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BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to the preparation of novel cyclisation substrates for steroidal compounds, and also relates to the conversion of these cyclisation substrates into novel steroidal compounds, in particular, 7α-substituted steroids of the oestrane series.
2. Prior Art and Other Information
The stereospecific cyclisation of a compound of formula I: ##STR3## into a compound of formula II: ##STR4## is described in 98 J.A.C.S. 1038 (1976).
Only the equatorial 11α-methyl derivative is formed. The cyclisation of a (pro)-11-hydroxy compound also results exclusively in the 11α-hydroxy steroid (98 J.A.C.S. 1039 (1976)).
When this cyclisation is performed in the (pro)-19-nor-series (R is H), it proves that no stereo-selectivity occurs (see T. M. Yarnell, Dissertation, Stanford University, July 1975, in 1976 DISSERTATION ABSTRACTS INTERN, 1976, B36 no. 10, page 5054). A mixture of 11α- and 11β-substituted steroids in molar proportions of about 1:1 is formed.
Related compounds by structure to those of formulae III-V of the instant invention and processes for converting 1-aryl-8,11-bis(ethylenedioxy)-3-dodecene compounds to 3-alkyl-2-[(E)-6'-(aryl)-3'-hexenyl]-2-cyclopentenones and subsequently via cyclopentenols to 17-substituted-Δ 1 ,3,5(10),13(17) -gonatetraenes are disclosed in British Pat. No. 1 448 873 and 95 J.A.C.S. 7501-7504 (1973).
The present invention provides a method of producing 7α-substituted analogues of the steroidal compounds disclosed in British Pat. No. 1 448 873 (such as 7α-methyl-oestrone by cyclizing 2-[(E)-6-aryl-3-hexenyl]-cyclopentenols of which the hexenyl group has been substituted in position 5. Steroids which may be prepared according to the method of the present invention are disclosed inter alia in U.S. Pat. No. 3,627,894 (7α-methyl-estrones), U.S. Pat. No. 3,574,197 (1-hydroxy-7α-methyl-estrane derivatives), U.S. Pat. No. 3,944,576 (7α-methoxymethyl-estrane derivatives) and U.S. Pat. Nos. 3,318,925/26/27/28/29 (7α-methyl-Δ 1 ,3,5(10) -estratriene derivatives).
SUMMARY OF THE INVENTION
Novel cyclisation substrates are disclosed of the formula: ##STR5## (a) R 1 is H or alkyl of one to four carbons; (b) R 2 is H or alkyl of one to four carbons, with the proviso that R 1 is H when R 2 is alkyl, and with the proviso that R 2 is H when R 1 is alkyl;
(c) R 3 is a leaving group selected from the group consisting of hydroxy, alkoxy of one to four carbons, alkoxyalkoxy of two to four carbons, acyloxy of one to about seven carbons, and trialkylsilyloxy of less than fifteen carbons;
(d) R 4 is hydrocarbyl of one to four carbons, a hydrocarbyl of one to two carbon atoms substituted by halogen or alkoxy of one to two carbons, or alkoxy of one to four carbons; and
(e) R 5 and R 5 ' each are H, OH, alkyl, or an esterified or etherified hydroxy-group of one to about ten carbons.
Surprisingly, it has now been found that the cyclisation of a cyclisation substrate with the formula III: ##STR6## leads stero-specifically to axially-substituted steroidal compounds of formulae IV and V having R 4 , R 5 and R 5 ' as described above: ##STR7## which after rotation, may be represented in shorthand notation by the formula: ##STR8## where R 5 (1) is R 5 when R 5 (2) is R 5 ' and R 5 (1) is R 5 ' when R 5 (2) is R 5 , and which is more recognizable to those skilled in the art. R 6 is an alkyl moiety of from one to about four carbon atoms.
In formulae III, IV and V, most preferably R 1 and R 2 are H or CH 3 , R 3 is OH, R 4 is CH 3 , R 5 is OCH 3 or trialkylsilyloxy of three to twelve carbons, R 5 '=H and R 6 is CH 3 .
When R 5 is R 5 ', the resultant compounds are identical; when R 5 is not R 5 ', the cyclisation results in two isomers, the proportions of which are strongly influenced by the cyclisation conditions and the choice of the substituents R 5 and R 5 '.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The cyclisation substrates of formula III are novel compounds which may be prepared in several ways each of which are known to those skilled in the relevant pharmaceutical arts. The invention is therefor also characterized by the preparation of novel compounds with the general formula III in ways which are in themselves known to those in the relevant art. The invention is also characterized by the cyclisation of the novel cyclisation substrates of formula III to the novel and biologically active axially-substituted steroid compounds of formulae IV and V.
Referring to the Flow Diagram below, the cyclisation substrate III may, for example, be prepared through a series of steps, first by condensing in Reaction (or step) (a) an α-R 4 -β-arylpropanal (VI) with an ω-R 2 -5,5,8,8-tetra-alkoxyoctylidene-tri-arylphosphorane (VII or Wittig reagent), or the tetraalkyl thio-analogue thereof, under conditions which favor the E-configuration (Wittig-Schlosser reaction, see, for example, German Patent Specifications Nos. 1,270,545 and 1,279,678, and 5 ANGEW. CHEMIE, Int. Ed. 126 (1966).
The (E)-olefine-diketal (VIII) obtained is hydrolysed in step (b) under weakly acid conditions to a 1-aryl-8,11-di-oxo-11-alkyl-3-undecene (IX), after which the di-oxo compound (IX) is condensed to a 2-(6'-aryl-3'-hexenyl)-3-alkyl-2-cyclopenten-1-one (X). (Step (c)).
When R 2 is alkyl of one to four carbon atoms, the ketone obtained is reduced to an alcohol; and when R 2 is H, the ketone is reacted with a compound R 1 Li or R 1 Mg halogen.
(R 1 is alkyl (1-4 C)) to give a tertiary alcohol. The OH-group is optionally further esterified or etherified as known to those in the art.
It should be noted that the compound of formula VIII, where R 4 is alkoxy, can also be prepared by allowing ω-R 2 -6,9-bis(alkylidene-dichalcogen)-1-nonynyl-lithium (XIV) to react with an aryl-acetaldehyde (XV), and reducing the 1-(aryl)-2-hydroxy-8,11-bis(alkylidene-dichalocogen)-11-R 2 -3-undecyne (XVI) thus obtained to the corresponding undecene, followed by etherification of the 2-hydroxy group, according to the scheme: ##STR9##
The cyclisation substrate (III) obtained in Reaction (d) is subsequently cyclised with a Lewis acid under acid conditions, to give a tetracyclic compound with an axial R 4 -substituent.
In the cyclisation Reaction (step e), an effective amount of an aprotic or a protic Lewis acid is used and the reaction is performed in a non-nucleophilic protic or aprotic solvent. Examples of suitable solvents are formic acid, acetic acid, trifluoro-acetic acid, trifluoro- ethanol, benzene, saturated hydrocarbons such as pentane, hexane, cyclohexane, and halogenated hydrocarbons such as dichloromethane.
Examples of protic Lewis acids are carboxylic acids with a pK (20° C.) of less than about 4, and preferably less than about 2, such as, for example, trifluoro-acetic acid, trichloro-acetic acid, formic acid.
Examples of aprotic Lewis acids are stannic chloride, titanium tetrachloride, zinc chloride, zinc bromide, boron trifluoide. Aprotic Lewis acids are preferably used, in an amount of about 0.1 to about 10 moles per mole cyclisation substrate, and preferably about 0.5 to about 5 moles per mole. Stannic chloride is preferable.
The cyclisation reaction is usually carried out at a temperature below room temperature (about 20°-22° C.) and above -150° C. preferably at a temperature between about +10° C. and about -100° C.
The mixtures of "ortho"- and "para"- products ("ortho"=A-aromatic steroid substituted in position 1, "para"=A-aromatic steroid substituted in position 3 of compound IV-V, or compounds (IV/V, but rotated 180°) obtained in the cyclisation step (e) may be separated in the usual way known to those in the art, for example, by chromatography or by crystallization. Racemates of intermediate or final products may be resolved to give the optical antipodes in the usual way.
As to the reaction steps (a)-(e) the following additional information can be given:
Reaction step (a) is usually carried out at a temperature between about -100° C. and about 0° C., preferably between about -75° C. and about -25° C. The solvent is usually an etheric solvent, such as diethyl ether, tetrahydrofuran and mixtures thereof. A preferred solvent is an 1:1 mixture of diethyl ether and tetrahydrofuran.
Reaction step (b) is usually carried out at a temperature between about 20° C. and 80° C., preferably between about 50° C. and 60° C. The solvent may be an etheric solvent, such as dimethoxyethane, or a mixture of water and an alcohol, such as ethanol. An 1:2 mixture of water and ethanol containing between 5 and 10 mmol HCl per liter, is very suited.
Reaction step (c) is usually carried out between about 60° C. and 80° C., preferably at about 80° C. The solvent is the same as used in step (b). An 1:2 mixture of water and ethanol containing between 5 and 10 mmol NaOH or an equivalent amount of KOH or trimethylbenzylammoniumhydroxide is very suited.
Reaction step (d): The reduction of the ketone to an alcohol is carried out with a complex metallic hydride, such as lithiumaluminiumhydride, di-isobutyl-aluminium-hydride, sodium-di-isobutylboronhydride, at a temperature between about -50° C. and 0° C., preferably between about -25° C. and 0° C. The reaction of the ketone with a compound R 1 Li or R 1 Mg halogen is usually carried out at a temperature between -70° C. and 0° C., preferably between -70° C. and -20° C. The solvent is usually an etheric solvent, preferably diethyl ether.
The reaction steps (a), (d), (e) and (f) are preferably carried out in an inert atmosphere (nitrogen or argon blanket).
Reaction step (e): When using a protic solvent, preferably a protic Lewis acid is used. A protic solvent, such as formic acid, trifluoro-acetic acid, trifluoro-ethanol, may also serve as protic Lewis acid. An aprotic solvent may be combined with either a protic Lewis acid or an aprotic Lewis acid.
Reaction step (f) is usually carried out in a solvent, such as diethyl ether, dimethylformamide, dimethylsulfoxide, benzene, toluene, at a temperature between -70° C. and -25° C., preferably between 0° C. and 20° C.
Reaction step (g): This reduction is preferably carried out with lithiumaluminiumhydride in tetrahydrofuran at a temperature between about 30° C. and 60° C., preferably between 55° C. and 58° C.
Reaction step (h) is carried out in an inert solvent, such as xylene or tetrahydrofuran, preferably in tetrahydrofuran in the presence of hexamethylphosphoramide. The "methylating" agent is a methylhalide or dimethylsulphate, preferably methyliodide. The base is preferably a metalhydride such as sodiumhydride. ##STR10##
In the Flow Diagram, R 1 , R 2 , R 3 , R 4 , R 5 , R 5 ' and R 6 have the meanings previously assigned. R 7 is an aryl hydrocarbon group with six or seven carbon atoms, preferably phenyl. X is an alkyl-chalcogen group, that is, alkoxy or alkyl-thio, each of one to about four carbon atoms, and preferably one to about two carbon atoms. The moiety (X) 2 is preferably an alkylidene-dichalcogen group, that is: alkylidene-dioxy or alkylidene di-thio with two to about three carbon atoms, for example ethylene-dioxy.
The following may be noted with respect to the substituents R 1 -R 2 and R 4 -R 6 inclusive:
One of R 1 and R 2 is preferably methyl or ethyl, most preferably methyl, while the other substituent is always H. R 3 as a "leaving" group is preferably alkoxy of one to four carbon atoms, for example methoxy; otherwise (1) alkoxyalkoxy of two to four carbon atoms, for example methoxymethoxy, 1'-ethoxyethoxy; (2) carboxyacyloxy of one to seven carbon atoms, for example acetoxy, propionyloxy, butyroxy, pivaloyloxy, valeryloxy, benzoyloxy; or (3) trialkylsilyloxy of less than fifteen carbons, for example, trimethylsilyloxy.
R 4 is (1) a hydrocarbon group of one to four carbons (preferably alkyl) optionally substituted by halogen, preferably chlorine, or alkoxy of one to two carbon atoms, most preferably methoxy, whereby hydrocarbon is understood to mean a monovalent radical consisting of hydrogen and carbon atoms and which is saturated or unsaturated aliphatic, alicyclic or araliphatic, or (2) more preferably, is alkoxy of one to four carbon atoms, most preferably methoxy.
Examples of R 4 hydrocarbons, some optionally substituted, are methyl, ethyl, butyl, chloromethyl, methoxymethyl, allyl, and 2'-chloro-allyl.
R 5 and R 5 ' each are preferably hydroxy, or in the alternative, etherified or esterified hydroxy of less than 10 carbon atoms; for example, (1) hydrocarbyloxy of one to eight carbon atoms, such as methoxy, ethoxy, cyclopentoxy, cyclohexenyloxy, and benzyloxy; (2) α-alkoxyalkoxy of two to four carbon atoms, such as methoxymethoxy, and α-ethoxyethoxy; (3) trimethylsilyloxy, t-butyldimethylsilyloxy, or tetrahydropyranyloxy, carboxyacyloxy of one to seven carbon atoms, such as acetoxy, pivaloyloxy, benzoyloxy.
If R 5 and/or R 5 ' is an oxy group, then the positions 2, 4 and 6 of the phenyl nucleus are activated in the cyclisation. Due to steric factors, position 4 takes no part in the reaction, and for R 5 ≠R 5 ' two products may therefore be formed as indicated above by the formula IV and V. As previously noted, the ratio of formation of these two products can be changed considerably in favor of one thereof by a suitable choice of R 5 and/or R 5 '. If R 5 is, for example, trimethylsilyloxy and R 5 ' is H, then much more "para" (position 6) product is formed than "ortho" (position 2) product.
If use is made as starting material of a β-arylaldehyde with R 5 and/or R 5 ' being a protected hydroxy group, then the protective group may remain intact during the various reaction steps, but it may also undergo modification. Certain protective groups known to those in the art are preferred for some reaction steps, while again other protective groups are preferred for other reaction steps. In the steps (a) and (b), for example, R 5 and/or R 5 ' is preferably methoxy or methoxymethoxy. In steps (c) and (d), R 5 and/or R 5 ' may without objection be hydroxy, while in step (e) R 5 and/or R 5 ' is preferably trimethylsilyloxy if the interest is primarily for the "position 6" product. Specifically, the "position 6" product for R 5 ' is H is most preferred since it may be used for the preparation of steroids similar to those occurring in nature.
In order to prepare the diketone of formula IX, it is also possible to start from the β-arylaldehyde of formula VI and allow this to react with 4-(5'-R 2 -2'-furyl)-butylidene-triarylphosphorane, according to the Wittig-Schlosser reaction, after which the furyl-(E)-olefine thus obtained is hydrolysed with acid, preferably acetic acid in the presence of a catalytic amount of sulphuric acid, and at 100°-110° C.
The cyclisation substrate contains two asymmetric centers, namely, the carbon atom carrying the substituent R 1 and the carbon atom carrying the substituent R 4 . The stereochemistry of the cyclisation product proves to be governed mainly by the latter center. The substituent R 4 in the cyclisation product surprisingly proves to occur predominantly in the axial configuration.
If use is made of a racemic cyclisation substrate as starting material, that is, a material with nearly equal amounts of the (R)-R 4 -substituted and (S)-R 4 -substituted compounds, then a racemic tetracyclic product consisting of 2 enantiomers is shown to be formed, while on grounds of the two asymmetric centers, without optical induction four stereo-isomers in equal amounts should be formed. That the asymmetric center with the substituent R 1 has little, if any, influence on the stereochemistry of the end product is proved by the fact that the (R)-R 1 -(R)-R 4 -substituted cyclisation substrate gives the same R 4 -axially substituted cyclisation product as the (S)-R 1 -(R)-R 4 -substituted cyclisation substrate.
It is indicated in formula III that the substituent R 4 may be present in the (R)-configuration or the (S)-configuration. If the racemate is used as starting material and the position isomerism of the aromatic ring is neglected, a racemate of an R 4 -axially substituted steroid compound with formula IV is formed in the cyclisation. If any optically active cyclisation substrate is used as starting material, for example, the (S)-R 4 -compound (R 4 is CH 3 ), then an optically active compound of formula IV (R 4 is CH 3 ) is formed.
On rotating formula IV through 180° in the plane of the drawing, it can more readily be established that an ent-7α-CH 3 Δ 1 ,3,5(10),13(17) -gonatetraene of formula XI has been formed: ##STR11##
By epoxidising this olefine, preferably by conversion into a 13,17-halohydrin, most preferably a chloro- or bromohydrin, and treatment of the halohydrin with a base, the ent-7α-CH 3 -13α,17α-epoxy compound of formula XII below is formed. (When a per-acid is used for direct epoxidation, the ent-7α-CH 3 -13β,17β-epoxy compound is formed). Opening of the epoxide ring under weakly acid conditions, preferably by use of an aprotic Lewis acid, for example BF 3 -di-ethyl ether, is conducive to migration of the substituent R 6 from position 17 to position 13, such that the ent-7α-CH 3 -13β-R 6 -17-ketone of formula XIII is formed from the ent-β-epoxide XII (the ent-α-epoxide gives rise to the ent-7α-CH 3 -13α-R 6 -17-ketone in this way). ##STR12##
The antipode can be converted into the natural 7α-CH 3 -13β-R 6 -Δ 1 ,3,5(10) -gonatrien-17-one in a corresponding fashion. When R 5 is methoxy, R 5 ' is hydrogen and R 6 is methyl, the 3-methyl ether of 7α-methyl-oestrone is obtained in this way.
The conversion of the Δ 13 (17) -olefine into the 13,17-halohydrin is carried out with a N-halo-carbonamide or -sulfonamide, such as N-chloro- or N-bromo-succinimide, N-chloro-toluenesulfonamide, in a mixture of water and an organic solvent, such as t-butanol, tetrahydrofuran, dimethoxyethane. Treatment of the 13,17-halohydrin with a base is carried out with an aqueous NaOH- or KOH-solution. The opening of the epoxide ring is carried out in an apolar aprotic solvent, for example hydrocarbons, such as benzene, or halogenated hydrocarbons, such as methylene chloride.
Thus, the present invention provides novel cyclisation substrates which give on cyclisation novel 7α-substituted steroidal cyclisation products. The cyclisation substrates as well as the cyclisation products are important novel intermediates for preparing well-known biological active 7α-substituted steroids.
Although the invention has been described with reference to specific embodiments above, numerous variations and modifications will become evident to those skilled in the art, without departing from the scope and spirit of the invention as described above, defined in the appended claims, and as shown in the following Examples:
EXAMPLE I
Preparation of dl-3-(m-methoxyphenyl)-2-methyl-1-propanol
(Precursor of Compound VI)
A solution of m-bromo-anisole (37.4 g, 0.2 mole) in dry tetrahydrofuran (200 ml) was added dropwise under nitrogen to magnesium shavings (4.8 g, 0.2 at.). The resultant solution was stirred for 30 minutes at room temperature, and was then warmed to 50° C.
Methallyl chloride (20 g, 0.22 mol) was added dropwise over a 30 minute period (weak exothermic reaction) after which the reaction mixture was stirred until it had cooled to room temperature (about 2 hours).
The reaction mixture, containing m-methallylanisole, was then cooled in ice to 5° C., and a solution of diborane in tetrahydrofuran (150 ml, 1 M, 0.15 mol) was added dropwise at such a speed that the temperature remained below but close to 15° C.
The whole was subsequently stirred for 1 hour at room temperature, after which 10% sodium hydroxide (150 ml) was added. While cooling in ice, 40 ml 30% by weight hydrogen peroxide was slowly added dropwise such that the temperature remained at about 40° C. The whole was stirred for a further 1 hour without external cooling. The excess hydrogen peroxide was decomposed by the slow addition of sodium sulphite solution (30 g in 150 ml water) while cooling with ice.
The reaction mixture was mixed with 300 ml N sulphuric acid and extracted with ether (2×250 ml). The extracts were dried with anhydrous sodium sulphate and evaporated to dryness. The residue was chromatographed on 600 g silica gel with hexane/ethyl acetate (80:20), giving 27.3 g (76% yield) of pure product.
EXAMPLE II
Preparation of dl-3-(m-methoxyphenyl)-2-methylpropanal
(formula VI: R 4 =CH 3 ; R 5 =OCH 3 )
First method. (R 5 '=H.)
Pyridinium chlorochromate (32 g, 0.15 mol) was suspended in dry dichloromethane. A single amount of 18 g (0.1 mol) 3-(m-methoxyphenyl)-2-methyl-1-propanol dissolved in dry dichloromethane (50 ml) was then added with vigorous stirring. The mixture was stirred for 2 hours at room temperature and was then mixed with hexane (250 ml) and filtered through HYFLO™. The filtrate was distilled under vacuum, giving 13.4 g pure product (75% yield) of boiling point 93°-96° C./0.5 mm.
EXAMPLE III
Preparation of dl-3-(m-methoxyphenyl)-2-methylpropanol
(formula VI: R 4 =CH 3 ; R 5 =OCH 3 )
Second method. (R 5 '=H.)
A mixture of m-bromo-anisole (18.7 g, 0.1 ml), methallyl alcohol (12 g, 0.16 mol), powdered sodium bicarbonate (12 g, 0.14 mol), palladium (II) chloride (0.30 g, 1.7 mmol), triphenylphosphine (0.45 g, 1.7 mmol) and dimethyl formamide was heated with stirring at 130° C. under nitrogen.
The reaction mixture was cooled, mixed with water and extracted with toluene (2×100 ml). The extracts were dried (anhydrous sodium sulphate) and evaporated to dryness, after which the residue was fractionated and distilled under vacuum. This resulted in recovery of 7.7 g starting material, boiling point 56° C./0.2 mm, and 5.9 g of product, boiling point 85°-86° C./0.2 mm yield (yield 33%, or 56% by weight on basis of m-bromo-anisole consumed).
EXAMPLE IV--REACTION (a)
Preparation of dl-(E)-1-(m-methoxyphenyl)-2-methyl-8,11-bis(ethylenedioxy)-3-dodecene
(formula VIII: R 4 =CH 3 ; R 5 =OCH 3 ; R 2 =CH 3 , (X) 2 =ethylenedioxy, R 5 '=H)
Phenyl-lithium in ether (48 ml of a 1.1 M solution, 0.053 mol) was added dropwise under nitrogen to a stirred suspension of 5,8-bis(ethylenedioxy)-nonyl-triphenylphosphonium iodide (Compound VII) (31.6 g, 0.05 mol) in dry tetrahydrofuran, cooled in ice. The red solution was stirred for a further 15 minutes without cooling, after which it was cooled to -70° C. The aldehyde (Examples II and III) (8.72 g, 0.049 mol), dissolved in dry tetrahydrofuran (20 ml), was added dropwise, after which the mixture was stirred for 5 minutes at -70° C. A further quantity of phenyl-lithium in ether (80 ml, 1.1 M, 0.088 mol) was added and the resultant red solution was warmed to -30° C. After 15 minutes, 15 ml methanol was added dropwise. The resultant mixture was mixed with water and extracted with ether. The ether extracts were dried (anhydrous sodium sulphate), filtered and evaporated to dryness under vacuum. The residue was chromatographed on 300 g silica gel with hexane/ethyl acetate 80:20, giving 13.2 g (67% yield) of a colorless oil.
EXAMPLE V--REACTIONS (b) and (c)
Preparation of dl-3-methyl-2-[(E)-6'-(m-methoxyphenyl)-5'-methyl-3'-hexenyl]-2-cyclopentenone
(formula X: R 4 =CH.sub. 3 ; R 2 =CH 3 ; R 5 =OCH 3 ; R 5 '=H)
A solution of the Wittig product from Example IV (10.1 g, 0.025 mol) in 250 ml ethanol (95%) and 125 ml 0.2 N hydrochloric acid was heated at 50°-55° C. for 2 hours to produce the analogue of compound IX, after which 25 ml 2 N NaOH and 225 ml 95% ethanol were added and the resultant solution was refluxed for 21/2 hours. The reaction mixture was reduced in volume to about 100 ml by evaporation under vacuum, after which it was extracted with ethyl acetate. The extracts were dried over anhydrous sodium sulphate and evaporated to dryness. The residue was chromatographed on 300 g silica gel with hexane/ethyl acetate 90:10. The product was obtained as a colorless oil (6.3 g, 85% yield).
EXAMPLE VI--REACTION (d)
Preparation of dl-3-methyl-2-[(E)-6'-(m-methoxyphenyl)-5'-methyl-3'-hexenyl]-2-cyclopentenol
(formula III: R 1 =H; R 2 =CH 3 ; R 3 =OH; R 4 =CH 3 ; R 5 =OCH 3 , R 5 '=H)
Lithium aluminium hydride (0.57 g, 0.015 mol) was slowly added at -20° C. to a solution of the cyclopentenone (Compound X) from Example V (3.0 g, 0.1 mol) in dry ether (100 ml). The mixture was warmed to 0° C. with stirring during a 30 minute period. The excess hydride was decomposed by cautious addition of saturated sodium sulphate solution. The ether layer was decanted from the resultant suspension. The suspension was washed twice with dry ether and the combined ethereal solutions were evaporated to dryness, giving 3.0 g (99% yield) product in the form of a colorless oil, which was not subjected to further purification.
EXAMPLE VII--REACTION (e)
Preparation of dl-1- and -3-methoxy-7α,17-dimethyl Δ 1 ,3,5(10),13(17) -gonatetraene
(formulae IV and V: R 4 =CH 3 ; R 5 =OCH 3 ; R 6 =CH 3 , R 5 '=H)
2.7 ml stannic chloride (7.3 g, 0.028 mol) was added dropwise at -70° C. under a nitrogen atmosphere to a solution of the cyclopentenol (Example VI) (3.0 g, 0.01 mol) in 165 ml dichloromethane. The mixture thus obtained was stirred for 15 minutes at -70° C., after which a solution of NaOH (3.3 g) in methanol (40 ml) was added dropwise such that the temperature did not rise above -60° C. The mixture obtained was diluted with ether and shaken with 85 ml 10% sodium hydroxide. The organic layer was separated and dried over anhydrous potassium carbonate. The solvents were removed by evaporation, and the residue (2.9 g) was chromatographed on 60 g silica gel with hexane/toluene 80:20 (400 ml) and hexane/toluene 70:30 (300 ml). Initially 0.90 g of a solid substance was obtained (melting point 100°-120° C.), and after crystallization from ethanol 0.79 g, melting point 120°-122° C. (28% by weight yield), consisting of the 1-methoxy-7α-methyl isomer. 1.10 g oil was subsequently isolated and on crystallization from ethanol this gave 0.80 g crystals, melting point 55°-60° C. (28% yield, consisting of the 3-methoxy-7α-methyl isomer). Evaporation of the mother liquors to dryness gave 0.30 g oil which consisted mainly of a mixture of the 3-methoxy-7α and 7β-methyl isomers.
EXAMPLE VIII
Preparation of dl-7α-methyloestrone, 3-methyl ether
(formula XIII: R 5 =OCH 3 ; R 6 =CH 3 , R 5 '=H)
A solution of 3-methoxy-7α-methyl-17-methyl-Δ 1 ,3,5 -gonatetraene (0.282 g, 0.001 mol) in t.butanol/water 9:1 (30 ml) was cooled in ice. N-chlorosuccinimide (0.265 g, 0.002 mol) was added to the suspension thus obtained, after which the reaction mixture was stirred for 1 hour at room temperature. Sodium bisulphite (0.10 g) and 10 ml 20% KOH solution were then added consecutively and the whole was stirred for 30 minutes at room temperature. Hexane (50 ml) was then added and the resultant aqueous layer was removed. The organic layer was evaporated to dryness under vacuum.
The residue, consisting of the 13α17α-epoxy derivative (Compound XII), was taken up in toluene (30 ml) and treated with boron trifluoride etherate (2 ml) for 1 minute at room temperature. The dark red reaction mixture was diluted with ether and shaken with saturated sodium bicarbonate solution. The organic layer was separated, dried over anhydrous Na 2 SO 4 , and evaporated to dryness. The residue was chromatographed on 30 g silica gel with hexane/ethyl acetate 9:1.
The product obtained was crystallized from ether/pentane, giving 107 mg of product, melting point 138°-142° C. (36% yield).
EXAMPLE IX
Preparation of dl-(E)-1-(m-hydroxyphenyl)-2-methyl-8,11-bis-(ethylenedioxy)-3-dodecene
(formula VIII: R 2 =CH 3 ; R 5 =OH; (X) 2 =ethylenedioxy, R 5 '=H)
A solution of (E)-1-(m-methoxyphenyl)-2-methyl-8,11-bis(ethylenedioxy)-3-dodecene (1.21 g, 0.003 mol, in Example IV) and KOH (1.6 g) in tri-ethylene glycol (16 ml) was heated at 200° C. for 2 hours. The reaction mixture was cooled, diluted with water, acidified with 4 N hydrochloric acid and extracted with chloroform (3×20 ml). The extracts were dried (anhydrous Na 2 SO 4 ) and evaporated to dryness. The residue was chromatographed on 35 g silica gel with hexane/ethyl acetate, 80:20 followed by 60:40.
In this way, 0.55 g of the starting material was obtained, followed by 0.41 g product as a colorless oil. Yield 64% on the basis of starting material consumed.
EXAMPLE X--STEP (c)
Preparation of dl-3-methyl-2-[(E)-6'-(m-hydroxyphenyl)-5'-methyl-3'-hexenyl]-2-cyclopentenone
(formula X: R 2 =CH 3 ; R 4 =CH 3 ; R 5 =OH), R 5 '=H.)
The product from Example IX (0.41 g) was caused to react in a way similar to that given in Example V. The reaction product was obtained as a colorless oil, 0.25 g, 84% by weight yield.
EXAMPLE XI
Preparation of dl-3-methyl-[(E)-6'-(m-t-butyl-dimethylsilyloxyphenyl)-5'-methyl-3'-hexenyl]-2-cyclopentenone
(formula X: R 2 =CH 3 ; R 4=CH 3 ; R 5 =t-butyl-dimethylsilyloxy, R 5 '=H).
The product from Example X (0.25 g, 0.9 mmol) was dissolved in dry dimethylformamide (1 ml). Imidazole (0.48 g, 7 mmol) and t-butyldimethylchlorosilane (0.30 g, 2 mmol) were added. After stirring for 3 hours at 38° C., water was added and the mixture obtained was extracted with ether. The extract was dried (anhydrous Na 2 SO 4 ) and evaporated to dryness. The residue was purified by chromatography (silica gel, hexane/ethyl acetate 80:20), giving 0.30 g product (85% yield) in the form of an oil.
EXAMPLE XII--STEPS (d) AND (e)
Preparation of dl-1- and 3-t-butyldimethylsilyloxy-7α,17-dimethyl-Δ 1 ,3,5(10),13(17) -gonatetraene
(formulae IV and V: R 4 =CH 3 ; R 5 =t-butyldimethylsilyloxy; R 6 =CH 3 ; R 5 '=H)
The product of Example XI (0.03 g) was reduced in a way analogous to that described in Example VI (Compound III). The cyclopentenol obtained was subsequently cyclised in a way corresponding to that of Example VII. The product mixture obtained from this reaction was separated by chromatography on silica gel, with hexane followed by hexane/toluene 9:1. In this way, the 1-silyloxy compound was first isolated (40 mg), followed by the 3-silyloxy compound (140 mg), both in the form of oils.
EXAMPLE XIII--REACTION (f)
Preparation of dl-1-(m-methoxyphenyl)-2-hydroxy-8,11-bis-(ethylenedioxy)-3-dodecyne
(formula XVI: R 2 =CH 3 ; R 5 =OCH 3 ; R 5 '=H; (X) 2 =ethylenedioxy.)
A 2 M solution of butyl-lithium in hexane (1.5 ml, 3 mmol) was added dropwise under nitrogen to a solution of 6.9-bis(ethylenedioxy)-1-decyne (0.76 g, 3 mmol) in dry tetrahydrofuran (15 ml). After stirring for 10 minutes, a solution of m-methoxyphenylacetaldehyde (0.45 g, 3 mmol) in dry THF (10 ml) was added dropwise. The mixture was stirred for 1 hour, mixed with water, and extracted with ethylacetate. The extracts were dried over anhydrous Na 2 SO 4 and evaporated to dryness. The residue was purified by chromatography with ether on 30 g silica gel, giving 0.76 g (63% yield) of product in the form of a colorless oil.
EXAMPLE XIV--REACTION (g)
Preparation of dl-(E)-1-(m-methoxyphenyl)-2-hydroxy-8,11-bis(ethylenedioxy)-3-dodecane
(formula VIII: R 2 =CH 3 ; R 4 =OH; R 5 =OCH 3 ; (X) 2 =ethylenedioxy, R 5 '=H)
A solution of the product from Example XIII (0.76 g) and lithium aluminium hydride (0.40 g) in dry tetrahydrofuran (20 ml) was heated for 4 hours at 58° C. The reaction mixture was cooled and the excess hydride was decomposed by addition of damp ether. The solution obtained after filtration was evaporated to dryness and the residue was chromatographed on 20 g silica gel with hexane/ethyl acetate 60:40, giving 0.50 g product (65% yield) in the form of a colorless oil.
EXAMPLE XV--REACTION (h)
Preparation of dl-(E)-1-(m-methoxyphenyl)-2-methoxy-8,11-bis(ethylenedioxy)-3-dodecene
(compound VIII: R 2 =CH 3 ; R 4 =OCH 3 ; R 5 =OCH 3 ; (X) 2 =ethylenedioxy, R 5 '=H)
The product from Example XIV (0.50 g) was dissolved in a mixture of dry tetrahydrofuran (14 ml) and hexamethylphosphoramide (1.4 ml). Sodium hydride (0.20 g, 50% suspension in mineral oil) and methyl iodide (2 ml) were added, and the resultant mixture was stirred for 2 hours at room temperature.
The reaction mixture was mixed with ether (50 ml) and washed with water. Drying, and removal of solvent by evaporation, gave a residue which was purified by chromatography on silica gel (20 g) with hexane/ethyl acetate 80:20, followed by 60:40.
The pure product was obtained as an oil, 0.40 g (77% yield).
EXAMPLE XVI (REACTIONS (b) AND (c)
Preparation of dl-3-methyl-2-[(E)-6'-(m-methoxyphenyl)-5'-methoxy-3'-hexenyl]-2-cyclopentenone
(compound X: R 2 =CH 3 ; R 4 =OCH 3 ; R 5 =OCH 3 , R 5 '=H)
In a way analogous to that of Example V, the product of Example XV was converted to the corresponding cyclopentenone, which was obtained as a colorless oil in a yield of 77% (0.23 g).
EXAMPLE XVII--REACTION (d)
Preparation of dl-1,7α- and dl-3,7α-dimethoxy-17-methyl-Δ 1 ,3,5(10),13(17) -gonatetraene
(compounds IV, V: R 5 =OCH 3 ; R 4 =OCH 3 ; R 6 =CH 3 , R 5 '=H)
The product from Example XVI (0.15 g) was reduced in a way analogous to that described in Example VI. The product thus obtained (0.145 g) was dissolved in 3 ml dry dichloromethane and added to a solution of stannic chloride (0.15 ml) previously cooled to -70° C., in dry dichloromethane (10 ml). After stirring for 30 minutes at -70° C., a solution of NaOH (1.0 g) in 90% methanol (10 ml) was added dropwise. The mixture was diluted with ether, washed with water, dried (anhydrous Na 2 SO 4 ) and evaporated to dryness. The residue was chromatographed on 25 g silica gel with toluene. The 1,7α-dimethoxy compound (30 mg, melting point 131°-134° C.) and the 3,7α-dimethoxy compound (40 g, melting point 110°-114° C.) were eluted consecutively. Further elution yielded a small amount of the 3,7β-dimethoxy compound.
EXAMPLE XVIII
Preparation of 2-(4-bromobutyl)furan
A solution of furan (23.8 g, 0.35 mol) in dry tetrahydrofuran (150 ml) was cooled to -15° C. A solution of n-butyl-lithium in hexane (150 ml, 2.2 M, 0.33 mol) was then added dropwise under nitrogen and the reaction mixture was then stirred for a further 21/2 hours at 0° C. The solution thus obtained was subsequently added over a period of about 1 hour under nitrogen to a solution of 1,4-dibromobutane (150 g, 0.7 mol) in dry tetrahydrofuran (225 ml) at -25° C.
The mixture obtained was stirred for a further 3 hours at 0° C. and for 15 hours at room temperature. A saturated cooking salt solution (200 ml) was then added, and the organic layer was removed and dried (anhydrous MgSO 4 ). Distillation under vacuum with the aid of a VIGREUX™ apparatus gave 44 g pure product (66% yield).
EXAMPLE XIX
Preparation of 8-bromo-1,4-bis(ethylenedioxy)octane
A mixture of the 2-(4-bromobutyl)furan of Example XX (20.3 g, 0.1 mol), benzene (120 ml), glycol (120 ml), concentrated sulphuric acid (12 ml) and tetra-n-butylammonium bromide (1.2 g) was boiled for 96 hours with the aid of an azeotropic water separator. The reaction mixture was cooled, and the benzene layer was separated. The glycol layer was washed with a few portions of benzene, after which the combined benzene layers were washed with saturated sodium bicarbonate until neutral. The benzene solution was dried over anhydrous MgSO 4 and solvent was removed by evaporation. The residue was chromatographed on silica gel (200 g) with hexane/ethyl acetate 8:2. This resulted in 7.5 g product (24% by weight yield) in the form of a colorless oil.
EXAMPLE XX
Preparation of 8-iodo-1,4-bis(ethylenedioxy)octane
The bromide from Example XIX (7.5 g, 0.024 mol) was dissolved in butan-2-one (70 ml), after which powdered potassium iodide (6.8 g, 0.04 mol) and pyridine (0.2 ml) were added. The mixture was refluxed for 11/2 hours, mixed with ether, and filtered. Evaporation yielded 8.2 g product (95% by weight yield).
EXAMPLE XXI
Preparation of 5,8-bis(ethylenedioxy)octyl-triphenyl phosphonium iodide
The iodide from Example XX (8.2 g, 0.023 mol) and triphenylphosphine (10 g, 0.038 mol) were dissolved in benzene (70 ml). The solution was boiled with stirring for 16 hours. After cooling, the benzene layer was decanted and the viscous residue was dissolved in a little acetone. Addition of ether gave 5.01 g (35% by weight yield) of a crystalline product, melting point 102°-104° C., while dilution of the mother liquor with ether gave a further 6.0 g (42% by weight yield) of less pure product (oil).
EXAMPLE XXII--STEP (a)
Preparation of dl-(E)-1-(m-methoxyphenyl)-2-methyl-8,11-bis(ethylenedioxy)-3-undecene
(formula VIII, R 2 =H; R 4 =CH 3 ; R 5 =OCH 3 ; (X) 2 =ethylenedioxy, R 5 '=H)
5,8-bis(ethylenedioxy)octyl-triphenylphosphonium iodide (3.1 g, 0.005 mol) was caused to react with dl-3-(m-methoxyphenyl)-2-methylpropanol (0.89 g, 0.005 mol) in a way fully analogous to that described in Example IV, giving 1.22 g pure product (63% yield).
EXAMPLE XXII--STEPS (b) AND (c)
Preparation of dl-2-[(E)-6'-(m-methoxyphenyl)-5'-methyl-3'-hexenyl]-2-cyclopentenone
(formula X: R 2 =H; R 4 =CH 3 ; R 5 =OCH 3 , R 5 '=H)
The product from Example XXII (1.22 g, 3.1 mol) was dissolved in a mixture of dimethoxyethane (120 ml) and N hydrochloric acid (40 ml). The solution was heated under nitrogen for 21/2 hours at 50°-60° C., cooled, and concentrated under vacuum to about 50 ml. The residue was extracted with ether (3×). The ether extracts were dried (anhydrous Na 2 SO 4 ) and evaporated to dryness. The residue (0.95 g), dissolved in a mixture of 190 ml 95% ethanol and 25 ml 0.2 N potassium hydroxide, was heated at 50° C. under nitrogen for 6 hours. The product was isolated in a way analogous to that described in Example VI, giving 0.35 g of a pure product (39% yield) in the form of a somewhat unstable colorless oil.
EXAMPLE XXIV--STEP (d)
Preparation of dl-2-[(E)-6'-(m-methoxyphenyl)-5'-methyl-3'-hexenyl]-1-methyl-2-cyclopenten-1-ol
(formula III: R 2 ×H; R 1 =CH 3 ; R 3 =OH; R 4 =CH 3 ; R 5 =OCH 3 , R 5 '=H)
The product from Example XXIII (0.284 g, 1 mmol) was dissolved in dry ether (15 ml) and cooled to -70° C. under nitrogen. Excess methyl-lithium in ether (1.5 ml, 2 M, 3 mmol) was added. After stirring for a further 10 minutes at -70° C., a few drops of saturated sodium sulphate solution were added. The mixture obtained was warmed, filtered and evaporated to dryness, giving the product in quantitative yield (0.30 g) in the form of a colorless oil.
EXAMPLE XXV--STEP (e)
Preparation of dl-1-methoxy- and dl-3-methoxy-7α,17dimethyl-Δ 1 ,3,5(10),13(17) gonatetraene
(formulae IV and V: R 6 =CH 3 ; R 4 =CH 3 ; R 5 =OCH 3 , R 5 '=H)
The product from Example XXIV (0.30 g) was cyclised in the way described in Example VII to give the 1-methoxy 7α-methyl-compound (0.07 g, melting point 119°-122° C.) and the 3-methoxy-7α-methyl-compound (0.08 g, melting point 55°-60° C.).
EXAMPLE XXVI
Preparation of dl-3-(m-methoxyphenyl)-2-methoxymethyl-propan-1-ol
Methyl-3-(m-methoxyphenyl)propionate (9.7 g, 0.05 mol) was added dropwise to a solution of lithium di-isopropylamide (0.05 ml) cooled to -78° C.; this latter solution had been obtained by mixing 5 g di-isopropylamine in dry tetrahydrofuran (50 ml) with butyl-lithium in hexane (23 ml, 2.16 M) at 0° C. under nitrogen. After stirring for 10 minutes at -78° C., chlorodimethyl ether (4.8 g, 0.06 mol) dissolved in dry hexamethyl-phosphoric acid triamide (4.5 g) was slowly added dropwise.
After stirring for a further 10 minutes, the reaction mixture was warmed to 0° C., mixed with water, and extracted with ether. The ether extracts were dried (anhydrous Na 2 SO 4 ) and evaporated to dryness. The residue was chromatographed on silica gel with hexane/ethyl acetate 80:20, giving 9.5 g methyl dl-3-(m-methoxyphenyl)-2-methoxymethyl-propionate in the form of a colorless oil (80% yield).
A solution of this ester (4.7 g, 0.02 mol) in dry ether (20 ml) was added to a suspension of lithium aluminium hydride (0.75 g, 0.02 mol) in dry ether (20 ml) cooled in ice. The reaction mixture was stirred for 1 hour at room temperature, after which saturated sodium sulphate solution was added dropwise with cooling. After filtering and removing solent by evaporation, 4.1 g product was obtained (100% yield) in the form of a colorless oil.
EXAMPLE XXVII INTER ALIA, REACTIONS (a)-(d)
Preparation of dl-3-(m-methoxyphenyl)-2-methoxymethylpropanal (formula VI: R 4 =CH 2 OCH 3 ; R 5 =OCH 3 ; R 5 '=H) and dl-7α-methoxymethyloestrone
The product of Example XXVI was oxidised in a way analogous to that described in Example II. The crude product was purified by chromatography on silica gel with hexane/ethyl acetate 80:20, giving a pure product, in the form of a colorless oil, in a yield of 74%.
The aldehyde obtained was converted, in an similar fashion to that described in the Examples IV-VI, into dl-3-methyl-2-[(E)-6'-(m-methoxyphenyl)-5'-methoxymethyl-3'-hexenyl]-2-cyclopentenol, which was cyclised and converted into the 3-methyl ether of dl-7α-methoxymethyloestrone in a way similar to that described in Examples VII and VIII.
EXAMPLE XXVIII--RECATIONS (a)-(e)
Preparation of dl-7α,18-dimethyloestrone, 3-methyl ether
In a way similar to that described in the Examples IV-VIII, the 3-methyl ether of dl-7α,18-dimethyloestrone was obtained starting from dl-3-(m-methoxyphenyl)-2-methylpropanal and 5,8-bis(ethylenedixoy)-decycltriphenyl phosphonium iodide. (Physical constants gonatetraenes: see Example XXXVI).
EXAMPLE XXIX
Preparation of dl-3-(3,5-dimethoxyphenyl)-2-methylpropionic acid ethylester
Ethylpropionate (10.2 g; 0.1 mol) was added dropwise to a solution of lithium-di-isopropylamide (0.1 mol) which was obtained by mixing at 0° C. under nitrogen 10 g di-isopropylamine in 100 ml dry tetrahydrofuran with n-butyllithium in hexane (45.5 ml; 2.2 M). After the addition of ethylpropionate (which was carried out at a temperature of -78° C.) the mixture was stirred at -78° C. for 10 minutes, whereafter a solution of 1,3-dimethoxybenzylbromide (23.0 g; 0.1 mol) in dry hexamethylphosphoric acid triamide (9 g) was added dropwise. The mixture was stirred at -70° C. for 10 minutes and then heated to 0° C. Water was added and the mixture was extracted with ether. The ether-extract was dried on Na 2 SO 4 and the solvent was evaporated. Destillation of the residue in vacuum gave 19.4 g pure product (77% yield), boiling point 150°-155° C./0.2 mm.
EXAMPLE XXX
Preparation of dl-3-(3,5-dimethoxyphenyl)-2-methylpropanal
(formula VI: R 4 =CH 3 ; R 5 =OCH 3 ; R 5 '=OCH 3 )
The ester of Example XXIX (12.6 g; 0.05 mol) was dissolved in dry toluene (100 ml). The solution was cooled under nitrogen to -70° C. and a solution of di-isobutylaluminiumhydride in toluene (44 ml; 1.2 M; 0.053 mol) was added dropwise in 15 minutes. The mixture obtained was stirred at -70° C. for 30 minutes, then mixed with water and ether and heated to room temperature. Sulphuric acid (2 N) was added until a clear solution was obtained. The organic layer was separated, washed with a sodium-bicarbonate-solution and dried on Na 2 SO 4 . Evaporation of the solvent gave 10.2 g (98% yield) product.
EXAMPLE XXXI--REACTION (a)
Preparation of dl-(E)-1-(3,5-dimethoxyphenyl)-2-methyl-8,11-bis-(ethylenedioxy)-3-dodecene
(formula VIII: R 2 =CH 3 ; R 4 =CH 3 ; R 5 =OCH 3 ; R 5 '=OCH 3 ; (X) 2 =ethylenedioxy)
5,8-bis(ethylenedioxy)-nonyltriphenylphosphoniumiodide (10.2 g; 0.049 mol) was caused to react with dl-3-(3,5-dimethoxyphenyl)-2-methylpropanal (10.2 g, 0.049 mol) in a way fully analogous to that described in Example IV, giving 17.0 g (80% yield) product in the form of a colourless oil.
EXAMPLE XXXII--REACTIONS (b) AND (c)
Preparation of dl-3-methyl-2-[(E)-6'-(3,5-dimethoxyphenyl)-5'-methyl-3'-hexenyl]-2-cyclopentenone
(formula X: R 2 =CH 3 ; R 4 =CH 3 ; R 5 =OCH 3 ; R 5 '=OCH 3 )
The product of Example XXXI (17.0 g; 0.039 mol) was converted in a way analogous to that described in Example V into the desired product (10.9 g; 85% yield, colourless oil).
EXAMPLE XXXIII--REACTIONS (d) AND (e)
Preparation of dl-1,3-dimethoxy-7α,17-dimethyl-Δ 1 ,3,5(10),13(17) -gonatetraene
(formula IV, V: R 4 =CH 3 ; R 5 =OCH 3 ; R 5 '=OCH 3 ; R 6 =CH 3 )
The product of Example XXXII (3.3 g; 0.01 mol) was reduced in a way analogous to that described in Example VI and the reaction product was cyclised in a way analogous to that described in Example VII. The cyclisation product was purified by chromatography on silicagel with hexane/ethylacetate 9:1, yielding 2.2 g product (70% yield, m.p. 80°-90° C.).
EXAMPLE XXXIV
Preparation of dl-1,3-dimethoxy-7α-methyl-Δ 1 ,3,5(10) -oestratriene-17-one
(formula XIII: R 5 =OCH 3 ; R 5 '=OCH 3 ; R 6 =CH 3 )
The product of Example XXXIII (1.56 g; 5 mmol) was converted into the corresponding oestrone derivative in a way analogous to that described in Example VIII. Yield 0.36 g (23%) product in the form of colourless crystals, m.p. 135°-140° C.
EXAMPLE XXXV
Preparation of dl-2-[(E)-6'-(m-methoxyphenyl)-5'-methyl-3'-hexenyl]-1-ethyl-2-cyclopenten-1-ol
(formula III: R 2 =H; R 1 =C 2 H 5 ; R 3 =OH; R 4 =CH 3 ; R 5 =OCH 3 ; R 5 '=H)
In a similar way as described in Example XXIV the product of Example XXIII (0.284 g, 1 mmol) was converted with excess ethyl-lithium into the desired product (0.3 g), R f (hexane/ethylacetate 8:2): 0.30 (SiO 2 ); NMR(CDCl 3 ): δ 0.93 (d, J=6, C-5'-methyl), 0.79 and 1.23 (t, J=7 and q, J=7, C 2 H 5 ), 3.74 (s, OCH 3 ), 5.3 (m, olefinic protons).
EXAMPLE XXXVI
Preparation of dl-1-methoxy- and dl-3-methoxy-7α-methyl-17-ethyl-Δ 1 ,3,5(10),13(17) -gonatetraene
(formulae IV and V: R 6 =C 2 H 5 ; R 4 =CH 3 ; R 5 =OCH 3 ; R 5 '=H)
In a similar way as described in Example VII the product of Example XXXV (0.3 g) was cyclised to give 0.05 g 1-methoxy compound (m.p. 95°-100° C.; R f (hexane/toluene 7:3)=0.58) and 0.07 g 3-methoxy compound (oil; R f (hexane/toluene 7:3)=0.35; NMR (CDCl 3 ): δ 0.86 (d, J=7, 7α-CH 3 ), 0.95 and 2.05 (t, J=7 and q, J=7, 17-C 2 H 5 ), 3.75 (s, OCH 3 ).
Physical constants of oily cyclisation substrates (cyclopentenols) and oily cyclisation products (7α-substituted Δ 1 ,3,5(10),13(17) -gonatetraenes) according to the invention:
The cyclopentenol of Example VI: R f (hexane/ethylacetate 6:4): 0.47 (SiO 2 ); NMR (CCl 4 ): δ 0.93 (d, J=6, C-5'-methyl), 1.59 (s, C-3-methyl), 3.70 (s, OCH 3 ), 4.5 (m, H at C-1), 5.26 (m, olefinic protons).
dl-3-Methyl-[(E)-6'-(m-t-butyl-dimethylsilyloxy-phenyl)5'-methyl-3'-hexenyl]-2-cyclopentenol (intra Example XII): R f (hexane/ethylacetate 8:2): 0.27 (SiO 2 ); NMR (CCl 4 ): δ 0.17 (s, Si(CH 3 ) 2 ), 0.95 (d, J=6, C-5'-methyl), 0.97 (s, Si-t-C 4 H 9 ), 1.60 (s, C-3-methyl), 4.5 (m, H at C-1), 5.3 (m, olefinic protons).
The 1-silyloxy-gonatetraene of Example XII: R f (hexane/toluene 9:1): 0.47 (SiO 2 ); NMR (CDCl 3 ): δ 0.15 (s, Si-CH 3 ), 0.23 (s, Si-CH 3 ), 0.75 (d, J=6.5, 7α-CH 3 ), 1.0 (s, Si-t-C 4 H 9 ), 1.63 (s, 17-CH 3 ).
The 3-silyloxy-gonatetraene of Example XII: R f (hexane/toluene 9:1): 0.36 (SiO 2 ); NMR (CDCl 3 ): δ 0.17 (s, Si(CH 3 ) 2 ), 0.83 (d, J=7, 7α-CH 3 ), 0.97 (s, Si-t-C 4 H 9 ), 1.61 (s, 17-CH 3 ).
dl-3-Methyl-2-[(E)-6'-(m-methoxyphenyl)-5'-methoxy-3'-hexenyl]-2-cyclopentenol (intra Example XVII): R f (hexane/ethylacetate 6:4): 0.27 (SiO 2 ); NMR (CDCl 3 ): δ 1.60 (s, C-3-methyl), 3.21 (s, C-5'-OCH 3 ), 3.79 (s, Ar-OCH 3 ), 3.70 (q, J=7, C-5'-H), 4.55 (m, C-1-H), 5.4 (m, olefinic protons).
The cyclopentenol of Example XXIV: R f (hexane/ethylacetate 8:2): 0.31 (SiO 2 ); NMR (CCl 4 ): δ 0.93 (d, J=6, C-5'-methyl), 1.25 (s, C-1-methyl), 3.70 (s, OCH 3 ), 5.1-5.5 (m, olefinic protons).
The cyclopentenol of Example XXVII: R f (hexane/ethylacetate 6:4): 0.31 (SiO 2 ); NMR (CDCl 3 ): δ 1.60 (s, C-3-methyl), 3.24 (d, J=6, C-5'-CH 2 -O), 3.28 (s, OCH 3 ), 3.74 (s, OCH 3 ), 4.55 (m, C-1-H), 5.30 (m, olefinic protons).
3-Methoxy-7α-methoxymethyl-Δ 1 ,3,5(10),13(17) -gonatetraene (intra Example XXVII): R f (toluene): 0.17 (SiO 2 ) NMR (CDCl 3 ): δ 1.62 (s, 17-CH 3 ), 3.25 (s, OCH 3 ), 3.75 (s, OCH 3 ), 3.12 and 3.50 (d, J=10 and dd J=4 and 10, 7α-CH 2 OR). (The 1-methoxy isomer, obtained as a byproduct, is a crystalline substance melting at 155°-158° C.).
dl-3-ethyl-2-[(E)-6'-(m-methoxyphenyl)-5'-methyl-3'-hexenyl]-2-cyclopentenol (intra Example XXVIII): R f (hexane/ethylacetate 6:4): 0.49 (SiO 2 ); NMR (CDCl 3 ): δ 0.95 (d, J=6, C-5'-methyl), 0.91 and 1.97 (t, J=7 and q, J=7, C 2 H 5 ), 3.75 (s, OCH 3 ), 4.5 (m, H at C-1), 5.3 (m, olefinic protons).
dl-3-Methyl-2-[(E)-6'-(3,5-dimethoxyphenyl)-5'-methyl-3'-hexenyl]-2-cyclopentenol (intra Example XXXIII): R f (hexane/ethylacetate 6:4): 0.40 (SiO 2 ); NMR (CDCl 3 ): δ 0.94 (d, J=6, C-5'-CH 3 ), 1.60 (s, C-3-methyl), 3.76 (s, 2x OCH 3 ), 4.5 (m, H at C-1), 5.3 (m, olefinic protons).
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Novel cyclization substrates are disclosed of the formula ##STR1## wherein: (a) R 1 is H or alkyl of one to four carbon atoms;
(b) R 2 is H or alkyl of one to four carbon atoms, with the proviso that R 1 is H when R 2 is alkyl, and with the proviso that R 2 is H when R 1 is alkyl;
(c) R 3 is a leaving group selected from the group consisting of hydroxy, alkoxy of one to four carbons, alkoxyalkoxy of two to four carbons, acyloxy of one to about seven carbons, and trialkylsilyloxy of less than fifteen carbons;
(d) R 4 is hydrocarbyl of one to four carbon atoms, a hydrocarbyl of one to two carbon atoms substituted by halogen or alkoxy of one to two carbons, or alkoxy of one to four carbon atoms; and
(e) R 5 and R 5 ' each are H, OH, alkyl, trialkylsilyloxy, or an esterified or etherified hydroxy-group of about one to ten carbon atoms.
A method is disclosed for the cyclization of the compounds of formula III leading to novel and biologically active compounds of the following formulae: ##STR2## having R 1 through R 5 ' as defined above, with R 6 being alkyl of from one to about four carbon atoms, among which are intermediates for preparing well-known biologically active 7α-substituted steroids, such as 7α-methyl-oestrone; 7α-methoxy-oestradiol and the like.
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CROSS-REFERENCE TO RELATED APPLICATION
[0001] The present application claims the benefit of Argentine Patent Application No. 20100101915 filed on 1 Jun. 2010, the entire disclosure of which is hereby incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to the field of vehicles used in pharmacy and cosmetic industries as carriers of active compounds, especially those vehicles based on natural vegetable oils and, more specifically, those based on jojoba oil.
DESCRIPTION OF THE BACKGROUND ART
[0003] Jojoba oil is obtained from the seed of Simmondsia Chinensis , which contains about 50% by weight of this oil, and which on account of its chemical structure is not a fat but a liquid wax.
[0004] This liquid wax is made of a mixture of straight chain monounsaturated fatty acid esters from 20 to 22 carbon atoms and homologous alcohols most of the same size, with an average chain length from 40 to 42 carbon atoms having one unsaturated hydrocarbon on each side of the ester bond (Wisniak, Jaime, The chemistry and technology of jojoba oil. American Oil Chemists Society, USA 1987). Its general formula is as follows:
[0000]
[0005] The unsaturated acids with the highest presence are eicosanoic acid (of 20 carbon atoms, C20), docosanoic acid (C22), with lower amounts of oleic acid (C18). Alcohols are mostly docosanoic alcohol and eicosanoic alcohol (Wisniak, Jaime, The chemistry and technology of jojoba oil. American Oil Chemists Society, USA 1987).
[0006] The intensive studies conducted and its use for more than 30 years in cosmetic products, show that jojoba oil is not toxic when it is applied on the human skin, or administered orally to mice, rats, marmots and rabbits (Verbiscar, Anthony; WO99/62451—Topical transdermal treatment).
[0007] Jojoba oil has been effectively used to treat different skin disorders together with other therapeutic agents, for example salicylic acid in the treatment of psoriasis, dandruff, acne and skin flaking. It is effective with zinc oxide in the treatment of contact dermatitis, cutaneous rash and allergic dermatitis. It is also effectively used for treating insect bites or fungal foot infections, as well as for treating first degree burns and sun burns, being a good protector against ultraviolet radiation during exposure to sun.
[0008] It is a first selection for treating wounds, even those associated with inflammatory processes and scars. It has been used as an auxiliary agent for the treatment of alopecia.
[0009] Jojoba oil is also successfully used for a wide range of disorders such as rheumatic pain and arthritis, otitis, ocular disorders, as well as in suppositories for treating anal fissures, hemorrhoids and non infectious vaginitis (El Mogy, Nabil Sadek; Patent Application US2003/0008022—Medical effect of Jojoba oil).
[0010] Jojoba oil esters are effective for promoting quick relief of infected zones or preventing future relapses. Jojoba oil is absorbed through the skin much more easily and quickly than other substances previously used without having to add surfactants or emollients (Purcell, Hal; U.S. Pat. No. 6,559,182 B1 (May 6, 2003), WO 2003/49674—Method of treatment of enveloped viruses using jojoba oil esters).
[0011] Jojoba oil can be used as a promoter of the therapeutic efficacy of other active principles, as it increases percutaneous absorption and accumulation in the epidermis, and is able to act as a carrier of the active principles to deep layers of the skin to perform their function. Examples of these active ingredients are anti-inflammatory drugs such as ibuprofen and ketoprofen; antifungal agents such as griseofulvin; liposoluble vitamins such as vitamin A, vitamin D and vitamin E; antineoplastic agents such as Taxol and Paclitaxel; hormonal agents such as testosterone, estrogen, cortisone and prostaglandins; as well as other antiviral agents such as nucleoside and immune response modulator analogue drugs (Purcell, Hal, U.S. Pat. No. 6,559,182 B1 (May 6, 2003), WO2003/49674—Method of treatment of enveloped viruses using jojoba oil esters).
[0012] However, jojoba oil itself, used as a vehicle, is only able to dissolve lipophilic active principles, but is not useful as a vehicle of hydrophilic active principles. Therefore, a new vehicle derived from jojoba oil and capable of carrying a wide range of active principles, either lipophilic or hydrophilic ones, and also exhibiting the advantages offered by products whose vehicle is aqueous in relation to the oily ones is desirable.
[0013] A composition containing derivative products of hydrolysed jojoba oil was described in U.S. Pat. No. 7,435,424. When this composition is included from 5% to 10% in other cosmetics, repellent or pesticides products, it increases the persistence of those products over an animal's skin or hair. In spite of this composition it is not itself an aqueous carrier that produces the dissolution of cosmetics or pharmaceuticals active principles, either lipophilics or hydrophilics.
[0014] An important field wherein the use of jojoba oil is also effective is the prevention and treatment of infections by virus such as herpes viruses, including but not limited to, Herpes simplex virus (HSV) type 1, mostly associated to facial infections on lips, mouth, nose and eyes; HSV type 2, mostly genital; varicella zoster virus also known as human herpes virus (HHV) type 3; HHV type 8, associated with Kaposi's sarcoma.
[0015] In this respect, it has been found that alcohols with a chain length from 16 to 20 carbons and at least one unsaturated carbon are effective in inhibiting replication of viruses with lipid coating in cell cultures; numerous studies have shown the antiviral activity of n-docosanol, and several patents support these publications (Verbiscar, Anthony; WO 2006/112938A1—Formulations useful for the treatment of varicella zoster virus infections and methods for the use thereof).
[0016] However, jojoba oil does not contain alcohols in free form but rather in esterified form. Therefore it is desirable to have a jojoba oil vehicle comprising the free alcohols which, considering their structural characteristics, are per se an active principle against lipid coated viruses.
SUMMARY OF THE INVENTION
[0017] Aqueous dispersions comprised of alcohols and acids obtained by hydrolysis of jojoba oil were developed.
[0018] Hydrolyzed jojoba oil products are treated by a process comprising neutralization of jojoba fatty acids with aliphatic organic amines dissolved in a co-solvent followed by the dispersion of both the neutralized fatty acids together with jojoba alcohols in an aqueous medium.
[0019] The products obtained named generically hydrolyzed jojoba oil (hereinafter HJO) are presented as high-viscosity, transparent, translucent or opaque, physically stable dispersions with a pH between 7.00 and 8.50.
[0020] The HJO is capable of carrying a wide range of pharmaceutical and cosmetic, either hydrophilic or lipophilic, active principles, preferably non-steroidal anti-inflammatory (NSAIDs), local anesthetics, antiviral and antifungal drugs, showing an important effect of promoting transdermal absorption.
[0021] The HJO remarkably broadens capacity and usefulness as a pharmaceutical and cosmetic vehicle compared to jojoba oil.
[0022] The HJO has the ability of emulsifying jojoba oil producing a semisolid product of bright texture named self-emulsified jojoba oil (hereinafter SEJO) useful as a skin-care cream. The SEJO is capable of carrying liposoluble and hydro soluble vitamins and other active principles of cosmetic use.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 shows the characterization of the hydrolysis products of Jojoba oil by 1 H-NMR. The assignments of main signals shows the disappearance of the original product (disappearance of the signals HC—COO—CH δ= 4 . 1 ppm characteristic of Jojoba oil ester group), and the presence of carboxylic acids (—HC—COOH, d=2.3 ppm) and the presence of alcohols (HC—OH, d=3.6 ppm) derived from jojoba wax in equal amounts in relation with the whole mass.
[0024] FIG. 2 shows the rheological behavior of the hydrolyzed jojoba oil product (WO), by a flow curve up to 60 rpm generated forward and backward at 25° C.
[0025] FIG. 3 shows analytical controls of the hydrolyzed jojoba oil product (HJO) by a titration curve of HJO with NaOH 0.05 N and with HCl 0.05 N.
[0026] FIG. 4 refers to a rat skin permeation assay of Diclofenac 1% w/w in HJO, determined by HPLC, wherein the promoting effect of transdermal permeability of the product HJO is noted.
[0027] FIG. 5 refers to a rat skin permeation assay of Acyclovir 5% w/w in HJO, determined by HPLC, wherein the promoting effect of transdermal permeability of the product HJO is noted.
DETAILED DESCRIPTION OF THE INVENTION
[0028] Procedure
[0029] Therefore, one embodiment of the invention is to provide a process for obtaining an aqueous dispersion of alcohols and salified acids from jojoba oil useful as a carrier in pharmaceutical and cosmetic compositions, comprising a first step wherein jojoba oil esters represented by the formula (I) are saponified by treatment with a base (II) to form a mixture of carboxylate (III) and jojoba alcohols (IV):
[0000]
[0030] wherein R1 and R2 are alkenes of C20-C22; M is an alkaline metal or alkaline earth metal; and n is 1 or 2.
[0031] The base (II) is preferably an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or an alkali earth metal such as calcium hydroxide, magnesium hydroxide. More preferably, the base (II) is sodium hydroxide [NaOH] or potassium hydroxide [KOH].
[0032] The reaction is conducted in a reaction medium comprising a methyl alcohol:H 2 O solution, preferably at a ratio of 99:1, and at boiling temperature, preferably from 60-70° C.
[0033] Afterwards, the solvent is evaporated to dryness by means of reduced pressure and the product is treated with an aqueous solution of a strong inorganic acid and/or organic acid in a sufficient amount to neutralize the fatty acid salts and the excess of base present in the reaction medium. Preferably, the inorganic strong acid is hydrochloric acid at concentrations from 1 to 10% w/v.
[0034] In this way, the solid or semisolid product obtained comprises mainly a mixture of acids and alcohols of jojoba oil, which are separated from the aqueous medium.
[0035] In an alternative procedure prior to solvent evaporation the product is acidified by means of a strong inorganic acid or an organic acid solution to neutralize the fatty acid metallic salts and the excess of base present in the reaction medium. Preferably, the strong inorganic acid is hydrochloric acid at concentrations of 1 to 30% w/v.
[0036] The product obtained comprises an upper layer of an oily liquid comprising mainly a mixture of acids and alcohols of jojoba oil and an aqueous layer which may have a precipitated solid comprising the salts resulting from the acidification process. The oily product is recovered and washed by water.
[0037] The following step comprises salification of fatty acids, at a ratio from 50 to 100% of the number of existing carboxylic groups by adding the appropriate proportion of an aliphatic organic amine.
[0038] Preferably, said aliphatic organic amine is selected from the group consisting of dialkyl (C 1 -C 6 ) amines, dihydroxyalkyl (C 1 -C 6 ) amines, trihydroxyalkyl (C 1 -C 6 ) amines, and mixtures thereof.
[0039] More preferably, the aliphatic organic amine used is selected from the group consisting of triethanolamine [(HOCH 2 CH 2 ) 3 N], diethanolamine [(HOCH 2 CH 2 ) 2 NH], tromethamine [(HOCH 2 ) 3 CNH 2 ], diethylamine [(CH 3 CH 2 ) 2 NH], and mixtures thereof.
[0040] The aliphatic organic amine is previously dissolved in a suitable volume of a co-solvent to obtain a co-solvent concentration in the final product from 15% to 25% w/w.
[0041] Preferably, the co-solvent is selected from the group consisting of ethyl alcohol [CH 3 CH 2 OH], propylene glycol [CH 3 CHOHCH 2 OH], and mixtures thereof.
[0042] Afterwards the product obtained from salification of the fatty acids by adding the aliphatic organic amine, which also contains the jojoba alcohols and the co-solvent, is dispersed in a sufficient amount of distilled or purified water to obtain a high viscosity product, physically stable at a pH from 7.00 to 8.50 that contains from 15% to 30% weight by weight of the salified product of the hydrolysis of the jojoba oil. This aqueous dispersion we named hydrolyzed jojoba oil (HJO).
[0043] Another embodiment of the present invention is a procedure for obtaining self-emulsified jojoba oil (SEJO) containing jojoba oil emulsified in the aqueous dispersion of alcohols and salified acids of hydrolyzed jojoba oil (HJO) according to the preceding discussion. Said procedure comprises the addition of jojoba oil to the hydrolyzed jojoba oil (HJO) at room temperature with vigorously mechanical stirring the mixture, to obtain the self-emulsified jojoba oil product (SEJO) as a semisolid product of homogeneous aspect and bright texture.
[0044] Another option for preparing this self-emulsified jojoba oil product (SEJO) involves first contacting the solution comprising the alcohols and fatty acids salified by the aliphatic organic amine dissolved in a co-solvent with the jojoba oil under gently stirring until the complete incorporation of the phases. Afterwards adding water slowly under moderate and constant stirring, to obtain a semisolid product of high viscosity, homogeneous aspect, and bright texture.
[0045] Preferably, the self-emulsified jojoba oil (SEJO) contains from 1% to 40% weight by weight of jojoba oil dispersed in the hydrolyzed jojoba oil product (HJO). More preferably, the SEJO contains 15% weight by weight of jojoba oil dispersed in the hydrolyzed jojoba oil product (HJO).
[0046] I) Thus, depending on the starting material used, different aqueous dispersions of hydrolyzed jojoba oil can be obtained, preferably the following:
[0047] i) Aqueous dispersion of alcohols and salified acids of hydrolyzed jojoba oil (HJO) obtained by treating the fatty acids with triethanolamine in ethanol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0048] ii) Aqueous dispersion of alcohols and salified acids of hydrolyzed jojoba oil (HJO) obtained by treating the fatty acids with diethanolamine in ethanol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0049] iii) Aqueous dispersion of alcohols and acids of hydrolyzed jojoba oil (HJO) obtained by treating the fatty acids with diethylamine in ethanol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0050] iv) Aqueous dispersion of alcohols and salified acids of hydrolyzed jojoba oil (HJO) obtained by treating the fatty acids with tromethamine in ethanol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0051] v) Aqueous dispersion of alcohols and salified acids of hydrolyzed jojoba oil (HJO) obtained by treating the fatty acids with triethanolamine in propylene glycol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0052] vi) Aqueous dispersion of alcohols and salified acids of hydrolyzed jojoba oil (HJO) obtained by treating the fatty acids with diethanolamine in propylene glycol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0053] vii) Aqueous dispersion of alcohols and salified acids of hydrolyzed jojoba oil (HJO) obtained by treating the fatty acids with diethylamine in propylene glycol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0054] viii) Aqueous dispersion of alcohols and salified acids of hydrolyzed jojoba oil (HJO) obtained by treating the fatty acids with tromethamine in propylene glycol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0055] ix) Aqueous dispersion of alcohols and salified acids of hydrolyzed jojoba oil (HJO) obtained by treating the fatty acids with triethanolamine in a mixture of ethanol and propylene glycol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0056] x) Aqueous dispersion of alcohols and salified acids of hydrolyzed jojoba oil (HJO) obtained by treating the fatty acids with diethanolamine in a mixture of ethanol and propylene glycol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0057] xi) Aqueous dispersion of alcohols and salified acids of hydrolyzed jojoba oil (HJO) obtained by treating the fatty acids with diethylamine in a mixture of ethanol and propylene glycol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0058] xii) Aqueous dispersion of alcohols and salified acids of hydrolyzed jojoba oil (HJO) obtained by treating the fatty acids with tromethamine in a mixture of ethanol and propylene glycol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0059] II) Also, from those 12 different salified products of hydrolyzed jojoba oil (HJO) described, it is possible to obtain several self-emulsified jojoba oils (SEJO) by emulsification of jojoba oil in each of them as follows
[0060] i) Self-emulsified jojoba oil (SEJO) comprising an emulsion from 1% to 40% weight by weight of jojoba oil in HJO obtained by treating the fatty acids with triethanolamine in ethanol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0061] ii) Self-emulsified jojoba oil (SEJO) comprising an emulsion from 1% to 40% weight by weight of jojoba oil in HJO obtained by treating the fatty acids with diethanolamine in ethanol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0062] iii) Self-emulsified jojoba oil (SEJO) comprising an emulsion from 1% to 40% weight by weight of jojoba oil in HJO obtained by treating the fatty acids with diethylamine in ethanol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0063] iv) Self-emulsified jojoba oil (SEJO) comprising an emulsion from 1% to 40% weight by weight of jojoba oil in HJO obtained by treating the fatty acids with tromethamine in ethanol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0064] v) Self-emulsified jojoba oil (SEJO) comprising an emulsion from 1% to 40% weight by weight of jojoba oil in HJO obtained by treating the fatty acids with triethanolamine in propylene glycol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0065] vi) Self-emulsified jojoba oil (SEJO) comprising an emulsion from 1% to 40% weight by weight of jojoba oil in HJO obtained by treating the fatty acids with diethanolamine in propylene glycol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0066] vii) Self-emulsified jojoba oil (SEJO) comprising an emulsion from 1% to 40% weight by weight of jojoba oil in HJO obtained by treating the fatty acids with diethylamine in propylene glycol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0067] viii) Self-emulsified jojoba oil (SEJO) comprising an emulsion from 1% to 40% weight by weight of jojoba oil in HJO obtained by treating the fatty acids with tromethamine in propylene glycol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0068] ix) Self-emulsified jojoba oil (SEJO) comprising an emulsion from 1% to 40% weight by weight of jojoba oil in HJO obtained by treating the fatty acids with triethanolamine in a mixture of ethanol and propylene glycol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0069] x) Self-emulsified jojoba oil (SEJO) comprising an emulsion from 1% to 40% weight by weight of jojoba oil in HJO obtained by treating the fatty acids with diethanolamine in a mixture of ethanol and propylene glycol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0070] xi) Self-emulsified jojoba oil (SEJO) comprising an emulsion from 1% to 40% weight by weight of jojoba oil in HJO obtained by treating the fatty acids with diethylamine in a mixture of ethanol and propylene glycol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0071] xii) Self-emulsified jojoba oil (SEJO) comprising an emulsion from 1% to 40% weight by weight of jojoba oil in HJO obtained by treating the fatty acids with tromethamine in a mixture of ethanol and propylene glycol and dispersed in a sufficient amount of water to obtain a transparent or quasi-transparent product of high viscosity containing from 15% to 30% weight by weight of the salified product of hydrolyzed jojoba oil.
[0072] III) From the HJO described in I) transparent or translucent dispersions of an NSAID, wherein the NSAID is added to the HJO in a concentration from 0.1% to 1%; and wherein preferred NSAID are: ketoprofen, ibuprofen, naproxen, flurbiprofen, diclofenac, indomethacin and piroxicam.
[0073] Therefore, each of the twelve hydrolyzed jojoba oils (HJO) described in I) can be utilized to carry an NSAID, thus obtaining a pharmaceutical composition.
[0074] IV) From several HJO described in I) opaque dispersions of antiviral agents may be obtained, wherein an antiviral agent is added to the HJO in a concentration from 0.5% to 5%; and wherein preferred antiviral agent are: acyclovir, penciclovir, idoxuridine.
[0075] Therefore, each of the twelve hydrolyzed jojoba oils (HJO) described in I) can be utilized to disperse an antiviral agent, thus obtaining a pharmaceutical composition.
[0076] V) From several HJO described in I) transparent or translucent dispersions of local anesthetic drugs comprising 0.5% to 5% of a local anesthetic agent in the HJO; and wherein preferred local anesthetics agents are: lidocaine, benzocaine, tetracaine or procaine.
[0077] Therefore, each of the twelve hydrolyzed jojoba oils (HJO) described in I) can be utilized to dissolve a local anesthetic agent, thus obtaining a pharmaceutical composition.
[0078] VI) From several self-emulsified jojoba oils (SEJO) described in II) useful for skin care it is possible to obtain new cosmetic products as a result of their ability to carry liposoluble vitamins, preferably vitamins A, D, and E, and hydro soluble vitamins, preferably vitamin C, as well as other cosmetic active principles.
EXAMPLES
Example 1
Obtaining an Aqueous Dispersion of Alcohols and Acids of Hydrolyzed Jojoba Oil (HJO)
[0079] 1) In a multi-neck round-bottom flask equipped with a condenser, magnetic stirring and a thermostatic bath at 60° C., was heated under reflux, 2.6 g of sodium hydroxide in 200 ml of a solution of methyl alcohol/H 2 O (99:1), until dissolution. Further 20 g of jojoba oil was added to this solution, and boiled for one hour and 30 minutes.
[0080] 2) The product of the hydrolysis was recovered through evaporation of the solvent at reduced pressure obtaining a solid, which at a temperature higher than 25° C. is a light yellowish semisolid product. Adding to the semisolid product 35 ml of water while stirring, 35 ml of 2 N hydrochloric acid solution, the product obtained was placed in a cool place during 24 hours.
[0081] 3) The aqueous phase was separated by decantation and the resulting product was washed with 100 ml of distilled water each time until the absence of chlorides in the washing liquids was verified with silver nitrate.
[0082] 4) This semisolid product at room temperature was dissolved in a solution comprising 2.5 ml of triethanolamine in 22 ml of ethyl alcohol. A homogeneous and stable solution of intense gold color, called “solution of hydrolyzed jojoba oil,” was obtained.
[0083] 5) Afterwards, the solution obtained was mixed with water, with gentle stirring to incorporate the phases completely thus obtaining a high-viscosity, transparent gel containing from 15% to 30% of the mixture of alcohols and salified acids of jojoba named hydrolyzed jojoba oil (HJO).
[0084] FIG. 2 shows the rheological behavior of the hydrolyzed jojoba oil (HJO), by a flow curve from 0 to 60 rpm generated forward and backward at 25° C.
[0085] FIG. 3 shows the neutralization level of carboxylic acids of jojoba oil, obtained by titration of HJO with NaOH 0.05 N and HCl 0.05 N
Example 2
Obtaining a Transparent or Translucent Dispersion of Diclofenac at a Concentration of 1% in an Aqueous Dispersion of Alcohols and Acids of Hydrolyzed Jojoba Oil (HJO)
[0086] To 50 ml of the solution of hydrolyzed jojoba oil obtained as described, in step 4, of Example 1, 1.00 g of Diclofenac was added under stirring, the mixture was warmed up to 40° C. to complete the solid's dissolution. 50 ml of water was slowly poured into the mixture while stirring to obtain a high-viscosity and transparent, homogeneous product.
[0087] FIG. 4 shows the results obtained by HPLC of a permeation assay to the product (HJO+Diclofenac 1% w/w) in rat skin, emphasizing the transdermal permeation promoting effect of the product.
Example 3
Obtaining an Opaque Dispersion of the Antiviral Acyclovir at a Concentration of 5% in an Aqueous Dispersion of Alcohols and Salified Acids of Hydrolyzed Jojoba Oil (HJO)
[0088] To 50 ml of hydrolyzed jojoba oil obtained as described in step 4, of Example 1, 5 g of Acyclovir as finely divided powder was slowly added while stirring to obtain a homogeneous dispersion. Then, 50 ml of water was slowly poured into the mixture while stirring to obtain an opaque semisolid product of fine texture and bright white color.
[0089] FIG. 5 shows the results obtained by HPLC of a permeation assay to the product (HJO+Aciclovir 5% w/w) in rat skin, emphasizing the transdermal permeation promoting effect of the product.
Example 4
Obtaining Self-Emulsified Jojoba Oil (SEJO)
[0090] Procedure A) 17.7 g of jojoba oil was added to 100 g of HJO while vigorously mixing to form a homogeneous, high-viscosity, brightly textured semisolid product. The SEJO obtained contains jojoba oil at a ratio of 15% w/w.
[0091] Procedure B) 17.7 g of jojoba oil was added to 55 ml of hydrolyzed jojoba oil solution obtained according to step 4 of Example 1, gently stirring the mixture until completing the incorporation of the phases. To this solution 55 ml of H 2 O was added slowly under stirring to form a homogeneous, high-viscosity and brightly textured semisolid product. The SEJO obtained contains jojoba oil at a ratio of 15% w/w.
Example 5
Obtaining a Cream with Vitamin A for Damaged Skin, from Self-Emulsified Jojoba Oil (SEJO)
[0092] A solution containing 600,000 IU of vitamin A Palmitate in 17.7 g of jojoba oil was added to 55 ml of hydrolyzed jojoba oil solution obtained as described in step 4 of Example 1, and the mixture was gently stirred until the complete incorporation of the phases. To this solution was dropped 55 ml of water under stirring to form a homogeneous, high-viscosity brightly textured semisolid product. The SEJO obtained contains 15% w/w of jojoba oil and 600,000 IU of vitamin A palmitate.
[0093] Therefore the above descriptions should not be construed as limiting, but merely as exemplifications of preferred embodiments.
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Processes for obtaining aqueous dispersions comprising alcohols and acids obtained by hydrolysis of jojoba oil. Hydrolyzed jojoba oil products are treated by a process comprising neutralization of jojoba fatty acids with aliphatic organic amines dissolved in a co-solvent followed by the dispersion of both the neutralized fatty acids together with jojoba alcohols in an aqueous medium. The products obtained, generically named hydrolyzed jojoba oil (HJO), promote transdermal absorption and are useful vehicles for carrying a wide range of pharmaceutical and cosmetic compositions, including pharmaceutical and cosmetic compositions comprising either lipophilic or hydrophilic active principles. The HJO can also be used to produce a semisolid, self-emulsified jojoba oil (SEJO), obtained by emulsifying the HJO in jojoba oil.
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This is a division of application Ser. No. 478,937 filed Nov. 25, 1983 now U.S. Pat. No. 4,507,385.
FIELD OF THE INVENTION
The present invention relates to a novel class of acrylonitrile copolymers, latex compositions comprising such copolymers and the use of such copolymers in forming protective coatings for photographic elements.
DESCRIPTION RELATIVE TO THE PRIOR ART
Protective coatings for photographic elements containing silver halide layers are well known. Protective coatings have been formulated for both the emulsion side, that is, the side of the element which carries the layer containing the silver halide in a hydrophilic binder, and the other side of the element, commonly referred to in the art as the support side or the base side. These coatings are designed to provide a variety of properties such as resistance to abrasion and resistance to static charging.
Certain photographic elements have further requirements which must be met by the base side protective overcoat. For example, the base side of the photographic element is often coated with an antistatic layer. This antistatic layer generally comprises a binder having dispersed therein a conductive compound. The protective coating is applied over the antistatic layer. Frequently, chemicals in photographic processing solution or in the environment are capable of reacting with the conductive compound in the antistatic layer, thus causing the antistatic layer to lose much of its conductivity. Thus, a protective layer for an element having a base side antistatic layer must be capable of chemically isolating the antistatic layer.
Certain types of photographic elements, including electrophotographic elements, have certain further requirements. Elements which are used in motion pictures are cleaned using chlorinated hydrocarbon solvents. In addition, the elements are duplicated in what is known in the art as a "wet gate" printer. In a wet gate printer, the printing gate is constructed so that the photographic element to be duplicated is immersed in a chlorinated hydrocarbon solvent during the duplicating exposure. Also, electrophotographic elements are often cleaned with standard, chlorinated film-cleaning solvents. A useful base side protective coating for these types of elements must be resistant to chlorinated hydrocarbon solvents.
Many base side overcoat compositions are deficient in one or more respects. One class of conventional overcoats is the acrylate polymers. These polymers provide excellent abrasion resistance, charging characteristics, ferrotyping resistance and other desirable properties. Unfortunately, however, they are readily removed or softened by chlorinated hydrocarbon solvents. Acrylate polymer protective overcoats are described in relation to the polyaniline imine salt-containing antistatic layers of U.S. Pat. No. 4,237,194.
Another class of polymers, such as some acrylonitrile copolymers, must be coated from organic solvents. There are several disadvantages to the use of only organic solvents for coating polymer layers. Elaborate and costly machinery is required to prevent escape of organic solvent vapors into the environment. In addition, the solvents themselves are costly and are generally flammable. Such solvents frequently cause the film base to curl. Control over curl is possible but not without compromising coating versatility or expenditure of additional energy.
It is readily apparent that there is a continuing need for aqueous-based overcoats for the base side of photographic elements. The need is particularly acute for elements which contain a layer, such as an antistatic layer, which must be chemically isolated and which must be protected from chlorinated hydrocarbon solvents.
SUMMARY OF THE INVENTION
The present invention provides a novel class of polymers from which protective overcoats for photographic elements, including electrophotographic elements, are formed from aqueous latex compositions. The overcoats are resistant to photographic processing solutions and chlorinated organic solvents commonly used in film cleaning and printing operations. The abrasion resistance of the overcoats is enhanced by the addition of anti-abrasion agents. The overcoats are uniformly coalesced, optically clear and exhibit no adverse effects on the properties of other layers such as the resistivity of antistatic layers.
The overcoats are formed from latex coating compositions comprising one or more novel polymers having the random structure
--A).sub.x, --B).sub.y and --C).sub.z ;
wherein
A represents a polymerized acrylonitrile monomer;
B represents a polymerized hydrophobic ethylenically unsaturated monomer;
C represents a polymerized ionically charged vinyl monomer;
x is from 10 to 90 weight percent;
y is from 5 to 40 weight percent except that when B is a vinyl halide monomer, y is 10 to 89.9 weight percent; and
z is from 0.1 to 10 weight percent.
The present invention also provides a photographic element, including an electrophotographic element, comprising a support and a layer of the present invention.
The polymers of the present invention form protective overcoats which are particularly useful with elements which contain an antistatic layer on the base side of the support. Thus, in another aspect of the present invention there is provided a photographic element wherein the side opposite the radiation-sensitive layer has thereon, in order, an antistatic layer overcoated with a layer of the present invention.
PREFERRED EMBODIMENTS
In a preferred embodiment. the polymers from which the overcoats are formed have the foregoing structure wherein
B is selected from the group consisting of alkyl acrylates and alkyl methacrylates wherein alkyl refers to groups having from 1 to 12 carbon atoms such as ethyl, propyl, butyl, octyl, ethylhexyl and cyclohexyl, and vinyl halides, etc;
C is selected from the group consisting of N-(2-methacryloyloxyethyl)-N,N,N-trimethylammonium methosulfate; N,N,N-trimethyl-N-vinylbenzylammonium chloride and N-(3-methacrylamidopropyl)-N,N,N-trimethylammonium chloride and sodium 2-acrylamido-2-methylpropanesulfonate;
x is from 20 to 80 weight percent;
y is from 10 to 30 weight percent except that when B is a vinyl halide monomer, y is 15 to 79.9 weight percent; and
z is from 0.1 to 2 weight percent.
DETAILED DESCRIPTION OF THE INVENTION
The polymers of the invention are conveniently prepared as a latex by known emulsion polymerization techniques. Descriptions of such techniques are disclosed in W. P. Sorenson and T. W. Campbell "Preparative Methods of Polymer Chemistry", 2nd Edition, N.Y., N.Y., Wiley (1968) and M. P. Stevens "Polymer Chemistry - an Introduction", Addison-Wesley Publishing Co., Reading, Mass. (1975).
Generally, the polymers are prepared by:
a. dissolving a surfactant and a polymerization catalyst in deoxygenated water;
b. mixing the solution of a) in a head tank with a mixture consisting of from 10 to 90 weight percent of a hydrophobic ethylenically unsaturated monomer; from 10 to 90 weight percent of acrylonitrile; and from 0.1 to 10 weight percent of a ionically charged vinyl monomer;
c. adding a solution of the surfactant and polymerization catalyst to a reactor;
d. adjusting the solution in the reactor to a pH of between 2 and 4;
e. heating the reactor;
f. reacting the mixture of b) by adding the mixture to the reactor over a period of about 1 hour;
g. continuing the reaction for at least 1 hour;
h. cooling the reactor and filtering the contents.
Useful hydrophobic ethylenically unsaturated monomers include methyl acrylate, ethyl acrylate, propyl acrylate, butyl acrylate, amyl acrylate, 2-ethylhexyl acrylate, octyl acrylate, t-octyl acrylate, 2-methoxyethyl acrylate, 2-butoxyethyl acrylate, 2-phenoxyethyl acrylate, cyanoethyl acrylate, benzyl acrylate, methoxybenzyl acrylate, furfuryl acrylate, tetrahydrofurfuryl acrylate, phenyl acrylate, vinylidene chloride, vinyl chloride, methyl methacrylate, ethyl methacrylate, propyl methacrylate, isopropyl methacrylate, butyl methacrylate, amyl methacrylate, hexyl methacrylate, cyclohexyl methacrylate, benzyl methacrylate, octyl methacrylate, 2-methoxyethyl methacrylate, 2-(3-phenylpropyloxy)ethyl methacrylate, furfuryl methacrylate, tetrahydrofurfuryl methacrylate, phenyl methacrylate, naphthyl methacrylate, styrene and substituted styrenes such as methylstyrene and t-butylstyrene and the like.
Examples of cationically charged vinyl monomers include N-(2-methacryloyloxyethyl)-N,N,N-trimethylammonium methosulfate; N,N,N-trimethyl-N-vinylbenzylammonium chloride and N-(3-methacrylamidopropyl)-N,N,N-trimethylammonium chloride.
Examples of anionically charged vinyl monomers include sodium 4-acryloyloxybutane-1-sulfonate, sodium 3-acryloyloxy-1-methylpropane-1-sulfonate, sodium 2-acryloyloxyethylsulfate, sodium 2-methacryloyloxyethylsulfate, sodium 3-acrylamidopropane-1-sulfonate, sodium acrylate, sodium p-styrenesulfonate, sodium vinylphenylmethanesulfonate, sodium 3-methylacryloyloxypropane-1-sulfonate, sodium 3-methacryloyloxypropane-1-methyl-1-sulfonate, sodium 4-methacryloyloxybutane-1-sulfonate, sodium 2-methacryloyloxyethyl-1-sulfate, 3-methacryloyloxypropane-1-sulfonic acid, zinc salt, sodium 3-acryloyloxypropane-1-sulfonate, sodium methacrylate, lithium methacrylate, N-[3-(N-phenylsulfonyl-N-sodiosulfamoyl)phenyl]acrylamide, N-[2-(N-methylsulfonyl-N-potassiosulfamoyl)ethyl]methacrylamide, ammonium p-styrenesulfonate and sodium 2-acrylamido-2-methylpropanesulfonate.
Useful surfactants include hexadecyltrimethylammonium bromide, representative of cationic surfactants and Igepal CO-730® (an ethoxylated nonylphenol) representative of non-ionic surfactants.
Useful catalysts include 2,2'-azobis(2-amidinopropane . hydrochloride), 2,2'-azobis(2-methylpropionitrile), and benzoyl peroxide.
Examples of polymers made according to the previously described method are disclosed in Table I. The weight percent of each monomer in each of the listed polymers is set out in parenthesis immediately following the polymer name.
TABLE I______________________________________Polymer Name______________________________________1 poly[n-butyl acrylate-co-acrylonit- rile-co-N--(2-methacryloyloxyethyl)- N,N,N--trimethylammonium methosulfate] (weight ratio 20/78/2);2 poly[ethyl acrylate-co-acrylonitrile- co-N--(2-methacryloyloxyethyl)-N,N,N-- trimethylammonium methosulfate] (weight ratio 23.9/76/0.1);3 poly[vinylidene chloride-co-acrylo- nitrile-co-N--(2-methacryloyloxyethyl)- N,N,N--trimethylammonium methosulfate] (weight ratio 73/25/1.6)4 poly[vinylidene chloride-co-acrylo- nitrile-co-N--(2-methacryloyloxyethyl)- N,N,N--trimethylammonium methosulfate] (weight ratio 58/40/1.6)5 poly(ethyl acrylate-co-acrylonitrile- co-sodium 2-acrylamido-2-methyl- propanesulfonate) (weight ratio) 23.9/76/0.1)______________________________________
The protective overcoat layers of the present invention are coated from a latex composition of the novel polymers. Abrasion resistance of the overcoats is enhanced by the addition of antiabrasion agents such as Poly 316 N-30® wax emulsion (a wax emulsion composition available from Chemical Corp. of America) to the latex. Other polyethylene wax emulsions as well as the emulsions of other synthetic and natural waxes which are substantially insoluble in chlorinated solvents are also useful. In addition, crosslinked silicones, waxes or polymers which provide a reduced surface coefficient of friction are useful. Such abrasion resistant agents are useful in amounts of from 0.5 to 10 percent based on the weight of polymer.
Ethylene carbonate or resorcinol, are optionally used as fugitive coalescents (plasticizers) to lower the polymer Tg during coating. Other commonly used coalescents such as butyl CARBITOL® acetate and ethyl CARBITOL® (Union Carbide Corp.) are also useful. Such coating aids are useful in amounts of from 10 to 50 percent based on the weight of polymer.
The weight percent solids in the coating composition which is useful to form the layers of the present invention varies widely. A useful range for the weight percent solids in the latex composition is generally between about 1 percent to about 20 percent.
The latex is coated to produce the protective layers of the present invention using any suitable method. For example, the compositions are coated by spray coating, fluidized bed coating, dip coating, doctor blade coating or extrusion hopper coating.
The coated layers are resistant to chlorinated hydrocarbon solvents and photographic processing compositions. By resistant to chlorinated hydrocarbon solvents is meant that the coated and dried layer is substantially unaffected when contacted with the described solvent.
The determination of whether a particular composition will be resistant to chlorinated hydrocarbon solvents is carried out by the following simple test. The composition of interest is coated on a suitable support such as a glass slide or a poly(ethylene terephthalate) support and allowed to dry. A sample of the element is then passed through an ultrasonically agitated bath of 1,1,1-trichloroethane at 40° C. such that its residence time in the bath is 8 to 10 seconds. The coating is then visually examined to determine the effect of this treatment. If the layer remains intact during this treatment, it is considered to be resistant to chlorinated hydrocarbon solvents.
By "resistant to photographic processing solutions" is meant that the layer is capable of chemically isolating underlayers from high pH solutions. One method of determining whether a layer such as a pH sensitive layer is chemically isolated is to include a pH indicator dye in the underlayer and observe the underlayer before and after contact with the solution. If there is little or no change, the underlayer is sufficiently isolated.
Photographic elements comprise a support, at least one radiation-sensitive layer and an overcoat layer of the present invention. The overcoat layer is the outermost layer on the base side of the photographic element. The other side of the photographic element, commonly referred to as the emulsion side, has as its outermost layer a hydrophilic layer. This hydrophilic layer is either the radiation-sensitive layer itself such as one containing silver halide, or an overcoat layer which is hydrophilic so as to facilitate processing of the element. This outermost hydrophilic layer optionally contains a variety of addenda such as matting agents, antifoggants, plasticizers and haze-reducing agents. The outermost hydrophilic layer comprises any of a large number of water-permeable hydrophilic polymers. Typical hydrophilic polymers include gelatin, albumin, poly(vinyl alcohols) and hydrolyzed cellulose esters.
The protective overcoat layers of the present invention are particularly useful over antistatic layers on the base side of a silver halide photographic element. Useful antistatic layers include those described in U.S. Pat. Nos. 3,399,995, 3,674,711 and 3,011,918 which relate to layers containing water-dispersible, particulate polymers. One particularly preferred antistatic layer is described in U.S. Pat. No. 4,070,189 which relates to the use of water-dispersible, particulate vinylbenzyl quaternary ammonium or phosphonium salt polymers. Another useful antistatic layer of this type is described in U.S. Pat. No. 4,294,739.
A preferred class of antistatic layer compositions includes a polyaniline imine salt semiconductor. Compositions of this type are described, for example, in U.S. Pat. Nos. 3,963,498 and 4,237,194. The compositions of U.S. Pat. No. 4,237,194 are particularly preferred because they exhibit high conductivity at low coverages of the semiconductor. The antistatic layer of this patent comprises a coalesced, cationically stabilized latex and a polyaniline imine acid addition salt semiconductor wherein the latex and the semiconductor are chosen so that the semiconductor is associated with the latex before coalescing. Particularly preferred latex binders include cationically stabilized, coalesced, substantially linear, polyurethanes.
Photographic silver halide radiation-sensitive layers are well-known in the art. Such layers are more completely described in Research Disclosure, December 1978, pages 22-31, item 17643. Research Disclosure is published by Industrial Opportunities, Ltd., Homewell, Havent, Hampshire, PO9 1EF, United Kingdom.
The photographic elements of the present invention include a support. Useful supports include those described in paragraph XVII of the above-identified Research Disclosure. Particularly useful supports include cellulose acetate and poly(ethylene terephthalate).
The following examples are presented to illustrate the practice of the present invention.
EXAMPLE 1
Preparation 1, Polymer 1, Table I
First, 6.6 g of hexadecyltrimethylammonium bromide surfactant, 26.6 g of 30% active Igepal CO-730® surfactant, and 11.2 g of 2,2'-azobis-(2-amidinopropane . HCl) were dissolved in 2500 g of deoxygenated water. The pH was adjusted to 2.3 with 10% H 3 PO 4 .
The resulting solution was mixed with a mixture consisting of 500 g of butyl acrylate, 1950 g of acrylonitrile, and 62.5 g of 80% active (50.0 g of polymerizable monomer) N-(2-methacryloyloxyethyl)-N,N,N-trimethylammonium methosulfate. This complex mixture is referred to as the head tank and is preferably kept at below room temperature.
A solution consisting of 18.4 g of hexadecyltrimethylammonium bromide surfactant, 56.7 g of 30% active Igepal CO-730® surfactant (GAF Corp.), and 1.3 g of 2,2'-azobis(2-amidinopropane . HCl) in 11,534 g of deoxygenated water was added to a reactor. The pH was adjusted to 2.3 with 10% H 3 PO 4 .
The reactor was heated to 75° C. and the head tank contents were added to the reactor over 2 hours. The reaction proceeded for 2.5 hours, and was then cooled and filtered. The product was a stable, 15% solids content latex.
EXAMPLE 2
A. Preparation and Testing of Coated Films of Polymer 1
Into a clean vessel 40 g of the latex prepared in Example 1, 3.0 mL of a 10% (wt/wt) solution of Igepal CO-630®, 3.0 ml of 10% Poly 316 N-30® wax emulsion containing 1.25% (wt/wt) of hexadecyltrimethylammonium bromide, 45 ml of water and 9 ml of 20% (wt/wt) resorcinol was added. The resulting latex dispersion was applied as a protective overcoat over conducting layers as described in Example 1 of U.S. 4,237,194 at a wet coverage of 1 ml/ft 2 (10.76 ml/m 2 ) and was dried and cured for 2 minutes at 120° C. to give an optically clear, coalesced film.
B. Performance Tests
Samples of the element prepared above were immersed in a warm (105° F.) photographic aqueous alkaline phenylenediamine color developer solution for 3, 6 and 9 minutes, then washed and dried. The pH of the developer was 11.0. Essentially no effect on the physical or electrical properties of the element was observed.
The same films were then passed through a simulated film-cleaning device in which the films were treated with ultrasonically agitated 1,1,1-tricholorethane at 105° F. (40° C.) for 8-10 seconds. Films were tested for electrical properties and scratch resistance after 1, 10 and 20 passes through the simulated cleaner. There was no change in appearance, and there were essentially no cleaner-induced effects on resistivity or scratch resistance as shown below.
______________________________________ Coating Single arm ScratchNumber Resistivity First Lineof Passes Ω/sq at 4 feet______________________________________ 0 3.0 × 10.sup.7 >100 g 1 2.7 × 10.sup.7 >100 g10 3.2 × 10.sup.7 >100 g20 3.2 × 10.sup.7 >100 g______________________________________
In the "single arm scratch test", a stylus was pulled across the surface of each film under various loads. The weight needed to cause the first scratch is recorded as the test result. The films resisted scratching for loads in excess of 100 grams.
To simulate wet-gate immersion printing, the films were immersed in perchloroethylene for 15, 30 and 60 seconds and then dried. Again, no effects were observed on the physical or electrical properties of the element.
EXAMPLE 3
By way of comparison, a latex dispersion and coated films were prepared exactly as in Example 1 except that the latex used was poly(n-butyl acrylate-co-methyl methacrylate) (20/80). Clear, coalesced films which showed no change in physical or electrical properties on treatment with aqueous alkaline phenylenediamine color developer solutions were obtained by coating and drying of the latex dispersions. Although these films are excellent barriers to penetration by aqueous processing solutions, these films were substantially removed in the simulated film cleaner with the remaining film being quite badly hazed after only a single pass through the simulated film cleaner.
EXAMPLE 4
Preparation of Polymer 3, Table 1
A reactor was charged with 6.84 kg of deoxygenated distilled water, 32.4 g of hexadecyltrimethylammonium bromide, 97.2 g of Igepal CO-730®, 5.4 ml of 0.1 NH 2 SO 4 , 405.0 g of acrylonitrile, 1,182.6 g of vinylidene chloride, 32.4 g of 80% active (25.9 g of polymerizable monomer) N-(2-methacryloyloxyethyl)-N,N,N-trimethylammonium methosulfate and 30 g of 2,2'azobis(2-amidinopropane . HCl).
