12 carbon atoms, often can lower their melting points. But, this may be at some cost in “dead eight” and reduced hydrogen capacity. As discussed above, certain substituents, e.g., nitriles and alkynes, can provide additional hydrogen capacity since each nitrile group can accommodate two molar equivalents of hydrogen.
The dehydrogenation catalysts suited for use in microchannel reactors generally are comprised of finely divided or nanoparticles of metals, and their oxides and hydrides, of Groups 4, 5, 6 and 8, 9, 10 of the Periodic Table according to the International Union of Pure and Applied Chemistry. Preferred are titanium, zirconium of Group 4; tantalum and niobium of Group 5; molybdenum and tungsten of Group 6; iron, ruthenium of Group 8; cobalt, rhodium and iridium of Group 9; and nickel, palladium and platinum of Group 10 of the Periodic Table according to the International Union of Pure and Applied Chemistry. Of these the most preferred being zirconium, tantalum, rhodium, palladium and platinum, or their oxide precursors such as PtO 2 and their mixtures, as appropriate.
These metals may be used as catalysts and catalyst precursors as metals, oxides and hydrides in their finely divided form, as very fine powders, nanoparticles or as skeletal structures such as platinum black or Raney nickel, or well-dispersed on carbon, alumina, silica, zirconia or other medium or high surface area supports, preferably on carbon or alumina.
Having described candidates for use a source of hydrogen and their use as fuels for vehicles, their conversion for on site use is described. To facilitate an understanding of the improved step of dehydrogenation of the liquid hydrogen fuel sources described herein, reference is made to FIG. 1 . FIG. 1 illustrates the use of three microchannel reactors with serial flow of a liquid fuel through the reactors. This reactor scheme illustrated in the flow diagram has been designed for to provide a constant volume of hydrogen to be generated within each channel of the microchannel reactors.
Microchannel reactors, which term is intended by definition to include monolith reactors, are well suited for the liquid phase dehydrogenation process. They offer ability to effect the dehydrogenation of hydrogen fuel sources while obtaining excellent heat transfer and mass transfer. In gas phase dehydrogenation, their main deficiency has been one of excessive pressure drop across the microchannel reactor. Compression of the gaseous reactants comes at a high cost. However, because, in accordance with this invention, the feed to the microchannel reactors is a liquid, the ability to pressurize the reactor becomes easy. One can pump the liquid fuel to a desired reaction pressure. Thus, pressure drop does not become an insurmountable problem as it is in gas phase production of hydrogen. And, as a benefit of the ability to pressurize, it is easy to generate high-pressure hydrogen as a product of the reaction.
Microchannel reactors and monolith reactors are known in the art. The microchannel reactors are characterized as having at least one reaction channel having a dimension (wall-to-wall, not counting catalyst) of 2.0 mm (preferably 1.0 mm) or less, and in some embodiments 50 to 500 μm. The height and/or width of a reaction microchannel is preferably 2 mm or less, and more preferably 1 mm or less. The channel cross section may be square, rectangular, circular, elliptical, etc. The length of a reaction channel is parallel to flow through the channel. These walls are preferably made of a nonreactive material which is durable and has good thermal conductivity. Most microchannel reactors incorporate adjacent heat transfer microchannels, and in the practice of this invention, such reactor scheme generally is necessary to provide the heat required for the endothermic dehydrogenation. Illustrative microchannel reactors are shown in US 2004/0199039 and U.S. Pat. No. 6,488,838 and are incorporated by reference.
Monolith supports which may be catalytically modified and used for catalytic dehydrogenation are honeycomb structures of long narrow capillary channels, circular, square or rectangular, whereby the generated gas and liquid can co-currently pass through the channels. Typical dimensions for a honeycomb monolith catalytic reactor cell wall spacing range from 1 to 10 mm between the plates. Alternatively, the monolith support may have from 100 to 800, preferably 200 to 600 cells per squared inch (cpi). Channels or cells may be square, hexagonal, circular, elliptical, etc. in shape.
In a representative dehydrogenation process, a liquid fuel 2 , such as N-ethyl carbazole, is pressurized by means of a pump (not shown) to an initial, preselected reaction pressure, e.g., 1000 psia and delivered via manifold 4 to a plurality of reaction chambers 6 within a first microchannel reactor 8 . (Overall dehydrogenation pressures may range from 0.2 to 100 atmospheres.) As shown, dehydrogenation catalyst particles are packed within the reactor chambers 6 , although, as an alternative, the catalyst may be embedded, impregnated or coated onto the wall surface of reaction chambers 6 . The reaction channel 6 may be a straight channel or with internal features such that it offers a large surface area to volume of the channel.
Heat is supplied to the microchannel reactor by circulating a heat exchange fluid via line 10 through a series of heat exchange channels 12 adjacent to reaction chambers 6 . The heat exchange fluid may be in the form of a gaseous byproduct of combustion which may be generated in a hybrid vehicle or hydrogen internal combustion engine or it may be a heat exchange fluid employed for removing heat from fuel cell operation. In some cases, where a liquid heat exchange fluid is employed, as for example heat exchange fluid from a fuel cell, supplemental heat may be added, by means not shown, through the use of a combustion gas or thermoelectric unit. The heat exchange fluid from a PEM (proton exchange membrane) fuel cell typically is recovered at a temperature of about 80° C., which may be at the low end of the temperature for dehydrogenation. By the use of combustion gases it is possible to raise the temperature of the heat exchange fluid to provide the necessary heat input to support dehydrogenation of many of the fuel sources. A heat exchange fluid from fuel cells that operate at higher temperatures, e.g., 200° C. from a phosphoric acid fuel cell, may also be employed.