The reaction was allowed to proceed for 10 hours. The product was cooled and filtered to give a stable, 20% solids content latex.
EXAMPLE 5
A blended latex coating dispersion was prepared as follows:
In a vessel were placed 20 g of a 15% (wt/wt) cationically stabilized latex of polymer 2, Table I; 15 g of a 20% (wt/wt) cationically stabilized latex of polymer 3, 3 ml of a 10% (wt/wt) solution of Igepal CO-630®, 3.0 ml of 10% Poly 316 N-30® wax emulsion containing 1.25% (wt/wt) of hexadecyltrimethylammonium bromide, 56.6 ml of water, and 2.4 ml of 50% (wt/wt) ethylene carbonate in water. Coated films of this dispersion were prepared and tested as in Example 2. The films were unaffected by alkaline photographic developers, by multiple exposures to the film cleaning treatment, or by immersion in perchloroethylene.
EXAMPLE 6
This example shows the effectiveness of overcoats formed from a latex composition of the invention comprising an anionic polymer.
A latex (19.4% solids) was prepared containing polymer 5 of Table I. The preparation was carried out as follows:
First, 1.0 g of Alipal CO-436® surfactant (58% active, GAF Corporation) and 0.25 g of sodium meta bisulfite were dissolved in 100 g of deoxygenated water. The pH was adjusted to 2.3 with 10% H 3 PO 4 .
The resulting solution was mixed with a mixture consisting of 23.9 g of ethyl acrylate, 76.0 g of acrylonitrile, and 0.1 g of sodium 2-acrylamido-2-methylpropanesulfonate. This complex mixture is referred to as the head tank and is preferably kept at below room temperature.
A solution consisting of 2.5 g of Alipal CO-436® and 0.5 g of potassium persulfate in 296 g of deoxygenated water was added to a reactor. The pH was adjusted to 2.3 with 10% H 3 PO 4 .
The reactor was heated to 75° C. and the head tank contents were added to the rector over 45 minutes. The reaction proceeded for 3 hours and was then cooled and filtered. The product was a stable, 19.4% solids content latex.
In addition to polymer 5, the latex also included 5 weight percent of Igepal CO-630®, 5 weight percent of Poly 316 N-30® and 20 weight percent ethylene carbonate.
Coatings were made over the same conducting layer used in Example 2. The coating had a slight uniform haze, survived 3 minutes in the processing bath used in Example 2, and was unchanged after 10 passes through the simulated film cleaner described in Example 2. The scratch resistance was outstanding before and after being passed through the simulated film cleaning device.
A coating on a poly(ethylene terephthalate) support having a subcoating was clear and survived 10 passes through the simulated film cleaning device.
The invention has been described in detail with particular reference to preferred embodiments thereof, but it will be understood that variations and modifications can be effected within the spirit and scope of the invention.
|
Novel polymers having the structure
--A).sub.x, --B).sub.y and --C).sub.z ;
wherein
A represents a polymerized acrylonitrile monomer;
B represents a polymerized hydrophobic ethylenically unsaturated monomer;
C represents a polymerized ionically charged vinyl monomer;
x is from 10 to 90 weight percent;
y is from 5 to 40 weight percent except that when B is a vinyl halide monomer, y is 10 to 89.9 weight percent; and
z is from 0.1 to 10 weight percent
The polymers are useful in forming protective over-coats for photographic elements.
| 2 |
[0001] This application takes priority from U.S. application Ser. No. 10/145,383 filed May 15, 2002, now pending, which takes priority from provisional patent application 60/291014 filed 5/16/01.
FIELD OF THE INVENTION
[0002] This invention relates to membranes and gels that are used to dehydrate organic streams and the preparation of novel mixed matrix composites useful in such processes. Membranes are comprised of a hydrophilic matrix containing at least one organic polymer and an inorganic metal oxide dispersed throughout the polymer. Gels made from the mixed matrix materials can be fabricated in a variety of shapes depending upon the container in which they are developed. The gels may be re-used in the dehydration process once they are stripped of their water content.
BACKGROUND OF THE INVENTION
[0003] Alcohols, in particular, 2-propanol (isopropyl alcohol-IPA), are being increasingly utilized in various industries as solvents and cleaning agents. Purification of alcohol streams when contaminated by water at certain concentrations becomes difficult due to the formation of azeotropic mixtures, composition wherein the ratios of the water and alcohol components in vapor and liquid are the same. Such azeotropic mixtures cannot be separated by normal distillation but only through complicated processes. Frequently, an additional substance is added to break down this azeotropic mixture. This additional substance must subsequently be completely removed and recovered from both product streams. Prior art processes using other membranes and gels did not provide the desirable properties of the processes of this invention.
[0004] The processes of the invention differ from microfiltration or ultrafiltration, processes wherein porosity is the key to preferential transport, and the flux rate depends upon molecular size. In the invention described herein using pervaporation/vapor permeation, molecular interaction between membrane and separated species is the determining factor rather than the molecular size. The main component of the pervaporation/vapor permeation process is the membrane material which determines the permeation and selectivity and hence the separation properties of the process.
[0005] A further criterion for the suitability of the per-vaporation membrane is its chemical and thermal stability. To obtain a high trans-membrane flow and a sufficient driving force, it is necessary to operate the pervaporation process at the highest possible temperatures. This means that the membrane will be in contact with a feed mixture containing a high concentration of organic components at high temperatures. To achieve an economical lifetime of the membranes all components of the membrane must be durable under aggressive conditions. The most common dehydration membrane reported in literature for use in pervaporation processes is prepared from polyvinyl alcohol (PVA).
[0006] Miyowasa (in U.S. Pat. Nos. 4,016,129 and 4,330,446) describes a hardenable coating comprising an aqueous dispersion of a silica polyvinyl alcohol complex prepared by the reaction between colloidal silica dispersion and polyvinyl-alcohol solution. However, this patent does not teach the casting solution of the invention for use in making membranes.
[0007] U.S. Pat. No. 4,148,689 to Hino, et. al. describes immobilization of microorganisms by hydrophilic complex gels by mixing a water-soluble polymer selected from PVA, gelatin and carboxymethylcellulose with tetraalkoxy-silane; hydrolyzing the resulting mixture by the addition of acid to form a homogenous complex for dispersing the microbial cells in the gelling mixture. This patent mentions that it is impossible to obtain the homogenous complex of the transparent gel when silica sol and silica gel were mixed with water soluble polymers. The problems addressed in this patent are not related to the process of the instant invention.
[0008] U.S. Pat. No. 4279752 describes uniform, porous PVA membranes. This process involves extracting the silica particles from the partially developed membrane. The reference is not related to use of a homogenous dispersion of silicon dioxide particles.
SUMMARY OF THE INVENTION
[0009] The present invention employs novel polymer/ceramic composite membranes composed of hydrophilic mixed matrix material and other compositions using such matrix materials as a mass transfer agent, are used to effect the alcohol/water separation. Matrix membranes described in the present specification contain at least one, and, possibly more than one, hydrophilic polymer along with nano-sized silicon dioxide particles dispersed throughout the membrane matrix that are cross linked using either an acid or an aldehyde. The incorporation of a dispersion of nano-sized silicon dioxide particles (5% to 40% being a preferred amount) results in improved wetting characteristics of the matrix as a result of water absorption by the SiOH groups.
[0010] The invention is demonstrated utilizing PVA and/or at least one amine polymer as a hydrophilic polymer and maleic acid or glutaraldehyde as cross linking agent. The polymer/ceramic membranes are fabricated into either homogenous or composites which are clear (without any phase separation) and are loaded with silicon dioxide particles.
[0011] In a preferred embodiment, the addition of a second polymer (for example, poly allylamine hydrochloride) into the PVA-silicon dioxide material produces a mixed matrix material that is homogenous, strong and clear without any phase separation between organic polymers and silicon dioxide particles i.e. without any settling out of the silicon dioxide particles. Additionally, the present invention provides a method for fabricating very thin films of the polymer/ceramic materials that are capable of dehydration of streams containing organic-containing streams.
[0012] This invention embodies mixed matrix gels of the aforementioned compositions which are prepared in a variety of shapes and show a remarkable degree of reversible water-absorbing properties. Mechanical and physical properties of the gels, such as extent of swelling in water, can be controlled by controlling the mixed matrix material composition.
DESCRIPTION OF DRAWINGS
[0013] FIG. Shows overall view of processes of pervaporation.
DETAILED DESCRIPTION
[0014] Pervaporation and vapor permeation are membrane-based operations by which relatively water-free alcohols can be produced in a simple and energy efficient manner. In pervaporation, water from a contaminated organic stream is preferentially transported across a thin membrane film. The source side of this membrane is wetted with the organic liquid. A vacuum or a sweep gas is used on the sink side of the membrane. The water is collected from the sink side by condensation.
[0015] Vapor permeation is similar to pervaporation with one major difference—vapors instead of liquid contact the source side of the membrane. In contrast to other membrane filter processes, pervaportation/vapor permeation works according to a solution diffusion mechanism.
[0016] For pervaporation and/or vapor permeation processes to be economical and efficient, ultra thin, hydrophilic films of appropriate polymer need to be deposited onto a highly porous support matrix. Such a combination will provide high throughput along with good mechanical stability to achieve the desired separation using minimum membrane area. Since water needs to be transported across the membrane, a high trans-membrane flow hydrophilic membrane must be used. The trans-membrane flow is a function of the composition of the feed. It is usually expressed as permeate amount per membrane area and unit time, e.g. kg/m 2 /hr, for the better permeating component.
[0017] Definitions: By mass transfer agent is meant a broad range of products that take up liquids such as water, including membranes used for pervaporation and vapor permeation but also including dessicants and sorbents. Gel structures or particles may function as sorbents in this context.
[0018] The term “gel” may also be used to refer to the coating used in the composite membranes, although the description herein uses the terms “gel” in example 6 and 7 refer to a product most likely used as desiccant.
[0019] It is often desirable to combine certain polymers to provide compositions having desirable properties of flexibility, adherence, and film formation with those of a suitable ceramic to provide hydrophilic mixed matrix materials for use in pervaporation/vapor permeation separation processes. The ceramic component materials are selected as membrane materials for this use in these separation processes based on their increased strength and thermal resistance.
[0020] The separation efficiencies of the different mixed matrix membranes were evaluated by comparing two values, flux and selectivity. These two values were evaluated by by varying of a number of conditions such as feed temperature, flow rate and permeate pressure. The use of properly selected absorbent with compatible polymer makes it possible to obtain a mixed matrix membrane having outstanding flux capabilities for given fluid mixtures.
[0021] Use of matrix composites described herein will facilitate a viable separation process because of the marked differences in their respective permeabilities through the hydrophilic mixed matrix membranes or gels. The matrix gels of the invention have high swelling capacity when placed in water but remain insoluble in water. The gels have reversible water absorbing properties and retain their shape characteristics after the removal of water and are reusable.
THE PERVAPORATION PROCESS
[0022] The mixed matrix materials described herein were fabricated using commercially available chemicals, including PVA, (99% hydrolyzed); polyallylamine hydrochloride; glutaric dialdhyde (glutaraldehyde), (50% by wt. solution in water); and maleic acid, (99%). Two types of backing materials were used for composite membrane preparation-1) METRICEL POLYPRO™, a porous mixed cellulosic ester material sold by Gelman Sciences, using a 0.1 micron pore size, and polyamide AK membranes obtained from Osmonics Corporation, USA. The polyamide membranes used were asymmetrical. The colloidal silica product was obtained from Nissan Chemical Industries, Ltd. (USA), under the names SNOWTEK-O™, and UP™. SNOWTEK O is a clear, aqueous colloidal silica sol having a pH of 2-4 and containing 21.5% by wt.nano-sized particles (10-20 nanometers) of silicon dioxide dispersed in water.
[0023] A schematic diagram of a pervaportation bench scale unit used is shown in fig. I. The feed tank ( 1 ) was a 20 liter stainless steel ASME pressure vessel. The feed consisting of IPA and water mixture, varying in water concentration from 5-20% wt, is made up in the feed tank by adding predetermined amounts of IPA and water. The feed mixture was circulated between the feed tank which contained a magnetic stirrer ( 2 ) and the pervaporation cell ( 5 ) in a closed loop using a gear-type liquid pump ( 3 ). Liquid flow rate was measured with a rotameter ( 6 ).
[0024] The temperature of the feed liquid was held constant by passing the feed through the inner tube of a tube-in-tube heat exchanger. The temperature of the shell fluid was controlled via a thermostate-regulated recirculating bath. The feed liquid temperature and the permeate vapor temperature were monitored by two thermistor thermometers inserted in the upper and lower compartment of the cell, respectively. The temperature gauge is shown at ( 9 ).
[0025] A vacuum gauge ( 10 ) monitored the downstream pressure and the vacuum system ( 8 ) stabilized the permeate pressure to below 1 torr. Permeate was collected in a cold trap ( 7 ) cooled with liquid nitrogen. After a pervaporation process had been initiated a three to four hour equilibration period was employed to reach the steady state mass transfer regime. After this initial period, steady state permeation collection was initiated. The tests were run batchwise over a time interval of two hours. The permeate liquid thus recovered was weighted and analyzed to evaluate permeation flux and selectivity. The total flux was simply calculated from the amount collected. The selectivity was calculated from the feed and permeate composition.
[0026] A stainless steel membrane filtration cell fabricated in house with an effective membrane area of 40.0 cm 2 was used in cross flow mode. The membrane was supported by a fritted stainless steel support. The cell was sealed by Viton O rings. The feed entered the cell at one end of the upper compartment, flowed along the length of the membrane and exited the cell at the opposite end of the upper compartment. The feed circulation across the test cell was 1500 ml./min. of the IPA/water mixture. Separation experiments were conducted at temperatures of 30° C. 40° C., 50° C., 60° C., 70° C. and 75 ° C. The feed samples were taken for each run, one at the beginning and another at the end of the process. The reported feed concentration was the average concentration of these two samples. One permeate sample was acquired during each run. The cold trap was first weighed after warming to room temperature and then the permeate sample was dissolved in 20-30 ml. of methanol. All feed samples and some permeate samples required dilution in methanol in order to fall within the analytical calibration range. All diluted samples were transferred immediately to 20 ml. vials and capped with Teflon lined septa. The composition of both feed and permeate were analyzed by direct injection gas chromatography. (GC) using HP 6890 series GC equipped with a flan ionization detector.
[0000] Mixed Matrix Materials
[0027] The mixed matrix membranes are comprised of organic polymer materials having a solid particulate absorbent incorporated therein. In a preferred embodiment of the invention, the organic polymer material will be selected from the group of materials having affinity for water. The solid particulate adsorbent material which is incorporated in the hydrophilic organic polymers, particles being nano-sized, said material possessing hydrophilic characteristics. When the membranes are prepared as composite membranes with a dense non-porous layer on a support material, the dense non-porous layer is applied to the support by solution casting followed by cross linking. An asymetrically porous support material, i.e. a porous support material which has pores of different average diameters on the front and the back, can be used. One readily available porous support material is reverse osmosis membrane.
[0028] Applying PVA based mixed matrix casting solution onto a porous backing layer forms a non-porous separating layer. Aqueous solutions of PVA may vary in concentration from a low level of 0.5 wt. % up to an upper limit determined by the solubility limit of polyvinyl alcohol (PVA) in water. The solubility limit of PVA in water depends upon the degree of hydrolysis and molecular weight of the polyvinyl alcohol. The optimum PVA concentration range is from 5 to 8 wt %.
[0029] After applying the mixed matrix polymer/ceramic solution to the porous backing layer, cross linking takes place during drying with use of the cross linking agent. Temperatures between room temperature and 200° C. accelerate the drying and cross linking. Preferred temperatures will normally be in the range of 80° C. to 180 ° C, more preferrably 100° C. to 150° C. The cross linking time is at least 1 minute, usually in the range of 1 to 60 min., preferably 5 to 30 min.
[0030] The gels may be formed by excluding a small quantity of water from the starting homogenous aqueous solutions. Gels insoluble in water having a variety of mechanical and physical properties as well as varied capacity for swelling in water can be prepared by controlling the initial mixed matrix material composition. The water-swollen mixed matrix gels, when dried, result in very hard materials that are greatly reduced in size compared to the starting water swollen gels. The hard materials show high swelling when placed again in water. Such a reversible water absorbing property can be attributed to the dispersed particulate silicon oxide.
EXAMPLE 1
[0031] To a granular PVA, water was added to yield PVA concentration in the range of 5-10 wt %. Clear and homogenous PVA solutions were obtained upon heating the mixture for 5 hours in an oven kept at 100° C. The solution was cooled to room temperature before use. A predetermined amount (0.15-1.00 g.) of cross linking agent (acid or aldehyde) was added to 25-30 g. of the polymer-containing solution and shaken well until the cross linker completely dissolved.
[0032] Next, 2-10 g. of a clear aqueous solution containing 21.5 wt % of nano-sized silicon dioxide particles was added and shaken well to obtain a clear mixed matrix solution. In some formulations a 10-15 wt % aqueous amine polymer solution was added and shaken well until all the components were homogeneously mixed. (Studies revealed that mixing is very important in order to a void phase separation and obtain clear and homogenous membranes.) Depending on the final membrane thickness required, the mixtures were diluted by addition of 0-30 g. of water. The mixtures were left to stand for 1-4 days at room temperature to facilitate the removal of bubbles. Stand-alone membranes were cast by spreading the solution on a neutral temporary medium such as clear Plexiglas. Glass is another example of a temporary neutral medium. Composite membranes may be cast on a backing material such as a reverse osmosis membrane.
[0033] Allowing the cast solutions to stand at room temperature for 0-6 hours to remove water results in the formation of a semi-dry membrane that is thinner and more viscous. The film is then cross linked at 150° C. for 5-120 minutes. Ten to sixty minutes before testing the membranes for their separation efficiency, the cross linked membrane is loaded in a solution of IPA/water (the same composition as the feed for which the membrane is to be used). This soaking was found to ease membrane handling and fixing in the test cell, especially for the membranes containing only one polymer.
EXAMPLE 2
[0034] Homogenous membranes using PVA were prepared according to the general method described in example 1 with the following modifications: Membranes were prepared without the addition of a second polymer. Maleic acid was employed as across linking agent with the cross linking carried out for either 30 or 90 minutes at 150° C. Dehydrations of IPA/water mixtures was carried out according to the procedure outlined above and results, flux vs. feed temperature, given in Table 1.
TABLE 1 Effect of SiO 2 and Crosslinking Time on dehydration of IPA for example 2. Feed concentration: IPA 80 wt. % and water 20 wt. % Permeate concentration: 97-98 wt. % water 0 wt. % SiO 2 30 wt. % SIO 2 30 wt. % SiO 2 Feed 30 min. cross 30 min. cross 90 min. cross Temperature linking linking linking (° C.) Total flux g/m 2 /hr Total flux g/m 2 /hr Total flux g/m 2 /hr — 75 12 40 79 100 45 50 146 181 77 60 209 320 137 70 389 495 213 75 550 670 261
[0035] The effects due to increase in the feed temperature and membrane cross linking time were on the expected lines, flux increasing with feed temperatures and decreasing with the increased cross linking time.
[0036] Table 1 also details the effects of SiO 2 presence and absence in the mixed matrix membranes that were cross linked for the same amount of time (30 minutes). At a given temperature, the presence of silicon dioxide particle in the membrane resulted in an increase of the water flux. The increased water flux can be attributed to the presence of SiO 2 in the crosslinked PVA matrix which may provide additional pathways for the separation of water. The membranes showed very good separation efficiency. The permeate always contained more than 98.5 wt. % water (compared to 20 wt. % in the feed).
EXAMPLE 3
[0037] Membranes were prepared according to the general procedure described in the example 1 with the following modification: Composite mixed matrix membranes were prepared by casting PVA/SiO 2 /polyallylamine hydrochloride polymer solution on Gelman Sciences backing. Table 2 lists the results obtained on carrying out the dehydration of a feed stream containing 90 wt. % IPA and 10 wt. % water mixture by pervaporation. The presence of poly (allylamine hydrochloride) in the membrane has two effects: a) it imparts flexibility to the mixed matrix material and b) it results in increasing the hydrophilic nature of the membrane. As a result, the water flux increased as compared to results shown in table 1 despite a decrease in the feed water concentration from 20 wt. % to 10 wt. %.
[0038] All had been cross linked for 30 minutes.
TABLE 2 Dehydration Results of Example 3 Feed Flux Flux Permeate Temperature (g/m 2 /hr.) (g/m 2 /hr) water ° C. IPA flux Water flux concentration 40 10 256 96.3 50 12 357 97.4 60 17 541 97 70 30 802 96.4
EXAMPLE 4
[0039] Effect of variation of the permeate pressure on the seperation of IPA/water is listed in table 3. Studies were conducted at a temperature of 60° C. The water flux showed only a marginal decrease (12%) on increasing the absolute downstream pressure from 2 to 25 mm. Hg. The concentration of water at all permeate pressures in the permeate was more than 96 wt. %. The results indicate that dehydration of IPA need not be carried out at very high vacuum.
TABLE 3 Effect of Permeate Pressure for Example 4 Permeate Flux Flux Permeate Pressure (g/m 2 /hr.) (g/m 2 -hr.) water mm/Hg IPA flux Water flux concentration 2 15 548 97.3 10 15 541 97.3 15 15 495 97.1 20 18 492 96.5 25 18 475 96.4
EXAMPLE 5
[0040] The separating layer of the composite membrane contains a mixture of polyvinyl alcohol and polyallyl-amine hydrochloride with nano-sized silicon dioxide particles dispersed throughout the membrane matrix and cross linked using gluaraldehyde. The backing used for preparing the composite membranes is commercially available polyamide reverse osmosis membrane obtained from Osmonics. The dry composite film was cross linked at 150° C. for 12 minutes resulting in a separation layer having the composition as shown in table 4.
TABLE 4 Composition of Separating Layer of Mixed Matrix Membrane (example 5). Material: wt % PVA 68 Glutaraldehde 7 SiO 2 15 Polyallylamine 10
[0041] The results of performing dehydration of IPA by pervaporation shown in table 5 are as follows: 10% water/90% IPA in feed flux=1050 gm/m 2 /hr at 60° C., 1600 g./m 2 /hr at 70° C. permeate=97+wt. % water. For comparison, these results are at least two times more than those reported in example 4 (under the same experimental conditions). Table 5 also shows the results obtained with a decreased feed water concentration (5% water/95% IPA). Although the feed water concentration decreased by half (5 wt. % from 10 wt. %) the total flux dropped by 4-5 times with only marginal increase in permeate composition. All results shown in table 5 were found to be reproducible during testing lasting over a period of more than 40 days.
TABLE 5 Dehydration Results of Example 5: Feed concentration: IPA 90 wt. %/water 10 wt. % Permeate concentration: 97-98 wt. % water. Total Flux Feed Temperature (° C.) (g/m 2 /hr.) 40 342 50 575 60 1072 60 1044 70 1614 70 1578 70 1631 Feed concentration: IPA 95 wt. %/water 5 wt. % Permeate concentration: 98-99 wt. % water. Total Flux Feed Temperature (° C.) (g/m 2 /hr.) 40 64 50 123 60 210 70 371
EXAMPLE 6
[0042] Preparation method for hydrophilic mixed matrix gels was as follows: 1) Homogenous PVA solutions in the range of 5-10% were prepared by the same procedure as described above for the membrane preparation. 2 ) A predetermined amount (0.15-1.0 g.) of cross linking agent taraldehyde was added to part of the above polymer ution and shaken well until the cross linker pletely dissolves. 3) Next, 6-10 g. of a silica sol such as SNOWTEX-O™ was added and shaken well to obtain a clear solution. The mixture was then either allowed to stand at room temperature for 20-45 days or heated in an oven at a temperature of 50-80° C. for 1-3 days. The viscosity of the solution increased and formed a gel that separated out from the container it was in during this process. The gel, a homogenous aqueous mixed material solution, pulls away from the side of the container as water is expressed out of the gel. The process by which the water comes off the gel may be referred to as “exclusion” from the homogenous aqueous solution. Gels produced by the process are swollen by, but are insoluble in, water. They have reusable and water sorbing characteristics. The gels acquire the shape of the container in which they develop and can thus be formed into a variety of different shapes. Gels having a variety of mechanical and physical properties, including their swelling ability in water can be prepared by controlling the initial mixed matrix material compositions.
EXAMPLE 7
[0043] The water swollen mixed matrix gels prepared according to example 6, when dried result in very hard materials that are greatly reduced in size compared to the starting water-swollen gels. The dry and hard materials show high swelling when placed again in water without any disintegration. Reversible water absorbing properties with retention of shape can be attributed to the dispersed particulate silicon oxide. Table 6 lists the composition of the gels and their swelling in water.
TABLE 6 Gel composition and swelling in water (for example 7) 59.0 wt % PVA 38.0 wt. % SiO 2 Water swollen 3.0 wt. % glutaraldehyde state Dry material state Length 4.6 cm. 3.3. cm. Diameter 1.8 cm. 1.1 cm. Volume 11.71 cm 3 3.14 cm. 3 Weight 11.3909 g. 4.8638 g. Water uptake 6.5271 g. Swelling % 134% (g/g) Swelling % volume 273%
EXAMPLE 8
[0044] DSC (Differential Scanning Calorimetry) and TGA (Thermogravimetric analysis) measurements were carried out on polymer/ceramic mixed matrix membranes and gels. The results shown in table 7 indicate all the mixed matrix materials to have high glass transition temperatures relative to typical PVA material. Although there is a decrease in the glass transition temperature due to the inclusion of polyallylamine hydrochloride membranes fabricated from such mixed matrix material are still glassy and, as such, can be safely employed for high temperature dehydration operations. TGA results indicate a more gradual weight loss at high temperatures (300-600° C.) in all mixed matrix containing silicon dioxide particles (especially the hard materials obtained on drying water swollen gels) even at temperatures well over 600° C.
TABLE 7 Glass Transition Temperatures (Tb) for example 8. Material Tg (° C.) Example 5 poly (vinyl) 206 alcohol/silicon dioxide/poly (allylamine) and cross linked using glutaraldehyde Example 7 poly (vinyl) 365 alcohol/silicon dioxide and cross linked using glutaraldehde Pure polyvinyl alcohol 85 (for comparison)
[0045] While silicon dioxides are used in the examples, other oxides such as zeolites or aluminum oxide may be used. It would also be clear to one skilled in the art that other organic polymers known in the art as equivalents may be used in the practice of this invention.
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Polymer-ceramic mixed matrix compositions contain one or more organic polymers and a nano-sized dispersion of inorganic metal oxide particles which are dispersed throughout the composition. Materials have use in making membranes that act as transfer agents.
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RELATED APPLICATIONS
The application claims the benefit of U.S. Provisional Patent Application Ser. No. 60/025,764, filed Sep. 23, 1996.
FIELD OF THE INVENTION
The invention relates generally to rolls of wrapped material that have a hollow fiber core and, particularly, to an insert that is mounted within the hollow fiber core.
BACKGROUND OF THE INVENTION
The present invention solves a problem encountered by rolls of material, such as paper, that are wrapped around a hollow fiber core. The fiber core is typically made from pressed paperboard which has enough rigidity to support the rolled material. When placed on a machine which allows the rolled material to unwind, the fiber core is held and serves as the axis around which the roll of material rotates. Preferably, the unwinding process occurs with stability such that the only motion is rotational.
The manner in which the fiber core is held is critical to the performance of the unwinding process. Typically, a tapered chuck is inserted at each end of the hollow fiber core. The tapered chuck initially exerts a known amount of pressure at its contact points within the hollow fiber core. As the roll is rotated, the dynamic forces associated with the rotation are transferred through the hollow core and into the tapered chuck. Moreover, to maintain a constant rate at which the material is unwrapped, the roll must gradually increase its angular speed as more material is removed from the roll. Ultimately, the increased speeds and dynamic forces result in a marring of the inside surface of the hollow fiber core by the tapered chuck at the contact points. Eventually, the damage to the hollow fiber core may become so great that the severe wobbling of the roll is experienced which can result in a catastrophic failure. Considering that these rolls can weigh from several hundred pounds to several thousand pounds and are rotating at several hundred revolutions per minute, such a failure can result in extensive damage to the machinery and injury to personnel in the immediate area.
One solution to this problem has been to use large metal inserts that fit within the hollow fiber core. However, these metal inserts, which are usually made of steel, weigh thirty pounds or more and are, consequently, difficult to manually transport and position. Moreover, they are expensive since detailed machining is necessary for this insert to tightly fit within the core and perform the necessary process.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1A is a side view of an end view of a collett used in the present invention;
FIG. 1B is a plan view of the collett in FIG. 1A;
FIG. 1C is a cross-section of a portion of the collett taken along line 1C--1C in FIG. 1B;
FIG. 2A is a side view of an arbor used in the present invention;
FIG. 2B is a plan view of the arbor in FIG. 2A; and
FIG. 3 is a perspective view of the arbor and collett being used on a paper roll assembly.
DETAILED DESCRIPTION OF THE INVENTION
Referring initially to FIGS. 1A-1C, a collett 10 includes a base portion 12 with a bottom surface 13. The base portion 12 has a base diameter BD which has a dimension that depends on the size of the hollow fiber core in which the collett 10 is to be inserted. Typically, the size of base diameter BD is less than or about equal to the outer diameter of the fiber core in which it is to be inserted.
A side wall 14 projects upwardly away from the base portion 12. The side wall 14 includes a series of slots 16 which continue substantially along the height of the side wall 14. As shown, there are eight slots 16 which segregate the side wall 14 into eight equal segments. At the bottom of each slot 16 is a gap 17 which is larger than the slot width SW to provide additional flexibility to the segments of the side wall 14. Again, the size of the slot width SW is dependent on the application but is generally between about 0.020 inch and about 0.100 inch. The need for flexibility in the side wall 14 is discussed below.
The collett 10 has an internal bore 18 which is defined by the side wall 14. The bore 18 is not completely cylindrical as is best seen by reviewing FIG. 1C which is a cross-section through the side wall 14 taken along line 1C--1C in FIG. 1A. The side wall 14 has an inner surface 20 and an outer surface 22 which are slightly off from being perpendicular with the base portion 12. The inner surface 20 extends from the base portion 12 at an angle α from the normal line and has an inner diameter ID adjacent to the base 12. In a preferred embodiment, angle α is in the range from about 2° to about 6°. Likewise, the outer surface 22 projects from the base portion 12 at an angle β away from the normal line and has an outer diameter OD adjacent to the base 12. In a preferred embodiment, angle β is the range from about 0.25° to about 4°. Consequently, the inner surface 20 which defines the bore 18 and the outer surface 22 both have a slight frustoconical shape.
Furthermore, angle α is larger than angle β so that when the side wall 14 is forced out by the arbor 30 (described below with reference to FIGS. 2A-2B), the outer surface 22 will expand past the normal line relative to the base portion 12. This ensures that the outer surface 22 tightly engages the interior surface of the fiber core.
FIGS. 2A-2B illustrate an arbor 30 which cooperates with the collett 10 of FIGS. 1A-1C. The arbor 30 includes a circular bulkhead 32 that has a bulkhead width BW which is approximately the same size as the base diameter BD of the base 12 of the collett 10 in FIG. 1A. An expander projection 34 extends upwardly from the bulkhead 32 and includes an internal width IW and an expander projection width EPW. The expander projection 34 of the arbor 30, as will be described in detail below, is for engaging the outer surface 22 of the side wall 14 of the collett 10 so as to expand it into the fiber core 62. The arbor 30 also includes two slots 36 located on the bulkhead 32 which allow for the insertion of a tool to separate the collett 10 from the arbor 30, as is described below, if these two components remain engaged.
Like the side wall 14 of the collett 10 described above, the projection 34 includes a tapered portion 38. The tapered portion 38 typically extends along about half the height of the projection 34. The tapered portion 38 facilitates the insertion of the arbor 30 into the collett 10. The angle γ at which the tapered portion 38 deviates from the normal line is usually in the range from about 1° to about 5°. This angle γ is usually less than the angle α on the inner surface 20 as shown in FIG. 1C.
FIG. 3 illustrates the use of the collett 10 and the arbor 30 on a roll 60 of material that is, for example, paper. The roll 60 includes an inner fiber core 62 around which the material of the roll 60 is wrapped. The types of machinery which support the roll 60 and allow the roll 60 to rotate varies. However, each type of machinery must have a pair of supporting arms 70 on either side of the roll 60 which support the roll 60. And, each arm 70 must include a spindle 72 on which the roll 60 spins.
To assemble the components, the arbor 30 is mounted on the spindle 72. The collett 10 is then placed into the fiber core 62 which is facilitated by the outer surface 22 (FIGS. 1A-1C) of the collett 10 being tapered. The arm 70 on which the spindle 72 resides is then moved in the insertion direction denoted by arrow I toward the roll 60. The arbor 30, which is mounted on the spindle 72, is inserted into the bore 18 (FIGS. 1A-1C) of the collett 10 which is made easy due to the tapered portion 38 of the projection 34. The expander projection width EPW of the projection 34 of the arbor 30 is slightly smaller (e.g. about 0.002 inch to about 0.015 inch) than the inner diameter ID of the side wall 14. As the insertion process continues, the projection 34 engages the inner surface 20 of the side wall 14, which is tapered inwardly at angle α, to force the outer surface 22 of the side wall 14 to tightly engage the inner surface of the hollow fiber core 62. The slots 16 and the larger gaps 17 at the bottom of the slots 16 provide flexibility to the side wall 14 in that they permit the radial outward movement of each segment of the side wall 12. The press-fit engagement between the outer surface 22 of the side wall 14 and the inner surface of the fiber core 62 is enough to sustain an appropriate contact pressure between the collett 10 and the fiber core 62 even when they are subjected to the strenuous dynamic forces of operation.
After a roll 60 has its wrapped material completely removed through the rotation of the roll 60, the arm 70 moves away from the fiber core 62. The tight engagement between the collett 10 and the fiber core 62 is then removed and the collett 10 can be pulled from the fiber core 62. If the collett 10 is not removable from the fiber core 62 by hand, then a simple tool, such as a screwdriver, can be used to pry the collett 10 from the fiber core 62. If the collett 10 remains on the arbor 30, then a simple tool, like the screwdriver, can be inserted into the slots 36 (FIGS. 2A-2B) to pry the collett 10 from the arbor 30.
The collett 10 is made of a durable polymeric material, such a nylon, which will not deform under the compressive stresses when it is pressed into the fiber core 62. Consequently, it is not heavy and poses no risk of injury when being transported, unlike current devices which perform a similar function that are made of steel and are, consequently, very heavy. Furthermore, if the collett 10 becomes damaged, then the damaged collett 10 can be recycled and replaced by a new collett 10. Because the colletts are made of a polymeric material such as nylon, they are easily manufactured and are, therefore, very inexpensive in comparison to comparable steel devices.
The arbor 30 is made of a metal, usually a hardened steel, which allows it to force the collett 10 into the fiber core 62 without the risk of being inelastically compressed during the process. Although the arbor 30 is metallic, and therefore heavier than the collett 10, it does not need to be removed each time a new roll 60 is to be mounted on the spindle 72. Consequently, once the arbor 30 is mounted on the spindle 72, it can be continuously inserted into and retracted from the fiber cores 62 of the rolls 60.
While the present invention has been described with reference to one or more particular embodiments, those skilled in the art will recognize that many changes may be made thereto without departing from the spirit and scope of the present invention. Each of these embodiments and obvious variations thereof is contemplated as falling within the spirit and scope of the claimed invention.
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A device for mounting a roll of material that includes a fiber core around which the material is placed. The device includes a lightweight, polymeric collett that is inserted into the fiber core. The polymeric collett has a plurality of individual segments that expand radially with respect to a central axis of the roll of material. Each of the plurality of individual segments includes an inner wall and an outer wall. The inner walls of the plurality of individual segments define a cavity. The outer walls engage an interior surface of the fiber core. An arbor engages the inner walls of the plurality of individual segments and forces them outwardly to place the outer walls into tight, frictional engagement with the interior surface of the fiber core.
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CROSS REFERENCE TO RELATED APPLICATION
This is a division of application Ser. No. 09/054,397, filed Apr. 3, 1998 now U.S. Pat. No. 6,026,135. Reference numerals used in the parent application have been retained herein for cross-reference consistency.
This application claim benefit to provisional application Ser. No. 60/041,929 Apr. 4, 1997.
FIELD OF THE INVENTION
The invention relates to apparatus and method for depositing a substantive, highly visible, yet temporary mark on a surface, the mark being formed of a superabsorbant polymer, water and dye mixture.
BACKGROUND OF THE INVENTION
While the invention is described in the context of marking the location of mines, it is anticipated that the novel mark can be applied wherever a location needs to be identified.
In the process of identifying mines, it needs to be marked for subsequent neutralization, usually by digging it out of the ground. The existing line marking and other spray paint means are substantially without mass, are difficult to place on ground and are only visible if viewed substantially straight on. Further, paints and the like are usually associated with toxicity and are semi-permanent. There is opportunity and a need for a temporary, environmentally friendly and highly visible marking scheme.
SUMMARY OF THE INVENTION
It is critical that the location of a possible mine be reliably marked for subsequent neutralization. Once an object has been confirmed as a mine, the object or the ground in which it lies is marked by placing a substantive, visible and temporary mark on the ground.
In a broad aspect, a process is provided comprising mixing a dry granular, free-flowing superabsorbent polymer powder with liquid, preferably water, and dye to form a semi-solid gel and depositing the gel onto the surface to be marked. The dye makes the gel very visible, the bulk of the gel makes it more easily visible, the nature of the gel makes it temporary; easily dispersed with time, sunlight or water.
The above process is effected using apparatus comprising a ram used to eject the gel from a mixing chamber without introducing excess mechanical agitation and thus without causing significant breakdown. Preferably the apparatus comprises a first cylinder with a ram moveably therein to alternately open to form a gel mixing chamber and then close to eject the gel contents. Further, a second cylinder and ram is provided, preferably directed through a manifold to supply the liquid. The manifold can also co-ordinate the introduction of liquid and dry polymer powder into the first cylinder.
The resultant mark is bulky and thus highly visible from the side. The mark's visibility continues for several hours and after its useful life, the mark degrades in an environmentally friendly manner, substantially disappearing completely in 48 hours under drying, sunlight or rain conditions.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic side view of a mine detecting vehicle;
FIG. 2 is a flow chart of the novel marking system;
FIG. 3 is a perspective view of the marking apparatus according to one embodiment of the marking system;
FIG. 4 is a perspective exploded view of the marking apparatus according to FIG. 3;
FIG. 5 a is a cross-sectional view through the center of the mixing and discharge manifold according to FIG. 3;
FIG. 5 b is a cross-sectional side view of the mixing and discharge manifold as sectioned through the center of the ram chambers according to FIG. 3;
FIG. 6 a is a schematic cross-sectional view of the apparatus in the powder charging position;
FIG. 6 b is a schematic cross-sectional view of the apparatus in the powder discharging position;
FIG. 7 is a cross-sectional view of a hydraulic actuator and ram used for both the water ram and the product ram; and
FIG. 8 is flow chart of the water and product ram cycles for taking on water and powder respectively, mixing and making the gel product and discharging the gel product.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Having reference to FIG. 1, a mine detector vehicle comprises leading sensors 2 , 3 , 4 , a remote-controlled detection vehicle 5 , a trailing sensor 6 and a following command vehicle 7 . The illustrated vehicle is described in great detail in the co-pending parent application.
The leading sensors identify targets of interest (“TOI”). The trailing sensor 6 is a device, mounted in a maneuverable trailer 20 , which is capable of confirming whether a TOI is a mine.
A marking system is located on trailer 20 and comprises a marking assembly 201 for placing a physical mark on the ground at the confirmed location of a mine. Subsequently, the mark is referenced for safely re-locating the mine for neutralization.
Having reference to FIGS. 2, 3 , a marking assembly 201 is provided comprising novel apparatus and method. Generally, as described below, a dry granular longchain polymer powder is mixed with a highly visible dye and water. The polymer swells to form a gel product having a wet volume about 20 times the dry powder volume. This highly visible gel product is deposited on the ground at the position which is to be marked. The gel product has a physical bulk which is more easily visible than is a substantially mass-less mark. Combined with a highly visible dye, the mark very effective. When placed on the ground to mark the presence of a mine, the location is safely and clearly marked for several or more hours before planned degradation lessens its effectiveness.
More specifically, and having reference to FIG. 2, the marking system comprises a gel production and marking assembly 201 , water supply tank 202 and pump 203 , a hydraulic power circuit 204 and a 24VDC controller 205 .
Turning to FIG. 3, the assembly 201 for making and depositing the gel product comprises a dry powder hopper 206 , a metering head 207 , a mixing and injecting manifold 208 , a water ram 209 , a gel product ram 210 and a gel product discharge tube 211 . The gel product or mark 212 is discharged onto the ground 213 from the discharge tube 211 .
In more detail and referring to FIGS. 3-6 b, the hopper 206 is mounted atop a base plate 214 . The hopper 206 is located above the metering head 207 for permitting gravity discharge of its dry powder through a hopper discharge port 215 (seen in FIG. 6 a, 6 b ). The metering head 207 comprises: a guide block 217 sandwiched between a top metering plate 216 and a bottom isolating plate 218 . The metering head 207 itself is sandwiched between the hoppers base plate 214 and the manifold 208 .
The hopper's base plate 214 , metering plate 216 , guide block 217 , isolating plate 218 and manifold 208 are stacked and incorporate seals between each component. The hopper base plate 214 , guide block 217 and manifold 208 are in fixed space relation to each other using two opposing sets of four bolts 219 each, and are spaced from each other by the metering and isolating plates 216 , 218 . The metering and isolating plates 216 , 218 are laterally movable using a double acting hydraulic actuator 220 . The actuator 220 is connected to a slider bracket 221 which links the metering and isolating plates 216 , 218 together for synchronous, sliding movement.
The guide block 217 has a “H”-shaped cross section for forming a pair of upper side walls 222 and a pair of lower side walls 223 for containing the metering and isolating plates 216 , 218 during sliding movement.
Each of the hopper base plate, metering plate, guide block, isolating plate and manifold have complementary ports formed therethrough for gravity passage of the dry powder. Dry powder discharges through the hopper port 215 . A metering port 224 is formed in the metering plate 216 . Port 225 is formed through the guide block 217 . Port 226 is formed through isolating plate 218 . Finally, a port 227 is formed through the manifold 208 .
The hopper base plate port 215 is laterally shifted from the guide block and manifold ports 225 , 227 so that at no time is there a continuous path from the hopper 206 through to the manifold 208 . The guide block port 217 is always aligned with the manifold port 227 .
The metering and isolating plates 216 , 218 are movable between a powder charging position (FIG. 6 a ) and a powder discharging position (FIG. 6 b ).
In the powder charging position, the metering port 224 (and isolating port 226 ) are actuated with actuator 220 so as to align with the hopper base plate port 215 . This action takes the metering and isolating ports 224 , 226 out of alignment with the guide block port 225 .
In the discharging position, the metering port 224 (and isolating port 226 ) are actuated to align with the guide block port 225 for discharging metered powder through the manifold port 227 .
Best seen in FIG. 4, oblong seals 228 , 229 are situated in the two interfaces between the hopper base plate 214 , metering plate 216 , and guide block 217 . The oblong shape of the two seals 228 , 229 maintains a continuous seal between the hopper base plate port 215 and metering plate port 224 , and between the metering plate port 224 and guide plate port 225 throughout the powder charging and discharging positions.
Circular seals 230 , 231 are situated in the two interfaces formed between the guide block 217 , the isolating plate 218 and the manifold 208 . The isolating plate port 226 moves into the circular sealed area in the discharge position. In the powder charging position, the isolating plate port 226 moves out of the sealed area for isolating the manifold 208 from the metering head 217 .
Beneath the manifold 208 is mounted a pair of hydraulically operated rams; the water ram 209 and the gel product ram 210 . Best seen in FIG. 7, rams 209 , 210 have pistons 232 movable within cylinders 233 . The pistons 232 have annular seals 234 for forming a water chamber 235 a and product chamber 235 b within their respective cylinders 233 . The pistons 232 are independently operated with double acting hydraulic actuators 236 . The cylinders 233 seal to the underside of the manifold 208 , secured with long studs 245 . Each hydraulic actuator 236 has a piston rod 237 having a first end 238 and a second end 239 . A hydraulic piston 240 and annular piston seals 241 are mounted at the piston rod's first end 238 . The hydraulic piston 240 is operable within a hydraulic cylinder 242 separated from the water and product chambers 235 a, 235 b by bulkhead 243 and annular seal 244 . The water and product pistons 232 are mounted at the second ends 239 of the piston rods 237 . A first hydraulic port 246 (FIG. 3 and fancifully depicted in dotted lines in FIG. 7) in the bulkhead 243 introduces hydraulic fluid to the hydraulic actuator 236 to drive the piston rod 237 and its respective water and product piston 232 away from the manifold 208 , forming their respective water and product chambers 235 a, 235 b. A second hydraulic port 247 introduces hydraulic fluid to the hydraulic actuator to drive its respective water and product piston 232 towards the manifold 208 for ejecting the contents of their respective chambers 235 a, 235 b.
The manifold port 227 extends completely through the manifold 208 from the metering head 207 to the product chamber 235 b of the product ram 210 located directly below the port 227 (FIGS. 4, 6 a, 6 b ).
Having reference to FIGS. 5 a, 5 b, the manifold 208 routes powder, water and product gel to and from the water and product rams 209 , 210 . A first passage 250 extends from the water ram 209 and chamber 235 a, through the manifold 208 and into the product ram 210 and chamber 235 b. The water passage 250 is interrupted with a valve, such as a check valve 251 for permitting water flow from the water chamber 235 a to the product chamber 235 b but not in the reverse direction. The first passage 250 exits into the product chamber 235 b through discharge 252 , angled downwardly towards the product ram's piston 232 . A second passage 253 extends from the product chamber 253 b, through the manifold 208 and to a gel product outlet port 254 . A product discharge tube (FIG. 3) conducts gel product from the outlet port 254 to the marking site. Port 255 is provided for routing water supply through a third passage 256 to the water chamber 253 a. The third passage 256 is fitted with a check valve 257 to permit water to enter the water chamber 253 a but not exit that way.
A superabsorbant powdered long chain polymer is used such as Potassium Polyacrylate, polycarbonate or polymer available under the tradename “DriMop” or SaniSorb” from Multisorb Technologies, Inc., Buffalo, N.Y. These and other similar polymers are often used in liquid spill control and activate when mixed with water to form a gel product. When mixed at ratio of about 95:5 water:powder by volume the polymer powder absorbs nearly 20 times its volume in water and forms a semi-solid gel. The gel is not robust and breaks down under mechanical agitation and UV exposure. About 97% of the polymer is biodegradable.
Environmentally friendly, forestry-marking dyes are available in liquid form as “Fluorescent Dye” from Forestry Suppliers, Inc., Jackson, Miss. Some dyes are suitable for use with potable water such as “Rhodamine WT”.
In operation, dye is premixed with water (for Fluorescent Dye, concentrations of about 0.1% are sufficient). The hopper is filled with powdered polymer.
Having reference to FIGS. 6 a, 6 b, the metering and isolation plates 216 , 218 are cycled between the charging and discharging positions in the respective figures. The position of the metering and isolating plates 216 , 218 dictates the timing of product ram 209 charging with powder and the ejection of gel product.
The charging/discharging cycle is illustrated in FIG. 8 .
When actuated to the charging position (FIG. 6 a ), the following occurs. The ⅞″ diameter by ½″ deep metering port 224 is moved to the charging position under the hopper discharge port 215 for accepting a metered volume of the polymer powder. The isolation plate 218 seals the manifold 208 from the metering head 207 and hopper 206 .
While the metering and isolation plates 216 , 218 are still at the charging position, the following steps can occur. The water ram 209 is actuated to move water from the water chamber 235 a, through the first passage 250 and into the product chamber 235 b for mixing with polymer powder present from the previous cycle. Air is bled from the product chamber 235 b while water is transferred. The water and powder mix to form the gel product. The product ram 210 is then actuated for pressurizing and ejecting the gel product out through the manifold's second passage 253 and the discharge tube 211 without subjecting the gel product to excessive mechanical agitation or flow-back into the metering head 207 or hopper 206 .
When actuated to the discharging position (FIG. 6 b ), the following occurs. The metering plate port 224 is positioned to discharge the metered polymer through the aligned guide block 217 , isolation plate 218 and manifold ports 227 so that it enters the product chamber 235 b of the product ram 210 . The metering plate 216 seals the hopper discharge port 215 . As it is disadvantageous to contaminate the guide block isolation plate ports 217 , 218 of the metering head 207 , it is necessary to return the metering and isolation plates 216 , 218 to the charging position before mixing the gel product and discharging it.
If the discharge point of the discharge tube 211 is known relative to the location of the object or site to be marked then the tube so directed to that location for discharge of the marking gel product.
If the marking apparatus is not going to be used right away, it is flushed with water to clean the product chamber 235 b, manifold port 227 , second passage 253 and product discharge tube 211 of gel product.
Optionally, powdered dye can be added to the polymer powder before mixing.
Once discharged, the product gel has the following advantages:
it is visible even from the side due to its bulk, and highly visible due to the dye, visibility continuing for several hours and in even low light conditions using a fluorescent dye;
the gel components are easily obtained, stored and are inexpensive;
the apparatus is simple, requires little maintenance and easy to operate; and
after its useful life of several hours, the mark (gel product) degrades in an environmentally friendly manner, substantially disappearing completely in 48 hours under drying, sunlight or rain conditions.
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Apparatus and process for marking a surface with a highly visible and substantive mark comprising mixing a dry granular, free-flowing superabsorbent polymer powder with liquid, preferably water, and dye to form a semi-solid gel and depositing the gel onto the surface to be marked. The marking apparatus comprises a chamber for mixing the gel and a ram used to eject the gel from the chamber without excess mechanical agitation and without causing significant breakdown of the gel. The dye makes the gel very visible, the bulk of the gel makes it more easily visible, the nature of the gel makes it temporary; easily dispersed with time, sunlight or water.
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FIELD OF THE INVENTION
[0001] The present invention is directed to a printing unit with at least one printing group. The printing group includes at least two cylinders which are shiftable, with respect to each other, between three positions.
BACKGROUND OF THE INVENTION
[0002] A printing unit is known from DE 44 30 693 A1. A double printing group, consisting of two transfer cylinders forming a print position and the associated forme cylinders, can be driven by a common drive motor. A transfer cylinder can be brought into two positions, a print-on and a print-off position, by the provision of eccentric seating.
[0003] EP 0 862 999 A2 discloses a double printing group in which the two transfer cylinders, which together form a print position, are not in a driven connection with each other. Instead, each has a drive motor together with the associated forme cylinder. In addition to on and off positions, the two transfer cylinders can be brought into a third position in relation to each other, in which third position, a web can be passed between the two transfer cylinders during the printing operation.
[0004] A device for putting cylinders into contact is known from DE 44 01 289 A1. Besides an out of contact position of the cylinders, it is possible with this device to set two different contact positions of the cylinders in relation to each other for different thicknesses of the web of material. In this case, a support element having two different stops is provided for the setting.
[0005] DE 93 11 113 U1 shows a double printing group through which a web of printed material can be guided, in a contactless manner, in a print-off position. The contactless passage is achieved by the use of guide rollers which are arranged upstream and downstream of the print position.
[0006] In DE 198 03 663 A1 the intention is to maintain, if possible, a print position during a flying plate change. This is achieved, inter alia, by use of a forme cylinder which can be driven independently of the associated transfer cylinder. During the plate change, the transfer cylinder continues to work as a counter-pressure cylinder, together with the web, and is in a driven connection with the counter-pressure cylinder.
[0007] U.S. Pat. No. 5,265,529 discloses cylinders which can be brought into three different positions. The various end positions can be adjusted, with respect to the contact position, in accordance with defined paper thicknesses etc. by the use of adjusting devices. Stops limit the contact path toward the others cylinders.
[0008] A drive mechanism for a printing unit is known from DE 198 53 114 A1. By the introduction of intermediate gear wheels into a drive train, the gear wheel engagement in the drive mechanism is independent, to a large extent, of the position of the cooperating cylinders.
SUMMARY OF THE INVENTION
[0009] The object of the present invention is directed to providing a printing unit.
[0010] In accordance with the present invention, this object is attained by providing a printing unit with at least one printing group. That at least one printing group can include a transfer cylinder which is drivable by a drive motor and which can be selectively positioned in one of three positions. A shiftable stop can be used to define at least two of these positions. The printing group may include two cylinders which act together to form a gap or nip. These two cylinders can be driven by a common drive motor. The two cylinders can be in contact with each other in a first position and can be moved apart to either of two separated positions as a function of the operating situation of the drive mechanism for the printing group.
[0011] The advantages to be gained by the present invention primarily lie in that by use of three positions, a “regular” removal of one cylinder from contact with another cylinder is made possible, for example in case of a change in the production, during stops, etc. is made possible. Also the removal out of contact of the cylinders to a distance which, for example, permits the contactless passage of the web, which, for example, is part of a printing operation, through the printing gap can be accomplished.
[0012] Bringing the cylinders out of contact, to a relatively large spacing distance, permits the contactless passage of a web, without additional guide rollers, which prevent the “fluttering” or oscillation of the web. The additional guide rollers might also possibly result in reducing the quality of fresh prints.
[0013] If the cylinders of a printing group can be driven together by a driven connection, which driven connection is maintained in every one of the cylinder positions, the release of a web during the printing operation is possible with a reduced number of drive motors.
[0014] The possibility of removing an entire printing group from the printing process is advantageous wherein, however, the web continues to run between the transfer cylinders. Because of the continuing engagement of the positive driven connections, the relative position of the cylinders, in respect to each other, is maintained on the one hand. On the other hand, a set-up operation, by use of a single drive motor, is made possible in the case of one drive motor per printing group with steel cylinders, or a double printing group and, by use of only one auxiliary motor in the case of one drive motor for two double printing groups, for example printing tower, H-printing unit, or two bridge printing units.
[0015] If two printing groups, each with its own drive motor, are provided, two printing groups, which are arranged one behind the other in the conveying direction, allow two-color printing (1/1+1/1=2/2), or single printing on both sides with the first (1/1+0/0) or the second (0/0+1/1) printing group in alternation. Thus, with an appropriate configuration of a gear wheel engagement, in regard to the position of the cylinders, in which the web is freely guided through the printing gap, a set-up operation is possible in alternation between the first and the second printing group, for example during operation with a flying plate change.
[0016] The regulation of the drive mechanism of the printing group and of a stop for blocking a release under defined operating conditions, or for the prevention of the cylinders making contact under certain operating conditions, permit the release, along with assured high safety of the gears of the driven connection and of an operator, as well as interference-free continued printing.
[0017] Three possible defined positions for the transfer cylinder exist. The center position, or the respective stop position, is selectively taken up, or becomes effective, as a function of the driving situation such as, for example, the number of revolutions, or the cylinder coupling state.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] Preferred embodiments of the present invention are represented in the drawings and will be described in greater detail in what follows.
[0019] Shown are in:
[0020] [0020]FIG. 1, a schematic top plan view of a printing group in accordance with the present invention, in
[0021] [0021]FIG. 2, a schematic side elevation view of a driven connection of a printing group, in
[0022] [0022]FIG. 3, a schematic side elevation view of a mechanism for pivoting a cylinder, in
[0023] [0023]FIG. 4, a schematic side elevation view of a printing unit with two printing groups, and in
[0024] [0024]FIG. 5, a schematic side elevation view of a driven connection of the printing unit in accordance with FIG. 4.
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0025] A printing unit of a printing press, in particular a printing unit of a web-fed rotary printing press, has a printing gap 02 , in which a web 06 , for example a paper web 06 , can be guided, all as may be seen in FIG. 1.
[0026] In the preferred embodiment depicted in FIG. 1, the two cylinders 03 , 04 forming the printing gap 02 are embodied as transfer cylinders 03 , 04 , and in particular as rubber blanket cylinders 03 , 04 , to each of which a further cylinder 07 , 08 , for example a forme cylinder 07 , 08 , is assigned. Inking or dampening systems, which are not specifically represented, are also provided. One of the two cylinders 03 , 04 forming the printing gap 02 can alternatively be embodied as a counter-pressure cylinder 04 , 03 , for example as a satellite or steel cylinder, which cylinder 04 does not carry any ink.
[0027] The ends of the four cylinders 03 , 04 , 07 , 08 of the printing group 01 , which is embodied as a double printing group 01 , are each rotatably seated in a frame of the printing press, which frame is not represented. In this case, at least one of the two transfer cylinders 03 , 04 , for example the transfer cylinder 03 , has a bearing 09 , depicted in FIG. 3 which permits a relative position change of the two transfer cylinders 03 , 04 with respect to each other, in particular a change Δ “a” of a distance “a” between the two transfer cylinders, as seen in FIG. 1. In the preferred embodiment represented in FIG. 3, bearings 10 for the remaining cylinders 04 , 07 , 08 are not further discussed and are each provided with the reference numeral 10 .
[0028] In a variation of the subject invention, as represented in dashed lines in FIG. 3, the second transfer cylinder 04 also has a bearing 09 , which is represented in dashed lines, and which also allows a position change. In this case, the two bearings 09 are coupled with each other in a manner, which is not specifically shown, in such a way that, when actuated, they perform a synchronous movement, however in opposite directions.
[0029] The transfer cylinders 03 , 04 can be brought into at least three different positions, i.e. spacings a1, a2, a3, in relation to each other, wherein the transfer cylinders 03 , 04 , in a first position AN or “in contact,” are placed against each other with a first spacing a1=0. In a second position AB or “out of contact,” cylinders 03 , 04 are spaced apart from each other at a second spacing a2 wherein a3>a2>0. In a third position AUS, or “removed from each other”, the cylinders 03 , 04 are spaced apart from each other at a third spacing a3 at a sufficient distance that, during the printing operation, the paper web 06 can be guided through the printing gap 02 , for example without touching the transfer cylinders 03 , 04 , which may now run slower or which may be stopped for the purpose of a set-up. Stopping of the paper web 06 , or drawing it in to the printing group 01 is also possible, while independently thereof, the cylinders 03 , 04 , 07 , 08 are accessible for a set-up operation such as, for example washing, pre-inking, printing forme change, rubber blanket change, putting images on the forme cylinder 07 , 08 or the like. In the second, out of contact position AB, the two transfer cylinders 03 , 04 are out of contact with each other, but the drawn-in web 06 can be maintained in contact with one of the adjustable cylinders 03 , 04 in order to, for example, maintain web guidance. Moreover, moving the cylinders 03 , 04 to the first, contacting position AN requires a considerably shorter actuating path than would be required if the cylinders 03 , 04 were in the third, removed from each other position AUS.
[0030] In the preferred embodiment, the four cylinders 03 , 04 , 07 , 08 are in a positive driven connection with each other by use of driven gear wheels 16 , 17 , 18 , 19 , which are arranged on journals 11 , 12 , 13 , 14 at the cylinder end faces, as seen in FIG. 1. The geometry of the gear wheels 16 , 17 , 18 , 19 , as well as of the bearing(s) 09 is selected in such a way that the driven connection is maintained in every one of the three positions AN, AB, AUS of the two cylinders 03 , 04 . The cylinders 03 , 04 , 07 , 08 , which are in driven connection, are driven via a drive gear 21 , for example a drive gear wheel 21 or a drive pinion 21 of a drive motor 22 , which drive gear 21 meshes with one of the gear wheels 16 , 17 , 18 , 19 of the cylinders 03 , 04 , 07 , 08 In the configuration shown in FIG. 1, the drive gear 21 meshes with the driven gear wheel 16 of the forme cylinder 07 . However, driving one of the cylinders 03 , 04 , 07 , 08 , or one of the journals 11 , 12 , 13 , 14 , by use of the drive motor 22 , can also take place directly and coaxially.
[0031] In the preferred embodiment, the three positions AN, AB, AUS are made possible by utilization of the bearing 09 , which bearing 09 is configured as an eccentric bearing 09 for the transfer cylinder 03 , for example as a three-ring or as a four-ring bearing, preferably as a three-ring bearing because of the reduced cost outlay. This position change of the cylinder 03 takes place by pivoting an axis of rotation R of the transfer cylinder 03 around a pivot axis S of the bearing 09 . The possibly additional eccentric bearing 09 for the second transfer cylinder 04 is shown in dashed lines. Further possible eccentric bearings for the forme cylinders 07 , 08 , for example to accomplish additional movements of those cylinders in or out of contact, are not taken into consideration in the drawings. The journals 11 , 13 , 14 of the remaining cylinders 04 , 07 , 08 are represented by solid lines in FIG. 3, and are centered by way of example.
[0032] If one of the two cylinders 03 , 04 forming the printing gap 02 is not conveying ink, either the transfer cylinder 03 , 04 , or the other cylinder 04 , 03 , or both, can be seated by the use of an eccentric bearing 09 .
[0033] In FIG. 1, the two transfer cylinders 03 , 04 are removed from each other in the third position AUS at a distance a=a3, for example in which 5 mm≦a3≦10 mm, in particular a3˜8 mm in such a way that the paper web 06 can pass through the printing gap 02 without contact. In accordance with the representation in FIG. 2, the gear wheels 17 , 18 of the transfer cylinders 03 , 04 are just in engagement with each other, something that could not be seen in the schematic representation in FIG. 1. An axis of rotation R of the transfer cylinder 03 , or of its pinion gear 17 , can be selectively brought into each one of the three positions AN, AB, AUS, which are identified by the crosses in FIG. 2, by pivoting the eccentric bearing 09 around a pivot axis S.
[0034] By way of example, FIG. 3 represents the drive mechanism for the position change of an arrangement in accordance with the above mentioned principle. FIG. 3 shows the journal 12 of the transfer cylinder 03 in the first position AN, in which first position AN, the transfer cylinders 03 , 04 , which cannot be seen in FIG. 3, have been placed into contact with each other. The eccentric bearing 09 can be pivoted, for example, by operation of pivoting a lever 23 via a coupler 24 inside a bushing, not represented, of circular cross section. For example, pivoting the lever 23 in a clockwise direction causes the pivoting of the eccentric bearing 09 also in a clockwise direction, and therefore causes a movement of the journal 12 away from the bearing of the second transfer cylinder 04 , i.e. a change of the cylinders 03 , 04 into the second position AB or, with further pivoting, into the third position AUS. In case of an eccentric seating of the second transfer cylinder 04 , the latter can be moved synchronously with cylinder 03 and in the opposite direction with respect to cylinder 03 by the use of a second coupler 25 , which second coupler 25 is indicated by dashed lines in FIG. 3.
[0035] The driving of the coupler 24 is provided by the use of a one-armed lever 23 , whose free end is in operative connection with a threaded spindle 27 , which spindle 27 can be rotated by a motor 26 . A rotation of the threaded spindle 27 in one or the other direction causes the pivoting of the lever 23 , and therefore causes the pivoting of the eccentric bearing 09 in the one or in the other direction. However, the driving of the eccentric bearing 09 could also take place via a cylinder, which cylinder can be charged with a pressure medium, or also by a drive mechanism that is directly working together with the bearing 09 .
[0036] If the transfer cylinder 03 , or the transfer cylinders 03 , 04 , is orare in its or their first position AN, pivoting of the transfer cylinder 03 into the second position AB is possible by an appropriate pivoting of the lever 23 . However, pivoting of the transfer cylinder 03 into the third position AUS has been structured so that this pivoting movement can be blocked. The out-of-contact path of the cylinders 03 , 04 , or the distance “a” between the cylinders 03 , 04 , can be selectively limited to the position AB, or can be expanded as far as into the position AUS, by the provision of a stop 28 , whose position can be changed, or which can be pivoted.
[0037] In the preferred embodiment, to accomplish this result, the stop 28 , for example which may be a free end of a second one-armed lever, can be positioned into the movement radius of the free end of the lever 23 by an actuating device 30 , for example by use of a cylinder 30 which can be charged with a pressure medium. During “normal” printing operations, i.e. during the change between the first two positions AN, AB, this lever 28 also advantageously acts as a stop for the defined out of contact position AB. The use of this lever 28 as a stop is particularly advantageous in the case in which the first lever 23 is driven by a mechanism, such as a cylinder which can be charged with a pressure medium, since positioning of the first lever 23 in an “intermediate position” by using pressure alone, for example, is practically not possible.
[0038] The actuating device 30 for the stop 28 can be controlled by a control device 29 , which is shown only in FIG. 5 in such a way that a change of cylinder 03 from the first or the second position AN, AB into the third position AUS is prevented by the stop 28 at least in the case in which the printing group 01 , or the transfer cylinders 03 , 04 are operated above a defined threshold number of revolutions, or at the production number of revolutions. The stop 28 is only released into the position AUS when the printing group 01 has been stopped, or is operated at a number of revolutions below a threshold number of revolutions, or is in a set-up operation, i.e. a number of revolutions asynchronous in relation to the production number of revolutions.
[0039] In an advantageous embodiment, at least the third position AUS can be detected by a signal emitter, which is not specifically represented, for example by a limit switch, wherein the signal is also supplied to the control device 29 .
[0040] If the printing group 01 can be driven by its own drive motor 22 independently of a further printing group, the angular speed, or the number of revolutions of the drive motor 22 , or of one of the cylinders 03 , 04 , 07 , 08 , or the circumferential speed at the transfer cylinder 03 , for example, are determined and supplied to the control device 29 , in which a comparison with the existing operational state is performed. If, for example, the condition exists, in which the printing group 01 is being operated in readiness for production, or is operating above a threshold value, the stop 28 is placed into its effective position, in which effective position of stop 28 a position change of the cylinder 03 or cylinder 04 into the third position AUS is blocked.
[0041] It is also advantageous for the protection of the drive connection and the press operators if the printing group 01 can be operated with cylinders in the position AUS only in defined modes of operation, for example only during set-up operations, i.e. when the cylinders are driven at a limited number of revolutions. A maximum number of revolutions can also be preset for this, for example, which maximum number of revolutions can correspond to the threshold number of revolutions for the change from the position AB into the position AUS. This can be preset by use of the control device 29 for controlling the drive motor 22 . In this case, an acceleration, independently of the running of the paper web 06 , to a number of revolutions which is synchronous with the printing operation can only take place in a position which is located between the positions AUS and AN and is limited in the direction AUS by the stop 28 , for example in the position AN. The limitation is preferably provided via the electronic elements, i.e. for example via the control device 29 .
[0042] The control device 29 also prevents a change of the cylinder 03 or cylinders 03 , 04 from the position AUS, or from the position AB, into the position AN if, in the course of the operation of the printing press, i.e. when the paper web 06 passes through the printing gap 02 , the printing group 01 does not run at a number of revolutions which is synchronous with the running speed of the paper web 06 , or if the printing group 01 is not in a driven connection with the drive motor 22 .
[0043] The above-described device, as well as the above-described operational situations, also apply to printing groups 01 whose cylinders 03 , 04 forming the print position 02 , one of which is possibly also embodied as a satellite cylinder form a driven connection which is independent of the drive mechanism of the forme cylinders 07 , 08 and which is driven by its own drive motor. Thus, for example, in a rubber- against-rubber printing group, the two transfer cylinders 03 , 04 can be driven by one drive motor, and the two forme cylinders 07 , 08 can be driven by one by or two further drive motors which are suitable for the production operation.
[0044] This also applies if one or if several transfer cylinders 03 , 04 are driven together with a satellite cylinder, and the associated forme cylinders 07 , 08 are driven separately.
[0045] In a further preferred embodiment of the present invention, the printing group 01 can also be driven together with a second printing group 31 , as seen in FIG. 4, which second printing group 31 has gear wheels 32 , 33 , 34 , 36 of two further transfer cylinders and two further forme cylinders by a common drive motor 37 , with only the gear wheels 32 , 33 , 34 , 36 of cylinders of the second printing group 31 being represented in FIG. 4. In this case, it is advantageous, if driving takes place from the drive motor 37 via one gear wheel 38 , or 39 in the direction toward the printing groups 01 , or 31 , respectively. At least one of the gear wheels 38 , 39 is embodied so that by use of a coupling 41 , 42 , as seen FIG. 5 it can be selectively connected with, or disconnected from, the gear wheel 16 of the first printing group 01 , or the gear wheel 42 of a forme cylinder 43 of the second printing group 31 . This can, for example, be accomplished by the use of gear wheels 38 , 39 which are displaceable in the axial direction.
[0046] The information regarding an open coupling state of each of the coupling 41 , 42 is sent to the control device 29 , for example via limit switches, which are not specifically represented, whereupon the pivoting of the associated transfer cylinder into the position AN is prevented by the control device 29 . If the printing group 01 , 31 runs synchronously with the production and/or the engaged coupling 41 , 42 , the change into the position AUS is blocked via the actuating device 30 and the stop 28 , as seen in FIG. 3. For controlling the actuating device 30 , it is also possible to utilize the number of revolutions of the printing group 01 , 31 , or of the transfer cylinder 03 , and to process it in the control device 29 .
[0047] [0047]FIG. 4 and FIG. 5 show a printing unit embodied in the form of an H-printing unit, wherein the lower printing group 31 is disengaged and a pivotable transfer cylinder, that is associated with the gear wheel 33 , is in the third position AUS. The upper printing group 01 is engaged and the transfer cylinder 03 is in the first, in contact position AN.
[0048] In a preferred embodiment, which is not depicted , one of the two gear wheels 38 , 39 can also be embodied as a double gear wheel 38 , 39 , which cannot be coupled, wherein one half of the double gear wheel meshes with the gear wheel 16 , 32 of the forme cylinder 07 , 43 , and the other half meshes with the gear wheel 21 of the drive motor 37 . In an advantageous embodiment, the halves can be embodied to be displaceable in relation to each other for registration, for example between the two printing groups 01 , 31 , or between further units of the printing press.
[0049] In all cases in which two printing groups 01 , 31 can be driven by a common drive motor 37 , it is advantageous, for the purpose of set-up operations, to provide an auxiliary drive mechanism, which is not specifically represented, in the drive connection of a printing group 01 , 31 which auxiliary drive mechanism can be disengaged.
[0050] The mode of functioning of the printing unit in accordance with the present invention is as follows:
[0051] As is the case with customary double printing groups, the printing groups 01 , 31 of the printing unit can each be operated during “normal” printing operations selectively in a position AN and AB. It is also additionally possible to guide the paper web 06 during the printing operation through the printing group 01 , or 31 while this printing group 01 , 31 is not participating in the printing operation, i.e. is inactive. To this end, the printing group 01 , or 31 , or its transfer cylinders 03 , 04 , are pivoted into the position AUS. As long as the printing group 01 , 31 is operated at a number of revolutions above a threshold number of revolutions, and/or a coupling 41 , 42 possibly located between the drive motor 37 and the printing group 01 , 31 is closed, the change into the third position AUS is blocked.
[0052] If the drive mechanism of the printing group 01 , or 31 is no longer operated synchronously with the running of the paper web 06 , or is operating at a number of revolutions below the threshold number of revolutions, pivoting of the transfer cylinders 03 , 04 into the position AUS is released by the control device 29 in that the stop 28 is brought into an ineffective position. This can take place either when the drive motor 22 driving the printing group 01 , or the printing group 31 , are no longer driven synchronously with the paper web 06 , but instead are in a set-up operation, or are stopped. If the printing group 01 , 31 is driven by a common drive motor 37 via a switchable coupling 41 , 42 , the release takes place, for example, on the basis of the open coupling state of the coupling 41 , 42 .
[0053] For the purpose of accelerating the printing speed, or the printing number of revolutions, the printing group 01 , 31 must initially be brought out of the position AUS into an intermediate position, for example into the position AB. The printing group 01 , 31 can then be returned into the position AN only when the circumferential speed, or the corresponding number of revolutions, corresponds to that of the paper web 06 .
[0054] In the case of the embodiment of the printing unit with two printing groups 01 , 31 , a 2/2 printing operation, and also an alternating 1/1 printing operation, for the purpose of a flying plate change, can take place by use of the printing unit. To this end, one of the printing groups 01 , 31 is placed into the position AN, while the other printing group 31 , 01 is placed into the position AUS. Now a set-up operation, for example a plate change, is possible in connection with the printing group placed in the position AUS.
[0055] In an advantageous embodiment, the printing group 31 , 01 must now first be brought into the intermediate position again, for example into the second, out of contact position AB, before the printing group 31 , 01 can again be accelerated. If the number of revolutions of the printing group 31 , 01 has again been synchronized with the running of the web, i.e. has been accelerated again and engaged, if required, the blockage for movement into the first, in contact position AN is removed, and the printing group 31 , 01 can again be brought into the position AN. It is now possible, for example, to bring the first printing unit 01 , 31 into the third, removed from each other, position AUS for set-up as soon as the number of revolutions drops below the threshold number of revolutions, or the respective coupling 42 , 41 is released.
[0056] While preferred embodiments of a printing unit, in accordance with the present invention, have been set forth fully and completely hereinabove, it will be apparent to one of skill in the art that various changes in, for example, the type of web being printed, the overall structure of the printing press and the like could be made without departing from the true spirit and scope of the present invention which is accordingly to be limited only by the appended claims.
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A printing unit contains at least one printing group which is comprised of at least two cylinders which cooperate to form a printing nip. At least these two cylinders are interconnected in a positive fit by a drive. The two cylinders can be engaged with one another in a first position (ON), or disengaged from one another in a second position (OFF). The two cylinders can also be disengaged from each other at a spacing distance in a third position (STOP). That spacing distance is sufficient to allow a web in the printing operation to be guided between the two cylinders without making contact with the two cylinders.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application is a divisional of U.S. Patent Application Ser. No. 11/742,980, filed May 1, 2007, which claims the benefit of U.S. Provisional Patent Application No. 60/746,228, filed May 2, 2006, and which is a continuation-in-part of U.S. patent application Ser. No. 11/535,916, filed Sep. 27, 2006, which claims the benefit of U.S. Provisional Patent Application No. 60/721,450, filed Sep. 28, 2005, and which is a continuation-in-part of U.S. patent application Ser. No. 10/429,435, filed May 5, 2003, the entireties of which are hereby incorporated by reference.
TECHNICAL FIELD
This invention relates to implants and instruments for use in cutting and preparing bone, for example, in total and partial knee arthroplasty. Such instruments are applicable in other total and partial joint replacement surgeries which include, but are not limited to the hip, the shoulder, the ankle, the elbow, the joints of the hand, the joints of the wrist, the joints of the foot and the temporal mandibular joint, articulating joints such as the knee and hip, and also motion segments of the spine.
BACKGROUND OF THE INVENTION
A joint, such as the ankle, knee, hip or shoulder, generally consists of two or more relatively rigid bony structures that maintain a relationship with each other. In the case of the spine, a motion segment generally consists of two vertebral bodies, a disc and two facet joints. Soft tissue structures spanning the bony structures hold the bony structures together and aid in defining the motion of one bony structure relative to the other. In the knee, for example, the bony structures are the femur, tibia and patella. Soft tissue structures spanning the knee joint, such as muscles, ligaments, tendons, menisci, and capsule, provide force, support and stability to facilitate motion of the knee. Muscle and tendon structures spanning the knee joint, as in other joints of the body and in the spine provide dynamics to move the joint in a controlled manner while stabilizing the joint to function in an orderly fashion. The joint is dynamically stabilized by contraction of primary muscles to move the joint in a desired direction combined with antagonistic muscle contraction to direct resultant joint loads within favorable orientation limits relative to the bony structures of the joint. It is believed that proprioceptive feedback provides some of the control or balance between primary and antagonistic muscle contraction.
In an articulating joint, a smooth and resilient surface consisting of articular cartilage covers the bony structures. In the spine, the disc, consisting of an annulus and a nucleus, spans the space between adjacent vertebral bodies and two facet joints provide articulation posteriorly. The articular surfaces of the bony structures work in concert with the soft tissue structures spanning the joint to form a mechanism that defines the envelop of motion between the structures. Within a typical envelop of motion, the bony structures move in a predetermined pattern with respect to one another. When articulated to the limits of soft tissue constraint, the motion defines a total envelop of motion between the bony structures. In the knee, the soft tissue structures spanning the joint tend to stabilize the knee from excessive translation in the joint plane of the tibiofemoral compartments. Such tibiofemoral stability enables the femur and tibia to slide and rotate on one another in an orderly fashion. The motion of the patella relative to the femur in the patellofemoral compartment is related to tibiofemoral motion because the patella is linked at a fixed distance from the tibia by the patellar ligament.
Current methods of preparing a joint to receive implants that replace the articular surfaces or motion segments involve an extensive surgical exposure. In traditional total knee arthroplasty, the surgical exposure, ligament release and sacrifice of the anterior cruciate ligament must be sufficient to permit the introduction of guides that are placed on, in, or attach to the femur, tibia or patella, along with cutting blocks to guide the use of saws, burrs and other milling devices, and other instruments for cutting or removing cartilage and bone to provide a support surface for implants that replace the artificial surfaces or motion segment. For traditional knee joint replacement, the distal end of the femur may be sculpted to have flat anterior and posterior surfaces generally parallel to the length of the femur, a flat end surface normal to the anterior and posterior surfaces, and angled flat surfaces joining the above mentioned surfaces, all for the purpose of receiving a prosthetic device. In general these are referred to as the anterior, posterior, distal and chamfer cuts, respectively. In current total knee arthroplasty proper knee alignment is attained by preoperative planning and x-ray templating. Anterior-posterior (A/P) and lateral x-ray views are taken of the knee in full extension. The mechanical axis of the tibia and of the femur is marked on the A/P x-ray. The angle between these lines is the angle of varus/valgus deformity to be corrected. In the A/P view, the angle of the distal femoral resection relative to the femoral mechanical axis, hence the angle of the femoral implant, is predetermined per the surgical technique for a given implant system. Similarly, the angle of the tibial resection relative to the tibial mechanical axis, hence the angle of the tibial implant, is predetermined per the surgical technique for a given implant system. The femoral resection guides are aligned on the femur to position the distal femoral resection relative to the femoral mechanical axis and the tibial resection guides are aligned on the tibia to position the proximal tibial resection relative to the tibial mechanical axis. If the cuts are made accurately, the femoral mechanical axis and the tibial mechanical axis will align in the A/P view. Once the femur and tibia have been resected, the medial and lateral collateral ligaments may be released to balance the knee. Soft tissue balancing is generally done with the knee in full extension. The spacing between the femur and tibia at full extension is used to guide ligament release to attain an appropriate extension gap.
Typically, an appropriate extension gap is evidenced by parallel orientation of the distal femoral resection to the tibial plateau resection and with a gap sufficient to accommodate the femoral and tibial implants. This approach addresses knee alignment and balancing at full extension. Knee alignment and tissue balance at 90.degree. of flexion is generally left to surgeon judgment and knee alignment and tissue balance throughout the range of motion has not been addressed in the past. In aligning the knee at 90.degree. the surgeon rotates the femoral component about the femoral mechanical axis to a position believed to provide proper tensioning of the ligaments spanning the knee.
Current implants and instruments for joint replacement surgery have numerous limitations. These relate to the invasiveness of the procedure and achieving proper alignment, soft tissue balance and kinematics of the joint with the surgical procedure. Such difficulties are present in all joint replacement surgery. Although the spinal disc is not an articular joint, interest in restoring the kinematic function of a degenerated disc has lead to spinal arthroplasty incorporating metal and/or plastic articulating surfaces. Polymers, including hydrogels and urethanes, have also been used to restore spinal disc function. Such spinal implants are preferably placed via minimally invasive surgical approaches and restore motion and kinematics, hence require accurate alignment and orientation of the implant components one to another. In addition, the kinematics of a spinal motion segment are defined by the combined motion across the disc which is a function of the annulus, nucleus, anterior ligament, posterior ligament, facet joint articulation and muscles spanning the motion segment. A spinal motion segment is the motion between adjacent vertebral bodies.
A difficulty with implanting modular knee implants in which the femur or tibia is resurfaced with multiple components has been achieving a correct relationship between the components. For ease of description, multiple components comprising a component such as a femoral component will be referred to as subcomponents. For example, a modular femoral component may include subcomponents for the trochlea, the lateral femoral condyle and the medial condyle, and reference to a “femoral component” includes subcomponents in the case of a multi-piece femoral component.
In the case of a plurality of subcomponents resurfacing the distal femur or proximal tibia, the orientation and alignment of the subcomponents to each other has largely not been addressed. This may account for the high failure rates in the surgical application of free standing compartmental replacements used individually or in combination. Such compartmental replacements include medial tibiofemoral compartment, lateral tibiofemoral compartment, patellofemoral compartment and combinations thereof. Component malalignment may account for the higher failure rate of uni-compartmental implants relative to total knee implants as demonstrated in some clinical studies. When considering bi-compartmental and tri-compartmental designs, orientation and alignment of subcomponents, as well as components, is critical to avoid accelerated wear with a mal-articulation of the implant.
Surgical instruments available to date have not provided trouble free use in implanting multi-part implants wherein the distal femur, proximal tibia and posterior patella are prepared for precise subcomponent-to-subcomponent and component-to-component orientation and alignment. While current femoral alignment guides aid in orienting femoral resections relative to the femur and current tibial alignment guides aid in orienting tibial resections relative to the tibia, they provide limited positioning or guidance relevant to correct subcomponent-to-subcomponent alignment or orientation. Nor do such alignment guides provide guidance relevant to soft tissue balance (i.e. ligament tension to restore soft tissue balance). Moreover, they provide limited positioning or guidance relevant to correct flexion/extension orientation of the femoral component, to correct axial rotation of the femoral component, nor to correct posterior slope of the tibial component. For the patellofemoral joint, proper tibiofemoral alignment is required to re-establish proper tracking of the patella as defined by the lateral pull of the quadriceps mechanism, the articular surface of the femoral patellar groove and maintaining the tibiofemoral joint line. For optimum knee kinematics, femoral component flexion/extension and external rotation orientation, tibial component posterior slope and ligaments spanning the joint work in concert maintaining soft tissue balance throughout the knee's range of motion.
For patients who require articular surface replacement, including patients whose joints are not so damaged or diseased as to require whole joint replacement, the implant systems available for the knee have unitary tri-compartmental femoral components, unitary tibial components, unitary patellar components and instrumentation that require extensive surgical exposure to perform the procedure.
It would be desirable to provide surgical methods and apparatuses that may be employed to gain surgical access to articulating joint surfaces, to appropriately prepare the bony structures, to provide artificial, e.g., metal, plastic, ceramic, or other suitable material for an articular bearing surface, and to close the surgical site, all without substantial damage or trauma to associated muscles, ligaments or tendons, and without extensive distraction of the joint. To attain this goal, implants and instruments are required to provide a system and method to enable articulating surfaces of the joints to be appropriately sculpted using less or minimally invasive apparatuses and procedures, and to replace the articular surfaces with implants suitable for insertion through small incisions, assembly within the confines of the joint cavity and conforming to prepared bone support surfaces.
BRIEF SUMMARY OF THE INVENTION
The present invention is related to implants and instruments for use in less and minimally invasive total knee replacement surgery. More particularly, this invention relates to instruments for cutting and preparing bone. Such bone cutting instruments are applicable in total and partial knee arthroplasty. In addition, such instruments are applicable in other total and partial joint replacement surgery to include, but not limited to the hip, the shoulder, the ankle, the elbow, the joints of the hand, the joints of the wrist, the joints of the foot and the temporal mandibular joint. Such instruments are also applicable to motion segments of the spine to include, but not limited to the spinal disc and the facet joints. For the purposes of this document, the term joint will be used to refer to articulating joints such as the knee and hip, and also motion segments of the spine.
The present invention provides a system and method for partial or total joint replacement, that is to resurface one or more of the bony surfaces of the joint or motion segment, which involves less or minimally invasive surgical procedures which can be used to place implants that restore joint kinematics. The instruments and implants disclosed accomplish accurate bone and soft tissue preparation, restoration of anatomical alignment, soft tissue balance, kinematics, component to component orientation and alignment, subcomponent to subcomponent orientation and alignment, and implant fixation through limited surgical exposure.
Proper alignment and positioning of the implant components and subcomponents are enabled by instruments guided by the soft tissue structures of the knee to guide bone resections for patient-specific anatomical alignment and component orientation. The medial and lateral tibial articular surfaces and the patellar articular surface are generally prepared with planar resections. The medial and lateral femoral condyles and trochlea are kinematically prepared. Such instrumentation is referred to as Tissue Guided Surgery (TGS) and is described in U.S. Pat. No. 6,723,102 and is incorporated by reference in its entirety.
Proper alignment of the femoral, tibial and patellar implants requires proper anatomical alignment of the knee joint throughout the range of motion. By using the soft tissue structures spanning the knee to guide bone resection, TGS instrumentation established proper soft tissue balancing throughout the range of motion. Current knee implant systems generally balance soft tissue structures in full extension only. In a typical TGS knee procedure the knee joint is exposed through a small medial patellar incision. The anterior and posterior cruciate ligaments are left intact. Applicants believe that the instrument system will function in cases where the anterior cruciate ligament is partially or completely compromised. In one embodiment of the invention described herein, the medial and lateral tibial articular surfaces are removed with planar resections and bone sculpting instruments are placed on the resected surfaces in the medial and lateral tibiofemoral compartments. Each sculpting instrument is extended to load against its respective femoral condyle and the knee is flexed and extended to kinematically prepare the femoral condyles. Alternatively, the knee can be positioned at specific flexion angles. At each knee flexion angle each sculpting instrument is extended to load against its respective femoral condyle to prepare a planar surface on respective femoral condyle. Sculpting instruments are retracted and the knee is flexed to the next specific angle and each sculpting instrument is extended to load against its respective femoral condyle to prepare multiple planar surfaces. Optionally, the sculpting instruments can be structured to prepare a curved, hemi-spherical or contoured surface as may be required to match various support surfaces on a mating unitary femoral implant or a femoral implant structured with a plurality of sub-components.
As the femoral condyles are sculpted by TGS instruments, varus/valgus alignment at full extension is periodically checked. Intracompartmental distraction of the sculpting instrument is biased to the medial or lateral tibiofemoral compartment for valgus or varus correction, respectively. Alternatively, medial and lateral femoral condyles are prepared simultaneously until appropriate resection depth is reached on one condyle. The sculpting instrument in this compartment is replaced with a spacer and preparation of the other femoral condyle is continued until anatomical align of the knee is attained. When the femoral mechanical axis and tibial mechanical axis align, the knee is properly aligned. The surfaces of the femoral condyles have been progressively prepared by the TGS instruments guided by knee kinematics established by soft tissue structures spanning the knee. Therefore, proper knee alignment and soft tissue balance is attained throughout the range of motion.
In an alternative technique, each tibiofemoral compartment is prepared independently. The knee joint is exposed as described above. One of the tibiofemoral compartments is prepared first, typically the one with more severe pathology. The respective tibial articular surface is resected as described above and a sculpting instrument placed on the resection. The sculpting instrument is extended to load against the femoral condyle. The knee is flexed and extended until the appropriate resection depth is reached. The sculpting instrument is replaced with a spacer. The remaining tibiofemoral compartment is prepared next by resecting the tibial articular surface as described above. Placing a sculpting instrument onto the resected surface and extending the sculpting instrument to load against the femoral condyle. The knee is flexed and extended while monitoring varus/valgus alignment. Femoral condyle resection is continued until the desired anatomical alignment of the knee is attained.
The patellofemoral compartment is prepared in a manner similar to the tibiofemoral compartments. The patellar articular surface is removed with a planar resection. Spacers are placed in the medial and lateral tibiofemoral compartments to maintain knee kinematics. A bone sculpting instrument is placed on the resected patella and extended to load against the femoral trochlea. The knee is flexed and extended to kinematically prepare the femoral trochlea. Trochlear resection is complete when the desired resection depth is attained. The surgical technique described above has preparation of the patellofemoral compartment following preparation of the femoral condyles. The sequence can be reversed with the patellofemoral compartment being prepared first, a spacer placed in the patellofemoral compartment to maintain knee kinematics followed by preparation of the tibiofemoral compartments. In this case the tibiofemoral compartments can be prepared simultaneously or independently. Alternatively, the femoral trochlea can be resected with a cutting guide placed on the distal femur or medial to the trochlea. A surgical saw, either oscillating or reciprocating, is placed on or through the cutting guide to resect the femoral trochlea.
Alternatively, the femoral condyles and trochlea are prepared simultaneously. The articular surfaces of the tibia and patella are removed with planar resections. Bone sculpting instruments are placed on the medial and lateral tibial resections and the patellar resection. Bone is resected from the femoral condyles and trochlea as described above. Resection depth is monitored on each condyle and the trochlea. When appropriate depth is reached in one compartment that sculpting instrument is replaced with a spacer and sculpting of remaining surfaces is continued. Once a spacer has been placed into one of the tibiofemoral compartments, resection of the other femoral condyle is continued until desired knee alignment is attained. If resection of both femoral condyles is completed before completion of the trochlear resection, the sculpting instrument in the remaining tibiofemoral compartment is replaced with a spacer and sculpting of the trochlea is continued to the appropriate depth.
Femoral, tibial and patellar bone resections attained with TGS instrumentation are properly positioned and orientated for anatomic knee alignment, soft tissue balance and kinematic function throughout knee range of motion. Using these bone support surfaces to position and orientate the femoral, tibial and patellar components, respectively, will maintain anatomic knee alignment, soft tissue balance and kinematic function. In general, the tibial and patellar resections are planar, making placement of the corresponding implant components, which have planar support surfaces, straight forward. The femoral resection is not planar, and the relative position of the lateral condyle, the medial condyle, and the trochlear resections to one another is a function the kinematics of a given patient. Therefore, the femoral implant should accommodate this variability.
In an alternative embodiment surgical navigation is used in conjunction with TGS instrumentation to kinematically prepare the femur, tibia and patella to support knee implant components. Surgical navigation technologies applicable to this approach include, but are not limited to, image and image free navigation systems and Hall Effect based navigation systems. The knee joint is exposed as described above. Navigational trackers are attached to the femur, tibia and patella. If a tracker can not be attached to the patella, then tracking of the patella is done periodically or at discrete points during the procedure with a tracking stylus. Pre-operative alignment and kinematics of the knee are measured per the protocol for the navigation system being used. The tibial plateau and patella are prepared as described above. Alternatively, the navigation system is used to position tibial resection guides for resection of the medial and lateral tibial articular surfaces. The navigation system may be used to align a patellar resection guide for resection of the patella. The anterior and posterior cruciate ligaments are left intact. Bone sculpting instruments are placed in the medial and lateral tibiofemoral compartments and the patellofemoral compartments. The sculpting instruments are extended to load against the respective condyle or trochlea. The knee is repeatedly flexed and extended to initiate bone resection in all three compartments. The navigation system monitors and displays femoral resection depths for each compartment throughout the range of motion while monitoring knee alignment and kinematics. The navigation system indicates when appropriate resection depth is attained on one of the femoral condyles and signals the surgeon to replace that sculpting instrument with a spacer. Femoral resection is continued until the navigation system indicates that desired knee alignment is attained. The surgical navigation system monitors trochlear resection depth and notifies the surgeon when the desired depth is attained. If appropriate trochlear resection depth is attained before completing femoral condylar resection, then a spacer can be placed in the patellofemoral compartment and femoral condylar resection continued. This technique describes using surgical navigation in conjunction with TGS instrumentation to prepare the three compartments of the knee simultaneously. In addition, surgical navigation can be used in conjunction with TGS instrumentation to prepare the knee compartments in the sequences and combinations previously described.
The sculpting instruments in the TGS instrumentation can be instrumented with sensors to measure intracompartmental distraction force and distraction distance. Such instrumentation enables monitoring of soft tissue balance during sculpting throughout the full range of motion. Force and displacement sensors can be attached to the ligaments spanning the knee as complementary measurements of soft tissue balance, distraction force and distraction displacement. Instrumented sculpting instruments also enable monitoring resection depth during sculpting throughout the full range of motion. Load cells are placed in a sculpting instrument to measure distraction force. Alternatively, if hydraulic pressure is used to extend the sculpting instrument, then pressure sensors are used to measure distraction force by multiplying pressure applied by the cross sectional area of the hydraulic actuator or bladder or balloon. Displacement sensors are placed in a sculpting instrument to measure distraction distance. Alternatively, if hydraulics pressure is used to extend the sculpting instrument, then change in volume of fluid delivered to the hydraulic actuator or bladder or balloon by calibrating the distraction device for displacement vs. volume change. Distraction load and distraction displacement readout can be with a digital readouts, bar graph or other graphical display. The readout can also be displayed in a surgical navigation system display. Such instrumented sculpting instruments can be used with each of the procedures and embodiments described above. Pressure to the hydraulic actuator or bladder may be provided by a syringe pump, or by a pre-charged compliant bladder designed to maintain a relatively constant pressure in the fluid over a workable change in volume required to activate the actuators or bladders used to distract the joint. Alternately, the distraction force can be applied by threaded mechanisms, inclined ramps or other mechanical means.
In a more sophisticated embodiment TGS instrumentation is integrated with surgical navigation, intracompartmental distraction and displacement sensors, and programmable controllers to provide simultaneous closed loop control of the femoral resections. This application specific robotic system sculpts the femoral condyles and trochlea while the surgeon repeatedly flexes and extends the knee. The knee joint is access as previously described. A surgical navigation system and navigation trackers are applied as previously described and pre-operative alignment and knee kinematics are measured and archived. The tibia and patella are resected as previously described. Hydraulically extended sculpting instruments with integral distraction force and distraction displacement sensors are placed into the three compartments of the knee. The sculpting instruments are extended to load against the respective femoral surface. lntracompartmental distraction force in each compartment can be controlled by independent closed loop controllers with distraction force as the feedback. Alternatively, distraction displacement is used for the closed loop feedback for one or more of the sculpting instruments. The robotic TGS instrument system applies a preliminary intracompartmental distraction force to the medial and lateral tibiofemoral compartments and to the patellofemoral compartment, and indicates to the surgeon that the system is ready to start femoral resection. The surgeon repeatedly flexes and extends the knee while the robotic TGS instrument system monitors resection depth, knee alignment and knee kinematics throughout the full range of motion. The robotic TGS instrument system is programmed to control intracompartmental distraction force to advance resection depth in each compartment at generally the same rate until a preset condyle resection depth is attained, at which point the system prompts the surgeon to replace that sculpting instrument with a spacer. The system then monitors knee alignment while the surgeon continues to flex and extend the knee until the navigation system indicates desired knee alignment is attained. Replacement of the patellofemoral sculpting instrument with a spacer is prompted by the system when a preset trochlear resection depth is attained which may occur before or after completion of condyle resections. Alternatively, the robotic TGS instrument system is programmed to vary intracapsular distraction force between medial and lateral compartments with higher distraction force on the side requiring more bone removal and reduced distraction force in the other tibiofemoral compartment. Tibiofemoral intracompai mental distraction force is controlled in this manner until desired knee alignment is attained.
In another embodiment of the sculpting instrument the cutting elements are designed for two modes of operation; on for cutting and off for no cutting. In the case of a sculpting instrument that uses shaving elements for bone cutting the blades are deployed for cutting and retracted for no cutting. Blade deployment and retraction is manual. Alternatively, blade deployment and retraction is actuated mechanically or hydraulically. For the procedures and embodiments described above, this on/off sculpting instrument eliminates the need for spacers. When the desired resection depth or knee alignment is attained the respective sculpting instrument is turned off. In the case of the robotic TGS instrument system, the system controller is programmed to turn respective sculpting instruments on and off to control resection depth in each compartment to attain a preset knee alignment while the surgeon is flexing and extending the knee. The system displays independent intracompartmental resection depths, knee alignment, soft tissue balance and other variables of interest and prompts the surgeon when desired knee alignment is attained. In another control mode, the robotic TGS instrument system is programmed to monitor resection depth, intracompartmental distraction force and distraction displacement, and knee kinematics continuously throughout the knee's full range of motion and actively control bone resection in each compartment to vary resection throughout the range of motion to provide uniform soft tissue balance, alignment and kinematics throughout the range of motion.
Although the application of the TGS instrumentation system to the knee is described in detail herein, it is clear that the TGS instrumentation system is applicable to other total joint arthroplasty and to spinal arthroplasty is a similar manner. The combination of TGS instrumentations with navigation and with closed loop control and robotics can have application in other joint and spinal arthroplasty applications.
The present invention includes methods for sculpting the articular surface of a first bone that normally articulates in a predetermined manner with a second bone. One method includes fixing one or more bone-sculpting tools to the second bone, sculpting the articular surface of the first bone by articulating the bones with respect to each other, and applying a distracting force between the bone-sculpting tool and the second bone. Optionally, sculpting the articular surface of the first bone by positioning one of the bones with respect to the other, and applying a distracting force between the bone-sculpting tool and the second bone. The distracting force is applied so as to tension the soft tissue structures spanning the knee and force the bone-sculpting tool into the first bone, in which the force applying is operated at least in part under load control. An alternative method includes fixing one or more bone-sculpting tools to the second bone, sculpting the articular surface of the first bone by articulating or positioning one of the bones with respect of the other, and applying a first distraction force between the tibia and femur so as to tension the soft tissue structures spanning the knee. With the first distraction force applied, a second distraction force, independent of the first distraction force, is applied between the bone-sculpting tool and the second bone so as to force the bone-sculpting tool into the first bone. The first distraction force is operated at least in part under load control. The second distraction force is operated at least in part under load control as material is removed from the femur, said material removal continuing until bone-sculpting tool advances to a desired orientation and position relative to the second bone.
In some methods, applying the distracting force includes applying a fluid under pressure, in which the load control includes controlling the fluid pressure. Controlling the fluid pressure can include controlling a gaseous fluid pressure or a liquid fluid pressure, in various embodiments. The method may include measuring the load between the two bones and controlling the distracting force at least in part as a function of the measured load. In some methods, the force applying is controlled under load control, followed by displacement control after a displacement limit is reached. The displacement control can include mechanically limiting the range of displacement.
In some such methods, the load control is at least in part performed by an automatic controller which automatically controls the distraction force at least in part as a function of the load. The load control may be at least in part performed under manual control, in which a human controls the distraction force at least in part in response to a load read-out value.
Some embodiments utilize barrel cutters. One apparatus includes a frame having a space within, an outside region without, and a plurality of cutting cylinders rotatably disposed within the frame. A drive member can be externally accessible from outside of the frame, and the drive member operably coupled to rotate the cutting cylinders. In some embodiments, the housing has a posterior region for inserting into a mammalian body, an anterior region opposite the posterior region, a right side and a left side both extending between the posterior and anterior regions, in which the drive member is a shaft which protrudes outside of the housing through the right and/or left sides.
In some barrel cutter embodiments, the drive member is operably coupled to the cutting cylinders through gears. In others, the drive member is operably coupled to the cutting cylinders through a flexible drive loop. Some embodiments also include a fluid inlet port and outlet port in fluid communication with the housing interior for providing irrigation and tissue debris removal. Embodiments may also include a plurality of nested telescoping platforms, the platforms having an interior, an extended configuration and a collapsed configuration, in which the platforms can be urged from the collapsed configuration to the extended configuration through direct or indirect application of fluid pressure to the platforms interior. Some embodiments include two barrel cutter device coupled side by side in substantially the same plane, and which may be coupled to transfer applied torque between the first and second devices. In some embodiments two barrel cutters may be powered independently.
The present invention also provides belt cutter embodiments. One apparatus includes a frame having a posterior region for inserting into a mammalian body, an anterior region opposite the posterior region, a posterior roller rotatably coupled to the frame posterior region, an anterior roller rotatably coupled to the frame anterior region, and a cutting belt looped around both the posterior and anterior rollers. The apparatus can further include a drive member operably coupled to the anterior roller to rotatably drive the anterior roller and cutting belt.
In some belt cutters, the cutting belt includes a plurality of apertures therethrough, where which the apertures may optionally have a raised trailing edge. Some embodiments also include a posterior tissue protector coupled to the frame to protect tissue from the cutting belt posterior region. The belt cutter may have an anterior frame member coupled to the frame anterior portion. The drive member may be externally accessible from outside the frame, with the drive member disposed along an anterior-posterior axis, or disposed perpendicular to an anterior-posterior axis, in various embodiments.
Some belt cutter apparatus further include a housing base operably coupled to the frame for protecting tissue from a bottom portion of the cutting belt. A tensioning arm can be operably coupled to the anterior and posterior roller for adjusting belt tension in some embodiments.
Some embodiment cutting belts have a longitudinal axis, a substantially planar surface, and a plurality of outer cutting ridges disposed on the belt outer surface. The belt may have a plurality of inner ridges disposed on the belt inner surface. The ridges are oriented substantially perpendicular to the belt longitudinal axis in some embodiments, and are oriented at between about a 20 and a 70 degree angle with respect to the longitudinal axis in other embodiments. The belt may have a first set of substantially parallel cutting ridges on the belt outer surface, and a second set of substantially parallel cutting ridges on the belt outer surface, in which the first and second set of ridges cross each other to form a diamond shape pattern. In some belts, a first set of substantially parallel ridges are disposed on the belt outer surface, a second set of substantially parallel ridges are disposed on the belt outer surface, where the first and second set of ridges are disposed at least a 20 degree angle with respect to each other. Cutting belts can be tensioned and supported on rollers. A posterior tissue protector is present in some embodiment devices. Some cutting belts have a hole trailing edge that forms a grater. One cutting belt has a cutting pattern with alternating, opposing, inclined ridges partially spanning the belt. Cutting teeth can be directed anteriorly in direction of belt movement (i.e. the belt is rotating so as the superior surface is moving generally in an anterior direction) to urge the femur in an anterior direction while cutting.
The present invention also provides various reciprocating cutter embodiments. One such embodiment includes a frame having a posterior region for inserting into a mammalian body, an anterior region opposite the posterior region, and a substantially planar upper cutting element having a cutting surface. The apparatus also includes a drive member operably coupled to the cutter element so as to drive the cutting element to move substantially within a plane, in which the drive member is accessible from outside of the frame. In some embodiments, the drive member operable coupling is through an offset or eccentric cam. Some drive members are disposed along an anterior-posterior axis, while others are disposed orthogonal to an anterior-posterior axis, in various embodiments. Some embodiments include at least 2 upper cutting elements, each configured to operate in substantially the same plane.
In some reciprocating cutters, the upper cutting element cuts primarily only when moved in one direction, but not the opposite direction. In others, the upper cutting element cuts when moved in one direction and also in the opposite direction. Some embodiments have adjacent sub-components or sub-cutting elements 180.degree. out of phase to each other. Some embodiments have two or more sub-cutting elements; some have four to six.
The present invention also provides an expandable apparatus for cutting into mammalian bone, where the apparatus can include a frame having a posterior region for inserting into a mammalian body, an anterior region opposite the posterior region, and at least one upper cutting element having a cutting surface. The apparatus also includes an extendable body operably coupled to the bottom portion, the extendable body having a first configuration, and a second configuration, in which the apparatus has a greater height in the second configuration than in the first configuration.
In some embodiments, the extendable body is directly coupled to the housing, while in others the extendable body is at least partially received within the housing. Some extendable bodies include a bellows. The bellows can include inward and/or outward folds. The extendable body may include a balloon or bladder received within an expandable housing having a rigid top and bottom and side panels having inward and/or outward folds. The bladder can be formed of polyethylene terephthalate (PET), nylon, polyethylene (PE), urethane, or other materials. The extendable body may include at least one leg received into the housing. The extendable body can include an expandable envelope, which may be nested within another structure. Some embodiments include at least two nested structures, one at least partially nested within the other. The nested structures can include nested, telescoping structures. The cutting element having the extendable body can include a cutting element selected from the group consisting of cutting cylinders, cutting belts, and reciprocating cutting planar surfaces.
A shaver cartridge apparatus is also provided by the present invention. The apparatus can include a frame having a posterior region for inserting into a mammalian body, an anterior region opposite the posterior region, and a removable cartridge. The removable cartridge can have an upper surface bearing a plurality of cutting elements, with the cartridge slidably coupled to the frame to allow for movement of the cutting elements with respect to the frame, and a drive member operably coupled to the cartridge so as to reciprocatingly drive the cartridge, where the drive member is accessible from outside of the frame. In some embodiments, the drive member is rotatably coupled to an off-center cam, where the off-center cam reciprocatingly drives the removable cartridge. The apparatus can have a protected, non-cutting posterior end region for protecting tissue.
The present invention also provides an apparatus for simultaneously cutting into two or more distinct regions of mammalian bone. The apparatus can include a first frame having a posterior region for inserting into a mammalian body and an anterior region opposite the posterior region, and a second frame having a posterior region for inserting into a mammalian body and an anterior region opposite the posterior region. The first and second frames can have a first and second respective moveable cutting body including a an upper cutting surface capable of cutting into tissue and bone. The apparatus can include a first drive member operably coupled to the first cutting body, a second drive member operably coupled to the second cutting body, and at least one connecting member for maintaining the first and second frames in spaced apart relation to each other.
In some embodiments, the first and second moveable cutting bodies are each a rotating cylinder having cutting surfaces, while in other embodiments the first and second moveable cutting bodies are reciprocating cutting surfaces each bearing cutting elements. In still other embodiments, the first and second moveable cutting bodies are each closed loop belts bearing cutting elements, wherein the belts are driven by the drive members to move in a longitudinal direction.
Various other aspects are provided by the present invention, in various embodiments. Some devices are driven by a flexible drive belt that is a continuous loop. Some cutting surfaces have cutting teeth or abrasive material. Some cutters can expand in height using telescoping platforms. Guide posts may be used in some embodiments. The height expansion can be accomplished with a mechanical cam, screw mechanism, scissors jack, or a bladder. This may be via hydraulics in a bladder or in a piston/cylinder, via mechanical scissors, via mechanical cam, or via a spacer or shim. A stand alone telescoping or otherwise extendable section is used in some embodiments, which can be placed below or within a cutter body.
The present invention also provides an apparatus for cutting into two or more distinct regions of mammalian bone. The apparatus can include an expandable apparatus for cutting into mammalian bone, where the apparatus can include a frame having a posterior region for inserting into a mammalian body, an anterior region opposite the posterior region, and at least one upper cutting element having a cutting surface, and a stand alone telescoping or otherwise extendable apparatus having a posterior region for inserting into a mammalian body, an anterior region opposite the posterior region, and at least one extendable body. The cutting apparatus is placed in a first distinct region of mammalian bone. The telescoping section is placed in a second distinct region of mammalian bone. The apparatus can include a drive member operably coupled to the cutting apparatus, and optionally at least one connecting member for maintaining the cutting apparatus in spaced apart relation to the telescoping apparatus. In some embodiments, the telescoping section includes one or more extendable bodies. The telescoping section can have an extendable body directly coupled to the housing, while in others the extendable body is at least partially received within the housing. The extendable body having a first configuration, and a second configuration, in which the apparatus has a greater height in the second configuration than in the first configuration.
Some cutters are made primarily from stainless steel. The frame and housing can be made of suitable plastics, such as Polyetheretherketone (PEEK).
Unless otherwise noted, some embodiments of the barrel cutter, reciprocating, and belt cutter devices according to the present invention can have a frame length of between about 10 mm and 90 mm, and a width of between about 10 mm and 50 mm. Others have a frame length of between about 10 mm and 90 mm, and a width of between about 40 mm and 100 mm. Still others may have a frame length of less than about 10 cm and a width of less than 10 cm. Yet others may have a frame length of less than about 2 cm and a width of less than about 1 cm.
Unless otherwise noted, some embodiments of the barrel cutter, reciprocating, and belt cutter devices according to the present invention can be used by operating two or more cutters at the same time. One cutter can be placed in the medial tibiofemoral compartment and one placed in the lateral tibiofemoral compartment. One cutter may be placed in the patellofemoral compartment as well. Any combination of these may be used. The cutters may have a common drive member, or they may have individual drive members. They can be distracted independently, or be distracted (i.e. deployed) as a set. Each may be deployed under “load” control or under “displacement” control, or a combination thereof. Each may be initially deployed under “load” control, then changed to “displacement” control, or visa versa. As they deploy, the frame may constrain the cutting elements in a plane parallel to the base of the frame, or allow the plane of the cutting elements to angulate relative to the base of the frame.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a barrel cutter having transversely mounted rotatable cylindrical cutting elements, irrigation ports, and a drive shaft.
FIG. 2 is a perspective view of a cylindrical cutting element having a central drive recess suitable for use in some string driven barrel cutters, for example, that of FIG. 12 .
FIG. 3 is a perspective view of another cylindrical cutting element suitable for use in some end driven barrel cutters, for example, that of FIG. 1 .
FIG. 4 is a perspective view of a reciprocating cutter having an upper, substantially planar cutting element.
FIG. 5 is an exploded view of the reciprocating cutter of FIG. 4 , showing the irrigation ports and the reciprocating drive shaft mechanism.
FIG. 6 is a perspective view of the barrel cutter of FIG. 1 .
FIG. 7 is a top, cross-sectional view, taken through the cutting element centers, of the barrel cutter of FIG. 1 , showing the bevel gear drive for driving the barrel cutters.
FIG. 8 is a side, cross-sectional view, taken though the drive gears, of the barrel cutter of FIG. 1 , showing the end driven cutter elements and gear drive train.
FIG. 9 is a top, schematic view of the barrel cutter of FIG. 1 .
FIG. 10 is a side, elevation view of the barrel cutter of FIG. 1 .
FIG. 11 is an exploded view of the barrel cutter of FIG. 1 .
FIG. 12 is a perspective view of a string driven barrel cutter having a bottom telescoping platform, a side drive shaft, and which can use the cutter element of FIG. 2 .
FIG. 13 is a side, cross-sectional view of the string driven barrel cutter of FIG. 12 , taken through the drive loop.
FIG. 14 is an exploded view of the string driven barrel cutter of FIG. 12 .
FIG. 15 is a perspective view of the string driven barrel cutter of FIG. 12 , shown in a collapsed configuration.
FIG. 16 is a side, cross-sectional view of the string driven barrel cutter of FIG. 12 , taken through the drive loop, shown in an expanded telescope configuration.
FIG. 17 is an exploded view of the string driven barrel cutter of FIG. 12 , with the telescoping platforms shown in an expanded, configuration.
FIG. 18 is a perspective view of a belt cutter having a linear tensioning frame using a screw mechanism to tension the cutting belt.
FIG. 19 is an exploded view of the belt cutter of FIG. 18 having a linear tensioning frame.
FIG. 20 is an exploded view of another belt cutter, having a hinge tensioning frame using a scissors mechanism to tension the cutting belt.
FIG. 21 is a perspective view of a reciprocating cutter having a substantially planar upper cutting element and a side drive shaft.
FIG. 22 is an exploded view of the reciprocating cutter of FIG. 21 , showing irrigation ports and plenum, and an off-set cam reciprocating mechanism within.
FIG. 23 is perspective view of an expandable telescoping bladder, shown in a collapsed configuration.
FIG. 24 is a perspective view of an expandable housing, suitable for receiving the bladder of FIG. 23 within.
FIG. 25 is a perspective, cutaway view, and a non-cutaway view, of the bladder of
FIG. 23 disposed within the platform of FIG. 24 , shown in a collapsed configuration.
FIG. 26 is a perspective, cutaway view, and a non-cutaway view, of the bladder of FIG. 23 disposed within the platform of FIG. 24 , shown in an expanded configuration.
FIG. 27 is a perspective view of a dual belt cutter positioned in the knee joint.
FIG. 28 is a perspective view of a belt cutter.
FIG. 29 is a perspective view of a knee joint with the tibial plateaus resected.
FIG. 30 is a lateral side view of the knee with a telescoping cutter positioned in the lateral tibiofemoral joint.
FIG. 31 is a medial side view of the knee with a telescoping cutter positioned in the medial tibiofemoral joint.
FIG. 32 is lateral side view of the knee with a telescoping cutter positioned in the patellofemoral joint.
FIG. 33 is a schematic top view of a reciprocating drive top cutting element and drive shaft.
FIG. 34 is a perspective view of dual barrel cutters, which can be similar to the barrel cutters of FIG. 12 , shown in position in the tibiofemoral compartments.
FIG. 35 is a perspective view of dual barrel cutters, for example the barrel cutters of FIG. 12 .
FIG. 36 is a perspective view of dual reciprocating cutters shown in position in the tibiofemoral compartments.
FIG. 37 is a perspective view of dual barrel cutters positioned in the knee joint.
FIG. 38 is a perspective view of dual belt cutters, for example the belt cutters of FIG. 20 , shown in position in the tibiofemoral compartments.
FIG. 39 is a perspective view of dual belt cutters, for example the belt cutters of FIG.
20 .
FIG. 40 is an end elevation view of a reciprocating cutter, having the telescoping platform in an extended configuration.
FIG. 41 is an end elevation view of the reciprocating cutter of FIG. 40 , having the telescoping platform in a retracted or collapsed configuration.
FIG. 42 is an exploded view of the reciprocating cutter of FIG. 40 , showing the retainer for securing the top cutting element.
FIG. 43 includes orthogonal views and a perspective view of a cutting belt.
FIG. 44 includes orthogonal views of a cutting belt.
FIG. 45 includes orthogonal views of a cutting belt.
FIG. 46 includes orthogonal views of a cutting belt.
FIG. 47 includes perspective views of a cartridge for use in removing bone.
FIG. 48 includes exploded views of the cartridge of FIG. 47 .
DETAILED DESCRIPTION OF THE INVENTION
Some embodiments of the invention include replacing the articulating surfaces of the knee with implants. Supporting information is included in current patents and patent applications, to include U.S. Pat. Nos. 6,482,209 and 6,723,102, herein incorporated by reference.
The present application includes disclosure of bone-sculpting tools for preparing the femoral condyles and trochlea. Sculpting instruments, sculpting instrumentation, sculpting devices, sculpting apparatus and bone-sculpting tools are interchangeable terms. It should be noted that tissue guided surgery and the sculpting device embodiments are applicable to other joints in the body, to include but not limited to the hip, shoulder, ankle; and motion segments of the spine, to include the disc and facet joints. The femoral cutter (sculpting devices) described herein include a shaver (as initially described in U.S. Pat. No. 6,428,209), a barrel cutter, a reciprocating cutter and a belt cutter. Various embodiments of each are presented.
FIG. 1 illustrates a barrel cutter designed with multiple cylindrical cutting elements 103 . The barrel cutter can be designed with one or more cutting elements 103 . In one embodiment the barrel cutter is designed with five cutting elements 200 (as shown in FIG. 12 ).
The area of contact between the bony surfaces of the tibiofemoral and patellofemoral compartments moves along the surface of the femur, within each compartment, as the knee flexes and extends. This movement is greater on the lateral side due to rotation of the tibia. Hence, it is desirable to have a cutting surface sized to remove bone as the location of the contact area moves over the surface of the femur. In one embodiment the cutting elements 103 are small in diameter and spaced closely together. The overall cutting surface area as shown in FIG. 1 has a cutting surface length 108 , a cutting surface width 109 , and is sized to accommodate the movement of the medial or lateral tibiofemoral contact area during knee flexion and extension and the width of the medial or lateral femoral condyle. In general, in some embodiments, the cutting surface length may range from approximately 10 mm to 90 mm and the cutting surface width may range from 10 mm to 50 mm, for cutters designed to be placed in either tibiofemoral compartment. In another embodiment in which the tibial plateau is resected, the cutting surface width matches that of the mediolateral width of the distal femur, which may range from approximately 40 mm to 100 mm.
FIGS. 1 , 6 , 7 , 8 , 9 and 10 , illustrate one embodiment of a barrel cutter, in which the cutting elements 103 are supported by a cutter housing 107 and a side plate 102 . Cutter housing 107 is separated from drive housing 101 by spacer plate 111 , and from side plate 102 by spacer plate 110 . Side plate 102 can be secured using fasteners 1000 (shown in FIG. 10 ). Side plate 102 can also include top attachment holes 900 (shown in FIG. 9 ). Optionally, two barrel cutters can be used simultaneously to prepare the medial and lateral femoral condyles. In a left knee the shown barrel cutter is placed in the medial tibiofemoral compartment. A barrel cutter (not shown) structured as the mirror image of the barrel cutter shown is placed in the lateral tibiofemoral compartment. Each barrel cutter structured with four attachment holes 900 to which a cross bar (not shown) can be attached with threaded fasteners (not shown) to stabilize and orient one barrel cutter to the other. Alternatively, each barrel cutter can be placed in respective tibiofemoral compartments independently without connecting them together.
The drive housing 101 supports a drive shaft 100 . A rigid or flexible drive shaft extension (not shown) can be attached between the drive shaft 100 and a rotational power supply, such as a surgical power drill or a motor. FIG. 7 illustrates how input torque can be delivered to drive shaft 100 which is attached to a bevel gear set 700 and 701 (or bevel gears 1100 and 1101 in FIG. 11 ). FIG. 8 illustrates how torque is transferred to drive gear 805 by shaft 702 . From the cutter drive gear 800 , torque is transferred to a transfer gear 804 to a cutter drive gear 800 . Idler gears 803 are placed between subsequent cutter drive gears 800 to transfer torque to each of the cutting elements 103 . A lock pin 802 is placed into gear relief 801 and relief 303 to secure the gear to the cutter. In one embodiment, the cutter drive gears 800 are pinned to the cutter hub 302 (shown in FIG. 3 ). Referring to FIGS. 8 and 11 , the barrel cutter is structured to drive cutting elements 103 with drive shaft 100 connected to bevel gear 1100 . Bevel gear 1100 meshed with bevel gear 1101 which is connected to shaft 1105 which is connected to drive gear 805 which meshes with transfer gear 804 . Transfer gear 804 meshes with cutter drive gear 800 which meshes with idler gear 803 and torque is transferred to each cutting element via idler gear 803 and drive gear 800 combinations. Transfer gear 804 and idler gears 803 are supported by shafts 1109 . Shafts 1109 passing through and supported by clearance hole 1114 in side plate 102 and clearance hole 1115 in face plate 1102 . Face plate 102 is assembled with cutter housing 107 by threaded fasteners (not shown) passing through clearance holes 1116 in side plate 102 , clearance holes 1117 in face plate 1102 and into threaded holes 1106 in cutter housing 107 .
FIG. 3 illustrates that cutting element 103 has one or more cutting edges 106 , and in one embodiment there are four cutting edges 106 as shown in FIG. 3 . Cutting element 103 is supported on one end by a hub 301 and at the other end by a gear hub 302 . A cutter relief 300 is designed trailing the cutting edge 106 to enhance cutting.
FIGS. 1 , 6 and 11 illustrate features which beneficially flush bone debris out of the femoral cutter during operation. Sterile saline or other suitable fluid may be used for this purpose. The barrel cutter is designed with input port 104 and output port 105 . Irrigation fluid is delivered to the barrel cutter by a plastic tube (not shown) structured to attach to the barrel cutter at port 104 to be channeled through housing 101 , through face plate 1103 via irrigation input port 1107 , into channel 1104 leading to longitudinal hole 1111 in communication with each cutting element 103 relief channel 1112 . Irrigation fluid flows over cutting element 103 to be gathered in longitudinal hole 1113 in communication therewith. Irrigation fluid flowing through face plate 1103 via irrigation output port 1108 in communication with port 105 in housing 101 and into a plastic tube (not shown) structured to attach to housing 101 .
Durability, sharpness and cleanability are important for the function and use of the femoral cutter. Given the small size of the femoral cutters, a single use device is preferred to provide sharp cutting elements in each surgical case and to ensure durability of the device. Cost is an important factor in single use devices. The use of gears to drive the cutting elements is costly for two reasons, the cost of the gears and the cost of machining to hold tolerances for proper function of the gears. Hence, a less expensive drive means would be desirable.
FIG. 13 illustrates another embodiment of a barrel cutter, in which a string drive is used to drive each of the cutting elements. The string drive can be a continuous loop that is wrapped around each cutter and around an input shaft so that as the input shaft is rotated, each cutting element rotates. The string drive is designed with a drive loop 1300 , which may be a monofilament string, multi-strand woven string or cord; single or multi-strand wire; drive belt, V-belt or timing belt; or other flexible band that can be placed around or on the cutting elements to impart rotation. The drive loop 1300 is wrapped around a drive shaft 1202 one time as shown, or in another embodiment multiple times (not shown) to take advantage of the increased friction between the drive loop and shaft with multiple windings. The drive loop 1300 can be wrapped one or more times around each cutting element 200 .
FIG. 2 illustrates a cutting element 200 designed with a recess 203 for receiving drive loop 1300 . The cutting element can be supported by hubs 201 . Cutting element 200 includes cutting edges 202 , and chip relief 204 , formed as a circumferential groove in this embodiment. Cutting element 200 is structured with one or more cutting edges 202 . Each cutting edge 202 is structured with one or more chip reliefs 204 that improve cutting element's 200 chopping of articular cartilage present on the femoral condyle and in chopping bone to be removed. FIGS. 12 , 13 and 14 illustrate an embodiment in which the string drive is integral to the femoral cutter. Drive shaft 1202 and cutting elements 200 are supported by a common housing 1200 and 1201 , and a means for tensioning the loop drive 1300 is provided. Common housings 1200 and 1201 are held in alignment by alignment pins 1301 slidably received in holes 1400 . Common housings 1200 and 1201 structured to be adhesively bonded together between common faces 1404 and 1405 . In another embodiment (not shown) the drive shaft is supported in a separate housing and one or two flexible tubes connect the drive shaft housing to the cutting element housing. In an embodiment using one flexible tube the dive loop is wrapped around the drive shaft one or more times and passed through the flexible tube into the cutter housing wherein the loop drive is wrapped one or more times around each cutting element. In an embodiment using two flexible tubes, the drive loop would be an open loop in which the string is passed through one tube, into the cutting element housing, wrapped one or more times around each cutting element, routed out of the cutting element housing, through the second tube, into the drive shaft housing, then wrapped one or times around the drive shaft and connected to the other end of the drive loop. Alternatively, for the single or dual tube embodiments, the flexible tube may be rigid and made of steel, plastic or other suitable material.
FIG. 14 illustrates an embodiment in which drive shaft 1202 is designed with ridges 1401 and 1402 and a groove 1403 to guide drive loop 1300 . The opposing faces 1404 and 1405 of the housing can be brought together over alignment pins 1301 inserted into holes 1400 .
As described above, it is beneficial to expand the cutters within the patellofemoral compartment and tibiofemoral compartments. The barrel cutter is designed with a cylinder to provide axial expansion of the cutter. FIG. 13 illustrates that the cylinder may be of multiple stages as shown by telescoping platforms 1302 , 1303 and 1304 , which are held in place within housing 1200 and 1201 with telescoping platform 1203 . FIG. 13 shows the cylinder in a collapsed position. FIGS. 15 , 16 and 17 show the cylinder in an extended position.
FIGS. 4 and 5 illustrate a reciprocating cutter designed to be placed in either the tibiofemoral compartment and/or in the patellofemoral compartment. Cutting element 400 is designed with cutting teeth on top surface 500 . The cutting teeth may be continuous from side to side or include individual cutters staggered over the surface of the cutting element so as to provide uniform material removal over the surface of the cutting element. Alternatively, the top surface may have an abrasive texture to remove material. In either case, the surface of the cutting element may be continuous or may have holes to allow material removed from the femur to pass through.
Cutting element 400 is driven in a reciprocating fashion by applying torque to drive shaft. 404 . Torque may be supplied by a surgical power drill or a motor. A flexible or solid drive shaft can be used to connect the surgical power drill or motor to drive shaft 404 . A reciprocating drive groove 506 is formed by an upper boss 505 and a lower boss 504 , and having an upper groove wall 507 and a lower groove wall 508 . As the drive shaft spins, reciprocating drive groove 506 imparts a reciprocating motion to cutting element 400 . A hub 502 rides within reciprocating drive groove 506 and moves in an axial direction to drive cutting element 400 via cutter aim 501 . Drive shaft 404 includes an end hub 509 which is received in hub support 511 adjacent a reciprocating drive recess 510 and a drive shaft recess 512 . Distal end of drive shaft 404 is structured with hub 509 to align and support distal end of drive shaft 404 . Drive shaft 404 is supported in drive housing 402 and drive cover 401 each structured with hub support 511 to support distal end of drive shaft 404 and drive shaft support 512 to support drive shaft 404 . Clearance for lower boss 504 and upper boss 505 within drive housing 402 and drive cover 401 is provided by recess 510 . FIG. 33 illustrates that cam 3302 rides in the groove 3306 between bosses 3304 and 3305 while drive shaft 3303 rotates, resulting in a reciprocating motion of thin 3301 and cutting element 3300 . Cutting element 400 is supported by drive housing 402 . Drive shaft 404 and cutter arm 501 are held in relative position by drive housing 402 and enclosed by drive cover 401 .
FIGS. 40 , 41 , and 42 show that as cutting element 400 reciprocates, the posterior aspect of the cutting element 400 is beneficially guided and cutting element 400 is retained on the surface of the drive housing 402 . A retainer 4000 is visible on the underside of cutting element 400 . The retainer 4000 fits into cavity 4200 and is held vertically by a shoulder 4201 fitting into a groove 4202 . The cavity is elongated to allow reciprocating motion of the cutter element 400 .
FIGS. 21 and 22 illustrate an alternate embodiment having a cutting element 2100 structured to be supported on housing base 2101 . Said housing 2101 base structured to support drive shaft 2104 and enclose said drive shaft 2104 with housing cap 2103 . Drive shaft 2104 structured to oscillate cutting element 2100 . Off set cam 2200 is in communication with channel 2205 in cutting element 2100 arm 2206 . Housing base 2101 is structured with chamber 2214 to provide clearance for drive shaft 2104 bosses 2201 and 2202 . Drive shaft 2104 cylinder 2204 is slidably received in channel 2203 in housing base and in adjoining channel (not shown) in housing cap 2103 . Bosses 2201 and 2202 capture said channel 2203 to slidably retain drive shaft 2104 . As drive shaft 2104 rotates, cam 2200 rotates and slides within channel 2104 thereby moving cutting element back and forth within bosses 2215 protruding from housing base 2101 . Cutting surface 2207 structured to remove tissue when oscillated against adjoining bone. Cutting surface structure includes embodiments described here in, to include ridges, grit surface, protuberances, or other suitable cutting feature known to those skilled in the art. Reciprocating cutter is structured to telescope. Telescoping platform 2102 is structured to slidably assemble with housing base 2101 . Guide posts 2208 are slidably received in holes 2210 . The leading end of guide posts 2208 are structured with snap retainers 2209 that engage lips 2216 within holes 2210 . Tissue removed from the femur flows into chamber 2211 . Input hole 2212 is structured to attachably receive a tube (not shown) through which irrigation fluid flows into chamber 2211 . Irrigation fluid is transported out of chamber 2211 through output hole 2213 . Said output hole 2213 structure to attachably receive a tube (not shown) which may be connected to a vacuum system (not shown).
FIG. 5 illustrates that a port 515 brings irrigation fluid, e.g. sterile saline, into a cavity 514 behind cutting element 400 via opening 518 . The fluid exits the cavity via opening 519 and port 516 . As mentioned earlier, it is beneficial to wash debris from femoral resections away from the cutter.
FIGS. 4 and 5 illustrate a reciprocating cutter which can expand. A telescoping platform 403 is provided on the base of the cutter. Guide posts 503 align the telescoping platform 403 and limit travel by snap-in retainers 517 . Guide posts 503 are designed to fit into and snap into receiving holes 513 in the drive housing 402 .
FIG. 41 illustrates the reciprocating cutter in a fully collapsed position. The collapsed reciprocating cutter fits easily into a tibiofemoral compartment, or into the patellofemoral compartment. To tension the ligaments and capsule the reciprocating cutter can be expanded as shown in FIG. 40 . Expansion of the telescoping platform may be accomplished by a mechanical cam, screw mechanism or scissors jack (not shown), or by a bladder. Bladder designs are described below.
FIG. 18 illustrates yet another embodiment, a femoral cutter having a cutting belt 1800 . Cutting belt 1800 is supported on a frame and driven to move the cutting surface across the adjacent femoral condyle or trochlea. Cutting belt 1800 can be tensioned and supported on rollers. Torque is applied to the drive shaft 1803 by a surgical drill or motor with a flexible or rigid drive shaft as previously described. As the belt cutter is placed into a tibiofemoral compartment and operated, the tissue structures in the back of the knee need to be protected. A tissue protector 1804 is designed as part of the housing base 1801 for this purpose. A housing end cap 1805 may be seen at the anterior end.
FIG. 19 illustrates the femoral cutter of FIG. 18 in an exploded view. Cutting belt 1800 is supported on an idler roller 1906 having a shaft 1907 received within, and a drive roller 1903 having a drive shaft cylinder 1904 received within. Hole 1922 through idler roller 1906 snuggly receives shaft 1907 structured to press fit shaft 1907 in hole 1922 . Tensioning arm 1900 is structured with tabs 1916 protruding from distal end through which holes 1913 pass. Idler roller 1906 is positioned between tabs 1916 and shaft 1907 is slidably received through first hole 1913 , press fit through hole 1922 in idler roller 1906 , and slidably received in second hole 1913 . As for the drive roller 1903 , housing frame 1802 and housing end cap 1805 adjoin along interface 1807 . Hole 1912 extends along interface 1807 and slidably receives drive shaft 1803 . Hole 1905 through drive roller 1903 snuggly receives drive shaft 1803 structured to press fit drive shaft 1803 in hole 1905 . Drive shaft 1803 is press fit into hole 1905 . Boss 1915 protruding from housing frame 1802 is slidably received in channel 1914 in housing frame 1802 . Screws 1908 are assembled in threaded holes 1909 in housing frame 1802 . Assembled drive roller 1903 and drive shaft 1803 are slidably received by the portion of hole 1912 formed in housing frame 1802 . Skid 1902 is placed on said assembly and the combination placed inside cutting belt 1800 with said cutting belt positioned between bosses 1808 protruding from housing frame 1802 . Screws 1908 are advanced to properly tension cutting belt 1800 . Drive shaft 1803 is secured by the portion of hole 1912 formed in housing end cap 1804 . Housing end cap 1804 is assembled to housing frame with threaded fasteners (not shown) slidably received through holes 1917 and threaded into receiving holes (not shown) in housing frame 1802 . Skid 1901 is placed inside housing base 1801 and combination is placed onto assembled cutting belt 1800 , housing frame 1802 and housing end cap 1805 . Housing base 1801 is assembled to tensioning aim 1900 with threaded fasteners (not shown) slidably received through holes 1919 in tabs 1918 protruding from housing base 1801 . Said screws treadably received in threaded holes 1920 in tensioning arm 1900 . Hole 1921 in housing frame 1802 is structured to attachably receive a plastic tube to which operating room suction is applied to remove fluid and tissue debris from tissue and bone cutting.
As the cutting surface 1806 of cutting belt 1800 works against the femoral condyle or trochlea, compressive force is carried by a skid 1902 below the belt and structural support is provided to the frame by a second skid 1901 . Tissue is removed by one or more protuberances 1923 structured in the cutting belt 1800 . Such protuberances 1923 formed by stamping or pressing a form into cutting belt 1800 , or by attaching a formed or machined protuberance to the cutting belt 1800 . Such attachment by adhesive, welding, diffusion bonding, press fit or other attachable means know in the art. Cutting belt 1800 is fabricated from stainless steel, cobalt chromium molybdenum alloy, or other suitable metal. Alternatively, cutting belt 1800 may be fabricated from rubber, urethane, or other suitable polymeric material with embedded protuberances as described above. Optionally, said polymeric cutting belt may be reinforced by fibers, metal mesh or other suitable material to increase strength and durability. A polymeric cutting belt can have integral metal cutting elements with protuberances. Alternatively, the metal cutting elements can be abrasive. To tension the cutting belt 1800 , the housing frame 1802 is adjustable by turning two screws 1908 to advance a tensioning arm 1900 to increase tension on the belt cutter. The belt is driven in the direction shown in FIG. 19 by applying torque to the drive shaft 1803 which is attached to the drive roller 1903 . The belt slides across upper skid 1902 and lower skid 1901 , and turns on an idler roller 1906 . A surgical drill, or a motor, with a flexible drive shaft as previously described can be used to apply torque to the drive shaft 1803 .
To remove material from the femur, the cutting belt 1800 is designed with holes 1910 that create a rough edge when run against the femur. Alternately, the trailing edge 1911 of the hole 1800 is elevated to form a grater for more aggressive cartilage and bone removal (see the belt detail in FIG. 19 ). The cutting belt is formed by cutting or stamping the hole pattern in a strip of metal or other suitable material and welding or bonding the ends together to form a belt. Alternatively, the outer surface of belt 1800 can be abrasive.
FIGS. 43 , 44 and 45 illustrate alternate cutting belt embodiments fabricated from a strip that is welded or bonded (e.g. at 5307 ) into a belt or loop. In an alternate embodiment, a cutting pattern is chemically etched, stamped or machined into the outer surface of the cutting belt. As shown in FIG. 43 , ridges 5302 are formed into the outer surface 5300 of the cutting belt. The outer ridge pattern 5302 is perpendicular to the side 5303 of the belt. The inner surface 5301 may have a pattern chemically etched, stamped or machined in it to enhance traction with the drive roller described above, or the inner surface may be smooth or roughened. The inner ridge pattern 5304 is perpendicular to the side 5303 of the belt. The belt is farmed into a loop and the fastening edges 5305 and 5306 are welded or bonded together.
FIG. 44 shows an alternate embodiment, in which a cutting pattern is chemically etched, stamped or machined into the outer surface of the cutting belt. Ridges 5402 are formed into the outer surface 5400 of the cutting belt. The outer ridge pattern 5402 is inclined relative to the side 5403 of the belt. The inner surface 5401 may have a pattern chemically etched, stamped or machined in it to enhance traction with the drive roller described above, or the inner surface may be smooth or roughened. The inner ridge pattern 5404 is inclined relative to the side 5403 of the belt. The belt is formed into a loop and the fastening edges 5405 and 5406 are welded or bonded together.
FIG. 45 shows an alternate embodiment belt having a side 5503 , in which belt a cutting pattern is chemically etched, stamped or machined into the outer surface of the cutting belt. Alternatively, the outer surface of belt can be abrasive. Abrasive surface, as used herein, formed by grit blasting, plasma spray, bonding abrasive material, or other fabrication method known to one skilled in the art. Ridges 5502 are formed into the outer surface 5500 of the cutting belt. The outer ridge pattern 5502 is alternating, opposing, inclined ridges partially spanning the belt. The inner surface 5501 may have a pattern chemically etched, stamped or machined in it to enhance traction with the drive roller described above, or the inner surface may be smooth or roughened. The inner ridge pattern 5504 is a diamond pattern. The belt is formed into a loop and the fastening edges 5505 and 5506 are welded or bonded together.
FIG. 46 illustrates yet another embodiment, in which the cutting belt 5605 is made from a deep drawn can 5600 . A right cylinder is formed by deep drawing stainless steel or other suitable material. The can 5600 is open on one end 5601 and closed on the other 5603 . The closed end of the can is removed along cut line 5602 forming a continuous belt 5604 into which the patterns described above can be chemically etched, machined or stamped. For example, perpendicular ridges 5607 are chemically etched, stamped or machined into the outer surface of the cutting belt 5605 . For traction with the drive roller a ridge pattern may be formed into the inner surface of the belt. A perpendicular ridge pattern 5606 on the inner surface is shown in FIG. 46 . It should be noted that the outer and inner surface patterns described above can be used in any combination and that holes through the belt as previously described can be added.
FIG. 20 illustrates an alternate embodiment belt cutter in which the frame and tensioning mechanism uses a hinged frame. In this embodiment, the anterior tensioning frame 2001 having support face 205 and hole 204 , and the posterior tensioning frame 2002 are initially pinned together with one pin 2007 to form a hinge. Pin 2007 is slidably received through first hole 2010 then press fit through hole 2014 then slidably received in second hole 2010 . The tensioning frame 2001 and 2002 support drive roller 2003 that is press fit or attached to drive shaft 2006 received within a drive roller 2003 , and an idler roller 2004 rotating on a shaft 2005 . Idler roller 2004 is placed between tabs 2021 protruding from posterior tensioning frame 2002 . Shaft 2005 is slidably received through first hole 2020 and press fit through hole 2018 in idler roller 2004 then slidably received in second hole 2020 . Drive roller 2003 is placed between tabs 2022 . Drive shaft 2006 is slidably received through first hole 2019 and press fit through hole 2017 in drive roller 2003 then slidably received in second hole 2019 . The tensioning frame is angled about the pivot pin 2007 to allow placing the tensioning frame into the cutting belt 2000 . Once in place, the tensioning frame is opened into a straight position aligning the anterior and posterior tensioning frames, 2001 and 2002 , respectively. The tensioning frame is held in this position by placing locking pin 2012 into a receiving hole 2013 in the posterior tensioning frame 2002 that is now aligned with a receiving hole 2011 in the anterior tensioning frame 2001 . Pin 2012 is slidably received through first hole 2013 then press fit through hole 2011 the slidably received in second hole 2013 . The assembled tensioning frame includes a distal tissue protector 2009 , and a cutting belt which is supported in a housing base 2008 having a support face 2016 . Support faces 2016 of housing base 2008 are structured to snap fit on to tension frame assembly at adjoining support faces 2015 on anterior tensioning frame 2001 .
FIG. 28 illustrates another embodiment in which the belt cutter 2801 , having frame 2800 , drive shaft 2803 , and shaft 2804 , has the cutting teeth 2802 directed posteriorly, so as to force the femur posteriorly while cutting.
FIG. 29 illustrates how the tibial plateau can be prepared by resecting the articular surfaces leaving lateral support surface 2902 and medial support surface 2903 on which tissue guided femoral cutters are placed to prepare the adjacent femoral condyles. The medial 2903 and lateral 2902 support surfaces may be prepared at the same time thereby allowing simultaneous preparation of medial and lateral femoral condyles. Optionally, either medial 2903 or lateral 2902 support surface may be prepared initially followed by preparation of the adjacent femoral condyle. A spacer may be placed in the prepared tibiofemoral compartment followed by preparation of the adjacent tibial support surface followed by preparation of the adjacent femoral condyle. The medial and lateral tibial articular surfaces may be resected independently as shown in FIG. 29 in which case the tibial eminence 2907 is preserved. Alternatively, the anterior portion of the tibial eminence 2907 may be resected to allow for a bridge or connection between the medial and lateral tibial implants, or the tibial eminence 2907 may be resected. The medial and lateral tibial resections may be co-planar. Alternatively, the medial and lateral resection may be parallel, but not co-planar. In yet another embodiment the medial and lateral tibial resection may not be co-planar nor parallel. The femoral condyles may be resected independently, simultaneously, or in combination with the femoral trochlea. In one embodiment the femoral cutters telescope to distract the joint; either one or both of the tibiofemoral compartments and/or the patellofemoral compartment. Such distraction can be performed under constant load. Alternatively, such distraction may be at discrete displacement steps or distracted to a desirable displacement for condyle(s) and/or trochlea resection. Femoral condyle preparation is guided by the kinematics of the knee joint. The tibia 2901 moves in a predetermined fashion about the femur 2900 . This motion is determined by the soft tissue structures spanning the knee. The anterior cruciate ligament (ACL) 2905 and the posterior cruciate ligament (PCL) 2907 extend from the femoral intracondylar notch to the tibial eminence 2908 . The medial collateral ligament (MCL) 2906 extends from the medial side of the femur to the medial side of the tibia. The lateral collateral ligament (LCL) 2904 extends from the lateral side of the femur to the lateral side of the tibia. The ACL 2905 , PCL 2907 , MCL 2906 and LCL 2904 are the primary ligamentus structures guiding motion of the tibia relative to the femur.
In tissue guided surgery a femoral cutter may be placed in each tibiofemoral compartment and in the patellofemoral compartment. The cutting elements are held against the femur while the knee is flexed and extended in order to remove bone from the femur to prepare support surfaces for trochlear and/or condylar implants. Initially, it is beneficial to tension the ligaments spanning the knee and the joint capsule to stabilize the joint with the cutters in place and to provide uniform kinematic motion. As bone is removed it is beneficial to expand the cutters to maintain tension on the ligaments spanning the knee and the joint capsule. The cutters may be expanded incrementally to discrete heights, or variably under constant distraction force. In the first case, which is referred to as “displacement control,” spacers may be placed under the cutters to expand the cutter, or a hydraulic cylinder with incremental fluid filling may be designed into the cutter to expand the cutter, in the patellofemoral compartment or in either of the tibiofemoral compartments. In the second case, which is referred to as “load control,” a hydraulic cylinder, or a bladder, with pressure controlled fluid filling may be designed into the cutter to expand the cutter in the patellofemoral compartment or in the either of the tibiofemoral compartments.
FIGS. 30 , 31 and 32 illustrate that the medial and lateral femoral condyles may be prepared independently with a femoral cutter 3002 , placed in the lateral tibiofemoral compartment first to prepare the lateral femoral condyle. A spacer is placed in the lateral tibiofemoral compartment (not shown) after preparation of the lateral condyle, and the procedure is repeated by placing a femoral cutter 3102 in the medial tibiofemoral compartment. A bladder 3003 or 3103 may be used in conjunction with the lateral or medial femoral cutter, respectively.
FIG. 32 illustrates that the femoral trochlea may be prepared by placing a femoral cutter 3202 on the patella. The cutter can be structured to prepare a linear surface generally in a medial-lateral orientation and curved in a sagittal plane. Alternately, cutting elements 3206 as shown in inset of FIG. 32 , the cutter, structured with various cutting elements to include barrel cutters, belt cutters, reciprocating cutters or shavers, may be contoured to simulate the shape of the patellar groove. Telescoping bellows 3203 may be used as well.
FIGS. 34 and 35 illustrate two barrel cutters linked together. In preparing the medial and lateral tibiofemoral compartments it may be beneficial to place femoral cutters in each compartment and simultaneously prepare the medial and lateral femoral condyles. In the case of the barrel cutters, the two cutters are linked together with one cutter 3402 , having telescoping platform 3406 , placed in the lateral tibiofemoral compartment and the other cutter 3403 , having telescoping platform 3405 , placed in the medial tibiofemoral compartment. The connecting bridge 3404 transfers torque from drive shaft 3407 between the two femoral cutters. Alternately, the two cutters may be powered independently. The connecting bridge 3404 may be rigid and of fixed length or in another embodiment the connecting bridge 3404 is flexible and telescopes to enable independent positioning of the femoral cutters within each tibiofemoral compartment.
FIGS. 36 and 37 illustrate two reciprocating cutters linked together, with one cutter 3602 placed in the lateral tibiofemoral compartment and the other cutter 3603 placed in the medial tibiofemoral compartment. The connecting bridge 3604 transfers torque from drive shaft 3605 between the two femoral cutters. Alternately, the two cutters may be powered independently. The connecting bridge 3604 may be rigid and of fixed length or in a preferred embodiment the connecting bridge 3604 is flexible and telescopes to enable independent positioning of the femoral cutters within each tibiofemoral compartment.
FIGS. 27 , 38 and 39 illustrate two belt cutters linked together, to form a dual belt cutter 2707 , with one cutter 2702 or 3802 placed in the lateral tibiofemoral compartment (between femurs 2700 or 3600 and tibias 2701 or 3601 ) and the other cutter 2706 or 3803 placed in the medial tibiofemoral compartment. The connecting bridge 2703 or 3804 transfers torque between the two femoral cutters. Alternately, the two cutters may be powered independently. The connecting bridge 2703 or 3804 may be rigid and of fixed length or in a preferred embodiment the connecting bridge 2703 or 3804 is flexible and telescopes to enable independent positioning of the femoral cutters within each tibiofemoral compartment. A telescoping bladder 2705 may be placed under each belt cutter.
FIG. 23 illustrates a bladder, shown in a collapsed form. As described above, it is desirable to extend a femoral cutter once it has been placed in either of the tibiofemoral compartments or in the patellofemoral compartment. In one embodiment a fluid or gas filled bladder is placed under the femoral cutter to extend the bladder-cutter combination within the joint space. A bladder 2300 as shown in FIG. 23 can be made of a suitable material, such as, but not limited to, PET, nylon, polyethylene or urethane. In its collapsed faun the bladder 2300 is flat and can be filled via a port 2302 and neck 2301 in one end. Alternately, there may be two ports (not shown) to allow air to bleed from the bladder as fluid is injected into the bladder. The bladder may be compliant to enable expansion in all directions once placed between a femoral cutter and the tibia, or between a femoral cutter and patella. Alternatively, the bladder may be non-compliant to constrain bladder expansion to a designed volume.
In preparing the femoral articular surfaces the femoral cutters may require greater translational stability than what is provided by a free standing bladder. Such stability can be provided by designing a telescoping device within the cutter as described herein, then placing the bladder within this telescoping section. In addition, the bladder may be susceptible to puncture by instruments used in the surgical procedure or by the bony support surface. Hence, it may be desirable to house the bladder in an expandable platform that can be placed between the femoral cutter and the tibia or the patella.
FIGS. 24 , 25 and 26 illustrate an expandable housing which may have an expandable bladder housed within. The expandable housing may be fabricated out of metal, plastic or other suitable material. The top plate 2400 and bottom plate 2401 can be rigid or semi-rigid. The sidewalls 2402 and 2403 can fold either in on one another or out on one another to minimize thickness in a collapsed state (see FIG. 25 ). An opening 2404 is provided for the neck 2301 of the bladder.
FIG. 26 illustrates the housing as the bladder within is filled such that the expandable housing telescopes to a designed height. If filled with sterile saline or other suitable fluid that is incompressible the height of the expandable housing can be incrementally increased or decreased to facilitate appropriate femoral resection. Alternatively, the fluid can be introduced into the bladder 2300 within the expandable housing under pressure control in which case the distraction force within the tibiofemoral or patellofemoral compartment can be controlled to facilitate appropriate femoral resection.
FIGS. 47 and 48 illustrate a shaver being placed in a tibiofemoral joint and the knee flexed and extended to move the femoral condyle over the cutting elements of the shaver to remove material from the condyle. In another embodiment a reciprocating motion is applied to the shaver to enhance material removal from the condyle while the knee is flexed and extended. As shown in FIGS. 47 and 48 , a femoral shaver designed for use in either the medial or lateral tibiofemoral compartments provides a frame 5805 with a flat support surface for support on the prepared tibial plateau. The femoral condyle is sculpted by a set of cutting elements 5810 integral to a cartridge 5800 . Alternately, the cutting elements 5810 may be designed as an insert that fits into the cartridge 5800 . A rigid or flexible drive shaft extension (not shown) can be attached between the drive shaft 5802 and a rotational power supply such as a surgical power drill or a motor.
A reciprocating motion can be applied to the cartridge 5800 to enhance material removal from the femoral condyle. The cartridge shown is designed to move axially in a channel 5813 within the frame 5805 . In one embodiment a drive cam 5803 converts rotational input to the drive shaft 5802 via an off-set cam 5804 spinning in a transverse slot 5814 in the cartridge 5800 . The drive cam 5803 is supported in a bearing 5808 placed in a countersunk hole 5812 in the frame 5805 and held in place with a washer 5806 and a retainer 5807 .
As material is removed from the femoral condyle it is desirable to increase the height of the shaver accordingly that is to extend the shaver within the tibiofemoral compartment. The cartridge 5800 is free to move vertically in the frame 5805 . One or more shims 5801 , each having two arms 5811 designed to pass along side the drive cam 5803 , can be placed between the cartridge 5800 and frame 5805 to extend the shaver.
The description above is provided M order to illustrate various examples and embodiments of the invention and is not an exhaustive list of all combinations and variations of the present invention. It should be understood that various changes, adaptations and modifications may be made therein without departing from the spirit of the invention and the scope of the appended claims. The scope of the invention is provided in the claims which follow.
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Methods and devices for sculpting bones, particularly in preparation for implanting prosthetic devices to replace articulating bone joint surfaces. Improved bone removal devices including burr mills driven by gears and loop drives are provided. Reciprocating cutters and belt cutters are also provided. Some devices have either integral or removable expandable portions to vary the force and bone resection depth. Devices can have irrigation ports and plenums to remove bone fragments. Some cutters are dual cutters, adapted to remove bone in two or more regions, such as the knee joint, simultaneously.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a bone assessment apparatus and bone assessing method and more particularly to an apparatus and method for measuring physical parameters of a test part of a patient and computing data useful in diagnosing bone disorders by using measuring waves, such as an X-ray and an ultrasonic wave, transmitted and received through the test part.
2. Description of the Related Art
A bone assessment apparatus is disclosed in U.S. patent application Ser. No. 08/063,779 which can provide information useful for diagnosis of bone disorders through X-ray measurement or ultrasonic wave measurement. More specifically, physical parameters of a calcaneus or heel bone (hereinafter referred to as a test part), i.e. a bone mineral density calculated from an attenuation coefficient of an X-ray, and an ultrasonic wave propagation velocity, are obtained to compute a bone assessment index in order to determine whether or not the subject suffers from a bone disorder.
It is well known that, in transmitting and receiving an ultrasonic wave through a test part, an air layer existing between the ultrasonic transducers and the test part attenuates and reflects the ultrasonic waves, which degrades a measuring accuracy. For this reason, it has been performed to eliminate the air layer by filling the space between the transmitting/receiving devices and the test part with an acoustic matching material. Similarly, since X-rays are also attenuated if an air layer exists between the X-ray generator/detector and the test part, the air layer should be eliminated for keeping a measurement of precise bone mineral density. Thus, it has also been desired to provide a material equivalent to soft tissue such as skin or muscle between the test part and the transmitting/receiving devices.
In order to avoid the adverse affects of the air layer, a conventional apparatus has employed a bath containing water (preferably, distilled water containing a surface active agent) which functions both as a matching material for acoustic wave measurement and a soft tissue equivalent material for X-ray measurement. Then, the test part is immersed in the water, and ultrasonic waves and X-rays are irradiated through the water to the test part for measuring each of the physical parameters.
However, when a number of measurements are repeated by the conventional apparatus for many different patients, for example, at a mass checkup where only a primary diagnosis is made simply for deciding if the patient is suffered any bone disorder or not (this is called screening), many test parts are directly immersed in the coupling water in the bath, which quickly causes contamination of the water. Changing water at each time whenever a patient subject changes is not efficient.
SUMMARY OF THE INVENTION
This invention has been made to overcome the aforesaid problems in the conventional bone assessment apparatus. Therefore the object of the present invention is to realize an effective measurement without requiring a change of water by preventing the water from being contaminated even during a series of measurements of a number of patients.
In order to achieve the above objective, this invention provides a bone assessment apparatus using measuring waves irradiated to a test part, comprising devices for transmitting and receiving measuring waves through the test part, a measuring bath for containing a coupling liquid to exclude an air layer between the test part and the transmitting/receiving devices, and means for keeping the test part out of contact with the coupling liquid inside the measuring bath.
In another aspect of the invention, a bone assessment apparatus comprises devices for transmitting and receiving measurement waves through the test part, a measuring bath for containing a coupling liquid to exclude an air layer between the test part and the transmitting/receiving devices, a means removably provided in the measuring bath for keeping the test part out of contact with the coupling liquid, means for detecting the existence of the noncontacting means, and a data processor for computing diagnosis data based on the received measuring waves, said data processor being capable of correcting the diagnosis data computed from the received waves on the basis of a specific correction value assigned to each of the noncontacting means when the existence of the noncontacting means is detected by the detecting means.
According to a third aspect of the invention, a bone assessing method for transmitting and receiving measuring waves through a test part to diagnose the test part based on data obtained from the received waves, is also provided. This method comprises the steps of preparing a measuring bath filled with a coupling liquid, positioning the test part inside the measuring bath without contacting the coupling liquid, and transmitting and receiving the measuring waves through the test part.
The noncontacting means prevents a direct contact of the test part with the coupling liquid, which removes the necessity of changing the liquid due to contamination and realizes an efficient measurement even during a mass examination. The detecting means can detect a use of the noncontacting means, and the diagnosis data obtained from the measuring values is automatically corrected based on a specific correction value assigned to each of the noncontacting means. The noncontacting means is easily removable for quick change between a simple measurement with the noncontacting means and a precise measurement without the noncontacting means.
BRIEF DESCRIPTION OF THE DRAWINGS
The above and other objects, advantages and features of this invention will be more fully understood from the following detailed description in conjunction with the drawings, of which:
FIG. 1 is a schematic perspective view of an entire structure of the bone assessment apparatus;
FIG. 2 is a schematic perspective view of a measurement bath;
FIG. 3 illustrates a measuring condition of the bone assessment apparatus;
FIG. 4 is a perspective view of an immersion pouch according to the invention;
FIG. 5 is a perspective view of an attachment for attaching the pouch to the bone assessment apparatus;
FIG. 6 is a schematic side view of the measurement bath where the immersion pouch is actually attached by an attachment to a foot rest; and
FIG. 7 is a perspective view of another embodiment of the immersion pouch.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The preferred embodiments of the invention will now be described with reference to the drawings.
In FIG. 1, an entire structure of a bone assessment apparatus is shown which includes a measuring apparatus 10 and a control unit 12. As shown in the figure, the control unit 12 consists of a computer unit which includes a data processor for computing diagnosis data on the basis of measuring waves received at wave-receiving devices which will be described in detail below. The control unit 12 is connected to the measuring apparatus 10 via a cable 14. The measuring apparatus 10 comprises a measuring unit 16 and a chair 18 which may be integrally or separately constructed with the measuring unit 16. The measuring unit 16 includes a measuring bath 22, which will be described below, arranged under an opening 20, and in the measuring bath 22, a foot rest for supporting a heel of a patient as a test part is positioned, which also serves as a positioning means for appropriately positioning the heel. In this embodiment, the foot rest is employed to support the heel for diagnosis of a calcaneus or heel bone.
During measurement, a patient 100 sits on the chair 18 and places his foot 100a onto the foot rest through the opening 20. In this situation, X-rays and ultrasonic waves, which are used as measuring waves, are irradiated and transmitted to the calcaneus.
The measuring bath 22 is shown in FIG. 2, which is arranged under the opening 20 shown in FIG. 1. The measuring bath 22 contains water as coupling liquid which functions both as an acoustic matching material and a tissue-equivalent material required for measurement. The side walls of the bath 22 are made of, for example, an acrylic plate. The reason why the foot 100a should be immersed into the water is that the water has almost the same X-ray attenuation coefficient and acoustic wave propagation rate as those of a soft tissue. Thus, by filling the water in a space between the heel and the transmitting/receiving devices, the space can be considered as part of soft tissue. Under this condition, the boundary of soft tissue and the bone is clearly detected and an accurate measurement of bone mineral density can be achieved. Further, regardless of the volume or shape of soft tissue of the patient body, ultrasonic measurement can be performed accurately.
As shown in FIG. 2, an X-ray generator 24 and an X-ray detector 26 serving as a transmitter/receiver device are arranged outside the measurement bath 22, so as to be opposed to each other. The generator 24 and detector 26 can be moved on an X-Z plane by moving mechanism (not shown). Inside the measurement bath 22, ultrasonic transducers 28a and 28b are supported by arms 30a and 30b respectively, which serve as another transmitter/receiver device. These transducers 28a and 28b are also positioned on both sides of the heel so as to be opposed to each other. The arms 30a and 30b are driven by a transducer/arm moving mechanism (not shown) to move the ultrasonic transducers 28a and 28b on X-Z plane. As mentioned above, the foot rest 32 is positioned inside the measurement bath 22 for supporting the heel.
This invention is characterized in a noncontacting means for keeping the heel out of contact with the coupling liquid in the measuring bath 22. This noncontacting means is, for example, an immersion pouch 34 arranged inside the measuring bath 22. The immersion pouch 34 is removably attached by an attachment 36 onto the foot rest 32. This is very advantageous because a patient only inserts his heel 100b into the pouch 34 attached onto the foot rest 32 and a measurement is taken without contacting the water filling the measurement bath 22.
The immersion pouch 34 serving as the noncontacting means is shown in FIG. 4. The pouch 34 is made of, for example, a soft polyvinyl chloride. Thus, since the pouch material is so flexible as to easily fit to the shape of the patient's heel, an air layer between the heel and the inner wall of the pouch 34 is substantially eliminated, and the coupling liquid is prevented from flowing into the pouch 34. The hooks 38a,38b made of a hard polyvinyl chloride are provided on the upper edge of the immersion pouch 34, which are engaged with holes of the attachment 36 to attach the pouch 34. The immersion pouch 34 is sufficiently flexible to fit various shapes of patient's heels, as mentioned above. However, in order to ensure an acoustic matching between a patient's heel and the inner wall of the pouch 34, an acoustic matching jelly, which functions as a supplemental coupling agent, or a small quantity of water may be filled inside the pouch 34.
FIG. 5 shows an attachment 36 which has a substantially L-shape with approximately 90 degrees between two supporting planes for supporting a heel in a natural manner inside the measuring bath 22. Guide flanges 40a, 40b, 40c, and 40d are formed along the longitudinal edge of the attachment 36, which are engaged with the edges of the foot rest 32, respectively. At each of the upper edges of the attachment 36, there are formed holes 42a, 42b to which the hooks 38a, 38b of the immersion pouch 34 are removably engaged, respectively. A blocking plate 44 is provided at a predetermined position on the attachment 36 for use in a detection of whether or not the immersion pouch 34 is used in measurement. In this embodiment, the blocking plate 44 is integrally formed with the guide flange 40b.
An actual operation of the bone assessment apparatus according to this embodiment will now be described.
When an operator intends to conduct a screening (i.e. preliminary measurement), he sets an attachment 36, to which an immersion pouch 34 is attached, onto the foot rest 32. A patient inserts his heel 100b into the immersion pouch 34 without directly touching the water filling the measuring bath 22. With this result, contamination of the water can be prevented. The operator inputs information from an input terminal of the control unit 12 for indicating that the measurement is carried out using an immersion pouch 34. In response to this command, the control unit 12 operates so as to correct a deviation caused by use of the immersion pouch 34 and to provide a more precise measurement result. The deviation is caused when the ultrasonic wave passes through the wall of the immersion pouch 34 having a different acoustic impedance from that of the water, before reaching the patient's heel. For example, if a thickness of the soft polyvinyl chloride pouch 34 is 0.05 mm, approximately 0.1% of deviation arises in the resultant value of propagation velocity of the ultrasonic wave. In this embodiment, such a deviation is corrected in advance in order to immediately provide a relatively accurate measurement result.
When the operator intends to make a more precise measurement of physical properties of the heel bone, he can easily remove the immersion pouch 34 by simply removing the attachment 36 and carry out a measurement without including any deviation caused by the immersion pouch 34.
The correction of the deviation can be automatically made when detecting the blocking plate 44 formed in the attachment 36. FIG. 6 shows the attachment 36 actually mounted on the foot rest 32. As shown in this figure, a through-hole 46 is formed on the side wall of the foot rest 32 so as to laterally penetrate the foot rest 32. When the attachment 36 is mounted on the foot rest 32, the blocking plate 44 of the attachment 36 covers the through-hole 46. Before the measurement, a detection of the existence of the blocking plate 44 is made by moving the ultrasonic transducers 28a, 28b to the position of the through-hole 46 and transmitting and receiving the ultrasonic wave at that position. In this manner, the blocking plate 44 and the ultrasonic transducers 28a, 28b construct a detecting means. If the existence of the immersion pouch 34 is detected, in response to the detection result, the control unit 12 automatically switches the operation mode of the bone assessment apparatus into a screening mode. Then, the control unit 12 sets measuring parameters and processes so as to be suitable for screening, and corrects resultant diagnosis data on the basis of a predetermined correction value. The pouch detecting means may be constructed with another type of sensor, such as infrared sensor or magnetic sensor.
The through-hole 46 may be used for detecting a suitable water level filling the measuring bath 22, as is disclosed in Japanese Patent Application No. H5-45161.
Although the invention has been described with reference to a specific example, this is not limited to the embodiment. For example, although, in the embodiment, a soft polyvinyl chloride is used for the immersion pouch which should be flexible and fittable to a heel shape, another material such as an elastic rubber may be used. Further the pouch can be constructed to fit a toe shape.
Further, the immersion pouch is not necessarily attached via the attachment. For example, as shown in FIG. 7, a band 50 is provided to the upper opening of the pouch 48 to retain an ankle of a patient. In this case, the pouch 48 is used like a shoe, and the patient can put on the pouch 48 before immersing his foot in the water.
The immersion pouches 34, 48 shown in FIGS. 4 and 7 are used as an auxiliary member for a bone assessment apparatus. These pouches may be disposable.
The bone assessment apparatus of the invention is generally used for diagnosing physical properties of tissue by using an ultrasonic measurement and X-ray measurement, but can be applied to various apparatus as long as they utilize transmission/reception of ultrasonic wave and irradiation of X-ray directed to a test part of a patient which is immersed in a coupling liquid or the like.
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A bone assessment apparatus for transmitting and receiving measuring waves through a test part of a patient to diagnose the condition of the test part, includes a measuring bath containing a coupling liquid required for precise measurement and an immersion pouch for keeping the test part out of contact with the coupling liquid. The test part is inserted into the immersion pouch in the measuring bath without touching the coupling liquid. Even during the screening of a number of patients the coupling liquid is prevented, from being contaminated by the test parts of the patients and therefore it is not necessary to change the coupling liquid often. The use of the immersion pouch is detected by a detector to correct a deviation in diagnosis data obtained from the received measuring wave on the basis of a specific correction value assigned to each immersion pouch, thereby providing more precise diagnosis data.
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FIELD OF THE INVENTION
[0001] The present invention relates to an ankle-foot orthosis with a dual-adjustable range of motion limiter for limiting the range of pivotal movement of the foot. Even more particularly, this invention relates to an orthotic range of motion limiter that allows for ease of manufacture of an ankle-foot orthosis and that allows the degree of plantar flexion and dorsiflexion of the foot to be adjusted and or fixed.
BACKGROUND OF THE INVENTION
[0002] Hinged orthopedic braces having an adjustable range of pivotal movement, as disclosed by U.S. Pat. Nos. 5,022,390 (1991) and 5,328,444 (1994), both to Whiteside, are known in the art. The braces disclosed therein have adjustable stopping mechanisms to limit the range in pivotal movement of two hinged members of the brace relative to each other. The stopping mechanisms taught by the above-mentioned patents disclose an adjustable stop mechanism attached to one member of the brace that is positioned to come into contact with an abutment attached to the other member of the brace when the members are pivoted to a desired angle of restriction. To effect adjustment of this stopping mechanism, a hole must be drilled in the brace and a tool must be used.
[0003] Other ankle-foot orthotic devices such as U.S. Pat. Nos. 5,399,152 (1995) to Habermeyer et al. and 5,429,588 (1995) to Young et al. disclose ankle-foot orthoses designed to treat fractures and other injuries to the foot and ankle. Habermeyer discloses an apparatus that consists of two members pivotally connected. Each member provides surroundive fixation that is both removable and adjustable through the filling and evacuating of cushions within each member. Rear pivotal movement (plantar flexion) and front pivotal movement (dorsiflexion) are restricted by a bar with an attached abutment head contacting adjustable abutments located above and below the abutment head. One problem with this device is that the adjusting mechanism has multiple parts making it difficult and expensive to manufacture. Another problem with this device is that the parts are not easily replaceable by the wearer.
[0004] Young discloses an apparatus known in the art as a walker that consists of two members pivotally connected wherein plantar flexion and dorsiflexion are restricted between 22.5 degree of plantar flexion and 22.5 degree of dorsiflexion by adjustable screws contacting an upright side member. One problem with this device is that some wearers may require a greater range of motion than this device allows.
[0005] Still other foot and ankle devices such as U.S. Pat. Nos. 5,014,690 (1991) to Hepburn et al. and 5,144,943 (1992) to Luttrell et al. disclose dynamic splints, which apply an adjustable force inducing either plantar flexion or dorsiflexion.
[0006] U.S. Pat. No. 5,044,360 (1991) to Janke discloses a foot ankle device with two members that are pivotally attached. Dorsiflexion and plantar flexion are restricted through the use of interchangeable cams, which have differing cam surfaces that come into contact with a rotatable stop. The unique shape of each interchangeable cam determines at what point or angle in plantar flexion or dorsiflexion the rotatable stop contacts the cam surface and limits range of motion.
[0007] U.S. Pat. No. 4,919,118 (1990) to Morris discloses a short leg walker, which has a motion limiter consisting of, a shaft pivotally attached to one of the walker's members and a sliding block pivotally attached to the remaining member. Restriction of plantar flexion and dorsiflexion occurs when the sliding block engages adjustable stop members, which are located above and below the sliding block. By adjusting the positions of the stop members, the range of motion can be limited accordingly.
[0008] There remains a need to provide a strong yet lightweight comfortable ankle-foot orthosis, which can effectively limit the ankle-joint against a wide range of pivotal movement. There also remains a need to provide a strong yet lightweight comfortable ankle-foot orthosis which has few parts and which is simple and inexpensive to manufacture. Additionally, there remains a need to provide a strong yet lightweight comfortable ankle-foot orthosis, which has dual-adjustable stop members that are easy to adjust and replace, which is concealable under clothing or footwear, and which is custom fit for the wearer. Still further, there remains a need to provide a strong yet lightweight comfortable ankle-foot orthosis that can set the angle of plantar flexion of the foot and that can temporarily or permanently fix the angle of dorsiflexion, plantar flexion and pivotal movement of the foot.
SUMMARY OF THE INVENTION
[0009] Accordingly, it is an object of the present invention to provide a comfortable ankle-foot orthosis that is strong and lightweight, which can effectively limit a wide range of plantar flexion of the ankle-joint and which is quiet in operation.
[0010] It is another object of the present invention to provide an ankle-foot orthosis that has few parts, is quiet in use and which is simple and inexpensive to manufacture.
[0011] It is yet a further object of the present invention to provide an ankle-foot orthosis that has a dual-adjustable stop mechanism that is easy to operate, which is concealable under clothing or footwear, and which is custom fit for the wearer.
[0012] It is yet a further object of the present invention to provide an ankle-foot orthosis that can set and or adjust the angle of plantar flexion of a wearer's foot and that can rigidly fix the angle of plantar flexion, dorsiflexion and pivotal movement of the wearer's foot.
[0013] Other objects will, in part, be obvious and will, in part, appear hereinafter. The invention accordingly, comprises the features of construction, combination of elements and arrangements of parts, which will be exemplified in the following detailed description and the scope of the invention will be indicated in the claims.
[0014] According to one aspect of the invention, an orthotic device for limiting motion in a limb joint comprises a first orthotic member, a second orthotic member pivotally connected to said first orthotic member, a dual-adjustable stop mechanism comprising a first range of motion limiter removably connected to and adjustable within said first orthotic member and a second range of motion limiter removably connected to and adjustable within said second orthotic member, wherein said first range of motion limiter is axially aligned to impact said second range of motion limiter.
[0015] As to another aspect of the invention, the first range of motion limiter further comprises a first notched impact stop.
[0016] As to another aspect of the invention, the second range of motion limiter further comprises a second notched impact stop.
[0017] As to another aspect of the invention, the first impact stop and or said second impact stop are fabricated from a resilient material.
[0018] As to another aspect of the invention the resilient material is polyurethane.
[0019] As to another aspect of the invention the first range of motion limiter and or said second range of motion limiter further include a cap.
[0020] As to another aspect of the invention the cap is fabricated from a resilient material.
[0021] Another aspect of the invention is directed to an adjustable range of motion limiter for use with an orthotic device comprising a first surface and a second surface, wherein said first surface is notched.
[0022] As to another aspect of the invention the second surface is concave and substantially conforms to the curvature of an orthotic device wearer's limb.
[0023] As to another aspect of the invention the adjustable range of motion limiter includes a pair of convex sides.
[0024] According to yet another aspect of the invention an orthotic device for limiting motion in a limb joint comprising a first orthotic member, a second orthotic member pivotally connected to said first orthotic member, and at least one range of motion limiter removably connected to and adjustable within said first orthotic member and or said second orthotic member comprising a first surface and a second surface, wherein said first surface is notched.
[0025] As to another aspect of the invention the second surface is concave and substantially conforms to the curvature of an orthotic device wearer's limb.
[0026] As to another aspect of the invention the at least one range of motion limiter further comprises a pair of convex sides.
[0027] As to another aspect of the invention the at least one range of motion limiter is operatively connected to both the first orthotic member and the second orthotic member.
[0028] The present invention achieves those and other objectives by providing a comfortable ankle-foot orthosis that is both strong and lightweight and that provides a single unit dual-adjustable range of motion limiter that allows for easy and inexpensive manufacture and that is quiet in use.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] The preferred embodiments of the invention will hereinafter be described in conjunction with the appended drawings provided to illustrate and not to limit the invention, where like designations denote like elements, and in which:
[0030] FIG. 1 is a perspective view of an ankle-foot orthotic device employing a dual adjustable range of motion limiter in accordance with one embodiment of the present invention;
[0031] FIG. 2 is a side elevational view of the dual adjustable range of motion limiter of FIG. 1 ;
[0032] FIG. 3 is an end elevational view of the dual adjustable range of motion limiter of FIG. 1 ;
[0033] FIG. 4 is a perspective view of an ankle-foot orthotic device employing a dual adjustable range of motion limiter in accordance with one embodiment of the present invention;
[0034] FIG. 5 is an enlarged fragmentary cross-sectional view of the dual adjustable range of motion limiter of FIG. 4 taken along line X-X;
[0035] FIG. 6 is an enlarged fragmentary cross-sectional view of the dual adjustable range of motion limiter of FIGS. 2 and 3 taken along line X-X showing the ankle-foot orthotic device and the dual adjustable range of motion limiter as separated along line B-B;
[0036] FIG. 7 is an enlarged fragmentary cross-sectional view of the adjustable range of motion limiter of FIGS. 2 and 3 taken along line B-B;
[0037] FIG. 8 is an enlarged fragmentary cross-sectional view of the adjustable range of motion limiter of FIGS. 2 and 3 taken along line B-B showing the adjustable range of motion limiter as removed from the ankle-foot orthotic device;
[0038] FIG. 9 is an enlarged fragmentary cross-sectional view of the adjustable range of motion limiter of FIGS. 2 and 3 taken along line X-X showing the ankle-foot orthotic device and the adjustable range of motion limiter as separated along line B-B and showing a pair of resulting adjustable stops as repositioned within the ankle-foot orthotic device;
[0039] FIG. 10 is an enlarged fragmentary cross-sectional view of the adjustable range of motion limiter of FIGS. 2 and 3 taken along line X-X showing the ankle-foot orthotic device and the adjustable range of motion limiter as separated along line B-B and showing a pair of resulting adjustable stops as repositioned within the ankle-foot orthotic device and further including a pair of caps on said adjustable stops.
[0040] FIG. 11 is an enlarged fragmentary cross-sectional view of the adjustable range of motion limiter of FIG. 9 showing the pair of resulting adjustable stops as removed and replaced by a single adjustable range of motion limiter;
[0041] FIG. 12 is a perspective view of the ankle foot orthotic device of FIG. 11 .
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0042] Preferred embodiments of the present invention are illustrated in FIGS. 1-12 . Referring now to FIG. 1 an ankle-foot orthotic device for limiting the motion of a foot about an ankle joint is designated by numeral 10 . The present description is directed primarily to an ankle-foot orthotic device; however, the method of fabrication and use of orthotic device 10 can readily be applied to other joints of the human anatomy.
[0043] Orthotic device 10 has an ankle section 12 and a foot section 14 , hingedly linked to rotate about an axis A-A, by a pair of hinge mechanisms 2 and 4 (not shown). Hinge mechanisms 2 and 4 are fastened on opposite sides of orthotic device sections 12 and 14 using rivets, bolts, epoxy, or other fastening mechanism. Hinge mechanisms 2 and 4 may have moving parts like a door hinge or may be formed from a single piece of flexible material that will allow orthotic device sections 12 and 14 to pivot about axis A-A.
[0044] Ankle section 12 has an inner surface 22 for accepting a wearer's lower leg and an outer surface 24 . Ankle section 12 is shown provided with an optional adjustable ankle strap 18 for securing the orthotic device to the wearer's lower leg. Adjustable ankle strap 18 may employ a VELCRO, buckle, snap or other fastening system. Foot section 14 has both an inner surface 26 for receiving the wearer's heel and foot and an outer surface 28 . An optional adjustable foot strap (not shown) may be attached to foot section 14 for additional support in securing the orthotic device to the wearer's foot.
[0045] Orthotic device 10 is provided with a dual-adjustable range of motion limiter 30 . The dual-adjustable range of motion limiter 30 is preferably formed of a rigid plastic or metallic material. Referring now to FIGS. 2 and 3 a side view and an end view of the dual-adjustable range of motion limiter 30 are shown, respectively. Dual-adjustable range of motion limiter 30 includes a notched upper surface 34 , a curved lower surface 36 , a first end 38 and a second end 40 . It should be noted that the notched upper surface 34 may be internally or externally notched.
[0046] The dual-adjustable range of motion limiter 30 further includes a pair of convex sides 52 , 54 . In the present embodiment, the convex sides 52 , 54 include upper surfaces 52 a, 54 a and lower surfaces 52 b, 54 b. Alternatively, convex sides 52 , 54 may be curved or rounded as will be evident from the below description.
[0047] Orthotic device sections 12 and 14 are preferably formed of thermoplastic sheet material. This material is lightweight and can be shaped to intimately configure to the wearer's anatomy. To construct an ankle-foot orthotic device employing the present invention, initially, a single cast is made of the wearer's limb including the wearer's lower leg, ankle, heal and foot. From this cast a male mold (not shown) is made in configuration with the same shape of the wearer's limb. Next, the dual-adjustable range of motion limiter 30 is placed on a heal portion of the male mold as a single unit. An optional self-adhesive foam spacer (not shown) or other similar means may be employed to temporarily adhere the dual-adjustable range of motion limiter 30 to the male mold. Finally, heated sheets of thermoplastic material are superimposed over and vacuumed into intimate contact with the dual-adjustable range of motion limiter 30 and the male mold. The plastic sheets flow into a series of notches 42 of the notched upper surface 34 and around the pair of convex sides 52 , 54 of the dual-adjustable range of motion limiter 30 , thereby removably fixing the dual-adjustable range of motion limiter 30 within a thermoformed assemblage 50 (see FIG. 4 ).
[0048] Referring now to FIGS. 5 and 6 , after the thermoformed assemblage 50 is sufficiently cooled, it is sliced into two separate sections along cut line B-B, thus creating the ankle section 12 and the foot section 14 . In addition to separating the thermoformed assemblage 50 into two sections, the dual-adjustable range of motion limiter 30 is similarly sectioned in two, thus creating and revealing a first impact stop 66 having an impact end 70 and a second impact stop 68 having an impact end 72 . The impact stops 66 , 68 are held in position by a set of layers of thermoformed plastic sheet material 80 , 82 .
[0049] Referring now to FIGS. 7 and 8 , once the impact stops 66 , 68 have been exposed, either or both impact stops may be removed and or adjusted within their respective ankle and foot orthotic sections 12 , 14 . Preferably the layers of thermoformed plastic sheet material 80 , 82 encompassing the impact stops 66 , 68 and or the impact stops themselves are sufficiently pliable to allow the impact stops 66 , 68 to be pried out or otherwise removed from their orthotic sections.
[0050] Upon removal of the impact stops 66 , 68 from the ankle and foot orthotic sections 12 , 14 , a series of ridges 90 , 92 (which are formed when the layers of thermoformed plastic sheet material 80 , 82 are vacuumed into place around the series of notches 42 of the dual adjustable range of motion limiter 30 ) are revealed (See FIGS. 9 and 10 ). The uniform nature of the series of ridges 90 , 92 , allows impact stops 66 , 68 to be repositioned in multiple positions within the ankle and foot orthotic sections 12 , 14 . In this and other embodiments of the present invention, the series of angled notches 42 are shown situated along upper surface 34 . It is contemplated that notches or other similar indentations, protrusions or ridge configurations may be located or repositioned along other sides of the range of motion limiter 30 to achieve similar results.
[0051] In the present embodiment of the invention, repositioning either or both of the impact stops 66 , 68 , allows for the adjustment of the angle of plantar flexion of the wearer. As best shown in FIG. 9 , the closer the impact ends 70 , 72 are to each other (i.e., the further the impact stops 66 , 68 protrude from the ankle and foot orthotic sections 12 , 14 ), the smaller the angle of plantar flexion of the wearer is allowed.
[0052] In addition to repositioning the impact stops 66 , 68 , the wearer may replace either or both of the impact stops 66 , 68 with other, alternative impact stops having similar ridge configurations. For example, longer impact stops (not shown) may be used to further limit the wearer's angle of plantar flexion. Alternatively, referring now to FIG. 10 , a pair of end caps 104 , 106 may be placed over the impact ends 70 , 72 of the impact stops 66 , 68 . In the present embodiment, the end caps 104 , 106 are preferably fabricated from a resilient material such as polyurethane, which provides for quiet operation of the orthotic device 10 . The size of the end caps 104 , 106 may be adjusted to operatively control plantar flexion. In addition, the end caps 104 , 106 may be fixedly attached to impact ends 70 , 72 and or used to operatively remove and or reposition the impact stops 66 , 68 within the ankle and foot orthotic device sections 12 and 14 .
[0053] Referring now to FIG. 11 , a system for fixing the angle of ankle and foot orthotic device sections 12 and 14 with respect to each other and or for completely restricting both dorsiflexion and plantar flexion is shown. In the present embodiment of the invention, the impact stops 66 , 68 are removed and replaced with a single motion-limiting insert 110 . The motion-limiting insert 110 prevents orthotic device sections 12 and 14 from rotating relative to one another about axis A-A, thereby restricting both dorsiflexion and plantar flexion of the wearer.
[0054] Although the preferred embodiments of the present invention have been described herein, the above descriptions are merely illustrative. Further modifications of the invention herein disclosed will occur to those skilled in the respective arts and all such modifications are deemed to be within the scope of the invention as defined by the appended claims.
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An apparatus for quietly limiting motion at a limb joint having pivotally attached members for receiving the limbs of a joint and a dual-adjustable stop mechanism assembly operatively attached to the members for restricting movement at the joint. The dual-adjustable stop mechanism assembly includes at least one removably connected adjustable range of motion limiter.
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BACKGROUND OF THE INVENTION
The present invention relates to subterranean hydrocarbon recovery. More particularly, the present invention relates to methods and compositions for the in-situ thermal stimulation of hydrocarbons using peroxide-generating compounds.
Non-traditional sources of hydrocarbons are playing an increasingly important role in the oil and gas industry. Such non-traditional sources include gas hydrates, heavy oil, bitumen, and coal bed methane. Gas hydrates are a common form of a unique class of chemical compounds known as clathrates, in which a rigid, open network of bonded host molecules enclose, without direct chemical bonding, appropriately sized guest molecules of another substance. In the case of gas hydrates, water acts as the host molecule, enclosing gas molecules such as methane. Recent estimates indicate that gas hydrates, and in particular methane hydrates, may contain more organic carbon than all the world's coal, oil, and non-hydrate natural gas combined; thus, making them an important potential source of energy. Heavy oil (i.e., any petroleum with an API gravity less than 28 degrees) and bitumen (e.g., asphalt and mineral wax) are also important potential energy sources, as the total heavy oil and bitumen reserves of Canada and Venezuela alone are believed to equal the light oil reserves of Saudi Arabia. Similarly, coal bed methane is also becoming an increasingly important energy source, with the total coal bed methane reverses in the United States estimated to be between 400 and 850 trillion cubic feet.
A variety of methods have been employed to facilitate the recovery of these non-traditional sources of hydrocarbons. One method of thermal stimulation common in the recovery of these non-traditional sources involves in-situ combustion wherein oxygen is injected into a reservoir and the hydrocarbons are ignited in a controlled fire, either through spontaneous combustion or by using an ignition source. The heat generated by the burning of heavy hydrocarbons produces hydrocarbon cracking, vaporization of light hydrocarbons, and the generation of water, in addition to the deposition of heavier hydrocarbons known as coke. As the fire moves, the combustion front pushes ahead a mixture of hot combustion gases, steam, and water, which in turn reduces oil viscosity and displaces oil toward production wells.
In-situ thermal stimulation has also been used to recover coal bed methane. Generally, the rate and amount of methane that can be desorbed from materials contained within the physical coal structure is highly sensitive to the in-situ temperature of the coal. The higher the in-situ temperature, the greater the quantity of total methane that can be recovered and the faster the rate at which the recovery can be achieved. Typically, coal seams considered for methane extraction are found at relatively shallow depths, where the desorption isotherm of the methane is limited by the low temperature. In-situ heating increases the desorption rate and the amount of methane recoverable from the coal seam. In-situ heating may also change the physical structure of the coal to enhance the diffusivity and permeability of the coal, allowing more efficient drainage of methane gas from the surrounding volume of coal.
One variation on such in-situ combustion involves injecting hydrogen peroxide, instead of oxygen, into the formation to stimulate the production of hydrocarbons. Inside the formation, hydrogen peroxide decomposes in a highly exothermic reaction to form water and oxygen. The oxygen released by the decomposition of the hydrogen peroxide may then react with hydrocarbons in the formation or with the formation itself, generating carbon dioxide, water, and heat that can be used to reduce oil viscosity and displace oil toward production wells, similar to the in-situ combustion methods described above.
Unfortunately, in-situ thermal stimulation methods using peroxide-generating compounds, such as hydrogen peroxide, have been hampered by the premature decomposition of the compound before it reaches the desired location within the subterranean formation. Attempts to inhibit the decomposition by manipulating the concentration or pH of the peroxide-generating compound have met with limited success and have, in fact, been known to adversely affect the formations into which the compound is injected. Furthermore, safety issues involved with the pumping of peroxide-generating compounds have also limited the widespread application and usage of such compounds in the oilfield.
SUMMARY OF THE INVENTION
The present invention relates to subterranean hydrocarbon recovery. More particularly, the present invention relates to methods and compositions for the in-situ thermal stimulation of hydrocarbons using peroxide-generating compounds.
One embodiment of the present invention provides a method for stimulating hydrocarbon production in a subterranean formation, comprising: introducing a peroxide-generating compound into a desired location in a subterranean formation, wherein the peroxide-generating compound is substantially mechanically isolated from the subterranean formation until the peroxide-generating compound reaches the desired location; and allowing the peroxide-generating compound to generate peroxide in the desired location in the subterranean formation.
Another embodiment of the present invention provides a method for stimulating hydrocarbon production in a portion of a subterranean formation, comprising: introducing a peroxide-generating compound into a desired location in a subterranean formation, wherein the peroxide-generating compound further comprises a chemical moderator that acts to inhibit the reaction of the hydrogen peroxide within the subterranean formation; and later, allowing the peroxide-generating compound to generate peroxide in the desired location in the subterranean formation.
Another embodiment of the present invention provides a treatment fluid for stimulating hydrocarbon production from a subterranean formation, comprising peroxide-generating compound and a moderator.
The features and advantages of the present invention will be readily apparent to those skilled in the art upon a reading of the description of the preferred embodiments that follows.
DESCRIPTION OF PREFERRED EMBODIMENTS
The present invention relates to subterranean hydrocarbon recovery. More particularly, the present invention relates to methods and compositions for the in-situ thermal stimulation of hydrocarbons using peroxide-generating compounds.
In accordance with the present invention, an aqueous solution of a peroxide-generating compound, such as hydrogen peroxide, may be introduced into a subterranean formation and reacted to generate heat, oxygen, and other compounds such as water that may be used in the in-situ thermal stimulation of hydrocarbons. To offset the propensity of the peroxide-generating compounds to spontaneously decompose or react before reaching a desired location in the subterranean formation, particular embodiments of the present invention inhibit or control the reaction either by mechanically isolating the peroxide-generating compound from the environment or by chemically moderating the reaction of compound, or both.
Once the peroxide-generating compound is in the desired location in the subterranean formation, the exothermic reaction of peroxide may be useful in a number of applications relating to recovery of hydrocarbons. In particular, the present invention may be useful in methane hydrates, coal bed methane recovery, and heavy oil production. For example, the decomposition of the hydrogen peroxide into oxygen and water generates a considerable amount of heat (i.e., approximately 23 Kcal/gm-mole of H 2 O 2 ), and liberates oxygen that may react further with the hydrocarbons present in the subterranean formation to generate carbon dioxide and additional amounts heat and water. Depending on the concentration of the hydrogen peroxide, the water generated by the two reactions, along with the water already present in the hydrogen peroxide solution, may generate steam and/or hot water that itself may reduce the viscosity of the adjacent hydrocarbons. The viscosity of the adjacent hydrocarbons may also be reduced by the miscible solution of carbon dioxide generated by the reaction of oxygen with hydrocarbons in the formation, into hydrocarbons in the cooler regions of the reservoir. The heat generated by the various reactions may also facilitate the release of hydrocarbons from the formation. For example, in methane hydrate bearing formations, the in-situ thermal stimulation of the present invention may be used to melt methane hydrates contained within the formation material to release methane. In coal bed methane recovery, the heat released may also be used to affect the desorption isotherm of the coal bed, permanently changing the rank of the coal bed and causing the bed to release methane at a faster rate.
Generally, any peroxide or peroxide-generating compound may be used in accordance with the teachings of the present invention. One suitable peroxide-generating compound is hydrogen peroxide. Another is sodium percarbonate (or sodium carbonate peroxyhydrate), a granular product used as an alternative to perborate bleaches in household detergents that, when dissolved into water, releases H 2 O 2 and soda ash (sodium carbonate). The pH of the resulting solution is typically alkaline, which activates the H 2 O 2 . Hydrogen peroxide may be produced using any of a number of known methods. Some known methods include steam reforming, partial oxidation under pressure, coal gasification, and electrolysis of water. The most common industrial process for production of hydrogen peroxide is the anthraquinone process. In this process substituted anthraquinones which are dissolved in a suitable organic solvent mixture are hydrogenated to form the corresponding hydroquinones. The hydroquinones are then oxidized back to quinones with oxygen (typically in the form of air), simultaneously forming hydrogen peroxide, which can be extracted with water while the quinones are returned to the hydrogenation step. Other suitable methods for making and controlling hydrogen peroxide may be found in the Kirk-Othmer Encyclopedia of Chemical Technology, Third Ed., Vol. 13 (John Wiley & Sons, New York 1980). Other suitable peroxide-generating compounds will be apparent to one skilled in the art, with the benefit of this disclosure. Typically, the peroxide-generating compound is present in the treatment fluids of the present invention in an amount in the range of from about 10% to about 90% by weight of the solution. In particular embodiments, the peroxide-generating compound may be present in the treatment fluids in an amount in the range of from about 10% to about 50% by weight of the solution.
As mentioned above, peroxide-generating compounds have a propensity to prematurely decompose spontaneously or react in the well bore environment. These reactions may be affected by many factors, including, inter alia, temperature, pH, concentration, and the presence of potential catalysts. For example, the decomposition of the peroxide-generating compound may be hastened by raising the temperature, adjusting the pH to 7.0 or greater, or introducing decomposition catalysts, such as salts of iron, nickel, cobalt, or certain other metals. Generally, the rate of decomposition increases approximately 2.2 times for each approximate 10° C. rise in temperature in the range from about 20° C. to about 100° C., and about 1.5 times for each 10° F. rise from 68° F. to 212° F. Generally, decreasing temperatures have little effect on hydrogen peroxide until they drop substantially below 0° C. Crystals do not begin to appear in 35% and 50% solutions of hydrogen peroxide until about −33° C. (−27.4° F.) and −52.2° C. (−62° F.), respectively.
Particular embodiments of the present invention may employ one or more mechanical means to minimize the decomposition of the peroxide-generating compound until the compound is down hole. Generally, the holding tanks, pumps, and the like used to handle the peroxide-generating compound prior to its injection into the subterranean formation are constructed out of passivated, corrosion-resistant materials, such as stainless steel, specifically selected to minimize the decomposition of the hydrogen peroxide. Particular embodiments of the present invention may also mechanically isolate the peroxide-generating compound from the well bore environment itself until the compound reaches a desired location in the subterranean formation. In particular embodiments, this entails injecting the peroxide-generating compound into the formation using coiled tubing constructed from a material selected for its compatibility both with the corrosive demands of the peroxide-generating compound and with the physical demands placed on coiled tubing. Such compatible coiled tubing materials include, but are not limited to, QT 16Cr alloys, such as QT 16Cr30 and QT 16Cr80, available under the tradename “NITRONIC® 30, ” from Quality Tubing, Inc., of Houston, Tex. Other particular embodiments may employ other corrosion-resistant tubing, such as pure aluminum tubing, Type 304 stainless steel tubing, plastic-lined steel tubing, or tubing lined with crosslinked polyethylene (PEX), polyethylene, or some other peroxide-inert material.
Either alone or in combination with mechanical means, particular embodiments of the present invention may also use chemical means to minimize the decomposition of the peroxide-generating compound until the peroxide-generating compound reaches the desired location in the subterranean formation. Generally, these embodiments use a moderator to delay the decomposition of the peroxide-generating compound and may further use an initiator to catalyze the reaction once the peroxide-generating compound is in place in the formation.
A number of moderators are suitable in accordance with the teachings of the present invention, generally, suitable moderators are chelating or sequestering agents. While some moderators (such as stannate) are alkaline, most (such as phosphonic acids) are acidic and exhibit buffering properties which add acidity to the product. Colloidal stannate and sodium acid pyrophosphate (present from about 10 mg of moderator per liter of hydrogen peroxide to about 500 mg of moderator per liter of hydrogen peroxide) are effective moderators although organophosphonates (such as Dequest® products available from Monsanto Company of St. Louis, Mo.) are viable options. Other moderators include nitrate (aids in pH adjustment and corrosion inhibition) and phosphoric acid (aids in pH adjustment). Moreover, colloidal silicate can be used to sequester metals and thereby minimize H 2 O 2 decomposition. One suitable moderator is sodium acid pyrophosphate. Other moderators include, but are not limited to, other phosphonates, as well as chelants, such as ethylenediaminetetraacetic acid (EDTA), which may act as moderators through, inter alia, metal ion chelation.
As used herein, “moderator” refers to any substance that can be used to intentionally control or slow the rate of reaction of the peroxide-generating compound with the formation materials. Moderators should be distinguished from “stabilizers,” which are typically used to stabilize peroxide-generating compounds, such as hydrogen peroxide, from natural decomposition. In some embodiments the difference between a stabilizer and a moderator may be merely a matter of the concentration of the chosen compound. That is, at typical “stabilizing” concentrations, the compound may be inadequate for use as a moderator. However, in particular embodiments, a stabilizer may be used as a moderator in accordance with the teachings of the present invention when present at an adequate concentration.
Once the peroxide-generating compound reaches the desired location within the subterranean formation, an initiator may be used to catalyze the peroxide generation, which typically proceeds quickly once initiated. Generally, the initiator of the present invention comprises a metallic catalyst, such as iron or a metal ion, capable of catalyzing the decomposition of the peroxide-generating compound. Suitable initiators include catalysts such as iron, copper, manganese, or other transition metal compounds. Examples of suitable initiators placed into the formation include ferric chloride, copper chloride, sodium chloride, and other soluble metal ions placed in solution for the purpose of initiating the catalysis. These catalysts may also be used to speed up H 2 O 2 reactions that may otherwise take hours or days to complete. H 2 O 2 catalysis may occur either in solution (using soluble catalysts) or by using solid catalysts. The most commonly used solution initiator is iron, which when used with H 2 O 2 is referred to as Fenton's Reagent. The reaction typically requires a slightly acidic pH and results in the formation of highly reactive hydroxyl radicals. In particular embodiments, the minerals naturally present in the formation itself may act as an adequate initiator. Examples of suitable minerals that act as naturally occurring initiators that may be present in the formation include, but are not limited to, iron oxides and hydroxides (e.g., magnetite, hematite, ilmenite, limonite, goethite), carbonates (e.g., siderite, ferroan calcite, ferroan dolomite, ankerite rhodochrosite, magnesite), sulfides (e.g., pyrite, phyrrhotite, chalcopyrite, galena), sheet silicates (e.g., chlorite, serpentine, illite, illite/smectite), and chain silicates (e.g., the pyroxene group). In some embodiments, the minerals naturally present in the formation itself may act as an adequate initiator. However, in situations where the minerals present in the formation are absent or not present in sufficient quantities to act as an initiator within the desired timeframe, an initiator may be added to the formation as a pre-flush or as an after-flush.
Several methods are available for determining whether the minerals present in the formation are sufficient to initiate the reaction of the peroxide-generating compound. Generally, a sample of the formation is exposed to the peroxide-generating compound. If the peroxide-generating compound is too reactive with the formation, a moderator may be added. Moderator is added until the about 95% of the peroxide-generating compound remains unconsumed after a 24-hour period. In some embodiments, this level of moderator may then be scaled up by up by about 20% to ensure an adequate amount of moderator is present to prevent the premature decomposition of the peroxide-generating compound. With the benefit of this disclosure, one skilled in the art should be able to determine the proper amount of moderator for use in chosen formation. In some embodiments of the present invention, a moderator or moderators are included in concentrations of from about 10 mg of moderator per liter of hydrogen peroxide solution to about 500 mg of moderator per liter of hydrogen peroxide solution; however, when it is desired to all but completely stop the reaction, moderator may be included in concentrations of multiple grams of moderator per liter of hydrogen peroxide solution, for example, some embodiments may use 2 grams of moderator per liter of hydrogen peroxide solution. In other embodiments of the present invention, a moderator or moderators are included in concentrations of from about 25 mg of moderator per liter of hydrogen peroxide solution to about 250 mg of moderator per liter of hydrogen peroxide solution.
After the peroxide-generating compound has been introduced into the subterranean formation, and treated with any necessary initiator, the formation is typically shut-in for a period of about 48 hours or more. This helps to ensure that the peroxide generation and any subsequent reactions with the hydrocarbons or formation have gone to completion and to allow the heat and carbon dioxide produced to diffuse in the formation. After the shut-in period, the well may be put into production. The natural formation pressure, increased pressure due to the carbon dioxide and heat, and the reduced viscosity of the hydrocarbons act to stimulate the flow of hydrocarbons from the formation into the well bore. However, after a period of production, from several days to several months, it may be desirable to repeat the treatment to maintain an economic production rate.
The teachings of the present invention may also be useful in reservoir flooding operations, typically following stimulation treatments. In the reservoir flooding procedure, a peroxide-generating compound, such as hydrogen peroxide, is continuously injected into the well to help produce additional hydrocarbons. The peroxide-generating compound in the formation decomposes to produce heated water and oxygen in a front. The oxygen then reacts with the heavy oil or residual coke in the reservoir in a combustion front to produce more heat, water, and carbon dioxide to form a front of steam, hot water, carbon dioxide, and oil. The carbon dioxide may migrate and dissolve in the cooler oil ahead of the front. The resulting low viscosity, CO 2 -saturated oil can then flow outwardly through the resident oil toward a production well. As more carbon dioxide dissolves in the reservoir oil, a zone of continuously varying oil viscosity expands, extending from the combustion front to a zone of oil with normal reservoir properties, and resulting in the production of the oil. Additional amounts of the peroxide-generating compound injected in the formation forms an aqueous zone behind the combustion front with properties similar to water, but with a high energy potential for heating the reservoir matrix as needed. The cooler, injected peroxide-generating solution can push forward the combustion front, and also scavenge heat from the formerly heated formation (left over from the previous stimulation treatment) as it moves through the reservoir, assisting the generation of peroxide in the combustion front. In all, the hot water, steam, and carbon dioxide resulting from the reaction of the peroxide-generating compound immiscibly displaces warmer, low viscosity oil, which in turn displaces cooler, CO 2 -saturated oil, which in turn displaces reservoir oil into a production well bore, providing an economical way to increase the hydrocarbon production of a well.
The teachings of the present invention may also be useful in a number of applications relating to recovery of hydrocarbons from non-traditional sources. In general, the teachings of the present invention may be useful in the recovery of any hydrocarbon having a viscosity that may be reduced by heating the hydrocarbon above its in-situ temperature sufficient to enable enhanced production. More particularly, the present invention may be useful in methane hydrate recovery, coal bed methane recovery, and heavy oil production. In methane hydrate extraction, the in-situ thermal stimulation of the present invention may be used to melt methane hydrates to release methane. In-situ thermal stimulation may also be used to affect the desorption isotherm in coal bed methane recovery, permanently changing the “rank” of the coal bed such that the bed releases methane at a faster rate. The in-situ thermal stimulation of the present invention may also be used to reduce the viscosity of low temperature hydrocarbons in heavy oil production.
To facilitate a better understanding of the present invention, the following examples of preferred embodiments are given. In no way should the following examples be read to limit or define the scope of the invention.
EXAMPLES
Example 1
A formation core measuring one inch in diameter by one inch in length was taken from a California Diatomite formation containing a high amount of immobile residual heavy oil and was placed in approximately 100 mL solution of 20% hydrogen peroxide. No moderator or initiator was added. The formation core material initiated peroxide decomposition naturally, thus demonstrating that the core naturally contained some initiator compounds (likely minerals and/or precipitates).
Example 2
This, example demonstrates the effect of added moderator whereby a peroxide solution is moderated when in contact with a formation sample capable of rapid natural initiation.
The following basic procedure was followed. First, 5 grams of powdered coal (<200 mesh) was wetted with 1 mL of deionized water and placed in a 20 mL HDPE reactor at 80° F. Next, 5 mL of 3% hydrogen peroxide (prepared from 50% FMC technical grade H 2 O 2 and deionized water) containing 0.1% v/v of a non-ionic wetting surfactant (used to assure complete wetting of the hydrophobic coal particles). Finally, the evolved oxygen was collected in a gas collection tube and the volume recorded as a function of time.
Two tests were run using this procedure. The first was a control that was run using the above procedure without and added moderator. The second was run using the above procedure and also adding 0.2% w/v of sodium acid pyrophosphate moderator to the powdered coal before adding the hydrogen peroxide and surfactant.
Results of this test show that in the control test 8.8 mL of oxygen was liberated in two hours, as compared to 1.8 mL liberated in the test sample over two hours. After 5 hours, the control had liberated 12.8 mL of oxygen and the test had liberated only 5.25 mL of oxygen. After 24 hours, the control had liberated 16 mL of oxygen and the test had liberated only 12.9 mL of oxygen.
Thus, this example illustrates that the hydrogen peroxide reaction can be moderated when using hydrogen peroxide solutions capable of rapid initiation on naturally occurring formation material.
Example 3
Steel wool normally acts to initiate hydrogen peroxide decomposition. In this example, 50 mL of 3% peroxide solution containing 10 mpl NaCL was mixed with 0.1 g sodium acid pyrophosphate moderator and then 0.5 gm steel wool was added. Solutions containing the steel wool were first heated to 120° F. for 1 hour to simulate down hole conditions. The pH of the solution was about 4.4 with sodium acid pyrophosphate, 4.9 without sodium acid pyrophosphate.
After the one hour reaction period, solutions were filtered and titrated to test the level of hydrogen peroxide remaining (the amount remaining is a measure of the stability of the hydrogen peroxide solution). As seen in the data Table 1, solutions of hydrogen peroxide containing the added moderator did not show reaction to the steel wool in the one hour timeframe. By contrast, multiple control tests were run without the moderator addition. As seen, no appreciable hydrogen peroxide remained indicating complete reaction of all hydrogen peroxide after the one hour period in the control samples that did not contain added moderator.
TABLE 1
% H 2 O 2
Blend
decomposition
Blank
50 mL H 2 O 2
3
Control #1
50 mL H 2 O 2 , 0.5 g steel wool,
100
10 ppm NaCl
Control #2
50 mL H 2 O 2 , 0.5 g steel wool,
99
10 ppm NaCl
Control #3
50 mL H 2 O 2 , 0.5 g steel wool,
99
10 ppm NaCl
Control #4
50 mL H 2 O 2 , 0.5 g steel wool,
100
10 ppm NaCl
Test #1
50 mL H 2 O 2 , 0.5 g steel wool,
1
10 ppm NaCl along with 0.1 g
sodium acid pyrophosphate
moderator
Test #2
50 mL H 2 O 2 , 0.5 g steel wool,
2
10 ppm NaCl along with 0.1 g
sodium acid pyrophosphate
moderator
Thus, this example demonstrated the ability of a sodium acid pyrophosphate to act as a moderator in the presence of an otherwise rapidly initiating substance.
Example 4
An example of the suitability of QT 16Cr80 coiled tubing used for down hole delivery of hydrogen peroxide is illustrated.
In this example, standard solutions of hydrogen peroxide are prepared and were titrated to test the level of hydrogen peroxide remaining after being exposed to a “coupon” sample of QT 16Cr80. The tests were run over a period of about 48 hours. The difference between the solution in contact with the coupon versus the control solution is a measure of the stability of the hydrogen peroxide in contact with the coupon.
For each tested peroxide concentration (5%, 10%, and 35%) 100 mL of commercial grade hydrogen peroxide was placed in a beaker along with a coupon. Each beaker was tested at intervals along with a blank sample (containing no coupon).
TABLE 2
5% Hydrogen Peroxide.
% H 2 O 2
Interval (hr)
blank
With coupon
24
6.8
6.7
TABLE 3
10% Hydrogen Peroxide.
% H 2 O 2
Interval (hr)
blank
With coupon
1
9.5
11.7
24
9.6
11.8
48
9.9
11.8
TABLE 4
35% Hydrogen Peroxide.