In the embodiment shown, dehydrogenation is carried out in microchannel reactor 8 at a temperature of generally from about 60 to 300° C., at some pressure of hydrogen. Dehydrogenation is favored by higher temperatures, elevated temperatures; e.g., 200° C. and above may be required to obtain a desired dehydrogenation reaction rate. Because initial, and partial, dehydrogenation of the liquid fuel source occurs quickly, high pressures are desired in the initial phase of the reaction in order to facilitate control of the liquid to gas ratio that may occur near the exit of the reactor chambers. High gas to liquid ratios in reaction chambers 6 midway to the exit of the reactor chambers can cause the catalyst to dry and, therefore reduce reaction rate. In a favored operation, the residence time is controlled such that Taylor flow is implemented, in those cases where the catalyst is coated onto the wall surface of the reactor, or trickling or pulsating flow is maintained in those cases where the catalyst is packed within the reaction chamber. (The pulsing flow regime is described by many references (e.g. Carpentier, J. C. and Favier, M. AlChE J 1975 21 (6) 1213-1218) for convention reactors and for microchannel reactors by Losey, M. W. et al, Ind. Eng. Chem. Res., 2001, 40, p2555-2562 and is incorporated by reference.) By appropriate control of the gas/liquid ratio, a thin film of liquid organic compound remains in contact with the catalyst surface and facilitates reaction rate and mass transfer of hydrogen from the liquid phase to the gas phase.
After a preselected initial conversion of liquid fuel in microchannel reactor 8 is achieved, e.g. one-third the volume of the hydrogen to be generated, the reaction product comprised of hydrogen and partially dehydrogenated liquid fuel is sent by line 14 to gas/liquid or phase separator 16 . Hydrogen is removed at high pressure as an overhead via line 18 and a high pressure partially dehydrogenated liquid fuel source is removed as a bottoms fraction via line 20 . High pressure separation is favored to minimize carry over of unconverted liquid hydrocarbon fuel, which typically has a slightly higher vapor pressure than the dehydrogenated byproduct, and contamination of the hydrogen overhead. Advantageously, then the reaction product need not be quenched and thus rendered liquid in order to effect efficient separation of the partially dehydrogenated organic compound from the hydrogen and minimize carryover into the hydrogenated product. This is a favored feature in contrast to those dehydrogenation processes which use reactants such as isopropanol, cyclohexane and decalin where the dehydrogenation reaction products are in the gas phase.
The bottoms from gas/liquid separator 16 in line 20 is combined and charged to reaction chambers 22 in second microchannel reactor 24 at the same or higher temperature in order to maintain reaction rate. The cooled heat exchange fluid is removed from heat exchange channels 6 via line 26 and returned to the fuel cell, if liquid or, if the hydrogen exchange fluid is combustion gas, then it is often vented to the atmosphere via line 28 .
On recovery of the bottoms from gas/liquid separator 16 , the resulting and partially dehydrogenated liquid fuel may be further reduced in pressure than normally occurs because of the ordinary pressure drop which occurs in microchannel reactor. The pressure in second microchannel reactor 24 is preselected based upon design conditions but in general a pressure of from 30 to 200 psia can be employed for N-ethyl carbazole. The temperature of the previously but partially dehydrogenated liquid fuel in reaction chambers 22 is maintained in second microchannel reactor. Heat to second microchannel reactor 24 is supplied from heat exchange fluid line 10 via manifold 30 to heat exchange channels 31 . The use of a lower operating pressure in second microchannel reactor 24 than employed in the first microchannel reactor 8 allows for significant dehydrogenation at the design reaction temperature. Again conversion is controlled in second microchannel reactor in order to provide for a desirable liquid to gas ratio particularly as the reaction product approaches the end of the reaction chamber. The reaction product comprised of hydrogen and further partially dehydrogenation is removed via manifold 32 and separated in gas/liquid separator 34 . Hydrogen is removed as an overhead from gas/liquid separator 34 via line 36 and a further dehydrogenated liquid fuel is removed from the bottom of gas/liquid separator 34 via line 38 . Heat exchange fluid is withdrawn via line 39 from microchannel reactor 24 and returned to heat exchange fluid return in line 28 .
The final stage of dehydrogenation is carried out in third microchannel reactor 40 . The partially dehydrogenated liquid fuel in line 38 is introduced as liquid to reaction chambers 42 at the same or higher temperature, based on design. Heat is supplied for the endothermic reaction by heat exchange fluid in line 10 via manifold 44 to heat exchange channels 45 . As the dehydrogenation approaches equilibrium in final microchannel reactor 40 , i.e., where the final dehydrogenation reaction is carried out at a pressure at the end of the reactor, at or near atmospheric and at even less than atmospheric conditions if this is required to effect the desired degree of dehydrogenation, it is particularly important to maintain Taylor flow or pulsating flow as the case may be. Mass transfer of the hydrogen from the liquid phase to the gas phase at or near atmospheric pressure is quite limited. However, low hydrogen pressures favor completion of the dehydrogenation reaction.
The reaction product from third microchannel reactor 40 is passed to gas/liquid separator 46 via manifold 48 where hydrogen is recovered as an overhead via line 50 . The dehydrogenated liquid fuel is recovered as a bottoms fraction from gas/liquid separator 46 via line 52 and ultimately is sent to a hydrogenation facility. Then the dehydrogenated liquid fuel is catalytically hydrogenated and returned for service as a liquid fuel source.
In the event that the hydrogenation product in line 50 contains traces of organic compounds, these may be removed if desired by passing the gas stream through an adsorbent bed (not shown) or an appropriate separator for the trace organic impurity.
Although, the dehydrogenation process has been described employing 3 microchannel reactors, other apparatus designs and operating conditions may be used and are within the context of the invention. The operation parameters are one of process design. The use of multiple reactors, as described, allows for better control of gas/liquid ratios as dehydrogenation of the liquid fuel occurs in the reaction chambers as well as providing for optimized pressures in dehydrogenation of the various organic fuel sources.
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The present invention is an improved process for the storage and delivery of hydrogen by the reversible hydrogenation/dehydrogenation of an organic compound wherein the organic compound is initially in its hydrogenated state. The improvement in the route to generating hydrogen is in the dehydrogenation step and recovery of the dehydrogenated organic compound resides in the following steps:
introducing a hydrogenated organic compound to a microchannel reactor incorporating a dehydrogenation catalyst; effecting dehydrogenation of said hydrogenated organic compound under conditions whereby said hydrogenated organic compound is present as a liquid phase; generating a reaction product comprised of a liquid phase dehydrogenated organic compound and gaseous hydrogen; separating the liquid phase dehydrogenated organic compound from gaseous hydrogen; and, recovering the hydrogen and liquid phase dehydrogenated organic compound.
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PRIOR ART
Typical of the devices known in this field include those shown in the U.S. Pat. Nos. 3,780,987, to Craft, Dec. 25, 1973; Rapp, 3,378,231, Apr. 16, 1968, and Schneider, 3,222,032, Dec. 7, 1965.
All of these patents show various forms of low-profile leverage means or linkage systems designed to cooperate with jacking means built into or forming a permanent part of the jacking means. By low-profile is meant that the portion of the device which fits under the object to be lifted has a lesser height than the jack which provides the lifting power. Craft and Rapp provide scissoring leverage means powered by hydraulic or pneumatic jacking means forming a permanent part of the combination making for a somewhat bulky arrangement even in a collapsed storage position. Schneider shows a somewhat different type of linkage mechanism with an electrically powered drive means. As with Craft and Rapp, the Schneider device cannot be collapsed or folded into a very thin arrangement for storage, for example, in the trunk of an automobile, and as with the other prior art patents, Craft shows a device that would be heavier to handle because of the added weight of the integral power means.
BRIEF DESCRIPTION OF THIS INVENTION
The present improvement on the prior art provides a scissoring leverage system that can be folded into a very compact space and yet can be easily unfolded and arranged to coact with any one of a number of conventional jacking means to lift an object. In the preferred form here shown, the structure is designed to be folded so as to occupy a very small space so that it may be easily stored, for example, in the trunk of an automobile to be readily available for use with a separately stored hydraulic or mechanical jack.
The elongated scissoring leverage means here shown makes use of nested lever means having a pivot near the middle of their lengthwise dimension. At the jack engaging end of the lever system, a folding bail means is hingedly connected to one lever and the other lever has a bearing pad integral with it. In its stored position, the bail is folded down to lie in a position surrounding the end of the leverage system; in use it is raised upwardly into a position over the bearing pad on the other lever means. Any form of conventional jack may then be placed on the bearing pad to engage with the bail means. When the jack is operated, the levers are driven to cause the system to open like a pair of scissors.
The lifting end of the lever system that is the opposite end from the jack engaging end, has foot pad means integral with one of the levers and an object engaging pad means formed integral with the other lever. The pads are interfitted in their stored or inactive position to provide a thin bearing means that protrudes from the end of the leverage system for placement under the object to be lifted. These respective foot and object engaging pads integral with the respective levers, are adapted to be spread apart one relative to the other as the jack is driven in order to raise the object.
When the lifting operation has been completed, the jack can be operated to lower the object, for example, an automobile, so that the levers return to their nested relationship and the jack may be removed from engagement with the leverage system. The pad means can be pulled from under the object and the bail can then be folded into its aligned position with the nested levers to produce a leverage means that occupies a space having a minimum thickness so that the nested levers can be locked together for storage in a relatively limited space. The jack means is removed from the system before it is folded for storage so that the jack can be stored separately.
It is therefore an object of this invention to provide an improved scissoring type leverage system for lifting objects.
It is another object of the invention to provide a folding leverage system that occupies a minimum of storage space.
Another object is to provide a scissoring leverage system having separable jacking means for convenience in storage.
These and other objects will be explained more fully in the specification below.
IN THE DRAWINGS
FIG. 1 is a top plan view partly broken away, showing the leverage system in its folded condition;
FIG. 2 is a side elevation with a jack in place at the operative end of the leverage system; and
FIG. 3 is a side elevation showing the jack in its extended condition with the scissoring leverage system open, showing the motion used to lift an object.
DETAILED DESCRIPTION
In its preferred form, the scissoring leverage system shown herein includes an outer lever 10 and an inner lever 12 nested within lever 10 in the folded position of the system, as shown in FIGS. 1 and 2. The outer lever 10, as shown, is made in the form of a stiff, hollow, rectangular frame that is interengaged with the inner lever means 12 by a bearing axle 14 that extends through the nested levers at about their midpoint lengthwise of the levers. The inner lever is rigid structure made up of an assembly of a plurality of bar elements stiffened by cross braces welded thereto, the assembled spaced bars forming a smaller rectangular structure that easily fits within the space defined by the walls of the frame forming the rectangular lever 10 so that the two levers can be oscillated about axle 14 to act like a scissor when their ends are moved apart at one end as can be done with the motion of a jacking means in order to lift an object engaged on the end of the elevated lever at the other end of the system.
At their operative ends, the levers are adapted to cooperate with a jack means 16 and, for this purpose, there is a U-shaped bail, generally denoted 17, that has side arms 18 and 20 that are connected by stiff cross piece 22. The open ends of side arms are pivotally attached by hinge pins 24 and 26 to the outside of frame 10 near the operative end thereof, so that the bail can rotate from a standing position to a folded position over the end of the frame with cross piece 22 fitting over the end of the lever 10, as shown in FIG. 1. The U-shaped bail is adapted to be rotated from its folded position in line with lever 10 to a generally upright position standing at about right angles thereto, as shown in FIGS. 2 and 3.
The lever 12, as above described, is rectangular and is a composite frame structure that is made up of a plurality of longitudinally extending identically shaped bars that can be formed from a somewhat lighter weight metal than the thicker bar stock used for making the frame forming lever 10. The composite bar structure of lever 12 has internal spacers 27 supported on axle 14 and positioned between the bars. Lever 12 may also have one or more stiffening flanges welded thereto to render this lever sufficiently stiff to support the heaviest load for which the scissoring leverage system is designed to cooperate. At its operative end, lever 12 has a surface area 28 that provides a floor or support for the base of jack 16. The pivots 24 and 26 for the bail 17 are positioned to be spaced along the side walls from the end of the frame 10 a sufficient distance such that the cross bar 22 of the bail is disposed over the surface or floor means 28 when the bail is in its raised position.
At the other or lifting end of the leverage system, opposite from the operative end, the flat foot pads 30 and 32 are welded to the vertically disposed side supports 34 and 36 that are adapted to be bolted to the opposite sides of lever 10 respectively to provide spaced apart bearing supports for the object lifting end of the leverage system. The pads 30 and 32 extend under the side walls of the frame forming lever 12. The side walls of frame 10 can be supported and held spaced apart by a horizontally fitted cross bar or plate 38 welded to the underside of the vertical walls forming frame 10 for supporting the underside of lever 12 in its closed or nested position, shown in FIGS. 1 and 2. The rectangular frame forming lever 10 also includes a support at its operative end for the elongated stiff side walls to complete the stiff rectangular frame. For this purpose, the plate 40 is welded to the upper surface of the side walls of lever 10 at its operative end to extend over the top of the upper surface of lever 12.