% H 2 O 2
Interval (hr)
blank
With coupon
3
33.9
31.9
24
34.2
33.9
48
32.9
33.8
As evident in Tables 2 through 4, the rate of decomposition for the test samples exposed to the coupons was within the experimental error of blank solutions. Thus, this example illustrates that all three different concentrations of hydrogen peroxide tested were stable when in contact with the QT 16Cr80 coiled tubing coupons.
Example 5
This example demonstrates the effect of added initiator in a formation core that does not contain sufficient natural initiator.
In this example, 30 mL of 35% hydrogen peroxide was added to a 100 mL beaker along with core sample weighing approximately 10 g. The core sample consisted of a clean quartz arenite formation containing natural hydrocarbons but lacking any significant quantity of natural formation mineral initiators. The sample was approximately 70° F. Ten minutes after the hydrogen peroxide had been added, very little heat had been generated, and the temperature in the beaker had risen to only about 150° F. Next, 2 mL of 10% iron chloride (an initiator) was added and the temperature rapidly (within 15 minutes) rose to (and likely exceeded) the maximum measuring ability of the thermometer (220° F.).
Thus, this example illustrates that a hydrogen peroxide initiator can be used to enhance the temperature raising abilities of hydrogen peroxide in formations having insufficient natural initiators.
Example 6
To demonstrate the ability of a moderator to inhibit a reaction in progress, 30 mL of 35% hydrogen peroxide was added to a 100 mL beaker along with core sample weighing approximately 10 g. A 70° F. core sample consisted of a clean quartz arenite formation lacking any significant quantity of natural formation mineral initiators. After 10 minutes, very little heat had been generated, the temperature in the beaker had risen to only about 150° F. Next, 2 mL of 10% iron chloride (an initiator) was added and the temperature rapidly (within 15 minutes) rose to (and likely exceeded) the maximum measuring ability of the thermometer (220° F.). Next, 2 grams of sodium acid pyrophosphate (a moderator) was added and the temperature rapidly dropped to about 140° F.
Thus, this example shows that an appropriate moderator can be chosen to essentially stop the release of heat or to moderate the level of release.
Example 7
Initially, 30 mL of 35% hydrogen peroxide and 1 gram of pyrophosphoric acid disodium salt (a moderator) were added to a 100 mL beaker, the mixture in the beaker was about 70° F. Next, 12 mL of 10% iron chloride solution was added to the mixture and the temperature rapidly (in less than a minute) rose to (and likely exceeded) the maximum measuring ability of the thermometer (220° F.). Next, another 1 gram of sodium acid pyrophosphate was added to the mixture and the temperature rapidly fell to about 90° F. and visual inspection of the mixture showed that bubbling had stopped. Finally, another 10 mL of 10% iron chloride solution was added to the mixture and the temperature again began to rise and exceeded the maximum measuring ability of the thermometer (220° F.). This example demonstrates the ability to turn on and off the exothermic abilities of hydrogen peroxide.
Therefore, the present invention is well adapted to attain the ends and advantages mentioned as well as those that are inherent therein. While numerous changes may be made by those skilled in the art, such changes are encompassed within the spirit of this invention as defined by the appended claims.
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One embodiment provides a method for stimulating hydrocarbon production in a subterranean formation, comprising: introducing a peroxide-generating compound into a desired location in a subterranean formation, wherein the peroxide-generating compound is substantially mechanically isolated from the subterranean formation until the peroxide-generating compound reaches the desired location; and allowing the peroxide-generating compound to generate peroxide in the desired location in the subterranean formation. Another embodiment provides a method for stimulating hydrocarbon production in a subterranean formation, comprising: introducing a peroxide-generating compound into a desired location in a subterranean formation, wherein the peroxide-generating compound further comprises a chemical moderator that acts to inhibit the reaction of the hydrogen peroxide within the subterranean formation; and later, allowing the peroxide-generating compound to generate peroxide in the desired location in the subterranean formation. Another embodiment provides a treatment fluid for stimulating hydrocarbon production from a subterranean formation, comprising peroxide-generating compound and a moderator.
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FIELD OF THE INVENTION
[0001] The present invention relates to RNA extraction from biological materials containing RNA and a method for analyzing biological materials containing RNA.
BACKGROUND OF THE INVENTION
[0002] While DNA is the substance that carries the total genetic information of organisms, RNA is the substance that plays an important role in protein biosynthesis in vivo on the basis of genetic information. Lately, gene sequence information of a number of organisms has been clarified by analysis of DNA. As a consequence of this, the elucidation of gene functions by RNA analysis is of increasing importance, and the procedure to isolate RNA from biological materials has become essential. RNA analysis methods include principally reverse transcriptase-polymerase chain reaction (RT-PCR), Northern blotting, and the like.
[0003] To obtain satisfactory results in these analysis methods, the use of RNA with high purity is required. Particularly in the RT-PCR, RNA analysis becomes difficult when DNA is present with RNA. Accordingly, it is desired that RNA is isolated in high purity not contaminated with DNA, proteins, lipids, carbohydrates, and the like that are present in cells.
[0004] A commonly used RNA extraction method is AGPC method. The AGPC method includes the following steps: (1) Dissolve a biological material in a solution of guanidine thiocyanate, then add an acid buffer solution, phenol solution, and chloroform solution successively, and mix. (2) Separate the mixed solution by centrifugation to an aqueous phase containing RNA and an intermediate phase, between an organic phase and the aqueous phase, containing denatured proteins and insolubilized DNA. (3) Add ethanol or isopropanol to the aqueous solution containing RNA. (4) Precipitate selectively the insolubilized RNA by centrifugation.
[0005] Extraction methods of nucleic acids that neither use toxic chemicals such as phenol and chloroform nor require a relatively long-time consuming procedure such as ethanol precipitation or isopropanol precipitation include a method in which nucleic acids are recovered from agarose gel by taking advantage of the ability of nucleic acids to bind to silica in the presence of a chaotropic agent and another method in which nucleic acids are extracted from biological materials using a chaotropic agent and silica particles. However, these methods have no selectivity between RNA and DNA, and the nucleic acid extracts are present in a mixture of RNA and DNA. Therefore, a procedure to remove DNA contained in the nucleic acid extracts is sometimes required for RNA analysis. The removal of DNA is mainly carried out by DNase treatment, followed by a procedure to remove the enzyme as appropriate. In general, approximately one hour of treatment time with DNase is necessary for the procedure to remove DNA. Moreover, the removal of the enzyme requires complicated procedures such as phenol/chloroform extraction and ethanol precipitation, thus resulting in a loss of RNA.
[0006] There exists a selective extraction method of RNA by taking advantage of the ability of RNA to bind to silica in the presence of a chaotropic agent and an organic solvent (JP-A No. 187897/2002). In this method, the difference between the binding abilities of DNA and RNA to silica is controlled by adding ethanol, isopropanol, or the like to a chaotropic agent, thereby allowing RNA to bind to silica selectively. The selectivity of this method toward RNA is, however, insufficient, and a procedure to remove DNA contaminated in the nucleic acid extracts is needed.
SUMMARY OF THE INVENTION
[0007] The purpose of this invention is to provide a method to extract selectively RNA with high purity from biological materials containing RNA in a safe, rapid, and simple procedure and a method to analyze it.
[0008] The present inventors discovered that RNA binds to silica with very high selectivity in the presence of a predetermined concentration of a chaotropic agent and a predetermined concentration of an organic solvent, and have succeeded in establishing a method for selective extraction of RNA and a method for analyzing RNA of the present invention.
[0009] The present invention includes the steps of mixing a biological material containing RNA with a predetermined concentration of a chaotropic agent and a predetermined concentration of an organic solvent, allowing the mixed solution to contact a nucleic acid-binding solid phase, washing the nucleic-acid binding solid-phase to which RNA is bound, and eluting RNA from the nucleic-acid binding solid-phase having the bound RNA. Furthermore, the present invention relates to analyzing the obtained RNA by reverse transcriptase polymerase chain reaction.
[0010] According to the present invention, RNA can be extracted with very high purity. Since the extracted product hardly contains DNA, the RT-PCR method for analysis of RNA that is otherwise sensitive to DNA and the like can be carried out without any procedure of DNA removal that has a possibility to impair RNA. Therefore, RNA analysis of a biological sample can be accomplished with high accuracy.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 represents a nucleic acid-capture chip used in a first example and a second example;
[0012] FIG. 2 is an electrophoretogram of nucleic acid extracts in the first example;
[0013] FIG. 3 is an electrophoretogram of nucleic acid extracts in the second example;
[0014] FIG. 4 is an electrophoretogram of nucleic acid extracts in a comparative example; and
[0015] FIG. 5 is an electrophoretogram of RT-PCR products.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0016] The above and other novel features and effects of the present invention will hereinafter explained with reference to the accompanying drawings. It should be noted that these drawings are merely used for explanations and do not limit the scope of right of the present invention.
[0017] Biological materials containing RNA that become a subject of concern may include biological samples such as whole blood, serum, sputum, urine, tissues from a living body, cultured cells, and cultured microorganisms and materials containing crude RNA.
[0018] Solubilization of biological materials is carried out by a physical method that uses a mortar, ultrasound, microwave, homogenizer, or the like, a chemical method that uses a surface active agent, protein denaturant, or the like, or a biochemical method utilizing a proteinase, and by a method in combination of these methods.
[0019] Preferred examples of chaotropic agents are sodium iodide, potassium iodide, sodium thiocyanate, guanidine thiocyanate, guanidine hydrochloride, and the like.
[0020] An organic solvent that can be used is one or a combination of at least two compounds having two to ten carbon atoms that are selected from aliphatic ethers, aliphatic esters, and aliphatic ketones.
[0021] The aliphatic ethers that are preferably used are ethylene glycol dimethyl ether, ethylene glycol diethyl ether, propylene glycol dimethyl ether, propylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, tetrahydrofuran, and 1,4-dioxane.
[0022] The aliphatic esters preferably used are propylene glycol monomethyl ether acetate and ethyl lactate.
[0023] The aliphatic ketones preferably used are acetone, hydroxyacetone, and dimethyl ketone.
[0024] The selective RNA extraction method of the present invention is based on the effect of the selective binding of RNA to silica, and this effect can be obtained in the presence of a predetermined concentration of a chaotropic agent and a predetermined concentration of an organic solvent.
[0025] When guanidine thiocyanate is used as the chaotropic agent and diethylene glycol dimethyl ether is used as the organic solvent, RNA with high purity is obtained in good yield at a guanidine thiocyanate concentration ranging from 1.0 to 4.0 mol/l and a diethylene glycol dimethyl ether concentration ranging from 10 to 30% in the final mixed solution. In particular, RNA with very high purity is obtained in high yield at a guanidine thiocyanate concentration ranging from 1.5 to 2.0 mol/l and a diethylene glycol dimethyl ether concentration ranging from 15 to 25% in the final mixed solution.
[0026] When guanidine thiocyanate is used as the chaotropic agent and ethyl lactate is used as the organic solvent, RNA with high purity is obtained in good yield at a guanidine thiocyanate concentration ranging from 1.0 to 4.0 mol/I and an ethyl lactate concentration ranging from 20 to 40% in the final mixed solution. In particular, RNA with very high purity is obtained in high yield at a guanidine thiocyanate concentration ranging from 1.5 to 2.5 mol/l and an ethyl lactate concentration ranging from 25 to 35% in the final mixed solution.
[0027] Preferred examples of nucleic acid-binding solid phase include glass particles, silica particles, glass fiber filter paper, silica wool, or their crushed materials, and materials containing silicon dioxide such as diatomaceous earth.
[0028] The contact of nucleic acid-binding solid phase with the mixed solution is carried out by a method of stirring and mixing the solid phase and the mixed solution in a vessel or a method of passing the mixed solution through a column with the immobilized solid phase. After allowing the nucleic acid-binding solid phase and the mixed solution to contact each other, the solid phase is separated from the mixed solution.
[0029] Washing of the nucleic-acid binding solid phase with the bound nucleic acids is performed, for example, by allowing the solid phase to contact a washing solution, followed by separating the solid phase from the washing solution. It is preferred to use ethanol at a concentration of at least 75% for the washing solution so that the nucleic acids bound to the solid phase may not be eluted out and non-specifically bound substances may be removed efficiently.
[0030] Elution of nucleic acids from the nucleic acid-binding phase is carried out by means of allowing the solid phase to contact an elution solution and eluting the nucleic acids bound to the solid phase into the elution solution, followed by separating the eluate from the solid phase. The elution solution to be used is water, a low salt buffer, or the like that has been treated for removal of RNase or inactivation of RNase activity. When the elution is performed under warming, the elution efficiency is improved.
[0031] The eluate containing eluted nucleic acids may be immediately used for RT-PCR.
EXAMPLES
First Example
[0032] In the present example, RNA extraction from cultured cells was carried out using guanidine thiocyanate as a chaotropic agent and diethylene glycol dimethyl ether as an organic solvent.
[0033] Extraction of RNA
[0034] In a first step, 600 μl of a cell lysis solution (4 mol/l guanidine thiocyanate, 10 mmol/l MES-KOH, pH 6.5) was added to pellets of cultured mouse myeloma cells (ca. 10 6 cells)(Sp/O-Ag14; product of Dainippon Pharmaceutical Co., Ltd.), and the cells were disrupted by a homogenizer (Handy Micro Homogenizer; manufactured by Microtec Co., Ltd.), thereby releasing intracellular nucleic acids.
[0035] In a second step, 600 μl of each aqueous solution of diethylene glycol dimethyl ether (20, 40, 60, 80, and 100% by volume) was added, as an organic solvent, to the cell lysate after the first step. At this time, the concentrations of guanidine thiocyanate became 2 mol/l, and those of diethylene glycol dimethyl ether became 10, 20, 30, 40, and 50% by volume, respectively, in the mixed solution.
[0036] In a third step, a syringe (25 ml syringe; product of Terumo Corporation) was attached to a nucleic acid-capture chip made of polypropylene of which tip was packed with 5 mg of silica wool (B grade; Toshiba Chemical Corporation) as the nucleic acid-binding solid phase as shown in FIG. 1 , and the solution after the second step was aspirated and dispensed, thereby allowing the solid phase to contact nucleic acids for separation.
[0037] In a fourth step, 1,200 μl of a washing solution (aqueous solution of 80% by volume ethanol) was aspirated and dispensed of the nucleic acid-capture chip, thereby allowing the solid phase to contact the washing solution, and thus, substances bound non-specifically to the solid phase were separated and removed.
[0038] In a fifth step, 100 μl of an elution solution (DEPC-treated water) was aspirated and dispensed of the nucleic acid-capture chip, thereby allowing the solid phase to contact the elution solution and be separated finally from the latter, and thus, an eluate containing purified nucleic acids was obtained.
[0039] Evaluation of Extracted RNA
[0040] FIG. 2 shows the results of electrophoresis carried out for portions of the eluates on 1.25% agarose gel (Reliant RNA Gel System; product of FMC BioProducts) and its subsequent visualization by staining with ethidium bromide and taking a photograph under UV irradiation with a transilluminator. Lanes 1 and 2 represent nucleic acids extracted by the use of the aqueous solution of 40% by volume diethylene glycol dimethyl ether; lanes 3 and 4 represent nucleic acids extracted by the use of the aqueous solution of 60% by volume diethylene glycol dimethyl ether; lanes 5 and 6 represent nucleic acids extracted by the use of the aqueous solution of 80% by volume diethylene glycol dimethyl ether; and lanes 7 and 8 represent nucleic acids extracted by the use of the aqueous solution of 100% by volume diethylene glycol dimethyl ether.
[0041] Nucleic acids are separated by the electrophoresis according to their molecular weights. From the top of the electrophoretogram, bands corresponding to genomic DNA, 28S rRNA, 18S rRNA, and tRNA are shown, respectively. It is apparent from FIG. 2 that genomic DNA was hardly recognized and RNA with very high purity was obtained in high yield when the aqueous solution of 40% by volume diethylene glycol dimethyl ether was used. On the other hand, when the aqueous solutions of 60 to 100% by volume diethylene glycol dimethyl ether were used, it is apparent that the nucleic acid extracts contained large amounts of genomic DNA. In addition, when the aqueous solution of 20% by volume diethylene glycol dimethyl ether was used, nucleic acids were hardly obtained by the extraction.
Second Example
[0042] In the present example, RNA extraction from cultured cells was carried out using guanidine thiocyanate as the chaotropic agent and ethyl lactate as the organic solvent.
[0043] Extraction of RNA
[0044] The extraction of RNA of the present embodiment was conducted in the same manner as in the first embodiment except for the second step. The second step is described below.
[0045] In the second step, 600 μl of each aqueous solution of ethyl lactate (20, 40, 60, 80, and 100% by volume) was added, as the organic solvent, to the cell lysate after the first step. At this time, the concentrations of guanidine thiocyanate became 2 mol/l, and those of ethyl lactate became 10, 20, 30, 40, and 50% by volume, respectively, in the mixed solution.
[0046] Evaluation of Extracted RNA
[0047] FIG. 3 shows the results of electrophoresis carried out in the same manner as in the first embodiment. Lane 1 represents nucleic acids extracted by the use of the aqueous solution of 60% by volume ethyl lactate; lane 2 represents nucleic acids extracted by the use of the aqueous solution of 80% by volume ethyl lactate; and lane 3 represents nucleic acids extracted by the use of the aqueous solution of 100% by volume ethyl lactate.
[0048] It is shown here that genomic DNA was hardly recognized and that RNA with very high purity was obtained in high yield when the aqueous solution of 60% by volume ethyl lactate was used. On the other hand, when the aqueous solutions of 80 and 100% by volume ethyl lactate were used, it is apparent that the nucleic acid extracts contained large amounts of genomic DNA. In addition, when the aqueous solutions of 20 and 40% by volume ethyl lactate were used, nucleic acids were hardly obtained by the extraction.
Comparative Example
[0049] In the present embodiment, RNA extraction from cultured cells was carried out with the RNA extraction kit (RNeasy Mini Kit; product of Qiagen Inc.) that uses guanidine thiocyanate as the chaotropic agent and ethanol as the organic solvent. This method is based on the method disclosed in Patent document 1 described above.
[0050] Extraction of RNA
[0051] Extraction of RNA from pellets of cultured mouse myeloma cells (ca. 10 6 cells) that were the same as those used in the first embodiment was conducted using the RNeasy Mini Kit obtained from Qiagen according to the protocol attached to the kit.
[0052] Evaluation of Extracted RNA
[0053] FIG. 4 shows the results of electrophoresis carried out in the same manner as in the first embodiment. These results indicate that the nucleic acid extracts contained genomic DNA when the RNeasy Mini Kit was used.
[0054] RT-PCR with Nucleic Acid Extracts
[0055] RT-PCR was carried out using the nucleic acid extracts obtained in the first embodiment and those obtained by the method of the comparative example.
[0056] Nucleic acid solutions each containing 2.5 μg of total RNA were prepared, respectively, from the nucleic acids extracted according to the methods of the first embodiment and the comparative example without performing a DNA removal procedure. To each of these nucleic acid solutions was added a reverse transcriptase (SuperScript II; product of Invitrogen Corporation) and reagents for reverse transcription containing an oligo(dT) primer. The final volume was adjusted to 20 μl, and incubated for 50 min at 42 degrees C., thereby allowing cDNA to be synthesized by the reverse transcription reaction with mRNA as the template.
[0057] To 2 μl and 0.2 μl of the solution after the reverse transcription reaction were then added PCR primers targeted to a region of mouse β-actin gene not containing intron (Mouse β-actin RT-PCR Primer Set; product of Toyobo Co., Ltd.), a thermostable DNA polymerase (AmpliTaq Gold DNA polymerase; product of Applied Biosystems), and reagents for PCR. The final volume was adjusted to 50 μl, and a cycle of 94 degrees C. for 15 sec, 55 degrees C. for 30 sec, and 72 degrees C. for 1 min was repeated 30 times using a thermal cycler (GeneAmp PCR System 9600; manufactured by PerkinElmer, Inc.).
[0058] PCR was carried out using 2 μl and 0.2 μl of the non-reacted solution without subjecting to the reverse transcription reaction as negative controls and DNA originating from mouse β-actin gene that was supplied with the PCR primers (Mouse β-actin RT-PCR Primer Set; product of Toyobo Co., Ltd.) as a positive control.
[0059] After PCR reaction, the solution was subjected to electrophoresis on 3% agarose gel (Nusieve 3:1 Agarose; product of FMC BioProducts). FIG. 5 shows the results of the electrophoretogram that was visualized by taking a photograph under UV irradiation with a transilluminator after staining with ethidium bromide.
[0060] In FIG. 5 , lane 1 represents an amplified product that was obtained by the reverse transcription reaction using the nucleic acids extracted according to the method described in the first embodiment, followed by PCR amplification of 2 μl of the solution after the reverse transcription reaction. Lane 2 represents an amplified product that was obtained by the reverse transcription reaction using the nucleic acids extracted according to the method described in the first embodiment, followed by PCR amplification of 0.2 μl of the solution after the reverse transcription reaction. Lane 3 represents an amplified product that was obtained by direct PCR amplification of 2 μl of the unreacted solution in which the nucleic acids extracted according to the method described in the first embodiment were not subjected to the reverse transcription reaction. Lane 4 represents an amplified product that was obtained by direct PCR amplification of 0.2 μl of the unreacted solution in which the nucleic acids extracted according to the method described in the first embodiment were not subjected to the reverse transcription reaction.
[0061] Lane 5 represents an amplified product that was obtained by the reverse transcription reaction using the nucleic acids extracted according to the method described in the comparative example, followed by PCR amplification of 2 μl of the solution after the reverse transcription reaction. Lane 6 represents an amplified product that was obtained by the reverse transcription reaction using the nucleic acids extracted according to the method described in the comparative example, followed by PCR amplification of 0.2 μl of the solution after the reverse transcription reaction. Lane 7 represents an amplified product that was obtained by direct PCR amplification of 2 μl of the unreacted solution in which the nucleic acids extracted according to the method described in the comparative example were not subjected to the reverse transcription reaction. Lane 8 represents an amplified product that was obtained by direct PCR amplification of 0.2 μl of the unreacted solution in which the nucleic acids extracted according to the method described in the comparative example were not subjected to the reverse transcription reaction. Lane 9 represents an amplified product that was obtained by PCR amplification using DNA originating from mouse β-actin gene as the positive control.
[0062] From these results, the amplified product of 540 bp originating from mouse β-actin gene was confirmed in lanes 1, 2, 5, 6, 7, and 9. The amplified product was not confirmed when the nucleic acids extracted according to the method of the first embodiment were not subjected to the reverse transcription reaction (Lanes 3 and 4). This suggests that the amplified product (Lanes 1 and 2) after the reverse transcription reaction was derived from mRNA and that RT-PCR can be carried out without removing genomic DNA from the nucleic acid extracts.
[0063] On the other hand, the nucleic acids extracted according to the method described in the comparative example gave rise to an amplified product when 2 μl of the unreacted solution without being subjected to the reverse transcription reaction was used (Lane 7). This product is an amplification product derived from the genomic DNA that was contained in the nucleic acid extracts. Accordingly, an amplified product that was obtained by PCR using 2 μl of the solution after the reverse transcription reaction (Lane 5) is likely to be a mixture of amplification products derived from mRNA and genomic DNA, which suggests that RT-PCR does not function properly in this case. When RT-PCR is carried out with the nucleic acids extracted according to the method of the comparative example, it is therefore necessary to remove genomic DNA in advance from the nucleic acid extracts.
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A method to extract RNA with high purity from biological materials containing RNA in a safe, rapid, and simple procedure and a method to analyze it are provided. The procedure includes the steps of mixing a biological material containing RNA with a predetermined concentration of a chaotropic agent and a predetermined concentration of an organic solvent, allowing the mixed solution to contact a nucleic acid-binding solid phase, washing the nucleic-acid binding solid-phase to which RNA is bound, and eluting RNA from the nucleic-acid binding solid-phase having the bound RNA. Furthermore, the obtained RNA is analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) or the like.
| 2 |
FIELD OF THE INVENTION
This invention is a surgical device. In particular, it is a catheter section having a number of radially placed holes through the catheter section wall and a catheter assembly including that section. That catheter assembly may be used in accessing and treating a tissue target within the body, typically one which is accessible through the vascular system. Central to the invention is the use of a braided metallic reinforcing member in the catheter section, typically of super-elastic alloy ribbon, situated in such a way to provide an exceptionally thin wall, controlled stiffness, high resistance to kinking, and complete recovery in vivo from kinking situations. The orifices in the section are optimally placed in the interstices between the turns of the braid. The braid may have a single pitch or may vary in pitch along the axis of the catheter or catheter section. The braided ribbon reinforcing member typically is placed between a flexible outer tubing member and an inner tubing member to produce a catheter section which is very flexible but highly kink resistant.
The catheter sections made according to this invention may be used alone or in conjunction with other catheter sections either made using the concepts shown herein or made in other ways. The more proximal sections of the catheter assembly are often substantially stiffer than the more distal sections due to the presence of stiff polymeric tubing or metallic tubing or composited materials in the stiffer section.
BACKGROUND OF THE INVENTION
Catheters are increasingly used to access remote regions of the human body and, in doing so, delivering diagnostic or therapeutic agents to those sites. In particular, catheters which use the circulatory system as the pathway to these treatment sites are especially practical. Catheters are also used to access other regions of the body, e.g., genito-urinary regions, for a variety of therapeutic and diagnostic reasons. One such treatment of diseases of the circulatory system is via angioplasty (PCA). Such a procedure uses catheters having balloons on their distal tips. It is similarly common that those catheters are used to deliver a radio-opaque agent to the site in question prior to the PCA procedure to view the problem prior to treatment.
Often the target which one desires to access by catheter is within a soft tissue such as the liver or the brain. These are difficult sites to reach. The catheter must be introduced through a large artery such as those found in the groin or in the neck and then be passed through ever-narrower regions of the arterial system until the catheter reaches the selected site. Often such pathways will wind back upon themselves in a multi-looped path. These catheters are difficult to design and to utilize in that they must be fairly stiff at their proximal end so to allow the pushing and manipulation of the catheter as it progresses through the body, and yet must be sufficiently flexible at the distal end to allow passage of the catheter tip through the loops and increasingly smaller blood vessels mentioned above and yet at the same time not cause significant trauma to the blood vessel or to the surrounding tissue. Further details on the problems and an early, but yet effective, way of designing a catheter for such a traversal may be found in U.S. Pat. No. 4,739,768, to Engelson. These catheters are designed to be used with a guidewire. A guidewire is simply a wire, typically of very sophisticated design, which is the "scout" for the catheter. The catheter fits over and slides along the guidewire as it passes through the vasculature. Said another way, the guidewire is used to select the proper path through the vasculature with the urging of the attending physician and the catheter slides along behind once the proper path is established.
There are other ways of causing a catheter to proceed through the human vasculature to a selected site, but a guidewire-aided catheter is considered to be both quite quick and somewhat more accurate than the other procedures. One such alternative procedure is the use of a flow-directed catheter. These devices often have a small balloon situated on the distal end of the catheter which may be alternately deflated and inflated as the need to select a route for the catheter is encountered.
This invention is an adaptable one and may be used in a variety of catheter formats. The invention utilizes the concept of combining one or more polymeric tubes with a metallic braid comprising ribbons of a super-elastic alloy. The construction technique has the benefit of producing catheter sections having small overall diameters but with exceptional strength, resistance to kinking, and recovery from kinking (even in vivo) should such kinking occur. This catheter may be used in conjunction with a guidewire, but the catheter body may also be used as a flow-directed catheter with the attachment of a balloon or in combination with a specifically flexible tip, as is seen, for instance, in U.S. Pat. No. 5,336,205 to Zenzen et al., the entirety of which is incorporated by reference.
The use of braids in a catheter body is not a novel concept. Typical background patents are discussed below.
There are a number of catheters discussed in the literature which utilize catheter bodies having multiply-wrapped reinforcing material. These catheters include structures having braided bands or ones in which the spirally wound material is simply wound in one direction and the following layer or layers are wound in the other.
Krippendorf, U.S. Pat. No. 2,437,542, describes a "catheter-type instrument" which is typically used as a ureteral or urethral catheter. The physical design is said to be one having a distal section of greater flexibility and a proximal section of lesser flexibility. The device is made of intertwined threads of silk, cotton, or some synthetic fiber. It is made by impregnating a fabric-based tube with a stiffening medium which renders the tube stiff yet flexible. The thus-plasticized tubing is then dipped in some other medium to allow the formation of a flexible varnish-like layer. This latter material may be a tung oil base or a phenolic resin and a suitable plasticizer. There is no indication that this device is of the flexibility described herein. Additionally, it appears to be the type which is used in some region other than in the body's periphery or in its soft tissues.
Similarly, U.S. Pat. No. 3,416,531, to Edwards, shows a catheter having braiding-edge walls. The device further has additional layers of other polymers such as TEFLON and the like. The strands found in the braiding in the walls appear to be threads having circular cross-sections. There is no suggestion of constructing a device using ribbon materials. Furthermore, the device is shown to be fairly stiff in that it is designed so that it may be bent using a fairly large handle at its proximal end.
U.S. Pat. No. 3,924,632, to Cook, shows a catheter body utilizing fiberglass bands wrapped spirally for the length of the catheter. As is shown in FIG. 2 and the explanation of the Figure at column 3, lines 12 and following, the catheter uses fiberglass bands which are braided, that is to say, bands which are spiraled in one direction cross over and under bands which are spiraled in the opposite direction. Additionally, it should be observed that FIG. 3 depicts a catheter shaft having both an inner lining or core 30 and an outer tube 35.
U.S. Pat. No. 4,425,919, to Alston, Jr. et al., shows a multilayered catheter assembly using multi-stranded flat wire braid. The braid 14 in FIG. 3 further covers an interior tubing or substrate 12.
U.S. Pat. No. 4,484,586 shows a method for the production of a hollow, conductive medical tubing. The conductive wires are placed in the walls of hollow tubing specifically for implantation in the human body, particularly for pacemaker leads. The tubing is preferably made of an annealed copper wire which has been coated with a body-compatible polymer such as a polyurethane or a silicone. After coating, the copper wire is wound into a tube. The wound substrate is then coated with still another polymer to produce a tubing having spiral conducting wires in its wall.
A document showing the use of a helically wound ribbon of flexible material in a catheter is U.S. Pat. No. 4,516,972, to Samson. This device is a guiding catheter and it may be produced from one or more wound ribbons. The preferred ribbon is a polyaramid material known as Kevlar 49. Again, this device is a device which must be fairly stiff. It is a device which is designed to take a "set" and remain in a particular configuration as another catheter is passed through it. It must be soft enough so as not to cause substantial trauma, but it is certainly not for use with a guidewire. It would not meet the flexibility criteria required of the inventive catheter described herein.
U.S. Pat. No. 4,806,182, to Rydell et al, shows a device using a stainless steel braid imbedded in its wall and having an inner layer of a polyfluorocarbon. The process also described therein is a way to laminate the polyfluorocarbon to a polyurethane inner layer so as to prevent delamination.
U.S. Pat. No. 4,832,681, to Lenck, shows a method and apparatus useful for artificial fertilization. The device itself is a long portion of tubing which, depending upon its specific materials of construction, may be made somewhat stiffer by the addition of a spiral reinforcement comprising stainless steel wire.
U.S. Pat. No. 4,981,478, to Evard et al., discloses a multi-sectioned or composite vascular catheter. The interior section of the catheter appears to have three sections making up the shaft. The most interior (and distal) section, 47, appears to be a pair of coils 13 and 24 having a polymeric tubing member 21 placed within it. The next, more proximal, section is 41, and FIG. 4 shows it to be "wrapped or braided" about the next inner layer discussed just above. The drawing does not show it to be braided but, instead, a series of spirally wrapped individual strands. Finally, the outermost tubular section of this catheter core is another fiber layer 49, of similar construction to the middle section 26 discussed just above.
Another catheter showing the use of braided wire is shown in U.S. Pat. No. 5,037,404, to Gold et al. Mention is made in Gold et al of the concept of varying the pitch angle between wound strands so to result in a device having differing flexibilities at differing portions of the device. The differing flexibilities are caused by the difference in pitch angle. No mention is made of the use of ribbon, nor is any specific mention made of the particular uses to which the Gold et al. device may be placed.
U.S. Pat. No. 5,057,092, to Webster, Jr., shows a catheter device used to monitor cardiovascular electrical activity or to electrically stimulate the heart. The catheter uses braided helical members having a high modulus of elasticity, e.g., stainless steel. The braid is a fairly complicated, multi-component pattern shown very well in FIG. 2.
U.S. Pat. No. 5,176,660 shows the production of catheters having reinforcing strands in their sheath wall. The metallic strands are wound throughout the tubular sheath in a helical crossing pattern so to produce a substantially stronger sheath. The reinforcing filaments are used to increase the longitudinal stiffness of the catheter for good "pushability". The device appears to be quite strong and is wound at a tension of about 250,000 lb./in. 2 or more. The flat strands themselves are said to have a width of between 0.006 and 0.020 inches and a thickness of 0.0015 and 0.004 inches. There is no suggestion to use these concepts in devices having the flexibility and other configurations described below.
Another variation which utilizes a catheter wall having helically placed liquid crystal polymer fibrils is found in U.S. Pat. No. 5,248,305, to Zdrahala. The catheter body is extruded through an annular die, having relatively rotating inner and outer mandrel dies. In this way, the tube containing the liquid crystal polymer plastic-containing material exhibits a bit of circumferential orientation due to the rotating die parts. At column 2, line 40 and following, the patent suggests that the rotation rate of the inner and outer walls of the die may be varied as the tube is extruded, with the result that various sections of the extruded tube exhibit differing stiffnesses.
U.S. Pat. No. 5,217,482 shows a balloon catheter having a stainless steel hypotube catheter shaft and a distal balloon. Certain sections of the device shown in the patent use a spiral ribbon of stainless steel secured to the outer sleeve by a suitable adhesive to act as a transition section from a section of very high stiffness to a section of comparatively low stiffness.
Japanese Kokai 05-220,225, owned by the Terumo Corporation, describes a catheter in which the torsional rigidity of the main body is varied by incorporating onto an inner tubular section 33, a wire layer which is tightly knitted at the proximal section of the catheter and more loosely knitted at a midsection.
None of the documents cited above provides a structure required by the disclosure and claims recited below, particularly when the flexibility and ability to resist kinks is factored into the physical description of the devices.
SUMMARY OF THE INVENTION
This invention includes an infusion catheter section made up of an inner liner and an outer covering and having a super-elastic alloy ribbon braid located between the liner and the covering. Located generally in the interstices between adjacent turns of the braid ribbon are a number of infusion orifices. The inner liner may be of a polymeric composition. The inner liner and the outer covering, should they be adjacent the braid and both polymeric, may be selected from polymers which are melt-compatible or melt-miscible with each other. In this way, adjacent polymeric layers hold fast to the braid located between them. More preferably, the outer liner is selected such that it is adherent to the inner liner.
The super-elastic alloy braid is, in its most basic form, a braid comprising a number of small super-elastic alloy ribbons wound and treated in such a way that the resulting braid is dimensionally stable and the braided ribbons do not twist. The more basic forms of braids used in this invention include those which are made up of an even number of equally sized ribbons. Half of the ribbons are woven in a clockwise direction (as viewed along the axis of the braid) and the remaining half of the ribbons are woven in a counterclockwise direction. The various ribbons may, of course, be of differing size but the sum of the ribbons used in a particular direction should equal those wound in the other direction. Any imbalance will typically cause a helical curl in the resulting catheter. The super-elastic alloy of choice contains nickel and titanium and is known generically as nitinol. Nitinol is an alloy of nickel and titanium which is blended and heat treated in a specific way to produce an alloy having exceptional resistance to plastic deformation upon physical strain. In addition to nickel and titanium, preferred compositions of the alloy may contain a modest amount, up to about 5%, or up to about 8%, of an iron group metal. Especially desired are ternary alloys containing at least about 1.5% (wt) of one or more alloying members selected from the group consisting of vanadium, chromium, manganese, iron, and cobalt, and particularly chromium or iron. The catheter section may additionally have other various layers of polymeric covering and liners as well as metallic tubing members desirably of braid or helical coils. Especially preferred liners comprise polytetrafluoroethylene (TFE) polymer. Hydrophilic coatings both on the interior and exterior are additionally contemplated.
The kink resistance of the catheter section is due to the presence and composition of the braid in cooperation with the tightly held polymers. In addition to exceptional kink resistance, the catheter section may be made in such a way that the wall is extraordinarily thin, particularly when compared to walls of catheters having equal strength but made solely of polymeric materials. The catheter section additionally is very resilient in that, unlike virtually any other commercial catheter, should the catheter section be kinked, the kink is self-healing. This resiliency means that the catheter need not be withdrawn from a patient's vasculature simply because the catheter has inadvertently kinked. Simple movement of the catheter will cure the kink. Kinking minimization is a matter of concern with many catheters in the marketplace today.
This invention additionally includes catheter sections with braids having more than one pitch or diameter or braid density in a section. The stiffness of the catheter section may be varied continuously by continuously varying the pitch or in a stepwise fashion by stepwise varying the pitch. The pitch may be varied during production of the braid or by changing the diameter of the braid after production. The braid may be partially constructed of polymeric fibers or carbon fibers either replacing a portion of the metallic ribbons or polymeric materials or placed in conjunction with a ribbon in the braid. Other metals, e.g., noble metals such as members of the platinum group or gold, may be used in the braid itself in much the same way to impart radio-opacity to the braid. To tailor the stiffness of the braid, the braid may first wound and portions of the ribbon then removed.
The infusion catheter section of this invention may be used as a catheter assembly by itself--obviously in conjunction with such necessary and ancillary components as a Luerlock and some manner of providing radio-opacity to the catheter. The infusion catheter section of this invention may be used in nose-to-tail configuration with other catheter sections of similar configuration or with catheter sections made in some other fashion.
The infusion catheter section is typically the distal-most section of a catheter assembly. However, it may be used in a catheter assembly having at least a.) a more distal section made up preferably of an inner liner and an outer covering and having a super-elastic alloy braid located between the liner and interior to the outer covering and b.) a more proximal section comprising a stiff polymeric or metallic tubing member, possibly with an inner lubricious liner. Other sections of these or other designs may be placed variously between the noted sections or distal of the distal braided section noted above.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows, in side view, a typical three-section catheter made using the concepts of this invention.
FIGS. 2, 3, and 4 show, in magnification, partial cross-sections of the inner portion of a catheter sections useful in this invention.
FIGS. 5, 6, and 7 show, in magnified cross-section, various catheters having sections of differing stiffness.
FIG. 8 shows, in magnification, partial cross-sections of the inner portion of a catheter section.
FIG. 9 shows, in magnified cross-section, a catheter having sections of differing stiffness.
FIG. 10 shows, in magnified, partial cross-section, an infusion catheter section made according to this invention.
FIGS. 11 and 12 show magnified side views of catheter sections made according to the invention.
FIG. 13 shows, in cross-section, a combination of a catheter section made according to this invention and an attendant valved guidewire made according to this invention.
DESCRIPTION OF THE INVENTION
This invention includes a kink-resistant catheter section containing at least an inner liner and a flexible outer member having a super-elastic alloy, ribbon braid located between the inner and outer members. Located generally in the areas between adjacent turns of the braid ribbon are a number of infusion orifices. The invention includes catheters comprising at least one such catheter section, typically distally located. The catheter section is configured so that it desirably has a critical bend diameter of no more than about 3 mm., preferably no more than 2 mm., and most preferably no more than 1 mm. Desirably, the catheter section self-recovers at least 95% of its original "straightness" after it has been subjected to kinking.
A typical multi-section catheter (100) which may incorporate the concepts of this invention is shown in FIG. 1. Such a catheter is described in more detail in U.S. Pat. No. 4,739,768, to Engelson, (the entirety of which is incorporated by reference) and is particularly suitable for neurological and peripheral vascular applications. Clearly, then, it is also suitable for less demanding service such as might be encountered in access and treatment of the heart. One difficulty which has arisen as higher demands for length have been placed on these catheters is that the diameter of the distal section necessarily becomes smaller and smaller. This is so since the longer catheters must reach ever smaller vascular areas. This smaller diameter requires a concomitant thinning of the wall section. The thinner section walls may kink or ripple when actively pushed along the guidewire or when vasoocclusive devices are pushed through the catheter's lumen. The typical configuration shown in FIG. 1 has a distal section (102) having significant flexibility, an intermediate section (104) which is typically less flexible, and a long proximal section (106) which in turn is least flexible. The distal section (102) is flexible and soft to allow deep penetration of the extraordinary convolutions of the neurological vasculature without trauma. Central to this invention is the presence of a kink resisting braid of the composition described below, in the distal section (102). That braid (not shown in this Figure) is situated with respect to the various orifices (109) such that the orifices (109) generally are between the turns of ribbon making up the braid. These orifices are used to infuse fluid treatments or diagnostic materials to the chosen site in the human body. Various known and often necessary accessories to the catheter assembly, e.g., one or more radio-opaque bands (108) at the distal region to allow viewing of the position of the distal region under fluoroscopy and a luer assembly (110) for guidewire (112) and fluids access, are also shown in FIG. 1.
The typical dimensions of this catheter are:
Overall length: 60-200 cm
Proximal Section (106): 60-150 cm
Intermediate Section (104): 20-50 cm
Distal Section (102): 2.5-30 cm
Obviously, these dimensions are not particularly critical to this invention and are selected as a function of the malady treated and its site within the body. Typical of the catheters made using this invention are those in the 2 French to 5 French range. The inner diameter of such catheters is then 10 mils to 42 mils.
Furthermore, a catheter made using this inventive concept need not be of three sections increasing stiffness as is shown in FIG. 1. The catheter may be of two discrete sections or may be of four or more discrete sections of differing flexibility. Through judicious choice of physical parameters for the catheter sections, the components may also have varying physical parameters (e.g., lubricity, flexibility, wall thickness, inner or outer layer member composition, etc.) within the sections.
Typically, although not necessarily, when a three section catheter is desired, the most proximal section (106) is the "more proximal" or "stiff" section described herein. Again, although not necessarily, when a three section catheter is desired, the most distal section (102) is the "more distal" or "least stiff" section. The mid section (104) may be braided and referred to as "more distal" if the situation warrants it. It is a rare infusion catheter that utilizes a more distal section which is stiffer than any of its more proximal sections.
An additional benefit of the invention is that the use of the super-elastic alloy braid permits the walls of the catheter to be comparatively thinner with no diminution of performance, e.g., crush strength or flexibility, and may provide an improvement in performance.
FIG. 2 shows a magnified partial cross-section of a catheter body or section (200) showing the most basic aspects of a braid-augmented catheter section. As shown there, the catheter body section has an outer covering member (202) and an inner liner member (204). Situated between outer member (202) and inner member (204) is braid member (206). As shown in FIG. 2, both outer member (202) and inner member (204) are polymeric. They may be of materials which tack to each other upon heating. They may also be melt-miscible. In some instances, they may contain adhesions or components which act in the manner of adhesives, but such is not necessary. Typically, for the simple variation shown in FIG. 2, the outer covering member (202) is of a material which is heatshrinkable (e.g., low density polyethylene) or may otherwise be coated onto the structure (e.g., polyurethanes) onto the inner member (204) and the braid (206). Preferred polymeric materials for the inner liner include polyethylene, polypropylene, polyvinyl chloride (PVC), ethyl vinyl acetate (EVA), polyurethanes, polyamides, polyethylene terephthalate (PET), and their mixtures and copolymers. Preferred materials further include the lubricious polymers such as fluoropolymers such as polytetrafluoroethylene (PTFE or TFE), ethylene-chlorofluoroethylene (ECTFE), fluorinated ethylene propylene (FEP), polychlorotrifluoroethylene (PCTFE), polyvinylfluoride (PVF), or polyvinylidenefluoride (PVDF). Especially preferred is TFE.
We have found that when a fluorcarbon polymer is used as the inner tubing member, it is useful to etch the outside surface of the member to provide a good surface to which the adjacent polymers will adhere. Certain procedures using, for instance, aliphatic hydrocarbons and powdered sodium metal or powdered sodium metal and anhydrous ammonia or sodium metal in naphthalene/tetrahydrofuran or commercial etchants such as TETRA-ETCH sold by Gore & Associates as the etching solution are known to be effective in such service.
Another useful class of polymers are thermoplastic elastomers, including those containing polyesters as components. Typical of this class is HYTREL. Additionally, an adhesive may be coated onto the outer surface of the inner liner tubing. Polyesters and polyimides, in particular, are suitable as adhesives.
An outer covering of polyethylene or of EVA or their mixtures, copolymers, etc. are excellent choices for the outer covering member. The polymer to be used as the outer covering is typically extruded into a tubing of appropriate size and thickness and then cross-linked to raise the melt temperature of the resulting tubing. The tubing is then inflated and perhaps stretched to give the included polymer a specific molecular orientation. The tubing, so treated, may then be slipped over the combination of inner liner (204) and braid (206) and heat shrunk into place.
A variety of other polymers may be used, depending upon the use to which the catheter section is placed. For instance, if the section (200) is used as a proximal section, the outer tubing may be a polyimide, polyamides (such as the Nylons), high density polyethylene (HDPE), polypropylene, polyvinylchloride, various fluorocarbon polymers (for instance: PTFE, FEP, vinylidene fluoride, their mixtures, alloys, copolymers, block copolymers, etc.), polysulfones, or the like. Blends, alloys, mixtures, copolymers and block copolymers of these materials are also suitable if desired.
If a more flexible section is required, the outer tubing member (202) may also be of a member selected from a more flexible material such as polyurethanes, low density polyethylene (LDPE), polyvinylchloride, THV, etc. and other polymers of suitable softness or a modulus of elasticity. For the most-preferred variation of this invention, polyurethanes are desirable.
FIG. 2 shows the results of a heat-shrinking the outer tubing member (202) onto the assembly of inner liner tube (204) and braid (206). Contact regions between the outer covering member (202) and inner liner member (204) are shown in the interstices between the open weave of the braid (206). Although the open area between turns of the braid is not absolutely necessary as a means of allowing contact between the inner liner (204) and the outer covering (202), such is quite desirable. Furthermore, when the outer covering member (202) is placed on the outer surface of the catheter section (200) by dipping the inner assembly of braid (206) and inner member (204) into a molten or latex liquid, the contact is inevitable.
We have found that when using polyurethane as either the outer covering member (202) per se or as an inner portion of the outer covering member (202) (e.g., beneath a polyethylene layer), a suitable method for applying the polyurethane to the braid entails placement of a polyurethane tubing over the braid, placement of a polyethylene "shrink-wrappable" tubing over the polyurethane tubing, and heating the combination to pull the polyurethane down to the braid surface using the polyethylene tubing as the mover. The polyethylene may be removed or left in place.
The wall thickness of the outer tubing member (202) may be as thin as 0.5 mils. and as thick as 10 mils., depending upon catheter usage, section of the catheter chosen, polymer choice, and style of catheter.
Typically, a wall thickness of the inner liner (204) will be between 0.5 and 3.0 mils. These dimensions are obviously only ranges and each catheter variation must be carefully designed for the specific purpose to which it is placed.
Each of the polymers noted herein may be used in conjunction with radio-opaque filler materials such as barium sulfate, bismuth trioxide, bismuth carbonate, powdered tungsten, powdered tantalum, or the like so that the location of various portions of the catheter sections may be radiographically visualized within the human body.
As will be discussed below, it is within the scope of this invention to have multiple polymeric layers exterior of the braid (206) as well as multiple polymeric liner members interior to braid (206). Furthermore, it is within the scope of the invention to include multiple braids and/or flat ribbon coils between or amongst the various polymeric layers.
It is also within the scope of this invention to coat at least one of the exterior surface of outer member (202) and the inner surface of inner liner (204) with a lubricious layer, which either is chemically bonded to the layer or is physically coated on the relevant surface. A description of suitable procedures for producing such lubricious coatings is found at U.S. patent application Nos. 08/060,401 ("LUBRICIOUS CATHETERS"), filed May 12, 1993; 08/235,840 (METHOD FOR PRODUCING LUBRICIOUS CATHETERS"), filed Apr. 29, 1995; and 08/272,209 ("LUBRICIOUS FLOW DIRECTED CATHETER"), filed Jul. 8, 1994, the entirety of which are incorporated by notice.
The metallic braid (206) shown in FIG. 2 is made up of a number of metallic ribbons. A majority of the metallic ribbons in braid (206) are of a member of a class of alloys known as super-elastic alloys.
Preferred super-elastic alloys include the class of titanium/nickel materials known as nitinol--alloys discovered by the U.S. Navy Ordnance Laboratory. These materials are discussed at length in U.S. Pat. Nos. 3,174,851 to Buehler et al., 3,351,463 to Rozner et al., and 3,753,700 to Harrison et al. Commercial alloys containing up to about 5% or up to about 8% or more, of one or more other members of the iron group, e.g., Fe, Cr, Co, are considered to be encompassed within the class of super-elastic Ni/Ti alloys suitable for this service. Most preferred are alloys containing 1.5-2.5% Cr and having a transition temperature of less than 0° C.
When using a super-elastic alloy, an additional step may be desirable to preserve the shape of the stiffening braid. For instance, with a Cr-containing Ni/Ti super-elastic alloy which has been rolled into a 1×4 mil ribbon and formed into a 16-member braid, some heat treatment is desirable. Braids which are not treated in this way may unravel during subsequent handling or may undertake changes in diameter or braid member spacing during that handling. In any event, the braid is placed onto a mandrel, usually metallic, of an appropriate size. The braid is then heated to a temperature of 650 °-750° F. for a few minutes, possibly (but not necessarily) annealing the constituent ribbon. After heat treatment, the braid retains its shape and the alloy retains its super-elastic properties.
Metallic ribbons (202 and 206) that are suitable for use in this invention are desirably between 0.25 mil and 3.5 mil in thickness and 2.5 mil and 12.0 mil in width. By the term "ribbon", we intend to include elongated shapes, the cross-section of which are not square or round and may typically be rectangular, oval or semi-oval. They should have an aspect ratio of at least 0.5 (thickness/width). In any event, for super-elastic alloys, particularly nitinol, the thickness and width may be at the lower end of the range, e.g., down to 0.30 mil and 1.0 mil, respectively. Currently available ribbons include sizes of 0.75 mil×4mil, 1 mil×3 mil, 1 mil×4 mil, 2 mil×6 mil, and 2 mil×8 mil.
The ribbons making up the braid (206) shown in FIG. 2 may also contain a minor amount of non-super-elastic alloy materials. Although metallic ribbons are preferred as the ancillary materials because of their strength-to-weight ratios, fibrous materials (both synthetic and natural) may also be used. Preferred, because of cost, strength, and ready availability are stainless steels (SS304, SS306, SS308, SS316, SS318, etc.) and tungsten alloys. In certain applications, particularly smaller diameter catheter sections, more malleable metals and alloys, e.g., gold, platinum, palladium, rhodium, etc. may be used. A platinum alloy with a few percent of tungsten is preferred partially because of its radio-opacity.
Suitable non-metallic ribbons include high performance materials such as those made of polyaramids (e.g., KEVLAR) and carbon fibers.
The braids utilized in this invention may be made using commercially available tubular braiders. The term "braid" is meant to include tubular constructions in which the ribbons making up the construction are woven radially in an in-and-out fashion as they cross to form a tubular member defining a single lumen. The braids may be made up of a suitable number of ribbons, typically six or more. Ease of production on a commercial braider typically results in braids having eight or sixteen ribbons.
The braid shown in FIG. 2 has a nominal pitch angle of 45°. Clearly the invention is not so limited. Other braid angles from 20° to 60° are also suitable. An important variation of this invention is the ability to vary the pitch angle of the braid either at the time the braid is woven or at the time the braid is included in the catheter section or sections.
FIG. 3 shows a variation of a braid-augmented catheter section in which the braid (206) is used in a catheter section (208) having two portions of different diameter. The larger diameter portion (210) utilizes the braid with a nominal braid angle of 45 degrees and a smaller diameter portion (212) in which the same braid has a braid angle of 30 degrees. This diminution in catheter diameter may be accomplished in a number of different ways. For instance, inner liner (214) may be sized with two different diameters in the respected different portions (210 and 212) of the catheter section. The braid (206) may then be stretched axially as it is placed upon that liner. When the outer covering (216) is placed on the braid (206), the braid (206) will retain its multi-diameter configuration. This variation has the benefit of being quite simple in construction and yet provides a variety of different flexibilities to the catheter section without a significant change in the materials of construction.
FIG. 4 shows a variation of a catheter section (201) having a tapered section (203). The braid (205) changes its pitch from one end of the tapered section (203) to the other. Judicious choice of polymers allows a smooth transition from the larger adjacent section (207) to the smaller (typically) more distal section (209). The transition section (203) found in FIG. 4 is especially useful in catheters which are used to incorporate high flows of liquid material when the catheter is used for treatment or diagnosis. The smooth transition allows the catheter to be used with ease due to the lower friction through the joint.
The variations shown above have each shown a single-ribbon wind. Single-ribbon winds permit the braid to contain the maximum amount of open area between ribbons in the braid. However, the various catheter sections need not be made with a single ribbon wind.
The invention described herein is intended to encompass multiple-wind braids. That is to say that a plurality of ribbons are placed side-by-side and woven together as shown with the the single ribbon weave above. However, some of the benefits of the invention may be diminished as the density of the ribbons in the catheter section is increased. That is to say that the stiffness of the catheter section substantially increases as the number of ribbons used in a multiple-ribbon weave is increased. The catheter sections shown in the Figures may be combined in a variety of manners to produce a composite catheter assembly. As mentioned above, the typical vascular catheter is made up of a number of sections, typically each more flexible than the section more proximal.
FIGS. 5-7 show various ways to use braided catheter sections in producing a catheter with sections of differing stiffness.
FIG. 5 shows another variation of a catheter assembly made using multiple layers of braided sections. This catheter assembly (240) uses a proximal section (242) made up of a number of layers but including an inner braid (244) and an outer braid (246). The inner braid (244) also extends down into and extends through the length of midsection (248). In this variation, the inner liner member (250) coextends, is coaxial with, and is internal to the inner braid (244). A middle layer of a polymeric tubing (254) extends from the proximal end of the catheter distally. A further outer covering (256) covers braid (246).
Designs such as shown in FIG. 5 is one of exceptional stiffness in the proximal section (242). Although not critical for most neurological applications, such a catheter design has exceptional torque transmission. Such a catheter design may be desirable where a catheter is used for coronary or peripheral access.
A catheter design desirable for peripheral or coronary access is shown in FIG. 6. In this variation, catheter assembly (260) includes a tubing liner (262) which extends throughout the complete catheter assembly (260) from proximal section (264) through midsection (266) to distal section (268). More importantly, the braid (270) also coextends the length of inner liner (262). Differences in flexibility for the respective sections are provided by the use of polymeric tubing members (272) for the proximal section (264) and midsection tubing member (274) for the catheter assembly midsection (266). Various orifices (269) are shown in the distal end section (268) and will be discussed further below. The absence of additional polymeric members other than the outer polymeric covering (276) renders distal section (268) the most flexible.
FIG. 7 shows a preferred variation of the invention in which the braided member (275) is surrounded by an inner polyurethane layer (277) and an upper polyurethane layer (279). The innermost layer (281) is a tubular member comprised of a polyfluorocarbon such as PTFE which preferably has been etched (as discussed above) so to provide a good bond with the adjacent polyurethane layer. The outermost layer (283) is also made of a polyurethane. The distal section contains a number of orifices (269). The section (285) also is shown with a radio-opaque band (287) in the distal end. In such a variation, the various polyurethanes vary in hardness according to their position on the section. For instance, the outermost layer (283) and the upper layer (279) might be one having a Shore 75A-85A hardness; the inner layer (277) might be a Shore 55D polyurethane or the like. Various spacers and adhesives have been omitted from the depiction of the variations to simplify those drawings.
The braid-augmented catheter sections may be used in conjunction with other catheter portions which are more proximal to the individual sections discussed above. FIG. 8, for instance, depicts, in partial cross section, a typical joint as might be found between a more-proximal section comprising metallic tubing (e.g., "hypotube") and a braided more-distal section. In this instance, the more distal-section of the invention is adjacent the more-proximal catheter section of the invention. In particular, the braid (408) in the more-distal section (400) is soldered or welded or otherwise attached (406) to the more-proximal segment (402). Orifices (269) are shown in the distal section. An outer covering (404) such as has been discussed above may be applied to the outer surface of both the moredistal section (400) and the more-proximal segment (402). The outer covering (404) may be a material of suitable flexibility and compatibility such as a polyurethane or low density polyethylene and obviously may be covered or coated with a lubricious polymeric material such as a hydrophilic polymer material, e.g., one containing polyvinylpyrrolidone. The more-distal catheter section (400), as well as the stiffer more-proximal section, may include a lubricious inner layer (not shown), e.g., a Teflon or similar, as has been discussed above.
FIG. 9 depicts in partial cross-section another variation of the invention in which a more-distal segment (430) is attached to the more-proximal segment (432) via a conical or scarf joint (434). In this variation the depicted sections have a common lubricious inner layer (436), e.g., a Teflon or similar, as has been discussed above. This inner layer (436) is optional and need not be found in each such segment. Nevertheless, the inner layer provides for a number of benefits: it may form the cover for a mandrel upon which the adjacent layer (438) and then upon which the braid (408) may be wound or braided. As noted, the inner layer may be omitted, particularly in the more proximal region (432) since the majority of materials which are suitable for the more proximal section are very "hard" and suitably slippery for passage of guidewires and the like. The more-proximal section (432) may be a simple tubular member comprising unfilled, filled, or fiber-reinforced, tough, polymeric materials preferably having high flexural moduli. Examples generically include polyamides (Nylons 6, 66, 69, 610, 612, 46, 11, and aromatic polyamides such as supplied by DuPont, Huls, etc.), polyamide-polyimides (such as those supplied by Amoco Performance Products), polyimides (both thermoset and thermoplastic), polycarbonates, LCP's, acetals (such as Delrin), and (preferably) stiffer polyolefins such as polypropylene or high density polyethylene, etc.
To integrate the more proximal region (432) of the catheter assembly with materials found in adjacent regions, the choice of materials for the proximal section is desirably a polyamide which is melt-miscible with a polymeric component found in the next more distal segment. In this preferred instance, the more distal region (430) may(for instance) have a covering (440) of polyurethane, a block copolymer of a polyether and a polyamide (e.g., a PEBAX), or a low durometer Nylon. Such polymers are melt miscible with the Nylon of the more distal section (432). The outer covering (440) and the more distal section (432) may be covered or coated with a lubricious polymeric material such as a hydrophilic polymer material. It is also highly desirable to choose a translucent or transparent polymer for this section to assist the physician in use of the catheter assembly.
FIG. 10 shows in partial impartial cross-section of highly desirable variation of a catheter (500) made according to this invention. The catheter section (500) shown in FIG. 10 (along with FIGS. 11, 12, and 13) are typically used as a distal-most section of a catheter assembly as discussed above. FIG. 10 shows the relationship of a number of orifices (502) as they pass through the outer polymeric layer (504) through braid (506) and finally through interpolymeric layer (508). In particular, it should be noted that the ribbons of braid (506) are wound with sufficient space between them that the orifices (502) may be placed in the interstices between coil ribbon turns. The various orifices (502) shown in FIG. 10 are depicted as having generally the same diameter and are a straight line. The invention is not so limited however. Other combinations of orifice size and configuration are acceptable and in some cases are desirable. As has been noted above, these orifices (502) are used to allow passage of therapeutic and diagnostic fluids from the interior lumen of the catheter section into the region outside the catheter section. In many catheters having distally placed orifices such as are found here, there is a tendency to kink using the orifices as the center of those kinking regions. In the structure such as is shown in FIG. 10, the braid (506) significantly lessens the tendency of the catheter section (500) to kink in any way and particularly lessen the problem of kinking around the orifices (502).
FIG. 11 shows an outside view of a catheter distal tip (510) and depicts two desirable features of such distal tips made according to the invention. In particular, it shows the use of a proximal radio-opaque band (512) and a distal radio-opaque band (514). Use of such bands bracketing the region in which the various orifices (516) is found allows the tending physician to more specifically place the region in the desired treatment or diagnostic site.
Further, the series of orifices 516 shown in catheter section (510) is depicted in sizes which are not the same. This, as noted above, is a feature of this invention which may be used in a variety ways. The depiction shown in FIG. 11, the diameter of the orifice (516) which is most distal has the largest diameter. The smallest diameter orifice is most proximal. In this way, fluids which are introduced through the lumen of the catheter section (510) is distributed into the region to be treated in a fashion which is more even than would be the case with orifices (502) shown in FIG. 10. This is a problem in ordinary hydrodynamics easily solved by one of ordinary skill in the flow art.
FIG. 12 also depicts a variation of the inventive section having two features of significance to the invention. In this instance, only a single radio-opaque bank (518) is shown in catheter section (520). In this instance, the various orifices (522) are found in a variety of sizes and are arranged in a generally spiral fashion about the exterior of the catheter section surface (520). This allows placement of the fluid within the catheter in a spray pattern generally surrounding the exterior of catheter section (520).
FIG. 13 shows, in combination, catheter section (530) in combination with a guidewire assembly (532) having a valving region (534). Guidewire assembly (532) is also shown with a leading coil (536) which may be radio-opaque and may be formable by the user. A number of orifices (536) are also shown in the wall of the catheter. The valving section (534) of guidewire assembly (532) is used in such a way that it may allow exit of fluids from the interior lumen of catheter section (530) in selected regions through a number of the orifices (536). In this way, the guidewire assembly (532) is simply used as a controlling device to further enhance control of the fluid flow of therapeutic or diagnostic materials into the selected body opening or site.
This invention has been described and specific examples of the invention have portrayed. The use of those specifics is not intended to limit the invention in any way. Additionally, to the extent that there are variations of the invention which are within the spirit of the disclosure and yet are equivalent to the inventions found in the claims, it is our intent that those claims cover those variations as well.
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This is a catheter section having a number of radially placed holes through the catheter section wall and a catheter assembly including that section. That catheter assembly may be used in accessing and treating a tissue target within the body, typically one which is accessible through the vascular system. Central to the catheter section is the presence of a braided metallic reinforcing member, typically of super-elastic alloy ribbon, situated in such a way to provide an exceptionally thin wall, controlled stiffness, high resistance to kinking, and complete recovery in vivo from kinking situations. The orifices in the section are optimally placed in the interstices between the turns of the braid. The braid may have a single pitch or may vary in pitch along the axis of the catheter or catheter section. The braided ribbon reinforcing member typically is placed between a flexible outer tubing member and an inner tubing member to produce a catheter section which is very flexible but highly kink resistant. The catheter sections made according to this invention may be used alone or in conjunction with other catheter sections either made using the concepts shown herein or made in other ways. The more proximal sections of the catheter assembly are often substantially stiffer than the more distal sections due to the presence of stiff polymeric tubing or metallic tubing or composited materials in the stiffer section.
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BACKGROUND OF THE INVENTION
This invention relates to a meat chopper which cuts edible live-stock such as cattle, porker, sheep, etc. into halves along its backbone. In particular, it belongs in a type of the choppers which provide automatic repetitive operation for longitudinal chopping of meat and bones.
As means of vertically chopping edible live-stock along its backbone by inversely suspending the carcass, a chopping method and sawing method have been well known. In the former case, however, the bone chips tend to become embedded in the meat, rendering it unpleasant for eating, and in the case of reciprocating sawing method the carcase to be cut tends to move or swing thus causing reduced cutting efficiency. Furthermore, the use of the chain-saw, which is still the most popular system today, must be avoided because it has been revealed that Raynaud's disease can occur in chain saw operators. On the other hand, the conventional hand chopper method is poor in its working efficiency, being unsuitable for mass production although it is free from the various disadvantages described in the abovementioned sawing method. From the massproduction point of view, the chain saw system, with its processing capacity of 20-30 head per hour, has been the best.
The primary purpose of this invention is to create and provide a vertical meat chopper having a high speed mass processing capacity of 200-300 head per hour, i.e. about ten times as much as that of conventional type chopper, achieved as a result of the newly introduced system wherein the inductive operating mechanism permits speedy, accurate, smooth and easy positioning for cutting, whilst correction of cutting direction is provided in addition to the automatic chopping system, completely overcoming the deficiencies of the sawing system.
The secondary purpose of this invention is to create and provide a vertical meat chopper bringing about an improvement in safety and working efficiency, by providing a control mechanism for the lowering operation, with the object of preventing danger in the event of a quick and extensive lowering of the automatic chopping system, when the reaction to the chopping force is suddenly lost during the cutting operation or during meat delivery or shut-down period of the chopper, etc.
SUMMARY OF THE INVENTION
A vertical meat chopper consisting of:
(a) a mechanism allowing a speedy and smooth inductive operation in XYZ directions with a guide post vertically erected on the floor as its datum axis;
(b) a chopper casing provided on the fore end of the thrust shaft which is supported by said mechanism and is freely movable forewards and backwards;
(c) wedge projections provided on both sides of said casing;
(d) a means whereby one end of the chopper is pivoted by said casing and the other end is left free;
(e) a blade provided along the lower edge of said chopper;
(f) a pair of stanchions both projected downward from each side of said casing, which provide the means of positioning, space retaining and guiding for swing-down operation of said chopper; and
(g) an automatic driving means to reciprocate said chopper in vertical direction.
In addition, a mechanism controlling accidental drop of the chopper is provided by attaching a rack and pinion mechanism, ratchet mechanism and an engaging and disengaging means for the ratchet, to said mechanisms.
BRIEF DESCRIPTION OF THE DRAWINGS
The drawings show an embodiment of this invention:
FIG. 1 is a perspective view mainly showing left side.
FIG. 2 is a horizontal sectional plan view taken along line 2--2 in FIG. 1.
FIG. 3 is a vertical sectional left side view taken along line 3--3 in FIG. 2.
FIG. 4 is a vertical sectional left side view taken along line 4--4 in FIG. 2.
FIG. 5 is a perspective view showing an example of the chopper claimed in this invention.
FIG. 6 is a vertical sectional left side view same as FIG. 3, showing another embodiment of the chopper driving mechanism.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The invention will be more fully understood from the following description of preffered embodiments taken in conjunction with the attached drawings.
An inductive operating mechanism in three directions, axes X, Y and Z shall be first explained.
A guide post 7 made of such as H-shape steel is fixed perpendicularly on a floor 8 with the required height. On the other hand, pins 10, 10a, 10b and 10c are respectively projected on the same side plane from four corners of a base plate 9 and furthermore, each of said pins is fitted with four pieces of grooved guide rollers 11, 11a, 11b and 11c, two pieces each on its top and bottom in such a way as to allow free rotation. Said base plate 9 is installed in the vertical direction in such a way that it is able to move freely and that both ends of a vertical plate 7a on one side of said guide post 7 made of H-shape steel is held from outside by each groove of said four rollers. From the other side of said base plate 9, guide shafts 12 and 12a are projected in parallel with each other with the required space in the horizontal direction and with equal height and length. A bearing 13, having sufficient length for installation, is provided between said pair of guide shafts. From both ends of said bearing, a pair of brackets 14 and 14a are projected upward and are loose-fitted on said guide shafts 12 and 12a respectively so that each bracket is able to slide to the left and right along each guide shaft. Numeral 15 is a stopper fixed between the fore ends of said guide shafts. Being securely suspended from guide shafts 12 and 12a in left and right direction by a pair of brackets 14 and 14a, said long bearing 13 extends in the back and forth direction, thus supporting long thrust shaft 16 and allowing free sliding and movement thereof in the back and forth direction. It is desirable to design said thrust shaft 16 so that it is capable of some angular movement in circumferential direction, so that it is able to follow the direction of a carcass suspended out of line, and to cut the carcase in a slightly oblique and downward direction. On one end of the thrust shaft 16, a control box 17 with "two hand action handle" is fixed and, on the other end, a chopper casing 18 is fixed. Said base plate 9 and a weight 19 suspended on the other side of said guide post 7 (see FIG. 2) are connected through a pair of sheaves 21 and 21a installed on the top of guide post 7 with a wire 20, whereby the total weight loaded on said base plate is counter-balanced by said weight. Numeral 22 is a connecting pin for the end of said wire projected from the base plate 9.
Secondly, an automatic chopping mechanism shall be explained as follows:
As aforementioned, the chopper casing 18 is fixed to the other end of the thrust shaft 16, and wedge projections 23 and 23a are respectively provided on both sides of said casing 18 to push open chopped meat in left and right direction. Since a chopper 24 is projected downward from the lower edge of the casing 18, one end of it being pivoted to the casing 18 with a supporting shaft 25, said chopper can be installed in such a way that its free end can make an angular swing around supporting shaft 25 in vertical direction. A blade 24a is provided at the lower end of the chopper 24. It is more desirable to make said lower end of the chopper 24 obtuse by bending it obliquely upward in direction from a swing-down center 24b to its fore end as shown in FIGS. 3 and 6, than to make it straight, because cutting operation can proceed, with the recommended obtuse shape, under such conditions where the center of the object to be chopped is cut open deeper than the surrounding part, consequently preventing the object from being moved by repetitive swing-down pressure of the chopper 24. Thus, the object can be held steady, allowing an easy and fast chopping operation. On the other hand, the pair of stanchions 26 and 26a are respectively suspended from both sides of the casing 18 and fixed, whereby positioning for the swing-down operation of the chopper 24, maintenance of swing-down space and guiding of blade are controlled. Reciprocating movement in vertical swing-down operation of the chopper 24 is obtained by a means in which the lower end of a piston rod 29 for an air cylinder 28 is pivoted by the upper end of a link 27 pivoted to the middle part of the chopper and an air press-in change-over valve (not shown in drawings) for ports 30 and 31 provided on the top and bottom ends of said air cylinder 28 is repeatedly operated, for instance, with a twin timer 32 installed in the control box 17. Shifting control of the change-over valve may also be carried out by ON/OFF operation of a solenoid (not shown in drawings). Numeral 33 is a push-button switch for change-over operation provided in the control box 17.
The following is another example of the chopper driving system, explained with reference to FIG. 6:
The upper end of the link 27 is pivoted to the fore end of a crank arm 34, and a worm wheel 36 is provided on a crank shaft 35. On the other hand, a driving gear 38 on the driving shaft of a motor 37 is engaged with a driven gear 40 on worm shaft 39. After sufficiently reducing the revolutions of said motor 37 with worm mechanism by engaging a worm 41 fixed on said worm shaft 39 with said worm wheel 36, said rotating motion is changed to reciprocating movement by a crank mechanism to give vertical reciprocal motion to the chopper 24. Numeral 42 is an electric power supply cable for driving the motor. It is desirable to run said cable to the control box 17 through the hollow portion in said thrust shaft 16 to facilitate the control operation.
The system claimed in this invention allows sufficiently speedly and reliable processing of meat chopping by employing the related operation of said automatic chopping mechanism and said inductive mechanism. It is, however, desirable that the operation should always be safe and free of accident risk, and this should always be borne out in actual operation. This can be realized by constructing said automatic chopping mechanism in such a way that the movement of said mechanism allows free upward movement along the guide post 7, while the lowering movement is controlled by quick brake action whenever required, in its downward movement.
Detailed below is an example of such construction:
A rotatable shaft 43 is installed through said base plate 9 with its one end fixed to a pinion 44 and other end fixed to a ratchet wheel 45. A rack 46 is fixed along said guide post 7 in vertical direction and engaged with said pinion 44 and on the other hand, a pin 47 is projected from said base plate and a ratchet 48 is fitted, being supported by said pin. Said ratchet 48 and said ratchet wheel 45 are then engaged with each other so that said base plate 9 is disengaged in the lifting movement and locked in the lowering movement as shown in FIG. 4. The ratchet 48 is always under pressure towards the engaging direction by a coiled spring 49 wound around the pin 47 and, at the same time, its construction is such as to artificially engage ordisengage the ratchet only in the case where a jaw 51 of a control lever 50, the fore end of which is pivoted by said pin 47, actuates in such a direction as to push a jaw 52 provided on the base end of said ratchet 48. Therefore, a solenoid 53 is provided and the other end of said control lever 50 is pivoted by the fore end of a displacement rod 54 operated by said solenoid. A wiring circuit is laid out in such a way that ON/OFF control of said solenoid 53 can be remote-controlled by a push-button switch 55 installed in said control box 17.
Function of the system claimed in this invention is as follows:
The control lever 50 connected to the rod 54 comes to the position shown by full-line in FIG. 4 since solenoid 53 is disenergized when the push-button switch 55 is kept open. The ratchet 48 is constantly in engagement with the ratchet wheel 45, being actuated by the coiled spring 49. Because of said ratchet engagement, the pinion 44 located on the same axis as said ratchet wheel 45 is freely rotatable against the rack 46 in the lifting direction but lowering is prevented. Therefore, it is possible to bring the main unit of the system to the unused position by pushing up the same to the top of the guide post 7, or the main unit can be pushed up to the top of the guide post 7, as in the above case, when the process is transferred from the preceding chopping process to the delivery of the meat to be subsequently processed. In case of the latter, a chopped object 58 is delivered into working position by a hanger which is transported by a conveyor as shown in FIG. 5. It is, therefore, necessary to move the chopper casing 18 fixed on the fore end of the thrust shaft 16 toward bearing 13 by fully pulling the control handle toward the operator in order to prevent the chopper casing from blocking the delivery route.
After the object 58 is correctly positioned and held steady, casing 18 shall be inserted between the hind legs of inversely suspended the object 58 by pushing the control handle foreward. Then, the solenoid 53 shall be energized by turning OFF the push-button switch 55, the rod 54 shall be drawn in and the ratchet 48 shall be disengaged from the ratchet wheel 45 by pressing the jaw 52 of the ratchet 48 with the jaw 51 of the control lever 50. As a result of the above operation, the restriction on one way rotation of the pinion 44 is removed, allowing the descent of the chopper casing 18. Thus, a pair of the stanchions 26 and 26a projected downward from said casing come in contact with the root of the hind legs to stop the lowering.
Then, said stanchions 26 and 26a shall be adjusted and placed on the coccyx of the object by again operating the control handle.
When other push-button switch 33 is turned OFF after completion of the abovementioned adjustment, the twin timer 31 actuates to alternately force in air to the ports 30 and 31 of the air cylinder 28, allowing the piston rod 29 to perform its reciprocating movement in the vertical direction, the movement being transmitted to the chopper 24 through the link 27.
Since a part 24b of the blade 24 at the position of said stanchions 26 and 26a is projected extremely downward as the center of swing-down operation, the chopper 24 is correctly swung down onto the coccyx positioned with correct, continuous and repetitive movement. Consequently, the coccyx is definitely broken by the chopper and the meat around the coccyx is cut open by the other parts of the chopper blade.
The object to be chopped does not receive any impact force deviating in a forward or backward direction when the chopper 24 is swung down, because the blade of the chopper 24 has an obtuse angle shape longitudinally rising with the same inclination from the swing-down center 24b. Therefore, chopping operation can always be carried out with the object held stationary, so that it does not slide forward or backward.
When the chopping direction is seen to be deviating to the left or right due to some failure, the push-button switch 55 shall immediately pressed to de-energize the solenoid 53 so that the ratchet wheel 45 is engaged with the ratchet 48, thus stopping the lowering of the chopper 24 and holding the same at the height it had reached. Then, the chopping direction shall be corrected by operating control handle to obtain normal alignment.
The reaction force caused by the impact produced when the chopper 24 is swung down onto the object 58, is transmitted to the base plate 9 at a moment centered on the guide shafts 12 and 12a. The base plate 9 is fitted to the guide plate 7, being supported by the guide rollers 10, 10a, 10b and 10c which are spaced vertically. Therefore, said the reaction force does not hinder the lowering operation because it does not act to lift or raise said base plate 9.
It is also possible to correct chopping direction or prevent troubles in lowering operation by handle operation alone without the ratchet mechanism, if operator is skilled. In such a case, a device to lock the base plate 9 at the extreme-top end of the guide post 7 (not shown in drawings) would be sufficient.
The automatic chopping mechanism with chopper system which is free from the defects inherent in the sawing system, and the inductive operating mechanism which freely operates thereof, being coupled together, the system claimed in this invention allows a speedy, reliable, smooth and easy meat chopping operation in addition to a close operating capability: For example, it allows processing of a remarkably large quantity of meat, e.g. about ten times as much as that processable by conventional systems. Furthermore, the lowering control device of automatic chopping mechanism employed in the system which guarantees working safety, increases the working efficiency to a much greater extent, affording the meat processing business an immense advantage.
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There is a mechanism allowing a speedy and smooth inductive operation in XYZ directions with a guide post erected on a floor.
A chopper casing is provided on the fore end of a thrust shaft being supported by said mechanism and being freely movable forewards and backwards. Wedge projections are provided on both sides of the casing. A pair of stanchions both project downward from each side of the chopper for positioning, space retaining and guiding for swing-down operation of a chopper.
One end of the chopper is pivoted to the casing, other end thereof is left free and along the lower edge thereof provides a blade which reciprocates in vertical direction by an automatic driving means.
A mechanism controlling accidental drop of the chopper is provided by attaching a rack and pinion, a ratchet and ratchet wheel.
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BACKGROUND OF THE INVENTION
Cholecystokinin (CCK) is a neuropeptide with a widespread distribution in brain. CCK receptors are classified into two types; CCK A and CCK B , both of which are present in brain (Woodruff, G. N. and Hughes, J., 1991, Ann. Rev. Pharmacol. 31, 469-501).
Devazepide is a selective antagonist of CCK A receptors. The chemical name and structure of devazepide are:
1H-indole-2-carboxamide, N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-, or (L 364718) and ##STR1##
L-365,260 is a selective antagonist of CCK B receptors. The chemical name and structure of L-365,260 is (R)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-methylphenyl)urea and ##STR2##
Other CCK antagonists are lorglumide and loxiglumide. Lorglumide is DL-4-(3,4-dichlorobenzoylamino)-5-(dipentylamino)-5-oxopentanoic acid and loxiglumide is (±)-4-[(3,4-dichlorobenzoyl)amino]-5-[(3-methoxyproxyl)pentylamino]-5-oxo-pentanoic acid.
These CCK A and CCK B antagonists are described in U.S. Pat. No. 4,791,215 and U.S. Pat. No. 4,820,834. These documents are hereby incorporated by reference.
The above patents cover compounds of the instant invention, methods for preparing them, and several uses thereof.
The uses disclosed are gastric acid secretion disorders, gastrointestinal motility, pancreatic secretions, dopaminergic functions, analgesics, psychic disturbances, anorexia, weight increases in farm animals, and pathological cellular growth such as tumors.
Other CCK antagonists include compounds (J. Med. Chem. 1991, 34, 1505-8) of formula ##STR3## or a pharmaceutically acceptable salt thereof wherein
X o is hydrogen, fluorine, chlorine, methoxy, or trifluoromethyl;
X m is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, propoxy, trifluoromethyl, cyclopentyloxy, MeS, or NMe 2 ;
X P is hydrogen, fluorine, chlorine, bromine, methoxy, or X m and X p together form --OCH 2 O--;
Y is hydrogen, fluorine, bromine, chlorine, or methoxy; and
R is hydrogen or methyl.
These CCK-B receptor ligands are also useful as agents in the treatment of depression.
Other compounds (presented at the 23rd Central 24th Great Lakes Joint Regional American Chemical Society Meeting; Abstract No. 306) useful in treating depression are those of formula ##STR4## or a pharmaceutically acceptable salt thereof,
wherein R is 2,3-dichloro, hydrogen, 4-trifluoromethyl, 4-chloro, 4-bromo, 4-methyl, 4-ethyl, 4-isopropyl, 4-methoxy, 4-OCH 2 Ph, 3-trifluoromethyl, 3-methyl, 3-methoxy, 3-trifluoromethyl, 4-chloro, 3,4-dichloro, 3,4-(CH 2 ) 3 , 3,4-(CH 2 ) 4 , 2-trifluoromethyl;
R 2 is hydrogen or methyl; and
R 3 is hydrogen or methyl.
Other compounds useful for treating depression are those of formula ##STR5## or a pharmaceutically acceptable salt thereof wherein R 4 is 3-pyridyl, 4-pyridyl, 1-naphthyl, 2-naphthyl, 3-quinolinyl, 6-quinolinyl, n-Bu, c-hexyl, CH 2 Ph, CH 2 Ph-3,4-diCl, (CH 2 ) 2 Ph, (CH 2 ) 2 Ph-2-Cl, or (CH 2 ) 3 Ph.
Other compounds useful for treating depression are those of formula ##STR6## or a pharmaceutically acceptable salt thereof wherein
R 1 is 4-trifluoromethyl or 4-bromo;
R 2 is hydrogen, 2-chloro, 3-cyano, 3-methoxy, 4-N(Me) 2 , 2-methoxy, 2,3-dichloro, 3-CONH 2 , 4-NO 2 ;
R 3 is hydrogen, 2-chloro, 3-chloro, 4-chloro, 3-methoxy, or 4-methoxy.
Especially useful are compounds of formula IV wherein R 1 is 4-CF 3 , R 2 is 2-Cl, and R 3 is hydrogen and wherein R 1 is 4-Br, R 2 is 2-Cl, and R 3 is 2-Cl.
Other compounds useful in treating depression are those of formula ##STR7## or a pharmaceutically acceptable salt thereof wherein
R 1 is 4-bromo or 4-trifluoromethyl;
R 2 is phenyl, 3-pyridyl, or n-butyl; and
R 3 is 1-naphthyl, phenyl, or n-butyl.
Other compounds useful in treating depression are those of formula ##STR8## or a pharmaceutically acceptable salt thereof wherein
X is absent, CH 2 , oxygen, or sulfur, and R is trifluoromethyl, bromine, or chlorine.
Other compound useful are selected from: ##STR9## or a pharmaceutically acceptable salt thereof.
Especially useful as agents for depression are CCK antagonists
1-pyrazolidinecarboxamide, N-(4-bromophenyl)-3-oxo-4,5-diphenyl-, trans-,
1-pyrazolidinecarboxamide, 5-(2-chlorophenyl)-3-oxo-4-phenyl-N-[4-trifluoromethyl)phenyl]-, trans-, and
1-pyrazolidinecarboxamide, N-(4-bromophenyl)-5-(2-chlorophenyl)-3-oxo-4-phenyl-, trans-.
The above references do not disclose the use of CCK antagonists for treating depression.
Depression can be the result of organic disease, secondary to stress associated with personal loss, or idiopathic in origin. There is a strong tendency for familial occurrence of some forms of depression suggesting a mechanistic cause for at least some forms of depression. The diagnosis of depression is made primarily by quantification of alterations in patients' mood. These evaluations of mood are generally performed by a physician or quantified by a neuropsychologist using validated rating scales such as the Hamilton Depression Rating Scale or the Brief Psychiatric Rating Scale. Numerous other scales have been developed to quantify and measure the degree of mood alterations in patients with depression, such as insomnia, difficulty with concentration, lack of energy, feelings of worthlessness, and guilt. The standards for diagnosis of depression as well as all psychiatric diagnoses are collected in the diagnostic and Statistical Manual of Mental Disorders (Third Edition Revised) referred to as the DSM-III-R manual published by the American Psychiatric Association, 1987.
The compounds of the instant invention have an antidepressant action in patients with major and minor forms of depression.
SUMMARY OF THE INVENTION
The present invention relates to a novel therapeutic use of known compounds, CCK A and CCK B antagonists, their derivatives, and pharmaceutically acceptable salts. The present invention concerns a method for treating depression in a mammal in need of such treatment.
The treatment comprises administering in unit dosage form an amount effective to treat depression of a CCK A or CCK B antagonist or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment.
Preferred compounds include but are not limited to CCK A antagonists devazepide, lorglumide, and loxiglumide.
Preferred compounds include but are not limited to CCK B antagonist L-365,260 and LY262691.
Pharmaceutical compositions of a compound of the present invention or its salts are produced by formulating the active compound in dosage unit form with a pharmaceutical carrier. Some examples of dosage unit forms are tablets, capsules, pills, powders, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers containing either one or some larger number of dosage units and capable of being subdivided into individual doses. Some examples of suitable pharmaceutical carriers, including pharmaceutical diluents, are gelatin capsules; sugars such as lactose and sucrose; starches such as corn starch and potato starch, cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, and cellulose acetate phthalate; gelatin; talc; stearic acid; magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma, propylene glycol, glycerin; sorbitol; polyethylene glycol; water; agar; alginic acid; isotonic saline, and phosphate buffer solutions; as well as other compatible substances normally used in pharmaceutical formulations. The compositions of the invention can also contain other components such as coloring agents, flavoring agents, and/or preservatives. These materials, if present, are usually used in relatively small amounts. The compositions can, if desired, also contain other therapeutic agents.
The percentage of the active ingredient in the foregoing compositions can be varied within wide limits but for practical purposes it is preferably present in a concentration of at least 10% in a solid composition and at least 2% in a primary liquid composition. The more satisfactory compositions are those in which a much higher proportion of the active ingredient is present.
Routes of administration of a subject compound or its salts are oral or parenteral. For example, a useful intravenous dose is between 100 and 800 mg and a useful oral dosage is between 200 and 800 mg.
A unit dosage form of the instant invention may also comprise other compounds useful in the therapy of depression.
A typical dose is, for example, from 600 to 2400 mg per day given in three individual doses.
Useful individual doses are from 5 mg to 50 mg parenterally or from 5 mg to 600 mg enterally or a compound or a pharmaceutically acceptable salt thereof.
A skilled physician will be able to determine the appropriate situation in which subjects are susceptible to or at risk of minor or major depression for administration by methods of the present invention.
DETAILED DESCRIPTION
The present invention relates to a method of treating depression which comprises administering a therapeutically effective amount of at least one compound or a pharmaceutically acceptable salt thereof of D,L-glutamic acid and D,L-aspartic acid of formulae: ##STR10## wherein n is 1 or 2
R 1 is a phenyl group mono-, di-, or tri-substituted with linear or branched C 1 -C 4 groups, which may be the same or different, or with halogens, with a cyano group or with a trifluoromethyl group;
R 2 is selected from the group consisting of morpholino, piperidino, and amino with one or two linear, branched, or cyclic alkyl group substituents containing from 1 to 8 carbon atoms which may be the same or different.
The present invention also relates to a method of treating depression which comprises administering a therapeutically effective amount of at least one compound or a pharmaceutically acceptable salt of a compound of formula ##STR11## wherein
R 1 is H, C 1 -C 6 linear or branched alkyl, loweralkenyl, lower alkynyl, --X 12 COOR 6 , --X 11 cycloloweralkyl, --X 12 NR 4 R 5 , X 12 CONR 4 R 5 , --X 12 CN, or --X 11 CX 3 10 ;
R 2 is H, loweralkyl, substituted or unsubstituted phenyl (wherein the substituents may be 1 or 2 of halo, loweralkyl, loweralkoxy, loweralkylthio, carboxyl, carboxyloweralkyl, nitro, -CF 3 , or hydroxy), 2-, 3-, 4-pyridyl, ##STR12## wherein
R 4 and R 5 are independently R 6 or in combination with the N of the NR 4 R 5 group form an unsubstituted or mono or disubstituted, saturated or unsaturated, 4-7 membered heterocyclic ring or benzofused 4-7 membered heterocyclic ring, or said heterocyclic ring or said benzofused heterocyclic ring which further comprises a second heteroatom selected from O and NCH 3 and the substituent(s) is/are independently selected from C 1-4 alkyl;
R 6 is H, loweralkyl, cycloloweralkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted phenylloweralkyl wherein the phenyl or phenylloweralkyl substituents may be 1 or 2 of halo, loweralkyl, loweralkoxy, nitro, or CF 3 ;
R 7 and R a 7 are independently α- or β-naphthyl, substituted or unsubstituted phenyl (wherein the substituents may be 1 or 2 of halo, --NO 2 , --OH, --X 11 R 4 R 5 , loweralkyl, CF 3 , CN, SCF 3 , C═CH, CH 2 SCF 3 , ##STR13## OCHF 2 , SH, SPh, PO 3 H-loweralkoxy, or loweralkylthio, COOH), 2-, 3-, 4-pyridyl, ##STR14##
R 8 is H, loweralkyl, cycloloweralkyl, --X 12 CONH 2 , --X 12 COOR 6 , --X 12 -cycloloweralkyl, --X 12 NR 4 R 5 , ##STR15##
R 9 and R 10 are independently H, --OH, or --CH 3 ;
R 11 and R 12 are independently loweralkyl or cycloloweralkyl;
R 13 is H, loweralkyl, acyl, O, or cycloloweralkyl;
R 14 is loweralkyl or phenylloweralkyl;
R 15 is H, loweralkyl, ##STR16## or --NH 2 ;
R 18 is H, loweralkyl, or acyl;
p is 0 when its adjacent ══ is unsaturated and 1 when its adjacent ══ is saturated except that when R 13 is O, p═1, and is unsaturated;
q is 0 to 4;
r is 1 or 2;
X 1 is H, --NO 2 , CF 3 , CN, OH, loweralkyl, halo, loweralkylthio, loweralkoxy, --, X 11 COOR 6 , or --X 11 NR 4 R 5 --;
X 2 and X 3 are independently H, --OH, --NO 2 , halo, loweralkylthio, loweralkyl, or loweralkoxy;
X 4 is S, O, CH 2 , or NR 18 or NR 8 ;
X 5 is H, CF 3 , CN, --COOR 6 , NO 2 l, or halo;
X 6 is O or HH;
X 7 is O, S, HH, or NR 15 ;
X 8 is H, loweralkyl;
X 9 and X a 9 are independently NR 18 or O;
X 10 is F, Cl, or Br;
X 11 is absent or C 1-4 linear or branched alkylidene;
X 12 is C 1-4 linear or branched alkylidene;
--is a saturated or unsaturated bond; or ##STR17## wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , p, q, r, X 1 , X 2 , X 3 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , and X 12 are as defined above, ##STR18##
R 7 is α- or β-naphthyl, substituted or unsubstituted phenyl (wherein the substituents may be 1 to 2 of halo, --NO 2 , --OH, --X 11 NR 4 R 5 , loweralkyl, CF 3 , CN, SCF 3 , C═CH, CH 2 SCF 3 , ##STR19## OCHF 2 , SH, SPh, PO 3 H, loweralkoxy, loweralkylthio, or COOH), 2-, 3-, 4-pyridyl; ##STR20##
R 16 is alpha or beta naphthyl or 2-indolyl;
R 18 is H or loweralkyl; and
═ is a saturated or unsaturated bond.
Certain CCK A and CCK B antagonists were tested in the Porsolt test, an animal model of depression, and in the "open field test" in the olfactory bulbectomised rat model of depression.
Methods
1. Porsolt Test (Behavioral Despair)
This test is based on the original method of Porsolt, et al (1977), Porsolt, R. D., La Pichon, M., and Jalpe, M. Depression: a new animal model sensitive to antidepressant treatment, Nature 266:730-732. On the first day of the experiment, the rats were plunged individually into a container 40 cm high, 18 cm diameter containing 15 cm of water at a temperature of 25° C. The animals were left to swim in the water for 15 minutes before being removed, allowed to dry, and returned to their home cage. Twenty-four hours later the procedure was repeated but on this occasion the duration that the rats remained immobile in a 5-minute observation period was recorded.
Animals received their first dose 15 minutes after removal from the water on the first day. They received the second dose 1 hour prior to the second placement in the water. Experiments were carried out in olfactory bulbectomised and in nonoperated animals.
Standard antidepressants such as desipramine caused a significant reduction in immobility in this test.
Results
1. Porsolt Test (Behavioral Despair)
The results obtained are shown in Table 1 below.
TABLE 1______________________________________Group Time Immobile(s)______________________________________Vehicle Median 159(n = 8) ST DEV 54 Q1-Q3 151-239Devazepide Median 100*(n = 8) ST DEV 380.1 mg/kg) Q1-Q3 77-144______________________________________ST DEV = Standard DeviationQ1-Q3 = Interquartile range *P <0.005 Mann Whitney U Test***P < 0.001
Table 1 shows the effect of devazepide in the Porsolt test in nonoperated animals. Devazepide (0.5 mg/kg) caused a significant decrease in immobility, indicating antidepressant activity.
2. Open Field Test in Olfactorv Bulbectomised Animals
This apparatus is essentially as described by Gray & Lalljee, Gray, J. A. and Lalljee, B. (1974): Sex differences in emotional behavior in the rat: correlation between the `open field` defecation and active avoidance. Anim. Behav. 22: 856-861. The open field consisted of a circular base, 90 cm in diameter which was divided into 10 cm squares by faint yellow lines. The wall surrounding the base consisted of a 75 cm high aluminum sheet. Illumination was provided by a 60 watt bulb, positioned 90 cm above the floor of the apparatus. All measurements were carried out in a darkened room in the morning. Each animal was placed in the center of the open field apparatus and the following parameters were measured over a 3 minute period:
a) Ambulation: the number of squares crossed;
b) Rearing: the number of times the rat simultaneously raised both forepaws off the floor of the apparatus;
c) Grooming: the number of times the rat stopped and groomed itself; and
d) Defecation: the number of fecal boli deposited.
Experiments were carried out in sham operated rats and in rats with olfactory bulbectomy performed as described by Cairncross, K. D., Wren, A. F., Cox, B., and Schrieden, H. (1977): Effects of olfactory bulbectomy and domicile on stress induced corticosteroid release in the rat, Physiol. Behav. 19:4845-487.
Since the CCK A antagonist, art recognized devazepide, demonstrated activity in the recognized behavioral despair model, CCK A receptor antagonists will be effective in the treatment of depression in man.
CCK B antagonists are also effective in the treatment of depression in man.
Scheme I below illustrates a method for preparing the above compounds. ##STR21##
Compounds 1 and 2 are commercially available. They are reacted at 160° C. in ET 3 N and Ac 2 O to produce an acid of formula 3. The acid is dissolved in methanol. HCl is bubbled through the reaction mixture for about 10 minutes. This is then stirred at reflux for several hours. HCl is again bubbled through the reaction mixture. This is stirred at reflux overnight. This is then concentrated in a vacuum and the residue taken up in ether, washed with water, NaHCO 3 and brine, dried over MgSO 4 , and concentrated in a vacuum to produce an ester of formula 3. This is mixed and stirred with NH 2 NH 2 .H 2 O at reflux for 24 hours and then cooled. Water is added slowly until a solid begins to separate; about 400 mL of H 2 O are added. Cool in an ice bath, filter, and wash to produce a compound of formula 4.
A desired compound of formula 4 is then mixed and stirred with a compound of formula 5 at room temperature overnight. Then it is concentrated in a vacuum. A compound of formula 6 is produced.
Such final products are, for example,
1-pyrazolidinecarboxamide, N-(4-bromophenyl)-3-oxo-4,5-diphenyl-, trans-,
1-pyrazolidinecarboxamide, 5-(2-chlorophenyl)-3-oxo-4-phenyl-N-[4-trifluoromethyl)phenyl]-, trans-, and
1-pyrazolidinecarboxamide, N-(4-bromophenyl)-5-(2-chlorophenyl)-3-oxo-4-phenyl-, trans-.
Examples of formulations of the subject compounds and of salts thereof are illustrated by the following.
EXAMPLE 1
Injectables
1 mg to 100 mg/mL
Devazepide for Injection USP q.s.
The compound or a suitable salt thereof is dissolved in, for example, ethanol, and passed through a 0.2-micron filter. Aliquots of the filtered solution are added to ampoules or vials, sealed and sterilized.
EXAMPLE 2
Capsules
5 mg, 100 mg, 200 mg, 300 mg or 400 mg
Devazepide, 250 g
Lactose USP, Anhydrous q.s. or 250 g
Sterotex Powder HM, 5 g
Combine the compound and the lactose in a tumble blend for 2 minutes, blend for 1 minute with the intensifier bar, and then tumble blend again for 1 minute. A portion of the blend is then mixed with the Sterotex Powder, passed through a #30 screen, and added back to the remainder of the blend. The mixed ingredients are then blended for 1 minute, blended with the intensifier bar for 30 seconds, and tumble blended for an additional minute. The appropriately sized capsules are filled with 141 mg, 352.5 mg, or 705 mg of the blend, respectively, for the 50 mg, 125 mg, and 250 mg containing capsules.
EXAMPLE 3
Tablets
50 mg, 100 mg, 200 mg, 300 mg,
400 mg, 500 mg or 600 mg
Devazepide
Corn Starch NF, 200 g
Cellulose, Microcrystalline, 46 g
Sterotex Powder HM, 4 g
Purified Water q.s. or 300 mL
Combine the corn starch, the cellulose, and the compound together in a planetary mixer and mix for 2 minutes. Add the water to this combination and mix for 1 minute. The resulting mix is spread on trays and dried in a hot air oven at 50° C. until a moisture level of 1 to 2 percent is obtained. The dried mix is then milled with a Fitzmill through a #RH2B screen, and added back to the milling mixture and th total blended for 5 minutes by drum rolling. Compressed tablets of 150 mg, 375 mg, and 750 mg, respectively, of the total mix are formed with appropriate sized punches the 50 mg, 125 mg, or 500 mg containing tablets.
L-365,260 could also, for example, be used in Examples 1 to 3 above.
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The invention concerns cholecystokinin antagonists useful in the treatment major and minor forms of depression. Especially useful are CCK A antagonists such as devazepide and CCK B antagonists such as L-365,260 and LY262691.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is being filed as a Divisional Application in accordance with 37 C.F.R. 1.53(b). The Parent Application of this Divisional Application is application Ser. No. 09/835,783 filed Apr. 11, 2001 now U.S. Pat. No. 6,417,355.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention involves a new class of compounds, geminal-bis(difluoramino)-substituted heterocyclic nitramines, and the production thereof. More specifically, this invention involves the production of 3,3 -bis(difluoramino)octahydro-1,5,7,7-tetranitro-1,5-diazocine (TNFX), which may be formulated into explosives and pro pellant oxidizers.
2. Description of the Related Art
The synthesis of certain examples of this class of compounds, geminal-bis(difluoramino)-substituted heterocyclic nitramines, is difficult and nonintuitive. The certain examples that are particularly synthetically difficult are molecules that incorporate the geminal-bis(difluoramino)alkylene [C(NF 2 ) 2 ] component and the nitramine component [N—NO 2 ] in close proximity, especially when separated by only a methylene (CH 2 ) link in order to maintain a low fuel-to-oxidizer component ratio and con comitantly high oxygen balance in the product molecule. This invention involves 3,3-bis(difluoramino)octahydro-7,7-dinitro-1,5-diazocine derivatives (a heretofore unknown specific class of compound) and novel precursors to these new derivatives, by the use of certain key intermediates and reagents which allow formation of this target structural subcomponent.
The calculated performance improvements expected from geminal-bis(difluoramino)-substituted heterocyclic nitramines when formulated into explosives and propellants has been reported. [Miller, Materials Research Society Proceedings 1996, 418, 3].
Methodology for preparing a geminal-bis(difluoramino)-substituted nitrogenous heterocycle has been reported in Chapman et al. Journal of Organic Chemistry 1998, 63, 1566, incorporated herein by reference, who describe the preparation of 3,3,7,7-tetrakis(difluoramino) octahydro -1,5-bis(4-nitrobenzenesulfonyl)-1,5-diazocine; this intermediate was converted to the corresponding nitramine, 3,3,7,7-tetrakis(difluoramino) octahydro-1,5-dinitro-1,5-diazocine, given the acronym HNFX as discussed in Chapman et al, Journal of Organic Chemistry 1999, 64, 960, incorporated herein by reference.
Methodology for preparing a structurally similar geminal-dinitro-substituted nitrogenous heterocycle has been reported by Cichra and Adolph [ Synthesis 1983, 830], who describe the preparation of octahydro-1,3,3,5,7,7-hexanitro-1,5-diazocine.
However, the preparation of asymmetric octahydro -1,5-diazocine derivatives incorporating both geminal-dinitro and geminal-bis(difluoramino) substituents has not been previously described. A particularly attractive target compound in terms of providing this asymmetric functionality would be 3,3-bis(difluoramino)octahydro-1,5,7,7-tetranitro-1,5-diazocine, given by us the acronym TNFX by analogy to the acronyms HNFX and RNFX. The incorporation of both functionalities provides a difluoramino component desired for energetic combustion of metallized-fuel propellant formulations, and the gem-dinitro component provides higher oxygen balance (for more-complete combustion) than analogous all-difluoramino derivatives.