At the lifting end of the system, the nested lever 12 has a flat object engaging pad 42 fixedly attached to its underside, the pad being of a size to interfit between the pads 30 and 32 with its upper surface in a common plane with the upper surfaces of these spaced apart foot pads, as shown in FIGS. 1 and 2 when the levers are nested together. The plurality of elongated bars forming lever 12 are designed to be stiffened and held in an assembled position by end plates 44 and 46 welded across the ends of the aligned bars forming the lever. Other stiffening means, such as the L-shaped cross pieces 48, 50 and 52, may also be welded across the top of the plurality of bars forming lever 12. The upper surface of these bars between cross pieces 50 and 52 may serve as the floor means 28 for supporting jack 16, the cross pieces 50 and 52 holding the base of the jack in position on the operative end of lever 12 when the other part of the jack is engaged under the cross piece 22 of the U-shaped bail attached to lever 10.
The levering structure described above is designed to be folded in a manner to occupy a minimum of space. The arms 18 and 20 and cross piece 22 of the U-shaped bail fit around one end of the lever structure 10 and the nested lever 12 when the leverage means is in storage and the interfitted foot pads 30 and 32 and the object supporting pad 42 all nest together at the lifting end of the system. The one lever 12 nests within the other lever 10 and the rigid outer lever fully encloses the nested lever in the storage position so that when the bail is turned to its inactive position, a very compact generally rectangular structure is provided that can be easily stored. Suitable means may be provided to hold the folded leverage means in this compact shape and, referring to FIG. 1, a means such as a rod 54 may be fitted into apertures formed in ears 56 and 58 integral with levers 10 and 12 respectively. If needed, another rod 60 may be positioned in aligned apertures in levers 10 and 12 to hold the bail 17 in its folded position.
When the system is to be put into use, bars 54 and 60 are removed and the levers are positioned adjacent the object to be lifted with foot pads 30 and 32 and the object supporting pad 42 at the lifting end of the system in position under the object. The bail 17 is then raised and any available jack means is placed upon the support 28 on the upper surface of lever 12 while the cross piece 22 of the bail is engaged over the other active end of the jacking means. When the jack is operated, it is elongated between floor 28 and the cross piece to raise the bail 17 hinged to lever 10 relative to the floor 28 that is integral with lever 12, causing the leverage system to open like a scissors, turning on axle 14 whereby the object is lifted as pad 42 is raised relative to foot pads 30 and 32. The spaced apart foot pads 30 and 32 provide a very stable base for the object as it is raised by the leverage system.
The object may be lowered by reversing the action of the jacking means 16. The levers 10 and 12 turn about axle 14 to return to their nested relationship. The pads 30 and 32 and the object support pad 42 return to their interfitted relationship when the levers are fully nested so that they may be removed from under the object and the system may be folded again to occupy a minimum of space. The locking pins 54 and 60 can be put in place and the leverage system can then be returned to its storage place. The jack being a separate element, can be stored in its usual place so that this very useful scissoring type leverage system may be comfortably stored away until needed again in the future.
It is to be noted that any form of jack means can be used that can be fitted to this leverage system. As shown, a hydraulic jack 16 is disposed between surface 28 and the cross piece 22 of the bail. It will be noted that as the levers move farther apart around axle 14, that the bail can turn about its hinged or pivotal connection with lever 10 on pins 24 and 26 to remain in a position to receive the direct thrust from the jack so that the lever spreading effort of the jack is always exerted at the best angle possible relative to each lever. The universal adjustability of the bail 17 makes it possible to fit any suitable jacking means between floor 28 and bail 17 of this leverage system whereby to obtain the desired lifting effort for transmittal to an object to be lifted.
While not intending to be limited to any specific dimensions, by way of illustration a leverage system of this design has been constructed as above described with an outer dimension of 8 inches in width, 36 inches in length and, when the bail is folded down as shown in FIG. 1, having a thickness of 2 inches. While making use of such a scissoring type leverage system, the elongated construction allows the operator to work at a convenient and safe distance from the object to be lifted while still exerting the necessary effort, within the limitations of the jack, to move the object.
The above describes the preferred form of this invention. It is possible that modifications may occur to those skilled in the art that will fall within the scope of the following claims.
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A leverage device for use with various jacking means may be folded to occupy a minimum of space during storage but can be unfolded and set in an operative condition to be made fully functional to cooperate with various conventional jacking devices, the device providing a scissoring action for raising and lowering an object when the jack is actuated.
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This is a nationalization of PCT/FR02/03660 filed Oct. 24, 2002 and published in French.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to roll forming apparatus for fabricating sections, in particular metal sections.
2. Description of the Related Art
There exists prior art roll forming apparatus that can operate with different sets of pairs of profiling heads according to the type of section to be fabricated.
Conventionally, when it is required to change from fabricating one type of section to another, the roll forming apparatus must be stopped and all of the pairs of roll forming heads situated on the roll forming line, i.e. on the path followed by the plate to be roll formed, must be replaced one by one.
This takes a very long time and seriously compromises the productivity of the roll forming apparatus.
Furthermore, this operation necessitates the use of lifting equipment such as a traveling overhead crane, which is hazardous for personnel and can cause serious accidents.
SUMMARY OF THE INVENTION
An object of the present invention is to remedy these drawbacks.
The above object of the invention is achieved with roll forming apparatus of the type able to operate with different sets of pairs of roll forming heads according to the type of section to be fabricated, characterized in that said pairs of heads are mounted on carriages that can slide both ways in a direction transverse to the roll forming line, so that one set can be replaced by another set with minimum handling.
Thanks to these features, it suffices to slide the carriages to install the required set of pairs of roll forming heads, which considerably reduces the down time of the roll forming apparatus and eliminates the risks inherent to the lifting operations used in the prior art.