SUMMARY OF THE INVENTION
The present invention relates to 3,3-bis(difluoramino)octahydro-1,5,7,7-tetranitro -1,5-diazocine (TNFX) and precursors leading to TNFX and provides a process for the preparation of TNFX having the formula:
A preferred embodiment of the present invention relates to methods for the preparation of certain new geminal-dinitro-1,5-diazocine derivatives which are suitable precursors leading to TNFX. The invention also involves novel and nonintuitive methods for the preparation of TNFX, a specific member of a general class of compounds with the substructure 3,3-bis(difluoramino)octahydro-7,7-dinitro-1,5-diazocine. TNFX is produced by the use of intermediates which allow formation of the target structural subcomponents, octahydro-3,3-dinitro-1,5-diazocine and a more specific substructure of 3,3-bis(difluoramino)octahydro-7,7-dinitro-1,5-diazocine.
In a preferred embodiment of the present invention, the substitution on heterocyclic precursors' nitrogen atoms is significant. The nitrogen atoms of heterocyclic precursors (such as diazocines) must be suitably substituted, or “protected,” during the process of difluoramination to allow this process to proceed to geminal-bis(difluoramino)alkylene derivatives. Without suitable protection of proximate multiple nitrogens, especially those separated from reacting carbonyl sites by a short bridge, such as methylene, the process of difluoramination of ketone intermediates does not proceed to geminal-bis(difluoramino)alkylene derivatives. The result is mono(difluoramino) alkylene derivatives or no reaction at all.
In a preferred embodiment of the present invention, the method of making a 3,3-bis(difluoramino)octahydro -1,5,7,7-tetranitro-1,5-diazocine comprises reacting a hexahydro-7,7-dinitro-1,5-bis(nitrobenzenesulfonyl)-1,5-diazocin-3(2H)-one with a difluoramine source to produce a 3,3-bis(difluoramino)octahydro-7,7-dinitro-1,5-bis(nitrobenzenesulfonyl)-1,5-diazocine and reacting said 3,3-bis(difluoramino)octahydro-7,7-dinitro-1,5-bis(nitrobenzenesulfonyl)-1,5-diazocine with a highly reactive nitrating reagent in the presence of a strong Lewis acid, such as antimony pentafluoride, boron triflate or boron fluorosulfonate.
An object of a preferred embodiment of the present invention is to create a novel explosive and propellant oxidizer involving geminal-bis(difluoramino)-substituted heterocyclic nitramines.
Another object of a preferred embodiment of the present invention is to provide a method of producing 3,3-bis(difluoramino)octahydro-1,5,7,7-tetranitro-1,5-diazocine (TNFX).
Yet another objective of object of a preferred embodiment of the present invention is provide a method of producing TFNX in appreciable yield by removing the electron withdrawing nitrobenzene sulfonyl nitrogen protecting groups on 3,3-bis(difluoramino)octahydro-7,7-dinitro-1,5-bis(nitrobenzenesulfonyl)-1,5-diazocine with sufficiently reactive nitrating reagent.
BRIEF DESCRIPTION DRAWINGS
FIG. 1 is a diagram of a general reaction path of a preferred embodiment of the present invention, which details the diazine intermediates.
FIG. 2 is a diagram of the a general reaction path of a preferred embodiment of the present invention, which details the steps for conversion of hexahydro-7,7-dinitro-1,5-bis(2-nitrobenzenesulfonyl)-1,5-diazocin-3(2H)-one to TNFX.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to 3,3-bis(difluoramino)octahydro-1,5,7,7-tetranitro-1,5-diazocine (TNFX)and provides a process for the preparation of TNFX having the formula:
A preferred embodiment of the process of the present invention utilizes diazocine intermediates, which are suitable for eventual conversion to TNFX. The reaction path of a preferred embodiment of the present invention, generally, is described in FIG. 1 . In FIG. 1, the % yield is the experimental % yield of 2 A through 9 A and 2 B through 9 B,
2 A through 9 A represents the experimental results where Ns is o-nosyl
derivative and
2 B through 9 B represents the experimental results where Ns is p-nosyl
derivative respectively.
In addition to o-nosyl and p-nosyl, the sulfonyl substituents, Ns, may include alkanesulfonyl, halosulfonyl, or arenesulfonyl substituents, but the arenesulfonyl must have electron-withdrawing subsitituents on the phenyl rings. For example, the nitro group (NO 2 ) is a suitable electron-withdrawing subsitituent. Any single or multiple electron-withdrawing subsitituent(s) that collectively lower(s) the basicity of the arenesulfonyl-protected nitrogens below that of the oxygen will be suitable. Similarly, alkanesulfonyl protecting groups may be electronegatively substituted to impart the same property on the protected nitrogens. In general, the sulfonyl substituent must have an inductive substituent constant (σ 1 or F) of a value greater than that of unsubstituted benzenesulfonyl, approximately 0.58. Examples of preferable sulfonyl substituents are halosulfonyl, any regioisomer of fluoroarenesulfonyl, such as 2-,3- and 4-fluoro-substituted arenesulfonyl, polyhaloalkanesulfonyl, polyhaloarenesulfonyl, any regioisomer of cyanoarenesulfonyl, such as 2-,3- and 4-cyano-substituted arenesulfonyl, polycyanoarenesulfonyl, any regioisomer of nitroarenesulfonyl, such as 2-,3- and 4-nitro-substituted arenesulfonyl and polynitroarenesulfonyl.
The synthetic sequence leading to TNFX involves substitution on heterocyclic precursors' nitrogen atoms. The nitrogen atoms of heterocyclic precursors (such as diazocines) must be suitably substituted, or “protected,” during the process of difluoramination to allow this process to proceed to geminal-bis(difluoramino)alkylene derivatives. Without suitable protection of proximate multiple nitrogens, especially those separated from reacting carbonyl sites by a short bridge, such as methylene, the process of difluoramination of ketone intermediates does not proceed to geminal-bis(difluoramino)alkylene derivatives. A preferred embodiment of the present invention is illustrated in FIG. 2 .
In addition to the preferred p-nosyl substituent illustrated above several other sulfonyl subsitituents may be utilized. The sulfonyl substituents may include alkanesulfonyl, halosulfonyl, or arenesulfonyl substituents, but the arenesulfonyl must have electron-withdrawing subsitituents on the phenyl rings. For example, the nitro group (NO 2 ) is a suitable electron-withdrawing subsitituent. Any single or multiple electron-withdrawing subsitituent(s) that collectively lower(s) the basicity of the arenesulfonyl-protected nitrogens below that of the oxygen will be suitable. Similarly, alkanesulfonyl protecting groups may be electronegatively substituted to impart the same property on the protected nitrogens. In general, the sulfonyl substituent must have an inductive substituent constant (σ 1 or F) of a value greater than that of unsubstituted benzenesulfonyl, approximately 0.58. Examples of preferable sulfonyl substituents are halosulfonyl, any regioisomer of fluoroarenesulfonyl, such as 2-,3- and 4-fluoro-substituted arenesulfonyl, polyhaloalkanesulfonyl, polyhaloarenesulfonyl, any regioisomer of cyanoarenesulfonyl, such as 2-,3- and 4-cyano-substituted arenesulfonyl, polycyanoarenesulfonyl, any regioisomer of nitroarenesulfonyl, such as 2-,3- and 4-nitro-substituted arenesulfonyl and polynitroarenesulfonyl.
The synthetic sequence leading to TNFX is continued from the intermediates detailed in Scheme 1, especially the immediately previous intermediate, hexahydro -7,7-dinitro-1,5-bis(nitrobenzenesulfonyl)-1,5-diazocin-3(2H)-one, by transformations effecting difluoramination of the carbonyl group (i.e., conversion to a gem-bis(difluoramino)alkylene component), which is accomplished by conversion of the ketone carbonyl group in a reaction with difluoramine or difluorosulfamic acid in the presence of a strong acid acid such as sulfuric acid (including fuming sulfuric acid). The subsequent (sequent) nitrolyses of the nitrobenzenesulfonyl N-protecting groups in order to prepare the corresponding bisnitramine, TNFX, as shown in Scheme 2 above.
The latter steps of the sequence (i.e., the N-nitrolyses) are particularly difficult, and the successful conditions leading to nitrolysis to the bisnitramine (TNFX) are particularly novel and nonintuitive, due to the highly deactivating nature of the numerous electron-withdrawing and sterically hindering groups attached to the nitrolyzed nitrogens. The adverse effects of electron-withdrawing and sterically hindering groups on susceptibility of protected nitrogens to N-nitrolysis have been previously reviewed by Chapman et al. Journal of Organic Chemistry 1999, 64, 960, incorporated herein by reference. In highly deactivated amides (N-protected amines), such as suitable precursors to HNFX and TNFX, N-nitrolysis requires the use of a highly reactive nitrating reagent such as protonitronium (NO 2 H 2 + ), formed via protonation of a nitronium (NO 2 + ) source in a very strong acid, i.e., a superacid. The highly reactive nitrating reagent protonitronium (NO 2 H 2 + ) is more efficiently formed in systems combining a superacid with a strong Lewis acid, in order to increase the acidity of the system. The system trifluoromethanesulfonic acid-antimony pentafluoride is used in a preferred embodiment of the present invention. Other examples of superacid systems suitable for formation of protonitronium may utilize other perfluoroalkanesulfonic acids, fluorosulfonic acid, or hydrogen fluoride in the presence of certain Lewis acids. Other Lewis acids which may be suitable for forming protonitronium in combination with superacids include a variety of halides and pseudohalides of main group elements and of certain transition metals such as tantalum. The formation of protonitronium in other superacid systems has been described by Olah et al., Journal of Organic Chemistry 1995, 60, 7348, who use the superacid system trifluoromethanesulfonic acid-triflatoboric acid. In the present preparation of TNFX, the cumulative deactivating effects of electronegative and bulky β,β-bis(difluoramino)alkyl and β,β-dinitroalkyl substituents on the diazocine nitro gens (imparting a pseudoneopentyl steric environment to them), and the electron-withdrawing nitrobenzenesulfonyl N-protecting groups, rendered the intermediate 3,3-bis(difluoramino)octahydro -7,7-dinitro-1,5-bis(nitrobenzenesulfonyl)-1,5-diazocine resistant to nitrolysis even by the strong nitrating system nitric acid-trifluoromethanesulfonic acid, as had been successfully used for previous preparations of HNFX. A modification of the nitrating system was required in order to generate sufficient protonitronium ion (in situ) to effect N-nitrolysis of the nitrobenzenesulfonyl protecting groups and generate the desired TNFX in appreciable yield. Thus, the addition of a strong Lewis acid to the system with nitric acid-trifluoromethanesulfonic acid rendered the nitrating reagent sufficiently reactive to remove both N-protecting groups under appropriate conditions to generate TNFX. In a preferred embodiment of the present invention, the strong Lewis acid antimony pentafluoride is used, but other Lewis acids such as boron triflate or boron fluorosulfonate may be utilized.
Further, the use of para-nitrobenzenesulfonyl-protected diazocines is shown as a preferred embodiment in Scheme 2. The use of ortho-nitrobenzenesulfonyl-protected diazocines produced desired nitramine(s) in only low (though detectable) yield, tentatively due to competing C-nitration at the initially unsubstituted para positions of ortho-nitrobenzenesulfonyl protecting groups. Resultant 2,4-dinitrobenzenesulfonyl protecting groups are subsequently much more difficult to remove than mononitrobenzenesulfonyl protecting groups, and TNFX is formed only to a small extent by successful competition of N-nitrolysis of two ortho-nitrobenzenesulfonyl protecting groups against C-nitration of the para position(s) of protecting groups.
The most desirable product, TNFX, exhibits further attractive attributes in addition to its combination of difluoramino and C-nitro substituents. Samples of TNFX have exhibited the property of crystal polymorphism, as determined by X-ray diffraction analysis. Thus, one polymorph of TNFX shows a higher density than the single crystal form of HNFX that has been observed to date, proving that polymorphism in 3,3,7,7-tetrasubstituted octahydro-1,5-dinitro-1,5-diazocines is a feasible phenomenon to induce, as had been computationally predicted for HNFX though not yet experimentally observed.
EXAMPLES
Example 1
Preparation of hexahydro-7,7-dinitro-1,5-bis(4-nitrobenzenesulfonyl)-1,5-diazocin-3(2H)-one ethylene ketal (“Ns”=p-nitrobenzenesulfonyl)
To a stirred solution of 1 (5.30 g, 58.8 mmole) and potassium carbonate (21.54 g, 155.8 mmole) in water (100 mL) maintained at 0° C. was added p-nosyl chloride (29.27 g, 132.1 mmole) in THF (60 mL) dropwise. Upon completion of the addition, the reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure to remove THF. The solid was filtered. After washed with water, methylene chloride and dried, compound 2a was afforded as a pale yellow solid (25.57 g, 95%); 2a was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:1). Removal of solvent and recrystallization from acetone and hexanes gave a colorless crystalline solid: mp 210-212° C. (sub.). 1 H NMR (acetone-d 6 ): δ2.96 (m, 2 H), 3.11 (m, 2 H), 3.78 (m, 1 H), 4.40 (d, J=5.49 Hz, 1 H), 6.89 (t, 2 H), 8.11 (d, J=9.16 Hz, 4 H), 8.42 (d, J=9.15, 4 H). 13 C NMR (acetone-d 6 ): δ47.4, 69.8, 125.2, 129.2, 147.5, 151.0. MS (CI/NH 3 ): m/z 478 (M + +1+NH 3 , 100). Anal. Calcd for C 15 H 16 N 4 O 9 S 2 : C, 39.13; H, 3.50; N, 12.17. Found: C, 39.46; H, 3.55; N, 11.86.
To a stirred solution of 2a (10.28 g, 22.35 mmole) in acetone (300 mL) maintained at 0 20 C. was added dropwise a mixture of CrO 3 (5.82 g, 58.2 mmole) in water (15 mL) containing concentrated sulfuric acid (6 mL). After the addition was complete, the reaction mixture was stirred vigorously at room temperature overnight and poured into ice-water. Solid was filtered, washed with water and dried. Compound 3a was obtained as a white solid (9.31 g, 91%), which was recrystallized from acetone and hexanes to give a colorless crystalline solid: mp 212° C. (dec). 1 H NMR (acetone-d 6 ): δ4.12 (d, J=5.50 Hz, 4 H), 7.19(t, 2 H), 8.09 (d, J=9.16 Hz, 4 H), 8.39 (d, J=9.15 Hz, 4 H). 13 C NMR (DMSO-d 6 ): δ49.1, 124.3, 127.9, 146.1, 149.4, 199.9. MS (CI/NH 3 ): m/z 476 (M + +1+NH 3 ,100). Anal. Calcd for C 15 H 14 N 4 O 9 S 2 : C, 39.30; H, 3.08; N, 12.22. Found: C, 39.23; H, 3.03; N, 11.79.
A mixture of ketone 3a (12.29 g, 26.83 mmole), ethylene glycol (6.06 g, 97.63 mmole), and p-toluenesulfonic acid monohydrate (˜0.5 g) in toluene (200 mL) was heated under reflux for 3 days using a Dean-Stark apparatus to remove water. After cooling, the solid was filtered, washed with water and methylene chloride. Compound 4a was obtained as a light gray solid (12.12 g, 90%) that was recrystallized from DMF and water to give a colorless crystalline: mp 237° C. (dec). 1 H NMR (DMSO-d 6 ): δ2.99 (d, J=6.41 Hz, 4 H), 3.59 (s, 4 H), 7.99 (d, J=9.15 Hz, 4 H), 8.13 (t, 2 H), 8.37 (d, J=8.84 Hz, 4 H). 13 C NMR (DMSO-d 6 ): δ45.9, 65.0, 106.7, 124.2, 127.8, 146.7, 149.3. MS (CI/NH 3 ): m/z 520 (M + +1+NH 3 , 100). Anal. Calcd for C 17 H 18 N 4 O 10 S 2 : C, 40.64; H, 3.61; N, 11.15. Found: C, 40.63; H, 3.44; N, 11.11.
To a refluxed solution of 4a (1.01 g, 2.01 mmole), potassium carbonate (0.72 g, 5.21 mmole) in acetone (50 mL) was added dropwise a solution of 3-bromo-2-(bromomethyl)propene (0.46 g, 2.15 mmole) in acetone (20 mL) in 1 h. The resulting mixture was heated with stirring under reflux overnight and acetone was evaporated. After the residue was washed with water and dried, a yellow solid was afforded which was recrystallized from acetone and hexanes to give 5a as a colorless crystalline solid (0.85 g, 76%): mp 199-201° C. 1 H NMR (CDCl 3 ): δ3.42 (s, 4 H), 3.81 (s, 4 H), 4.06 (s, 4 H), 5.22 (s, 2 H), 8.04 (d, J=9.16 Hz, 4 H), 8.38 (d, J=9.16 Hz, 4 H). 13 C NMR (CDCl 3 ): δ53.1, 54.0, 65.3, 106.6, 120.9, 124.4, 128.8, 140.0, 144.3, 150.3. MS (CI/NH 3 ): m/z 572 (M + +1+NH 3 ,100). Anal. Calcd for C 21 H 22 N 4 O 10 S 2 : C, 45.48; H, 4.00; N, 10.10; S, 11.56. Found: C, 45.57; H, 4.02; N, 9.65; S, 11.31.
A mixture of ozone in oxygen was bubbled into a stirred solution of 5a (0.98 g, 1.77 mmole) in methylene chloride (100 mL) at −78° C. until the solution turned to blue; then oxygen was continued to bubble into it to remove excess ozone. To the solution was added excess of methyl sulfide. Upon completion of the addition, the mixture was slowly warmed up to room temperature. After stirred for 1 h, solvent was removed under reduced pressure. The residue was washed with water, filtered, washed with water, acetone and dried to afford 6a as a white solid (0.94 g, 95%): mp 244° C. (dec). 1 H NMR (DMSO-d 6 ): δ3.58 (s, 4 H), 3.92 ( d, J=2.74 Hz, 8 H), 8.10 (d, J=8.24 Hz, 4 H), 8.39 (d, J=9.16 Hz, 4 H). 13 C NMR (DMSO-d 6 ): δ55.1, 64.8, 106.5, 124.7, 128.7, 142.9, 150.1, 202.3. MS (CI/NH 3 ): m/z 574 (M + +1+NH 3 ,100). Anal. Calcd for C 20 H 20 N 4 O 11 S 2 : C, 43.16; H, 3.62; N, 10.07; S, 11.52. Found: C, 42.95; H, 3.60; N, 9.83; S, 11.43.
A mixture of 6a (4.00 g, 7.19 mmole), sodium acetate (2.75 g, 33.52 mmole), hydroxylamine hydrochloride (1.02 g, 14.68 mmole) in ethanol (200 mL) was heated with stirring under reflux for 24 h, then cooled to room temperature and poured into ice-water. The precipitate was collected by filtration and dried. A white solid was afforded (3.76 g, 91%) which was recrystallized from acetone and hexanes to give 7a as a colorless crystalline: mp 213° C. 1 H NMR (DMSO-d 6 ): δ3.30 (s, 2 H), 3.58 (s, 2 H), 3.83 (s, 2 H), 3.84 (s, 2 H), 4.01 (s, 2 H), 4.07 (s, 2 H), 8.08 (dd, J=9.16 Hz, 2.75 Hz, 4 H), 8.38 (m, 4 H),11.3 (s, 1 H). 13 C NMR (DMSO-d 6 ): δ45.0, 50.2, 54.0, 54.3, 64.5, 106.3, 124.3, 124.7, 128.5, 142.8, 144.8, 149.7, 150.0, 152.1. MS (CI/NH 3 ): m/z 589 (M + +1+NH 3 ,100). Anal. Calcd for C 20 H 21 N 5 O 11 S 2 : C, 42.03; H, 3.70; N, 12.25; S, 11.22. Found: C, 41.97; H, 3.75; N, 12.12; S, 11.35.
A suspension of 7a (1.75 g, 3.06 mmole) in methylene chloride (100 mL) was heated with stirring under reflux and a solution of 100% nitric acid (15 mL), ammonium nitrate (0.32 g, 4.00 mmole) and urea (0.23 g, 3.83 mmole) in methylene chloride (50 mL) was added dropwise in 1 h. Upon completion of the addition, the reaction mixture was heated under reflux for 1.5 h, cooled to 0° C., and then iced water (150 mL) was added followed by removal of methylene chloride in a vacuum. The resulting mixture was filtered and a pale yellow solid was afforded. The dried solid was stirred in acetone for 20 min and filtered to give a white solid which was identical with compound 6a (0.83 g, 49%). The filtrate was evaporated and the residue was washed with methylene chloride; 8a was afforded as a white solid (0.64 g, 33%) that was recrystallized from acetone and hexanes to give a colorless crystalline: mp 258° C. (dec). 1 H NMR (DMSO-d 6 ): δ3.45 (s, 4 H), 3.93 (s, 4 H), 4.58 (s, 4 H), 8.09 (d, J=8.24 Hz, 4 H), 8.44 (d, J=9.15 Hz, 4 H). 13 C NMR (DMSO-d 6 ): δ50.2, 55.5, 64.9, 105.7, 118.2, 124.8, 129.1, 141.2, 150.5. MS (CI/NH 3 ): m/z 650 (M + +1+NH 3 , 100). Anal. Calcd for C 20 H 20 N 6 O 14 S 2 : C, 37.98; H, 3.19; N, 13.29. Found: C, 38.19; H, 3.15; N, 12.93.
Example 2
Preparation of hexahydro-7,7-dinitro-1,5-bis(4-nitrobenzenesulfonyl)-1,5-diazocin-3(2H)-one (“Ns”=p-nitrobenzenesulfonyl)
A mixture of 8a (0.64 g, 1.01 mmole) and concentrated sulfuric acid (1 mL) in methylene chloride (20 mL) was stirred at room temperature for 3 days followed by addition of iced water (50 mL). The resulting mixture was filtered and the solid was washed with water, acetone and dried, compound 9a was afforded as a white solid (0.55 g, 92%): mp 230° C. (dec). 1 H NMR (DMSO-d 6 ): δ4.29 (s, br, 4 H), 4.92 (s, br, 4 H), 8.14 (d, J=8.24 Hz, 4 H), 8.48 (d, J=8.24 Hz, 4 H). 13 C NMR (DMSO-d 6 ): δ54.2, 60.2, 120.3, 125.1, 129.3, 140.4, 150.7, 202.7. MS (CI/NH 3 ): m/z 606 (M + +1+NH 3 , 25). Anal. Calcd for C 18 H 16 N 6 O 13 S 2 : C, 36.74; H, 2.74; N, 14.28. Found: C, 36.80; H, 2.80; N, 13.80.
Example 3
Preparation of 3,3-bis(difluoramino)octahydro -7,7-dinitro-1,5-bis(4-nitrobenzenesulfonyl)-1,5-diazocine
In a jacketed tube reactor, 2.0 mL of 30% fuming sulfuric acid plus 10 mL of trichlorofluoromethane were cooled to −25° C., and 2.0 g of difluoramine was condensed into the mixture, which was then warmed to +10° C. (to melt the acid layer) and recooled to −15° C. Solid hexahydro-7,7-dinitro-1,5-bis(4-nitrobenzenesulfonyl)-1,5-diazocin-3(2H)-one (9a, 0.21 g, 0.36 mmol) was added via a solid addition funnel and then washed in with 10 mL trichlorofluoromethane. The mixture was stirred, sealed, at −15° C. for 3 hours and then poured onto ice; the reactor was washed with dichloromethane and then water. The quenched mixture was basified with saturated aqueous sodium bicarbonate to reach a pH of 2, and then extracted with dichloromethane (4×100 mL). The solute was redissolved in hot dichloromethane; chloroform was added; and the mixture was concentrated by rotary evaporation. Precipitate from the dichloromethane-chloroform mixture was filtered off and then redissolved in acetone. The remaining glassware was washed off with acetone, which solution was filtered through a medium-porosity glass frit. Acetone solutions were collected and evaporated to dryness. To the solute was added 25 mL chloroform, 10 mL dichloromethane, and 5 mL acetone, and the mixture was boiled. Dichloromethane was removed by rotary evaporation, and the precipitate was filtered off. The filtered solid as well as the solid residue stuck to the recrystallization flask were dried in a vacuum desiccator. The product was analyzed by NMR to be an acetone adduct of 3,3-bis(difluoramino)octahydro-7,7-dinitro- 1,5-bis(4-nitrobenzenesulfonyl)-1,5-diazocine (0.2358 g); m.p. 208° C. (explodes). 1 H NMR (acetone-d 6 ): δ2.09 (s), 4.58 (s, br, 4 H), 4.76 (s, 4 H), 8.31 (d, J=9.1 Hz, 4 H), 8.57 (d, J=9.1 Hz, 4 H). 1 H NMR (DMSO-d 6 ): δ2.09 (s), 4.47 (s, 4 H), 4.59 (s, br, 4 H), 8.19 (d, J=9.0 Hz, 4 H), 8.51 (d, J=9.0 Hz, 4 H). 13 C NMR (DMSO-d 6 ): δ30.7, 49.4, 52.9, 97.8, 118.3, 125.2, 129.9, 140.3, 150.9. 19 F NMR (acetone-d 6 ): δ29.9.
The acetone solvent adduct was dried in a vacuum oven at 50 -55° C. for three days, producing pure bis(difluoramino)octahydro -7,7-dinitro-1,5-bis(4-nitrobenzenesulfonyl)-1,5-diazocine (90% yield). 1 H NMR (DMSO-d 6 ): δ4.47 (s, 4 H), 4.59 (s, br, 4 H), 8.18 (d, J=8.8 Hz, 4 H), 8.51 (d, J=8.9 Hz, 4 H). 1 H NMR (CDCl 3 ): δ4.18 (s, br, 4 H), 4.54 (s, 4 H), 8.01 (d, J=9.0 Hz, 4 H), 8.48 (d, J=8.9 Hz, 4 H). 19 F NMR (CDCl 3 ): δ29.3.
Example 4
Preparation of hexahydro-7,7-dinitro-1,5-bis(2-nitrobenzenesulfonyl)-1,5-diazocin-3(2H)-one ethylene ketal (“Ns”=o-nitrobenzenesulfonyl)
To a stirred solution of 1 (2.38 g, 26.4 mmole) and potassium carbonate (9.35 g, 67.7 mmole) in water (100 mL) maintained at 0° C. was added o-nosyl chloride (11.71 g, 52.8 mmole) in THF (50 mL) dropwise. Upon completion of the addition, the reaction mixture was stirred at room temperature overnight. Layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine and then dried over magnesium sulfate. Removal of solvent gave 2b as a pale yellow solid (9.67 g, 80%). Recrystallization from ethyl acetate and hexanes afforded a white solid: 1 H NMR (acetone-d 6 ): δ3.08 (m, 2 H), 3.26 (m, 2 H), 3.89 (m, 1 H), 4.56 (d, J=5.49 Hz, 1 H), 6.56 (t, 2 H), 7.92 (m, 6 H), 8.09 (m, 2 H). MS (CI/NH 3 ): m/z 478. Anal. Calcd for C 15 H 16 N 4 O 9 S 2 : C, 39.13; H, 3.50; N, 12.17. Found: C, 38.99; H, 3.49; N, 11.80.
To a stirred solution of 2b (0.48 g, 1.04 mmole) in acetone (20 mL) maintained at 0° C. was added dropwise a mixture of CrO 3 (0.30 g, 3.0 mmole) in water (0.63 g) containing concentrated sulfuric acid (0.63 g). After the addition was complete, the reaction mixture was stirred vigorously at room temperature overnight and poured into ice-water. Solid was filtered, washed with water and dried. Compound 3b was obtained as a white solid (0.43 g, 90%), which was recrystallized from acetone and water to give a colorless crystalline solid: mp 165° C. (dec). 1 H NMR (acetone-d 6 ): δ4.23 (d, J=4.58 Hz, 4 H), 6.90 (t, 2 H), 7.82-8.05 (m, 8 H). MS (CI/NH 3 ): m/z 476. Anal. Calcd for C 15 H 14 N 4 O 9 S 2 : C, 39.30; H, 3.08; N, 12.22. Found: C, 39.25; H, 3.30; N, 12.14.
A mixture of ketone 3b (3.30 g, 7.21 mmole), ethylene glycol (1.50 g, 24.17 mmole), and p-toluenesulfonic acid monohydrate (˜0.5 g) in benzene (150 mL) was heated under reflux for 3 days using a Dean-Stark apparatus to remove water. After cooling, the solvent was removed and the residue was recrystallized from DMF and water. Compound 4b was obtained as a colorless crystalline (3.20 g, 89%): mp 195-197° C. 1 H NMR (acetone-d 6 ): δ3.35 (d, J=6.41 Hz, 4 H), 3.69 (s, 4 H), 6.56 (t, 2 H), 7.90 (m, 6 H), 8.05 (m, 2 H). HRMS (FAB): Calc for C 17 H 19 N 4 O 10 S 2 (MH + ) 503.0543, found m/z 503.0546. Anal. Calcd for: C 17 H 18 N 4 O 10 S 2 C, 40.64; H, 3.61; N, 11.15. Found: C, 40.67;H, 3.63; N, 11.00.
To a refluxed solution of 4b (0.54 g, 1.08 mmole), potassium carbonate (0.43 g, 3.11 mmole) in acetone (50 mL) was added dropwise a solution of 3-bromo-2-(bromomethyl)propene (0.23 g, 1.07 mmole) in acetone (30 mL) in 1 h. The resulting mixture was heated with stirring under reflux overnight and acetone was evaporated. The residue was dissolved in methylene chloride washed with water and dried over magnesium sulfate. Removal of solvent gave a pale yellow solid (0.51 g, 86%). The crude product was purified by passing through silica gel, eluting with ethyl acetate and hexanes, and the resulting solid was recrystallized from ethyl acetate and hexanes, affording a colorless crystalline solid, 5b: mp 150-151° C. 1 H NMR (CDCl 3 ): δ3.55 (s, 4 H), 4.01 (s, 8 H), 5.26 (s, 2 H), 7.70 (m, 6 H), 8.02 (m, 2 H).
A mixture of ozone in oxygen was bubbled into a stirred solution of 5b (3.26 g, 5.88 mmole) in methylene chloride (250 mL) at −78° C. until the solution turned blue; then oxygen was bubbled into it to remove excess ozone. To the solution was added excess dimethyl sulfide. Upon completion of the addition, the mixture was slowly warmed up to room temperature. After stirring for 1 h, solvent was removed under reduced pressure; 6b was obtained as a white solid (3.20 g, 98%) which was recrystallized from methylene chloride and hexanes to give a colorless crystalline solid: mp 219° C. (dec). 1 H NMR (DMSO-d 6 ): δ3.67 (s, 4 H), 3.94 (s, 4 H), 4.06 (s, 4 H), 7.90 (m, 4 H), 8.04 (m, 4 H). HRMS (FAB): Calc for C 20 H 21 N 4 O 11 S 2 : (MH + ) 557.0648, found m/z 557.0652.
A mixture of 6b (2.14 g, 3.85 mmole), sodium acetate (1.97 g, 24.00 mmole), and hydroxylamine hydrochloride (0.54 g, 7.77 mmole) in ethanol (200 mL) was heated with stirring under reflux for 48 h, and then cooled to room temperature and poured into ice-water. The precipitate was collected by filtration and dried. A white solid was afforded (2.13 g, 97%), which was recrystallized from acetone and hexanes to give 7b as a colorless crystalline solid: mp 220° C. (dec). 1 H NMR (acetone-d 6 ): δ3.56 (s, 2 H), 3.70 (s, 2 H), 3.97 (s, 4 H), 4.19 (s, 2 H), 4.45 (s, 2 H), 7.92 (m, 6 H), 8.11 (m, 2 H), 10.51 (s, 1 H). HRMS (FAB): Calc for C 20 H 22 N 5 O 11 S 2 : (MH + ) 572.0757, found m/z 572.0749. Anal. Calcd for C 20 H 21 N 5 O 11 S 2 : C, 42.03; H, 3.70; N, 12.25; S, 11.22. Found: C, 42.12; H, 3.91; N, 12.17; S, 11.03.
A suspension of 7b (0.39 g, 0.68 mmole) in methylene chloride (30 mL) was heated with stirring under reflux, and a solution of 100% nitric acid (5 mL), ammonium nitrate (81 mg, 0.96 mmole) and urea (82 mg, 1.37 mmole) in methylene chloride (15 mL) was added dropwise over 1 h. Upon completion of the addition, the reaction mixture was heated under reflux for 2 h, cooled to room temperature, washed with water, aqueous sodium bicarbonate, brine and dried over magnesium sulfate. Removal of solvent produced a white solid. The dried solid was stirred in methylene chloride for 20 min and filtered to give 8b as a white solid (0.20 g, 46%), which was recrystallized from DMF and water to afford a colorless crystalline solid: mp 245° C. (dec). 1 H NMR (DMSO-d 6 ): δ3.57 (s, 4 H), 3.90 (s, 4 H), 4.83 (s, 4 H), 7.87-8.10 (m, 8 H). 13 C NMR (DMSO-d 6 ): δ50.3, 55.3, 64.9, 105.4, 118.2, 124.8, 128.7, 130.0, 132.9, 135.5, 147.9. The filtrate was concentrated; a white solid was obtained which was identical with 6b (0.16 g, 42%).
Example 5
Preparation of hexahydro-7,7-dinitro-1,5-bis(2-nitrobenzenesulfonyl)-1,5-diazocin-3(2H)-one (“Ns”=o-nitrobenzenesulfonyl)
A mixture of 8b (0.80 g, 1.27 mmole) and concentrated sulfuric acid (1 mL) in methylene chloride (20 mL) was stirred at room temperature for 3 days, followed by addition of ice-water (50 mL). The resulting mixture was filtered, and the solid was washed with water and dried; compound 9b was afforded as a white solid (0.65 g, 87%). 1 H NMR (acetone-d 6 ): δ4.47 (s, 4 H), 5.24 (s, 4 H), 8.06 (m, 8 H). 13 C NMR (DMSO-d 6 ): δ54.9, 60.2, 120.5, 125.7, 128.1, 129.7, 133.6, 136.1, 148.0, 202.6.
Example 6
Preparation of 3,3-bis(difluoramino)octahydro-7,7-dinitro-1,5-bis(2-nitrobenzenesulfonyl)-1,5-diazocine
By a procedure similar to that of Example 3, difluoramination of 0.20 g hexahydro-7,7-dinitro-1,5-bis(2-nitrobenzenesulfonyl)-1,5 -diazocin-3(2H)-one (9b) produced 0.1495 g (65% yield) of pure 3,3-bis(difluoramino)octahydro-7,7-dinitro-1,5-bis(2-nitrobenzenesulfonyl)-1,5-diazocine after recrystallization from acetone-chloroform; m.p. 225-228° C. (dec). 1 H NMR (acetone-d 6 ): δ4.67 (s, br, 4 H), 5.02 (s, 4 H), 8.01-8.21 (m, 8 H). 13 C NMR (acetone-d 6 ): δ50.6 (quintet, J=7.0 Hz), 53.7, 98.0 (m), 118.9, 126.3, 129.5, 132.4, 134.0, 137.3, 149.6. 19 FNMR (acetone -d 6 ): δ629.3.
Example 7
Preparation of 3,3-bis(difluoramino)octahydro-1,5,7,7-dinitro-1,5-diazocine (TNFX)
To 10 mL of triflic acid was added 1.0 mL of 98-100% nitric acid at ambient temperature, and the mixture was stirred for 1 hour. To this mixture cooled in an ice-water bath was slowly added solid 3,3-bis(difluoramino)octahydro-7,7-dinitro-1,5-bis(4-nitrobenzenesulfonyl)-1,5-diazocine (49.6 mg) via a solid addition funnel. The resulting suspension was warmed to 55° C. in an oil bath. After recooling in an ice-water bath, another 1.0 mL nitric acid was added, and the mixture was rewarmed to 55° C. Another 10 mL triflic acid was added dropwise, and the mixture was stirred at 55° C. overnight. Additional triflic acid was added dropwise to make a total of 40 mL of solution, and the solution was stored in an oven at 55° C. After 14 days, one-fourth of the reaction solution was separated, and to this portion was added ˜10% by volume of antimony pentafluoride. After two days of storage of this solution at room temperature, most of the triflic acid was vacuum-distilled at 55° C.; the residue was quenched onto ice-water, neutralized to pH 7 with aqueous sodium carbonate, and extracted with dichloromethane. Chromatography of the solute (silica gel, chloroform-dichloromethane) separated 3,3-bis(difluoramino)octahydro-1,5,7,7-dinitro-1,5-diazocine (TNFX) from by-products, and its identity was confirmed by X-ray crystallography. 1 H NMR (acetone-d 6 ): δ5.14 (s, br, 4 H), 5.50 (s, 4 H). 19 F NMR (acetone-d 6 ): δ29.7.
Although the description above contains many specificities, these should not be construed as limiting the scope of the invention but as merely providing an illustration of the presently preferred embodiment of the invention. Thus the appended claims and their legal equivalents should determine the scope of this invention.
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This invention involves a new class of compounds, certain geminal-dinitro-substituted heterocycles, including geminal-bis(difluoramino)-substituted heterocyclic nitramines and the production thereof. More specifically, this invention involves the production of 3,3-bis(difluoramino)octahydro-1,5,7,7-tetranitro-1,5-diazocine (TNFX), which may be formulated into explosives and propellant oxidizers. The method of making a 3,3-bis(difluoramino)octahydro-1,5,7,7-tetranitro-1,5-diazocine comprises reacting a hexahydro-7,7-dinitro-1,5-bis(nitrobenzenesulfonyl)-1,5-diazocin-3(2 H)-one with a difluoramine source to produce a 3,3-bis(difluoramino)octahydro-7,7-dinitro-1,5-bis(nitrobenzenesulfonyl)-1,5-diazocine and reacting said 3,3-bis(difluoramino)octahydro-7,7-dinitro-1,5-bis(nitrobenzenesulfonyl)-1,5-diazocine with a highly reactive nitrating reagent in the presence of a strong Lewis acid, such as antimony pentafluoride, boron triflate or boron fluorosulfonate.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a method and apparatus for producing a sheet of dough. It especially relates to a method and apparatus for producing a sheet of bread dough from a dough mixture that consists of powdered materials, including flour and ice.
2. Description of Prior Art
Many attempts have been made to instantly provide dough of a good quality whenever it is needed. In the prior art methods raw materials are mixed with water and kneaded to form a lump of dough. The lump of dough is extruded from an extruder, and then sheeted, cut and then shaped and fermented to produce dough products.
However, these prior art methods have several problems. Namely, the mixing and kneading process needs operators' skills in judging whether the materials are uniformly mixed with water and whether the gluten in the kneaded dough is sufficiently developed. It has been generally said that within a limited period of time the constant production of a uniform mixture of powder and liquid is difficult. The amount of water for making dough is usually less than that of powdery materials so that the powdery materials tend to gather to form a hard mass. In order to eliminate it, a long period of time for kneading is required. Once dough is kneaded, fermentation starts progressing in the dough due to the yeast contained in it. This fermentation cannot be stopped until the dough is completely baked or is frozen. Therefore, the discontinuation of fermentation before such processes means scrapping the dough. Further, in the above-mentioned kneading process, the network of the tissue structure of a well-developed gluten is liable to be destroyed due to a squeezing force exerted on the dough by the extruder. Hence, an extra process, such as a resting process, is needed to recover the lost tissue structure.
SUMMARY OF THE INVENTION
Accordingly, one of the objects of this invention is to provide an improved method and apparatus for providing a sheet of high-quality dough without causing any of the prior art problems.
Another object of this invention is to provide an improved method and apparatus for instantly and efficiently providing a sheet of dough of a high quality.
Still another object of this invention is to provide an improved method and apparatus for easily and constantly providing a sheet of dough adaptable to instantly produce high-quality dough products.
In accordance with these and other objects, this invention provides an improved method of producing a sheet of dough comprising the steps of mixing powdered materials for making bread, including flour, yeast, sugar, and fats and oils, with particles of ice, such that the particles of ice do not melt, to make them into a dough mixture composed of particles, forming the dough mixture into a continuous belt-like dough mixture having a uniform width and thickness such that the particles of ice do not melt, melting the particles of ice to make the belt-like dough mixture hydrated, and stretching the continuous hydrated belt-like dough mixture, thereby making a continuous sheet of dough and thereby generating a gluten network in the dough sheet.
In accordance with another aspect of this invention, it provides an apparatus for producing a sheet of dough comprising a mixing means for mixing powdered materials, including flour, yeast, sugar, and fats and oils, for making bread, with particles of ice, to make them into a dough mixture, a forming means for forming the dough mixture into a continuous belt-like dough mixture, a freezing chamber for holding the mixing means and the forming means in an environment such that the particles of ice do not melt, a melting chamber for melting the particles of ice, disposed adjacent and downstream of the freezing chamber, and a stretcher disposed downstream of the melting chamber.
In the method of this invention, by keeping the ice frozen and by preventing the flour from being hydrated, the above-mentioned dough mixture is kept in a powdered state until it is formed into a belt-like dough mixture. Thus, since the mixing process is carried out between all particles, namely the powdered materials are mixed with the particles of ice, they can be uniformly mixed with each other. Therefore, when the particles of ice in the belt-like dough mixture are melted, a uniformly hydrated belt-like dough mixture is obtained, in which all the ingredients, including flour, yeast, sugar, and fats and oils, are uniformly dispersed.
The hydrated belt-like dough mixture is then stretched by exerting a shearing stress on the dough mixture to make a sheet of dough so as to generate a gluten tissue structure in the sheeted dough. The dough sheet thus prepared has a well-developed gluten for producing products of a high quality.
The dough mixture remaining in the mixing and forming means can be left in the freezing chamber as it is. The preserved dough mixture can be used any time in response to need for feeding dough into an apparatus for making bread. It can also be supplied for consumers' home uses.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic side view, partly in section, of an embodiment of the apparatus of this invention, illustrating the sequence of the steps for producing a sheet of dough of the first embodiment of the method of this invention.
FIG. 2 is a schematic perspective view of a hopper and a forming belt conveyor, forming a part of the apparatus of this invention.
FIG. 3 is a schematic side view, partly in section, of a second embodiment of the apparatus of this invention, illustrating the sequence of the steps for producing a sheet of dough of a second embodiment of the method of this invention.
FIG. 4 is a schematic side view, partly in section, of a third embodiment of the apparatus of this invention, illustrating the sequence of the steps for producing a sheet of dough of a third embodiment of this invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The apparatus of the first embodiment of this invention will now be explained by referring to FIGS. 1 and 2. It consists of a freezing chamber 7, a melting chamber 8, a forming conveyor 5, a transfer conveyor 9, and stretching means 10.
In the freezing chamber 7, a mixing bowl 2, a hopper 4, and a part of the forming conveyor 5, are provided. Passages 1, for feeding powdered dough materials and ice into the mixing bowl 2, are provided at the top of the freezing chamber 7. A pair of mixing blades 3 is provided at the end of a shaft downwardly extending into the mixing bowl 2. The shaft and and bowl 2 are pivoted on brackets 21 and 22, respectively. The bracket 21 is mounted to the inner wall of the freezing chamber 7. The bracket 22 is mounted to an elevating means 20 that is fixed to the inner wall of the freezing chamber 7 so that the mixing bowl 2 can be moved up and down and turned upside down at desired angles, as illustrated by the broken lines in the figure.
The hopper 4 is provided below the mixing bowl 2 for receiving mixed materials, namely, a dough mixture 6. The forming conveyor 5 runs near the bottom of the hopper 4 and is composed of the conveying belt 51 wound around two end rolls, one of which is driven by a motor (not shown) and flexible walls 52 outwardly projecting from both the longitudinal edges of the conveying belt 51. The flexible walls 52 can be made of rubber or many metal plates abutting end-to-end so that they can be move around the ends of the conveyor 52. The hopper 4 rests on the upstream end of the conveyor 5, as shown in FIG. 2. An outlet 41 for discharging the dough mixture 6 is provided at the bottom of the hopper 4. In the freezing chamber 7 a subzero environment is maintained so that the powdered materials and the mixed dough mixture 6 are processed and stored in a powdery state. An opening is provided on the front wall of the freezing chamber 7 to transfer the formed dough mixture 6' through it. Adjacent the opening, on the outside of the freezing chamber 7, is provided a melting chamber 8. The temperature within the melting chamber 8 is maintained substantially above the freezing point. There are two methods of melting the particles of ice contained in the formed belt-like dough mixture 6', namely, one forcible and one natural. However, in this invention the forcible methods, such as the direct irradiation of a hot wind or microwaves to the formed dough mixtures 6', are effective. The melting chamber 8 works in the same manner as the above-mentioned opening for the freezing chamber 7, and another opening is provided on its front wall. The forming conveyor 5 passes through these openings for the melting chamber 8, and its downstream end projects outside. The transfer conveyor 9, for carrying the formed hydrated belt-like dough mixture 6", is provided adjacent the end of the forming conveyor 5. The transfer conveyor 9 is driven by a motor (not shown).
A stretching means 10 is provided downstream of the transfer conveyor 9. The stretching means consists of a plurality of conveyors, connected in series, that consist of an intake conveyor 11, a middle conveyor 12, and an outlet conveyor 13 and a group of rollers 14. The rolls of conveyors 11, 12, and 13 are driven by respective motors (not shown) such that the speed of each of the plurality of conveyors is stepwisely increased in the downstream direction of progress of the sheeted dough. The rollers 14 are driven by a mechanism (not shown) such that each revolves while revolving in an elliptical orbit provided over and along the plurality of conveyors 11, 12, and 13. The rollers 14 are driven by an assembly consisting of bevel gears, sprockets, and chain belts. The lower straight part of the elliptical orbit is spaced out a predetermined interval apart from the surface of the conveying belts of the plurality of conveyors 11, 12, and 13 so that the dough mixture passing therethrough is compressed and stretched.
FIG. 3 shows a stretching station 10' of the second embodiment of this invention, which contains a plurality of the stretching means 10 and a folder 18. In the stretching station 10' a predetermined length of the stretched dough mixture is continuously folded by the folder 18, and then repeatedly stretched, so that a highly-elastic bread dough with a well-developed gluten is obtained. The folder 18 is disposed adjacent the previous take-out conveyor 13. It provides an oblong channel through which the sheeted dough is passed. The channel is driven by a mechanism (not shown) to be moved in the forward and backward directions along the course of the progress of the bread dough, so that the dough discharged on the conveyor is folded as shown in the figure. The folded dough is then stretched by the second stretching means 10 to form a dough sheet. FIG. 4 shows the third embodiment of this invention, which uses another stretching means 10". This stretching means 10" consists of a roll 15 and a conveyor 16. The roll 15 reciprocates on a straight path spaced apart a certain interval apart from the surface of the conveying belt of the conveyor 16, while rolling at a speed substantially synchronized with that of the conveyor 16. The dough mixture being carried on the conveyor 16 is stretched in the direction of the progress of the dough mixture by the reciprocating movements of the roller 15.
The operation of the embodiments of this invention will now be explained. In the mixing bowl 2, after the powdered materials, including flour and other materials, are uniformly mixed with particles of ice, the mixing bowl 2 is lowered and turned upside down to discharge the dough mixture 6 into the hopper 4. The dough mixture 6 is formed into a belt-like shape by the forming conveyor 5 and then discharged from the outlet 41 of the hopper 4. Since the flexible walls 52 are provided on both sides of the forming conveyor 5, the belt-like dough mixture 6', in a powdery state, does not fall from the sides.
When the belt-like dough mixture 6' passes through the melting chamber 8, the particles of ice are thawed to make the belt-like dough mixture 6' hydrated, and the hydrated dough mixture 6" is moved onto the transfer conveyor 9. The hydrated belt-like dough mixture 6" is stretched, while its upper surface is pressed down by the rollers 14, and a shearing stress, which is generated by the differences in the speeds of conveyors 11, 12, and 13, is exerted on it. This causes a shearing deformation in the tissue structure of the dough mixture so that a gluten network is generated. Further, when the rollers 14, which revolve over a common orbit, move on the lower straight part of the orbit, they strike the dough mixture. This results in the same effect as mentioned above, and generates a gluten network.
The reciprocating roller 15, shown in FIG. 4, also shows a stretching effect that generates a shearing deformation similar to that mentioned above. Namely, the rolling movements of the roller 15, whose speed is substantially synchronized with that of the conveyor 16, cause a shearing deformation to be generated during the progress of the dough mixture.
The following table shows the formulation ratios of raw materials, namely, the ingredients for French bread dough, in an embodiment of this invention:
Ingredients (Parts by Weight)
Enriched wheat flour (12% wheat protein): 100.0
Yeast: 3.0
Sugar: 2.0
Shortening: 2.0
Dough conditioner: 1.8
Water: 55.0
The following table shows the processing conditions of an embodiment of this invention:
Processing conditions
Mixing and kneading time: 10 min
Conveying speed of intake conveyor: 4 m/min
Conveying speed of middle conveyor: 8 m/min
Conveying speed of outlet conveyor: 16 m/min
Dough thickness at intake conveyor: 50 mm
Dough thickness at outlet conveyor: 20 mm
Temperature in melting chamber: about 60-70 C.
Average particle size of flour: 100 microns
Range of particle size of ice: 20-500 microns
Although the embodiments of this invention are explained relative to bread dough, they are also effective to manufacture other kinds of dough for pastry, pizzas, or noodles.
EFFECTS OF THE INVENTION
As explained above, the method and apparatus of this invention eliminate the conventionally required kneading step, and enable the instant production of a sheet of bread dough of a high quality with a uniform width and thickness. The efficiency of producing bread dough is greatly improved by this invention. This brings about a great industrial effect in the field.
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A method and apparatus for producing a sheet of dough, wherein powdered materials, including flour, yeast, sugar, and fats and oils, for making bread, are mixed with particles of ice, such that the particles of ice do not melt, to make them into a dough mixture. The dough mixture is formed into a continuous belt-like dough mixture having a uniform width and thickness such that the particles of ice do not melt, and then the particles of ice are melted to make the belt-like dough mixture hydrated. Finally continuous hydrated belt-like dough mixture is stretched so that a continuous sheet of dough having a gluten network is provided.
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GOVERNMENT INTEREST
[0001] This invention was made with Government support under Grant No. 96-35300-3719 awarded, by the National Science Foundation. The Government has certain rights in the invention.
FIELD OF THE INVENTION
[0002] This invention is in the field of pine tree breeding and selection. In particular, this invention relates to methods and compositions for identifying pine trees that harbor the null cinnamyl alcohol dehydrogenase (CAD) allele (cad-n1).
BACKGROUND OF THE INVENTION
[0003] Global consumption of wood products is projected to increase 25% over current levels by 2015 (McLaren 1999). Full citations for the references cited herein are provided before the claims. Forest plantations are increasingly important to meet these global demands because their faster growth rates result in much more harvestable volume per unit area than natural forests (Hagler 1996, Sedjo 1999). Thus, reliance on plantations reduces the need to harvest natural forests, allowing them to be used for other societal purposes. In fact, as little as 5 to 10% of the total area of world's forests would be required to meet global demands for wood products if this area were devoted to fast-growing plantations (Hagler 1996, Sedjo and Botkin 1997). Further, the faster growth rates mean high rates of carbon sequestration that may mitigate the effects of global warming. These facts, coupled with the declining area available for commercial forest harvests due to deforestation and government restrictions, have led to a global effort to increase plantation growth rates per unit area above current values through both classical and new technologies (Fox 2000).
[0004] Viewed as an agricultural crop, timber is the single highest-valued crop in the USA and loblolly pine ( Pinus taeda L) is the most important commercial tree species in the USA. Each year more than 900 million seedlings are used to establish loblolly pine plantations on more than half a million hectares (Pye et al. 1997). The total acreage of the loblolly pine plantation estate is estimated at more than 12 million hectacres (Byram et al. 1999). Loblolly pine is also important for its ecological and biological importance in native forests. Its native range spans 14 states from southern New Jersey south to central Florida and west to Texas. In these natural forests it is the dominant tree species on 11.7 million ha (Baker and Langdon 1990). Thus, loblolly pine is nearly equal in its distribution between native and planted forests totaling 23.7 million hectares. By comparison, the total expanse of plantations of hybrid poplar in the Pacific Northwest is approximately 25,000 ha (Nuss 1999), which is only 0.2% of the area planted in loblolly pine.
[0005] Due to its overwhelming commercial importance, tree breeding programs for loblolly pine began in the 1950's, and virtually all forest products companies and state agencies are involved in genetic improvement programs (more than 30 organizations) (Byram et al. 1999, Li et al. 1999). These programs have used classical methods of selection, genetic testing and breeding to make demonstrable genetic progress. Unfortunately the progress is hindered, compared to that in agricultural crops, by the large size and long-lived nature of pines (eight years in field tests to make selections followed by another five or more years to complete breeding). For these reasons, most loblolly pine programs are only in their second or third cycle of breeding after nearly 50 years, when in some crops more than one cycle is completed in a single year.
[0006] Loblolly pine ( Pinus taeda L.) is the most intensively grown tree species in the USA for pulp and solid wood products with plantations exceeding 12 million hectares. The extraction of lignin from wood during the production of pulp and paper requires the use of costly chemicals that are toxic to the environment. Significant progress towards increasing pulping efficiency has been achieved in poplar through the genetic manipulation of genes involved in lignin biosynthesis (Baucher et al., 1996, Hu et al., 1999; Pilate et al., 2002). One of the key enzymes successfully targeted, cinnamyl alcohol dehydrogenase (CAD), catalyzes the final step in the synthesis of monolignols by converting cinnamaldehydes to cinnamyl alcohols. Field-grown transgenic poplar with reduced-CAD allowed easier delignification, using smaller amounts of chemicals and yielded more high quality pulp without an adverse effect on growth (Pilate et al., 2002).
[0007] A null CAD allele (cad-n1) has been discovered in the loblolly pine clone 7-56 which is heterozygous for the null allele (MacKay et al., 1997). Homozygous seedlings (cad-n1/cad-n1) obtained by selfing, contain between 0-1% of wild type CAD activity (MacKay et al., 1997) and display a brown-red wood phenotype. The expression level of cad transcript in shoot, megagametophyte and xylem tissues was 20 times less in cad-n1 homozygous plants compared to wild type (MacKay et al., 1997).
[0008] Deficiency of CAD in cad-n1 homozygotes only slightly reduces lignin content but drastically alters lignin composition (MacKay et al., 1997; Ralph et al., 1997; Lapierre et al., 2000; MacKay et al., 2001). The major lignin composition change was attributed to the incorporation of dihydroconiferyl alcohol (DHCA), a minor component of most lignins, but elevated to levels 10-fold higher in cad-n1 homozygous trees. Coniferaldehyde, the substrate of CAD, and vanillin are also present in increased levels while the coniferyl alcohol component of normal lignin decreased.
[0009] The mutation has a variable effect on pulping efficiency, depending on the age of the trees and whether the mutation is present in a homozygous or heterozygous state. In totally CAD-deficient trees (cad-n1/cad-n1), delignification was significantly easier but the pulp yields were relatively low (˜33%) compared to normal trees (48%) (Dimmel et al., 2001). In 4-6 year old partially CAD-deficient trees (heterozygous) delignification increased in efficiency by ˜20% and yields were similar to wild type (Dimmel et al., 2002). In contrast to these younger trees, a small sample of 14 year old partially CAD-deficient trees displayed no major differences in ease of delignification and pulp yield (Dimmel et al., 2002).
[0010] In addition to lignin composition changes, the cad-n1 allele appears to be associated with increased stem-growth traits in heterozygous trees (Wu et al., 1999). This growth promotion correlates to an increase in debarked volume of 4-year old trees (14%) (Wu et al., 1999) that is also observed in 14-year old trees (Dimmel et al., 2002). A likely explanation could be that trees harboring the cad-n1 allele may invest fewer resources into the production of monolignols, allowing reallocation of resources towards growth. Promotion of growth was also observed in transgenic poplar with the lignin biosynthetic enzyme 4-coumarate:coenzyme A ligase (4CL) down-regulated (Hu, et al., 1999).
[0011] For the above reasons, it is desirable to be able to select pine trees that harbor the null CAD allele (cad-n1). Traditionally, the mutation has been diagnosed using CAD isozyme analysis on haploid megagametophytes obtained from seed or by using genetic markers closely linked to the mutation (MacKay et al., 1997). These prior art methods are slow and tedious. It takes numerous years for pine tree seedlings to produce suitable seed for CAD isozyme marker analysis. In addition, linked genetic marker analysis is slow and often yields inaccurate results. There is thus a tremendous need to develop methods that allow rapid and accurate identification of pine trees that harbor the null CAD allele (cad-n1).
SUMMARY OF THE INVENTION
[0012] In order to meet these needs, the present invention relates to the identification of a sequence mutation responsible for the loss of function associated with the cad-n1 allele. This mutation was identified during single nucleotide polymorphism (SNP) discovery within the cad gene of loblolly pine. Identification of this mutation allows breeders to accurately determine the presence, absence and/or copy number of the cad-n1 allele in their germplasm before it reaches sexual maturity.
[0013] The present invention is directed to a method of identifying a loblolly pine tree harboring a null CAD allele (cad-n1) wherein the pine tree contains a cad gene and the cad gene has a fifth exon. A pine tree is said to “harbor” or contain the null CAD allele if it is homozygous for the null CAD allele (cad-n1/cad-n1) or is heterozygous for the null CAD allele (cad-n1/cad). Pine trees that are homozygous for the wild type CAD allele (cad/cad) do not harbor the null CAD allele. This sequence differs from the wild type sequence of the fifth exon of the cad gene depicted in SEQ ID NO:1. It is expected that there will be some genetic variation in the wild type cad gene sequence resulting in slight differences in the wild type sequence compared to SEQ ID NO:1.
[0014] In one format, the method includes identifying a pine tree containing a two base pair adenosine insertion in the fifth exon of the cad gene wherein the DNA sequence of the two base pair adenosine insertion includes the nucleotide sequence depicted in SEQ ID NO:3 or the complement thereof.
[0015] The present invention is further directed to a method of selecting a loblolly pine tree harboring a null CAD allele (cad-n1) wherein the pine tree contains a cad gene and the cad gene has a fifth exon. The method includes a) providing a sample including DNA from the pine tree wherein the DNA includes the cad gene; b) determining whether the fifth exon contains a two base pair adenosine insertion wherein the nucleotide sequence of the fifth exon containing the two base pair adenosine insertion includes the nucleotide sequence depicted in SEQ ID NO:3 or the complement thereof wherein the identification of the two base pair adenosine insertion is indicative of a pine tree harboring a null CAD allele (cad-n1) and c) identifying a sample containing the two base pair adenosine insertion to thereby select a loblolly pine tree harboring a null CAD allele (cad-n1).
[0016] The present invention is further directed to a method of identifying a loblolly pine tree harboring a null CAD allele (cad-n1) wherein the method includes a) providing a sample including DNA from the pine tree wherein the DNA contains a cad gene and the cad gene has a fifth exon; b) performing template-directed dye-terminator incorporation and fluorescence polarization detection (FP-TDI) on the DNA to determine whether the fifth exon in the sample contains a two base pair adenosine insertion wherein the nucleotide sequence of the fifth exon containing the two base pair adenosine insertion includes the nucleotide sequence depicted in SEQ ID NO:3 wherein the two base pair adenosine insertion is indicative of a pine tree harboring a null CAD allele (cad-n1) and c) selecting a sample containing the two base pair adenosine insertion in the cad gene to thereby identify a loblolly pine tree harboring a null CAD allele (cad-n1).
[0017] The present invention is further directed to a method of identifying a loblolly pine tree harboring a null CAD allele (cad-n1) by first providing a sample including DNA from the pine tree wherein the DNA contains a cad gene and the cad gene has a fifth exon wherein the DNA in the sample is amplified by PCR using PCR primers wherein the sequences of the primers is SEQ ID NO:11 and SEQ ID NO:12. Next, template-directed dye-terminator incorporation and fluorescence polarization detection (FP-TDI) is performed on the DNA using oligonucleotides having nucleotide sequences SEQ ID NO:13 and SEQ ID NO:14 to determine whether the fifth exon of the cad gene in the sample contains a two base pair adenosine insertion wherein the nucleotide sequence of the fifth exon containing the two base pair adenosine insertion includes the nucleotide sequence depicted in SEQ ID NO:3 wherein the two base pair adenosine insertion is indicative of a pine tree harboring the null CAD allele (cad-n1). Finally, samples are selected containing the two base pair adenosine insertion in the cad gene to thereby identify a loblolly pine tree harboring a null CAD allele (cad-n1).
[0018] The present invention is further directed to a method of identifying a loblolly pine tree homozygous for the null CAD allele (cad-n1/cad-n1) wherein the pine tree contains a cad gene and the cad gene has a fifth exon, by identifying a pine tree, wherein the pine tree contains DNA with a two base pair adenosine insertion in the fifth exon of the cad gene wherein the DNA sequence of the two base pair adenosine insertion includes the nucleotide sequence depicted in SEQ ID NO:3 or the complement thereof. In this format, the selected pine tree does not contain DNA with wild type sequence for the fifth exon of the cad gene wherein the wild type sequence is depicted in SEQ ID NO:1.
[0019] The present invention is further directed to a method of identifying a loblolly pine tree heterozygous for the null CAD allele (cad/cad-n1) wherein the pine tree contains a cad gene and the cad gene has a fifth exon, by identifying a pine tree, wherein the pine tree contains DNA with a two base pair adenosine insertion in the fifth exon of the cad gene wherein the DNA sequence of the two base pair adenosine insertion includes the nucleotide sequence depicted in SEQ ID NO:3 or the complement thereof. In this format, the pine tree also contains wild type sequence for the fifth exon of the cad gene wherein the wild type sequence is depicted in SEQ ID NO:1 or the complement thereof.
[0020] The present invention is further directed to a method of identifying a loblolly pine tree homozygous for the wild type CAD allele (cad/cad) wherein the pine tree contains a cad gene and the cad gene has a fifth exon by identifying a pine tree, wherein the pine tree lacks DNA with a two base pair adenosine insertion in the fifth exon of the cad gene wherein the DNA sequence of the two base pair adenosine insertion includes the nucleotide sequence depicted in SEQ ID NO:3 or the complement thereof to thereby identify a pine tree homozygous for the wild type CAD allele (cad/cad).
[0021] In the methods of the invention, the identifying step may be performed on a sample isolated from a pine tree, a pine tree seedling, a pine tree tissue culture, a pine tree cell culture or a pine tree megagametophte. The sample may also be from pine bark, pine needle, pine tissue or pine seed.
[0022] In the methods of the invention, the two base pair adenosine insertion may be identified by any genotyping assay that relies on the detection of the presence or absence of the double adenosine insertion mutation. Such methods include DNA sequencing, PCR assays and single base pair extension assays.
[0023] The single base pair extension assay may be template-directed dye-terminator incorporation and fluorescence polarization detection (FP-TDI).
[0024] In one format of the invention, the FP-TDI assay may include the use of oligonucleotides wherein the sequences of the oligonucleotides are SEQ ID NO: 13 or SEQ ID NO: 14. The FP-TDI assay may also include the use of PCR to amplify DNA prior to the FP-TDI assay. In the PCR assay, oligonucleotides such as those depicted in SEQ ID NO:11 and SEQ ID NO:12 may be utilized.
[0025] The present invention is further directed to an isolated oligonucleotide having a nucleotide sequence selected from SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14.
[0026] In another format, the present invention is directed to a kit for the detection of the null CAD allele (cad-n1) in loblolly pine. The kit may include an oligonucleotide such as SEQ ID NO:13 or SEQ ID NO:14.
[0027] The kit may further include materials to perform PCR reactions. Such materials to perform PCR reactions may include PCR primers such as those depicted in SEQ ID NO:11 and SEQ ID NO:12. The kit may further include one or more buffers. The kit may also include directions for using the kit.
BRIEF DESCRIPTION OF THE DRAWINGS
[0028] FIG. 1 shows the position of the cad-n1sequence mutation within the cad gene and the effect of the frame-shift on amino acid sequence. A portion of the wild type cad DNA sequence is depicted as SEQ ID NO:1 with the corresponding amino acid sequence depicted as SEQ ID NO:2. A portion of the cad-n1 DNA sequence is depicted as SEQ ID NO:3 with the corresponding amino acid sequence depicted as SEQ ID NO:4.
[0029] FIG. 2 shows a single base extension assay design for both the forward and reverse reactions. Forward (1528F) and reverse (1528R) assay primer positions and the corresponding fluorescent dideoxynucleotide terminator incorporated for the wild type and cad-n1 allele are also depicted. The sequences depicted in the figure are SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8.
[0030] FIG. 3 shows the detection of the cad-n1 sequence mutation in 96 samples analyzed by the forward and reverse Template-directed Dye-terminator Incorporation and Fluorescence Polarization detection (FP-TDI) assay. Plants are grouped as control (heterozygous), control (homozygous wild type), control (homzygous null), negative controls and unknown plants.
DETAILED DESCRIPTION OF THE INVENTION
[0031] Loblolly pine clone 7-56 is heterozygous for the null cad allele (cad/cad-n1) (MacKay et al., 1997). Selfing of these heterozygous 7-56 clones produce 25% homozygous mutant seedlings: (cad-n1/cad-n1), 50% heterozygous seedlings (cad/cad-n1) and 25% homozygous wild type seedlings: (cad/cad). The homozygous cad-n1 seedlings contain between 0-1% of wild type CAD activity. Field-grown transgenic poplar with reduced-CAD allows for easier delignification, using smaller amounts of chemicals and yields more high quality pulp without an adverse effect on growth. As such, loblolly pine tree breeders have a stong interest in being able to rapidly identify such cad-n1 homozygous plants. It would be particularly useful if a mutation in the cad gene could be identified that was associated with the reduced CAD activity in homozygous plants. Identification of such a mutation would enable the use of various rapid molecular genetic assays for the identification of (cad-n1/cad-n1), (cad/cad-n1) and (cad/cad) trees and seedlings. The present invention is directed to methods and compositions useful for indentifying and distinguishing (cad-n1/cad-n1), (cad/cad-n1) and (cad/cad) trees and seedlings.
[0032] As discussed in the Example, SNP discovery within the cad gene was performed on haploid megagametophyte DNA from clone 7-56 and 31 other unrelated individuals. A two-base pair adenosine insertion was identified unique to clone 7-56, known to be deficient in CAD activity. The insertion was located in the second codon of exon five and creates a frame-shift that generates a premature stop codon ( FIG. 1 ). Seventeen haploid megagametophytes from the heterozygous 7-56 clone were assayed by isozyme gel electrophoresis and DNA sequence analysis to confirm the sequence mutation discovered was associated with CAD-deficiency. In every case, the two-base pair adenosine insertion corresponded with the absence of CAD activity and therefore provides a means for rapidly identifying and distinguishing (cad-n1/cad-n1), (cad/cad-n1) and (cad/cad) trees and seedlings.
[0033] Plants homozygous for the null cad allele (cad-n1/cad-n1) will contain DNA having the two base adenosine insertion in the fifth exon of the cad gene (at positions 4 and 5 of SEQ ID NO:3) but will not contain wild type DNA for the fifth exon of the cad gene as depicted in SEQ ID NO:1. As such, these plants harbor or contain the null CAD allele but do not harbor or contain the wild type CAD allele.
[0034] Plants homozygous for the wild type cad allele (cad/cad) will not contain DNA having the two base adenosine insertion in the fifth exon of the cad gene (at positions 4 and 5 of SEQ ID NO:3) but will instead only contain wild type DNA for the fifth exon of the cad gene as depicted in SEQ ID NO:1. Such plants do not harbor or contain the null CAD allele but do harbor the the wild type CAD allele.
[0035] Plants heterozygous for the null cad allele (cad-n1/cad) will contain DNA having the two base adenosine insertion in the fifth exon of the cad gene (at positions 4 and 5 of SEQ ID NO:3) and will also contain wild type DNA for the fifth exon of the cad gene as depicted in SEQ ID NO:1. As such, these plants harbor both the null CAD allele and the wild type CAD allele.
[0036] The two-base pair adenosine insertion (at positions 4 and 5 of SEQ ID NO:3) or lack thereof (the wild type sequence, SEQ ID NO:1) can be rapidly identified by numerous methods well known to those of skill in the art. Such methods include any genotyping assay that relies on the detection of the presence or absence of the double adenosine insertion mutation. Such methods include but are not limited to PCR amplification reactions, single base extension assays, primer extension assays, DNA sequencing assays and assays utilizing molecular probes [i.e. Taqman & Fluorescence Resonance Energy Transfer, (FRET)] assays and other techniques.
[0037] Primer extension is a simple, robust technique for analyzing single nucleotide polymorphisms (SNPs) such as the two base pair adenosine insertion in SEQ ID NO:3 or the complement thereof. This process is illustrated in FIG. 2 and in the Example. A primer with its 3′ end directly flanking the SNP is annealed to the amplified target and induced to extend by a single ddNTP complementary to the polymorphic base. Based on the molecular weight difference between ddNTPs, extension products vary in weight depending on the incorporated nucleotide. Such extension products can be correlated and identified with a particular sequence and then utlized to detect the particular sequence.
[0038] DNA sequencing is a technique utilized to determine the sequence of nucleotides in a particular DNA molecule such as the presence or absence of the two base pair adenosine insertion in SEQ ID NO:2. Typical sequencing reactions include appropriate sequencing buffers, nucleotides, dideoxy nucleotides, DNA polymerase and one or more oligonucleotide primers. Clones containing the 5th exon of the cad gene can be sequenced with sequencing primers that flank the cloned insert, e.g. T7 polymerarse primers. Alternatively, PCR products containing the 5th exon of the cad gene, prepared, for example, as described below, can be sequenced directly.
[0039] The polymerase chain reaction (PCR) is a technique utilized to amplify DNA and can be utlized to detect differences in sequences such as the two base pair adenosine insertion in SEQ ID NO:3 of the complement thereof. Typical PCR reactions include appropriate PCR buffers, nucleotides, DNA polymerase and one or more oligonucleotide primers. Any primer amplifying exon 5 of the cad gene can be utilized. Such primers can be designed by procedures well known in the art, for example those procedures described on the UK Human Genome Mapping Project Resource Centre web site. The primers may be located within 3000 base pairs of exon 5 in pine DNA. Generally, primers should be at least 18 nucleotides in length to minimize the chances of encountering problems with a secondary hybridization site on the vector or insert. Primers with long runs of a single base should generally be avoided. It is generally important to avoid 4 or more G's or C's in a row. For cycle sequencing, primers with melting temperatures in the range 52-58 degrees C., as determined by the (A+T)2+(C+G)4 method, generally produce better results than primers with lower melting temperatures. Primers with melting temperatures above 65 degrees C. should also be avoided because of potential for secondary annealing. If the template is a high “G-C” templates, then a primer with a Tm in the 60-70 degrees C. range may be desirable. It is then advisable to do the sequencing reaction with annealing and extension at 60 C. Primers generally have a G/C content between 40 and 60 percent. For primers with a G/C content of less than 50%, it may be necessary to extend the primer sequence beyond 18 bases to keep the melting temperature above the recommended lower limit of 50 degrees C. Primers should be “stickier” on their 5′ ends than on their 3′ ends. A “sticky” 3′ end as indicated by a high G/C content could potentially anneal at multiple sites on the template DNA. A “G” or “C” is desirable at the 3′ end but the first part of this rule should apply. Primers should not contain complementary (palindromes) within themselves; that is, they should not form hairpins. If this state exists, a primer will fold back on itself and result in an unproductive priming event that decreases the overall signal obtained. Hairpins that form below 50 degrees C. generally are not such a problem. Primers should generally not contain sequences of nucleotides that would allow one primer molecule to anneal to itself or to the other primer used in a PCR reactions (primer dimer formation). If possible, it is generally useful to run a computer search against the vector and insert DNA sequences to verify that the primer and especially the 8-10 bases of its 3′ end are unique.
[0040] Specific PCR primers, such as those depicted as SEQ ID NO:11 and SEQ ID NO:12, may be utilized in the reaction. Reaction products can be sequenced as described above or separated by gel electrophoresis, e.g. size gel electrophoresis, to identify those pine trees harboring or not harboring the CAD null allele.
[0041] Various modifications of general DNA sequencing, PCR and primer extension techniques are possible as detailed in Short Protocols in Molecular Biology, 4th Edition ed. F. M. Ausubel, R. Brent, D. D. Moore, K. Struhle, Massachusetts General Hospital and Harvard Medical School (2001) Molecular Cloning, Molecular Cloning, Sambrook et al. (2000) both of which are hereby incorporated by reference.
[0042] While specific oligonucleotide primer sequences are described herein, it is understood that substantially identical oligonucleotide primer sequences to those described herein will also work to permit detection of the two base pair adenosine insertion in SEQ ID NO:3 or the complement thereof that is absent from SEQ ID NO:1. The term “substantially identical” oligonucleotide primer sequences means that a oligonucleotide primer comprises a sequence that has preferably at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, or 89%, more preferably at least 90%, 91%, 92%, 93%, or 94%, and most preferably at least 95%, 96%, 97%, 98%, or 99% sequence identity, compared to a reference oligonucleotide sequence using standard alignment programs using standard parameters.
[0000] Pine Tree Plant Material
[0043] The two base pair mutation identifying the mutant cad gene can be detected in pine DNA or possibly RNA from pine tissue, pine cells, or pine cellular extracts. Such pine tissue, pine cells, or pine cellular extracts can be isolated from pine trees, pine tree seedlings, pine tree cell culture material, pine tree tissue culture material, pine tree seeds, pine tree needles, bark, tissue and pine tree megagametophytes. Pine seeds, tissue and wood samples can be isolated as described in MacKay, et al. Mol. Gen. Genet. 247, 537-545 (1995) which is hereby incorporated by reference in its entirety. DNA can be extracted from pine needles and megagametophytes as described in Doyle, et al. Focus 12, 13-15 (1987) which is hereby incorporated by reference in its entirety.
[0000] Kits
[0044] The present invention is also directed to a kit for the rapid and convenient identification of cad/cad-n1; cad/cad and cad-n1/cad-n1 pine trees. The kit may be any kit useful for detecting the presence (depicted in SEQ ID NO:3) or the absence (depicted in SEQ ID NO:1) of the two base pair adenosine insertion in the fifth exon of the CAD gene. The kit may be a primer extension kit, a PCR kit or a DNA sequencing kit. All of the kits include primers useful in the various detection assays such as those described herein. The kits would also include buffers, nucleotides and directions for use. The invention will be better understood be reference to the following non-limiting Example.
EXAMPLE
[0000] Materials and Methods
[0000] Plant Material
[0045] Four plant material sources were used for the identification and testing for the presence of the cad-n1 allele: (1) A panel of 32 loblolly pine megagametophytes (Weyerhaeuser Company Federal Way, Wash., USA), including one megagametophyte from clone 7-56, was used for SNP discovery within the cad gene, (2) 167 clones (CellFor Inc., Vancouver, BC, Canada) resulting from nine crosses, using clone 7-56 or 7-56 offspring as parents, was used for testing the FP-TDI assay, (3) A selection of 242 first-generation clones (North Carolina State University Cooperative Tree Improvement Program and Weyerhaeuser Company Federal Way; Wash., USA) from the natural range of loblolly pine was used for estimating the frequency of the cad-n1 allele, and (4) 96 progeny from the VERIFICATION population (Brown et al., submitted) of the QTL pedigree (Groover et al., 1994) was used for investigating the cad-psl locus.
[0046] Seeds from loblolly pine clone 7-56 were germinated and the haploid megagametophytes were removed for CAD isozyme analysis or DNA extraction. CAD isozyme assays were performed as described by MacKay et al. 1995. All DNA extractions were performed using the Plant DNAeasy kit (Qiagen, Valencia, Calif., USA) in either the single tube or 96-well format.
[0047] All primers for PCR and their purpose are described in Table 1 and their relative position within the cad gene shown in FIG. 1 .
TABLE 1 Sequence of oligonucleotide primers listed by their function. Purpose Forward primer Reverse primer Discovery CADF2- CADR2- (PCR and CCTCTGTTATGTGCAGGGGTTACA CGAAGTGCAACGGCTCTGG sequencing) (SEQ ID NO:9) (SEQ ID NO:10) FP CADF8- CADR2- TDI (PCR) TGAAAAGATGATGTGCGCCAA CGAAGTGCAACGGCTCTGG (SEQ ID NO:11) (SEQ ID NO:12) FP- CAD1528F- CAD1528R- TDI assay ATCCGTTGTGTTGCAGGAA GTAATCTAGGCTCTCTGCTGCTT (SEQ ID NO:13) (SEQ ID NO:14)
[0048] All PCR reactions were performed on ˜20 ng template in a total volume of 25 μl. Each reaction comprised of 0.8 μM of each primer; 0.65 units of HotStarTaq DNA polymerase (Qiagen, Valencia, Calif., USA); 1×PCR buffer containing 1.5 mM Mg; 100 μM each of dATP, dCTP, dGTP, dTTP (Applied Biosystems, Foster City, Calif., USA). Amplification was performed on a PTC100 thermocycler (MJ Research, Waltham, Mass., USA) with the following parameters: Initial denaturation step of 95° C. for 15 min (for activation of HotStarTaq) followed by 37 amplification cycles of 30 sec at 95° C., 30 sec at 60° C. and 2 min at 72° C.
[0049] DNA Sequencing and Analysis
[0050] To provide template for sequencing, 5 μl of PCR product was treated with IU of exonuclease I (USB, Cleveland, Ohio, USA) and IU of shrimp alkaline phosphatase (USB, Cleveland, Ohio, USA) and incubated at 37° C. for 1 hr followed by a heat inactivation step of 85° for 15 minutes. The primers that were used during PCR were also used for sequencing (SEQ ID NO:9 and SEQ ID NO:10). Cycle sequencing was performed using ABI Prism big dye terminator mix (Applied Biosystems, Foster City, Calif., USA) using standard conditions as supplied by the manufacturer. Reactions were run on an ABI 377 Automated DNA sequencer using standard ABI protocols. Sequencher (GeneCodes, Ann Arbor, Mich., USA) was used to assemble sequences into a contig where polymorphic differences could be easily visualized. The cad cDNA and translated protein sequence used for alignment in this study had the genbank accession numbers Z37992 and CAA86073 respectively. The intron and exon structure of the cad gene was inferred from a Pinus radiata genomic sequence (AF060491).
[0051] Detection of the cad-n1 allele using Template-directed Dye-terminator Incorporation and Fluorescence Polarization detection (FP-TDI).
[0052] Template for the assays was amplified using the primers CADF8 and CADR2 (SEQ ID NO:11 and SEQ ID NO:12) as described in Template-directed Dye-terminator Incorporation and Fluorescence Polarization detection (FP-TDI) the PCR section. The assay design for the forward and reverse reaction is shown in FIG. 2 and the primer sequences listed in Table 1. FP-TDI reactions were performed using the Acycloprime-FP SNP detection kit (Perkin Elmer Life Sciences, Boston, Mass.) as described by the manufacturer, except thermocycling conditions were altered to 25 cycles consisting of 95° C. for 15 seconds and 54° C. for 30 seconds. Fluorescence polarization was measured on a Wallac Victor 2 plate reader (Perkin Elmer Life Sciences, Boston, Mass.) with the manufacturer's recommended filter sets and G-Factor calibration.
[0000] Results and Discussion
[0053] Discovery of the cad-n1 Sequence Mutation
[0054] SNP discovery within the cad gene was performed on haploid megagametophyte DNA from clone 7-56 and 31 other unrelated individuals. A two-base pair adenosine insertion was identified unique to clone 7-56, known to be deficient in CAD activity. The insertion was located in the second codon of exon five and creates a frame-shift that generates a premature stop codon ( FIG. 1 ). Seventeen haploid megagametophytes from the heterozygous 7-56 clone were assayed by isozyme gel electrophoresis and DNA sequence analysis to confirm the sequence mutation discovered was associated with CAD-deficiency. In every case, the two-base pair adenosine insertion corresponded with the absence of CAD activity (data not shown).
[0055] Genotyping of the cad-n1 Mutation by FP-TDI
[0056] Design of the forward and reverse FP-TDI assays are shown in FIG. 2 . Trial testing of the assay was performed on 167 plants obtained from nine different crosses involving clone 7-56 or progeny from 7-56. Results from a subset of 96 plants using the forward and reverse FP-TDI assay are shown in FIG. 3 . Controls were included that consisted of all three possible genotype classes and blanks that contained no DNA. Samples that did not fall clearly into a genotype cluster (1-2%) were not scored. When both the forward and reverse reaction results were combined, all plants were accurately assigned to a genotype class and no contradictory genotypes were observed. The absence of homozygous cad-n1 clones was expected based on the parental genotypes used to construct the nine crosses tested.
[0057] Analyzing an indel mutation by single-base extension has the potential for giving a false result if a substitution occurs in the position examined ( FIG. 2 ). For example, if the first nucleotide of codon 241 (G) is substituted to an adenosine (forward assay) or the first base of codon 240 (G) is substituted to an adenosine (reverse assay) a false positive result for the cad-n1 allele would occur. Both of these positions require nonsynonymous amino acid changes to occur, alanine to threonine in the forward and glutamine to lysine in the reverse. These nonsynonymous changes were not observed in any of the clones present on the SNP discovery panel or in a selection of 242 first-generation clones. If both the forward and reverse assay are performed, the probability of an error occurring due to nucleotide substitutions would be extremely low.
[0058] Since the FP-TDI assay is based on single-base extension it should be amenable to other platforms such as the SureScore SNP Genotyping Kit (Invitrogen, Carlsbad, Calif., USA) and SNaPSHOT (Applied Biosystems, Foster City, Calif., USA).
[0059] SureScore, an integrated system that requires no specialized instrumentation, makes accessible genomic analysis tools that have traditionally been out of reach for many laboratories. The SureScore Kit includes primer design software, a 96-well assay kit, and data analysis software. The primer design software is used to design amplication and SNP-IT capture primers. The kit allows for genotyping to be conducted on up to 96 samples per SureScore strip-well plate, and commonly available equipment such as a 96-well plate washer and reader can be accommodated. Once the assay is completed, the kit provides data analysis software to interpret experimental results
[0060] The single base extension reaction for the FP-TDI assay utilizes an internal extension primer, which is designed so that its 3′ end anneals adjacent to the polymorphic base-pair. The reaction is essentially a sequencing reaction containing only dye-terminator nucleotides. Since there are no typical nucleotides, all that can occur is the addition of a single fluorescently-labeled dideoxynucleotide (F-ddNTP), which then cannot be extended further. In the FP-TDI assay, the identity of the base added (or bases if a heterozygote) will be discerned via measuring fluorescence polarization.
[0061] Primers and dNTPs left over from the original PCR are removed or degraded before running the singe-base extension reaction. Residual PCR primers are problematic because they can compete with the extension primer, effectively extending multiple targets, which would ruin the results. Residual dNTPs are problematic because they can allow extension to proceed beyond a single base.
[0062] The SNaPSHOT® system works by single base extension and then gel electrophoresis on a sequencer such as those provided by ABI.
[0063] Frequency of the cad-n1 Allele
[0064] Frequency of the cad-n1 allele was estimated by analyzing the 242 first generation clones that were distributed across the present-day range of loblolly pine (from Texas to Florida and extending north to Delaware). The mutation was not detected in any of the clones analyzed using the forward FP-TDI assay, confirming the rareness of this mutation. The frequency of cad-n1 might be higher in some populations, such as in the region where 7-56 was discovered (Williamsburg, N.C., USA), however much more extensive sampling would be required.
[0065] The frequency of cad-n1 in loblolly pine breeding populations and plantations will likely increase due to the inclusion of 7-56 as an elite parent in numerous co-operative and private breeding programmes. The diagnostic tool presented here will allow breeders to rapidly screen for the presence of the cad-n1 allele in their germplasm. Screening of additional loblolly pine populations could be performed to identify new select trees harboring the cad-n1 allele.
REFERENCES
[0066] The following references cited herein are hereby incorporated by reference in their entirety.
[0067] Baucher, M., Chabbert, B., Pilate, G., Van Doorsselaere, J., Tollier, M., Petit-Conil, M., Comu, D., Monties, B., Van Montagu, M., Inze, D., Jouanin, L., and Boerjan, W. (1996) Red xylem and higher lignin extractibility by down-regulating a cinnamyl alcohol dehydrogenase in poplar. Plant Physiol. 112, 1479-1490
[0068] Dimmel, D. R., MacKay, J. J., Althen, E. M., Parks, C. J., and Sederoff, R. R. (2001) Pulping and bleaching of CAD-deficient wood. J. Wood Chem. Technol. 21, 1-17.
[0069] Dimmel, D. R., MacKay, J. J., Courchene, C., Kadla, J., Scott, J. T., O'Malley, D. M., and McKeand, S. E. (2002) Pulping and bleaching of partially CAD-deficient wood. J. Wood Chem. Technol. 22, 235-248.
[0070] Groover, A., Devey, M., Lee, J., Megraw, R. and Mitchell-Olds, T. (1994) Identification of quantitative trait loci influencing wood specific gravity in an outbred pedigree of loblolly pine. Genetics 138, 1293-1300
[0071] Hsu, T. M., Chen, X., Duan, S., Miller, R. D., and Kwok, P. Y. (2001) Universal SNP genotyping assay with fluorescence polarization detection. Biotechniques 31, 560-570 (2001)
[0072] Hu, W. J., Harding S. A., Lung, J., Popko, J. L., Ralph, J., Stokke, D. D., Tsai, C. J., and Chiang, V. L. (1999) Repression of lignin biosynthesis promotes cellulose accumulation and growth in transgenic trees. Nat. Biotechnol. 17, 808-812
[0073] Kwok, P. Y. (2002) SNP genotyping with fluorescence polarization detection. Human Mutation 19, 315-323
[0074] Lapierre, C., Pollet, B., MacKay, J. J., and Sederoff, R. R. (2000) Lignin structure in a mutant pine deficient in cinnamyl alcohol deydrogenase. J. Agric. Food Chem. 48, 2326-2331
[0075] MacKay, J. J., Liu, W., Whetten, R., Sederoff, R. R., and O'Malley, D. M. (1995) Genetic analysis of cinnamyl alcohol dehydrogenase in loblolly pine: single gene inheritance, molecular characterization and evolution. Mol. Gen. Genet. 247, 537-545
[0076] MacKay, J., O'Malley, D. M., Presnell, T., Booker, F. L., Campbell, M. M., Whetten, R. W., and Sederoff, R. R. (1997) Inheritance, gene expression, and lignin characterisation in a mutant pine deficient in cinnamyl alcohol dehydrogenase. Proc. Natl. Acad. Sci. USA 94, 8255-8260
[0077] Pilate, G., Guiney, E., Holt, K., Petit-Conil, M., Lapierre, C., Leple, J., Pollet, B., Mila, I., Webster, E. A., Marstorp, H. G., Hopkins, D. W., Jouanin, L., Boerjan, W., Schuch, W., Cornu, D., and Halpin, C. (2002) Field and pulping performances of transgenic trees with altered lignification. Nat. Biotechnol. 20, 607-612.
[0078] Ralph, J., MacKay, J. J., Hatfield, R. D., O'Malley, D. M., Whetten, R. W., and Sederoff, R. R. (1997) Abnormal lignin in a loblolly pine mutant. Science 277, 235-239
[0079] Vanin, E. F. (1985) Processed pseudogenes: characteristics and evolution. Annu. Rev. Genet. 19, 253-272
[0080] Wu, R. L., Remington, D. L., MacKay, J. J., McKeand, S. E., and O'Malley, D. M. (1999) Average effect of a mutation in lignin biosynthesis in loblolly pine. Theor. Appl. Genet. 99, 705-710
[0081] MacKay, J. J., Liu, W., Whetten, R., Sederoff, R. R., and O'Malley, D. M. (1995) Genetic analysis of cinnamyl alcohol dehydrogenase in loblolly pine: single gene inheritance, molecular characterization and evolution. Mol. Gen. Genet. 247, 537-545
[0082] MacKay, J., O'Malley, D. M., Presnell, T., Booker, F. L., Campbell, M. M., Whetten, R. W., and Sederoff, R. R. (1997) Inheritance, gene expression, and lignin characterisation in a mutant pine deficient in cinnamyl alcohol dehydrogenase. Proc. Natl. Acad. Sci. USA 94, 8255-8260
[0083] Pilate, G., Guiney, E., Holt, K., Petit-Conil, M., Lapierre, C., Leple, J., Pollet, B., Mila, I., Webster, E. A., Marstorp, H. G., Hopkins, D. W., Jouanin, L., Boerjan, W., Schuch, W., Comu, D., and Halpin, C. (2002) Field and pulping performances of transgenic trees with altered lignification. Nat. Biotechnol. 20, 607-612.
[0084] Ralph, J., MacKay, J. J., Hatfield, R. D., O'Malley, D. M., Whetten, R. W., and Sederoff, R. R. (1997) Abnormal lignin in a loblolly pine mutant. Science 277, 235-239
[0085] Wu, R. L., Remington, D. L., MacKay, J. J., McKeand, S. E., and O'Malley, D. M. (1999) Average effect of a mutation in lignin biosynthesis in loblolly pine. Theor. Appl. Genet. 99, 705-710.
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Loblolly pine ( Pinus taeda L.) is the most important commercial tree species in the USA harvested for pulp and solid wood products. Increasing the efficiency of chemical pulping may be achieved through the manipulation of genes involved in the lignin biosynthetic pathway. A null allele of cinnamyl alcohol dehydrogenase (CAD) has been discovered in the loblolly pine clone 7-56 which displays altered lignin composition. During identification of single nucleotide polymorphisms (SNPs) in the cad gene, a two-base pair adenosine insertion located in exon five and unique to clone 7-56 was discovered. The sequence mutation causes a frame-shift predicted to result in premature termination of the protein. For routine detection of the mutation, a diagnostic assay was developed utilising Template-directed Dye-terminator Incorporation and Fluorescence Polarization detection (FP-TDI).
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[0001] The present application is a continuation of application Ser. No. 12/454,393, filed May 18, 2009, now U.S. Pat. No. 7,828,800; which is a continuation of application Ser. No. 08/480,908, filed Jun. 7, 1995, now U.S. Pat. No. 7,534,254; which is incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates generally to interbody spinal fusion implants, and in particular to spinal fusion implants configured to restore and maintain two adjacent vertebrae of the spine in anatomical lordosis.
[0004] 2. Description of the Prior Art
[0005] Interbody spinal fusion refers to the method of achieving bony bridging between adjacent vertebrae through the disc space, the space between adjacent vertebrae normally occupied by a spinal disc. Numerous implants to facilitate such a fusion have been described by Cloward, Brantigan, and others, and are known to those skilled in the art. Generally, cylindrical implants offer the advantage of conforming to an easily prepared recipient bore spanning the disc space and penetrating into each of the adjacent vertebrae. Such a bore may be created by use of a drill. It is an anatomical fact that both the cervical spine and the lumbar spine are normally lordotic, that is convex forward. Such alignment is important to the proper functioning of the spine. Commonly, those conditions which require treatment by spinal fusion are associated with a loss of lordosis.
[0006] Therefore, there exists a need for spinal fusion implants that permit for the restoration of anatomical lordosis.
SUMMARY OF THE INVENTION
[0007] The present invention is directed to a variety of interbody spinal fusion implants having at least a partially frusto-conical configuration. In the preferred embodiment, the spinal fusion implants of the present invention have a body that is partially or fully frusto-conical shape substantially along the portion of the implant in contact with the adjacent vertebrae of the spine. The spinal fusion implants of the present invention have an external thread for engaging the adjacent vertebrae of the spine and have an insertion end and a trailing end. The external thread may have a variable or constant thread radius and/or a constant or variable thread height measured from the body of the implant.
[0008] The spinal fusion implants of the present invention may be further modified so that while the upper and lower surfaces are portions of a frusto-cone, at least one side portion may be truncated to form a planar surface that is parallel to the central longitudinal axis of the implant to form straight walls. These implants may have a more tapered aspect at the insertion end of the implant to facilitate insertion. The spinal fusion implants of the present invention may be relatively solid and/or porous and/or hollow, and may have surface roughenings to promote bone ingrowth and stability.
[0009] The spinal fusion implants of the present invention may have wells extending into the material of the implant from the surface for the purpose of holding fusion promoting materials and to provide for areas of bone ingrowth fixation. These wells, or holes, may pass either into or through the implant and may or may not intersect. The spinal fusion implants of the present invention may have at least one chamber which may be in communication through at least one opening to the surface of the implant. Said chamber may have at least one access opening for loading the chamber with fusion promoting substances. The access opening may be capable of being closed with a cap or similar means.
[0010] The spinal fusion implants of the present invention offer significant advantages over the prior art implants:
1. Because the spinal fusion implants of the present invention are at least partially frusto-conical in shape, those that taper from the leading edge to the trailing edge are easy to introduce and easy to fully insert into the spinal segment to be fused. In another embodiment, where the trailing edge of the implant is larger than the leading edge, the implant utilizes a tapered forward portion and an increasing thread height relative to the body from the leading edge to the trailing edge to facilitate insertion. 2. The shape of the implants of the present invention is consistent with the shape of the disc, which the implants at least in part replace, wherein the front of the disc is normally taller than the back of the disc, which allows for normal lordosis. The implants of the present invention are similarly taller anteriorly than they are posteriorly. 3. The spinal fusion implants of the present invention conform to a geometric shape, which shape is readily producible at the site of fusion, to receive said spinal fusion implants.
[0014] The spinal fusion implants of the present invention can be made of any material appropriate for human implantation and having the mechanical properties sufficient to be utilized for the intended purpose of spinal fusion, including various metals such as cobalt chrome, stainless steel or titanium including its alloys, various plastics including those which are bio-absorbable, and various ceramics or combination sufficient for the intended purpose. Further, the spinal fusion implants of the present invention may be made of a solid material, a mesh-like material, a porous material and may comprise, wholly or in part, materials capable of directly participating in the spinal fusion process, or be loaded with, composed of, treated of coated with chemical substances such as bone, morphogenic proteins, hydroxyapatite in any of its forms, and osteogenic proteins, to make them bioactive for the purpose of stimulating spinal fusion. The implants of the present invention may be wholly or in part bioabsorbable.
OBJECTS OF THE PRESENT INVENTION
[0015] It is an object of the present invention to provide a spinal fusion implant that is easily inserted into the spine, having a tapered leading end;
[0016] It is another object of the present invention to provide a spinal fusion implant that tapers in height from one end to the other consistent with the taper of a normal spinal disc;
[0017] It is yet another object of the present invention to provide a spinal fusion implant that is capable of maintaining anatomic alignment and lordosis of two adjacent vertebrae during the spinal fusion process;
[0018] It is still another object of the present invention to provide a spinal fusion implant that is self stabilizing within the spine;
[0019] It is yet another object of the present invention to provide a spinal fusion implant that is capable of providing stability between adjacent vertebrae when inserted;
[0020] It is still another object of the present invention to provide a spinal fusion implant that is capable of participating in the fusion process by containing, being composed of, or being treated with fusion promoting substances;
[0021] It is further another object of the present invention to provide a spinal fusion implant that is capable of spacing apart and supporting adjacent vertebrae during the spinal fusion process;
[0022] It is still further another object of the present invention to provide a spinal fusion implant that is consistent in use with the preservation of a uniform thickness of the subchondral vertebral bone;
[0023] It is another object of the present invention to provide a spinal fusion implant having a shape which conforms to an easily produced complementary bore at the fusion site; and
[0024] It is a further object of the present invention to provide a frusto-conical spinal fusion implant which may be placed side by side adjacent to a second identical implant across the same disc space, such that the combined width of the two implants is less than sum of the individual heights of each implant.
[0025] It is a further object of the present invention to provide a frusto-conical spinal fusion implant which may be placed side by side adjacent to a second identical implant across the same disc space, such that the combined width of the two implants is less than sum of the individual lengths of each implant.
[0026] These and other objects of the present invention will become apparent from a review of the accompanying drawings and the detailed description of the drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] FIG. 1 is a side elevational view of the spinal fusion implant of the present invention having a body that is frusto-conical with an external thread having a substantially uniform radius.
[0028] FIG. 1A is an enlarged fragmentary view along line 1 A of FIG. 1 illustrating the surface configuration of the implant of FIG. 1 .
[0029] FIG. 1B is an enlarged fragmentary view along line 1 A of FIG. 1 illustrating an alternative embodiment of the surface configuration of the implant of the present invention made of a cancellous material.
[0030] FIG. 1C is a cross sectional view along lines 1 C- 1 C of FIG. 1B illustrating the alternative embodiment of the surface configuration of the implant of the present invention made of a cancellous material.
[0031] FIG. 1D is an enlarged fragmentary view along line 1 A of FIG. 1 illustrating an alternative embodiment of the surface configuration of the implant of the present invention made of a fibrous mesh-like material.
[0032] FIG. 1E is a fragmentary view along line 1 A of FIG. 1 illustrating an alternative embodiment of the surface configuration, of the implant of the present invention comprising a plurality of spaced apart posts.
[0033] FIG. 1F is an enlarged fragmentary sectional view along lines 1 F- 1 F of FIG. 1E illustrating the surface configuration of the implant of FIG. 1E .
[0034] FIG. 2 is an alternative embodiment of the spinal fusion implant of the present invention having a frusto-conical body with an external thread radius and thread height that are not constant.
[0035] FIG. 3 is as cross sectional view along line 3 - 3 of the implant of FIG. 2 .
[0036] FIG. 4 is a side elevational view of an alternative embodiment of the spinal fusion implant of the present invention.
[0037] FIG. 5 is a side elevational view and partial cut-away of a segment of the spinal column in lordosis showing the spinal fusion implant of FIG. 4 being implanted with a driving instrument from the posterior approach to the spinal column.
[0038] FIG. 6 is a side elevational view of an alternative embodiment of the spinal fusion implant of the present invention having a frusto-conical body and truncated sides.
[0039] FIG. 7 is an end view along line 7 - 7 of the spinal fusion implant of FIG. 6 shown placed beside a second identical implant shown in hidden line.
[0040] FIG. 8 is a side elevational view of an alternative embodiment of the spinal fusion implant of the present invention having a body with an irregular configuration.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0041] Referring to FIG. 1 , a side elevational view of the spinal fusion implant of the present invention generally referred to by numeral 20 is shown. The implant 20 has a body 22 that is frusto-conical in shape such that the body 22 has a diameter (root diameter) that is generally frusto-conical. The body 22 has an insertion end 24 and a trailing end 26 . The insertion end 24 may include a tapered portion 25 to facilitate insertion of the spinal implant 20 . In the preferred embodiment, when the implant 20 is inserted from the anterior aspect of the spine, the body 22 of the implant 20 has a maximum diameter at a point nearest to the trailing end 26 and a minimum diameter at a point nearest to the insertion end 24 .
[0042] The implant 20 has an external thread 28 having a substantially uniform radius R 1 measured from the central longitudinal axis L 1 of the implant 20 . The outer locus of the external thread 28 (major diameter) has an overall configuration that is substantially parallel to the longitudinal axis L 1 . While the major diameter of the implant 20 is substantially uniform, the external thread 28 may be modified at the leading edge by having initially a reduced thread radius to facilitate insertion of the implant 20 and may also be modified to make the external thread 28 self-tapping. In the preferred embodiment, the external thread 28 has a first thread 30 of a lesser radius than the radius R 1 of the remainder of the external thread 28 to facilitate insertion of the implant 20 . The second thread 32 has a greater radius than the first thread 30 , but is still shorter than the radius R 1 of the remainder of the external thread 28 which is thereafter of constant radius.
[0043] The body 22 is frusto-conical substantially along the portion of the body 22 in contact with the adjacent vertebrae of the spine which allows for creating and maintaining the adjacent vertebrae of the spine in the appropriate angular relationship to each other in order to preserve and/or restore the normal anatomic lordosis of the spine. The substantially uniform radius R 1 of the external thread 28 of the implant 20 allows engaging the bone of the adjacent vertebrae in a position that counters the forces which tend to urge the implant 20 from between the adjacent vertebrae in the direction opposite to which the implant 20 was implanted. The greater thread height measured from the body 22 near the leading end 24 of the implant 20 provides greater purchase into the vertebral bone and again enhances the stability of the implant 20 . Further, the configuration of the external thread 28 increases the surface area of the implant 20 in contact with the vertebrae to promote bone ingrowth.
[0044] The implant 20 has a recessed slot 34 at its trailing end 26 for receiving and engaging insertion instrumentation for inserting the implant 20 . The recessed slot 34 has a threaded opening 36 for threadably attaching the implant 20 to instrumentation used for inserting the implant 20 .