According to other features of the invention:
said roll forming apparatus includes carriages supporting a plurality of pairs of roll forming heads belonging to separate sets,
said roll forming apparatus includes separate groups of carriages supporting pairs of roll forming heads belonging to different sets,
said roll forming apparatus includes first and second sets of pairs of roll forming heads mounted side by side on a first group of carriages and third and fourth sets of pairs of roll forming heads mounted side by side on a second group of carriages independent of said first group,
said roll forming apparatus includes at least one double-acting ram for moving each of said carriages,
said roll forming apparatus includes two double-acting rams mounted in opposition for moving each of said carriages to place selectively carriages of said first group in one of the following three positions: heads inactive, first set of heads active, second set of heads active, and to place selectively the carriages of said second group in one of the following three positions: heads inactive, third set of heads active, fourth set of heads active,
one ram is longer than the other ram to allow for the overall size of a motor for driving pairs of roll forming heads supported by the corresponding carriage,
said roll forming apparatus includes means for preventing it from starting before said carriages have reached an alignment enabling the use of one of said sets,
said means comprise a plurality of holes formed in said carriages and disposed so as to be aligned when said alignment is reached and a laser beam adapted to pass through all of said holes when said alignment is reached,
said carriages are mounted on wheels rolling on rails and said rails comprise recesses disposed to index the positions of said carriages corresponding to the use of each of said sets,
said roll forming apparatus includes gantries provided with wedges adapted to support said carriages when said wheels are in said recesses.
BRIEF DESCRIPTION OF THE DRAWINGS
Other features and advantages of the roll forming apparatus according to the invention will become apparent on reading the following description and examining the accompanying drawings, in which:
FIG. 1 is a partial perspective view of roll forming apparatus according to the invention,
FIGS. 1 a and 1 b show details of FIG. 1 to a larger scale,
FIG. 2 is a perspective view of a carriage of the roll forming apparatus supporting first and second pairs of roll forming heads belonging to respective different sets,
FIG. 2 a shows a detail of FIG. 2 to a larger scale,
FIG. 3 is a bottom view of a portion of the roll forming apparatus shown in FIG. 1 , and
FIGS. 4 a , 4 b , 4 c are diagrams showing three positions that each carriage can occupy.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Further scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
Refer now to FIG. 1 , which shows that the roll forming apparatus 1 according to the invention comprises a plurality of carriages Ci disposed transversely to the roll forming line indicated by the arrow F.
The person skilled in the art will understand that the expression “roll forming line” refers here to the path to be taken by each plate to be roll formed inside the roll forming apparatus 1 , between its entry 3 and its exit 5 .
It will be noted that the carriages Ci for which i is even (i=2p) are offset transversely, i.e. in the direction shown by the arrow T perpendicular to the arrow F, relative to the carriages Ci in which i is odd (i=2p+1) for reasons that are explained later.
These two groups of carriages are respectively referred to hereinafter as the “even carriage group” and the “odd carriage group”.
Refer next to FIG. 2 , in which it can be seen that each carriage Ci includes first and second pairs P 1 i and P 2 i of roll forming heads disposed side by side, i.e. aligned with each other in the direction T.
It will be noted that in the present context the expression “roll forming head” means a plurality of discs Di, preferably metal discs, supported by a common shaft Ai, each pair of heads P 1 i , P 2 i thus being formed of two such pluralities of discs Di, Dj mounted on two parallel shafts Ai, Aj.
It will be noted that, for reasons of clarity only, these pairs of heads are not shown in FIG. 1 .
The combination of pairs P 1 i for which i is even, P 1 i for which i is odd, P 2 i for which i is even, and P 2 i for which i is odd defines four respective sets of pairs of heads, each of which sets produces sections of a particular type.
It is therefore clear that the term “set of pairs of heads” refers to all of the pairs of heads placed one after the other in the direction F (see FIG. 1 ) for producing a predetermined type of section.
Each carriage Ci further comprises a gear motor Mi for driving the two pairs of heads P 1 i and P 2 i which is supplied with power by appropriate electrical connections, not shown.
The discs Di, Dj of each pair of heads turn in opposite directions to confer the required shape progressively on the plates fed to the roll forming apparatus 1 . This is known in the art.
Each carriage Ci has wheels Ri on which the carriage slides on corresponding rails RAi (see FIG. 1 ).
As can be seen in the FIG. 1 a detail view, the rails RAi comprise recesses CRi adapted to receive the wheels Ri.
Referring again to FIG. 1 , it will also be noted that the roll forming path is delimited by a first gantry Π 1 and a second gantry Π 2 .
As can be seen in the FIG. 1 b detail view, a plurality of wedges CAi are fixed to the gantries and adapted to cooperate with shoulders Ei formed on each carriage Ci (see the FIG. 2 a detail view) when the wheels Ri are in the recesses CRi.
It will also be noted (see FIG. 1 ) that double-acting rams Vi are disposed between each carriage Ci and a fixed support S connected to the floor.
Referring next to FIGS. 3 , 4 a , 4 b and 4 c , it is seen that each carriage Ci is in fact connected to the fixed support S by two double-acting rams V 1 i and V 2 i having a common piston Ti.
The ram V 1 i connected to the carriage Ci is preferably longer than the ram V 2 i connected to the fixed support S.
The rams are fed by appropriate hydraulic connections, not shown.
Referring more specifically to FIGS. 4 a , 4 b and 4 c , it can be seen that each carriage Ci can occupy three different positions corresponding to different situations of the rams V 1 i and V 2 i.
The position shown in FIG. 4 a corresponds to the situation in which the rams V 1 i and V 2 i are both extended.
The even carriage group is in this position in FIGS. 1 and 3 .
The carriages are therefore as far as possible from the fixed support S, and neither the pairs of heads P 1 i nor the pairs of heads P 2 i are in the roll forming area between the gantries Π 1 and Π 2 : these heads are therefore inactive.
The position shown in FIG. 4 b corresponds to the situation in which the ram V 1 i is extended and the ram V 2 i is retracted.
The odd carriage group is in this position in FIGS. 1 and 3 .
In this position, the pairs of heads P 2 i are in the roll forming area: these heads are therefore active.
The position shown in FIG. 4 c corresponds to the situation in which the rams V 1 i and V 2 i are retracted (this position is not shown in FIGS. 1 and 3 ).
In this position, the pairs of heads P 1 i are in the roll forming area: these heads are therefore active.
The roll forming apparatus 1 preferably includes means for preventing it from starting if the carriages Ci have not reached an alignment enabling use of the required set of pairs of heads.
As can be seen in FIGS. 2 and 2 a , such means can comprise holes TRi formed in each carriage Ci and a laser beam RL disposed to pass through the holes TRi of all the carriages Ci when said alignment is reached and thus to illuminate a photoelectric cell CP to authorize starting of the roll forming apparatus.
The mode of operation and the advantages of the roll forming apparatus follow directly from the foregoing description.
To fabricate metal sections, metal plates are passed from the entry 3 to the exit 5 in the direction F between the gantries Π 1 and Π 2 (see FIG. 1 ).
When the carriages Ci are in the position shown in FIGS. 1 and 3 , the plates therefore pass between the roll forming heads of the pairs P 2 i for which i is odd.
Thus sections of a first type are obtained.
To obtain sections of the type corresponding to the sets of heads P 1 i in which i is odd, it suffices to place the odd carriage group in the position shown in FIG. 4 c and for the even carriage group to remain in the position shown in FIG. 4 a.
To obtain sections of the type corresponding to the sets of heads P 2 i for which i is even, it suffices to place the odd carriage group in the position shown in FIG. 4 a and the even carriage group in the position shown in FIG. 4 b.
To obtain sections of the type corresponding to the sets of heads P 1 i for which i is even, it suffices to place the odd carriage group in the position shown in FIG. 4 a and the even carriage group in the position shown in FIG. 4 c.
As is now clear, the roll forming apparatus 1 can fabricate four different types of section simply by sliding the carriages Ci accordingly before commencing fabrication.
It is therefore no longer necessary, as it was in the prior art, to lift each pair of roll forming heads by means of a traveling overhead crane in order to replace it with another pair, which considerably reduces the roll forming apparatus down time and eliminates all risks to personnel associated with lifting operations.
It will be noted that because the rams V 1 i are longer than the rams V 2 i each pair of heads P 1 i , P 2 i can be positioned accurately between the two gantries Π 1 and Π 2 , because the additional length of the rams V 1 i compared to the rams V 2 i substantially corresponds to the axial length of the gear motor Mi.
When it is required to move a carriage Ci from the position shown in FIG. 4 c (heads P 1 i active) to the position shown in FIG. 4 b (heads P 2 i active), the relatively long ram V 1 i is operated.
When it is required to move a carriage Ci from the position shown in FIG. 4 b (heads P 2 i active) to the position shown in FIG. 4 a (heads inactive), the relatively short ram V 2 i is operated.
When it is required to move a carriage Ci directly from the position shown in FIG. 4 c (heads P 1 i active) to the position shown in FIG. 4 a (heads inactive), the rams V 1 i and V 2 i can be operated simultaneously.
Of course, to return the carriage to its starting position, the reverse procedure to that just described is carried out.
The recesses CRi formed in the rails RAi (see FIG. 1 a ) index the positions of the carriages Ci to improve further the accuracy of the transverse positioning of the pairs of heads P 1 i , P 2 i.
By cooperating with the shoulders Ei (see FIGS. 1 b and 2 a ), the wedges CAi completely immobilize each carriage Ci once the wheels Ri are in line with the recesses CRi corresponding to the required positions.
The holes GRi and the laser beam RL (see FIGS. 2 and 2 a ) prevent the roll forming apparatus from starting before all of the carriages Ci have reached the position corresponding to the type of section to be fabricated.
Of course, the present invention is not limited to the embodiment described and shown, which is provided entirely by way of illustrative example.
For example, the roll forming apparatus according to the invention could comprise only one group of carriages each supporting a plurality of pairs of roll forming heads belonging to separate sets.
Likewise, the roll forming apparatus according to the invention could comprise separate groups of carriages each supporting only one pair of roll forming heads belonging to a given set.
The invention being thus described, it will be apparent that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and all such modifications as would be recognized by one skilled in the art are intended to be included within the scope of the following claims.
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A contour roll former capable of operating with different sets of pairs of roll forming heads depending on the type of extruded profile to be produced. The contour roll former includes pairs of heads mounted on carriages capable of sliding horizontally back and forth along a direction transverse to the forming line, so that it is possible to replace one set with another with minimum handling, requiring only horizontal movement of the carriages.
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CROSS-REFERENCE TO RELATED APPLICATION
The pump described herein forms the subject matter of an application for a piston pump for use in gasifying fine grained and dust-like fuel, filed as Ser. No. 878,747 by Ulrich GEIDIES simultaneously herewith.
BACKGROUND OF THE INVENTION
The present invention relates to a process for gasifying fine grained and dust-like solid fuel at an elevated pressure by passing the fuel by way of a pressurized lock basin into the gasifier.
One of the central problems of this type of gasification (partial oxidation) is the conveyance of the fuel into the gasifying chamber which is at a greatly elevated pressure.
To solve this problem a process has been proposed in which the fine grained or dust-like fuel is mixed with a suitable liquid, preferably water or low boiling hydrocarbons to form a suspension. The suspension is then condensed by means of a pump to the pressure level of the gasifier. The liquid is subsequently subjected to evaporation which causes a fluidization of the fuel particles which thus are gasified in a comparatively finely divided condition.
The shortcoming of this process lies in the fact that the evaporated liquid either takes part in the gasification and thus undesirably affects its results or that complex special installations are necessary to effect a prior separation and recirculation of the liquid.
Experiments have also been carried out (without publication) to convey the fuel from the supply tank which is under normal pressure into a space which is at elevated pressure by using a system of two lock basins which are alternatingly depressurized for filling and pressurized for evacuation. However, this approach proved to require expensive apparatus and substantial energy was necessary for the compression because of the alternating depressurization and condensing of an inert gas in the lock basins. This resulted in a substantial increase of the cost.
The assignee of the present case in its plant has also experimented with a system where the fine grained and dust-like fuel was directly advanced into the pressurized gasifier chamber by means of piston pumps, that is without using a mash with an auxiliary liquid. These tests were based on the assumption that an agglomeration of the moving fuel was not only unavoidable but desirable. The tests were therefore carried out in a manner that the fuel was condensed in a channel-like passage between the chambers of different pressure to form a sealing plug which was supposed to provide the sealing of the chamber at higher pressure against the space at atmospheric pressure. However, it was found that with this method the sealing plug did not provide an adequate gas and pressure seal. Besides, the grain size of the initial fuel could not be retained with this procedure. Instead, an agglomeration took place which resulted in briquette-like bodies.