[0045] Referring to FIG. 1A , the implant 20 has an outer surface 38 that is porous to present an irregular surface to the bone to promote bone ingrowth. The outer surface 38 is also able to hold fusion promoting materials and provides for an increased surface area to engage the bone in the fusion process and to provide further stability. The pores of the outer surfaces 38 are microscopic in size having a diameter that is less than 1 mm, in the range of 50-1000 microns, with 250-500 microns being the preferred diameter. It is appreciated that the outer surface 38 , and/or the entire implant 20 , may comprise any other porous material or roughened surface sufficient to hold fusion promoting substances and/or allow for bone ingrowth and/or engage the bone during the fusion process. The implant 20 may be further coated with bioactive fusion promoting substances including, but not limited to, hydroxyapatite compounds, osteogenic proteins and bone morphogenic proteins. The implant 20 is shown as being solid, however it is appreciated that it can be made to be substantially hollow or hollow in part.
[0046] Referring to FIG. 1B , an enlarged fragmentary view along line 1 A of FIG. 1 illustrating an alternative embodiment of the surface configuration 38 of the implant of the present invention made of a cancellous material is shown. The cancellous material 50 , similar in configuration to human cancellous bone, having interstices 52 such that the outer surface 38 has a configuration as shown in FIGS. 1B and 1C . As the implant of the present invention may be made entirely or in part of the cancellous material 50 , the interstices 52 may be present in the outer surface 338 and/or within the entire implant to promote bone ingrowth and hold bone fusion promoting materials.
[0047] Referring to FIG. 1D , an enlarged fragmentary view along line 1 A of FIG. 1 illustrating an alternative embodiment of the surface configuration of the implant of the present invention made of a fibrous mesh-like material is shown. The mesh-like material 60 comprises strands 62 that are formed and pressed together such that interstices 64 , capable of retaining fusion promoting material and for allowing for bone ingrowth, are present between the strands in at least the outer surface 38 of implant of the present invention.
[0048] Referring to FIGS. 1E and 1F , a fragmentary view along line 1 A of FIG. 1 illustrating an alternative embodiment of the surface configuration 38 of the implant of the present invention comprising a plurality of spaced apart posts 70 is shown. The posts 70 have a head portion 72 of a larger diameter than the remainder of the posts 70 , and each of the interstices 74 is the reverse configuration of the posts 72 , having a bottom 76 that is wider than the entrance to the interstices 74 . Such a configuration of the posts 70 and interstices 74 aids in the retention of bone material in the surface 38 of the implant and further assists in the locking of the implant into the bone fusion mass created from the bone ingrowth. As the bone ingrowth at the bottom 76 of the interstices is wider than the entrance, the bone ingrowth cannot exit from the entrance and is locked within the interstice 74 . The surface of the implant provides for an improvement in the available amount of surface area which may be still further increased by rough finishing, flocking or otherwise producing a non smooth surface.
[0049] In the preferred embodiment, the posts 70 have a maximum diameter in the range of approximately 0.1-2 mm and a height of approximately 0.1-2 mm and are spaced apart a distance of approximately 0.1-2 mm such that the interstices 74 have a width in the range of approximately 0.1 to 2 mm. The post sizes, shapes, and distributions may be varied within the same implant.
[0050] In the preferred embodiment, for use in the lumbar spine, the implant 20 has an overall length in the range of approximately 24 mm to 32 mm with 26 mm being the preferred length. The body 22 of the implant 20 has a root diameter at the insertion end 24 in the range of 8-20 mm, with 14-16 mm being the preferred root diameter at the insertion end, and a root diameter at the trailing end 26 in the range of 10-24 mm, with 16-18 mm being the preferred diameter at the trailing end 26 , when said implants, are used in pairs. When used singly in the lumbar spine, the preferred diameters would be larger.
[0051] In the preferred embodiment, the implant 20 has a thread radius R 1 in the range of 6 mm to 12 mm, with 9-10 mm being the preferred radius R 1 . For use in the cervical spine, the implant 20 has an overall length in the range of approximately 10-22 mm, with 12-14 mm being the preferred length. The body 22 of the implant 20 has a root diameter at the insertion end 24 in the range of 8-22 mm, with 16-18 mm being the preferred root diameter at the insertion end when used singly, and 8-10 mm when used in pairs. The body 22 of the implant 20 has a root diameter at the trailing end 26 in the range of 10-24 mm, with 18-20 mm being the preferred root diameter at the trailing end 26 when used singly, and 10-12 mm when used in pairs; a thread radius, R 1 in the range of approximately 4-12 mm, with 9-10 mm being the preferred radius R 1 when inserted singularly and 5-7 mm when inserted side by side in pairs.
[0052] Referring to FIG. 2 , an alternative embodiment of implant 20 is shown and generally referred to by the numeral 120 . The implant 120 has a body 122 similar to body 122 of implant 120 and has an external thread 128 having a radius R 3 measured from the central longitudinal axis L 3 of the implant 120 . The thread radius R 3 is not constant throughout the length of the implant 120 and the external thread 128 has a thread height that is also not constant with respect to the body 122 of the implant 120 . In the preferred embodiment, the implant 120 has an external thread 128 with a radius R 3 that increases in size from the insertion end 124 to the trailing end 126 of the implant 120 .
[0053] Referring to FIG. 3 , a cross sectional view along line 3 - 3 of the implant 120 is shown. The implant 120 has an outer wall 144 surrounding an internal chamber 146 . The large and small openings 140 and 142 may pass through the outer wall 144 to communicate with the internal chamber 146 . The internal chamber 146 may be filled with bone material or any natural bone growth material or fusion promoting material such that bone growth occurs from the vertebrae through the openings 140 and 142 to the material within internal chamber 146 . While the openings 140 and 142 have been shown in the drawings as being circular, it is appreciated that the openings 140 and 142 may have any shape, size configuration or distribution, suitable for use in a spinal fusion implant without departing from the scope of the present invention.
[0054] The openings 140 and 142 are macroscopic in size having a diameter that is greater than 1 mm. The large openings 140 have a diameter in the range of 206 mm, with the preferred diameter being 3.5 mm; and the small openings have a diameter in the range of 1-2 mm, with 1.5 mm being the preferred diameter.
[0055] The implant 120 has a cap 148 with a thread 150 that threadably attaches to the insertion end 124 of the spinal fusion implant 120 . The cap 148 is removable to provide access to the internal chamber 146 , such that the internal chamber 146 can be filled and hold any natural or artificial osteoconductive, osteoinductive, osteogenic, or other fusion enhancing material. Some examples of such materials are bone harvested from the patient, or bone growth inducing material such as, but not limited to, hydroxyapatite, hydroxyapatite tricalcium phosphate; or bone morphogenic protein. The cap 148 and/or the spinal fusion implant 120 may be made of any material appropriate for human implantation including metals such as cobalt chrome, stainless steel, titanium, plastics, ceramics, composites and/or may be made of, and/or filled, and/or coated with a bone ingrowth inducing material such as, but not limited to, hydroxyapatite or hydroxyapatite tricalcium phosphate or any other osteoconductive, osteoinductive, osteogenic, or other fusion enhancing material. The cap 148 and the implant 120 may be partially or wholly bioabsorbable.
[0056] Referring to FIG. 4 , a side elevational view of an alternative embodiment of the spinal fusion implant of the present invention generally referred to by numeral 520 is shown. The implant 520 has a body 522 having a root diameter that is frusto conical in the reverse direction as that implant 20 shown in FIG. 1 , in order to preserve and/or restore lordosis in a segment of spinal column when inserted from the posterior aspect of the spine. The body 522 has an insertion end 524 and a trailing end 526 . In the preferred embodiment, the body 522 of the implant 520 has a minimum diameter at a point nearest to the trailing end 526 and a maximum diameter at a point nearest to the insertion end 524 . The insertion end 524 may have an anterior nose cone portion 530 presenting a tapered end to facilitate insertion.
[0057] The implant 520 has an external thread 528 having a substantially uniform radius R 6 measured from the central longitudinal axis L 6 of the implant 520 such that the external diameter of the external thread 528 (major diameter) has an overall configuration that is substantially parallel to the longitudinal axis L 6 . It is appreciated that the thread 528 can have a major diameter that varies with respect to the longitudinal axis L 6 , such that the major diameter may increase from the insertion end 524 to the trailing end 526 or the reverse. The external thread 528 has a thread height measured from the body 522 that increases from the insertion end 524 to the trailing end 526 .
[0058] Referring to FIG. 5 , a segment of the spinal column S is shown with the vertebrae V 1 and V 2 in lordosis and an implant 520 shown being inserted from the posterior aspect of the spinal column S with an instrument driver D. The implant 520 is inserted with the larger diameter insertion end 524 first in order to in initially distract apart the vertebrae V 1 and V 2 which then angle toward each other posteriorly as the implant 520 is fully inserted. It is appreciated that the insertion of implant 520 does not require the adjacent vertebrae V 1 and V 2 to be placed in lordosis prior to insertion, as the full insertion of the implant 520 itself is capable of creating the desired lordotic angular relationship of the two vertebrae V 1 and V 2 .
[0059] In the preferred embodiment, for use in the lumbar spine, the implant 520 has an overall length in the range of approximately 24 m 30 mm, with 26 mm being the preferred length. The body 522 of the implant 520 has a root diameter at the insertion end 524 in the range of 12-22 mm, with 16 mm being the preferred root diameter at the-insertion end, and a root diameter at the trailing end 526 in the range of 10-20 mm, with 14 mm being the preferred diameter at the trailing end 526 . In the preferred embodiment, the implant 520 has a thread radius R 6 in the range of 6 mm to 12 mm, with 8 mm being the preferred radius R 6 .
[0060] Referring to FIG. 6 , an alternative embodiment of the spinal fusion implant of the present invention generally referred to by the numeral 620 and a partial fragmentary view of a second identical implant, generally referred to by the numeral 621 are shown. The implant 620 has a body 622 that is partially frusto-conical in shape similar to body 22 of implant 20 shown in FIG. 1 , and has an insertion end 624 and a trailing end 626 . The body 622 of the implant 620 has truncated sides 670 and 672 forming planar surfaces that are parallel to the longitudinal axis L 7 . In this manner, two implants 620 and 621 may be placed side by side, with one of the sides 670 or 672 of each implant with little space between them, such that the area of contact with the bone of the adjacent vertebrae is maximized. It is appreciated that the body 622 may also be cylindrical in shape and have truncated sides 670 and 672 .
[0061] The implant 620 has an external thread 628 having a radius R 6 measured from the central longitudinal axis L 7 that may be constant, such that the major diameter or outer locus-of the external thread 628 has an overall configuration that is substantially, cylindrical. It is appreciated that the external thread 628 may have a thread radius R 7 that is variable with respect to the longitudinal axis L 7 such that the major diameter or outer locus of the external thread 628 has an overall configuration that is substantially frusto-conical.
[0062] Referring to FIG. 7 , an end view of the implant 620 placed beside implant 621 is shown. The implant 620 has a thread radius that is substantially constant and has a thread height measured from the body 622 that is greater at the sides 670 and 672 . In this manner, two implants 620 and 621 can be placed beside each other with the external thread 628 of each implant interdigitated allowing for closer adjacent placement of the two implants as a result of the substantial overlap of the external thread 628 at the side 670 or 672 of the implants.
[0063] Referring to FIG. 8 , an alternative embodiment of the implant of the present invention is shown and generally referred to by the numeral 700 . The implant 700 is similar in configuration to implant 20 shown in FIG. 1 , except that the body 722 has an irregular configuration. The configuration of the body 722 has a root diameter D which is variable in size throughout the length of the implant 700 and, as shown in this embodiment, comprises larger diameter portions 750 and smaller diameter portions 752 . It is appreciated that each of the large diameter portions 750 may be of the same or different diameter and each of the smaller diameter portions 752 may be of the same or different diameter.
[0064] The outer surface of the body 722 of implant 720 may be filled with fusion promoting substances such that the smaller diameter portions 752 may hold such fusion promoting substances. If so filled, the composite of the implant 700 and the fusion promoting material could still produce an even external surface of the body 722 if so desired.
[0065] While the present invention has been described in detail with regards to the preferred embodiments, it is appreciated that other variations of the present invention may be devised which do not depart from the inventive concept of the present invention. In particular, it is appreciated that the various teachings described in regards to the specific embodiments herein may be combined in a variety of ways such that the features are not limited to the specific embodiments described above.
[0066] Each of the features disclosed in the various embodiments and their functional equivalents may be combined in any combination sufficient to achieve the purposes of the present invention as described herein.
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The present invention is directed to a variety of interbody spinal fusion implants having at least a partially frusto-conical configuration. An external thread is employed to increase implant stability and implant surface area, and for the purpose of advancing the spinal fusion implant into the fusion site. The spinal fusion implants of the present invention may be relatively solid or hollow and may have surface roughenings to promote bone ingrowth and stability. The spinal fusion implants of the present invention may have wells extending into the material of the implant from the surface for the purpose of holding fusion promoting materials and to provide for areas of bone ingrowth fixation.
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CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional Patent Application 61/606,388, entitled “Adjustable, decorative support for the elevation of drip irrigation emitters and sprinklers/sprayers,” filed on Mar. 3, 2012, and the subject matter thereof is incorporated herein by reference thereto. This application also references the Applicant's U.S. Provisional Patent Application 61/574,480 entitled “Adjustable, decorative support for the elevation of drip irrigation emitters and sprinklers/sprayers,” filed on Aug. 3, 2011, and expressly abandoned on Mar. 2, 2012.
TECHNICAL FIELD
[0002] The present application relates generally to the field of brackets. More specifically, the present invention comprises a bracket that supports a water supply tube that delivers water significantly above the elevation level of the main water supply tube of a drip irrigation system or any other irrigation water delivery systems. Additionally, the present invention relates generally to drip irrigation systems, and more particularly to an adjustable, decorative bracket that supports the elevation of water delivery and drip irrigation emitters and sprinklers/sprayers.
BACKGROUND ART
[0003] The origin of drip irrigation dates back centuries to the Middle East with devices and methods to irrigate plants effectively with extremely limited water supplies. Drip irrigation evolved from using unglazed clay pots filled with water that were buried next to plant roots to the presently used modern drip irrigation systems consisting of polymer tubing and plastic drip irrigation fittings of various sizes and shapes.
[0004] Today's commercial industrial and residential drip irrigation systems capably and efficiently supply water to vegetation at ground level through a network of tubing and various types of drippers, emitters, and sprayers. The water is typically delivered at the elevation level of a main water supply tube of a drip irrigator, which is typically located at ground level. A typical drip irrigation system consists of a valve connected to a water supply that controls the delivery of water to an area to be irrigated. The valve is usually located at ground level and typically connected to a timer that opens and closes it on some preset schedule. A main irrigation tube extends from this valve throughout the area to be irrigated. This tube is attached to the valve at one end and capped at the other end so it maintains pressure when the valve is opened. This main tube either lies on top of the ground or is buried just beneath the ground surface. Smaller tubes are then attached to this main tube and extended to exactly where the water is to be delivered, usually right at the root of the plants to be watered, where some kind of drip emitter is attached. All of the components of the typical drip irrigation system are located at ground level.
[0005] Practical application of currently known networks of tubing, drippers, emitters, and sprayers often demands that dripper, sprayer, or sprinkler fittings be elevated above the elevation level of the main water supply tube of the distribution system to maximize usefulness and effectiveness of the delivery method.
[0006] Currently used devices that irrigate vegetation with a drip irrigation system with an elevated delivery point of water, such as spraying water from above, consist of a semi-rigid or rigid plastic or polypropylene tube or “riser,” generally six inches to eighteen inches in length, that is supported by a ground stake or other means to elevate the device above the landscape to be watered. A mini sprinkler or sprayer is attached at the top of the stake and the water supply tube is attached at the bottom to connect to a main water source, which enables the sprinkler or sprayer to be elevated above vegetation, spray over the vegetation, and thus cover a large area of ground and vegetation, with the caveat that the vegetation so watered is suited to this type of water delivery from above rather being suited to be soaked via the soil under the vegetation or dripping at ground level near the roots of the vegetation.
[0007] There are many disadvantages to currently known methods of watering vegetation. The plastic risers are limited in height, extending no more than eighteen inches above the ground. These risers typically are placed directly in the vegetated area where maintenance requires access that may damage or trample plants. Additionally, to utilize the mobility these methods offer often requires a considerable length of tubing to facilitate placement throughout the vegetated area. Long stretches of loose tubing are inconvenient to place, create tripping hazards, and the movement of excess tubing damages plants. The tubing is also prone to damage by animals and by routine work in the vegetated area performed by maintenance workers using tools such as shovels or spades. In lieu of regularly relocating an elevated sprayer or sprinkler currently used, multiple sprayers can be used on the system, which reduces the pressure in the overall system and also results in coverage overlap, thus increasing water use and overwatering some areas.
[0008] An alternative method to water delivery to vegetation also currently used is attaching a thin metal rod available in lengths up to thirty-six inches with a sprinkler/sprayer attached at one end of the rod, where the sprinkler/sprayer attaches to a water supply tube. The thin metal rod can then be inserted into the ground sufficiently deep enough that the rod will not fall over, with a water supply tube attached at the top of the rod to feed the sprayer or sprinkler. Thus, the sprinkler or sprayer is elevated as high as thirty inches above the ground. The disadvantage with this method of elevating the water distribution is potential instability of the rod, because the water supply tube attached at the top of the rod may pull on the rod. This configuration is also easily toppled by people tripping over this device or by animals, birds, or strong winds.
[0009] Both of the above mentioned configurations of devices currently used often require that the rods used in the devices are positioned in the middle of the vegetation which makes it difficult to reach, reset, or adjust the rods without damaging vegetation. There is a substantial risk of damage to the water supply tube, emitter, sprinkler or sprayer, and/or to the vegetation when these systems fall or are knocked down and are not quickly reset. Additionally, tubing that is cut or otherwise damaged results in water waste at the site and a resulting loss of pressure. Additionally, soil might be introduced into and contaminate the distribution system resulting in clogged emitters, sprayers or sprinklers that disrupt water delivery.
[0010] Large-scale commercial or agricultural users of watering systems such as nurseries that elevate irrigation above vegetation use various structures or frameworks built from wood or other materials. A water supply tube is supported above the vegetation and sprinklers or sprayers are attached at regular intervals to these structures, providing a uniform distribution of water to the plants located below. These kinds of systems must be custom built specifically for the building, greenhouse, or field in which they will be utilized and are expensive.
[0011] Currently available devices for elevating the height of water delivery from an irrigation system are inadequate for delivery of water to a receptacle above ground, particularly one located higher than three feet above ground. Currently known devices that elevate an emitter, sprayer or sprinkler to deliver water to areas on a plane higher than that of the drip irrigation system, such as a raised garden, hanging planter, or a bird bath or pet or wildlife water receptacle, is a do-it-yourself endeavor, that requires a customized approach. The endeavor usually consists of attaching a length of distribution tubing to a main water supply source and then draping the tube to a desired height above the vegetation, or using tape or wire to secure the distribution tube to the base of a bird bath or other receptacle and then running the tube up and over the lip of the bird bath or receptacle where the tube is secured or anchored in some way in order to distribute water as desired.
[0012] Many methods might be used in attempts to secure a water distribution tube to a rod, a basin, or some other structure, including but not limited to hooks, brads, screws, nails, tape, wire, string, and clamps. The tube might be similarly attached to more than one separate upright structures of some kind, in some fashion, to secure the tube at the desired height above vegetation and then position and hold the tube end in place in some way in order to direct water in the manner and direction desired. For example, in the case of distributing water to a free-standing basin or receptacle such as a bird bath, this might be as simple as draping the tube over the lip of the bird bath basin and securing it to the edge of the basin in some fashion. This method can be precarious, even though functional. The tube could be accidentally kicked loose, or come loose from any natural force such as wind or from action by birds or other animals, thus failing to fill the receptacle as desired and wasting water if not promptly corrected.
[0013] Sun and weather can quickly prove corrosive to tape and result in the tube falling from its desired position. Water is wasted and pressure reduction results from an open tube end on the system, causing other emitters or sprinklers on the same system not to receive adequate water in cases where the emitter is dislodged or comes loose, potentially resulting in injury and damage to vegetation. These flaws become particularly likely as the height of the tubing above the plane of the primary distribution system increases.
[0014] The apparatus of the present invention overcomes the disadvantages of those irrigation systems currently known and used. Advantages of the present invention include providing an apparatus and method for securing and directing water flow in drip irrigation or other water supply systems significantly above the plane of the water supply that is safe, stable, adjustable, flexible, and that does not risk damage to vegetation. The apparatus of the present invention extends the functionality of an irrigation system beyond simple irrigation to filling many types of receptacles for other purposes and comprises an apparatus that is easily maintained with off-the-shelf parts by “do-it-yourselfers.”
[0015] Further, the apparatus of the present invention is aesthetically pleasing and positively contributes to the overall appearance and design of a well-managed and planned yard, vegetation plot, or garden area. The horizontal displacement of the apparatus comprising tubing to a position displaced from its support is hidden within a cavity disposed in the apparatus and provides a clean appearance.
[0016] Advantages of the present invention include providing tubing that is adjusted horizontally, is securely supported, and is directed upward, downward, or in any other desired configuration, and is disposed on the apparatus in a location that provides for water delivery as required or desired. The tubing is securely fastened, either on one side of a supporting element comprising a rod or any other rigid support, or disposed through an opening in the supporting element, and fastened on an opposite side of the supporting element to any height required or desired.
[0017] Another advantage of the apparatus of the present invention is that it supplies water significantly above the elevation level of a main water supply tube of a drip irrigation system or any other irrigation water delivery system, as well as at ground level. This allows the apparatus of the present invention to be adapted to be useful in a plurality of scenarios, including but not limited to a terraced landscape, a birdbath, or a hanging pot.
[0018] The resulting apparatus of the present invention is thus cost-effective, uncomplicated, highly versatile, and effective, and comprises adapted components currently known for timely, efficient, and economical manufacturing, application, and utilization.
[0019] A number of advantages of one or more aspects of some embodiments of the adjustable, decorative support bracket of the present invention include the following.
[0020] Water supply emitters, sprinklers, sprayers or other fittings are elevated to a desired or required height greater than the eighteen (18) inches of poly risers currently used, or the thirty (30) inches of a wire tube support currently used. Water distribution is directed upward, downward, horizontally, or in a plurality of directions from an elevated position to suit a desired purpose.
[0021] A sturdy, stable, attractive, adjustable, flexible, and easily movable method for irrigating or water delivery is provided for watering plants in elevated gardens or hanging baskets and sprinkling or spraying water from a location above vegetation. A sturdy, stable, attractive, adjustable, flexible, and easily movable method is provided by the present invention to adapt an irrigation system to non-irrigation uses including filling elevated water receptacles such as bird baths, pet dishes, and small wildlife watering troughs.
[0022] Certain amounts of water are also distributed to a receptacle, raised planter, vegetation plot, or garden at precise times during the day or night using timers and electronic valve systems common in water delivery systems.
[0023] A stable support element is anchored outside the area to be watered instead of inside the area to be watered, where plants might be damaged in moving, repairing or replacing elements comprised by the present invention. An adaptable support comprising a vertical support visually enhances any environment and secures and hides the distribution tube. The water supply tubing is secured to prevent accidents or damage to the apparatus of the present invention resulting from tripping or animals. The present invention comprising tubing and fittings is adaptable, easily modified, maintained and replaced by laypersons and with readily available off-the-shelf parts.
[0024] Heat, cold, water, weather, and sun resistance is provided by using the present invention. An inexpensive and durable solution to elevating this type of water distribution is provided by using the present invention. Simple vertical and horizontal adjustment is provided by using the present invention.
[0025] Tube support uprights are used that, in various embodiments, provide additional utility such as fencing, wildlife perches, habitats, or feeders, sun shades, or planters. Tube support uprights are used that in various embodiments are fitted with decorative or artistic attachments or accessories to enhance appearance or functionality. Water is delivered in an environmentally friendly manner that reduces water waste and supports wildlife.
[0026] Certain embodiments of the invention have other steps or elements in addition to or in place of those mentioned above. The steps or element will become apparent to those skilled in the art from a reading of the following detailed description when taken with reference to the accompanying figures.
SUMMARY OF THE INVENTION
[0027] The present invention comprises a
[0028] A water delivery system comprising:
a bracket comprising:
a support; a base variably attached to said support; an extension attachably disposed on said base; and
a tube disposed adjacent to said support and through an opening within said base and said extension.
2. The tube of claim 1 further comprising a water delivery tube.
3. The base of claim 1 wherein said base is variably attached to said support to provide water at a variety of heights.
4. The water delivery system of claim 1 further comprising fasteners securing said tube to said support.
5. The water delivery system of claim 1 further comprising a sprinkler attached to an end of said water delivery tube.
6. The water delivery system of claim 1 further comprising a sprayer attached to an end of said water delivery tube.
7. The base of claim 1 comprising a support arm connecting upper and lower support panels
8. A method of delivering water comprising:
providing a bracket attached to a support; variably attaching a base to the support; attaching an extension to the base; and attaching a tube to the said support and through an opening within the base and the extension.
9. The method of delivering water of claim 8 further comprising attaching a sprinkler to one end of the water delivery tube and attaching a main water supply to the other end of the water delivery tube.
10. The method of delivering water of claim 8 wherein the water delivery tube is directed vertically.
11. The method of delivering water of claim 8 wherein the water delivery tube is directed horizontally.
12. The method of delivering water of claim 8 wherein the water delivery tube is positioned at a variable height above vegetation.
BRIEF DESCRIPTION OF THE DRAWINGS
[0038] FIG. 1 illustrates a side view of the bracket of the present invention comprising a min-sprayer;
[0039] FIG. 2 illustrates side view of the bracket of the present invention comprising a drip irrigator;
[0040] FIG. 3 illustrates a perspective view of the bracket of the present invention comprising an extension fully extended;
[0041] FIG. 4 illustrates a perspective view of the bracket of the present invention comprising an extension fully retracted;
[0042] FIG. 5 illustrates a perspective view of one side of one embodiment of a base of the present invention;
[0043] FIG. 6 illustrates a perspective view of another side of one embodiment of a base of the present invention;
[0044] FIG. 7 is a top and side perspective view of one embodiment of the extension of the present invention shown in FIG. 2 ;
[0045] FIG. 8 is a bottom and side perspective view of one embodiment of the extension of the present invention shown in FIG. 2 ;
[0046] FIG. 9 is a top and side perspective view of one embodiment of a vertical support housing of the present invention;
[0047] FIG. 10 is a top perspective view of one embodiment of a vertical support housing of the present invention; and
[0048] FIG. 11 illustrates a top and front exploded perspective view of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0049] The best mode for carrying out the invention will be described herein. The following embodiments are described in sufficient detail to enable those skilled in the art to make and use the invention. It is to be understood that other embodiments would be evident based on the present disclosure, and that system, process, or mechanical changes may be made without departing from the scope of the present invention.
[0050] In the following description, numerous specific details are given to provide a thorough understanding of the invention. However, it will be apparent that the invention may be practiced without these specific details. In order to avoid obscuring the present invention, some well-known system configurations, and process steps are not disclosed in detail.
[0051] The figures illustrating embodiments of the system are semi-diagrammatic and not to scale and, particularly, some of the dimensions are for the clarity of presentation and are shown exaggerated in the drawing figures.
[0052] The same numbers are used in all the drawing figures to relate to the same elements. The embodiments have been numbered first embodiment, second embodiment, etc. as a matter of descriptive convenience and are not intended to have any other significance or provide limitations for the present invention.
[0053] For expository purposes, the term “horizontal” as used herein is defined as a plane parallel to the plane or surface of the bracket system, regardless of its orientation. The term “vertical” refers to a direction perpendicular to the horizontal as just defined. Terms, such as “above”, “below”, “bottom”, “top”, “side” (as in “sidewall”), “higher”, “lower”, “upper”, “over”, and “under”, are defined with respect to the horizontal plane, as shown in the figures. The term “on” means that there is direct contact among elements.
[0054] In one or more embodiments of the present invention, the drip tube support bracket of the present invention comprises a base and an extension. The base is formed such that it can be attached to a vertical support or structure at some height above the plane of a drip irrigation or other water supply system so that it securely houses an extension that is adjusted horizontally to extend the reach of the end of the bracket, and thus the delivery point of water, away from the support or structure.
[0055] In one embodiment of the present invention, a base comprises a side comprising an opening through which an extension is disposed in a similarly shaped and sized indentation and also disposed in an opening in a side of the base. The method of use of the apparatus of the present invention comprises moving the extension through the opening in the base and guiding the extension so that it is supported, stable, and is anchored at a plurality of extension points. A water supply tube is subsequently directed from the plane of the water supply by attaching the tube to a rigid supporting structure as well as the indentation. The tube is then disposed within one end of the extension at the location where an emitter or other water distribution fitting is attachably disposed.
[0056] One end of the extension comprises an insertion element that accommodates a water supply tube in a plurality of dispositions, including a downward orientation, in order, for example, to fill a basin or receptacle, or an upward orientation, for example, in order to support a spray or sprinkler attachment for water distribution.
[0057] One embodiment of the bracket of the present invention is illustrated in FIG. 1 through FIG. 11 .
[0058] FIG. 1 is a side view illustrating bracket 5 comprising a plurality of elements. Bracket 5 is disposably attached to a supporting element comprising a drip irrigation tube which is disposed in an opening disposed in the support. In this preferred embodiment, bracket 5 comprises sprayer 20 that supplies water to vegetation. FIG. 1 illustrates bracket 5 comprising extension 8 disposably and movably attached to base 6 to preferably provide horizontal extension or retraction of extension 8 out of or into base 6 . Base 6 is disposably attached to support 12 at any height desired or required for the delivery of water to vegetation. Water supply tube 14 is disposably attached to a main water supply tube (not shown) and disposably attached to support 12 from ground level along support 12 via fasteners 18 , preferably comprising tube clamps.
[0059] Water supply tube 14 is disposed in opening 15 in support 12 and passes through the support and is disposed in and passes through the interior of base 6 and extension 8 . Tube 14 is directed vertically near one end of extension 8 using a fastener comprising a 90 degree fitting as well as a short section of tube 14 (not shown). Tube 14 is attachably disposed to sprayer 20 , providing water to vegetation.
[0060] FIG. 2 is a side view illustrating bracket 5 comprising a plurality of elements. Bracket 5 is disposably attached to a support comprising an opening. A drip irrigation tube is disposed within the opening. Bracket 5 comprises drip emitter 20 that supplies water to vegetation or to any receptacle including but not limited to a bird bath or watering trough. FIG. 2 illustrates bracket 5 comprising tube 14 disposed in opening 15 , directed to one end of extension 8 and then directed downward and disposably attached to drip emitter 20 .
[0061] Bracket 5 comprises any number of materials manufactured using a plurality of processes to create a wide variety of alternative embodiments of the present invention. One embodiment of bracket 5 comprises a manufactured product created by an injection molding process from Acrylonitrile Butadiene Styrene (ABS), which is a high gloss, impact-resistant polymer that provides excellent functionality and balances durability and appearance with affordable manufacturing cost. Other embodiments of the present invention 5 comprise embodiments stamped or formed from a plurality of metals; cast from a variety of different metals including but not limited to brass, bronze, or aluminum; cast from composite materials; cast from polymers, resins, or structural fiberglass; made from cast materials that are subsequently machined; made from metal that has been welded and then machined; or constructed by adapting similarly shaped objects to this purpose.
[0062] FIG. 3 illustrates a perspective view of the bracket of the present invention comprising the extension fully extended. FIG. 3 illustrates a bottom, side perspective view of bracket 5 comprising extension 8 fully extended from base 6 . Base 6 comprises upper and lower arm support panels 6 p and support arm 6 a . Opening 6 h is disposed in and preferably centered in upper and lower arm support panels 6 p and comprises an opening for mounting base 6 to be disposed within. Opening 6 h is positioned vertically providing access to attachably dispose a fastener comprising a screw, nail, or any other fastener, in order to attach base 6 to support 12 .
[0063] FIG. 4 illustrates an embodiment of the bracket with extension 8 in a retracted position in which upper opening 8 t (not shown) and tube support 8 f disposed opposite upper opening 8 f are disposed outside base 6 comprising front opening 6 f (not shown).
[0064] FIG. 5 illustrates a perspective view of one side of one embodiment of a base of the present invention. FIG. 6 illustrates a perspective view of another side of the embodiment of a base of the present invention.
[0065] Support arm 6 a is attachably disposed to upper and lower support panels 6 p , shown in FIGS. 3 and 4 . Support arm 6 a thus connects upper and lower support panels 6 p . In the embodiment shown, support arm 6 a and upper and lower support panels 6 p comprise a single element. Support arm 6 a comprises a hollow element extending from support panels 6 p and attachably disposed to support 12 . Support arm 6 a comprises opening 6 b , extension guide slots 6 g , extension guide tab 6 t that protrudes from the inside of the upper portion of support arm 6 a , front opening 6 f through which extension 8 is disposed, and spring catch 6 c forming the lower edge of front opening 6 f.
[0066] Base 6 comprises extension 8 . Extension 8 is disposed within rear opening 6 b which is disposed in base 6 . Extension 8 is also disposed within front opening 6 f of base 6 prior to disposing base 6 on support 12 . Stabilizing slot 8 s disposed in extension 8 , as illustrated in FIG. 7 , is disposed onto tab 6 t on the inside, top side of opening 6 f at the front of base 6 during the process of disposing extension 8 through rear opening 6 b , as illustrated in FIG. 6
[0067] Tab 6 t , when disposed in stabilizing slot 8 s , provides lateral stability for extension 8 when extension 8 is less than fully extended keeping extension 8 centered within opening 6 f throughout its length of travel. Support arm 6 a comprises guide slots 6 g on both side walls, along its length, and parallel to the line of the upper wall of base 6 . Posts 8 p disposed on the sides of extension 8 are secured within guide slots 6 g disposed on the sides of support arm 6 a when fully inserted into support arm 6 a . Posts 8 p maintain the vertical stability of extension 8 as extension 8 moves throughout its range of movement, thus keeping extension 8 parallel with the ground and perpendicular to upright 12 .
[0068] Extension 8 is easily adjusted to the desired horizontal position after being fully inserted into support arm 6 a by moving extension 8 out of support arm 6 a or moving extension 8 in and allowing catch 6 c to lock into any of the sets of indentations 8 n disposed in extension 8 .
[0069] FIG. 7 is a top and side perspective view of one embodiment of the extension of the present invention shown in FIG. 2 . FIG. 8 is a bottom and side perspective view of one embodiment of the extension of the present invention shown in FIG. 2 .
[0070] In this embodiment, extension 8 comprises a multi-sided structure comprising indentation 8 c disposed in extension 8 in which tube 14 is disposed within span indentation 8 c and adjacent to tube support 8 f . Tube support 8 f is disposed adjacent to one side of extension 8 , thus creating lower opening 8 d for tube 14 to exit extension 8 in a downward orientation and supporting tube 14 , and creating opening 8 t in the top wall of extension 8 opposite tube support 8 f that allows tube 14 to exit extension 8 vertically.
[0071] Indentations 8 n are disposed on one side of the side walls of extension 8 . Spring catch 6 c securely attaches extension 8 both vertically by applying upward pressure, keeping upper face of extension 8 flush with the inside of opening 6 f , and also securely attaches extension 8 horizontally with the upward edge of spring catch 6 c disposed securely in indentations 8 n on both sides of extension 8 . Side posts 8 p protrude from the side walls at one side of extension 8 and fit into guide slots 6 g disposed in base 6 . Extension 8 comprises a dimension such that extension 8 fits inside front opening 6 f of base 6 . comprises another dimension such that when extension 8 is retracted into base 6 , upper opening 8 t and tube support 8 f disposed opposite upper opening 8 f remain disposed exterior of front opening 6 f of base 6 .
[0072] FIG. 9 is a top and side perspective view of one embodiment of a vertical support housing of the present invention. FIG. 10 is a top perspective view of one embodiment of a vertical support housing of the present invention. FIGS. 9 and 10 illustrate vertical support housing 10 vertically securably attached to tube 14 , preferably to another section of tube 14 (not shown) providing for water to be directed vertically through opening 8 t which is disposed in extension 8 . This directional change is accomplished by the use of a ninety (90) degree fitting (not shown) disposed in tube 14 which directs the water flow vertically. To accomplish this, tube 14 is extendably disposed through opening 8 t where an appropriately sized ninety (90) degree tube fitting (not shown) is attached and positioned such that it points vertically when disposed in and secured to extension 8 .
[0073] The section of tube 14 is then attached to another side of the ninety (90) degree fitting (not shown). The section of tube 14 is disposed between rocker legs 10 r of vertical support housing 10 , and also disposed through vertical tube passage 10 p whereby side flanges 10 s securably attach tube 14 in a vertical position once vertical support housing 10 is securably attached within extension 8 . The ninety (90) degree tube fitting (not shown) is disposed flush with vertical support housing 10 whereby the section of tube 14 extends substantially from vertical tube passage 10 p . Vertical support housing 10 wherein tube 14 is disposed, and connected by the ninety (90) degree fitting (not shown) is then disposed within opening 8 t so that back tab 10 b moves under the rear edge of opening 8 t.
[0074] Vertical support housing 10 comprises front tab 10 f . Once fully inserted, vertical support housing 10 is rotatably disposed on rocker legs 10 r until front tab 10 f . is movably disposed adjacent to an edge of opening 8 t and vertical support housing 10 is movably disposed in a direction closer to an end of extension 8 until vertical support housing 10 is secured by catch 10 c is disposed adjacent to rear edge of opening 8 t . A sprinkler or sprayer fitting is then secured to one end of the section of tube 14 as desired.
[0075] In another embodiment, support 12 comprises a structure including but not limited to a building, a wall, a fence, a tree, or a free-standing rigid support made of any suitable material, in any size, and with a cross-section of any shape (square, rectangular, circular, or flat) sufficiently rigid and strong to support bracket 5 of the present invention. In the embodiment illustrated in FIG. 1 and FIG. 2 , for example, a standard piece of lumber with a cross-section sufficient to adequately support the bracket in use at the height above the ground required for placement of the bracket to effectively deliver water is employed. The bracket is easily attached to such a support with two fasteners comprising screws.
[0076] FIG. 11 illustrates a top front exploded perspective view illustrating a disassembled embodiment of the present invention. FIG. 11 illustrates extension 8 positioned to be inserted through a side of base 6 as well as vertical support housing 10 positioned to be inserted into an opening on a side of extension 8 after the extension has been positioned within the base.
[0077] The method of use of bracket 5 of the present invention is illustrated in FIG. 1 and FIG. 2 . In the embodiment shown, bracket 5 is assembled by positioning extension 8 into base 6 from a side whereby posts 8 p are secured in guide slots 6 g . Base 6 is subsequently attachably disposed to support 14 and secured using fasteners comprising screws (not shown). Extension 8 is movably disposed to a desired position where extension 8 is secured by catch 6 c when disposed in indentations 8 n . A section of tube 14 is then attached to support 12 so that tube 14 extends the combined length of base 6 and extension 8 . Tube 14 is positioned such that the tube is disposed exterior to either upper opening 8 t or lower opening 8 d of extension 8 . Tube 14 is securely disposed adjacent to a side of support 12 or is disposed through a pre-drilled opening in support 12 and securely disposed adjacent to a side of support 12 .
[0078] FIG. 1 illustrates the bracket securely disposed adjacent to vertical support 12 with tube 14 disposed within and extending from an opening in support 12 . Tube 14 is then secured to a side of support 12 by tube clamps 18 and secured to the ground where tube 14 is connected to a water supply. In this embodiment, tube 14 is directed vertically at one end of extension 8 by vertical support housing 10 . A mini-sprinkler or sprayer 61 is attachably disposed adjacent to tube 14 .
[0079] FIG. 2 shows the bracket in the same embodiment as FIG. 1 but configured without vertical support housing 10 and tube 14 directed out the end of extension 8 through the lower opening 8 d in a downward fashion with a drip emitter 61 attached.
[0080] An end of tube 14 is connected to a water supply when the tube is configured to deliver water at the height and in the manner desired. Typically, in a residential drip irrigation system, a water supply comprises a tube that is connected to a valve at one end and is either capped at the other end or reconnected to itself near the point of origin at the valve to create a loop. The valve is typically controlled by an automatic timer to open and close the valve at set times for set intervals. The amount of water delivered is controlled by the amount of time the water is scheduled to run in combination with the flow rate of drip emitter(s), sprinklers, or sprayers 20 used.
[0081] Alternately, a simple control valve is spliced into tube 14 between a water supply and any particular drip emitter, sprinkler or sprayer 20 so the volume of water is restricted or shut off. Alternatively, tube 14 is connected to an adapter by which it is connected directly to a hose or faucet. In this configuration, the water is manually fed to the emitter, sprinkler or sprayer by turning the water on or off.
[0082] There are many design and manufacturing alternate embodiments of the bracket of the present invention. The embodiment described above as illustrated in FIG. 1 through FIG. 11 comprises a multi-piece apparatus that is mounted at any height and is easily adjustable horizontally within some limited range. However, in instances in which no horizontal variability is required, the bracket is manufactured as a one piece decorative support for tube 14 that accommodates tube 14 and the emitters, sprayers, or sprinklers required for the particular configuration of water delivery. In this embodiment, the bracket mimics the appearance of the embodiment illustrated in FIG. 1 through FIG. 11 by manufacturing it such that support arm 6 a is similar in length to the embodiment illustrated in FIG. 1 through FIG. 11 comprising a support arm 6 a and extension 8 and comprising an end similar to the end of extension 8 . Thus, extension 8 is eliminated together with those elements of base 6 that are associated with extension 8 comprising guide slots 6 s , tab 6 t , and catch 6 c.
[0083] A one piece embodiment of the present invention comprises any other form or design that serves the function and purpose of elevating a water supply tube to some level above the ground and directing attached emitters, sprinklers, or sprayers for delivery of water to a receptacle or to deliver water to vegetation at a lower height.
[0084] Conversely, there are situations where more horizontal variability is required than is provided by the embodiment illustrated in FIG. 1 through FIG. 11 . In this situation, an extension is manufactured in two or more pieces, of variable length and construction, to allow tube 14 to be extended horizontally at a greater distance from support 12 . This is accomplished in a variety of methods. Several separate pieces are fastened to each other, added, or removed in order for the extension to be adjustable in length as required.
[0085] Also in this embodiment, a section is attached at the end of extension 8 by a fastener comprising a bolt and wing nut to enable rotation of the piece in a horizontal direction and then secured to direct the water appropriately. This is the case, for example, where the bracket must be placed at an angle to the receptacle or area to be watered that is not conducive to efficient delivery of the water to the affected area or receptacle.
[0086] Yet another embodiment comprising horizontal variability comprises a one piece base or extension comprising a plurality of sections that telescope similar to that of a collapsible radio antenna. Thus, the length of the extension is adjusted as required or desired.
[0087] Vertical adjustability is provided via elements comprising a track along with the bracket that is attached to support 12 in a vertical orientation with fasteners comprising screws. The bracket is movably disposed vertically on the track and is secured to a desired position. There are a plurality of track configurations and materials, including a material identical to base 6 material. Thus, the present invention is adjusted to a desired height and then secured with a variety of fasteners.
[0088] In a final embodiment, base 6 of the present invention comprises extensions 8 that serve a variety of purposes related to the delivery of water through automatic drip irrigation systems to elevations significantly above the level of a water line. Regardless of the actual design of base 6 and extension 8 , the base and extension are constructed such that extension 8 fits into base 6 , and is adjustable horizontally. This allows for any number of different extensions 8 , all of which fit base 6 and adjust horizontally. Each of the different extensions 8 perform in a different capacity with respect to the end delivery of water. For example, one extension 8 , the preferred embodiment, routes the drip tube and emitter over the lip of a bird bath and directs the drip tube downward to deliver water into the bird bath.
[0089] A different extension 8 is configured such that mini sprinklers or sprayers are attached. Still another extension 8 raises the drip tube to a height where it is continued along the ground to deliver water from drippers, which is useful in a raised garden area. Another embodiment of extension 8 fills pet water containers.
[0090] The of the various embodiments of the present invention comprising an adjustable, decorative support bracket described herein is used in any number of applications where it is necessary or desired to elevate the delivery point of water in an irrigation system or other type of water supply system in ways that extend functionality and provide stable, safe, adjustable, and aesthetically appealing solutions.
[0091] Furthermore, the bracket of the present invention provides the following additional advantages. The bracket is mounted at a plurality of any heights on a plurality of stable supports; the bracket permits water to be directed from the bracket through the use of a plurality of fittings and attachments comprising sprinklers, sprayers, drippers, and misters; the bracket is easily installed, configured, and maintained using readily available off-the-shelf elements; water supply tubes are secured to eliminate tripping hazards, damage by animals, or damage to vegetation; water supply tubes can be hidden to improve the aesthetics of a garden area; and the bracket allows regular filling of receptacles for wildlife in a manner that is efficient and conserves water.
[0092] Although the description above contains much specificity, this should not be construed as limiting the scope of the embodiments but as merely providing illustrations of some of several embodiments. For example, the bracket comprises other cross sectional shapes including but not limited to triangular, oval, or cylindrical. The bracket comprises one piece or several pieces configured and adjustable in any of a variety of ways including, but not limited to telescoping “antenna-like” sections, interlocking sections, or sections connected by screws or bolts. Thus, the scope of the embodiments should be determined by the appended claims and their legal equivalents rather than by the examples given.
[0093] While the invention has been described in conjunction with a specific best mode, it is to be understood that many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing description. Accordingly, it is intended to embrace all such alternatives, modifications, and variations that fall within the scope of the included claims. All matters previously set forth herein or shown in the accompanying drawings are to be interpreted in an illustrative and non-limiting sense.
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The present invention relates generally to a water delivery system comprising a rigid support, an adjustable extension attachably disposed on a base wherein a water supply tube is disposably attached to the rigid support and within the extension. The water supply tube is flexibly and variably positioned from ground level to any desired height. Any type of sprinkler, sprayer, or other kind of water distributor is attachably secured to the water supply tube to provide water to vegetation or containers inexpensively, efficiently, and esthetically.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application is an improvement over U.S. Pat. No. 5,896,588, which issued on Apr. 27, 1999, and is entitled “Multi-Layer Knee Pad Construction.”
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the field of protective padding devices in general, and in particular to a multi-layer, waterproof, cushioned pad construction for garments.
2. Description of Related Art
As can be seen by reference to the following U.S. Pat. Nos. 4,831,666; 4,920,577; 5,134,726; and, 5,592,689, the prior art is replete with myriad and diverse protective knee pad constructions.
While all of the aforementioned prior art constructions are more than adequate for the basic purpose and function for which they. have been specifically designed, they are uniformly deficient with respect to their failure to provide a simple, efficient, and practical protective garment pad construction that can be ironed onto the interior knee or elbow portion of a garment to provide a low profile waterproof, cushioned pad construction that will protect the user's knees or elbows.
As any gardener, construction worker, or parent with small children is all too well aware, the presence of a protective knee covering is an absolute necessity under virtually all circumstances.
As a consequence of the foregoing situation, there has existed a longstanding need for a new and improved type of garment pad construction that employs a multilayer construction that is waterproof, cushioned, and low friction, and the provision of such a construction is a stated objective of the present invention.
BRIEF SUMMARY OF THE INVENTION
Briefly stated, the improved garment pad construction that forms the basis of the present invention comprises in general an outer contact layer, a waterproof layer, a padded layer and an inner overlap layer that are operatively associated with one another in a specific fashion and are adapted to be operatively connected to a selected interior surface of a garment so that the presence of the pad construction is not readily apparent.
As will be explained in greater detail further on in the specification, the outer and inner layers are joined together in a specific fashion to form a sealed chamber that envelops the waterproof layer and the padded layer wherein the waterproof layer frictionally engages both the outer layer and one side of the padded layer, and the other side of the padded layer only frictionally engages the inner overlap layer.
In addition, the friction-only contact between the waterproof and padded layers resists the bunching of those layers within the chamber formed by the inner and outer layers.
Furthermore, this invention also contemplates fabricating the waterproof layer from two generally identical rectangular sheets of neoprene whose inner surfaces are in frictional contact with one another and whose outer surfaces are in frictional contact with the padded layer and the outer contact layer to further reduce any bunching that might normally occur within the chamber formed by the inner and outer layers.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
These and other attributes of the invention will become more clear upon a thorough study of the following description of the best mode for carrying out the invention, particularly when reviewed in conjunction with the drawings, wherein:
FIG. 1 is a perspective view of the protective garment pad construction that forms the basis of the present invention in use;
FIG. 2 is a rear perspective view of the knee pad construction;
FIG. 3 is a cross-sectional view taken through line 3 — 3 of FIG. 2;
FIG. 4 is an exploded rear perspective view of the first version of the preferred embodiment of this invention; and,
FIG. 5 is an exploded rear perspective view of the second version of the preferred embodiment of this invention.
DETAILED DESCRIPTION OF THE INVENTION
As can be seen by reference to the drawings, and in particular to FIG. 3, the improved multi-layer garment pad construction that forms the basis of the present invention is designated generally by the reference number 10 . The pad construction 10 comprises in general a waterproof layer 11 , a padded layer 12 , an outer adhesive layer 13 , and an overlap layer 14 . These layers will now be described in seriatim fashion.
As shown in FIGS. 3 and 4, in the first version of the preferred embodiment, the waterproof layer 11 comprises a single generally rectangular sheet of neoprene rubber material 20 having an enlarged thickness T 1 , which provides a generally resilient waterproof barrier for the pad construction 10 .
In addition, the padded layer 12 comprises a generally rectangular sheet of padding material 30 such as non-woven cotton batting, fleece, or the like wherein the overall dimensions and thickness of the waterproof layer 11 and the padded layer 12 are essentially the same.
Still referring to FIGS. 3 and 4, it can be seen that the outer contact layer 13 comprises an enlarged generally rectangular sheet of cloth fabric 40 preferably fabricated from a poly/cotton blend material and having an outer face 40 A provided with a heat activated adhesive for securing the outer adhesive layer 13 to the interior surface 101 of a garment 100 such as the elbow portion of a shirt or jacket or the knee portion of a pair of pants.
Furthermore, the inner overlap layer 14 comprises a reduced dimension generally rectangular sheet of low friction material 50 such as a poly/blend fabric having an inner face 50 A provided with a heat activated adhesive coating; wherein, the exterior dimensions of the inner overlap layer 14 are slightly larger than the exterior dimensions of the waterproof 11 and padded layers and substantially smaller than the exterior dimensions of the outer adhesive layer 13 such that the inner overlap layer 13 may be fixedly engaged to the outer adhesive layer 14 by either the heat activated adhesive coating 50 A or by stitching 51 to captively engage the padded layer 12 and the waterproof layer 11 intermediate the inner 13 and outer 14 layers in a well recognized fashion.
Turning now to FIG. 5, it can be seen that the only difference between the first and second preferred embodiments of this invention is the fact that in the second version of the preferred embodiment, the waterproof layer 11 comprises a pair of generally identical rectangular sheets of neoprene material 20 ′ and 20 ″ having thicknesses T 2 and T 3 respectively; wherein, the combined value of thicknesses T 2 and T 3 is equal to the thickness T 1 in the first version of the preferred embodiment wherein the preferred value of T 1 is approximately ?????????????
It should be noted at this juncture that in both versions of the preferred embodiment there is only frictional engagement between the opposed surfaces of the waterproof layer 11 and the padded layer 12 , as well as between the waterproof layer 11 and the outer adhesive layer 14 and the padded layer 12 relative to the overlay layer 13 . The reason for this relationship being not only ease of fabrication of the pad construction 10 , but also to minimize the possibility that the waterproof layer 11 and/or the padded layer 12 will become bunched within the sealed chamber formed between the outer adhesive layer 14 and the inner overlay layer 13 .
It should further be noted that the use of the pair of neoprene sheet 20 ′ 20 ″ in the second version of the preferred embodiment further enhances this anti-bunching feature of the finished pad construction 10 in that both of the neoprene sheets 20 ′ and 20 ″ are movable relative to one another.
Although only an exemplary embodiment of the invention has been described in detail above, those skilled in the art will readily appreciate that 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.
Having thereby described the subject matter of the present invention, it should be apparent that many substitutions, modifications, and variations of the invention are possible in light of the above teachings. It is therefore to be understood that the invention as taught and described herein is only to be limited to the extent of the breadth and scope of the appended claims.
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A multi-layer garment pad construction ( 10 ) for attachment to the interior surface ( 101 ) of a garment ( 100 ) on the knee or elbow portion. The construction ( 10 ) including a waterproof layer ( 11 ) and a padded layer ( 12 ) frictionally associated with one another and also frictionally associated respectively with an outer adhesive layer ( 13 ) and an inner overlap layer ( 14 ) which are fixedly joined to one another to form a sealed chamber surrounding the waterproof ( 11 ) and padded ( 12 ) layers.
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This application is a continuation-in-part of Ser. No. 10/127,642, filed Apr. 22, 2002 now abandoned.
BACKGROUND OF THE INVENTION
The present invention relates generally to a plant pot, and more particularly to a wall-hanging pot which keeps the suitable water and air supplies so as to encourage the healthy growth of plants. The prior art abounds with plant pots or planters using different types of methods to hang pots on a wall and/or to control water level in pots or planters. Numerous such prior art pots are disclosed in United States patents as exemplified by U.S. Pat. Nos. Des. 307,877 to White; Des. 409,854 to Rehmert et al.; 4,837,972 to Reed; 4,499,688 to Droll; 4,912,875 to Tardif; 5,042,197 to Pope; and 5,487,517 to Smith.
While these prior art plant pots might be hung on a wall, overhead beam, or handrail and/or control water level in the pot, all suffer from numerous deficiencies and disadvantages. Some of them can be hung on a wall but are not easily removable from the wall. Some of them involve complicated parts or systems to control water level. The present invention overcomes these deficiencies and disadvantages in that it provides a new and improved wall-hanging plant pot with a water level control device that keeps the suitable moisture and air supplies in the pot for longer period.
SUMMERY OF THE INVENTION
The wall-hanging plant pot of the present invention generally comprises a wall hanger, a container with one or more projections for holding a plant and soil, a water level control device, and a cap for controlling the flow of excess water.
It is an object of the present invention to provide an improved wall-hanging plant pot which can be easily hung on a wall, detached from the wall, and placed in a different place without using special tools.
It is another object of the present invention to provide an improved wall-hanging plant pot which controls the water level and keeps the suitable moisture and air supplies in the pot.
It is a further object of the present invention to provide an improved wall-hanging plant pot which allows excess water to gradually be drained for longer periods through a bottom opening by slightly loosening the cap or which can be taken indoor without drippings of water by tightening the cap.
It is yet a further object of the present invention to provide an improved wall-hanging plant pot which is simple and inexpensive in construction, which may be easily used at home or in other environments, for growing and displaying plants.
Other objects, features, and advantages of the present invention will become apparent from the following detailed description and from the appended drawings in which like numbers have been used to designate like parts throughout the several views.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of the wall-hanging plant pot of the present invention.
FIG. 2 is a front elevational, exploded view of the wall-hanging plant pot of the present invention.
FIG. 3 is a front elevational, partially broken away and in section, view of the present invention having a plant and soil.
FIG. 4 is a perspective view of the second embodiment of the wall-hanging plant pot of the present invention.
FIG. 5 is a front elevational, exploded view of the second embodiment of the wall-hanging plant pot of the present invention.
FIG. 6 is a perspective view of the third embodiment of the wall-hanging plant pot of the present invention.
FIG. 7 is a front elevational, exploded view of the second embodiment of the wall-hanging plant pot of the present invention.
FIG. 8 is a perspective view of the water control device of the present invention.
FIG. 9 is a perspective view of the wall hanger of the first and second embodiment of the present invention.
FIG. 10 is a perspective view of the wall hanger of the third embodiment of the wall-hanging plant pot of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to the drawings, wherein like numerals represent like parts throughout, reference numeral 10 generally designates the wall-hanging plant pot of the present invention. As best seen in FIGS. 1 and 2, the wall-hanging plant pot 10 generally comprises a screw or nail 54 , a wall hanger 48 , a container 22 with one or more projections 30 , and a cap 42 . As best seen in FIGS. 2 and 9, the wall hanger 48 includes a prong 50 and a screw-resting portion 52 . As best seen in FIG. 2, the container 22 includes an upper opening 24 , an upper annular portion 26 having one or more projections 30 with an opening 32 therein, an outwardly extending shoulder 28 , a wall 34 , and a lower portion 36 having an opening 40 surrounded by external threads 38 with a single vertical slot in said external threads 38 . As best seen in FIG. 8, a water level control device 12 includes an upper portion 14 having a plurality of openings 20 , a side wall 16 , and a lower opening 18 . As best seen in FIGS. 2 and 5, a cap 42 includes a central opening 44 and internal threads 46 .
The several components of the wall-hanging plant pot 10 is best assembled from its exploded, separated, condition as shown in FIG. 2 to its assembled, joined, condition as shown in FIGS. 1 and 3 in the following order:
a. The water level control device 12 is inserted within the lower opening 40 of the container 22 through the upper opening 24 .
b. The cap 42 is threadedly engaged with the threads 38 on the lower portion 36 of the container 22 .
c. The small plant 136 and soil 132 are placed in the container 22 .
d. The wall hanger 48 is attached to the container 22 by placing the prong 50 into the opening 32 in the projection 30 of the container 22 .
e. The fully assembled container 22 and the wall hanger 48 are then hung on a wall by placing the screw-resting portion 52 of the wall hanger 48 onto a screw or nail 54 attached to the wall.
After the wall-hanging plant pot 10 is assembled and the plant and soil are placed in the pot as generally explained, water or premixed solution is added to the container 22 . The excess water is drained through the openings 20 in the upper portion 14 of the water level control device 12 , and suitable amount of water 134 below the openings 20 remains at the bottom of the container 22 and is gradually absorbed by the soil 132 . The excess water drained through the openings 20 is released through the lower opening 40 of the container 22 by slightly loosening the cap 42 . The water level control device 12 and the container 12 can be held together by press-fit, and the height of the water level control device 12 can be adjusted by changing the depth of the insertion. The flow of excess water from the opening 40 can be controlled by adjusting the tightness of the cap 42 .
A second embodiment of the wall-hanging plant pot is depicted in FIGS. 4 and 5 with like reference numerals referring to like parts. The embodiment depicted in FIGS. 4 and 5 differs from that disclosed in FIGS. 1-3 in the type of the container for holding a plant and soil. The container for the second embodiment includes two parts, an insert ring and a reservoir.
Referring now to FIGS. 4 and 5, the second embodiment of the wall-hanging plant pot comprises a screw or nail 54 , a wall hanger 48 , an insert ring 58 , a water level control device 12 , a reservoir 86 , a cap 42 . As best seen in FIG. 5, the insert ring 58 includes a central opening 60 , an upper annular portion 62 having one or more projection 64 with an opening 66 therein, an outwardly extending shoulder 68 , annular groove 70 , a lower annular portion 72 , a lower tapered portion 74 , a plurality of grippers 76 , and a plurality of slits 78 . As still best seen in FIG. 5, a reservoir 80 includes an upper opening 82 , a wall 84 , a lower portion 86 having an opening 90 surrounded by external threads 88 with a single vertical slot in said external threads 38 .
The wall-hanging plant pot of the second embodiment is assembled to the condition generally depicted in FIG. 4 in the following order. First, insert ring is inserted into the upper opening 82 of the reservoir 80 . Second, the water level control device 12 is inserted into the opening 90 of the reservoir 80 , and then the cap 42 is threadedly engaged with the threads 88 on the lower portion 86 of the reservoir 80 .
The insert ring 58 and reservoir 80 can be held together by friction fit. The grippers 76 and the slits 78 provide resiliency to the lower section (not numbered) of the insert ring 58 to enable the insert ring 58 to fit within the opening 82 of the reservoir 80 of varying internal dimensions. The grippers 76 penetrate the surface of the inner wall 84 of the reservoir 80 to secure the reservoir 80 to the insert ring 58 .
Referring now to FIGS. 6 and 7, the third embodiment of the wall-hanging plant pot comprises a screw or nail 54 , a wall hanger 92 , an adapter 98 , a reservoir 120 , a water level control device 12 , and a cap 42 . As best seen in FIG. 7, the wall hanger 92 includes a plurality of prongs 94 and a screw-resting portion 96 . As still best seen in FIG. 7, the adapter includes a plurality of projections 104 having an opening 106 therein, a central opening 100 , an upper outer portion 102 , an outwardly extending shoulder 108 , a groove 110 , a lower outer portion 112 , a tapered portion 114 , a plurality of grippers 116 , and a plurality of slits 118 . As best seen in FIG. 7, the reservoir 120 includes an upper opening 122 , a side wall 124 , and a lower portion 126 having a lower opening 130 surrounded by threads 128 with a single vertical slot in said external threads 38 .
The wall-hanging plant pot of the third embodiment is assembled to the condition generally depicted in FIG. 6 in the following order. First, the adapter 98 is inserted into the upper opening 122 of the reservoir 120 . Second, the water level control device is inserted into the lower opening 130 of the reservoir 120 , and then the cap 42 is threadedly engaged with threads 128 on the lower portion 126 of the reservoir 120 . Finally, the wall hanger 92 is attached to the adapter 98 by placing each prong 94 of the wall hanger 92 in the opening 106 on the projection 106 of the adapter 98 .
The adapter 98 and reservoir 120 can be held together by friction fit. The grippers 116 and the slits 118 provide resiliency to the lower section (not numbered) of the adapter 98 to enable the adapter 98 to fit within the upper opening 122 of the reservoir 120 of varying internal dimensions. The grippers 116 penetrate the surface of the inner wall 124 of the reservoir 120 to secure the reservoir 120 to the adapter 98 .
While particular embodiments of this invention have been shown in the drawings and described above, it will be appreciated that the invention is susceptible to modifications, variations, and adaptations without departing from the proper scope and fair meaning of the accompanying claims.
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A wall-hanging plant pot with a water level control device which keeps suitable moisture and air supplies in the pot. The wall-hanging plant pot comprising a screw or nail, a wall hanger, a container with bottle-neck bottom having one or more projections and bottle-neck bottom, a water level control device, and a cap.
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BACKGROUND OF THE INVENTION
The present invention relates to a vehicle cornering headlamp system in which the direction of illumination of a headlamp is varied in association with a steering wheel turning operation.
A vehicle, especially an automobile, has headlamps for producing a light beam forward of the vehicle at night. The direction of illumination of the headlamps is fixed so that the main beam of light is applied directly forward of the vehicle. However, when the vehicle is traveling along a curve, the headlamps cannot sufficiently illuminate objects ahead of the vehicle. In other words, during travel along curves and in cornering, hazardously objects located in the path of the vehicle may not sufficiently be illuminated by the headlamps.
In order to overcome this difficulty, recently a vehicle cornering headlamp system has been proposed in which the direction of illumination of the headlamps is changed in association with steering wheel turning operations so that objects located in the actual path of the vehicle are sufficiently illuminated.
However, in the conventional vehicle cornering headlamp system, the variation of direction of illumination varied linearly with respect to the steering angle, that is, the change is the same in the case where the steering wheel is turned away from the straight-ahead steering position as in the case where the steering wheel is returned to the straight-ahead steering position, as shown by the graph in FIG. 11. As a result, the direction of illumination returns to the straight-ahead direction of the vehicle at the same time the steering wheel is returned to the straight-ahead steering position.
In the case where the vehicle travels around a curve, in general, the operator decelerates the vehicle before it reaches the curve, and, after the vehicle reaches the curve, accelerates the vehicle, then returns the steering wheel to the straightahead position before the vehicle reaches the end of the curve. When returning the steering wheel, studies have found that the driver's eyes are no longer on the curved part of the road, but on a linear extension of the curve. Due to the factors, the direction of illumination of the headlamp is not coincident with the direction of the driver's eyes immediately before the vehicle reaches the end of the curve; that is, the driver may feel the change of the direction of illumination of the headlamp inharmonious with the steering-wheel turning operation.
SUMMARY OF THE INVENTION
Accordingly, an object of the invention is to eliminate the above-described difficulties accompanying a conventional vehicle cornering headlamp system.
In a vehicle cornering headlamp system according to the invention, the gradient of a variation characteristic of the illumination direction with respect to the steering angle is made larger in the case where the steering wheel is returned towards the straight-ahead steering position than in the case where the steering wheel is turned away from the straight-ahead steering position.
Accordingly, with the vehicle cornering headlamp system of the invention, the direction of illumination is returned to the straight-ahead direction of the vehicle earlier than the steering wheel.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graphical representation showing a variation characteristic of illumination direction with a steering angle, which representation is used for a description of the operating principles of a vehicle cornering headlamp system according the the invention;
FIG. 2 is an explanatory diagram, partly as a block diagram, showing the arrangement of an example of a vehicle cornering headlamp system of the invention;
FIG. 3 is a block diagram showing the arrangement of a control signal generating circuit in the vehicle cornering headlamp system shown in FIG. 2;
FIG. 4 is an external perspective view of a headlamp the direction of illumination of which is changed with the vehicle cornering headlamp system of the invention;
FIG. 5 is an external perspective view of a speed reduction drive mechanism coupled to an electric motor in the vehicle cornering headlamp system;
FIG. 6 is a circuit diagram, partly as a block diagram, showing the arrangement of a servo motor control circuit in the vehicle cornering headlamp system shown in FIG. 2;
FIG. 7 is a timing chart for a description of a direction-of-illumination changing operation effected when the steering wheel is turned clockwise away from the straight-ahead steering position in the vehicle cornering headlamp system of the invention;
FIG. 8 is a sectional plan view of the headlamp shown in FIG. 4;
FIG. 9 is a timing chart for a description of a direction-of-illumination changing operation effected when the steering wheel is turned counterclockwise away from the straight-ahead steering position;
FIG. 10 is also a timing chart for a description of the operation of the control signal generating circuit shown in FIG. 3; and
FIG. 11 is a graphical representation showing a variation characteristic of illumination direction with steering angle in a conventional vehicle cornering headlamp system.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
A vehicle cornering headlamp system constructed in accordance with the invention will now be described in detail.
FIG. 1 is a graphical representation indicating an illumination direction variation characteristic for a description of the principals of the cornering headlamp system according to the invention. As is apparent from FIG. 1, the variation characteristic of the headlamp angle with steering angle in the case where the steering wheel is turned clockwise (or counterclockwise) away from the straight-ahead (0° ) steering position is made different from the variation characteristic in the case where the steering wheel is turned towards the straight-ahead steering position, namely, the latter characteristic has a larger gradient than the former. Therefore, before the steering wheel is returned to the straight forward steering position, the center line of illumination of the headlight is returned to the straight-ahead direction of the vehicle. Accordingly, a variation characteristic of the illumination direction with steering angle corresponding to the movement of the driver's eyes can be obtained by suitably establishing the headlamp swing-back characteristic. The inventors have found through experiments that an illumination direction variation characteristic excellent in a sense of human engineering can be obtained by making the inclination of the variation characteristic of headlamp swing angle with steering angle in the case where the steering wheel is returned towards the straight-ahead steering position twice as large as the inclination of the variation characteristic in the case where the steering wheel is turned away from the straight-ahead steering position.
An example of a cornering headlamp system of the invention based on the above-described principle is shown in FIG. 2. In FIG. 2, reference numeral 1 designates a rotary disc which is turned in association with the steering wheel, and 2, a photosensor composed of two pairs of light-emitting elements and light-detecting elements (not shown). The rotary disc 1 is turned clockwise (in FIG. 1) when the steering wheel is turned clockwise, and it is turned counterclockwise when the steering wheel is turned counterclockwise. A plurality of slits la of like configuration are formed in the peripheral portion of the rotary disc 1 at equal angular intervals. The light-emitting elements and the light-detecting elements of the photosensor 2 are disposed on opposite sides of the rotary disc 1 in such a manner that the light-emitting elements confront the light-detecting elements through the slits 1a. In the photosensor 2, a first photointerrupter, composed of one of the two pairs of light-emitting elements and light-detecting elements, and a second photointerrupter, composed of the other pair, are juxtaposed. As the rotary disc 1 turns clockwise or counterclockwise, the slits 1a pass through the first and second photointerrupters so that electrical pulse signals equal in waveform and shifted by 90° in phase are generated by the first and second photointerrupters. These signals are applied through input terminals 3a and 3b to a control signal generating circuit 3.
The control signal generating circuit 3, as shown in FIG. 3, includes: an up/down switching circuit which receives the pulse signals through the input terminals 3a and 3b, detects the direction of rotation of the rotary disc 1, i.e., the direction of turning of the steering wheel, from the phases of the electrical signals thus received, and provides "up" signals or "down" signals, the number of pulses of which corresponds to the amount of turning of the steering wheel counterclockwise or clockwise; a prescaler 32 which receives the "up" signals and the "down" signals through the output terminals 31a and 31b of the up/down switching circuit 31, and provides prescaled "up" and "down" signals through the output terminals 32a and 32b, the period of these signals being twice as large as that of the inputted "up" signals and "down" signals; a first up/down counter 33 which receives the "up" signals and the "down" signals from the prescaler 32 and increase or decrease the count value in accordance with the number of "up" signal or " down" signal pulses; a first decoder 34 which receives the count value of the up/down counter 33 and provides an "H" level output only when the . count value is zero; a second up/down counter 36 which receives the outputs of three-input OR gates 351a and 351b as an "up" input and a "down" input, respectively; a second decoder 37 which receives the count value of the second up/down counter 36 and provides an "H" level output only when the count value is zero; a D/A (digital-to-analog) converter 38 which receives the count value of the second up/down counter 36 and applies a voltage corresponding to the count value thus received to the inverting input terminal (-) of a comparator CP; and a sawtooth wave generator 39 for applying a sawtooth wave reference voltage having a period of 20 msec to the noninverting input terminal (+) of the comparator CP. The count values of the up/down counters 33 and 36 are zero (reference value) when the steering wheel is at the straight-ahead steering position.
The "up" signals and the "down" signals outputted by the prescaler 32 are further applied to AND gates 352a and 352b and AND gates 352d and 352e, respectively. The "up" signals and the "down" signals provided by the up/down switching circuit 31 are further applied to AND gates 352c and 352f, respectively. The output of the decoder 34 is applied to the remaining-input terminals of the AND gates 352b and 352e. The outputs of the AND gates 352a through 352c are applied to the three-input OR gate 351a, and the outputs of the AND gates 352d through 352f are applied to the three-input OR gate 351b. The MSB (most significant bit) of the count value of the up/down counter 36 is applied through an invertor 353a to an AND gate 352g and directly to an AND gate 352h. That is, when the count value of the up/down counter 36 is higher than zero, an "L" level signal is applied, as the MSB, to the invertor 353a and the AND gate 352h, and when the count value is lower than zero, an "H" level signal is applied, as the MSB, to the invertor 353a and the AND gate 352h. The output of the decoder 37 is applied through an invertor 353b to the remaining input terminals of the AND gates 352g and 352h. The output of the AND gate 352g is applied to the AND gates 352a and 352f, and the output of the AND gate 352h is applied to the AND gates 352c and 352d.
In the control signal generating circuit 3 thus constructed, the voltage provided at the inverting input terminal of the comparator CP by the D/A converter 38 is at the middle of the vertical width of the sawtooth wave reference voltage provided at the noninverting input terminal of the comparator CP by the sawtooth wave generator 39. Therefore, the control signal outputted by the comparator CP is a periodic pulse signal having a duty ratio of 50%. As the count value of the up/down counter 36 is increased (or decreased), the voltage provided at the inverting input terminal of the comparator CP is increased (or decreased) according to the count value thus increased (or decreased). Accordingly, when the steering wheel is turned clockwise (or counterclockwise) away from the straight-ahead steering position, the duty ratio of the control signal outputted by the comparator CP is increased (or decreased) from 50%. That is, the pulse width of the control signal periodically outputted by the comparator CP changes with the steering angle: it is increased when the steering wheel is turned clockwise, and it is decreased when the steering wheel is turned counterclockwise. The control signal provided at the output terminal 3c of the control signal generating circuit 3 is applied to a servo motor control circuit 4 through its input terminal 4a.
The servo motor control circuit 4, as shown in FIG. 2, includes a position shift detecting circuit 41 which receives the control signal on an input terminal 4a; a motor drive time calculating circuit 42 and a direction-of-rotation discriminating circuit 43 which receive the outputs of the position shift detecting circuit 41; and AND gate circuit 44 which receives the outputs of the motor drive time calculating circuit 42 and the direction-of-rotation discriminating circuit 43; a motor driver 45 for driving an electric motor 46 according to the output of the AND gate circuit 44; and a potentiometer 47 whose output voltage changes with the angular position of rotation of the electric motor 46.
The direction of illumination of a headlamp (FIG. 4) installed on the vehicle is changed by the torque of the electric motor 46 controlled by the servo motor control circuit 4. This will be described in more detail. When current is applied to the electric motor 46 in the direction of the arrow A in FIG. 2, the output shaft 46a (FIG. 5) of the electric motor 46 is turned clockwise. As a result, the torque of the motor is applied through a crown gear 46b and a worm gear 46c to a sub-reflector 5b rotatably provided behind a headlamp 5a (FIG. 4) to turn the sub-reflector 5b in such a manner that the direction of illumination of the headlamp 5 is shifted to the right as viewed by the operator. When current is applied to the electric motor 46 in the direction of the arrow B (FIG. 2), the torque of the motor is applied through the crown gear 46b and the worm gear 46c to the sub-reflector 5b so that the direction of illumination of the headlamp 5 is shifted to the left as viewed by the operator.
The crank gear 46b and the worm gear 46c coupled mechanically to the output shaft 46a of the electric motor 46 form a speed reduction drive mechanism 51. The speed reduction drive mechanism 51 is incorporated into the headlamp 5 on the rear side. The torque of the speed reduction drive mechanism 51 is transmitted through a link 52 to the sub-reflector 5b to swing the latter to the right or to the left. When the electric motor 46 is not operated, a "zero" mechanism 53 operates to forcibly return the sub-reflector 5b to the central position-of its swing so that the direction of illumination of the headlamp is held directly forward of the vehicle. The speed reduction drive mechanism 51 is coupled to the potentiometer 47. A servo motor control board 48 on which the above-described position shift detecting circuit 41, motor drive time calculating circuit 42, direction-of-rotation discriminating circuit, AND gate circuit 44 and motor driver 45 are constructed is provided below the potentiometer 47, as shown in FIG. 5.
The arrangements of the position shift detecting circuit 41, the motor drive time calculating circuit 42, and the direction-of-rotation discriminating circuit 43 in the servo motor control circuit 4 are shown in FIG. 6 in more detail. The position shift detecting circuit 41 includes NOR gates 41a and 41b, inverters 41c and 41d, inverting-input AND gates 41e and 41f, an NPN transistor Q1, a comparator CP1, a resistor R1, and a capacitor C1. The potential at the connecting point P1 of the collector of the transistor Q1, the resistor R1, and the capacitor C1 is applied to the noninverting input terminal of the comparator CP1. The motor drive time calculating circuit 42, is composed of an OR gate 42a which receives the outputs of the inverting-input AND gates 41e and 41f in the position shift detecting circuit 41; and NPN transistor Q2 to the base of which the output of the OR gate 42a is applied; a comparator CP2; resistors R2 through R5; and capacitors C2 and C3. In the motor drive time calculating circuit 42, the potential at the connecting point of the capacitor C2 and the resistor R2 which is connected to the collector of the transistor Q2 is applied to the noninverting input terminal (+) of the comparator CP2, and a divided voltage Vb outputted by a voltage divider composed of the resistors R4 and R5 is applied to the inverting input terminal (-) of the comparator CP2. The direction-of-rotation discriminating circuit 43 includes NOR gates 43a and 43b, to first input terminals of which the outputs of the negative logic input AND gates 41e and 41f in the position shift detecting circuit 41 are respectively applied. The outputs of the NOR gates 43a and 43b are applied to first input terminals of inverting-input AND gates 44a and 44b in the AND gate circuit 44, respectively. The output of the comparator CP2 in the motor drive time calculating circuit is applied to the remaining second input terminals of the inverting input AND gates 44a and 44b.
The operation of the cornering headlamp system thus constructed will be described beginning with its fundamental operation.
It is assumed that the steering wheel is at the straight-ahead steering position, and the sub-reflector 5b is at the central position of its swing, so that the center line of the illuminating pattern of the headlamp 5 extends directly forward of the vehicle. In this case, the count value of the up/down counter 36 is zero, and therefore a periodic pulse signal having a duty ratio of 50% is provided, as a control signal to the servo motor control circuit 4, at the output terminal 3c by the control signal generating circuit 3. When, under this condition, the steering wheel is turned clockwise, for instance, the count value of the up/down counter 36 is decreased in accordance with the amount of clockwise rotation of the steering wheel, and the voltage provided at the inverting input terminal of the comparator CP through the D/A converter 38 decreases. On the other hand, pulse signals outputted by the comparator CP, that is, the control signal applied to the servo motor control circuit 4 through the output terminal 3c of the control signal generating circuit 3, increases in duty ratio, and the pulse width of the control signal is increased in accordance with the amount of clockwise rotation of the steering wheel.
It is assumed that, as the steering wheel is turned clockwise from the straight-ahead steering position, the control signal applied to the servo motor control circuit 4 increases in duty ratio, with the pulse width of the control signal increasing as shown in part (a) of FIG. 7; that is, the pulse width W provided when the steering wheel is at the straight-ahead steering position is increased to W1. The control signal is applied to the position shift detecting circuit 41 in the servo motor control circuit. Upon the rise of the control signal (point a in part (a) of FIG. 7) the base voltage of the transistor Q1 is set to the "L" level (low logic level - the point a in part (b) of FIG. 7), so that the transistor Q1 is rendered nonconductive. As the transistor Q1 is nonconductive, the capacitor C1 is charged through the resistor R1 so that the potential at the connecting point P1 of the capacitor C1 and the resistor R1, i.e., the potential at the noninverting input terminal of the comparator CP1 increases (point a in part (c) of FIG. 7). On the other hand, in this operation, the voltage provided at the inverting input terminal of the comparator CP1 through the potentiometer 47 (Va in part (c) of FIG. 7) has a value corresponding to the present angle of rotation of the electric motor 46 (2.5V in this instance). Therefore, when the potential at the connecting point Pl, which is applied to the noninverting input terminal, exceeds the voltage Va at the inverting input terminal, the output of the comparator CP1 is raised to the "H" level (high logic level-point b in part (d) of FIG. 7).
When the base voltage of the transistor Q1 is raised to the "H" level at the fall of the control signal as indicated in part (a) of FIG. 7 (point c in part (b) of FIG. 7), immediately the potential at the noninverting input terminal becomes substantially equal to ground potential (point c in part (c) of FIG. 7), and therefore the output of the comparator CP1 is set to the "L" level (point c in part (d) of FIG. 7). That is, the output of the comparator CP1 is raised to the "H" level, creating a pulse width ΔW determined by the difference between the pulse width W1 of the control signal and the pulse width W provided when the steering wheel is at the straight-ahead steering position (ΔW =W1-W). The output of the comparator CP1, i.e., an "H" level signal having the pulse width ΔW, is provided at the output terminal of the negative logic input AND gate 41e (part (h) of FIG. 7), thus being applied, as an amount of position shift between a target direction of illumination determined according to the steering angle and the actual direction of illumination, to the motor drive time calculating circuit 42 and the direction-of-rotation discriminating circuit 43.
Parts (e), (f), (g) and (i) of FIG. 7 show the outputs of the NOR gate 41b, invertor 41c, invertor 41d, and inverting input AND gate 41f, respectively.
The output of the inverting input AND gate 41e, which is applied to the motor drive time calculating circuit 42, is applied through the OR gate 42a to the base of the transistor Q2 (part (j) of FIG. 7). As a result, the transistor Q2 is rendered conductive for the duration of the pulse width ΔW, and therefore the capacitor C2 is discharged through the resistor R2, and the voltage at the noninverting input terminal of the comparator CP2 decreases (point b in part (k) of FIG. 7). When the voltage at the noninverting input terminal becomes lower than the output voltage (Vb in part (k) of FIG. 7) of the voltage divider composed of the resistors R4 and R5, the output of the comparator CP2 is set to the "L" level (point d in part (1) of FIG. 7). When the transistor Q2 is rendered nonconductive at the point c in part (j) of FIG. 7, the capacitor C2 in charged through the resistor R3, and the voltage at the noninverting input terminal of the comparator CP2 gradually increases. When the voltage at the noninverting input terminal exceeds the divided voltage Vb provided at the inverting input terminal (point e in part (k) of FIG. 7), the output of the comparator CP2 is raised to the "H" level (point e in part (1) of FIG. 7). That is, the output of the comparator CP2 is maintained at the "L" level for a period of time τ corresponding to the pulse width ΔW which has been detected as an amount of position shift between a target direction of illumination determined from a steering-wheel steering angle and an actual direction of illumination. This output (position shift calculating signal) of the comparator CP2 is applied to the inverting input AND gate 44a and 44b in the AND gate circuit 44.
In the above-described embodiment, the charge time constant determined by the values of the capacitor C2 and the resistor R3 is large than the discharge time constant determined by the values of the capacitor C2 and the resistor R2. It goes without saying that the period of time τ (position shift calculating time) corresponding to the pulse width W can be adjusted by changing the charge time constant and the discharge time constant.
In the direction-of-rotation discriminating circuit 43, the outputs of the NOR gates 43a and 43b (parts (m) and (n) of FIG. 7), are changed to the "L" level and "H" level, respectively, at the rise of the position shift detecting signal having the pulse width W provided by the inverting input AND gate 41e in the position shift detecting circuit 41. The position shift calculating signal provided by the comparator CP2 a period time τ 1 after the change is outputted through the inverting input AND gate 44a (part (o) of FIG. 7). In response to the "H" level position shift calculating signal being outputted by the inverting input AND gate 44a, voltages at the output terminals 45a and 45b of the motor driver 45 are changed to the "H" level and "L" level, respectively, from "M" (middle)" level (parts (q) and (r) of FIG. 7), as a result of which drive current is caused to flow through the electric motor 46 in the direction of the arrow A (FIG. 6). Therefore, the output shaft 46a of the electric motor 46 is rotated clockwise to turn the sub-reflector 5b (FIG. 4) so that the center line of the illumination pattern of the headlamp 5 is shifted to the right (the steering wheel turning direction) as viewed by the operator (see FIG. 8).
When the center line of the illumination pattern of the headlamp 5 is shifted to the right in the above-described manner, the voltage Va provided at the inverting input terminal of the comparator CP1 by the potentiometer 47 is increased in accordance with the angle of rotation of the output shaft 46a of the motor 46, the pulse width ΔW of the next pulse of the position shift detecting signal obtained in response to the next control signal outputted by the control signal generating circuit 3 is decreased, and the position shift calculating time τ corresponding to the pulse width ΔW is decreased. These operations are repeatedly carried out. When the pulse width ΔW of the position shift detecting signal becomes zero, the target direction of illumination coincides accurately with the actual direction of illumination of the headlamp 5.
As the direction of illumination of the headlamp 5 approaches the target direction, the position shift calculating time τ is decreased, and the drive current supplied to the electric motor 46 is interrupted during the period of the control signal; that is, for every period of the control signal, the drive current is intermittently supplied only for the position shift calculating time τ. However, after interruption of the supply of drive current, the motor 46 keeps rotating due to inertia, and since the period of the control signal is short, the direction of illumination of the headlamp 5 will coincide with the target direction as if the sub-reflector turned linearly. In this operation, as the direction of illumination of the headlamp 5 approaches the target direction, the drive current supplying time is decreased. As a result, overrunning of the motor 46 can be prevented when the actual direction of illumination coincides with the target direction.
In the case where, on the other hand, the steering wheel is turned counterclockwise from the straight-ahead steering position, the count value of the up/down counter 36 is increased, and the voltage at the inverting input terminal of the comparator CP is increased in accordance with the increasing count value of the up/down counter 36. Therefore, the duty ratio of the control signal applied to the servo motor control circuit 4 is decreased.
It is assumed that, as the steering wheel is turned counterclockwise from the straight-ahead steering position, the duty ratio of the control signal is decreased, and the pulse width of the control signal is decreased, as shown in part (a) of FIG. 9; that is, the pulse width W provided when the steering wheel is at the straight-ahead steering position is decreased to W2. In this case, at the rise of the control signal, the transistor Q1 is rendered nonconductive and the potential at the noninverting input terminal of the comparator CP1 is increased (point al in part (c) of FIG. 9). When the potential at the noninverting input terminal of the comparator CP1 exceeds the voltage Va at the inverting input terminal (point cl in part (c) of FIG. 9), the output of the comparator CP1 is raised to the "H" level (point c1 in part (d) of FIG. 9) while the base potential of the transistor Q1 is raised the "H" level (point c1 in part (b) of FIG. 9). Therefore, at this time instant, the transistor Q1 is rendered conductive, whereupon the potential at the noninverting input terminal of the comparator CP1 becomes substantially equal to ground potential, and therefore the output of the comparator CP1 is set to the "L" level instantaneously.
On the other hand, the output of the inverting-input AND gate 41f is raised to the "H" level at the fall of the control signal shown in part (a) of FIG. 9 (point b1 in part (i) of FIG. 9), and is set to the "L" level by the "H" level output of the comparator CP1. That is, the output of the inverting input AND gate 41f is raised to the "H" level with a pulse width ΔW' equal to the difference between the pulse width W provided when the steering wheel is at the straight-ahead steering position and the pulse width W2 provided when the steering wheel is turned counterclockwise (ΔW'=W-W2). The "H" level signal having the pulse width ΔW' is applied, as an amount of position shift between a target direction of illumination determined according to the actual steering angle and the actual direction of illumination of the headlamp, to the motor drive time calculating circuit 42 and the direction-of-rotation discriminating circuit 43.
Upon reception of the position shift detecting signal having the pulse width ΔW', the motor drive time calculating circuit 42 generates a pulse of the position shift calculating signal having a width τ' corresponding to the pulse width ΔW' (part (1) of FIG. 9). On the other hand, in the direction-of-rotation discriminating circuit 43, the outputs of the NOR gates 43a and 43b (parts (m) and (n) of FIG. 9) are changed to the "H" level and "L" level, respectively, at the rise of the position shift detecting signal. The position shift calculating signal provided a period time τ 1 ' after this change is outputted through the inverting input AND gate 44b (part (p) of FIG. 9). According to the "H" level position shift calculating signal outputted by the inverting input AND gate 44b, voltages at the output terminals 45a and 45b of the motor driver 45 are changed to the "L" level and "H" level, respectively, from "M" levels (parts (q) and (r) of FIG. 9), as a result of which drive current is caused to flow in the motor 46 in the direction of the arrow B for the position shift calculating time τ'. Therefore, the output shaft 46a of the motor 46 is rotated counterclockwise to turn the sub-reflector 5b so that the direction of illumination of the headlamp 5 is shifted to the left (the direction in which the steering-wheel is turned) as viewed by the operator.
When the direction of illumination of the headlamp 5 is shifted to the left in the above-described manner the voltage Va provided at the inverting input terminal of the comparator CP1 by the potentiometer 47 is decreased in accordance with the angle of rotation of the output shaft 46a of the motor 46, the pulse width ΔW' of the next pulse of the position shift detecting signal obtained in response to the next control signal pulse outputted by the control signal generating circuit 3 is decreased, and the position shift calculating time τ' corresponding to the pulse width ΔW' is decreased. These operations are repeatedly carried out. When the pulse width ΔW' of the position shift detecting signal reaches zero, the target direction of illumination will coincide with the actual direction of illumination of the headlamp 5.
In the cornering headlamp system performing the fundamental operation as described above, the difference between a direction-of-illumination changing operation effected in the case where the steering wheel is turned away from the straight-ahead position and a direction-of-illumination changing operation effected in the case where the steering wheel is turned back towards the straight-ahead steering position will be described with reference to the timing chart shown in FIG. 10.
When the steering wheel is turned counterclockwise from the straight-ahead steering position, the rotary disc 1 shown in FIG. 2 is turned counterclockwise, so that electrical pulse signals shifted by about 90° in phase are applied to the up/down switching circuit 31 through the terminals 3a and 3b (the point a in parts (a) and (b) of FIG. 10). The up/down switching circuit 31 detects the clockwise steering operation from the phases of the pulse-shaped electrical signals, and outputs "up" signal pulses, the number of which corresponds to the amount of clockwise rotation of the steering wheel, through its output terminal 31a (point b in part (c) of FIG. 10). The "up" signals pulses outputted by the up/down switching circuit 31 are applied to the prescaler 32, from which they are outputted as "up" signal pulses having twice the period, through the output terminal 32a of the prescaler 32 (point b in part (e) of FIG. 10). The "up" signals produced by the up/down switching circuit 31 are further applied to the AND gate 352c. In this operation, the output of the decoder 37 is at the "H" level (point b in part (s) of FIG. 10), and therefore the output of the AND gate 352h is at the "L" level (point b in part (i) of FIG. 10). Accordingly, the "up" signal pulses produced by the up/down switching circuit 31 cannot pass through the AND gate 352c, that is, they are not applied, as a count-up signal to the up/down counter 36. On the other hand, the "up" signals outputted by the prescaler 32 pass through the AND gate 352b (point b in part (k) of FIG. 10) because the output of the decoder 34 is at the "H" level (point b in part (g) of FIG. 10), so that "up" signal pulses are applied, as a count-up input signal, to the up/down counter 36 through the OR gate 351a (point b in part (p) of FIG. 10).
In the up/down counter 36, the count value is increased from zero in response to the "up" signal pulses applied thereto through the OR gate 351a; that is, the count value is increased by one at the fall of each of the "up" signal pulses (point c in part (p) of FIG. 10). The output voltage of the D/A converter 38 increases with the increasing count value of the up/down counter 36 (point c in part (r) of FIG. 10), and the duty ratio of the control signal outputted by the comparator CP decreases with the increasing output voltage of the D/A converter 38.
On the other hand, the "up" signal pulses provided at the output terminal 32a of the prescaler 32 are further applied, as a count-up input signal, to the up/down counter 33, so that the count value of the latter is increased from zero; that is, the count value is increased by one at the fall of each of the "up" signal pulses. In response to the count value thus increased, the output of the decoder 34 is set to the "L" level (point c in part (g) of FIG. 10), so that the AND gates 352b and 352e are closed. On the other hand, as the count value of the up/down counter 36 increases from zero, the output of the decoder 37 is set to the "L" level (point c is part (s) of FIG. 10), and the MSB (most significant bit) of the count value provided by the up/down counter 36 is set to the "L" level, as a result of which the output of the AND gate 352g is raised to the "H" level (point c in part (h) of FIG. 10), and the AND gates 352a and 352f are opened. In this operation, the output of the AND gate 352h is maintained at the "L" level (point c in part (i) of FIG. 10), and therefore the AND gates 352c and 352d are held open. As a result, thereafter the "up" signal pulses provided at the output terminal 32a (point d in part (j) of FIG. 10). The "up" signal pulses thus passed through the AND gate 352a are applied, as a count-up input signal, to the up/down counter 36 through the OR gate 351a.
In other words, when the steering wheel is turned counterclockwise away from the straight-ahead steering position, "up" signals pulses in a number which corresponds to the, amount of counterclockwise rotation of the steering wheel are supplied through the output terminal 31a of the up/down switching circuit 31, and the count value of the up/down counter 36 is increased at the fall of each of the "up" signal pulses of doubled period which are provided at the output terminal 32a of the prescaler 32 in response to the "up" signal pulses outputted by the up/down switching circuit 31. The output voltage of the D/A converter 38 is increased with the increasing count value of the up/down counter 36, the duty ratio of the control signal provided by the comparator CP is decreased with the increasing output voltage of the D/A converter 38, and with the control signal thus decreased in duty ratio the direction of illumination is changed in correspondence to the steering angle when the steering wheel is turned counterclockwise away from the straight-ahead steering position.
When the steering wheel, after being turned counterclockwise away from the straight-ahead steering position as described above, is turned clockwise back towards the straight-ahead steering position, the phases of the pulse signals inputted through the terminals 3a and 3b are inverted (point e in part (a) and (b) of FIG. 10). The up/down switching circuit 31 detects the clockwise steering operation from the phases of the pulse signals, and outputs "down" signals indicative of the amount of clockwise rotation of the steering wheel through the output terminal 31b (point f in part (d) of FIG. 10). In response to the "down" signals outputted by the up/down switching circuit 31, the prescaler 32 provides "down" signals of doubled period at the output terminal 32b (point f in part (f) of FIG. 10). In this operation, since the AND gates 352d and 352e are maintained closed, the "down" signals outputted by the prescaler 32 will not be applied as count down input signals to the up/down counter 36.
On the other hand, the "down" signals outputted by the up/down switching circuit 31 are further applied to the AND gate 352f, and in this operation the AND gate 352f is maintained open. Therefore, the "down" signals are passed through the AND gate 352f (point f in part (o) of FIG. 10), and are applied as count-down input signals to the up/down counter 36 through the OR gate 351b (point f in part (q) of FIG. 10). The count value of the up/down counter 36 is decreased at the fall of each of the "down" signal pulses inputted through the OR gate 351b, and the output voltage of the D/A converter 38 is decreased with the decreasing count value of the counter 36 (point g in part (r) of FIG. 10).
In other words, when the steering wheel, after being turned counterclockwise, is turned clockwise towards the straight-ahead steering position, "down" signal pulses in a number indicative of the amount of rotation of the steering wheel are applied to the up/down counter 36 through the output terminal 31b of the up/down switching circuit 31, and thus the count value of the counter 36 is decreased at the fall of each of the "down" signal pulse thus applied. The output voltage of the D/A converter 38 is decreased with the decreasing count value of the counter 36, the duty ratio of the control signal provided by the comparator CP is increased with the decreasing output voltage of the D/A converter 38, and with the control signal thus increased in duty ratio the direction of illumination is changed in correspondence to the steering angle when the steering wheel is turned towards the straight-ahead steering position. In this case, the "down" counting operation of the up/down counter 36 is carried out at half the period of the "down" signals outputted by the prescaler 32. Therefore, in the case where the steering wheel is turned counterclockwise away from the straight-ahead steering position and then turned clockwise back towards the straight steering position, the count value is zeroed when the steering wheel is turned back towards the straight-ahead steering position through half the steering angle through which the steering wheel was turned (point h in part (r) of FIG. 10); that is, the line of illumination of the headlamp is swung back so as to be in the straight-ahead direction of the vehicle earlier than the steering wheel is returned to the straight-ahead steering position.
While the invention has been described with reference to the case where the steering wheel is turned counterclockwise from the straight-ahead steering position and then turned clockwise towards the straight-ahead steering position, it goes without saying that the above description is equally applicable to the case where the steering wheel, after being turned clockwise from the straight-ahead steering position, is turned counterclockwise towards the straight-ahead steering position. Similarly, in the case where the steering wheel is turned clockwise or counterclockwise from a position other than the straight-ahead steering position, the inclination of the illumination direction variation characteristic can be made larger in the case where the steering wheel is turned back towards the straight-ahead steering position than in the case where the steering wheel is turned away from the straight-ahead steering position.
As described above, in the vehicle cornering headlamp system of the invention, the inclination of the variation characteristic of the direction of illumination with respect to the steering angle is made larger in the case where the steering wheel is turned back towards the straight-ahead steering position than in the case where the steering wheel is turned away from the straight-ahead steering position, and therefore the center line of the illumination pattern of the headlamp is swung back so as to be in the straight-ahead direction of the vehicle earlier than the steering wheel is returned to the straight-ahead steering position. Accordingly, an illumination direction variation characteristic which corresponds to the movement of the driver's eyes and is excellent in a sense of human engineering is obtained.
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A vehicle cornering headlamp system in which the direction of illumination of the headlamps of an automobile are made to follow the actual direction of movement of the vehicle, except that the direction of illumination is returned to the straight-ahead direction more quickly than it is moved away therefrom, thereby more accurately following the usual eye movement of the driver. For this purpose, a control signal is generated which has a pulse width indicative of the steering angle but which has a variation characteristic with respect to steering angle which is larger when the steering wheel is turned back towards the straight-ahead position than when the steering wheel is turned away from the straight-ahead position.
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CROSS-REFERENCE TO RELATED PATENT APPLICATION
[0001] This application claims priority to and the benefit of U.S. Patent Application No. 61/050,992, filed on May 6, 2008, in the United States Patent and Trademark Office, the entire content of which is incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to a modular rack assembly. While there are a variety of modular rack assemblies that have been designed to store various items, they are not easily configurable for shipping. Further, conventional modular racks are not formed of a simple construction and may be expensive to manufacture and difficult to assemble and adjust.
SUMMARY OF THE INVENTION
[0003] An embodiment of the present invention provides an end support unit for supporting the ends of at least one front and one rear cross beam including: a generally vertical front support post having at least one column of slots along its length for receiving at least one slot engaging member of the front cross beam; a generally vertical rear support post having at least one column of slots along its length for receiving at least one slot engaging member of the rear cross beam; a generally horizontal upper brace fixedly attached to and extending from the upper end of the front support post to the upper end of the rear support post; a generally horizontal lower brace fixedly attached to and extending from the lower end of the front support post to the lower end of the rear support post; and at least one diagonal brace fixedly attached to and extending diagonally between the front support post and the rear support post.
[0004] The upper brace may have at least one hole for receiving the shaft of a connector for securely mounting a secondary component to the end support unit.
[0005] The lower brace may have at least one hole for receiving the shaft of an anchor for securely anchoring the end support unit to a floor location or a connector for securely mounting a secondary component to the end support unit.
[0006] The slots may be key-hole shaped. The slot engaging members may be rivets. The slots may be wedge-shaped. The slot engaging members may be lances.
[0007] The end support units may be about 3 inches wide, about 17 inches deep, and about 36 inches high.
[0008] The support posts may be c-shaped. The braces may be c-shaped.
[0009] Another embodiment of the present invention provides an end support unit assembly including an upper end support unit stacked on top of a lower end support unit for supporting the ends of at least one front and one rear cross beam. Each end support unit includes: a generally vertical front support post having at least one column of slots along its length for receiving at least one slot engaging member of the front cross beam; a generally vertical rear support post having at least one column of slots along its length for receiving at least one slot engaging member of the rear cross beam; a generally horizontal upper brace fixedly attached to and extending from the upper end of the front support post to the upper end of the rear support post; a generally horizontal lower brace fixedly attached to and extending from the lower end of the front support post to the lower end of the rear support post; at least one diagonal brace fixedly attached to and extending diagonally between the front support post and the rear support post; and a pair of connectors extending through holes in the lower brace of the upper end support unit and the upper brace of the lower end support unit to secure the upper end support unit to the lower end support unit.
[0010] Each connector may include a bolt, a lock washer, and a nut.
[0011] Another embodiment of the present invention provides a storage rack including: at least one left end support unit and at least one right end support unit for supporting the ends of at least one front and one rear cross beam. Each end support unit includes: a generally vertical front support post having at least one column of slots along its length for receiving at least one slot engaging member of the front cross beam; a generally vertical rear support post having at least one column of slots along its length for receiving at least one slot engaging member of the rear cross beams; a generally horizontal upper brace fixedly attached to and extending from the upper end of the front support post to the upper end of the rear support post; a generally horizontal lower brace fixedly attached to and extending from the lower end of the front support post to the lower end of the rear support post; and at least one diagonal brace fixedly attached to and extending diagonally between the front support post and the rear support post; at least one front cross beam, wherein the at least one front cross beam is mounted on and extending between the left and right front support posts of the left and right end support units; at least one rear cross beam, wherein the at least one rear cross beam is mounted on and extending between the rear support posts of the right and left end support units at about the same elevation as the front cross beam; and at least one shelf panel, wherein the at least one shelf panel is supported at its front and rear edges by at least one front and rear cross beam.
[0012] The storage rack may include four pairs of front and rear cross beams, four shelves, and four end support units, and wherein the disassembled storage rack is packaged in a space that is about 39 inches by about 17 inches by about 16 inches.
[0013] The front and rear cross beams may include at each end an L-shaped flange with a pair of slot engaging members extending inwardly from the flange to engage the slots.
[0014] The front and rear cross beams may include a ledge for receiving the shelf panel.
[0015] Another embodiment of the present invention provides a work bench assembly including: right and left end support units for supporting the ends of at least one front and one rear cross beam. Each end support unit includes: a generally vertical front support post having at least one column of slots along its length for receiving at least one slot engaging member of the front cross beam; a generally vertical rear support post having at least one column of slots along its length for receiving at least one slot engaging member of the rear cross beam; a generally horizontal upper brace fixedly attached to and extending from the upper end of the front support post to the upper end of the rear support post; a generally horizontal lower brace fixedly attached to and extending from the lower end of the front support post to the lower end of the rear support post; at least one diagonal brace fixedly attached to and extending diagonally between the front support post and the rear support post; an upper front cross beam extending between the upper ends of the front support posts of the right and left end support units; an upper rear cross beam extending between the upper ends of the rear support posts of the right and left end support units; a lower rear cross beam extending between a lower portion of the rear support posts of the right and left end support units; a top panel having front and rear edge portions supported at its front and rear edge portions by the upper front cross beam and upper rear cross beam; right and left upright supports mounted to and extending upwardly from a rear portion of the right and left end support units; a cross beam mounted to and extending between the upper ends of the right and left upright supports; and a generally vertical panel extending between at least a portion of the right and left upright supports and below the cross-beam that extends between the upper ends of the upright supports.
[0016] The generally vertical panel may include pegboard.
[0017] The generally vertical panel may include upper and lower pegboard panels connected by an elongated strip connector having a generally H-shaped cross-sectional configuration that forms a pair of grooves for receiving the lower end of the upper pegboard panel and the upper edge of the lower pegboard panel.
[0018] The workbench assembly may further include a cover mounted over the upper braces.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] The accompanying drawings, together with the specification, illustrate exemplary embodiments of the present invention, and, together with the description, serve to explain the principles of the present invention.
[0020] FIG. 1 is a front perspective view of a storage rack according to an embodiment of the present invention.
[0021] FIG. 1 a is a cross-sectional view of a portion of the storage rack of FIG. 1 .
[0022] FIG. 2 is a front perspective view of a storage rack according to another embodiment of the present invention.
[0023] FIG. 3 is an exploded view of the storage rack shown in FIG. 2 .
[0024] FIG. 4 is a front perspective view of a storage rack according to another embodiment of the present invention.
[0025] FIG. 5 is perspective view of the components of the storage rack shown in FIGS. 2-4 arranged for shipping.
[0026] FIG. 6 is an end-view of the exemplary storage racks shown in FIGS. 2-4 assembled for shipping.
[0027] FIG. 7 is a perspective view of a storage rack according to another embodiment of the present invention.
[0028] FIG. 8 is a perspective view of a storage rack according to another embodiment of the present invention.
[0029] FIG. 9 is a perspective view of a storage rack according to another embodiment of the present invention.
[0030] FIG. 10 is a perspective view of a storage rack according to another embodiment of the present invention.
[0031] FIG. 11 is a perspective view of a storage rack according to another embodiment of the present invention.
[0032] FIG. 12 is a perspective view of a storage rack according to another embodiment of the present invention.
DETAILED DESCRIPTION
[0033] In the following detailed description, only certain exemplary embodiments of the present invention have been shown and described, simply by way of illustration. As those skilled in the art would realize, the described embodiments may be modified in various different ways, all without departing from the spirit or scope of the present invention. Accordingly, the drawings and description are to be regarded as illustrative in nature and not restrictive. Like reference numerals designate like elements throughout the specification.
[0034] With reference to FIG. 1 there is shown a boltless storage rack assembly 10 according to an embodiment of the present invention. The rack assembly 10 comprises right and left end support units 12 , each end support unit 12 comprising a front support post 13 , a rear support post 14 , an upper brace 18 , a lower brace 20 , and a diagonal brace 22 . The upper, lower and diagonal braces 18 , 20 , 22 are fixedly attached at their ends, preferably by welding, to the front and rear support posts 13 and 14 . The front and rear support posts 13 and 14 include at least one column of aligned slots 16 for receiving slot engaging members of cross beams 26 , 28 . The front and rear support posts 13 and 14 of the end support units 12 may include right and left columns of slots 16 . Front cross beams 26 are boltlessly mounted at their ends to the front posts 13 of right and left end support units 12 . Rear cross beams 28 are likewise boltlessly mounted at their ends to the rear support posts 14 of the right and left end support units 12 at the same elevations as the front cross beams 26 .
[0035] It is understood that the cross-sectional configuration of the support posts and braces may vary as desired. In the embodiment shown in FIG. 1 , the cross-sectional configuration of the posts and braces are generally C-shaped.
[0036] Likewise the cross-sectional configuration of the cross beams may vary as desired. In the embodiment of FIG. 1 , the cross beams 26 , 28 have cross-sectional configurations as shown in FIG. 1 a. Here, the cross beams have a ledge for receiving a shelf panel 32 . The cross beams 26 and 28 have an L-shaped flange 29 at each end. A pair of slot engaging members (in this case lances) 30 extend inwardly from the flange 29 to engage wedge-shaped slots 16 in the support posts 13 and 14 .
[0037] The slots 16 and slot engaging members 30 may also vary as desired. For example, in another exemplary embodiment, the slots have a key-hole shape and the slot engaging members are rivets that extend inwardly from the ends of the cross beams.
[0038] The dimensions of the end support units 12 and cross beams 26 and 28 may also vary. In one embodiment, the end support units 12 are about 3 inches high and about 17 inches deep. In one embodiment, the length of the cross beams is about 39 inches so that the overall width of the rack is about 41 inches.
[0039] With reference to FIGS. 2 and 3 , there is shown a stacked rack assembly 38 according to an embodiment of the present invention. The stacked rack assembly 38 comprises right and left end support assemblies 40 , each end support assembly 40 including a pair of end support units 12 a, 12 b stacked one on top of the other. The upper end support unit 12 a is securely mounted to the lower end support unit 12 b with connectors 42 , e.g., bolts which extend through holes 24 in the lower brace 20 of the upper end support unit 12 a and aligned holes 24 in the upper brace 18 of the lower end support unit 12 b. The bolts 42 are secured with appropriate lock washers and nuts. It is to be understood that any suitable connector may be used.
[0040] A plurality of front and rear cross beams 26 and 28 are boltlessly mounted to the front and rear support posts 13 and 14 of the end support units 12 that make up the end support assemblies 40 . Shelf panels 32 are positioned between and supported at their front and rear edge portions by the front and rear cross beams 26 and 28 . As shown, the stacked rack assembly 38 can be anchored at a particular floor location by means of anchors 28 or the like which extend through holes 24 in the lower brace 20 of the lower end support unit 12 b and into the floor. The type of anchor will vary depending on the material of the floor. For example, expandable wedge anchors, sleeve anchors, etc., as are well-known in the art may be used with concrete floors, whereas leg bolts or the like may be used for wood floors.
[0041] Another modular rack assembly 44 according to an embodiment of the present invention is shown in FIG. 4 . As shown in this embodiment, the upper and lower end support units 12 a and 12 b may be secured together by means of front and rear cross beams 26 and 28 wherein the upper slot engaging members 30 at each end of the cross beams engage the lowest slot 16 in the front and rear posts 13 and 14 of the upper end support unit 12 a and the lower slot-engaging members 30 of the cross beams engage the uppermost slot 16 of the front and rear post 13 and 14 of the lower end support unit 12 b. In this way, seating of the slot-engaging members 30 into the slots 16 secures the upper and lower end-support units 12 a and 12 b together. Optionally, the upper and lower end support units 12 a and 12 b may be further secured together by bolts 42 or the like, as described with respect to FIGS. 2 and 3 .
[0042] One of the benefits of the present invention is that a 72-inch high by 17 inch deep by 41 inch wide rack assembly having four pairs of front and rear cross-beams and four shelves may be packaged in a space having the dimensions 39 inches by 17 inches by less than 16 inches. This allows the rack assembly to be packaged in a container that is 40 inches by 18 inches by 16 inches. Such a packaged arrangement provides significant cost savings as compared to racks having 72-inch long side support units. For example, this set of dimensions enables three packages to fit on a standard forty inch by forty-eight inch pallet. An exemplary arrangement of the components for packaging is shown in FIGS. 5 and 6 .
[0043] The end support units 12 may also be used as intermediate support units in larger shelf and/or bench assemblies. For example, FIG. 7 shows another exemplary assembly comprising four end-support units 12 used to form an elongated workbench with three shelf panels 32 .
[0044] FIG. 8 shows another exemplary assembly including left and middle support assemblies 40 a, 40 b, which each include three stacked end support units 12 . The right support assembly 40 c includes two stacked end support units 12 . Cross-beams 26 and 28 are mounted between the left and middle end-support assemblies 40 a and 40 b to provide support for four shelf panels 32 . Cross-beams 26 and 28 are mounted on and extended between the middle and right support unit assemblies 40 b and 40 c to provide three shelf panels 32 , as shown. FIGS. 9 and 10 show other exemplary assemblies using end support units 12 .
[0045] The present invention also provides work benches that utilize the benefits of the end support units 12 described above. With the reference to FIG. 11 , there is provided a work bench 50 with a pair of opposing right and left end support units 12 , and front and rear cross-beams 26 and 28 are mounted on and extend between the left and right front and rear support posts 13 and 14 of the right and left end support units 12 at the top of the support posts 13 and 14 . For stabilization, a lower rear cross-beam 28 extends between the rear posts 13 of the right and left end support units 12 at a lower portion of those support posts. A panel 32 is supported at its front and rear edge portions by the upper front and rear cross beams 26 and 28 .
[0046] A cover 52 is mounted over the upper braces 18 of the right and left end support units 12 to create a generally flat surface at about the same level as the top surfaces of shelf panel 32 . In an embodiment of the present invention, the cover 52 has the same cross-sectional configuration as the support posts 13 , 14 of the end-support units 12 , but without the slots.
[0047] A pair of upright supports 54 extend upwardly from the rearward portion of the end support units 12 . In an embodiment of the present invention, the uprights supports 54 are made of the same material and have the same cross-sectional configuration of the support posts 13 , 14 of the end-support units 12 . The upright supports 54 have a generally horizontal flange 56 at their lower ends. The flange 56 extends forwardly and has a hole that aligns with holes in the cover 52 and upper brace 18 of the end support units 12 . The upright supports 54 may be secured to the end support units 12 by connectors, such as bolts as previously described. A cross-beam 58 is mounted at its ends to and extends between top ends of the left and right upright supports 54 . In the embodiment shown, there is provided a pegboard assembly 60 which extends between the left and right upright supports 54 and between the top of the workbench 50 and the cross-beam 58 at the upper end of the upright supports 54 . The pegboard assembly 60 preferably comprises two pegboard panels 62 a and 62 b connected together by a plastic strip connector 64 having an H-shaped cross-sectional configuration. Such a connector 64 comprises a pair of grooves or recesses for receiving the lower edge of the upper pegboard panel 62 a and the upper edge of a lower pegboard panel 62 b.
[0048] In the exemplary embodiment shown in FIG. 11 , the workbench 50 comprises a drawer assembly. Any suitable drawer assembly may be used. Likewise, the workbench 50 could be provided with a lower shelf for storage purposes, if desired.
[0049] With reference to FIG. 12 , there is shown another exemplary workbench constructed according to another embodiment of the present invention. As can be seen, the workbench comprises two workbench assemblies as generally as described in FIG. 11 , except that the middle end support unit 12 and upright support 54 provide common support for both workbench units.
[0050] While the present invention has been described in connection with certain exemplary embodiments, it is to be understood that the invention is not limited to the disclosed embodiments, but, on the contrary, is intended to cover various modifications and equivalent arrangements thereof.
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An end support unit for supporting the ends of at least one front and one rear cross beam including: a front support post having a column of slots along its length for receiving at least one slot engaging member of the front cross beam; a rear support post having a column of slots along its length for receiving at least one slot engaging member of the rear cross beam; an upper brace fixedly extending from the upper end of the front support post to the upper end of the rear support post; a lower brace fixedly extending from the lower end of the front support post to the lower end of the rear support post; and a diagonal brace extending diagonally between the front support post and the rear support post.
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The present application is a divisional application based upon U.S. patent application Ser. No. 08/169,655, filed Dec. 16, 1993, which was a continuation-in-part of U.S. patent application Ser. No. 07/777,739, filed Oct. 15, 1991, now U.S. Pat. No. 5,410,132, and of U.S. patent application Ser. No. 08/092,050, filed Jul. 15, 1993, now U.S. Pat. No. 5,410,133, which in turn is a divisional of U.S. patent application Ser. No. 07/681,004, filed Apr. 5, 1991, now U.S. Pat. No. 5,229,562. The benefit of the filing dates of which are claimed under 35 U.S.C. §120; these applications and patents are incorporated by reference.
FIELD OF THE INVENTION
The present invention relates to the consolidation and forming of organic matrix composites, more specifically, the present invention relates to methods and apparatus for inductively heating, forming and consolidating resins to make organic matrix composites.
BACKGROUND OF THE INVENTION
Fiber-reinforced resin (i.e., organic matrix) composite materials have become widely used, have a high strength-to-weight or high stiffness-to-weight ratio, and desirable fatigue characteristics that make them increasingly popular in weight, strength or fatigue critical applications.
Prepregs consisting of continuous, woven, or chopped fibers embedded in an uncured matrix material are cut to the desired shape and then stacked in the desired configuration of the composite part. The prepreg may be placed (laid-up) directly upon a tool or die having a forming surface contoured to the desired shape of the completed part or the prepreg may be laid-up in a flat sheet and the sheet may be draped over a tool or die to form to the contour of the tool.
After being laid-up, the prepreg is consolidated (i.e., cured) in a conventional vacuum bag process in an autoclave (i.e., a pressurized oven). The pressure presses the individual layers of prepreg together at the consolidation/curing temperatures that the matrix material flows to eliminate voids and cures, generally through polymerization.
In autoclave fabrication, the composite materials must be bagged, placed in the autoclave, and the entire heat mass of the composite material and tooling must be elevated to and held at the consolidation or curing temperature until the part is formed and cured. The formed composite part and tooling must then be cooled, removed from the autoclave, and unbagged. Finally, the composite part must be removed from the tooling.
To supply the required consolidation pressures, it is necessary to build a special pressure box within the autoclave or to pressurize the entire autoclave, thus increasing fabrication time and cost, especially for low rate production runs.
Autoclave tools upon which composite materials are laid-up are typically formed of metal or a reinforced composite material to insure proper dimensional tolerances and to withstand the high temperature and consolidation forces used to form and cure composite materials. Thus, autoclave tools are generally heavy and have large heat masses. The entire heat mass of the tool must be heated along with the composite material during curing and must be cooled prior to removing the completed composite part. The time required to heat and cool the heat mass of the tools adds substantially to the overall time necessary to fabricate a single composite part.
In composite parts requiring close tolerances on both the interior and exterior mold line of the part, matched autoclave tooling must be used. When matched tooling is used, autoclave consolidation pressure is used to force the matched tooling together to consolidate the composite material and achieve proper part dimensions. Matched tooling is more expensive than open faced tooling and must be carefully designed to produce good results, adding to part fabrication costs.
An alternative to fabricating composite parts in an autoclave is to use a hot press. In this method, the prepreg is laid-up, bagged (if necessary), and placed between matched metal tools that include forming surfaces that define the internal and external mold lines of the completed part. The tools and composite material are placed within the press and then heated. The press brings the tools together to consolidate and form the composite material into the final shape. Fabricating composite parts in a hot press is also expensive due to the large capital expense and large amounts of energy required operate the press and maintain the tools.
Generally, in hot press operations, to obtain close tolerances, the massive, matched tooling is formed from expensive metal alloys having low thermal expansion coefficients. The tooling is a substantial heat sink that takes a large amount of energy and time to heat to composite material consolidation temperatures. After consolidation, the tooling must be cooled to a temperature at which it is safe to remove the formed composite part thus adding to the fabrication time.
Another contributor to the cost of fabricating composite parts is the time and manpower necessary to lay up individual layers of prepreg to form a part. Often, the prepreg must be laid up over a tool having fairly complex contours that require each layer of prepreg to be manually placed and oriented. Composite fabrication costs could be reduced if a flat panel could be laid-up flat and then formed into the shape of the part.
One method used to reduce the costs of fabricating composite materials is to lay up a flat panel and then place the flat panel between two metal sheets capable of superplastic deformation as described in U.S. Pat. No. 4,657,717. The flat composite panel and metal sheets are then superplastically deformed against a metal die having a surface contoured to the final shape of the part. Typically, the dies used in such superplastic forming operations are formed of stainless steel or other metal alloys capable of withstanding the harsh temperatures and pressures. Such dies have a large thermal mass that takes a significant amount of time and energy to heat up to superplastic forming temperatures and to cool down thereafter.
Attempts have been made to reduce composite fabrication times by actively cooling the tools after forming the composite part. These attempts have shortened the time necessary to produce a composite part, however, the time and energy expended in tool heat up and cool down remains a large contributor to overall fabrication costs.
The present invention is a method and apparatus for consolidating and forming organic matrix composites that avoid some of the above-identified disadvantages of the prior art.
SUMMARY OF THE INVENTION
The present invention is a method and apparatus for consolidation of organic matrix composites using inductive heating. In the present invention, the dies or tooling for the organic matrix composite parts are made from a material that is not susceptible to inductive heating. Examples of usable tool materials are ceramics or resin composites. The tooling is strengthened and reinforced with fiberglass rods or other appropriate reinforcements to withstand the temperatures and pressures used to form the composite materials. Such materials decrease the cost of tool fabrication and also generally reduce the thermal mass and weight of the tooling. Since the tooling used in the present invention is not susceptible to inductive heating, it is possible to use the tooling in combination with inductive heating elements to heat the composite material. The present invention allows the composite material to be inductively heated without heating the tools significantly. Thus, the present invention can reduce the time and energy required to fabricate a composite part.
Graphite or boron reinforced organic matrix composites may be sufficiently susceptible because of their reinforcing fibers that they can be heated directly by induction. Most organic matrix composites require a susceptor in or adjacent to the composite material to achieve the necessary heating. The susceptor is heated inductively and transfers its heat to the composite material.
The present invention reduces the time and energy required to consolidate resin composite prepreg lay-ups for a composite. Because induction focuses the heat on the workpiece rather than the tool, there is less mass to heat or cool. Inexpensive composite or ceramic tooling can also be used. The lower operating temperature of the tools decreases problems caused by different coefficients of thermal expansion between the tools and the workpiece in prior art forming systems. The present invention also provides an improved method for fabricating composite parts to close tolerances on both the internal and external mold line of the part.
In a method for consolidating/or and forming organic matrix composite materials, an organic matrix composite panel is laid up and then placed adjacent a metal susceptor. The susceptor is inductively heated and then heats the composite panel by thermal conduction. A consolidation and forming pressure is applied to consolidate and form the organic matrix composite panel at its curing temperature.
Generally, the composite panel is enclosed between two susceptor sheets that are sealed to form a pressure zone around the composite panel. This pressure zone is evacuated in a manner analogous to convention vacuum bag processes for resin consolidation. The workpiece (the two susceptors and composite panel) is placed in an inductive heating press on the forming surfaces of dies having the desired shape of the molded composite part, and is pressed at elevated temperature and pressure (while maintaining the vacuum in the pressure zone) to consolidate the composite panel into its desired shape.
The workpiece may include three susceptors sealed around their periphery to define two pressure zones. The first pressure zone surrounds the composite panel and is evacuated and maintained under vacuum. The second pressure zone is pressurized to help form the composite panel.
One preferred apparatus for consolidating and forming the organic matrix composite panels uses ceramic or composite dies. An induction coil is embedded in the dies. When the coil is energized with a time varying current, induction heats the susceptors which in turn heats the composite panel by conduction. Pressure is applied to at least one side of the composite panel to consolidate and form it when it reaches the desired consolidation temperature.
It is preferred to use reinforced, cast phenolic or ceramic dies. Reinforcing rods are embedded within the dies to increase their strength by compressing the dies. The phenolic or ceramic dies may be reinforced with chopped reinforcing fibers, with a mat or weave of continuous fibers or with other reinforcements. The die usually includes a cavity adapted to receive a tool insert. The tool insert may include a forming surface that defines the shape of the molded composite part. In this way, different parts can be made simply by changing the insert rather than needing to replace the entire die.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of an apparatus, for consolidating and forming organic matrix composite panels;
FIG. 2 is a schematic cross-sectional view of the apparatus of FIG. 1;
FIG. 3 is a perspective view illustrating the induction coil;
FIG. 4 is a cross-sectional view of a flexible coil connector;
FIG. 5 is a partially exploded, partially cut away view of a portion of the apparatus of FIG. 1;
FIG. 6A is an enlarged cross-sectional view of part of an organic matrix composite panel after it has been placed within the tooling but before consolidation and forming has begun;
FIG. 6B is an enlarged cross-sectional view of part of an organic matrix composite panel after consolidation and forming has begun;
FIG. 6C is an enlarged cross-sectional view of part of an organic matrix composite panel after consolidation and forming has been completed;
FIG. 7 is a flow chart showing an embodiment of the method of consolidation and forming of the present invention;
FIG. 8 is a partial perspective view of an organic matrix composite part including a close tolerance attachment section; and
FIG. 9 is an enlarged cross-sectional view of tooling for forming a close tolerance section in a part using matched tooling.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
In FIG. 1, the inductive heating and forming apparatus 10 includes tools or dies 20 and 22 mounted within an upper 24 and a lower 26 strongback, respectively. The strongbacks are each threaded onto four threaded column supports or jackscrews 28. The jackscrews can be turned using a bellows or other actuation mechanisms to move the upper strongback or lower strongback up or down in relation to each other.
Each strongback 24 and 26 provides a rigid, flat backing surface for the upper and lower die 20 and 22 to prevent the dies from bending and cracking during repeated consolidation and forming operations. Preferably, the strongbacks should be capable of holding the dies to a surface tolerance of ±0.003 inches per square foot of the forming surface in the toolbox. Such tolerances help to insure that proper part tolerances are achieved. The strongbacks may be formed of steel, aluminum, or any other material capable of handling the loads present during forming. However, materials that are nonmagnetic such as aluminum or some steel alloys are preferred to avoid any distortion to the magnetic field produced by the induction coils described below. In some circumstances, the dies may be strong enough without the strongbacks.
Both the upper 20 and lower 22 dies hold inserts 46 and 48 (FIGS. 2 and 5) and are reinforced with a plurality of fiberglass rods 32 (FIG. 5) that extend both longitudinally and transversely in a grid through each die. Each die may be attached to its strongback by any suitable fastening devices such as bolting or clamping. In the preferred embodiment, both dies are mounted on support plates 76 (FIG. 5) which are held in place on the respective strongbacks through the use of clamping bars 77 (FIGS. 1 and 5). The clamping bars 77 extend around the peripheral edges of the support plates 76 and are bolted to the respective strongbacks through the use of fasteners (not shown).
The dies are not susceptible to inductive heating. A composite or ceramic material that has a low coefficient of thermal expansion, good thermal shock resistance, and relatively high compression strength is preferred such as a castable fused silica ceramic.
A plurality of induction coils 35 (FIG. 1) extend longitudinally through the length of the upper and lower dies. In the preferred embodiment, four separate induction coils 35 are used, however, other numbers of induction coils could also be used. Each induction coil 35 is formed from a straight tubing section 36 that extends along the length of each die and a flexible coil connector 38 that joins the straight tubing sections 36 in the upper die 20 to the straight tubing sections in the lower die 22. The induction coils 35 are connected to an external power source or coil driver 50 and to source of coolant by connectors 40 located at the ends of the inductive coils.
A composite panel is formed from prepreg laid-up on a contoured surface of a tool and is secured within the upper 20 and lower 22 dies as described in detail below. The upper 24 and lower 26 strongbacks and thus upper 20 and lower 22 dies are then brought together. The composite panel is then inductively heated to the consolidation temperature to promote resin flow and polymerization, as described in greater detail below.
Cavities 42 and 44 (FIG. 2), respectively, in the dies are sized to hold an upper 46 and a lower 48 tool insert. The upper tool insert 46 includes a contoured forming surface 58 that has a shape corresponding to the desired shape of the outer mold line surface of the composite part to be formed. The lower tool insert determines the inner mold line. The tool inserts generally are not susceptible to inductive heating. In the preferred embodiment, the tool inserts are formed of a castable dielectric phenolic or ceramic.
The tool inserts could be formed as an integral part of the dies. The separate die and tool insert configuration shown is preferred because it allows different tool inserts having different forming surfaces to be used in the same dies, simplifying the replacement task for changing the tooling and reducing the tooling costs.
Each die surrounds and supports the respective tool insert and holds the straight sections 36 of the induction coils in proper position in relationship to the tool insert. In the preferred embodiment, the interior 70 of the dies is formed of a castable phenolic or ceramic and the exterior sides of the toolboxes are formed from precast composite phenolic resin blocks 72. In some applications, it is preferable to reinforce the phenolic or ceramic resins with chopped fibers or nonwoven or woven reinforcing mats.
To increase the strength of the phenolics or ceramics fiberglass reinforcing rods 32 are used. The rods 32 extend both longitudinally and transversely through the precast blocks 72 and the interior 70 and are then post-tensioned through the use of tensioning nuts 74 after casting the interior 70. Post-tensioning the reinforcing rods 32 maintains a compressive load on the blocks 72, interior 70 and the tool inserts to maintain the tolerances of the upper and lower tool inserts and to prevent cracking or damage of the dies are tool inserts during consolidation and forming operations.
The straight tubing sections 36 of the induction coils 35 are embedded within the dies, and extend parallel to the bottom surface of the respective tool inserts. The induction coils may be contained within the tool inserts.
In FIG. 2, a workpiece 60 including an organic matrix composite panel is shown already laid-up and placed between the upper 46 and lower 48 tool inserts. The detailed structure of the workpiece will be described in detail below. The workpiece 60 is heated to a forming and consolidation temperature by energizing the coils 35.
When the workpiece 60 reaches the consolidation temperature at which the matrix flows, gas pressure is applied to the workpiece by pressure sources 52 and 54. Pressure source 52 provides a pressure to the upper surface of the workpiece 60 through a conduit 62 that passes through the upper die 20 and upper tool insert 46, while pressure source 54 applies a pressure to the lower surface of the workpiece 60 through a conduit 64 that passes through the lower die 22 and lower tool insert 48.
In FIG. 2, the composite workpiece 60 is shown partially deformed upwardly toward the forming surface 58. The pressure applied to the workpiece 60 is maintained until the workpiece has formed to the contour of the forming surface 58 and the matrix resin has consolidated. The pressure sources 52 and 54 may apply an equal or a differential pressure to both the upper and lower surfaces of the workpiece 60.
Pin holes (not shown) may be formed in the upper and lower tool inserts to vent gas trapped between the workpiece 60 and the forming surface 58 as the workpiece deforms. Such pin holes can be coupled to a flow meter to monitor the progress of the workpiece's deformation.
When the workpiece 60 is formed and consolidated, the induction coils 35 are de-energized, and the pressure relieved. The upper 46 and lower 48 tool inserts and upper 20 and lower 22 dies are separated. The composite part is removed.
Inductive heating is accomplished by providing an alternating electrical current to the induction coils 35 within which the workpiece is positioned. This alternating current produces an alternating magnetic field in the vicinity of the inductive coils that heats the workpiece via eddy current heating.
Curved sections 84 extending between the straight sections 36 (FIG. 4) in the coils 35 are flexible, to accommodate the opening and closing of the upper 20 and lower 22 dies. The curved sections 84 and straight sections 36 are joined at fittings 86 into one or more induction coils or helixes to produce a magnetic field schematically illustrated by field lines 90 in FIG. 3. Each straight section 36 and curved section 84 preferably comprises a copper tube having an interior longitudinal passage 96 through which a cooling fluid (such as water) may be pumped to cool the coils during operation.
FIG. 4 illustrates a preferred construction for each curved section 84. Each curved section includes a pair of fittings 86, each of which includes a relatively small diameter section 92 dimensioned to fit snugly within a straight section 36, and a larger diameter flange 94. The flange 94 regulates the distance the fittings 86 extend into the straight sections 36. The passage 96 extends through each fitting 86, each curved section 84, and each straight section 36.
A braided flexible conductor 98 extends through passage 96 and is joined between flanges 94 by a suitable method such as brazing or soldering. Finally, a flexible, insulating jacket 100 is placed around the conductor 98 and extends between the flanges 94 to contain the conductors and cooling fluid. One commercial vendor through which a suitable design cable can be obtained is Flex-Cable located at Troy, Mich.
The frequency at which the coil driver 50 (FIG. 2) drives the coils 35 depends upon the nature of the workpiece 60. Current penetration of copper at 3 kHz. is approximately 0.06 inches, while penetration at 10 kHz. is approximately 0.03 inches. The shape of the coil also has a significant effect upon the magnetic field uniformity. Field uniformity is important because temperature uniformity in the workpiece is directly affected by the uniformity of the magnetic field. Uniform heating insures that different portions of the workpiece will reach the forming and consolidation temperature of the composite material at approximately the same time. Solenoidal type induction coils provide a uniform magnetic field, and are therefore preferred. Greater field uniformity is produced in a workpiece that is symmetric around the center line of the induction coil. The additions of variations, such as series/parallel induction coil combinations, variable turn spacings and distances between the part and the induction coil can be established by standard electrical calculations.
Dielectric materials for the tool inserts and dies are generally thermally insulating. Thus, the tool inserts and dies tend to trap and contain heat within the workpiece. Since the dies and tool inserts are not inductively heated, and act as insulators maintaining heat within the workpiece, the present invention requires far less energy to form and consolidate the composite panel than conventional autoclave or resistive hot press methods.
The forming operation of the present invention also takes much less time than prior art forming operations because time is not expended elevating the large thermal mass of either the dies or tool inserts prior to forming and consolidating the composite panel. Only the workpiece itself is heated by the coils. Thus, forming temperatures are achieved more rapidly and when the driver 50 is de-energized, the dies and the workpiece cool rapidly to a temperature at which the part may be removed, saving time and energy. In addition, the thermal cycle is not limited by the heating and cooling cycle of the equipment and tools so the thermocycle may be better tailored to the material used.
In FIG. 7, block 130, a composite panel 110 is laid-up from individual layers of prepreg. The composite panel 110 is placed between a first sheet 112 and second sheet 114 of a susceptor (block 132) to form a workpiece. The susceptors are welded around the periphery thus forming a pressure zone 117 between the susceptors surrounding the composite panel 110. The resulting workpiece is then placed within the upper 46 and lower 48 tool inserts, block 136.
The periphery of the workpiece, including the area containing the sealing weld 116, is clamped between the edges of the upper 46 and lower 48 tool inserts to form a pressure zone 119 between the lower tool insert 48 and the workpiece 60 and a pressure zone 120 between the upper tool insert 46 and the workpiece 60.
In cases where the lower tool insert 48 is formed of a material that is somewhat porous, it is advantageous to place a third susceptor 122 between the lower tool insert 48 and the first sheet 112 to serve as a pressure barrier between the workpiece 60 and the lower tool insert 48. When a third susceptor 122 is used, it is also advantageous to weld it to the first sheet 112 around the periphery at weld 116, thus forming the pressure zone 119 between the first sheet 112 and third sheet 122 as opposed to between the first sheet 112 and the lower tool insert 48. In order to ensure that the periphery of the upper and lower tool inserts are sealed it is also advantageous to use an O-ring seal 124 around the periphery of the upper and lower tool inserts.
After placing the workpiece between the upper 46 and lower 48 tool inserts and bringing the tool inserts together to form pressure zones 117, 119 and 120, the air from within the pressure zone 117 surrounding the composite panel 110 is evacuated (block 137). Pulling a vacuum around the composite panel 110 helps to reduce voids or in the completed composite part. Pulling a vacuum in the pressure zone 117 also helps to ensure that the first sheet 112 and second sheet 114 remain tightly against the composite panel 110 during consolidation and forming which in turn helps to prevent wrinkles and flaws in the surface of the completed part.
After pulling a vacuum in pressure zone 117, the coils 35 are energized by the coil driver 50 with a time varying electrical field (block 138) to heat the susceptors inductively to the forming and consolidation temperature of the composite panel 110. Heat is transferred by conduction into the composite panel 110, so it too reaches consolidation temperature.
Pressure zone 119 is pressurized (block 140) to force the susceptors and composite panel 110 upwardly, as shown in sequential FIGS. 6A-C, until the upper surface of the workpiece conforms to the forming surface 58 of the upper tool insert. The pressure within the pressure zone 119 is maintained until the composite panel 110 has fully formed and consolidated.
During forming, it may be advantageous to pressurize the pressure zone 120 between the upper tool insert 46 and the second sheet 114. Pressurizing pressure zone 120 places a force on the workpiece which helps to consolidate the composite panel 110 and regulates the rate at which the workpiece deforms. In some applications, it may be advantageous to pressurize and maintain pressure zones 119 and 120 at the same pressure for a period of time to help consolidate the composite panel 110 prior to the forming procedure. As the forming procedure begins, the pressure in pressure zone 120 can then be maintained slightly lower than the pressure in pressure zone 119 or can be decreased over time to allow the pressure in pressure zone 119 to deform the workpiece upwardly into contact with the forming surface 58. In the preferred embodiment, it has been found advantageous to form the susceptors from aluminum or an aluminum alloy.
After completing consolidation, the induction coils 35 are shut off and the workpiece and tool inserts are allowed to cool to a temperature at which the formed composite panel 110 may be removed from the tool inserts and first 112, and, then, from, the second 114 sheets (blocks 142-146). Although there is some heat transfer between the workpiece and the tool inserts, it is insufficient to heat the tool inserts or dies substantially.
In one example of composite consolidation and forming in accordance with the present invention, a composite panel formed of 48 layers of thermoplastic PEEK/IM6 prepreg 3/8 inch thick was consolidated and formed. PEEK is a polyetheretherketone. IM6 is a designation for a commercially available carbon fibercloth. Three aluminum sheets having a thickness of 1/16 inch were placed around the composite panel and the resulting workpiece was placed in the tool inserts and inductively heated to a temperature of 720° F. by induction heating in five minutes time. The panel was maintained at 720° F. for two minutes and then cooled for twenty minutes. Pressure zone 119 was then pressurized to approximately 250 psi while pressure zone 117 was vented to atmospheric pressure. The pressure zone 120 was not pressurized. The pressure in pressure zone 119 was maintained for 22 minutes to consolidate and cure the composite panel. The times and pressures described above are for representative purposes only and would differ depending upon the composite material used and the thickness and complexity of the formed part.
The present invention is applicable to all types of organic matrix composites that is not limited to the example discussed above. For example, the present invention may be used to consolidate/cure both thermal setting and thermoplastic composites including epoxies, bismaleimides and polyimides.
Another problem with prior art composite forming and consolidation procedures has been difficulty in forming a close tolerance outer mold line while also maintaining a close tolerance inner mold line on a composite part. In FIG. 8, the tolerances of the outer mold line surface 150 of the wing skin 148 must be closely maintained to ensure that an efficient aerodynamic surface is achieved. The tolerances of the inner mold line surface 152 of the wing skin must also be maintained at a dose tolerance in a buildup area 154 where the wing skin is joined to a spar 144 to ensure that the wing skin 148 and spar 144 can be joined together along joining surface 156 through the use of fasteners 158 without the use of shims. It is not as critical to control the inner mold line surface in areas 160 where the wing skin is not attached to other structures.
As shown in FIG. 9, composite panel 162 is placed within three sheets 164, 166, and 168 to form a workpiece that is placed within upper and lower tool inserts 170 and 173, respectively. The composite panel includes a buildup area 174 having additional layers of prepreg so that the buildup area is thicker than the surrounding composite panel. Additional layers of prepreg are used in the buildup area to reinforce the composite panel in the area where the spar 144 (FIG. 8) is to be attached.
Similar to the preferred embodiment, the upper tool insert 170 includes a forming surface 172 that is contoured to define the outer mold line of the composite panel 162 after it is formed. The lower tool insert 173 includes a raised portion 180 whose upper surface 182 defines the lower surface of the workpiece after forming. The raised portion 180 is spaced a proper distance from the buildup area 174 to maintain a close tolerance on the interior mold line surface of the composite panel 162 in the buildup area 179 during forming and consolidation.
The pressure zone formed between sheets 164 and 166 is evacuated. The induction coils are energized to inductively heat the sheets and, thus, composite panel 162. The pressure zone 184 formed between sheets 164 and 168 is then pressurized to force the workpiece upwardly into contact with the forming surface 172 and to exert hydrostatic force on the sides 186 of the buildup area 174 to help maintain the required tolerances.
To ensure that proper part tolerances are maintained in the buildup area 174, it may be advantageous to weld sheets 164 and 168 together along the edges of the buildup area 174 along weld line 188. The weld line 188 help ensure that the pressure within pressure zone 184 does not force sheets 164 and 168 apart in the buildup area 174.
Depending upon the application, it may be advantageous to maintain different pressures in pressure zone 184 at different locations on the composite part. Welding the first sheet 164 and third sheet 168 together along a weld line defines different pressure zones between the sheets that may be pressurized at different pressures.
Holes are drilled in the build-up section 174 of the wing skin to receive fasteners 158 to join the spar 144 to the wing skin (FIG. 8).
While preferred embodiments of the invention has been illustrated and described, those skilled in the art will appreciate that various changes can be made therein without departing from the spirit and scope of the invention.
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A die for use in an induction heating workcell incorporates segments of the induction coil in spaced array within a cast ceramic or phenolic body. A peripheral compression frame, typically of phenolic, surrounds the die body and applies a compressive load to the body through lateral and transverse reinforcing rods that are cast into the body. Matched dies close to trap heat in a workpiece at the center of the induction coil.
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This application is the United States national stage of International Application No. PCT/IN2007/000190, filed May 11, 2007, which was published under PCT Article 21 in English as International Publication No. WO 2007/132480, and which claims benefit of Indian Patent Application No. 842/CHE/2006 filed May 12, 2006 and the text of application 842/CHE/2006 is incorporated by reference in its entirety herewith.
FIELD OF INVENTION
The present invention relates to a composition comprising a viral antigen, a first protein and a second protein and primary sugar and secondary sugar. The present invention also relates to the use of a viral antigen, a first protein and a second protein for the manufacture of a pharmaceutical composition, preferably a vaccine. The present invention furthermore relates to a method of treatment or prevention of virus associates diseases in humans. Moreover, the present invention relates to a method of adapting a virus to a suitable cell-line.
The invention is also useful for the production of virus suspensions suitable for making stable, live/inactivated, monovalent and/or polyvalent, liquid/lyophilized rotavirus vaccine compositions for oral and/or nasal or any other suitable route of administration in human.
BACKGROUND OF THE INVENTION
Rotavirus infection is the greatest cause of diarrhea related deaths in infants and young children. Every year rotavirus gastroenteritis causes the deaths of 310,000-590,000 infants and young children, worldwide. International health agencies have promoted the development of rotavirus vaccine as the best method for the prevention of morbidity and mortality associated with rotavirus infection. In 1997 and, again, in 2000, the WHO recommended that all new rotavirus vaccines should be tested in Asia and Africa and that this testing should be performed concurrently with trials conducted in the United States and Europe. By doing this safety and efficacy of vaccines might be demonstrated in poor, developing countries early during development, thereby accelerating the availability of new vaccines to the children who are most in need of them.
All rotavirus vaccines developed to date have been based on live rotavirus strains that have been isolated from humans or animals and in vitro reassorted and adapted to cell culture, formulated for oral delivery. Both monovalent and multivalent animal based strains have demonstrated efficacy as candidate vaccines. RotaShield (Wyeth-Ayerst) was licensed but then was withdrawn.
The human rotavirus strain 116E, natural human-bovine reassortant, naturally attenuated
is characterized as a human G9 strain into which a single bovine VP4 gene, homologous to P[11] gene segment is naturally introduced. The I321, strain is characterized as a G10P [11] is composed primarily of bovine genes and has only two gene segments, VP5 and VP7 of human origin. These two rotavirus vaccine strains individually have been prepared as pilot lots of monovalent oral rotavirus vaccine liquid formulations for clinical trials to be conducted in India.
Bharat Biotech International Ltd. (BBIL) obtained the human rotavirus strains, 116E and I321 from National Institute of Health (NIH) under the material transfer agreement with National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, USA. The complete genomic sequence of rotavirus strains 116E and I321 is reported. The original 116E (G9[P11]) and I321 (G10P[11]) were adapted to grow in cell culture by passages in primary African green monkey kidney (AGMK) cells then in MA104 cell substrate and later in Serially Passaged AGMK (SPAGMK). MA104 and SPAGMK cell substrates are not approved by National Regulatory Authorities (NRA) for commercial vaccine production. Hence it is preferable to adapt 116E and I321 and other rotavirus vaccine strains to approved, certified, licensed and fully characterized cell substrate like Vero cell substrate and/or human diploid cells like MRC-5.
WO 02/11540 describes rotavirus vaccine formulations which include buffering agents appropriate for oral administration of rotavirus vaccines. The formulations disclosed in WO 02/11540 also include compounds to stabilize the vaccine compositions against potency loss. More specifically, the compositions disclosed in WO 02/11540 comprise a sugar, phosphate and at least one carboxylate. The stabilities achieved with the formulations of WO 02/11540 vary greatly, and especially at temperatures over 20 degrees Celsius appear to show considerable losses in potency. Accordingly, it was an object of the present invention to provide for alternative compositions of a viral antigen, preferably compositions of rotavirus, which show a good stability.
The objects of the present invention are solved by a composition comprising a viral antigen, a first protein different from said viral antigen, said first protein being selected from human serum albumin (HSA) and recombinant human albumin (rHA), a second protein different from said viral antigen, which second protein is at least partially hydrolyzed, said second protein being selected from lactalbumin. The second protein confers enhanced stability to the vaccine formulation than either of the protein alone.
In one embodiment the composition further comprises three different disaccharides, wherein, preferably, said three different disaccharides are selected from sucrose, lactose, maltose, trehalose, cellobiose, gentobiose, melibiose and turanose. Where as sucrose is used as primary sugar and secondary sugar is selected from the combination of sucrose, lactose, maltose and trehalose. The combination of sugars at particular concentrations further confers stability to the vaccine formulation containing protein additives. The term “primary sugar”, as used herein, is meant to refer to a sugar that is present in a composition with other sugars, at an amount greater than of any of the other sugars present. Such other sugars are herein also referred to as “secondary sugars”. The “primary sugar” may also be referred to herein as “bulk sugar”.
In one embodiment said second protein which is at least partially hydrolyzed is selected from lactalbumin hydrolyzate, yeast hydrolyzate, peptone, and gelatin hydrolyzate.
In one embodiment said first protein is present in the formulation in an amount in the range of from 0.1% (w/v) to 2% (w/v), preferably 0.1% (w/v) to 0.45 (w/v) and said second protein which is at least partially hydrolyzed is present in the formulation, as at least partial hydrolyzate, in an amount in the range of from 0.01% (w/v) to 10% (w/v).
Preferably, said three different disaccharides, or said primary sugar and said at least two secondary sugars are one of the following combinations:
a) sucrose, lactose and maltose, b) sucrose, maltose and trehalose, c) sucrose, lactose and trehalose, d) maltose, lactose and trehalose.
Preferably, the amount of said three different disaccharides together in the formulation is from 20% (w/v) to 70% (w/v).
In a preferred embodiment the amount of sucrose, if present, is from 40% (w/v) to 55% (w/v), preferably 50% (w/v), the amount of lactose, if present, is from 0.1% (w/v) to 10.0% (w/v), preferably 0.5% (w/v), the amount of maltose, if present, is from 0.1% (w/v) to 10.0% (w/v), preferably 0.5% (w/v), and the amount of trehalose, if present, is from 0.1% (w/v) to 10.0% (w/v), preferably 0.5% (w/v).
In one embodiment said viral antigen is a live virus, such as a live attenuated virus, wherein, preferably, said live virus is selected from the group comprising rotaviruses.
Preferably, said live virus is a human live virus, such as human rotavirus.
In a particularly preferred embodiment said human rotavirus is rotavirus strain 116E or I321.
In one embodiment, the composition according to the present invention comprises a live rotavirus at a titre in the range of from 10 4 to 10 7 FFU/0.5 ml, human serum albumin in the range of from 0.1% (w/v) to 0.45% (w/v), lactalbumin hydrolysate in the range of from 0.01% (w/v) to 10% (w/v), and either
a) sucrose at an amount in the range of from 40% to 55% (w/v), and
lactose at an amount in the range of from 0.1% to 10.0% (w/v), and
maltose at an amount in the range of from 0.1% to 10.0% (w/v),
or
b) sucrose at an amount in the range of from 40% to 55% (w/v), and
maltose at an amount in the range of from 0.1% to 10.0% (w/v), and
trehalose at an amount in the range of from 0.1% to 10.0% (w/v).
In one embodiment the composition according to the present invention further comprises a buffer to adjust the pH of said composition to a value in the range of from 6.8 to 7.8, wherein, preferably, said buffer is a phosphate/citrate buffer.
In one embodiment the composition according to the present invention is made up in Eagles Minimum essential medium, wherein, preferably, it is buffered in a phosphate/citrate buffer at a pH between 6.8 and 7.8.
Preferably, said phosphate/citrate buffer is approximately 310 mM phosphate and approximately 100 mM citrate.
In one embodiment the composition according to the present invention is a vaccine.
The preparation of stable vaccine formulation presents significant challenges. The interactions between the incorporated excipients in the vaccine composition determine the formulation stability. Protein and sugar hydrogen bonding need to be dominant to result with stabilization of the vaccine. The effective contacts of sugar and antigenic protein vaccine should be with appropriate ratio to keep the vaccine stable. A critical sugar concentration is required to have number of protein and sugar hydrogen bonding to keep the vaccine stable for a given period of time, at a given temperature. Sugars have the ability to hydrogen bond to phospholipids membrane and proteins by substituting for structural water. The present study provides the stabilizers used to stabilize the live attenuated Rota virus 116 E and I321 against 2-8° C., 25° C. and 37° C. for an extended period of time.
Appropriate combination of the sugars and proteins with the buffering component preserve and allow the survival and activity of the virus on a long storage period. These additives give structural support to the suspended Rota Virus in the liquid state. Trehalose is preferred to use as stabilizer in vaccine formulation, since it stabilizes the protein structure of the virus and restore the potency on long storage. Combination of Sucrose and Maltose makes effective contacts of sugar and protein (vaccine) to keep the vaccine stable. Human serum albumin supported by Lactalbumin hydrolyzate play prominent role in effective contact of sugar and vaccine protein to keep the vaccine stable.
The objects of the present invention are also solved by the use of a viral antigen, a first protein and a second protein, each being as defined above, and, optionally, three different disaccharides, as defined above, for the manufacture of a composition according to the present invention, preferably for the manufacture of a vaccine, for the treatment or prevention of virus associated, preferably rotavirus associated diseases, such as diarrhea and gastroenteritis.
Preferably, said treatment or prevention comprises administering three oral doses of a safe and effective amount of the composition to an infant within 8-20 weeks of age at the time of dose 1.
Preferably, the use according to the present invention is for the prevention of a virus infection, preferably a rotavirus infection and/or rotavirus gastroenteritis in humans.
The objects of the present invention are also solved by a method of treatment or prevention of virus associated, preferably rotavirus associated diseases in humans by administering to a human an effective amount of the composition according to the present invention.
Preferably, the method according to the present invention, comprises administering three oral doses of a safe and effective amount of the composition to an infant within 8-20 weeks of age at the time of dose 1.
In one embodiment the method according to the present invention, for the prevention of a virus infection, preferably a rotavirus infection and/or rotavirus gastroenteritis in humans.
The objects of the present invention are solved by a method of adapting a virus to a suitable cell line, such as Vero cells, comprising serially passaging said virus through cultures of said suitable cell line, each passage occurring in a medium in the presence of calcium chloride and trypsin.
Preferably, said calcium chloride is present in the range of from 0.1 mg/ml to 1 mg/ml, and said trypsin is present in the range of from 0.1 μg/ml to 30 μg/ml.
In one embodiment said serial passages comprise 2-20 passages, preferably 2-5 passages.
Preferably, each passage occurs over a time period in the range of from 24 hours to 10 days.
Preferably, said virus is human rotavirus.
The present inventors have found that by including a first protein selected from human serum albumin, recombinant human albumin and a second protein which is at least partially hydrolyzed, in a pharmaceutical composition, the stability of this composition with respect to its viral potency can be enhanced. Especially at temperatures 25° C. and 37° C., the compositions according to the present invention show an enhanced stability.
The phrase “the second protein is at least partially hydrolyzed”, as used herein, is meant to refer to a scenario, in which this second protein has been at least partially been broken down into its respective amino acid building blocks. The aforementioned phrase is therefore also meant to include scenarios, wherein the second protein does not exist as a complete molecule anymore, but only as a collection of fragments thereof. The aforementioned phrase is meant to also include a scenario wherein the second protein is fully hydrolyzed. All these scenarios are also meant to be included by the phrase “protein hydrolyzate”, such as “lactalbumin hydrolyzate”, which may include a fully hydrolyzed protein, i.e. a protein broken down into its respective amino acids, or a protein partially broken down, such that a collection of peptides and amino acids exist. Such protein hydrolyzates can be easily made by someone skilled in the art, for example by acid hydrolysis, or they can be commercially obtained.
The stabilizing effect achieved by the presence of the first protein and the second protein is optionally enhanced by the presence of a combination of three different disaccharides, or of a combination of a primary sugar and at least two secondary sugars. Preferred combinations are sucrose, lactose and maltose, and sucrose, maltose and trehalose. The compositions according to the present invention may be used as a vaccine for vaccination against virus infection and virus associated diseases. Preferably, these compositions are buffered at an appropriate pH, usually between 6 and 8, preferably between 6.8 and 7.8. For example, in one embodiment, the composition according to the present invention may be formulated in Eagles minimum essential medium. Preferably, this composition is buffered, for example using a phosphate/citrate buffer.
The present inventors have also devised a method of adapting a virus to a suitable cell-line, which method may be for example used with rotavirus. Such method is performed by serially passaging the virus through cell cultures, wherein the passaging occurs in the presence of calcium chloride and trypsin. This allows for an easy way of adapting virus to a given cell line and furthermore enables the production of virus at high titers.
More specifically and by way of example, the present inventors have adapted 116E and I321 rotavirus strains to Vero cells to produce high titer rotavirus harvest and further characterized the adapted 116E and I321 for making stable, live, monovalent, liquid rotavirus vaccine compositions. Prior to vaccination, oral antacid composition of citrate-bicarbonate buffer is given to buffer stomach acidity of the child.
All rotavirus vaccine strains reported till date are either natural, live, human bovine, naturally or artificially attenuated rotavirus strains or genetically engineered human, bovine strains with various combinations of VP4, VP7 and other genes of human, bovine rotavirus strains. The rotavirus strains 116E (G9P[11]) and I321 (G10P[11]) are natural human-bovine reassortant, naturally attenuated and confer substantial level of immunity in infants and young children. Also the ability of 116E strain to replicate in newborns without causing disease in presence of high titers of maternal antibody make it more promising live, naturally attenuated monovalent rotavirus vaccine candidate.
The present invention provides for pharmaceutical compositions of virus, preferably rotavirus, which show high stability and longevity especially at temperatures above 20° C. The present invention also provides a method for adapting rotavirus, e.g. natural human-bovine reassortant, naturally attenuated rotavirus strains 116E (G9P [11]) and I321 (G10P[11]) to suitable cells, e.g. Vero cells. The method include optimized dose of trypsin (0.1 μg/ml to 30 μg/ml) and/or calcium chloride (100 μg/ml to 1000 μg/ml) for virus activation and virus maintenance medium where high titer (10 4 to 10 8 FFU/ml) of virus harvest is within one to ten days. Also use of the adapted strains for making stable, live, monovalent, liquid rotavirus vaccine composition is envisaged. Furthermore, the present invention provides for the use of a viral antigen, a first protein, a second protein and, optionally, a combination of three different disaccharides for the manufacture of a composition according to the present invention for the treatment or prevention of virus associated diseases, preferably rotavirus associated diseases.
BRIEF DESCRIPTION OF FIGURES
FIG. 1 : Stability data for rotavirus liquid formulation with different stabilizers after storage at 2-8° C. for 50 weeks.
FIG. 2 : Stability data for rotavirus liquid formulations with different stabilizers after storage at 25° C.
FIG. 3 : Stability data for rotavirus liquid formulations with different stabilizers after storage at 37° C.
FIG. 4 : Stability data for rotavirus liquid formulation after storage at 2-8° C., 25° C. and 37° C. for sample 1.
FIG. 5 : Stability data for rotavirus liquid formulation after storage at 2-8° C., 25° C. and 37° C. for sample 2.
FIG. 6 : Stability data for rotavirus liquid formulation after storage at 2-8° C., 25° C. and 37° C. for sample 3.
FIG. 7 : Stability data for rotavirus liquid formulation after storage at 2-8° C., 25° C. and 37° C. for sample 4.
FIG. 8 : Stability data for rotavirus liquid formulation after storage at 2-8° C., 25° C. and 37° C. for sample 5.
FIG. 9 : Stability data for rotavirus liquid formulation after storage at 2-8° C., 25° C. and 37° C. for sample 6 and
FIG. 10 : Stability data for rotavirus liquid formulation after storage at 2-8° C., 25° C. and 37° C. for sample 7.
FIG. 11 : stability data for rotavirus lyophilized formulation after storage at 2-8° C., 25° C. and 37° C. for 50 weeks, for sample 1-4.
FIG. 12 : Quantitative (Immunoperoxidase Assay) assay of adapted rotavirus harvest at different trypsin concentrations
FIG. 13 : electropherotyping of 116E RNA on 10% polyacrylamide gel visualized by silver stain.
Lane Profile:
1 Rotavirus 116E, SPAGMK Reference
2 Rotavirus 116E, Final lot #61 4004
3 Mix of [Rotavirus 116E, SPAGMK Reference+Rotavirus 116E, Final lot #61 4004]
4 Rotavirus 116E, Final lot #61 4004
5 Rotavirus 116E, SPAGMK Reference
6 Rotavirus 116E, Bulk lot #61BP4004
7 Rotavirus 116E, Working Virus Bank
FIG. 14 : electropherotyping of Rotavirus I321 on 10% polyacrylamide gel visualized by silver stain.
Lane Profile:
1 Rotavirus I321, SPAGMK Reference
2 Rotavirus I321, Final lot #64 4004
3 Mix of [Rotavirus I321, SPAGMK Reference+Rotavirus I321, Final lot #64 4004]
4 Rotavirus I321, Final lot #64 4004
5 Rotavirus I321, SPAGMK Reference
6 Rotavirus I321, Bulk lot #64BP4004
7 Rotavirus I321, Working Virus Bank
DETAILED DESCRIPTION OF THE INVENTION
As required, detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the invention, which can be embodied in various forms. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present invention in virtually any appropriately detailed structure. Further, the terms and phrases used herein are not intended to be limiting but rather to provide an understandable description of the invention.
The terms “a” or “an”, as used herein, are defined as one or more than one. The term “plurality”, as used herein, is defined as two or more than two. The term “another”, as used herein, is defined as at least a second or more. The terms “including” and/or “having”, as used herein, are defined as comprising (i.e., open language).
The human rotaviruses exhibit a very narrow tissue culture host range. As a consequence, isolation and serial passage of various strains are usually performed in cell cultures such as simian MA-104 or primary monkey kidney (AGMK), both of which are unsuitable for vaccine production. The former cells have not been validated as a substrate for vaccine production and the latter cells are notorious for their contamination with various simian microbial agents including retroviruses.
Many well-characterized rotaviruses have been isolated, serially passaged and triply plaque-purified in commercially available laboratory cell culture systems not suitable for vaccine production. In those instances where it was necessary to use such viruses in vaccine development, the viruses were subsequently passaged and biologically cloned in a cell substrate certified for vaccine development and production. Ideally, virus to be used in vaccines should be isolated and passaged only in tissue culture cells certified to be acceptable for vaccine production. The Vero cell line and MRC-5 cell line meet this requirement because they support efficient growth of rotaviruses.
The present invention relates to compositions comprising a viral antigen and to a method of adaptation of rotavirus human-bovine natural reassortant and naturally attenuated strains 116E (G9P[11]) and I321 (G10P[11]) to Vero cells. The original 116E and I321 rotavirus vaccine strains were adapted to AGMK, MA104 and SPAGMK cell substrate. The SPAGMK is a cell line not approved by National Regulatory Authority (NRA) for commercial production of vaccines. Therefore it was preferable not only to adapt the rotavirus vaccine strains (116E, I321) to FDA or NRA approved cell substrates like Vero cells, human diploid cells, MRC-5 etc. but also to achieve the high titer harvest of the virus within shortest possible duration for commercial production of the rotavirus vaccine. As per data available in scientific literature, several methods for adaptation were studied but were not found satisfactory in terms of virus harvest yield and time period. The novel virus adaptation method in which use of calcium chloride and trypsin at various concentrations for different time periods, for the activation of the virus and in maintenance medium standardized by us was preferred for the mass production of rotavirus vaccine strains. For the oral rotavirus vaccine composition the virus is stabilized in a composition comprising a first protein selected from human serum albumin, recombinant human albumin, bovine serum albumin and porcine serum albumin, and a second protein which is at least partially hydrolyzed, said second protein being selected from human lactalbumin, bovine lactalbumin and porcine lactalbumin. Optionally and preferably, the composition also comprises a combination of three different disaccharides, said three different disaccharides, being selected from sucrose, lactose, maltose, trehalose, cellubiose, gentobiose, melibiose and turanose.
Further components which may be added to the composition include gelatine, gelatine hydrolysate, casitone, D-sorbitol, amino acids, such as alanine, histidine, arginine, glutamine and antibiotics. Before the vaccine administration an antacid composition, e.g. acitrate-bicarbonate buffer is orally administered to buffer stomach acidity, and to ensure delivery of the active vaccine.
According to an embodiment, adaptation of rotavirus vaccine strains 116E and I321 to Vero cell substrate (ATCC Number—CCL-81) for giving high titer virus harvest within ten days was achieved by standardization of calcium chloride concentration ranging from 100 μg/ml to 1000 μg/ml and/or trypsin concentration ranging from 0.1 μg/ml to 30 μg/ml at different time intervals of virus harvest. The virus harvest yield was assessed by ELISA as well as in terms of virus infectivity titers in suitable cell substrate by measuring Focus Forming Units (FFU)/ml.
It is known in the art that rotavirus infectivity is enhanced by trypsin cleavage of VP4 into VP5 and VP8 (7,8). VP5 permeabilizes the host cell membrane for the entry of the rotavirus.
The adapted rotavirus virus, vaccine candidate was further characterized by electropherotyping ( FIGS. 13 and 14 ) and nucleotide sequencing (data not shown).
The antibodies are raised against the rotavirus vaccine strains by following standard protocol for the preparation of immunodiagnostic and immunotherapeutic purposes.
The rotavirus vaccine strains are detected by reverse transcriptase polymerase chain reaction (RT-PCR) wherein the VP4 and VP7 gene and/or VP4 and VP7 gene selectively hybridizing nucleic acid is amplified by using forward and reverse primers for the VP4 gene (Type P11) and/or VP7 gene and a second primer, either within the (G9P [11], G10P [11]) VP4 gene and/or VP7 gene, or located in an adjacent gene.
The following examples are included solely to aid in a more complete understanding of the invention described and claimed herein. The examples do not limit the scope of the claimed invention in any fashion.
Example 1
The original rotavirus vaccine strains 116E (G9P[11]) and I321 (G10P[11]) were supplied by NIAID, NIH, Bethesda, USA to Bharat Biotech International Limited as Vaccine Starting Material strains, were grown in AGMK, MA104 and SPAGMK cell substrate. For the commercial production of rotavirus vaccine these rotavirus strains were adapted to Vero cell substrate and human diploid cells, MRC-5 cell substrate by serial passage of the rotavirus. Calcium chloride concentration ranging from 100 μg/ml to 1000 μg/ml and/or trypsin concentration ranging from 0.1 μg/ml to 30 μg/ml is evaluated for the activation of the rotavirus and in maintenance medium for time periods ranging from 24 hours to 10 days for high titer virus harvest, at each viral passage in the cell substrate. The yield of the virus in cell culture supernatant is assayed by Rotaclone ELISA kit for the detection of the rotavirus antigen on specific antirotavirus antibody precoated ELISA wells.
The infectivity titer of rotavirus pool is titrated in terms of Focus Forming Unit (FFU)/ml by immunoperoxidase Assay In short, the immunoperoxidase assay for rotavirus infectivity titers were estimated by growing confluent layers of MA104 cells in 24 well tissue culture plates. The cells are then washed twice and infected with activated Rotavirus diluted (Log dilutions) suitable and incubated for 12 hours. After incubation the cells were fixed in 3.5% Formalin and probed with Rotavirus antiserum. To this HRPO Conjugated secondary antibody is tagged and stained using AEC Chromogen.
The maximum rotavirus harvest could be achieved, ranging from 10 6 -18 8 FFU/ml at various trypsin concentrations within one to ten days ( FIG. 12 ).
Example 2
The rotavirus strains 116E and I321 can be characterized by number of methods, which are known in the art. These include, but are not limited to RT-PCR, RNA hybridization, sequence analysis and genus grouping i.e. RNA electropherotyping. Rotavirus of strains 116E and I321 have distinct RNA/RNA hybrid electrophoresis pattern, compared to other rotavirus strains. They have double-stranded RNA (dsRNA) genome consisting of 11 segments ranging in molecular weight from approximately 2.0×10 6 to 0.2×10 6 kilo Daltons, out of which VP4 protein is 88,000 Daltons, VP6 is 44,000 Daltons and VP7 is 38000 Daltons. The subtle difference in the mobility of the 11 genomic segments produces a characteristic Electrophoretic band pattern.
The electrophoretic band pattern of rotavirus strains 116E and I321 can be checked by isolation of genomic dsRNA by Phenol Chloroform method followed by purification with CC41 anion exchange matrix. The purified dsRNA is electrophoresed on 10% polyacrylamide Gel followed by silver staining for nucleic acids. The 11 segment banding pattern can be compared with the Reference standard of Rotavirus 116E and I321 ( FIGS. 13 and 14 ).
Example 3
The rotavirus strains 116E and I321 can be detected using reverse transcriptase polymerase chain reaction (RT-PCR). Generally, RT-PCR comprises contacting RNA obtaining from a sample containing virus with primers, which selectively hybridizes to the VP4 gene (type P11) and/or VP7 gene (type G9/G10) sequence and synthesizing the first strand of RT-PCR product. A second set of primers, either within the VP4 gene and/or VP7 gene, or located in an adjacent gene would serve as the primer for the second strand synthesis. Primers can have substitutions so long as enough complementary bases exist for selective hybridization.
Example 4
The following non-limiting example is presented to better illustrate the stability of liquid formulation prepared for Live, naturally attenuated oral rotavirus vaccine (116E and/or I321).
Stabilizers are general pharmaceutical excipients and/or specific chemical compounds, which interact and stabilize biological molecules, added to the vaccine and are used in conjunction with lower temperature storage.
The stability of rotavirus at different temperature range 2-8° C., 25° C. and 37° C. were tested in multiple combinations of stabilizer.
Vero Cells infected with rotavirus are harvested, clarified and purified in stabilizers and formulated as liquid preparation. The same lot of rotavirus harvested from infected Vero cells is used in different dose formulations. The liquid preparations of rotavirus vaccines are then incubated at 2-8° C., 25° C. and 37° C. for accelerated stability studies. For real time stability study the liquid preparations of rotavirus vaccines are incubated at 2-8° C. for 12 months. Following these incubations, virus titers were measured by Immunoperoxidase assay.
Moreover, a number of samples were produced to arrive at the composition according to the present invention:
Sample 1 formulated with Eagles Minimum essential medium buffered in 310 mM phosphate and 100 mM citrate containing Sucrose—50%, Lactose—0.5%, Maltose—0.5%, human serum albumin—0.4% and lactalbumin hydrolysate 0.05% at pH 7.4, had 0 day titre of 10^ 6.02 FFU/0.5 ml and at 2-8° C. shows no drop in titre after 50 weeks. ( FIGS. 1 & 4 )
At 25° C. sample 1 is stable up to 14 wks and there after a drop of 0.5 log titre after 24 weeks is observed. ( FIGS. 2 & 4 )
At 37° C. sample 1 shows a drop in titre is 0.7 log after 3 wks, further 1.41 log drop after 6 wks, and further 1.28 log drop after 8 wks and further 0.11 log drop after 10 wks. ( FIGS. 3 & 4 )
Sample 2 formulated with Eagles Minimum essential medium buffered in 310 mM phosphate and 100 mM citrate containing Sucrose—50%, Maltose-0.5%, Trehalose—0.5%, human serum albumin—0.4% and lactalbumin hydrolysate 0.05% at pH 7.4, had 0 day titre of 10^ 6.41 FFU/0.5 ml and at 2-8° C. shows 0.06 log drop in titre after 50 weeks. ( FIGS. 1 & 5 )
At 25° C. sample 2 shows a drop of 0.91 log after 24 weeks. ( FIGS. 2 & 5 )
At 37° C. Sample 2 shows a drop of 0.94 log after 3 weeks, further 1.78 log drop after 6 weeks, further drop of 3.18 log after 8 weeks, there was no drop in titre from 8 th week to 10 th week and further drop of 3.15 log after 10 weeks. ( FIGS. 3 & 5 )
Sample 3 formulated with Eagles Minimum essential medium buffered in 310 mM phosphate and 100 mM citrate containing Sucrose—50%, Maltose—0.5%, Trehalose—0.95%, human serum albumin—0.4% and lactalbumin hydrolysate 0.05% at pH 7.4, had 0 day titre of 10^ 6.22 FFU/0.5 ml and at 2-8° C. shows no drop in titre after 50 weeks. ( FIGS. 1 & 6 )
At 25° C. sample 3 shows no drop up to 12 weeks and after 24 weeks shows a drop of 0.88 log in titre. ( FIGS. 2 & 6 )
At 37° C. sample 3 shows 0.87 log drop after 3 weeks and a further drop of 0.52 log after 6 weeks a further drop of 1.27 log after 10 weeks and a further drop of 1.0 log after 12 weeks and dropped further to 0.3 log after 14 weeks. ( FIGS. 3 & 6 )
Sample 4 formulated with Eagles Minimum essential medium buffered in 310 mM phosphate and 100 mM citrate containing Sucrose—50%, Maltose—0.5, Lactose—0.5%, human serum albumin 0.4% at pH 7.4, had 0 day titre of 10^ 6.19 FFU/0.5 ml and at 2-8° C. shows no drop in titre after 50 weeks. ( FIGS. 1 & 7 )
At 25° C. sample 4 shows a drop of 0.53 log titre after 6 weeks and further drop of 0.42 log after 10 weeks and a further drop of 0.05 log titre after 16 weeks and further 1.73 log drop after 24 weeks. ( FIGS. 2 & 7 )
At 37° C. sample 4 shows a drop of 1.96 log titre after 3 weeks and a further drop of 1.43 log titre after 6 weeks ( FIGS. 3 & 7 )
Sample 5 formulated with Eagles Minimum essential medium buffered in 310 mM phosphate and 100 and mM citrate containing Sucrose—40%, Maltose—5%, and Lactalbumin hydrolysate—1.0% at pH 7.4, had 0 day titre of 10^ 6.35 FFU/0.5 ml and at 2-8° C. shows no drop in titre after 16 weeks and 0.15 log drop after 50 weeks. ( FIGS. 1 & 8 )
At 25° C. Sample 5 shows a 0.46 log drop in titre from the 0 day titre after 6 weeks. A further drop of 0.62 log titre is observed after 10 weeks. A further drop of 0.78 log in titre is observed after 16 weeks and a further drop of 2.06 log after 24 weeks. ( FIGS. 2 & 8 )
At 37° C. Sample 5 shows 1.04 log titre drop after 3 weeks from the 0 day titre and further drop of 1.58 log titre after 6 weeks. ( FIGS. 3 & 8 )
Sample 6 formulated with Eagles Minimum essential medium buffered in 310 mM phosphate and 100 mM citrate containing Sucrose—50%, Maltose—0.5%, Trehalose—0.5%, and human serum albumin 0.4% at pH 7.4, had 0 day titre of 10^ 6.19 FFU/0.5 ml and at 2-8° C. shows no drop in titre after 50 weeks. ( FIGS. 1 & 9 )
At 25° C. Sample 6 shows a 0.32 log drop in titre from the 0 day titre after 6 weeks. A further drop of 0.46 log titre is observed after 8 weeks. A further drop of 0.82 log in titre is observed after 16 weeks and a further drop of 1.36 log was observed after 24 weeks. ( FIGS. 2 & 9 )
At 37° C. Sample 6 shows 2.17 log titre drop after 3 weeks from the 0 day titre and further drop of 1.18 log titre after 6 weeks. ( FIGS. 3 & 9 )
Sample 7 formulated with Eagles Minimum essential medium buffered in 310 mM phosphate and 100 mM citrate containing Sucrose—50%, Trehalose—0.5%, and Lactalbumin hydrolysate—0.05%, Human Serum Albumin—0.4% at pH 7.4, had 0 day titre of 10^ 6.34 FFU/0.5 ml and at 2-8° C. shows 0.24 log drop in titre after 50 weeks. ( FIGS. 1 & 10 )
At 25° C. Sample 7 shows a 0.67 log drop in titre from the 0 day titre after 6 weeks. A drop of 3.43 log titre is observed after 24 weeks. ( FIGS. 2 & 10 )
At 37° C. Sample 7 shows 3.24 log titre drop after 8 weeks from the 0 day titre. ( FIGS. 3 & 10 )
The Lyophilized samples 1-4 are showing stability at 2-8° C., 25° C. and 37° C. up to 50 weeks with out any titre drop ( FIG. 11 ). The stabilizers used are the combinations of 0.1% to 1.0% HAS, 1% SPG (=sucrose phosphate glutamate), 1.2% L-Arginine, 1% D-Sorbitol, 1% Gelatin and 2% Trehalose. ( FIG. 11 )
It can be seen from FIGS. 1-6 that the samples according to the present invention, namely samples 1-3 show a much better longevity and stability at elevated temperatures above 25° C., especially for longer periods of time.
Hence, particularly preferred combinations in accordance with the present invention include human serum albumin as the first protein, lactalbumin hydrolysate as the second protein, and sucrose, maltose, trehalose, or sucrose, maltose, lactose as the combination of the three different disaccharides.
Example 5
The buffering agent or acid neutralizing agents need to be given orally before administration of oral liquid, live, naturally attenuated rotavirus vaccine formulation to neutralize stomach acidity. The buffering agent is not limited to citrate-bicarbonate buffer, phosphate buffer, succinate, lactate, maleate, fumarate etc.
Acid Neutralizing Buffer Composition (grams/liter): Sodium Citrate 9.6, Sodium Bicarbonate 25.6, pH 6.5 to 8.8
The acid neutralizing capacity (ANC) of the acid-neutralizing buffer can be measured by USP test.
The ANC of citrate-bicarbonate buffer can be 0.35 to 0.50 mEq/ml.
The effect of Citrate Bicarbonate Buffer (CB) on the Infectivity of Monovalent Rotavirus Vaccine in the presence and absence of simulated Gastric Juice (34.8 mEq HCl as simulated Gastric Juice) can be studied.
The rotavirus vaccine formulation along with citrate bicarbonate buffer in presence of 34.8 mEq HCl as simulated Gastric Juices drops 0.1 to 0.2 log rotavirus titer within two hours.
Example 6
For the preparation of lyophilized rotavirus vaccine formulation the rotavirus is stabilized in the stabilizing composition according to the present invention as exemplified in example 4. For lyophilization either the rotavirus bulk is dialyzed into stabilizer for the total removal of tissue culture medium or the rotavirus bulk is diluted 8-15 fold in stabilizer. The formulation has shown good stability studies results.
In the foregoing specification, specific embodiments of the present invention have been described. However, one of ordinary skill in the art appreciates that various modifications and changes can be made without departing from the scope of the present invention as set forth in the claims below. Accordingly, the specification and figures are to be regarded in an illustrative rather than a restrictive sense, and all such modifications are intended to be included within the scope of present invention. The benefits, advantages, solutions to problems, and any element(s) that may cause any benefit, advantage, or solution to occur or become more pronounced are not to be construed as a critical, required, or essential features or elements of any or all the claims. The invention is defined solely by the appended claims including any amendments made during the pendency of this application and all equivalents of those claims as issued
The features of the present invention disclosed in the specification, the claims and/or in the accompanying drawings, may, both separately, and in any combination thereof, be material for realising the invention in various forms thereof.
REFERENCES
1. Parashar U D, Hummelman E G, Bresee J S, Miller M A, Glass R I. Global illnesses and deaths caused by rotavirus disease in children. Emerg Infect Dis 2003; 9, 565-72.
2. World Health Organization (WHO). Report of the meeting on future directions for rotavirus vaccine research in developing countries. Geneva:WHO, 2000:1-56.
3. Bresee J S, Hummeman E, Nelson A S, Glass R I. Rotavirus in Asia: The value of surveillance for informing decisions about the introduction of new vaccines. J Infect Dis 2005; 192: S1-S5.
4. Glass R I, Bhan M K, Ray P, Bahal R, Parashar U D, Greenberg H, Rao D C, Bhandari N, Maldonado Y, Ward R L, Bernstein D I, Gentsch J R. Development of candidate rotavirus vaccines derived from neonatal strains in India. J Infect Dis 2005; 192: S30-S35.
5. Glass R I, Gentsch, Bhan M K, Bimal K. Rotavirus strain G9P11. United States Patent, U.S. Pat. No. 5,773,009, Jan. 30, 1998.
6. Jagannath M R, Vethanayagam Reddy B S, Raman S, Rao D. Characterization of human symptomatic rotavirus solates MP409 and MP480 having ‘long’ RNA electropherotype and subgroup I specificity, highly related to the P6[1], G8 type bovine rotavirus A5, from Mysore, India. Arch. Virology 2000, 145: 1-19.
7. Lopez S, Arias C F, Bell J R, Strauss J H, and Espejo R T. Primary structure of the cleavage site associated with trypsin enhancement of rotavirus SA11 infectivity. Virology 1985, 144:11-19.
8. Ericson B L, Graham D Y, Mason B B and Estes M K. Two types of glycoprotein precursors are produced by simian rotavirus SA11. Virology 1983, 127:320-332.
9. Denisova E, Dowling W, LaMonica R, Shaw R, Scarlata S, Ruggeri F, and Mackow E R. Rotavirus capsid protein VP5 permeabilizes membranes. Journal of Virology 1999, 73:3147-3153.
10. Gentsch J R, Glass R I, Woods P, et. al. Identification of group A rotavirus gene 4 type by polymerase chain reaction. J Clin Microbiol 1992, 30:1365-73.
11. Gentsch J R, Das B K, Jiang B, Bhan M K, and Glass R I. Similarity of the VP4 protein of human rotavirus strain 116E to that of the bovine B223 strain. Virology 1993, 194:424-430.
12. Stability of Pseudorabies virus during freeze drying and storage: Effect of suspending media” Ellen M Scott and W. Woodside. Journal of Clinical Microbiology. July 1976. p 1-5. Vol. 4
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The present invention relates to a composition comprising a viral antigen, a first protein and a second protein. Optionally, the composition also comprises three different disaccharaides, or, optionally, the composition comprises a primary sugar and at least one, preferably two secondary sugars. The present invention also relates to the use of a viral antigen, a first protein and a second protein for the manufacture of a composition, preferably a vaccine. The present invention furthermore relates to a method of treatment or prevention of virus associates diseases in humans. Moreover, the present invention relates to a method of adapting a virus to a suitable cell-line. The invention is also useful for the production of virus suspensions suitable for making stable, live/inactivated, monovalent and/or polyvalent, liquid/lyophilized rotavirus vaccine compositions for oral and/or nasal or any other suitable route of administration in human.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a divisional application of U.S. application Ser. No. 09/857,772, filed Jun. 11, 2001, which is the national stage under 35 U.S.C. 371 of international application PCT/IL99/00673, filed Dec. 9, 1999 which designated the United States, and which international application was published under PCT Article 21(2) in the English language.
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
[0002] The present invention concerns palladium-substituted bacteriochlorophyll derivatives, processes and intermediates for their preparation and pharmaceutical compositions comprising the same as well as their use in the field of in vivo photodynamic therapy and diagnosis and in vitro photodynamic killing of viruses and microorganisms.
Definitions And Abbreviations
[0003] BChl=bacteriochlorophyll a (Mg-containing 7, 8, 17, 18-tetrahydroporphyrin having a phytyl or geranylgeranyl group at position 17 3 , a COOCH 3 group at position 13 2 , an H atom at position 13 2 , an acetyl group at position 3 and an ethyl group at position 8).
[0004] BChlide=bacteriochlorophyllide a (the C-17 2 -free carboxylic acid derived from BChl a).
[0005] BPhe=bacteriopheophytin a (BChl in which the central Mg atom is replaced by two H atoms).
[0006] BPheid=bacteriopheophorbide a (the C-17 2 -free carboxylic acid derived from BPhe).
[0007] Pd-BPheid=Pd-bacteriopheophorbide a (the C-17 2 -free carboxylic acid derived from BPhe having a central Pd atom, a COOCH 3 group at position 13 2 , an H atom at position 13 2 , an acetyl group at position 3 and an ethyl group at position 8).
[0008] IUPAC numbering of the bacteriochlorophyll derivatives is used throughout the specification. Using this nomenclature, the natural bacteriochlorophylls carry two carboxylic acid esters at positions 13 2 and 17 2 , however they are esterified at positions 13 3 and 17 3 .
[0009] There has been an increasing interest in the utilization of photosensitizers for cancer therapy. According to this technique, known as photodynamic therapy (PDT), photosensitizers are applied for example to a tumor and the in situ photosentization produces compounds which intoxicate the malignant cells.
[0010] Photodynamic therapy using porphyrins and related compounds has, by now, a fairly long history. Early work, in the 1940s, demonstrated that porphyrin could be caused to fluoresce in irradiated tumor tissue. The porphyrins appeared to accumulate in these tissues, and were capable of absorbing light in situ, providing a means to detect the tumor by the location of the fluorescence. A widely used preparation in the early stages of photodynamic treatment both for detection and for therapy was a crude derivative of hematoporphyrin, also called hematoporphyrin derivative, HpD, or Lipson derivative prepared as described by Lipson and coworkers in J Natl Cancer Inst (1961) 26:1-8. Considerable work has been done using this preparation, and Dougherty and coworkers reported the use of this derivative in treatment of malignancy ( Cancer Res (1978) 38:2628-2635 ; J Natl Cancer Inst (1979) 62:231-237).
[0011] Dougherty and coworkers prepared a more effective form of the hematoporphyrin derivative which comprises a portion of HpD having an aggregate weight >10 kd. This form of the drug useful in photodynamic therapy is the subject of U.S. Pat. No. 4,649,151, is commercially available, and is in clinical trials.
[0012] The general principles of the use of light-absorbing compounds, especially those related to porphyrins, has been well established as a treatment for tumors when administered systematically. The differential ability of these preparations to destroy tumor, as opposed to normal tissue, is due to the homing effect of these preparations to the objectionable cells. (See, for example, Dougherty, T. J., et al., “Cancer: Principles and Practice of Oncology” (1982), V. T. de Vita, Jr., et al., eds. pp 1836-1844.). Efforts have been made to improve the homing ability by conjugating hematoporphyrin derivative to antibodies. (See, for example, Mew, D., et al., J Immunol (1983) 130:1473-1477.). The mechanism of these drugs in killing cells seems to involve the formation of singlet oxygen upon irradiation (Weishaupt, K. R., et al., Cancer Research 36:2326-232: (1976)).
[0013] The use of hematoporphyrin derivative or its active components in the treatment of skin diseases using topical administration has also been described in U.S. Pat. No. 4,753,958. In addition, the drugs have been used to sterilize biological samples containing infectious organisms such as bacteria and virus (Matthews, J. L., et al., Transfusion 28:81-83 (1988)). Various other photosensitizing compounds have also been used for this purpose, as set forth, for example, in U.S. Pat. No. 4,727,027.
[0014] In general, the methods to use radiation sensitizers of a variety of structures to selectively impair the functioning of biological substrates both in vivo and in vitro are understood in the art. The compounds useful in these procedures must have a differential affinity for the target biological substrate to be impaired or destroyed and must be capable of absorbing light so that the irradiated drug becomes activated in a manner so as to have a deleterious effect on the adjacent compositions and materials.
[0015] Because it is always desirable to optimize the performance of therapeutics and diagnostics, variations on the porphyrin drugs traditionally used in treatment and diagnosis have been sought. A number of general classes of photosensitizers have been suggested including phthalocyanines, psoralen-related compounds, and multicyclic compounds with resonant systems in general. Most similar to the compounds disclosed herein are various pheophorbide derivatives whose use in photodynamic therapy has been described in EPO Application 220686 to Nihon Metaphysics Company; ethylene diamine derivatives of pheophorbide for this purpose described in Japanese Application J85/000981 to Tama Seikayaku, K. K., and Japanese Application J88/004805 which is directed to 10-Hydroxypheophorbide-a. In addition, Beems, E. M., et al., in Photochemistry and Photobiology 46:639-643 (1987) disclose the use as photosensitizers of two derivatives of bacteriochlorophyll-a—bacteriochlorophyllin-a (also known as bacteriopheophorbide-a, which lacks the phytyl alcohol derivatized in bacteriochlorophyll-a) and bacteriochlorin-a (which lacks both the phytyl group and the Mg ion). These authors direct their attention to these derivatives as being advantageous on the grounds of enhanced water solubility as compared to bacteriochlorophyll-a.
[0016] EP 584552 and WO97/19081, both to Yeda Research and Development Co. Ltd., describe chlorophyll and bacteriochlorophyll derivatives and their use as PDT agents, and metaled bacteriochrophylls and their preparation by transmetalation of the corresponding Cd—BChl derivatives, respectively.
[0017] The problem remains to find suitable photosensitizers useful in photodynamic therapy and diagnosis which are optimal for particular targets and particular contexts. Thus, the invention provides an additional group of photosensitizing compounds which becomes part of the repertoire of candidates for use in specific therapeutic and diagnostic situations.
SUMMARY OF THE INVENTION
[0018] It has now been found, in accordance with the present invention, that the compounds of formula I, I′ or I″ below wherein A as defined below represents a substituent capable of allowing an efficient plasma transfer and cell membrane penetration, are useful as PDT agents and present the advantages of enhanced solubility, stability and/or efficiency, compared with the known compounds.
[0019] The invention thus concerns the compounds of formula I, I′ or I″
[0020] wherein
[0021] A represents OH,
[0022] OR 1 ,
[0023] —O—(CH 2 ) n —Y,
[0024] —S—(CH 2 ) n —Y,
[0025] —NH—(CH 2 ) n —Y,
[0026] —O—(CH 2 ) 2 —NH 2 ,
[0027] —O—(CH 2 ) 2 —OH,
[0028] —NH—(CH 2 ) n — + N O, X − ,
[0029] —NH—(CH 2 ) 2 —NH—BOC or
[0030] —N—(CH 2 —CH═CH 2 ) 2
[0031] wherein
[0032] R 1 represents Na + , K + , (Ca 2+ ) 0.5 , (Mg 2+ ) 0.5 , Li + , NH 4 ++ NH 3 —C (CH 2 OH) 3 , + NH 3 —CH 2 —(CHOH) 4 —CH 2 OH, + NH 2 (CH 3 )—CH 2 —(CHOH) 4 —CH 2 OH or + N(C n , H 2n , +1 ) 4 ;
[0033] R 2 represents H, OH or COOR 4 , wherein R 4 is C 1 -C 12 alkyl or C 3 -C 12 cycloalkyl;
[0034] R 3 represents H, OH or C 1 -C 12 alkyl or alkoxy;
[0035] n is 1, 2, 3, 4, 5 or 6,
[0036] Y is —NR′ 1 R′ 2 or — + NR′ 1 R′ 2 R′ 3 , X − wherein R′ 1 , R′ 2 and R′ 3 independently from each other represent —CH 3 or —C 2 H 5 ;
[0037] X is F, Cl, Br or I,
[0038] n′ is 1, 2, 3 or 4,
[0039] and wherein * denotes an asymmetric carbon and—represents a single saturated bond or a double unsaturated bond.
[0040] Furthermore, the present invention concerns processes for the preparation of the above new compounds.
[0041] Thus, in one aspect, it is herein described a method to effect the impairment or destruction of a target biological substrate which method comprises treating the target substrate with an amount of the compound of formula I, I′ or I″ effective to photosensitive said substrate followed by irradiating said target substrate with radiation in a wavelength band absorbed by the compound of formula I, I′ or I″ for a time effective to impair or destroy the substrate.
[0042] In other aspect, the invention is therefore directed to pharmaceutical compositions comprising at least a compound of formula I, I′ or I″ as an active agent, together with a pharmaceutically acceptable carrier. The compositions are useful for in vivo photodynamic therapy and diagnosis of tumors and for killing of cells, viruses and bacteria, parasites and fungi in samples and in living tissues by well-known photodynamic techniques.
[0043] Furthermore, the invention concerns the use of the compounds of formula I, I′ or I″ for the preparation of a pharmaceutical composition useful in photodynamic therapy.
[0044] The invention further concerns the use of the invention compounds for the preparation of compositions useful in diagnosis and ex vivo killing of bacteria, parasites, viruses and fungi.
[0045] The invention further concerns the acid chloride and anhydride of formulas II and III herebelow, respectively, as intermediates.
BRIEF DESCRIPTION OF THE DRAWINGS
[0046] [0046]FIG. 1 depicts the optical absorption spectrum of Pd-BPheid in a mixture of acetone and methanol/K buffer phosphate.
[0047] [0047]FIGS. 2 and 3 depict, respectively, low and high resolution mass spectra of Pd-BPheid conducted by Fast Atom Bombardement (FAB-MS).
[0048] [0048]FIG. 4 shows time-dependent morphological changes of A431 cells with Pd-BPheid or BChl-SerOMe post PDT. (In the Figures, Bchl-Ser stands for BChl-SerOMe, the seryl methyl ester of BChl.)
[0049] [0049]FIG. 5 shows phototoxicity of Pd-BPheid and BChl-SerOMe tested on ECV-304 cells.
[0050] [0050]FIG. 6 shows phototoxicity of Pd-BPheid and Pd-BPheid-ethyl ester on cultured M2R mouse melanoma cells. (A) pigments dissolved in 95% ethanol and further diluted to the indicated concentrations in culture medium+10% serum to 1% ethanol. (B) pigments dissolved directly in culture medium+10% serum.
[0051] [0051]FIG. 7 shows phototoxicity of Pd-BPheid on cultured M2R mouse melanoma and human H29 colon carcinoma cells.
[0052] [0052]FIG. 8 shows PDT of M2R mouse melanoma with Pd-BPheid (2.5 mg/Kg) dissolved in Cremophor and diluted in salt solution.
[0053] [0053]FIG. 9 shows PDT of M2R mouse melanoma with Pd-BPheid (2.5 mg/Kg) dissolved in salt solution and diluted with Cremophor.
[0054] [0054]FIG. 10 illustrates cure of primary C6 glioma tumors after PDT with Pd-BPheid or Pd-BPheid-SerOMe (in the Figure, Pd-Bchl-Ser).
[0055] [0055]FIG. 11 shows appearance of C6 glioma metastases in CD1 nude mice after surgery (amputation) or after PDT with Pd-BPheid or Pd-BPheid-SerOMe (in the Figure, Pd-Bchl-Ser).
DETAILED DESCRIPTION OF THE INVENTION
[0056] In a preferred embodiment, the compounds of the invention have the following formula with the optical configuration below:
[0057] wherein A is as above.
[0058] When the dotted lines representing the bond between C7 and C8 and C17 and C18 in the above structure is a saturated single bond, the carbon atoms numbered 7, 8, 17 and 18 are asymmetric carbon atoms. When R 2 or R 3 is H, C13 2 is an asymmetric carbon atom.
[0059] In the presence of oxygen or at the ambient air and under light action, the oxidation of the above C7-C8 and C17-C18 bonds may occur, resulting in compounds with double bonds at said positions C7-C8 and C17-C18.
[0060] The compounds of formula I′ and I″ of the present invention are oxidized forms of the compounds of formula I and can be obtained by the processes described in Chlorophyll , by Scheer H. (ed.), CRC Press, 1991, pp. 147-209.
[0061] In a preferred embodiment of the invention, the compounds are those wherein A is OR 1 .
[0062] In a most preferred embodiment, the compound of the invention is Pd-PBheid (also designated herein sometimes Pd—BChl—COOH), the compound of formula I wherein A is OH, having the following structure:
[0063] One of the processes for the preparation of the compounds of formula I wherein A is OH, comprises at least the steps of:
[0064] a) combined demetalation and hydrolysis of a M-BPheid-17 3 -Z compound wherein Z is phytyl, geranylgeranyl (gg) or SerOMe (seryl O-methyl ester) and M is a metal selected from Mg, Cd, or Zn;
[0065] b) incorporation of Pd with a Pd reagent into the compound obtained in (a), thus obtaining a Pd-BPheid, and, if desired,
[0066] c) subsequent reaction of the obtained Pd-BPheid with a corresponding compound of formula A-H, wheren A is other than OH for forming the corresponding R 1 salt or a compound wherein A is not OH.
[0067] In one preferred embodiment, the process is directed to the preparation of Pd-BPheid and bacteriochlorophyll a (Bchla) is demetalated and hydrolyzed in step (a), and the obtained bacteriopheophorbide (BPheid) is reacted with a Pd reagent in step (b) to produce the desired Pd-BPheid.
[0068] Another process for the preparation of the compound of formula I comprises at least the steps of:
[0069] a) transmetalation of a BChlide-17 3 -Z to obtain the corresponding Pd- BPheid-17 3 -Z wherein Z is phytyl, gg or Ser OMe,
[0070] b) hydrolysis of the obtained compound, and
[0071] c) optionally subsequent reaction of the obtained Pd-BPheid with a corresponding compound of formula R 1 —H or A—H for forming the corresponding R 1 salt or a compound wherein A is not OH.
[0072] In one preferred embodiment, the process is directed to the preparation of Pd-BPheid and bacteriochlorophyll a (Bchla) is transmetalated in step (a) to replace the native central Mg atom by Pd, and the obtained Pd-BPheid-17 3 -Z wherein Z is phytyl is hydrolized in step (b) to produce the desired Pd-BPheid.
[0073] Another process for the preparation of the compound of formula I comprises at least the steps of:
[0074] a) enzymatic hydrolysis of a BChlide-17 3 -Z wherein Z is phytyl or geranylgeranyl to obtain a Bchlide;
[0075] b) acidic demetalation of said BChlide of (a);
[0076] c) incorporation of Pd with a Pd reagent into the demetalated BPheid of (b); and
[0077] d) optionally subsequent reaction of the obtained Pd-BPheid with a corresponding compound of formula A—H, wherein A is other than OH, for forming the corresponding R 1 salt or a compound wherein A is not OH.
[0078] In the above processes for the preparation of compounds of formula I, the Pd reagent may be any convenient reactive compound providing Pd in such structures such as, for instance, Pd acetate and Pd chloride.
[0079] The incorporation of Pd in the procedures above can be achieved by a two-step procedure using Na ascorbate or ascorbic acid, or by a one-step procedure using 6-O-palmitoyl-L-ascorbic acid.
[0080] The compounds of the invention wherein A is different from OH and OR 1 may be obtained by reaction of the Pd-BPheid (Pd—BChl—COOH) with the corresponding A—H compound.
[0081] The compounds of formula II and III above are intermediates for the compounds of formula I of the invention. The acid chlorides of formula II, Pd-BPheid-COCl, may be obtained by using any agent suitable for forming acyl chlorides, such as for example SOCl 2 .
[0082] The acid anhydrides of formula III may be obtained by dehydration of the compounds of formula I, I′, I″ with acetic anhydride.
[0083] By reaction of these intermediates II and III with the corresponding compound AH, the compounds of formula I, I′ or I″ may be obtained.
[0084] The invention further comprises pharmaceutically acceptable salts of the free acids of formulas I, I′ and I″. The salts can be formed by methods well known in the art such as by reaction of the free acid or a salt thereof with inorganic or organic reagents such as, but not limited to, NaOH, KOH, calcium or magnesium suitable salts, LiOH, NH 4 OH, tetraalkylammonium hydroxide, e.g., tetraethylammonium hydroxide, or N-methylglucamine, glucamine and triethanolamine.
[0085] The compounds of the invention are for use in photodynamic therapy and diagnosis with respect to target biological substrates. By “target biological substrate” is meant any cells, viruses or tissues which are undesirable in the environment to which therapy or other corrective action, such as sterilization, is employed, or the location of which is desired to be known in an environment to which diagnosis is applied.
[0086] According to the present invention, the drug is injected into the subject, and permitted to reach an optimal concentration in the target substrate. Then the target substrate is exposed to radiation at a wavelength appropriate to the absorption spectrum of the compound administered. The effect of the compound can be enhanced by concomitant increase of the target substrate temperature.
[0087] For use in the method of the invention, the compounds of the invention are formulated using conventional excipients appropriate for the intended use. For systemic administration, in general, buffered aqueous compositions are employed, with sufficient nontoxic detergent to solubilize the active compound. As the compounds of the invention are generally not very soluble in water, a solubilizing amount of such detergent may be employed. Suitable nontoxic detergents include, but are not limited to, Tween-80, various bile salts, such as sodium glycholate, various bile salt analogs such as the fusidates. Alternate compositions utilize liposome carriers. The solution is buffered at a desirable pH using conventional buffers such as Hank's solution, Ringer's solution, or phosphate buffer. Other components which do not interfere with the activity of the drug may also be included, such as stabilizing amounts of proteins, for example, serum albumin, or low density- or high density-lipoprotein (LDL and HDL, respectively).
[0088] Systemic formulations can be administered by injection, such as intravenous (i.v.), intraperitoneal (i.p.), intramuscular, or subcutaneous (s.c.) injection, or can be administered by transmembrane or transdermal techniques. Formulations appropriate for transdermal or transmembrane administration include sprays and suppositories containing penetrants, which can often be the detergents described above.
[0089] For topical local administration, the formulation may also contain a penetrant and is in the form of an ointment, salve, liniment, cream, or oil. Suitable formulations for both systemic and localized topical administration are found in Remington's Pharmaceutical Sciences , latest edition, Mack Publishing Co., Easton, Pa.
[0090] For use ex vivo to treat, for example, blood or plasma for transfusion or preparations of blood products, no special formulation is necessary, but the compounds of the invention are dissolved in a suitable compatible solvent and mixed into the biological fluid at a suitable concentration, typically of the order of 1-100 μg/ml prior to irradiation.
[0091] For photodynamic therapeutic and diagnostic applications, suitable dosage ranges will vary with the mode of application and the choice of the compound, as well as the nature of the condition being treated or diagnosed. However, in general, suitable dosages are of the order of 0,01 to 50 mg/kg body weight, preferably 0,1 to 10 mg/kg. For topical administration, typically amounts on the order of 5-100 mg total are employed.
[0092] The general procedures for photodynamic ex vivo treatment are analogous to those described by Matthews, J. L., et al., Transfusion (supra).
[0093] Briefly, for systemic administration, a suitable time period after administration, typically from several minutes to two days is allowed to elapse in order to permit optimal concentration of the compounds of the invention in the target biological substrate. In general, this substrate will be a tumor vasculature, tumor cells or any other tumor component, and the localization of the compound can be monitored by measuring the optical absorption of the target tissue as compared to background. After optimization has been accomplished, the target biological substrate is irradiated with a suitable band of irradiation, in the range of 740-800 nm, or 500-600 nm or 700-900 nm at a rate of 5-750 mW/cm 2 , and a total energy of 100-1000 J/cm 2 .
[0094] For topical treatment, localization is immediate, and the corresponding radiation can be provided thereafter. For treatment of biological fluids ex vivo, radiation is applied after optimal binding/uptake by the target tissue is reached. The radiation fluence is on the order of 1-10 J/cm 2 . Because penetration of tissue is not required, lower total energy can be employed.
[0095] The compositions of the invention comprise at least one compound of formula I, I′ or I″ as defined above together with a physiologically acceptable carrier. These compositions may be in the form of a solution, a lipid emulsion or a gel or in the form of liposomes or nanoparticles. The suitable carrier is chosen to allow optimization of the concentration of the compound of the invention at the target substrate. Examples of such carriers, but not limited to, are “Tween 80”, polyethyleneglycol, e.g., PEG400, “Cremophor EL”, propylene glycol, ethanol, basil oil, bile salts and bile salts analogs and mixtures thereof. Liposome formulations can be based, for example, on dimyristoylphosphatidyl choline or phosphatidyl glycerol. The carrier may also comprise dipalmitoylphosphatidyl choline.
[0096] When nanoparticles are used, they may be in the form of PEG-coated poly(lactic acid) nanoparticles. In the form of lipid emulsions, low density lipoproteins and triglycerides are usually used.
[0097] In the composition of the invention, the invention compound(s) is (are) in an amount of 0.01 to 20%, preferably 0.05% to 5% by weight of the total weight composition.
[0098] The invention will now be illustrated by the following non-limiting examples.
EXAMPLES
Example 1
Preparation of Pd-BPheid
[0099] Pd-BPheid was prepared from BChla by the following 3-step procedure.
[0100] (a) Isolation of Bacteriochlorophyll a (BChla)
[0101] BChla was extracted form lyophilized bacteria Rhodovolum sulfidophilum as follows:
[0102] Lyophilized cells (100 gr) were ground to powder, washed 5 times with a total of 1250 ml acetone to partially wash away the carotenoids, the mixture was filtered and BChla was extracted from the solid with absolute methanol (≈1200 ml, 4-5 filtrations). After filtering, the dark blue-green solution was partly evaporated under vacuum, the concentrated solution (≈500 ml) was extracted 2-3 times with petrol ether (b.p. 80-100° C., ≈1300 ml) to further eliminate carotenoids, and the petrol ether phase was extracted twice with methanol (≈550 ml). This phase was then discarded, the combined methanol phase was evaporated under vacuum, and the blue-green residue was redissolved in methanol-acetone (1:3, v/v) and loaded on a DEAE-Sepharose column (3×10 cm) equilibrated with methanol-acetone (1:3, v/v). The BChla was eluted with methanol-acetone (1:3, v/v), the methanol-acetone mixture was evaporated and the dry Bchla was redissolved in an exact volume (for absorption spectrum) of ether and filtered through cotton wool to get rid of dissolved column material. After a final evaporation the solid pigment was stored under Argon in the dark at −20° C. Extraction yield: about 700 mg BChla per 100 g lyophilized cells.
[0103] The DEAE-Sepharose column was prepared as previously described (Omata and Murata, 1983, “Preparation of Chlorophyll a, Chlorophyll b and Bacteriochlorophyll a by column chromatography with DEAE-Sepharose C1-6B and Sepharose C1-6B”, Plant Cell Physiol 24:1093-1100). Briefly, DEAE-Sepharose was washed with distilled water and then converted to an acetate form by suspending it in a 1M sodium acetate buffer (pH=7). The slurry was washed 3 times with acetone and finally suspended in methanol-acetone (1:3, v:v) for storage at 5° C.
[0104] (b) Preparation of Bacteriopheophorbide (BPheid)
[0105] Crude Bchla extract as obtained in (a) (about 100 mg Bchla containing some residual carotenoides) was dissolved in 80% aqueous trifluoroacetic acid (about 15 ml) which had been bubbled with nitrogen for 10 min. The solution was stirred at ambient temperature for 2 h. Then the reaction mixture was poured into water (250 ml) and extracted with chloroform. The extract was washed twice with water and dried over anhydrous Na 2 SO 4 . After evaporation of the solvent the residue was chromatographed on Silica (3 cm×15 cm column, Kieselgel 60, Merck) and eluted with methanol in chloroform by step gradient: 2%, 5%, 10%, 15%. At the beginning, carotenoids and a small amount of bacteriopheophytin were washed out, followed by elution of allo-bacteriopheophytin and carotenoids. At 10% methanol in chloroform the product started to be collected and monitored by TLC (Kieselgel, chloroform-methanol, 9:1). The product (60 mg) was evaporated, and the residue taken up in CHCl 3 was filtered through UltraPore membrane to remove residual silica that could otherwise cause oxidations.
[0106] (c) Incorporation of Palladium into Bacteriopheophorbide (Bpheid)
[0107] BPheid (100 mg) as obtained in (b) and Pd-acetate (80 mg) were dissolved in dichloromethane (≈10 ml) and added to a suspension of 200 mg sodium ascorbate in 50 ml of methanol. The reaction mixture was stirred in a closed flask at room temperature, and samples from the reaction mixture were collected every 15-20 minutes and their optical absorption recorded. After about 4 hours, most of the BPheid absorption at 357 nm was replaced by the Pd-BPheid absorption at 330 and 390 nm.
[0108] The reaction mixture was transferred into a chlorofom/water solution (200 ml; 50:50 v/v) and shaken in a separatory funnel. The organic phase was collected, washed with water, dried over anhydrous sodium chloride, and evaporated. The dried material was added to 80 mg of Pd-Acetate and steps above were repeated until the residual absorption at 357 nm completely vanished and the ratio between the absorption at 765 nm (the peak of the red-most transition) and the absorption maximum at 330 nm reached the value of ≈2.4 (in chloroform).