In this process it was therefore necessary again to convert the formed sealing plug to a finely divided form because for the subsequent gasification it was absolutely necessary that the fuel was available in a loosened-up condition, that is, in fine grained or dust-like form. This re-comminution of the sealing plug constituted a substantial problem and this process was therefore not industrially used.
The present invention therefore has the object to provide for a process for gasification of fine grained and dust-like fuels at elevated pressure which avoids the difficulties described. It is in particular an object to provide for a process where the fuel is conveyed into the gasifying space in flowable and fluidizable form so that an intermediate re-comminuting of the fuel is not necessary.
It is also an object of the invention to provide for a process where the fuel can be conveyed in a comparatively simple manner from the supply tank which is at atmospheric pressure into the gasifying chamber which is at an elevated pressure without using for this purpose an auxiliary liquid.
SUMMARY OF THE INVENTION
The object of the invention is solved by passing the fuel from the supply tank which is at atmospheric pressure by pump means into a pressurized lock basin and therefrom into the gasifier without causing any agglomeration of the fuel during its movement. The pump means preferably are constituted by a solids pump, that is a pump adapted for moving solid or highly viscous media. This is in particular accomplished by filling the cylinder space of the solids pump only partially, and thus causing a condensation of the gaseous medium present in the remaining cylinder space. Thus, it is avoided that the essential properties of the fuel are undesirably affected by agglomeration. These properties include the grain size, the grain spectrum, the grain properties, the flow properties and the fraction of volatile components.
The amount of fuel conveyed can be adjusted not only by the partial filling of the solids pump, but also by adjusting the speed of its reciprocating movements.
The invention also contemplates to make the feeding of the fuel into the lock basin conditional upon the supply level in the supply tank by providing control switches in the lock basin which effect the starting or cutting out of the solids pump upon reaching specific minimum and maximum levels.
Preferably, the lock basin is maintained at a pressure equal or about equal to that of the gasifier. This implies that the process of the invention can be carried out both at a comparatively low gasification pressure such as about 5 atm above atmospheric as well as at a gasification pressure above 20 atm above atmospheric as it is customarily used presently in the gasification of coal dust. The gasification pressure may even be up to 80 atm above atmospheric. Actually, there are hardly any limitations regarding the conditions of the gasification or the type of fuel used. The conditions may be those customary in present gasification processes and details of the gasification process therefore are not further discussed herein.
The novel features which are considered as characteristic for the invention are set forth in particular in the appended claims. The invention itself, however, both as to its construction and its method of operation, together with additional objects and advantages thereof, will be best understood from the following description of specific embodiments when read in connection with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 illustrates an installation for carrying out the process of the invention, the showing being in diagrammatic form;
FIGS. 2 to 10 illustrate preferred embodiments of a piston pump for use in the process of the invention;
More particularly:
FIGS. 2 to 8 are vertical sections in simplified form illustrating the different positions of the piston during the complete run;
FIG. 9 is a horizontal section through a part of the piston and the cylinder; and
FIG. 10 illustrates another embodiment of the piston of the pump.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
With specific reference now to FIG. 1 it will be seen that the fine grained or dust-like fuel is passed through a supply duct 1 into the supply tank 2. The fuel then is passed by means of a valve 3 and duct 4 into the solids pump 5. This pump is permanently connected with its collecting pipe to the lock basin 6. The lock basin is under the same elevated pressure as the gasifier 7.
The basin is then partially filled with the fuel resulting in a condensing of the gas in the remaining space of the basin. Thus, an agglomeration is avoided and the fuel can be passed through the feeder valve 8 and the duct 9 into the gasifier 7 while still in flowable and fluidizable form.
The gasifier itself may be of well-known construction. It may, for instance, be a Koppers-Totzek gasifier.
The ducts 10 and 11 are the inlet ducts for the reaction media such as air or oxygen and hydrogen. The generated gas is then withdrawn through duct 16 from the gasifier while the slag is removed through the duct 17.
In the lock basin 6 switch contacts 12 and 13 are provided which upon reaching of a minimum or maximum, level of the fuel actuate through the impulse wires 14 and 15 the starting or switching off of the solids pump 5.
Pumps for Use in the Process of the Invention
There are various pumps that may be used in the process of the invention. One is the double piston pump of a design which has particularly been used for conveying thick highly viscous media or sludges with high contents of solids. A pump of this type is for instance the pump DRKP of the Seiler Company of Erlinsbach near Aarau, Switzerland.
In this pump two parallel hydraulically driven and electrically or pneumatically controlled pistons are used which alternately convey the fuel into a common collector tube which may be permanently attached to the pressurized lock basin. During the suction cycle of the pistons a vacuum is formed which permits to obtain the fuel by suction from the fuel bin which is at normal pressure.
A preferred piston pump specifically designed for the process of the invention is illustrated in FIGS. 2 to 10.
With reference first to FIG. 2 it will be seen that the pump in this case is provided with a tube or cylinder disposed horizontally which at its top side is connected with the pipe 4 from the supply tank 2 (see FIG. 1). One end of the cylinder 18 extends into the lock basin 6 (see FIG. 1). The cylinder at that place has an outlet opening 19. The flange 20 provides a gas and pressure seal between the cylinder 18 and the lock basin 6.
The other end of the cylinder is likewise provided with a gas- and pressure-tight seal. Within the cylinder a piston 22 is disposed for horizontal movement. Preferably, the piston has a round or oval cross section.
The piston in its central area is provided with a hollow space 23, thus forming two piston sections 22a and 22b.
It is noted, however, that as distinguished from the embodiment shown in FIGS. 2 to 8, the hollow space 23 may also have a spherical configuration which would permit a certain volume increase.
The actuation of the piston 22 may for instance be effected through a piston rod 24 which may be connected with a suitable, not shown, driving motor or similar.
In the position shown in FIG. 2 the hollow space 23 is in alignment with the pipe 4 and thus prepared for receiving fuel from the supply tank.
Laterally of the pipe 4 there are provided two outlet openings 25a and 25b which permit releasing the inert gas, which as will be discussed below may be used to drive the pump, and, if desired, withdrawing it through suitable ducts. The inert gas may for instance be nitrogen. These outlets will prevent portions of the inert gas from reaching the supply tank 2 through the pipe 4 and thus to interfere with the filling of the hollow space 23.
Near the end 21 of the cylinder there is an inlet duct 26 through which inert gas may be introduced into the space 27 rearwards of the piston 22, this gas being under the same or approximately the same pressure as is maintained in the lock basin 6. Through this pressure equalization between the lock basin and the space 26 a saving of energy necessary to move the piston is obtained since in that case only the friction and not the elevated pressure must be overcome when moving the piston.
There is furthermore provided at the inner wall of the cylinder 18 shortly ahead of the sealing flange 20 a recess 28 which is connected with a duct 29. The function of this duct will be discussed below.
In the position shown in FIG. 2 the fuel withdrawn from the supply tank 2 through the passage 4 drops directly into the hollow space 23. This is the terminal position of the piston to the left.
The piston then is moved to the right and reaches the position shown in FIG. 3 where the hollow space 23, which has been filled with fuel, moves into alignment with the duct 29. Through this duct inert gas is passed into the fuel until the pressure in the hollow space 23 is about equal to the pressure in the lock basin 6. The duct 29 is, for instance, provided with a three-way valve 30 which connects the duct with the supply duct 26 for the inert gas which also leads into the space 27 rearwards of the piston.
Instead of the three-way valve 30 any other suitable device such as provided by two separate valves may be used.
The three-way valve 30 is left in the position for introduction of the inert gas through the duct 29 until the piston moves further to the right as shown in FIG. 4. In this position it will be seen that the bottom edge 31 of the hollow space 23 has reached the edge of the outlet opening 19. As appears from this figure a notch 28 is provided in a wall of the cylinder which will permit the inert gas to enter the hollow space 23 both from the top and the bottom.
FIG. 5 then shows the right-hand terminal position of the piston 22 in which the complete evacuation of the hollow space through the discharge opening 19 takes place. This discharge opening is provided at the end of the cylinder 18 where the cylinder extends into the lock basin 6.
In the position shown in FIG. 5 the three-way valve 30 is adjusted to close the duct 29 so that no further inert gas is either introduced into or discharged from the cylinder.
As soon as all fuel from the hollow space 23 has been discharged into the lock basin, the piston is again moved in the reverse direction, that is from right to left.
If the piston then reaches the position shown in FIG. 6 where the lower edge 31 is in line with the righthand edge of the notch 28, the three way valve 30 is set to permit the inert gas to be discharged from the hollow space 23 through the ducts 29 and 32.
The discharge of gas is complete as soon as the piston 22 reaches the position shown in FIG. 7. The three-way valve is then adjusted to close the duct 29.
It will be understood that the position of the three-way valve 30 may also be automatically controlled depending on the position of the piston.
Upon further movement of the piston to the left the position shown in FIG. 8 will be reached where the filling of the hollow space with fuel is about again to commence. Following this position in FIG. 8, the position of FIG. 2 will be reached which has been described above and which constitutes the beginning of the next run.
The movement of the piston 22 both from left to right and in reverse direction may be carried out either in continuous or in discontinuous sequence.
It will be understood that in FIGS. 2 to 8 all reference numbers have the same meaning, but only those reference numbers are entered which are necessary for an understanding of the particular figure.
In FIG. 9 a horizontal section through the center part of the piston is shown. This figure shows the cross section of the hollow space 23 which corresponds about to the inside diameter of the passage 4. As will be seen the piston because of the central hollow space 23 may be considered to have two sections 22a and 22b.
FIG. 10 illustrates a different embodiment where these two sections 22a and 22b are joined by a narrow cross bar 33. The space around the cross bar then constitutes the hollow space 23 which is available for the fuel.
The drive mechanism for the piston 22 may be conventional, for instance may be of a hydraulic, mechanical or pneumatic design. The actuation as indicated in FIGS. 2 to 8 is then transmitted to the piston by the piston rod 24. It is, however, also possible that a direct pneumatic drive may be used in which the rearward space 27 may be employed to provide the necessary pressure impulse for the piston movement without use of any piston rod.
The piston 22 and the inner wall of the cylinder 18 must of course be provided with the necessary sealing and sliding elements (gaskets). These have not been shown in the drawing. Their number and design depend to a large extent on the existing pressure differential between the supply tank 2 and the lock basin 6.
The inert gas which is freed through the pressure release through duct 25a, 25b and 29 may also be collected and be passed into the supply tank 2 for purpose of dust removal from the fuel.
As indicated by the dot-dash lines in the different figures, the length of the piston and cylinder have not been fully shown. In actual practice the piston portion 22a as indicated in FIG. 2 must have a sufficient length that when the piston is at the right terminal position the hollow space 23 is in alignment with the exit opening 19, while simultaneously the passage 4 and the outlet openings 25a and 25b are closed through the piston.
On the other hand, as appears in FIG. 2 the piston section 22b must also have a sufficient length so that at the left terminal position the hollow space 23 is exactly in alignment with the passage 4 and the duct 29 and notch 28 are closed by this part of the piston.
The following is an example for the conveyance of coal dust of a bulk weight of 0.4 kg/l and a specific weight of 1.8 kg/l into a lock basin which is at a pressure of 30 atm above atmospheric. The following are the data applying to this example:
piston diameter: 300 mm
volume of the hollow space 23: 20 l
rate of loading of the hollow space: 80%
delivery performance: 7,860 kg/h per piston
required nitrogen amount: about 600 Nm 3 /h
If a lock basin system is used which comprises two lock basins which alternately are subjected to pressure release and condensation an amount of for instance 2000 Nm 3 /h of nitrogen would be necessary for the same delivery performance.
Without further analysis, the foregoing will so fully reveal the gist of the present invention that others can, by applying current knowledge, readily adapt it for various applications without omitting features that, from the standpoint of prior art, fairly constitute essential characteristics of the generic or specific aspects of this invention.
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Fine grained fuel such as coal dust is gasified at an elevated pressure by passing the fuel from a supply tank which is at atmospheric pressure by pump means into a pressurized lock basin and therefrom into the gasifier, the fuel during such movement retaining its loose consistency. This can be accomplished for instance by a solid piston pump which is only partially filled with the fuel. Thus, agglomerations are avoided and the fuel is directly conveyed into the gasifier in flowable and fluidizable form without the necessity of being reconverted into a finely divided form.
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