[0109] The dried reaction mixture was solubilized in a minimal volume of 2:1 chloroform:acetone and loaded on a CM-Sepharose column (150 mm×25 mm) that had been pre-equilibrated with acetone. The column was first washed with acetone and the eluted first fraction was discarded. The column was then washed with 9:1 acetone:methanol. Two bands became prominent and were washed out—the first was the major product and the second was an allomerized by-product (discarded). The product was concentrated almost to dryness and transferred into a 50:50 chlorophorm:water system in a separatory funnel. The mixture was thoroughly shaken and the organic phase was separated, dried over anhydrous sodium sulfate (or sodium chloride) and evaporated to dryness.
Example 2
Preparation of Pd-BPheid
[0110] (a) Isolation of Bchla
[0111] This step of the procedure was carried out as in Example 1(a) above.
[0112] (b) Preparation of Pd-Bpheid
[0113] 6-O-palmitoyl-L-ascorbic acid (246 mg, 593 μmol) was dissolved in MeOH (84 ml) and N 2 was passed through the solution. Bpheid (92 mg, 151 μmol) and Pd(CH 3 COO) 2 (83 mg, 370 μmol) were dissolved in CHCl 3 (34 ml, degassed with N 2 ) and added to the methanolic solution. The mixture was kept under inert atmosphere by stirring and the reaction progress was monitored by recording the absorption spectra of small reaction portions every few minutes. After ˜30 min. the reaction was completed and the solvents were evaporated.
[0114] (c) Purification of Pd-Bpheid
[0115] The crude Pd-BPheid was dissolved in CHCl 3 and loaded on a column packed with 15 g of 0.4%-Silica-Asc. Small volume of CHCl 3 (˜30 m)l was passed through the column and than the pigment was eluted using MeOH:CHCl 3 (1:99, ˜250 ml). Purity of the fractions was determined by TLC and optical absorption spectroscopy. Mass Spectroscopy and NMR detection were performed on representative samples. Yield: 82.5 mg of pure Pd-BPheid (76%).
[0116] For the preparation of the 0.4%-Silica-Asc, ascorbic acid (240 mg) was dissolved in 240 cc of EtOH:CHCl 3 :MeOH (60:60:120) mixture. Silica gel 60 (60 g, Merck, Cat. No. 107734, mesh 70-230) was added and the slurry mixture was stirred for 10 min. and then filtered at the pump. The yellowish Silica-Asc. was finally dried for ˜1 hr. at ˜50° C. This 0.4%-Silica-Asc. is ready to use as regular silica gel; its nature is less polar and it has some antioxidative properties.
Example 3
Preparation of Pd-BPheid
[0117] (a) Isolation of Bchla
[0118] This step was performed as in Example 1(a) above.
[0119] (b) Preparation of Chlorophyllase (Chlase)
[0120] Chlorophyllase (Chlase) was prepared from chloroplasts of Melia azedarach L ., Chine tree leafs. Fresh leaves (50 g) were ground for 2 min. in a blender containing 350 ml of acetone cooled to −20° C. The homogenate was filtered through four layers of gauze, and the filtrate was collected and left overnight at 4° C. for further precipitation. The acetone was removed by filtration, and the remaining powder was washed a few times with cold acetone to remove traces of Chlase and carotenoids until the filtrate was colorless. The Chlase acetone powder was finally dried in a lyophilizer and further stored at −20° C. Under these conditions, the enzyme preparation was stable for over 1 year without noticeable loss of activity. Yield: 20 g Chlase per 1 kg leaves were obtained.
[0121] (c) Synthesis and Purification of Bacteriochlorophyllide (BChlide)
[0122] Ascorbic acid (70 mg; Merck) was dissolved in water (9 ml), the pH of the solution was adjusted to 7.7 using 10 M KOH aqueous solution, and 1 ml of 0.5 M sodium phosphate buffer (pH 7.7) was added to maintain the pH during the reaction. Triton X-100 (about 80 μl) was added to achieve a final detergent concentration of 0.8% (v/v). Chlase acetone powder (200 mg) was homogenized in 6 ml of this solution using a Polytron homogenizer. The remaining solution was used to wash the instrument and was then combined with the homogenate. The enzyme solution was sonicated with 20 mg of solid BChla saturated with Argon and incubated in the dark for 6 hrs at 37° C., while stirring.
[0123] For purification, the reaction material was directly frozen (−20° C.) after 6 hrs of reaction and subsequently lyophilized. The dry residue was dissolved in acetone and sonicated and the solution was then subjected to a CM-Sepharose column equilibrated in acetone. The column was washed with acetone to elute unreacted material and then with 5% and 7% methanol (v/v) in acetone to elute Bacteriochlorophyllide (Bchlide) and Bacteriopheophorbide (Bpheid). The product was eluted with 25% methanol in acetone. The solvent was evaporated and the solid pigment was stored under Argon, at −20° C., in the dark. Reaction yield: 30-55%.
[0124] The CM-Sepharose for chromatography was prepared by first washing CM-Sepharose with water and then 3 times with acetone before packing a column and equilibrating in acetone. The chromatographic material could be reused after thorough rinsing with 2M NaCl aqueous solution until colorless, washed with water and resuspended in acetone.
[0125] (d) Incorporation of Palladium into the Bacteriopheophorbide (BPheid)
[0126] The procedure is the same as in Example 1 (c) above. HPLC of the dried material showed the main product in the form of two epimers which were chemically identical (88% of the entire mixture) and residual allomers. There was also a slight (0.5%) contamination of the starting material, BPheid.
Example 4
Characterization of the Compound Pd-BPheid
[0127] (a) Absorbance Spectra
[0128] The absorbance spectra of Pd-BPheid were determined with a UVICON spectrophotometer (1 cm pathlength) using a PM detector which is normalized to baseline. The sensitivity is 0.05.
[0129] Absorbance spectra of Pd-Bpheid in acetone and a mixture of methanol/K phosphate buffer are reported in Table 1 and in FIG. 1.
[0130] The absorbance spectrum of Pd-BPheid in plasma was red-shifted to 763 nm.
TABLE 1 Methanol/K Phosphate 20 mM pH 6.59 Acetone (70% / 30%) λ Absorbance λ Absorbance 753 nm 2.43 758 nm 1.25 530 nm 0.49 537 nm 0.324 385 nm 1.25 384 nm 0.535 331 nm 1.45 329 nm 0.777
[0131] The pic detection revealed the following peaks according to FIG. 1: at 758 nm: 1.2502; at 537 nm: 0.3239; at 384 nm: 0.5351; and at 329 nm: 0.7766.
[0132] (b) HPLC Detection of Pd-BPheid
[0133] A reverse phase HPLC method was developed to characterize the impurity profile and quantify the Palladium-BPheid.
Solid phase a C 8 Inertsil 5 μm, 250 × 4.6 mm Liquid phase methanol:potassium phosphate buffer 20 mM pH = 6.59 (70%:30%) Flow rate 1 ml/min Volume of injection 100 μl Detection 1-Spectroflow 783, Deuterium lamp: 385 nm 2-Spectroflow 757, Tungsten lamp: 753 nm
[0134] As shown in Table 2, HPLC analysis of the product Pd-Bpheid as obtained in Example 3 exhibited 7 peaks. The major peak represented 64 to 70% of the total products.
[0135] Solutions of Pd-BPheid stored in acetone at −20° C. were stable for at least 2-month period. When the stock solution was maintained at room temperature for 18 hours, no change in the HPLC profile was observed showing that Pd-Bpheid is a stable compound.
TABLE 2 HPLC Detection of Pd-BPheid Absorption % % spectra (wavelength Peak Detection 385 nm Detection 753 nm of maxima nm) B1 0.7 0.78 B2 3.4 4.31 754,537,384,330 C 1.07 1.25 D 2.49 2.76 758,535,384,330 E 64.11 69.98 758,537,384,329 F 9.62 3.61 753,531,358 G 13.56 14.46 758,537,384,329
[0136] (c) Characterization of Pd-BPheid by NMR
[0137] After a purification step of the Pd-BPheid prepared according to the Example 3, the percentage of the major peak was above 90%. This purification was conducted by a preparative HPLC C8. This purified compound was used for the characterization of the product by NMR and mass spectrometry.
[0138] Analysis of Pd-BPheid by NMR was carried out and the chemical shifts are listed in Table 3:
[0139] [0139] 1 H NMR and 13 C NMR
[0140] 2D 1 H NMR (COSY and NOESY)
[0141] 2D 1 H- 13 C NMR (HMQC and HMBC: reverse detection).
TABLE 3 1 H 13 C Chemical Shifts (ppm) Methyl Proton Carbon 1-CH 3 3,44 14,4 2-CH 3 3,07 33,1 3-CH 3 1,75 23,6 4-CH 3 1,06 10,8 5-CH 3 3,36 12,5 8-CH 3 1,65 23,9 10-CH 3 3,85 53,3 Meso α 9,11 101,5 β 8,50 102,9 δ 8,45 98,7 C—H 3-H 4,35 47,2 4-H 4,09 55,2 7-H 4,10 49,2 8-H 4,34 49,2 10-H 5,92 65,10 Others 4-CH 2 2,08; 2,22 30,6* 7′-CH 2 2,30; 2,52 30,6* 7″-CH 2 2,15; 2,35 35* Carbon without Proton 2-CO 199 9-CO 188 17-CO 2 H 170,2 10-CO 2 Me 174,3 1-C 141 2-C 135,6 5-C 126,9 6-C 130,1 11-C 142,3 12-C 158,5 13-C 159,5 14-C 151,5 15-C 140,5 16-C 152,5 17-C 109,8 18-C 152,3 19-C 158,6
[0142] (d) Characterization of Pd-BPheid by Mass Spectrometry
[0143] The mass spectrometry analysis of Pd-BPheid resulted in the spectra depicted in FIGS. 2 and 3. It was conducted by Fast Atom Bombardment (FAB) under low and high resolutions. The spectrometer was a “ZabSpec TOF Micromass” spectrometer; ionisation mod: LSIMS with Cs + , positive, acceleration: 8 kV; source temperature: 40° C.; solvent used: mNBA (meta-nitrobenzilic alcohol); input: lateral.
[0144] Results: iontype: M+; formula: C 35 H 36 N 4 O 6 106 Pd; theory: 714.1670 Z:1m/z theoretical 714.1670 m/z found 714.1689.
[0145] These results confirmed the NMR study: m/e=714 and confirmed the insertion of Palladium metal.
[0146] The chemical structure analyzed by NMR and mass spectrometry is the palladium derivative of the free acid form of BChl-Pd-BPheid.
Example 5
Biological Activity of Pd-Bpheid on Murine L1210 and Human ht29 Cells
[0147] (i) Cell Lines.
[0148] The murine leukemia cell line (L1210) was maintained in suspension culture using Fischer's medium supplemented with 10% horse serum, 1 mM glutamine, 1 mM mercaptoethanol and gentamicin. The RIF (Radiation induced Fibrosarcoma) tumor was maintained as specified by Twentyman et al. (1980, “A new mouse tumor model system (RIF-1) for comparison of end-point studies”, J Natl Cancer Inst 64:595-604). Cultures were grown in Weymouth's medium containing 10% fetal calf serum and gentamycin.
[0149] HT29 human colon adenocarcinoma cells were cultured in RPMI 1640 without phenol red and with 10% FCS. Cells were subcultured by dispersal with 0.25% trypsin in 0.02% EDTA and replated at a 1:5 split.
[0150] (ii) In Vitro Phototoxicity.
[0151] For studies on phototoxicity involving L1210 and RIF cells, light was provided by a 600 watt quartz-halogen source filtered with 10 cm of water and a 850 nm cut-off filter to remove IR. The bandwidth was further confined to 660±5 nm by an interference filter (Oriel). Cells in suspension (L1210) or adhering to 24 mm diameter cover slips were incubated in growth medium (with 20 mM HEPES pH 7 replacing NaHCO 3 for added buffering capacity) for 15 min in the presence of specified levels of sensitizers. The cells were then washed free from the sensitizer, and transferred to fresh media. Irradiations were carried out at 10° C. For some studies, the cells were then labeled with fluorescent probes and sites of photodamage were assessed. In other studies, the cells were then incubated for 60 min at 37° C. in fresh medium to allow apoptosis to proceed. Viability studies were carried out using 96-well plates and a 72-hour MTT assay, in quadruplicate.
[0152] For HT29 model, cells were incubated for 1 hour with different concentrations of Pd-Bpheid and irradiated by an halogen lamp or a titanium sapphire laser with 300 mW/cm 2 at 10 and 25 J/cm 2 .
[0153] (iii) Cell Viability.
[0154] Cell survival was assessed by the MTT reaction carried out 3 days after plating of 1,000-50,000 cells in 96 well plates. The color intensity was compared to a standard curve containing variable numbers of control cells. Absorbance at x nm was determined with a BioRad Plate reader. For L1210, growth in fresh medium was allowed to occur during the next 3 days, and cell numbers were similarly estimated using the MTT assay procedure.
[0155] (iv) Lipoprotein Binding.
[0156] Binding of Pd-BPheid to protein and lipoprotein compound of control human plasma was determined. Incubation of 250 μl plasma sample with 3 μM of the compound for 30 min at 37° C. Lipoprotein and protein components were then separated by density-gradient centrifugator. The gradients were fractionated, fractions diluted into 3 ml of 10 mM Triton X-100 detergent or of fluorescence at 750-800 nm determined upon excitation at 400 nm.
[0157] Results
[0158] (v) Phototoxicity Effect of Pd-BPheid on L1210 Cells.
[0159] L1210 murine leukemia cells were incubated with 1 μM Pd-BPheid for 30 min at 37° C. resulting in a 50% cell killing using a 75 mJ/cm 2 dose of light at 760±5 nm. A similar degree of cell killing in the RIF line required a 215 mJ/cm 2 light dose.
[0160] (vi) Phototoxicity Effect of Pd-BPheid on HT29 Cells.
[0161] The survival rate varied between 100% and 79% when HT29 cells were incubated with Pd-BPheid without light. The cellular survival rate decreased when the concentration of Pd-BPheid was higher and when the doses of energy delivered were increased. The Pd-BPheid photosensitizer dose causing a 50% death rate (also called LD 50 ) was 48 μM under an irradiation of 25 J/cm 2 . The excitation wavelength inducing the most important phototoxicity was 773 nm.
[0162] (vii) Sites of Photodamage.
[0163] Using mouse leukemia L1210 cells, Pd BPheid was highly specific mitochondrial photosensitizers with no detectable photodamage to the plasma membrane or to lysosomes. Such a result has been associated with rapid initiation of apoptosis.
[0164] (viii) Plasma Lipoprotein Binding.
[0165] Studies carried out indicated that Pd-BPheid bound to HDL>LDL>>> Albumin fractions of human serum, considered to be one determinant of PDT selectivity.
Example 6
Formulations of Pd-Bpheid: Solubilization and Stability of Pd-Bpheid in Solvents Used for Animal Experiments
[0166] Solutions of Pd-BPheid were made up in different formulations to obtain a concentration of 0.05 to 2%.
[0167] (a) Cremophor formulation was prepared as follows: 40 mg of Pd-BPheid was dissolved in 2 ml of Cremophor EL in a dry tube either by slow rotation of the vial until the solution had been completely free from particles, or using short pulses of a sonic oscillator probe. The tube was cooled such that temperature did not rise above 30° C. After the drug was solubilized, 0.6 ml of propylene glycol was added and again mixed either by slow rotation or with the sonic probe. Isotonic NaCl was then added in 0.1 ml portions to a total volume of 4 ml. The mixture should be clear after each addition, with no evidence of a precipitate. The compositions were briefly treated with the sonic probe after each addition of NaCl 0.9% taking care to keep the temperature below 25-30° C. The concentration of drug was assessed by measuring the absorbance at 757 nm after dilution into ethanol.
[0168] When 20 mg/kg of Pd-BPheid were used in experimental studies, this translated into 0.4 mg per 20 gram mouse. Since no more than 0.1 ml of Cremophor can be injected into a tail vein, the drug concentration was then 4 mg/ml.
[0169] (b) A modified Cremophor formulation was prepared as follows: 5 mg of Pd-BPheid was mixed with 0.4 ml of Cremophor EL. After dissolution, 0.12 ml of propylene glycol was added. Isotonic saline (1.48 ml) was then added in small portions, and the same was mixed after each addition. The final solution was completely clear and free from particles. An ultrasonic probe was used to aid in dissolving the drug, keeping the solutions below 25° C. by cooling as needed in an ice bath.
[0170] The determination of Pd-BPheid concentration in the Cremophor solution was performed by dilution into methanol. The absorbance spectrum was measured over 740-780 nm. The peak value was compared with the results from a known concentration of Pd-BPheid.
[0171] (c) Additional formulations were prepared using Tween 80 and ethanol to solubilize Pd-BPheid (1 mg Pd-BPheid/ml solution).
Example 7
In Vivo Toxicity Studies—Effect of Pd-Bpheid on Murine Tumor Models
[0172] Two sets of experiments involving murine tumor models were used to assess the phototoxicity of Pd-Bpheid.
[0173] (a) The photodynamic responsiveness of Pd-BPheid was firstly evaluated in two murine tumor models: BA—mammary adenocarcinoma and radiation induced fibrosarcoma (RIF-1)
[0174] Photodynamic therapy parameters: Mice with tumors measuring 5-7 mm in diameter were entered into PDT experiments. Three Pd-BPheid drug doses (1, 5 and 10 mg/kg) and two light doses (100 and 300 Joules/sq.cm) were evaluated. A formulation of Pd-BPheid dissolved in Cremophor was administered by i.v. tail injection. PDT light exposure was started either 15 minutes, 1 hour or 4 hours following injection. Three mice were treated under each treatment condition unless initial results demonstrated lethal toxicity or non-responsiveness. A titanium sapphire laser tuned to 757 nm was used as the light source for PDT. Laser generated light was coupled into quartz fibers for delivery of light to tumors. A light power density of 75 mW/sq.cm was used. Tumor size was measured 3 days per week following PDT treatments and the percentage of tumor cures (defined as no tumor recurrence for 40 days post treatment) was determined.
[0175] In vivo PDT Response: Tables 4 and 5 hereinafter provide summaries of the PDT treatment results for C3H mice transplanted with either the BA mammary carcinoma or the RIF-1 fibrosarcoma. Each table indicates the following parameters: 1) intravenous drug dose expressed in mg/kg; 2) laser treatment parameters, including the total light dose (J/cm 2 ), the wavelength (757 nm), the light dose rate (mW/cm 2 ), and the time interval (between treated for each group, 4) toxicity (four mice died shortly after treatment), 5) tumor regrowth (consisting of the number of days between PDT treatment and tumor recurrence), and 6) the number of mice (and percentage) with Pd-BPheid PDT induced tumor cures.
[0176] As shown herein, Pd-BPheid mediated PDT was found to induce both a classical and an efficient tumoricidal response in two mouse tumor models. PDT mediated tumor responsiveness was directly correlated with drug dose, light dose and time interval between drug administration and light treatment. Specifically, higher drug doses and/or higher light doses produced enhanced responses. The BA mammary carcinoma was found to be more responsive to Pd-BPheid mediated PDT than comparable PDT treatments of the RIF-1 fibrosarcoma. Pd-BPheid mediated PDT was effective when light treatments were initiated within 1 hour of drug administration, and was not effective when a 4-hour interval between drug administration and light treatment was used.
[0177] (b) In the second set of experiments, the phototoxicity of Pd-BPheid was assessed in a mouse tumor model transplanted with HT29 human colon adenocarcinoma.
[0178] Animal and tumor model: Solid tumor tissue (diameter 2 cm) removed from donor mouse immediately after death was mechanically crushed in 1 ml of 0.9% saline solution and the solution (0.1 ml) was injected s.c. into one hind leg of each mouse. Mice were included for experiments when the tumor diameter was 8-10 mm. Tumors were grafted s.c. in 8-week aged Swiss nude mice 10 days before experiment.
[0179] Phototoxic studies: 0.15 ml Pd-BPheid was injected i.v. at 15 mg/kg. Mice were anesthetized with thiopental at 40 mg/kg just before irradiation. At 30 min, 1 h, 4 h or 24 h after injection, mice were irradiated with a titanium sapphire laser at 300 mW/cm 2 , mean diameter were measured to adjust time irradiation to obtain 200 or 300 J/cm 2 . Control mice not injected with Pd-BPheid were also irradiated in same conditions. The tumor growth delay induced by PDT was analyzed by equivalence with tests realized in experimental radiotherapy. For in vivo studies and for each separate experiment, all results were the mean of 2 or 3 separate experiments and for each separate experiment, 2 mice were used for each experimental condition.
[0180] Concerning tumoral growth studies, results are expressed as tumoral index variations with reference (=1) corresponding to tumoral index from non-treated cells. The tumoral index was calculated as follows:
[0181] Tumoral index=(largest tumoral diameter+perpendicularly opposite diameter)/2.
[0182] Temperature variation studies: to assure that the thermic effect was not excessive, temperature variation was measured for the halogen lamp and the titanium sapphire laser irradiation using non-absorbing alumin-embedded microthermocouples.
[0183] The results of this experiment are the following:
[0184] (i) 763 nm Irradiation at 200 J/cm 2 :
[0185] A tumor growth decrease (as compared to controls) was observed for the conditions 30 min and 4 h after injection. A decrease of tumor index was observed up to 7 days for the conditions 1 h and 24 h after injection.
[0186] (ii) 763 nm Irradiation at 300 J/cm 2 :
[0187] A tumor growth decrease was observed (as compared to controls) for the conditions 30 min and 24 h after injection. A decrease of tumor index was observed up to 7 days for the conditions 1 h and 4 h after injection.
[0188] (iii) 300 J/cm 2 Irradiation 1 h After Injection:
[0189] A tumor growth decrease was observed (as compared to controls) for the condition 773 nm up to 5 days and for the conditions 753 nm and 763 nm up to 12 days. The maximum tumor growth decrease was observed for 763 nm.
[0190] (iv) 300 J/cm 2 Irradiation 24 h After Injection:
[0191] A tumor growth decrease was observed (as compared to controls) for the condition 753 nm up to 4 days and for the conditions 763 nm and 773 nm up to 12 days. The maximum tumor growth decrease was observed for 773 nm.
[0192] No excessive temperature variation was observed during halogen lamp or titanium sapphire irradiation of mice.
[0193] In summary of this study, the optimal wavelength of irradiation was found to be 773 nm. The delay between injection and illumination had an influence on the tumor response. At 764 nm, a one hour delay was shown to be the most efficient. When using a 773 nm wavelength, the most efficient delay was 24 hours.
TABLE 4 C3H/BA Mammary Carcinoma Response to Pd-BPheid Number of Toxicity Animals with Number of (Treatment Primary Tumor Drug Dose Light Animals Associated Regrowth (Days Summary (mg/Kg) Parameters Treated Death) to Recurrence (cures) % 1 i.v. 300 J/cm 2 1 0 1 (1 da) − 757 nm no response 75 mW/cm 2 15 min interval 5 i.v. 300 J/cm 2 3 0 + 757 nm 1 (41 days) 75 mW/cm 2 2 (40 days) 15 min 100% interval 5 i.v. 300 J/cm 2 3 0 1 (11 days) + 757 nm 2 (41 days) 75 mW/cm 2 66.6% 1 hr interval 10 i.v. 300 J/cm 2 3 0 + 757 nm 2 (41 days) 75 mW/cm w 1 (41 days) 1 hr 100% interval 10 i.v. 300 J/cm 2 2 0 2 (1 day) − 757 nm no response 75 mW/cm 2 4 hr interval 10 i.v. 100 j/cm 2 3 0 + 757 nm 2 (42 days) 75 mW/cm 2 1 (41 days) 15 min 100% interval 10 i.v. 100 J/cm 2 3 0 1 (5 days) + 757 nm 2 (40 days) 75 mW/cm 2 66.66% 1 hr interval
[0194] [0194] TABLE 5 RIF-1 Response to Pd-BPheid Number of Animals with Toxicity Primary Number of (Treatment Tumor Regrowth Drug Dose Light Animals Associated (Days to Summary (mg/Kg) Parameters Treated Death) Recurrence (cures) % 1 i.v. 300 J/cm 2 2 0 2 (1 da) − 757 nm no response 75 mW/cm 2 15 min interval 5 i.v. 300 J/cm 2 3 0 1 (5 days) + 757 nm 1 (12 days) 1 (40 days) 75 mW/cm 2 33.33% 15 min interval 5 i.v. 300 J/cm 2 3 0 1 (4 days) + 757 nm 1 (2 days) 75 mW/cm 2 1 (7 days) 1 hr interval 10 i.v. 300 J/cm 2 3 2 + 757 nm 2 (1 day) 1 (41 days) 75 mW/cm w 33.33% 15 interval 10 i.v. 300 J/cm 2 3 2 + 757 nm 2 (1 day) 1 (41 days) 75 mW/cm w 25% 1 hr interval 10 i.v. 300 J/cm 2 1 0 2 (1 day) − 757 nm no response 75 mW/cm 2 4 hr interval 10 i.v. 100 j/cm 2 3 0 2 (12 days) + 757 nm 1 (7 days) 75 mW/cm 2 15 min interval 10 i.v. 100 J/cm 2 3 0 2 (3 days) + 757 nm 1 (6 days) 75 mW/cm 2 1 hr interval
Example 8
Morphological Evaluation of A431 Human Epithelial Carcinoid Cells after Pd-BPheid and BChl-Ser Based PDT
[0195] This experiment was performed in order to examine the time-dependent morphological changes occurring after PDT with Pd-BPheid or BChl-SerOMe on A431 human epithelial carcinoid cells.
[0196] (i) Materials:
[0197] The Pd-BPheid was prepared as in Example 1 above and the serine methyl ester BChl-SerOMe was prepared as in EP 584552.
[0198] (ii) Light Source:
[0199] Halogen lamp (Osram, Germany, 100 W), with 4.5 cm water filter and cut off filter >650 nm. The cells were illuminated for 10 minutes, 15 mW/cm2, a total energy fluency of 9 J/cm 2 . For illumination, the culture plates were placed on a glass table to provide the light from the bottom.
[0200] (iii) Phototoxicity Study:
[0201] A431 cells (5×104 cells) were seeded in 3 cm dishes in duplicates and cultured to 75% confluency in Dulbecco's modified Eagle's medium (DMEM)+F12 (1:1), buffered with HEPES (25 mM, pH 7.4), fetal calf serum (FCS) with penicillin (0.06 mg/ml) and streptomycin (0.1 mg/ml). Pd-BPheid or BChl-Ser were added to the cells at the corresponding LD90 concentration (0.1 and 1 μM, respectively). After a 4-hour period the cells were washed with culture medium and the cells were illuminated with the light source above. Phase contrast microscopic examination was performed at different time points after illumination (0, 0.5, 4 and 24 hours post-PDT) using Zeiss Axiovert-35 light microscope (magnification ×320) equipped with a Contax 35 mm SLR camera. In the second dish of every duplicate, cell viability was assessed 24 hours post-PDT using neutral red viability assay (Zhang SZ., 1990 , Cell Biol Toxicol 6(2):219-234).
[0202] (iv) Results:
[0203] Both sensitizers caused significant changes in the cell morphology. Pd-BPheid caused a fast alteration in the cells membrane structure (30 minutes), the cells rapidly shrinked and fibrous connections were formed, connecting the cells membrane with the original focal adhesion points (fibrous phenotype). After 4 hours, 90% of the cells lost most qf their inner volume and a large portion of them detached from the dish, no further change was observed after 24 hours (FIG. 4, right column). Bchl-Ser showed a different pattern of time dependant morphological changes that could be observed only after 4 hours. Membrane blabbing was seen as dark vesicles budding out from the cells membrane. No significant volume decrease was observed over 24 hours and after this period most of the cells were attached to the dish but appeared hollow (blabbing phenotype, FIG. 4, Left column). Twenty four hours after illumination, neutral red viability assay was performed which confirmed 90±7% cell killing in both of the experimental groups. In FIG. 4, the fibrous phenotype is represented in the right column and the blabbing phenotype is represented in the left column. The solid white arrows show the formations of the fibers or the blabs.
Example 9
Photocytotoxicity of Pd-BPheid and BChl-SerOMe on the Human Bladder Carcinoma Cell Line ECV304
[0204] This experiment was carried out for assessing the photocytotoxic effects of the photosensitizers Pd-BPheid and BChl-SerOMe on ECV304 human bladder carcinoma cells.
[0205] (i) Materials:
[0206] As in Example 8(i).
[0207] (ii) Light Source:
[0208] As in Example 8(ii).
[0209] (iii) Phototoxicity Study:
[0210] ECV304 cells (2×10 4 cells per well) were cultured in M-199, 10% FCS with penicillin (0.06 mg/ml) and streptomycin (0.1 mg/ml) in 96-well to confluence (˜2×10 5 cells per well). Incubation with increasing concentrations of Pd-BPheid or BChl-SerOMe with the cells for 4 hours was followed by washing with fresh culture medium and illumination as described above Sec. 1. Twenty-four hours after illumination, cell viability was assessed using neutral red viability assay. The following controls were used: Light Control: irradiated cells, not treated with sensitizer; Dark Control: non-irradiated cells, treated with sensitizer in the dark; Untreated Control: cells not treated with sensitizer and unirradiated were used for calculation of 100% survival (Rosenbach-Belkin V. et al., 1996 , Photochem Photobiol 64(1) :174-181)
[0211] (iv) Results:
[0212] Both Pd-BPheid and BChl-SerOMe exhibited dose and light dependent cytotoxicity on ECV304 cells (FIG. 5). The corresponding LD 50 values are 19 and 1000 nM. Morphological changes post-PDT were consistent with the observations made with A431 cells (data not shown).
Example 10
PDT of Pd-BPheid and Pd-BPheid-ethyl Ester on M2R Mouse Melanoma Cells
[0213] The aim of this experiment was to test the effect of Pd-BPheid and Pd-BPheid-ethyl ester on M 2 R cells.
[0214] (i) Materials:
[0215] Pd-Bpheid was prepared as in Example 1 above and the Pd-Bacteriopheophorbide a ethyl ester (Pd-Bpheid-ethyl ester) was prepared as described in WO 97/19081.
[0216] (ii) Light Source:
[0217] As above in Example 8(ii) but cells were illuminated for 10 minutes, 12 mW/cm 2 , a total energy fluency of 7 J/cm 2 .
[0218] (iii) Phototoxicity Study:
[0219] M 2 R cells were cultured as monolayers in Dulbecco's modified Eagle's medium (DMEM)+F12 (1:1), buffered with HEPES (25 mM, pH 7.4). Fetal bovine serum (FBS) (10%), glutamine (2 mM), penicillin (0.06 mg/ml) and streptomycin (0.1 mg/ml) were included and the cells were grown at 37° C. in a humidified atmosphere containing 8% CO 2 . For phototoxicity analysis cells (1×10 4 cells/well) were cultured in 96-well plates for 24 hours to an approximate density of 2×10 4 cells/well. Pigments were dissolved directly in culture medium or in ethanol 95% and further diluted in culture medium to a final concentration of 1% ethanol. The diluted pigments were added and the cells were incubated in the dark for four hours at 37° C. Prior to illumination, the cells were washed once and replaced with fresh culture medium. The plates were then illuminated from the bottom for 10 minutes at room temperature and placed in the culture incubator at 37° C. in the dark. Cell survival was determined 24 hours later. The following control systems were used: Dark Control: untreated cells kept in the dark; Light Control: cells not treated with sensitizer that were illuminated; Dark Toxicity: cells treated with pigment but kept in the dark. Cell survival was determined by [ 3 H]-thymidine incorporation as described earlier (WO 97/19081).
[0220] (iv) Results:
[0221] As can be seen in FIG. 6A, when the pigments were dissolved in ethanol 95%, Pd-BPheid had a LD 50 of 0.03 μM, while the Pd-BPheid-ethyl ester had a LD 50 of 0.07 μM. When the pigments were dissolved directly in culture medium containing 10% serum, only the Pd-BPheid was fully active while the Pd-BPheid-ethyl ester was not active at all up to 1 μM, the highest concentration tested (FIG. 6B).
Example 11
PDT of Pd-BPheid on M2R Mouse Melanoma and Human HT29 Colon Carcinoma Cells
[0222] These experiments were aimed at determining the phototoxic effect of Pd-BPheid toward two cell lines: M2R mouse melanoma and human HT29 colon carcinoma cells.
[0223] (i) Materials:
[0224] Pd-Bpheid was prepared as in Example 1 above.
[0225] (ii) Light Source:
[0226] The light source was a Xenon fluorine LS3-PDT lamp (Bio-Spec, Russia), with 10 cm water filter and 720-850 nm light band. The cells were illuminated for 10 minutes, 12 mW/cm 2 , at a total energy of 7 J/cm 2 .
[0227] (iii) Phototoxicity Study:
[0228] Analysis was performed with the same protocol as described above (Example 10) with the following changes: Pd-BPheid was dissolved directly in medium containing 10% serum and then added to the cells. Survival of M2R cells was determined by [ 3 H]-thymidine incorporation and that of human HT29 cells with the MTT assay (Merlin J L et al., 1992 Eur J Cancer 28A:1452-1458).
[0229] (iv) Results:
[0230] As can be seen in FIG. 7, human colon HT-29 cells show lower sensitivity toward this pigment (LD 50 of 0.5 μM), while the M 2 R cells were about 10 times more sensitive (LD 50 of 0.03 μM).
Example 12
In Vivo PDT of M2R Mouse Melanoma Tumors with Pd-BPheid
[0231] The aim of this experiment was to study PDT of M2R mouse melanoma tumors in CD1 nude mice with 2.5 mg/Kg Pd-Bpheid.
[0232] (i) Materials:
[0233] P d-Bpheid was prepared as in Example 1 above.
[0234] (ii) Mice:
[0235] C D1 nude mice (25-30 g)
[0236] (iii) Anesthesia:
[0237] i.p injection of 50 μl of Ketamine/Rumpon (vol/vol=85/15).
[0238] (iv) Tumor Implantation:
[0239] Mice were implanted with 106 M2R cells on the back and tumors arose to the treatment size (7-8 mm) within 2-3 weeks.
[0240] (v) Light Source:
[0241] Osram150 W halogen photo-optic lamp 64643 (D. K. Keller et al 1999 , Int J Hyperthermia 15:467-474) equipped with λ=650-900 mn spectral window, 300 mW/cm-2. Illumination was for 30 min.
[0242] (vi) PDT Protocol:
[0243] The anesthetized mouse was i.v injected with the pigment and the tumor immediately illuminated. At the end of treatment the mouse was placed back in the cage. Photographs of the tumor were taken before and at the times indicated.
[0244] Experiment 1
[0245] Preparation of Sensitizer:
[0246] Two mg Pd-BPheid were dissolved in 0.25 ml Cremophor EL followed by 20 min sonication. 0.075 ml 1,2-propylene glycol were added and sonication was continued for another 15 min. Then 0.9 ml of 0.15 mM NaCl were added followed by 5 min sonication. The sample was centrifuged for 12 min at 13,000 rpm (Eppendorf). The final calculated concentration of Pd-BPheid based on spectrum in chloroform was 0.5 mg/ml.
[0247] PDT of Tumor:
[0248] Pd-BPheid 2.5 mg/kg was i.v injected to CD1-Nude mouse bearing M2R melanoma tumor. The tumor was illuminated for 30 min at 300 mW cm −2 . The temperature of the mouse skin tumor area was 37.7-38° C. The response of tumor was followed 1 and 4 days after treatment. The results are shown in FIG. 8.
[0249] Experiment 2
[0250] Preparation of Sensitizer:
[0251] Two mg Pd-BPheid were dissolved in 0.1 ml methanol, 0.1 ml 0.1 M KH 2 PO 4 , pH=8.0 and 0.9 ml PBS and sonicated for 10 min. The methanol was evaporated with Argon and 20% of Cremophor EL: 1,2-propylene glycol (3:1) was added following by 15 min sonication. The sample was centrifuged for 8 min on 13,000 rpm the final calculated concentration of Pd-BPheid based on spectrum in chloroform was 0.5 mg/ml.
[0252] PDT of Tumor:
[0253] Pd-BPheid 2.5 mg/kg (120 μl) was i.v administered to CD1-Nude mice bearing M2R melanoma tumor. The tumor tissue was illuminated for 30 min at 300 mW cm −2 . The temperature of the mouse skin tumor area was 37.7-38° C. The response of tumor was followed 1 and 4 days after treatment. The results are shown in FIG. 9.
[0254] Results
[0255] As shown in FIGS. 8 and 9, PDT of M2R melanoma tumors with 2.5 mg/Kg Pd-Bpheid as described above induces severe inflammatory response with necrosis of the tumor within 24 h.
Example 13
Pd-BPheid Based PDT Reduces Rate of C6 Glioma Metastasis Formation in Mice: Advantage over Surgery
[0256] These experiments were conducted in order to compare the therapeutic potential of Pd-BPheid and BChl-SerOMe based PDT, and the probability of metastasis spread by Pd-BPheid and BChl-SerOMe based PDT.
[0257] (i) Materials:
[0258] Pd-BPheid (prepared as in Example 1) or Pd-BPpheid-SerOMe 5 mg/kg in 20% Cremophor EL.
[0259] (ii) Light Source:
[0260] The light source was a Xenon fluorine LS3-PDT lamp (Bio-Spec, Russia), with 10 cm water filter and 720-850 nm light band.
[0261] (iii) Mice:
[0262] CD1 nude mice.
[0263] (iv) Tumors:
[0264] Mice were implanted with 10 6 C6 glioma cells in the foot of the hind leg. Tumors were treated when reached a length of 7-8 mm.
[0265] (v) Anesthesia:
[0266] 50 μl of Vetalar/Rumpon (vol/vol=85/15).
[0267] (vi) Analgesia:
[0268] Oxycodone (12 mg/liter) added in 5% sucrose drinking water, as of treatment (amputation or PDT) for one week.
[0269] (vii) Protocol:
[0270] Three groups (10 mice in each) were i.v. injected with 5 mg/Kg of sensitizer (Pd-BPheid or Pd-BPpheid-SerOMe) and immediately illuminated at 200 mw/cm 2 , for 30 minutes, and the animals were allowed to recover in the cage.
[0271] Groups 1 and 2:
[0272] Animals which received PDT Pd-Bpheid and Pd-BPpheid-SerOMe, respectively. Tumor response and metastasis formation in groin were followed for 4 weeks.
[0273] Group 3:
[0274] Animals which were amputated at the ankle joint (paired with group 1) and metastasis formation in groin was followed for 4 weeks. The parameters of response to PDT were the percent of animals with tumor necrosis and disappearance, out of the total number of treated animals. Metatstasis was manifested by appearance of tumors in the groin or elsewhere. The endpoints considered were: follow up for 4 weeks, spontaneous death, tumors reached a diameter of 2 cm, metastasis, whichever came first.
[0275] (viii) Results:
[0276] The results of tumor flattening (disappearance) are shown on FIG. 10. While on day 11 the response to Pd-BPheid was stronger than to Pd-BPheid-SerOMe (100% and 80% tumor flattening, respectively), later, on day 28, the percent of response was similar, about 60%. The decline in tumor flattening in the long term is due to some tumor re-growth in some of the treated animals, probably due to mismatch of light field and tumor area.
[0277] The results of metastasis appearance are shown in FIG. 11. The surgical treatment by leg amputation yielded a substantially higher percent of metastasis in comparison to PDT (up to 78%). In addition, the metastasis after amputation appeared much earlier. The frequency of metastasis after PDT with Pd-BPheid was the lowest (up to 23%). This result is similar to that obtained with Pd-BPheid-SerOMe and the main advantage of Pd-BPheid is delay of metastasis appearance. PDT with Pd-BPheid or Pd-BPheid-SerOMe are curative for C6 glioma tumors. Metastasis formation after PDT is substantially lower when compared with surgical treatment.
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Palladium-substituted Bacteriochlorophyll derivatives are administered to a subject suspected of having a tumor and the patient is then irradiated and the fluorescence of the suspected area is measured. A high fluorescence indicates a tumor site. A preferred derivative is Pd-Bacteriopheophorbide a.
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[0001] This application claims priority on U.S. Provisional Patent Appl. No. 60/486,735, filed Jul. 11, 2003.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The subject invention relates to a tool for removing golf spikes from a golf shoe.
[0004] 2. Description of the Related Art
[0005] Golf shoes include an array of spikes that are intended to hold the feet of a golfer stationary while the golfer completes his or her swing. The typical golf shoe has been formed with an array of threaded apertures that extend into the sole and into the heel. The typical golf spike has included a long metal projection that is sufficiently sharp to penetrate into the turf of the golf course. The projection has been formed unitarily with or mounted to a shank with an array of external threads configured for removable threaded engagement into the threaded apertures of the golf shoe. A disc-shaped base has extended outwardly between the pointed projection and the threaded shank. The disc is dimensioned and disposed for secure mounting adjacent the lower surface of the sole or heel when the shank is threaded into one of the apertures formed in the sole or heel.
[0006] Many golf courses now prohibit golf spikes with metal projections. Rather, most golf spikes now are formed entirely from plastic. The plastic golf spikes include a threaded plastic shank, a plastic disc adjacent the shank and a plastic projection or an array of plastic projections that extend from the disc in a direction opposite from the shank.
[0007] Golf spikes, and particularly the more recently used plastic golf spikes wear quickly and require replacement. A frequent golfer may change golf spikes several times during the course of a golfing season. Forces generated during normal wear of a golf shoe can deform the interengaged surfaces of the golf spike and the golf shoe sufficiently to complicate the threaded removal. As a result, a golfer typically must employ a tool to threadedly remove the golf spike. The golf spike removal process can be extremely difficult even with the benefit of a tool.
[0008] The typical golf spike includes a pair of diametrically opposed apertures that open to the lower face of the disc of the golf spike. The golf spike removal tool includes a pair of projections disposed and dimensioned to be received in the diametrically opposed apertures formed in the disc of the golf spike. The golfer inserts the projections of the tool into the apertures formed in the golf spike and then rotates the tool to remove the golf spike.
[0009] Golf spikes and golf shoes are manufactured by many different companies, and the respective companies have their own preferred arrangement for the holes formed in the disc of the golf spike. The differences relate to the sizes and shapes of the holes and the spacings between the holes. Thus, a tool may fit the apertures formed in one golf spike, but not in another. Some golf spike removal tools have a handle and a removable head. The golfer selects a head appropriate for the particular golf spikes on the golfer's shoes. The selected head then is mounted to the handle to permit removal of the golf spike.
[0010] The disc of the golf spike is formed from plastic, and hence the aperture for the golf spike removal tool extends into the plastic of the disc. Forces generated in an effort to remove a stubbornly wedged golf spike often will break or gouge the plastic near the apertures that are intended to accommodate the golf spike removal tool. Such damage to the disc can severely complicate the golf spike removal process and can render a conventional golf spike removal tool useless. The disc also can be damaged if the golfer inadvertently attempts removal with a tool that is not matched appropriately for the holes In the golf spike. In this regard, the differences between the apertures in the discs of different golf spikes often are fairly minor and might not be appreciated during the initial visual inspection of the golf spike. Hence, it is fairly common for a golfer to attempt removal with the wrong tool, thereby damaging the disc of the golf spike and substantially complicating the spike removal process. Golfers may resort to a conventional pair of pliers in an effort to remove a golf spike that has been damaged during an initial removal attempt. However, there are no good gripping surfaces on a golf spike and attempts to unthread a golf spike with a pair of pliers will seldom work.
[0011] In view of the above, it is an object of the subject invention to provide a golf spike removal tool that can be used with all golf spikes and that is effective for removing golf spikes where the spike has become interengaged very tightly in the golf shoe.
SUMMARY OF THE INVENTION
[0012] The subject invention relates to a universal golf spike tool having an elongate primary shank with proximal and distal ends. A handle is securely mounted to the proximal end of the primary shank and is configured for secure gripping by the golfer. The distal end of the primary shank has a pair of projections dimensioned for engagement in the apertures formed in a large number of golf spikes. Thus, the projections at the distal end of the primary shank can be used for engaging and removing a substantial number of commercially available golf spikes. However, the projections at the distal end of the primary shank will not fit all golf spikes. Additionally, some golf spikes may be worn sufficiently through usage to prevent the projections from being effective. In still other instances, the golf spike may be engaged so tightly that the projections will damage portions of the disc adjacent the apertures during efforts to remove the golf spike.
[0013] The tool of the subject invention further includes a supplemental shank that is telescoped relative to the primary shank. The supplemental shank has a distal end with plurality of projections that are sufficiently pointed to bite into the plastic disc of the golf spike. Thus, the pointed projections of the supplemental shank can be embedded into the plastic of the disc of the golf spike to effect removal of the golf spike in those situations where the projections at the distal end of the primary shank do not fit the apertures in the golf spike or where the golf spike has been too damaged to receive the projections at the distal end of the primary shank.
[0014] The primary shank preferably is hollow and the supplemental shank preferably is telescoped within the primary shank. Thus, the supplemental shank can be telescoped from a proximal position where the distal end of the entire supplemental shank is within the primary shank to a distal position where the supplemental shank projects distally beyond the primary shank. The primary and supplemental shanks may have cooperating means for keeping the supplemental shank either in a proximal position or in a distal position. For example, the primary shank may be formed with a generally J-shaped groove or a stepped groove, and the supplemental shank may be formed with a locking but that project through the J-shaped groove. Thus, the supplemental shank can be locked either in a proximal position or a distal position. The locking of the supplemental shank in the proximal position enables a golf spike removal effort to be undertaken using only the rigid projections at the distal end of the primary shank. The locking of the supplemental shank in the distal position enables a golf spike removal effort to be undertaken using the pointed projections at the distal end of the supplemental shank.
[0015] The tool of the subject invention also may include biasing means for biasing the supplemental shank either in a proximal direction or in a distal direction. In a preferred embodiment, the biasing means will be configured for urging the supplemental shank in the proximal direction. Thus, the tool is biased into a configuration where the sharply pointed projections of the supplemental shank are withdrawn. However, sufficient force on the supplemental shank will overcome the biasing forces exerted on the supplemental shank and will permit the supplemental shank to be locked in its distal position.
[0016] The tool of the subject invention can include an alternate arrangement of tips that can be telescoped into engagement with the rigid tips that project from the distal end of the primary shank. The alternate tips can be dimensioned and configured to enable the primary shank to be used with a larger number of commercially available golf spikes. In these situations, the supplemental shank will be used primarily in those situations where the golf spike has been damaged or wedged in the golf shoe.
[0017] The tool may have an overall T-shape with the handle extending transversely from the proximal end of the primary shank. The handle may be solid. Alternatively, the handle may be hollow and may be used to store a related tool, such as a brush for cleaning the spikes of the golf shoe.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1 is an exploded side elevational view of a golf spike removal tool in accordance with the subject invention.
[0019] FIG. 2 is a side elevational view of the assembled components of the tool with the supplemental shank in the proximal and retracted position.
[0020] FIG. 3 is a side elevational view of the golf spike removal tool with the supplemental shank in the distal and extended position.
[0021] FIG. 4 is a top plan view of the handle of the spike removal tool shown in FIGS. 1-3 .
[0022] FIG. 5 is a bottom plan view of the primary shank.
[0023] FIG. 6 is a bottom plan view of the supplemental shank.
[0024] FIG. 7 is a top plan view of an alternate handle.
[0025] FIG. 8 is a side elevational view of an alternate primary shank.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0026] A golf spike removal tool in accordance with the subject invention is identified generally by the numeral 10 in FIGS. 1-3 . The tool 10 includes a rigid handle 12 with a grip 14 and a mounting stub 16 , and shown in FIGS. 1-4 . The grip 14 of the handle 12 is illustrated as being substantially cylindrical with opposite first and second ends 18 and 20 . However, variations from a purely cylindrical shape are possible and may be preferable in certain situations. For example, narrowed regions to facilitate gripping can be provided at locations between the first and second ends 18 and 20 . Alternatively, a cross-shaped handle 12 A can be provided, as shown in FIG. 7 . The handle 12 shown in FIGS. 1-4 may be molded from a rigid and substantially solid plastic or metal material with sufficient strength to withstand the torque imposed upon the tool 10 during the removal of a golf spike. However, the handle 12 can be formed from a hollow plastic or metal material if the walls are sufficiently thick to give the necessary strength to the tool 10 for applying the torque to the golf spike. In the illustrated embodiment, the grip 14 of the handle 12 is substantially hollow and is open at the first end 18 thereof. In this embodiment, a supplemental tool, such as the brush 21 illustrated in FIG. 1 can be mounted into the open first end 18 of the hollow gripping section 14 . The brush 21 is useful for removing dirt and other debris from golf spikes.
[0027] The mounting section 16 of the handle 12 extends from a location substantially centrally between the first and second ends 18 and 20 of the grip 14 and defines a short rigid stub with an outside diameter “a”. The mounting stub 16 preferably is formed unitarily with the grip 14 .
[0028] The tool 10 further includes a primary shank 22 , as shown in FIGS. 1-3 and 5 . The primary shank 22 is a hollow cylindrical member formed from a metallic material and having an inside diameter “b” which is slightly greater than the outside diameter “a” of the mounting section 16 of the handle 12 . More particularly, the primary shank 22 includes an open proximal end 24 and an open distal end 26 . The inside diameter “b” permits the mounting stub 16 of the handle 12 to be telescoped into the open proximal end 24 of the primary shank 22 . Portions of the primary shank 22 near the proximal end 24 are formed with a threaded aperture 28 that is aligned radially. The aperture 28 is in a position that will align with the mounting stub 16 of the handle 12 when the mounting stub 16 is telescoped into the open proximal end 24 of the primary shank 22 . A mounting screw 29 is threadedly engaged in the aperture 28 and is securely engaged in the mounting stub 16 of the handle 12 to hold the handle 12 securely and substantially permanently to the proximal end 24 of the primary shank 22 .
[0029] The distal end 26 of the primary shank 22 is characterized by diametrically opposed projections 30 . The projections 30 are disposed and dimensioned to telescope into the apertures formed in the disc of a commercially available golf spike. Thus, the projections 30 at the distal end 26 of the primary shank 22 can be used to threadedly disengage some golf spikes from a golf shoe.
[0030] As noted above, there are many different types of golf spikes with removal apertures of different sizes, shapes and positions. The golf spike removal tool 10 of the subject invention preferably includes supplemental tips 30 a and 30 b . The supplemental tips 30 a and 30 b include mounting apertures (not shown) in one end that are dimensioned to be telescoped tightly over the projections 30 at the distal end 26 of the primary shank 22 . However, external dimensions of the supplemental tips 30 a and 30 b are different from one another and different from the projections 30 . Thus, the supplemental tips 30 a and 30 b can be removably engaged over the projections to adapt the tool 10 to a particular golf spike.
[0031] Portions of the primary shank 22 between the proximal and distal ends 24 and 26 are provided with a J-shaped cut-out 32 . The J-shaped cut-out 32 includes a long leg 34 with a proximal end 36 and a short leg 38 with a proximal end 40 . The distance between the proximal end 24 of the primary shank 22 and the proximal end 36 of the long leg 34 of the J-shaped cut-out 32 is less than the distance between the proximal end 24 of the primary shank 22 and the proximal end 40 of the shorter leg 38 . The cut-out can take other forms. For example, FIG. 8 shows an alternate primary shank 22 A with a C-shaped cut-out 32 A. The cut-out 32 A has proximal and distal legs 36 A and 40 A.
[0032] The tool 10 further includes a supplemental shank 42 , as shown in FIGS. 1-3 . The supplemental shank 42 is a generally cylindrical tube formed from a metal material and has a proximal end 44 and a distal end 46 . The supplemental shank 42 is shorter than the primary shank 22 . Additionally, the supplemental shank 42 defines an outside diameter “a” that is approximately equal to the outside diameter “a” of the mounting section 16 of the handle 12 .
[0033] The distal end 46 of the supplemental shank 42 is characterized by a plurality of sharply pointed projections 48 . Each projection 48 preferably has an axially aligned edge 49 disposed on the counterclockwise face of the projection 48 when viewed in a proximal-to-distal direction. Thus, the axially aligned edge 49 is effective for unthreading a golf spike as explained further herein. The supplemental shank 42 further includes a threaded aperture 50 at a location between proximal and distal ends 44 and 46 .
[0034] The tool 10 further includes a locking bolt 52 . The locking bolt 52 has a threaded shaft 54 at one end and a knarled head 56 at the opposed end. The threaded shaft 54 is dimensioned to pass through the J-shaped cut-out 32 in the primary shank and to threadedly engage in the aperture 50 of the supplemental shank 42 .
[0035] The illustrated embodiment of FIG. 1 shows an optional coil spring 62 within the primary shank 22 . One end of the coil spring 62 is connected to the mounting stub 16 of the handle 12 while the opposed end is connected to the supplemental shank 42 . The coil spring functions to bias the supplemental shank 42 toward the handle 12 .
[0036] The tool 10 is assembled by telescoping the mounting stub 16 of the handle 12 into the open proximal end 24 of the primary shank 22 . The screw 29 then is threaded through the aperture 28 in the primary shank 22 and is attached securely to the mounting section 16 to hold the primary shank 22 to the handle 12 . The proximal end 44 of the supplemental shank 42 then is telescoped in a distal-to-proximal direction into the open distal end 26 of the primary shank 22 . The supplemental shank 42 is moved into a position where the threaded aperture 50 in the supplemental shank 42 aligns with a portion of the J-shaped cut-out 32 in the primary shank 22 . The threaded shaft 54 of the locking bolt 52 then is passed through the J-shaped cut-out 32 and is threadedly engaged in the aperture 50 of the supplemental shank 42 . The tool 10 then may be packaged and sold in this assembled condition.
[0037] The locking bolt 52 can be tightened and loosened selectively against the outer circumferential surface of the primary shank 22 at locations near the J-shaped cut-out 32 . More particularly, the locking bolt 52 can be used to secure the supplemental shank 52 in a proximal position with the locking bolt 52 tightened at a location near the proximal end 36 of the long leg 34 of the J-shaped cut-out 32 . In this position, the pointed projections 48 at the distal end 46 of the supplemental shank 42 are retracted within the primary shank 22 . Alternatively, the locking bolt 52 can be loosened to move the supplemental shank 42 distally in the primary shank 22 and into a distal position. In the distal position, the locking bolt 52 is substantially adjacent the proximal end 40 of the short leg 38 of the J-shaped cut-out 32 . In this position, the pointed projections 48 at the distal end 46 of the supplemental shank 42 project distally beyond the projections 30 at the distal end 26 of the primary shank 22 .
[0038] The tool 10 can be used by initially attempting a golf spike removal with the supplemental shank 42 in the proximal position and retracted into the primary shank 22 . In some situations, the projections 30 at the distal end 26 of the primary shank 22 will not fit the removal apertures in the golf spike. In other situations, the golf spike will be sufficiently worn to prevent engagement of the projections 30 with the removal apertures. In still other situations, the golf spike will be wedged into the golf shoe and an initial attempt at removal will damage the golf spike sufficiently to impede the effectiveness of the projections 30 . In any of these situations, the locking bolt 52 is loosened and the supplemental shank 42 is moved into the distal position. The locking bolt 52 then is retightened adjacent the proximal end 40 of the short leg 38 of the J-shaped cut-out 32 . This loosening, movement and tightening of the locking bolt 52 can be carried out easily by gripping the large knarled head 56 of the locking bolt 52 between a thumb and forefinger. In this distal position, the projections 48 at the distal end 46 of the supplemental shank 42 project distally beyond the projections 30 at the distal end 26 of the primary shank 22 . The golfer can urge the pointed projections 48 into the plastic material of the disc on the damaged or wedged golf spike. The golfer then applies torque to the grip 14 of the handle 12 for removing the damaged or wedged spike.
[0039] While the invention has been described with respect to a preferred embodiment, it is apparent that various changes can be made without departing from the scope of the invention as defined by the appended claims. For example, the projections 30 at the distal end of the primary shank 22 can take many other configurations depending upon the specific shapes of the removal apertures in a golf spike that represents a major portion of the local market share. Similarly, the shapes of the points 48 at the distal end 46 of the supplemental shank 42 can take many other shapes, including a symmetrical point or a plural point projection.
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The golf spike removal tool includes a primary shank with opposite proximal and distal ends. A handle is secured to the proximal end of the primary shank and projections extend from the distal end of the primary shank for engaging apertures in a golf spike. A supplemental shank is telescoped relative to the primary shank and can be releasably engaged in either a first position or a second position with respect to the primary shank. The supplemental shank includes an array of sharply pointed teeth at the distal end thereof. The teeth project distally beyond the primary shank when the supplemental shank is in the distal position.
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TECHNICAL FIELD
[0001] The present invention relates to a modified flavin adenine dinucleotide-dependent glucose dehydrogenase, DNA encoding an amino acid sequence thereof, a vector containing the DNA, a transformant transformed with the vector, and a method for producing the modified FADGDH by culturing the transformant. Furthermore, the present invention relates to various technologies using a modified flavin adenine dinucleotide.
BACKGROUND ART
[0002] In recent years, incidence of diabetes has been displaying an upward trend every year. In Japan alone, a combined number of diabetics and potential diabetics is estimated to be ten million or more. Also due to a very high interest in lifestyle-related diseases, opportunities to self-manage blood sugar levels have been increasing. In response to such recent trend, it is important to develop technologies for self-measuring and managing blood sugar levels. Although many blood sugar measuring technologies have been put to practical use, electrochemical sensing is useful from the standpoints such as scaling down the amount of sample to a minute quantity, shortening a measuring time, and reducing the size of a device.
[0003] Enzymes whose substrate is glucose that exist in blood are utilized in a technique for sensing in blood sugar measuring technologies. Examples of such enzyme include glucose oxidase (EC 1.1.3.4). Glucose oxidase is advantageous in that it has a high specificity for glucose and is highly stable against heat. In a blood sugar sensor using glucose oxidase, measurement is performed by transferring, to an electrode via mediator, electrons generated in a process of oxidizing glucose so as to be converted into D-glucono-δ-lactone. However, glucose oxidase easily transfers protons generated in the reaction to blood-dissolved oxygen, which affects a measured value and thus has been problematic.
[0004] In order to avoid such a problem, pyrroloquinoline quinone-dependent glucose dehydrogenase (EC 1.1.5.2 (former EC 1.1.99.17)) has been used as an enzyme for blood sugar sensors. Hereinafter, pyrroloquinoline quinone-dependent glucose dehydrogenase is also represented as PQQGDH as appropriate. PQQGDH is advantageous in that it is not affected by the dissolved oxygen. However, PQQGDH has a low substrate specificity and has an activity also toward sugars other than glucose, such as maltose and lactose, and thereby, has been problematic since accurate measurement of glucose is difficult.
[0005] Therefore, flavin adenine dinucleotide is gathering attention as a glucose dehydrogenase that is not affected by dissolved oxygen and that has superior substrate specificity. Hereinafter, flavin adenine dinucleotide is represented as FAD as appropriate. Glucose dehydrogenase is represented as GDH as appropriate. Flavin adenine dinucleotide-dependent glucose dehydrogenase is represented as FADGDH. FADGDH is described in Non-patent Literature 1 to 6, and has been known for a long time.
[0006] Patent Literature 1 discloses a gene sequence and an amino acid sequence of an FADGDH derived from Aspergillus terreus . Patent Literature 2 discloses an FADGDH derived from Aspergillus oryzae . Patent Literature 3 discloses a modified FADGDH having an improved thermal stability, resulting from modifying an FADGDH derived from Aspergillus oryzae . Patent Literature 4 discloses a modified FADGDH having improved thermal stability and action to xylose, resulting from modifying an FADGDH derived from Aspergillus oryzae and an FADGDH derived from Aspergillus terreus . Patent Literature 5 discloses a glucose sensor using an FADGDH derived from Aspergillus terreus.
[0007] On the other hand, Non-patent Literature 7 indicates that, as a caution for SMBG (Self Monitoring Blood Glucose) devices, measured values obtained from many devices deviate from an acceptable range defined by ISO15197 in an environmental temperature condition such as in a low temperature range and a high temperature range, and may become a cause of medical accidents if the measured values show an extremely low value or a high value.
CITATION LIST
Patent Literature
[0008] PTL 1: WO 2004/058958
[0009] PTL 2: Japanese Patent Application No. 2007-289148
[0010] PTL 3: Japanese Patent Application No. 2008-237210
[0011] PTL 4: WO 2008/059777
[0012] PTL 5: WO 2006/101239
Non-Patent Literature
[0013] NPL 1: BIOCHIM BIOPHYS ACTA. 1967 July 11; 139(2): 265-76
[0014] NPL 2: BIOCHIM BIOPHYS ACTA. 1967 July 11; 139(2): 277-93
[0015] NPL 3: BIOCHIM BIOPHYS ACTA. 146(2): 317-27
[0016] NPL 4: BIOCHIM BIOPHYS ACTA. 146(2): 328-35
[0017] NPL 5: J BIOL CHEM (1967) 242: 3665-3672
[0018] NPL 6: APPL BIOCHEM BIOTECHNOL (1996) 56: 301-310
[0019] NPL 7: J CLIN LAB INST REAG 32(6), 2009: 707-713
SUMMARY OF INVENTION
Technical Problem
[0020] An objective of the present invention is to provide an enzyme that is further advantageous in terms of practical aspects when compared to publicly known enzymes for blood sugar sensors, and that can be used in a blood sugar level measuring reagent.
[0021] The present inventors have conducted examination focusing on abnormalities and variations of blood glucose levels caused by changes in the temperature of environments in which the levels are measured, and found that the following problems exist.
[0022] With regard to enzyme reaction conditions in a developmental stage, studies are performed centering on a specific temperature (for example, 37° C.). In contrast, room temperature is used by diabetics as the temperature for actually performing measurements of glucose using a glucose sensor. If fluctuation occurs in the reactivity of an enzyme due to temperature change, fluctuation occurs in measured values.
[0023] Correction functions that anticipate such reactivity fluctuation due to temperature are incorporated in some glucose sensors, however, such functions are not perfect.
[0024] Some publicly known FADGDHs have an action to xylose. Xylose is a monosaccharide that is used in digestion-and-absorption tests for carbohydrates. Therefore, when a patient undergoing a xylose absorption test uses a blood sugar sensor, the FADGDH react not only to blood glucose but also to xylose, and cause a problem where a measured value indicates a value higher than the right glucose level.
[0025] A publicly known FADGDH disclosed in Patent Literature 2 or Patent Literature 3 has a low specific activity for an enzyme to be used in a clinical test reagent, and has a disadvantage where a highly concentrated enzyme needs to be added for a clinical test.
Solution to Problem
[0026] Based on the above described examination, the present inventors have studied the temperature dependency of the publicly known FADGDH disclosed in Patent Literature 2 or Patent Literature 3. As a result, the present inventors have revealed that, with the FADGDH disclosed in Patent Literature 3, an activity value obtained at 25° C. is 63% and an activity value obtained at 5° C. is 40% when an activity value obtained at 37° C. is defined as 100%. In other words, it has been revealed that, depending on an environmental temperature used when measuring a glucose level, measurement precision of the FADGDH deteriorates. More specifically, there is a 37% reduction in activity from the activity value obtained at 37° C. to the activity value obtained at 25° C. Such activity fluctuation is a factor that prevents accurate measurement of glucose level using such an enzyme. This is because, for example, in some glucose sensors, glucose level is estimated based on an amount of a dehydrogenation product obtained from catalysis by GDH within a certain period of time.
[0027] In the present invention, an activity value at 25° C. of a pre-modified FADGDH is divided by an activity value thereof at 37° C. to obtain a value, and this value is converted so as to be 1; and a “temperature dependency value” for each modified object is obtained by dividing, by the value of the pre-modified FADGDH, a value that is obtained by similarly measuring activity values and performing a similar calculation.
[0028] If the temperature dependency value is 1.1, a calculated difference between those at 37° C. and 25° C. is about 30%, and a difference between those at 25° C. and 30° C. is estimated to be reduced to about 12-13%. When this is considered as a difference between a maximum value and a minimum value of data fluctuation, the temperature dependency value being 1.1 is preferable since this difference settles within about plus or minus 6-7%.
[0029] Further, if the temperature dependency is 1.2, a difference between those at 37° C. and 25° C. is about 24%, and a difference between those at 25° C. and 30° C. is estimated to be reduced to about 10%. When this is considered as a difference between a maximum value and a minimum value of data fluctuation, the temperature dependency being 1.2 is preferable since this difference settles within about plus or minus 5%.
[0030] Improvement in precision and accuracy of a measurement can be expected if the fluctuation of reactivity due to environmental temperature can be reduced. In the present application, smoothening of this optimum temperature peak is described as an improvement in temperature dependency.
[0031] The present inventors have conducted thorough research, and discovered, by substituting a specific amino acid in a publicly known FADGDH with another amino acid, a modified FADGDH whose temperature dependency has improved from that of a wild-type pre-modified FADGDH; and the present inventors have completed the present invention by setting up a glucose measurement system using the modified FADGDH.
[0032] In addition, the present inventors have examined the action to xylose of the FADGDH disclosed in Patent Literature 1 (cf. Patent Literature 4), and discovered that the FADGDH's action to xylose is about 10% when its reactivity toward glucose is defined as 100%. In other words, it was revealed that, measuring glucose level using this FADGDH has a disadvantage where accuracy of a measured value becomes impaired.
[0033] The present inventors have conducted thorough research, and discovered, by substituting a specific amino acid in a publicly known FADGDH with another amino acid, a modified FADGDH whose temperature dependency is improved from that of the pre-modified FADGDH and whose action to xylose is reduced; and completed the present invention.
[0034] In addition, the present inventors have found that the modified FADGDH, which is obtained by substituting an amino acid at a specific position of FADGDH with another amino acid, has an improved specific activity; and completed the present invention. The present inventors have made further improvements based on such findings, and completed the present invention.
[0035] In the following, representative modes of the present invention are shown.
[0036] Item A1. A protein of the following (A1) or (A2):
[0037] (A1) a protein having an amino acid sequence that contains, in an amino acid sequence shown in SEQ ID NO: 2, any of the amino acid substitutions set forth by the following (a):
[0038] (a) S60C, S60D, S60L, S60N, S60V, S60G, S60T, N504G, N504S, G59Y, G59F, G59M, G59T, G59C, G59L, G59H, G59K, G59Q, G59W, G59N, G59P, G59A, G59S, G59D, F58E, F58Q, F58S, F58T, F58A, F58I, F58M, F58Y, F58H, F58L, G53R, G53S, G53F, G53L, G53W, G53Y, and G53Q;
[0039] (A2) a protein that satisfies the following (i) to (iii);
[0040] (i) one having an amino acid sequence that contains, in an amino acid sequence having at least 60% homology with the amino acid sequence shown in SEQ ID NO: 2, an amino acid set forth by the following (b),
[0041] (b) 60C, 60D, 60L, 60N, 60V, 60G, 60T, 504G, 504S, 59Y, 59F, 59M, 59T, 59C, 59L, 59H, 59K, 59Q, 59W, 59N, 59P, 59A, 59S, 59D, 58E, 58Q, 58S, 58T, 58A, 581, 58M, 58Y, 58H, 58L, 53R, 53S, 53F, 53L, 53W, 53Y, and 53Q,
[0042] (ii) one having a glucose dehydrogenase activity, and
[0043] (iii) one having a temperature dependency that is superior to that of a protein having the amino acid sequence shown in SEQ ID NO: 2.
[0044] Item A2. The protein of (A1) according to item A1, wherein the amino acid substitution is any of the substitutions selected from the group consisting of S60C, S60D, S60L, N504G, N504S, G59Y, G59F, G59M, G59T, G59C, G59L, G59H, G59K, G59Q, G59W, G59N, F58E, F58Q, F58S, and F58T.
[0045] Item A3. The protein of (A2) according to item A1, wherein the protein includes any of the amino acids selected from the group consisting of 60C, 60D, 60L, 504G, 504S, 59Y, 59F, 59M, 59T, 59C, 59L, 59H, 59K, 59Q, 59W, 59N, 58E, 58Q, 58S, and 58T.
[0046] Item B1. A modified FADGDH that contains, in an amino acid sequence of an FADGDH shown in SEQ ID NO: 1 or SEQ ID NO: 2, an amino acid substitution at position 58 or at a position equivalent thereto, and that has an improved temperature dependency when compared to pre-modification.
[0047] Item B2. The modified FADGDH according to item B1, wherein the amino acid substitution is any of the substitutions selected from the group consisting of F58A, F58E, F58H, F58I, F58L, F58M, F58Q, F58S, F58T, and F58Y, or the modified FADGDH contains an equivalent amino acid substitution at a position equivalent thereto.
[0048] Item B3. A modified FADGDH that contains, in an amino acid sequence of an FADGDH shown in SEQ ID NO: 1 or SEQ ID NO: 2, an amino acid substitution at position 58 or at a position equivalent thereto, and that has a reduced action to xylose when compared to pre-modification.
[0049] Item B4. The modified FADGDH according to item B3, wherein the amino acid substitution is any of the substitutions selected from the group consisting of F58A, F58E, F58H, F58I, F58L, F58M, F58Q, F58S, F58T, and F58Y, or the modified FADGDH contains an equivalent amino acid substitution at a position equivalent thereto.
[0050] Item B5. A modified FADGDH that contains, in an amino acid sequence of an FADGDH shown in SEQ ID NO: 1 or SEQ ID NO: 2, an amino acid substitution at position 58 or at a position equivalent thereto, and that has an improved temperature dependency and a reduced action to xylose when compared to pre-modification.
[0051] Item B6. The modified FADGDH according to item B5, wherein the amino acid substitution is any of the substitutions selected from the group consisting of F58A, F58E, F58H, F58I, F58L, F58M, F58Q, F58S, F58T, and F58Y, or the modified FADGDH contains an equivalent amino acid substitution at a position equivalent thereto.
[0052] Item C1. A modified FADGDH that contains, in an amino acid sequence of an FADGDH derived from the genus Aspergillus , an amino acid substitution at position 59 or at a position equivalent thereto, and that has an improved temperature dependency when compared to pre-modification.
[0053] Item C2. The modified FADGDH according to item C1, wherein the FADGDH is derived from Aspergillus oryzae.
[0054] Item C3. The modified FADGDH according to item C2, wherein the FADGDH derived from Aspergillus oryzae has an amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 2.
[0055] Item C4. The modified FADGDH according to any of items C1 to C3, wherein the amino acid substitution of the FADGDH derived from the genus Aspergillus is any of the substitutions selected from the group consisting of G59A, G59C, G59D, G59F, G59H, G59K, G59L, G59M, G59N, G59P, G59Q, G59S, G59T, G59W, and G59Y, or the modified FADGDH contains an equivalent amino acid substitution at a position equivalent thereto.
[0056] Item C5. The modified FADGDH according to item C4, wherein the amino acid sequence of the FADGDH derived from the genus Aspergillus contains an amino acid substitution at position 59 or at a position equivalent thereto, and the modified FADGDH has a reduced action to xylose when compared to pre-modification.
[0057] Item C6. The modified FADGDH according to item C5, wherein the amino acid substitution of the FADGDH derived from the genus Aspergillus is any of the substitutions selected from the group consisting of G59C, G59D, G59K, G59M, G59Q, G59S, and G59T, or the modified FADGDH contains an equivalent amino acid substitution at a position equivalent thereto.
[0058] Item C7. The modified FADGDH according to item C6, wherein the amino acid sequence of the FADGDH derived from the genus Aspergillus contains an amino acid substitution at position 59 or at a position equivalent thereto, and the modified FADGDH has an improved temperature dependency and a reduced action to xylose when compared to pre-modification.
[0059] Item D1. A protein set forth by any of the following (Da) to (Dc).
[0060] (Da) A protein that contains, in an amino acid sequence shown in SEQ ID NO: 1, a substitution of an amino acid at position 504 with another amino acid.
[0061] (Db) A protein that contains, in an amino acid sequence shown in SEQ ID NO: 2, a substitution of an amino acid at position 504 with another amino acid.
[0062] (Dc) A protein that contains, in an amino acid sequence that has a homology not lower than 60% with at least either SEQ ID NO: 1 or SEQ ID NO: 2 and that encodes a protein having a glucose dehydrogenase activity, a substitution of an amino acid at a position equivalent to position 504 of SEQ ID NO: 1 or to position 504 of SEQ ID NO: 2 with another amino acid.
[0063] Item D2. The protein according to item D1, wherein the protein has a glucose dehydrogenase activity and has an amino acid sequence in which one or more amino acids are additionally deleted, substituted, or added (inserted) at a position other than the position having the substitution of an amino acid.
[0064] Item D3. The protein according to item D1, wherein N at position 504 or an amino acid at a position equivalent thereto is substituted with G or S.
[0065] Item E1. A protein set forth by any of the following (Ea) to (Ec).
[0066] (Ea) A protein that contains, in an amino acid sequence shown in SEQ ID NO: 1, a substitution of an amino acid at either position 53 or position 60 with another amino acid.
[0067] (Eb) A protein that contains, in an amino acid sequence shown in SEQ ID NO: 2, a substitution of an amino acid at either position 53 or position 60 with another amino acid.
[0068] (Ec) A protein that contains, in an amino acid sequence that has a homology not lower than 60% with at least either SEQ ID NO: 1 or SEQ ID NO: 2 and that encodes a protein having a glucose dehydrogenase activity, a substitution of an amino acid at a position equivalent to either position 53 or position 60 in SEQ ID NO: 1, or to either position 53 or position 60 in SEQ ID NO: 2 with another amino acid.
[0069] Item E2. The protein according to item El, wherein the protein has a glucose dehydrogenase activity and has an amino acid sequence in which one or more amino acids are additionally deleted, substituted, or added (inserted) at a position other than the position having the substitution of an amino acid.
[0070] Item E3. The protein according to item El, wherein: G at position 53 or an amino acid at a position equivalent thereto is substituted with any of the amino acids selected from the group consisting of F, L, Q, R, S, W, and Y; or S at position 60 or an amino acid at a position equivalent thereto is substituted with any of the amino acids selected from the group consisting of C, D, G, L, N, T, and V.
[0071] Item F1. A polynucleotide encoding an amino acid sequence of the protein according to any of items A1 to A3, B1 to B6, C1 to C7, D1 to D3, and E1 to E3.
[0072] Item F2. A vector that contains the gene according to item F1.
[0073] Item F3. A transformant transformed using the vector according to item F2.
[0074] Item F4. A method for producing a protein having a glucose dehydrogenase activity, the method comprising culturing the transformant according to item F3, and collecting the protein having a glucose dehydrogenase activity.
[0075] Item F5. A glucose assay kit comprising the protein according to any of items A1 to A3, B1 to B6, C1 to C12, D1 to D3, and E1 to E3.
[0076] Item F6. A glucose sensor comprising the protein according to any of items A1 to A3, B1 to B6, C1 to 12, D1 to D3, and E1 to E3.
[0077] Item F7. A method for measuring glucose level in a sample, the method comprising causing the protein according to any of items A1 to A3, B1 to B6, C1 to 12, D1 to D3, and E1 to E3, to act on a sample that contains glucose.
Advantageous Effects of Invention
[0078] A protein of the present invention is a glucose dehydrogenase that has superior temperature dependency. More specifically, the protein of the present invention is a glucose dehydrogenase whose activity is less influenced by a change in temperature of a usage environment. Therefore, when the protein of the present invention is used, measurement of glucose level in a sample can be performed more accurately without being influenced by a change in temperature of a usage environment. Since enzyme activity of the protein of the present invention is less influenced by a change in temperature of a usage environment, the protein allows accurate measurement of glucose level in a sample even, for example, at a temperature lower or higher than an ordinary room temperature. Thus, the protein of the present invention is useful as an enzyme to be used in a clinical test reagent for measuring blood glucose level.
[0079] The protein of the present invention not only has a reduced temperature dependency but also has a reduced action to xylose. Therefore, the protein of the present invention is superior for measurement of blood glucose level also from the standpoint of substrate specificity.
[0080] A method of the present invention allows efficient production of the new protein that has the superior property as described above.
[0081] The present invention allows creation of a new FADGDH that has a high specific activity and that is useful as an enzyme to be used in a clinical test reagent, and allows industrial production of the FADGDH in large quantity.
BRIEF DESCRIPTION OF DRAWINGS
[0082] FIG. 1 shows a change in activity of an FADGDH that has an amino acid sequence shown in SEQ ID NO: 2, which is caused by a change in temperature.
[0083] FIG. 2 is a comparison of an amino acid sequence of a wild-type FADGDH derived from Aspergillus oryzae (SEQ ID NO: 1), and an amino acid sequence of a wild-type FADGDH derived from Aspergillus terreus (SEQ ID NO: 3).
DESCRIPTION OF EMBODIMENTS
[0084] Details of the present invention are described in the following.
[0085] The present invention provides a protein of the following (A1) or (A2) (hereinafter, respectively represented as protein (A1) and protein (A2); and protein (A1) and protein (A2) are both represented as the protein of the present invention):
[0086] (A1) a protein having an amino acid sequence that contains, in an amino acid sequence shown in SEQ ID NO: 2, any of the amino acid substitutions set forth by the following (a):
[0087] (a) S60C, S60D, S60L, S60N, S60V, S60G, S60T, N504G, N504S, G59Y, G59F, G59M, G59T, G59C, G59L, G59H, G59K, G59Q, G59W, G59N, G59P, G59A, G59S, G59D, F58E, F58Q, F58S, F58T, F58A, F58I, F58M, F58Y, F58H, F58L, G53R, G53S, G53F, G53L, G53W, G53Y, and G53Q,
[0088] (A2) a protein that satisfies the following (i) to (iii);
[0089] (i) one having an amino acid sequence that contains, in an amino acid sequence having at least 60% homology with the amino acid sequence shown in SEQ ID NO: 2, an amino acid set forth by the following (b),
[0090] (b) 60C, 60D, 60L, 60N, 60V, 60G, 60T, 504G, 504S, 59Y, 59F, 59M, 59T, 59C, 59L, 59H, 59K, 59Q, 59W, 59N, 59P, 59A, 59S, 59D, 58E, 58Q, 58S, 58T, 58A, 581, 58M, 58Y, 58H, 58L, 53R, 53S, 53F, 53L, 53W, 53Y, and 53Q,
[0091] (ii) one having a glucose dehydrogenase activity, and
[0092] (iii) one having an improved temperature dependency when compared to a protein that has the amino acid sequence of SEQ ID NO: 2.
[0093] When the amino acid sequence shown in SEQ ID NO: 2 is used as a reference, protein (A1) has a specific amino acid substitution at a specific position in the amino acid sequence shown in SEQ ID NO: 2. The specific amino acid substitution at the specific position is any of the substitutions shown in the following.
[0094] (a): S60C, S60D, S60L, S60N, S60V, S60G, S60T, N504G, N504S, G59Y, G59F, G59M, G59T, G59C, G59L, G59H, G59K, G59Q, G59W, G59N, G59P, G59A, G59S, G59D, F58E, F58Q, F58S, F58T, F58A, F58I, F58M, F58Y, F58H, F58L, G53R, G53S, G53F, G53L, G53W, G53Y, and G53Q.
[0095] As shown in later described examples, protein (A1) has an improved temperature dependency when compared to a temperature dependency of an FADGDH that has an amino acid sequence shown in SEQ ID NO: 2. The amino acid at the specific position is an amino acid at position 60, 504, 59, 58, or 53 in the amino acid sequence shown in SEQ ID NO: 2. Protein (A1) may have substitutions of amino acids at two or more of the specific positions as long as the temperature dependency of protein (A1) is improved.
[0096] In the context of the present invention, an amino acid included in an amino acid sequence is represented by a single alphabet or three alphabets. For example, glycine is represented as Gly or G. A position of an amino acid in an amino acid sequence is specified using a number. For example, a case where serine located at the 80-th is substituted with cysteine, is represented as “S80C.” In addition, “80C” indicates that an amino acid at position 80 (or 80-th) is Cys(C) regardless of whether or not there is a mutation. For the representation of amino acids in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, methionine is given the number 1.
[0097] In the context of the present invention, SEQ ID NO: 1 shows an amino acid sequence of a wild-type FADGDH derived from Aspergillus oryzae . SEQ ID NO: 2 shows an amino acid sequence obtained by substituting glycine at position 163 with arginine and substituting valine at position 551 with cysteine in the amino acid sequence of SEQ ID NO: 1. A protein comprising the amino acid sequence shown in SEQ ID NO: 2 has a glucose dehydrogenase activity. Hereinafter, the protein comprising the amino acid sequence shown in SEQ ID NO: 2 is represented as an FADGDH of SEQ ID NO: 2 as appropriate. The amino acid sequences of SEQ ID NOS: 1 and 2 are disclosed in, for example, Patent Literature 2 or Patent Literature 3. Specific activities of an FADGDH having the amino acid sequence of SEQ ID NO: 1 and the FADGDH having the amino acid sequence of SEQ ID NO: 2 are almost equal and are both about 600U/A280.
[0098] Protein (A1) has the above described specific amino acid substitution in the amino acid sequence shown in SEQ ID NO: 2, and thereby has a property of an improved temperature dependency while retaining the glucose dehydrogenase activity.
[0099] Temperature Dependency
[0100] In the context of the present invention, a temperature dependency refers to a fluctuation characteristic of a protein's glucose dehydrogenase activity in association with a change in temperature of an environment in which the protein exists. An improvement in the temperature dependency refers to having a small change in enzyme activity associated with a change in the environmental temperature, and maintaining a more constant enzyme activity in a broad temperature range condition.
[0101] Whether a temperature dependency has improved is determined based on a temperature dependency of the FADGDH comprising the amino acid sequence shown in SEQ ID NO: 2, and, more specifically, is determined in accordance with the following (1) to (5).
[0102] (1) An activity value (U/ml) at 37° C. after 24 hours of processing is measured and is represented as A.
[0103] (2) An activity value (U/ml) at 25° C. after 24 hours of processing is measured and is represented as B.
[0104] (3) When A is defined as 100%, a relative value (%) of B is calculated and is represented as C.
[0105] (4) When a value of C for the FADGDH of SEQ ID NO: 2 is defined as 1, a relative value of C for a modified protein such as protein (A1) or the like is obtained, and is represented as D.
[0106] (5) As shown in the following Example B1, when the enzyme activity of the FADGDH of SEQ ID NO: 2 at 37° C. is defined as 100%, the enzyme activity of that at 25° C. is 63%. Therefore, when the value of C for a modified protein is larger than 63%, the value of D becomes larger than 1. Thus, as the value of D of a modified FADGDH departs from 1 and approaches 1.59, the temperature dependency becomes low and improved.
[0107] Since the protein of the present invention has an improved temperature dependency, the protein has a value of D that is at least larger than 1. The value of D is preferably not smaller than 1.05, more preferably not smaller than 1.1, further preferably not smaller than 1.15, still further preferably not smaller than 1.2, even further preferably not smaller than 1.25, and yet further preferably not smaller than 1.3.
[0108] The amino acid substitution included in the amino acid sequence of protein (A1) may be any of the substitutions listed in (a) above. From the standpoint of improving temperature dependency, the amino acid substitution is preferably any of S60C, S60D, S60L, S60N, S60V, N504G, N504S, G59Y, G59F, G59M, G59T, G59C, G59L, G59H, G59K, G59Q, G59W, G59N, G59P, G59A, G59S, F58E, F58Q, F58S, F58T, F58A, F58I, F58M, F58Y, G53R, G53S, G53F, G53L, G53W, G53Y, and G53Q. A modified FADGDH that has any of these amino acid substitutions has a value of D not smaller than 1.05.
[0109] More preferably, the amino acid substitution is any of S60C, S60D, S60L, N504G, N504S, G59Y, G59F, G59M, G59T, G59C, G59L, G59H, G59K, G59Q, G59W, G59N, F58E, F58Q, F58S, F58T, G53R, G53S, G53F, G53L, G53W, and G53Y. A modified FADGDH that has any of these amino acid substitutions has a value of D not smaller than 1.1.
[0110] Further preferably, the amino acid substitution is any of S60C, N504G, G59Y, G59F, G59M, G59T, G59C, G59L, F58E, and G53R. A modified FADGDH that has any of these amino acid substitutions has a value of D not smaller than 1.15.
[0111] Still further preferably, the amino acid substitution is any of S60C, N504G, G59Y, G59F, G59M, and G59T. A modified FADGDH that has any of these amino acid substitutions has a value of D not smaller than 1.2. Even further preferably, the amino acid substitution is either S60C or N504G. A modified FADGDH that has either of these amino acid substitutions has a value of D not smaller than 1.25. The most preferable amino acid substitution is S60C that provides a value of D not smaller than 1.3.
[0112] On the other hand, in addition to the improvement in temperature dependency, from a standpoint of having a reduced action to xylose (i.e., an improved substrate specificity), a preferable amino acid substitution is any of the substitutions selected from the group consisting of S60C, S60D, S60N, S60G, S60T, N504G, G59M, G59T, G59C, G59K, G59Q, G59W, G59D, F58E, F58Q, F58S, F58T, F58A, F58I, F58M, F58Y, F58H, F58L, G53R, G53S, G53F, G53L, G53W, G53Y, and G53Q. With regard to these amino acid substitutions, as long as the action to xylose is reduced and the temperature dependency is improved, two or more amino acid substitutions at different position may be included.
[0113] From a standpoint of further improving the temperature dependency and further reducing the action to xylose, a more preferable amino acid substitution is any of the substitutions selected from the group consisting of S60C, S60D, N504G, G59Y, G59M, G59T, G59C, G59K, G59Q, G59W, F58E, F58Q, F58S, F58T, G53R, G53S, G53F, G53L, G53W, and G53Y. Two or more of these amino acid substitutions may exist as long as the amino acids that are to be substituted are located at different positions.
[0114] Protein (A1) may have an additional mutation (substitution, addition, deletion, insertion of an amino acid) in the amino acid sequence as long as protein (A1) has a glucose dehydrogenase activity and has an improved temperature dependency. For example, protein (A1) may have amino acid substitutions at two or more different positions selected from the above described (a). Furthermore, an amino acid sequence obtained by substituting arginine at position 163 with glycine and substituting cysteine at position 551 with valine in the amino acid sequence of SEQ ID NO: 2, is the amino acid sequence (SEQ ID NO: 1) of the wild-type FADGDH. Therefore, in addition to the above specified amino acid substitutions, protein (A1) may have a substitution of the 163-th amino acid with glycine and a substitution of the 551-th amino acid with valine.
[0115] Protein (A2) satisfies the following requirements of (i) to (iii):
[0116] (i) one having an amino acid sequence that contains, in an amino acid sequence having at least 60% homology with the amino acid sequence shown in SEQ ID NO: 2, any of the amino acid set forth by the following (b),
[0117] (b) 60C, 60D, 60L, 60N, 60V, 60G, 60T, 504G, 504S, 59Y, 59F, 59M, 59T, 59C, 59L, 59H, 59K, 59Q, 59W, 59N, 59P, 59A, 59S, 59D, 58E, 58Q, 58S, 58T, 58A, 581, 58M, 58Y, 58H, 58L, 53R, 53S, 53F, 53L, 53W, 53Y, and 53Q,
[0118] (ii) one having a glucose dehydrogenase activity, and
[0119] (iii) one having an improved temperature dependency when compared to the protein having the amino acid sequence of SEQ ID NO: 2.
[0120] Thus, protein (A2) has an amino acid sequence that has an amino acid homology of at least 60% with the amino acid sequence shown in SEQ ID NO: 2, and includes at least one amino acid set forth by the above described (b). Furthermore, protein (A2) retains a glucose dehydrogenase activity and an improved temperature dependency when compared to the FADGDH of SEQ ID NO: 2.
[0121] The amino acid sequence that has a homology not lower than 60% with the amino acid sequence of SEQ ID NO: 2 and that encodes a protein having a glucose dehydrogenase activity include, for example, an amino acid sequence of a wild-type FADGDH derived from Aspergillus terreus shown in SEQ ID NO: 3. That amino acid sequence is disclosed in Patent Literature 5.
[0122] In the context of the present invention, a homology of amino acid sequences refers to a value obtained from a comparison using GENETYX software. For example, when a comparative analysis is performed on the amino acid sequence of the wild-type FADGDH derived from Aspergillus oryzae (SEQ ID NO: 1) and the amino acid sequence of the wild-type FADGDH derived from Aspergillus terreus (SEQ ID NO: 3) using the GENETYX software, the homology between the two is 63.5% (cf. FIG. 2 ). In addition, the homology between the amino acid sequence shown in SEQ ID NO: 2 and the amino acid sequence shown in SEQ ID NO: 3 is 63.4%.
[0123] The protein that has a glucose dehydrogenase activity and an improved temperature dependency, and that has an amino acid having a 60% homology with the amino acid sequence of SEQ ID NO: 2, can be produced by, for example, creating an alignment between SEQ ID NO: 3, and SEQ ID NO: 1 or SEQ ID NO: 2, and adding a mutation to a domain other than a preserved domain.
[0124] Domains that are estimated not to influence the enzyme activity and temperature dependency even when a mutation is added to the amino acid sequence, include domains located on a protein surface indicated from an X-ray crystal structure of the protein. Examples of those domains include positions 1 to 40, 111 to 190, 213 to 310, 340 to 397, 420 to 435, 455 to 492, 514 to 538, and 552 to 572.
[0125] The amino acid sequence of protein (A2) is not particularly limited as long as it satisfies the requirements of the above described (i) to (iii); however, the homology between the amino acid sequence of protein (A2) and the amino acid sequence shown in SEQ ID NO: 2 is preferably not smaller than 70%, more preferably not smaller than 80%, further preferably not smaller than 90%, and particularly preferably not smaller than 95%. It should be noted that an amino acid homology in the context of the present invention refers to an amino acid identity.
[0126] As a result of having any of the specific amino acids listed in the above described (b), protein (A2) has a temperature dependency that is superior to that of the FADGDH of SEQ ID NO: 2. Among the specific amino acids listed in the above described (b), a preferable amino acid is any of the amino acids selected from the group consisting of 60C, 60D, 60L, 60N, 60V, 504G, 504S, 59Y, 59F, 59M, 59T, 59C, 59L, 59H, 59K, 59Q, 59W, 59N, 59P, 59A, 59S, 58E, 58Q, 58S, 58T, 58A, 581, 58M, 58Y, 53R, 53S, 53F, 53L, 53W, 53Y, and 53Q.
[0127] The specific amino acid is more preferably any of the amino acids selected from the group consisting of 60C, 60D, 60L, 504G, 504S, 59Y, 59F, 59M, 59T, 59C, 59L, 59H, 59K, 59Q, 59W, 59N, 58E, 58Q, 58S, 58T, 53R, 53S, 53F, 53L, 53W, and 53Y.
[0128] The specific amino acid is further preferably any of the amino acids selected from the group consisting of 60C, 504G, 59Y, 59F, 59M, 59T, 59C, 59L, 58E, and 53R.
[0129] The specific amino acid is still further preferably any of the amino acids selected from the group consisting of 60C, 504G, 59Y, 59F, 59M, and 59T, even further preferably is any of the amino acids selected from the group consisting of 60C and 504G, and the most preferable amino acid is 60C.
[0130] As long as protein (A2) has an improved temperature dependency, a plurality of the specific amino acids exemplified above may exist in different positions of the amino acid sequence.
[0131] In addition to the improvement in temperature dependency, from a standpoint of having a reduced action to xylose (i.e., an improved substrate specificity), a preferable amino acid is any of the amino acids selected from the group consisting of 60C, 60D, S6ON, 60G, 60T, 504G, 59M, 59T, 59C, 59K, 59Q, 59W, 59D, 58E, 58Q, 58S, 58T, 58A, 581, 58M, 58Y, 58H, 58L, 53R, 53S, 53F, 53L, 53W, 53Y, and 53Q. Two or more of these amino acids may exist as long as the amino acids are located at different positions.
[0132] From a standpoint of further improving the temperature dependency and further reducing the action to xylose, a more preferable amino acid substitution is any of the amino acid substitutions selected from the group consisting of 60C, 60D, 504G, 59Y, 59M, 59T, 59C, 59K, 59Q, 59W, 58E, 58Q, 58S, 58T, 53R, 53S, 53F, 53L, 53W, and 53Y. Two or more of these amino acid substitutions may exist as long as the amino acids that are to be substituted are located at different positions.
[0133] In the present invention, an action to xylose is represented as a relative ratio % (taking glucose as 100%) of a reaction rate obtained when xylose is used as a substrate, to a reaction rate obtained when glucose is used as a substrate. A value of an action to xylose for the FADGDH comprising the amino acid sequence shown in SEQ ID NO: 2 is defined as 1, and a relative ratio % of each modified enzyme is calculated. Therefore, it is determined that the action to xylose is reduced when this value is small.
[0134] The modified FADGDH of the present invention preferably has a value of D not smaller than 1.05, more preferably has a value of D not smaller than 1.1, further preferably has a value of D not smaller than 1.15, and even further preferably has a value of D not smaller than 1.2.
[0135] The modified FADGDH of the present invention preferably is a modified FADGDH whose ratio of action to xylose is reduced to not higher than 0.9 when compared to pre-modification; and, further preferably, is reduced to not higher than 0.8 when compared to pre-modification.
[0136] With regard to the method for measuring the temperature dependency and the action to xylose, a later described method for measuring FADGDH activity is used.
[0137] In another embodiment, the present invention provides a protein set forth in the following.
[0138] B: A modified FADGDH that contains, in the amino acid sequence of the FADGDH shown in SEQ ID NO: 1 or SEQ ID NO: 2, an amino acid substitution at position 58 or at a position equivalent thereto, and that has an improved temperature dependency when compared to pre-modification.
[0139] In addition, one embodiment of the present invention is a modified FADGDH that contains, in the above described protein, any of the amino acid substitutions selected from the group consisting of F58A, F58E, F58H, F58I, F58L, F58M, F58Q, F58S, F58T, and F58Y, or contains an equivalent amino acid substitution at a position equivalent thereto, and that has an improved temperature dependency.
[0140] In another embodiment, the present invention provides a protein set forth in the following.
[0141] C: A modified FADGDH that contains, in the amino acid sequence of the FADGDH shown in SEQ ID NO: 1 or SEQ ID NO: 2, an amino acid substitution at position 59 or at a position equivalent thereto, and that has an improved temperature dependency when compared to pre-modification.
[0142] In addition, one embodiment of the present invention is a modified FADGDH that contains, in the above described protein, any of the amino acid substitutions selected from the group consisting of G59A, G59C, G59D, G59F, G59H, G59K, G59L, G59M, G59N, G59P, G59Q, G59S, G59T, G59W, and G59Y, or contains an equivalent amino acid substitution at a position equivalent thereto, and that has an improved temperature dependency.
[0143] In another embodiment, the present invention provides a protein set forth by the following.
[0144] D: A protein represented by the following (a) to (c):
[0145] (a) a protein that contains, in an amino acid sequence shown in SEQ ID NO: 1, a substitution of an amino acid at position 504 with another amino acid;
[0146] (b) a protein that contains, in an amino acid sequence shown in SEQ ID NO: 2, a substitution of an amino acid at position 504 with another amino acid; and
[0147] (c) a protein that contains, in an amino acid sequence that has a homology not lower than 60% with at least either SEQ ID NO: 1 or SEQ ID NO: 2 and that encodes a protein having a glucose dehydrogenase activity, a substitution of an amino acid at a position equivalent to position 504 of SEQ ID NO: 1 or to position 504 of SEQ ID NO: 2 with another amino acid.
[0148] In addition, one embodiment of the present invention is a protein in which, in the above described protein, N at position 504 or an amino acid at a position equivalent thereto is substituted with G or S.
[0149] In another embodiment, the present invention provides a protein set forth in the following.
[0150] E: A protein represented by any of the following (a) to (c):
[0151] (a) a protein that contains, in an amino acid sequence shown in SEQ ID NO: 1, a substitution of an amino acid at either position 53 or position 60 with another amino acid;
[0152] (b) a protein that contains, in an amino acid sequence shown in SEQ ID NO: 2, a substitution of an amino acid at either position 53 or position 60 with another amino acid; and
[0153] (c) a protein that contains, in an amino acid sequence that has a homology not lower than 60% with at least either SEQ ID NO: 1 or SEQ ID NO: 2 and that encodes a protein having a glucose dehydrogenase activity, a substitution of an amino acid at a position equivalent to either position 53 or position 60 in SEQ ID NO: 1, or to either position 53 or position 60 in SEQ ID NO: 2 with another amino acid.
[0154] In addition, one embodiment of the present invention is a protein in which, in the above described protein, G at position 53 or an amino acid at a position equivalent thereto is substituted with any of the amino acids selected from the group consisting of F, L, Q, R, S, W, and Y, or S at position 60 or an amino acid at a position equivalent thereto is substituted with any of the amino acids selected from the group consisting of C, D, G, L, N, T, and V.
[0155] In the context of the present invention, a position in a certain amino acid sequence is determined to be a position equivalent to position 79 of SEQ ID NO: 1 when, for example, the position corresponds to position 79 of SEQ ID NO: 1 after comparing primary structures of sequences (e.g., alignment) using the GENETYX software. In addition, knowledge regarding three-dimensional conformations may be used as a reference if necessary.
[0156] For example, based on comparison data of an alignment between the amino acid sequence of the wild-type FADGDH derived from Aspergillus oryzae (SEQ ID NO: 1) and the amino acid sequence of the wild-type FADGDH derived from Aspergillus terreus (SEQ ID NO: 3), a position equivalent to position 55 in the amino acid sequence shown in SEQ ID NO: 2 corresponds to G at position 51 in the amino acid sequence of the wild-type FADGDH derived from Aspergillus terreus . Similarly, a position equivalent to position 60 in the amino acid sequence shown in SEQ ID NO: 2 corresponds to S at position 56 of the wild-type FADGDH derived from Aspergillus terreus . A position equivalent to position 446 in the amino acid sequence shown in SEQ ID NO: 2 corresponds to L at position 442 in the amino acid sequence of the wild-type FADGDH derived from Aspergillus terreus. An amino acid at position 412 of SEQ ID NO: 1 or SEQ ID NO: 2 corresponds to an amino acid at position 408 of SEQ ID NO: 3 (cf. FIG. 2 ).
[0157] As the GENETYX software, for example, GENETYX WIN Version 6.1 sold by GENETYX Corporation may be used.
[0158] The above described protein also includes a protein that has a glucose dehydrogenase activity and that has an amino acid sequence in which one or more amino acids are additionally deleted, substituted, or added (inserted) at a position other than the position having the substitution of an amino acid.
[0159] Modified FADGDH having Reduced Action to Xylose The present invention also provides a modified FADGDH that has a reduced action to xylose when compared to pre-modification.
[0160] In addition, one embodiment of the present invention is a modified FADGDH that contains, in the amino acid sequence of the FADGDH shown in SEQ ID NO: 1 or SEQ ID NO: 2, an amino acid substitution at position 58 or at a position equivalent thereto, and that has a reduced action to xylose when compared to pre-modification.
[0161] Furthermore, one embodiment of the present invention is a modified FADGDH that contains, in the amino acid sequence of the FADGDH shown in SEQ ID NO: 1 or SEQ ID NO: 2, an amino acid substitution at position 59 or at a position equivalent thereto, and that has a reduced action to xylose when compared to pre-modification.
[0162] In addition, one preferable embodiment of the present invention is a modified FADGDH that contains, in the above described protein, any of the amino acid substitutions selected from the group consisting of F58A, F58E, F58H, F58I, F58L, F58M, F58Q, F58S, F58T, and F58Y, or contains an equivalent amino acid substitution at a position equivalent thereto.
[0163] Furthermore, one preferable embodiment of the present invention is a modified FADGDH that contains, in the above described protein, any of the amino acid substitutions selected from the group consisting of G59C, G59D, G59K, G59M, G59Q, G59S, and G59T, or contains an equivalent amino acid substitution at a position equivalent thereto.
[0164] A protein that contains, in the above described protein, a substitution of N at position 504 or an amino acid at a position equivalent thereto with G, has a reduced action to xylose when compared to pre-modification.
[0165] A protein that contains, in the above described protein, a substitution of G at position 53 or an amino acid at a position equivalent thereto with any of the amino acids selected from the group consisting of F, L, Q, R, S, W, and Y, or a substitution of S at position 60 or an amino acid at a position equivalent thereto with any of C, D, G, and N, has a reduced action to xylose when compared to pre-modification.
[0166] Modified FADGDH Having Improved Temperature Dependency and Reduced Action to Xylose
[0167] A protein of the present invention is a modified FADGDH that has an improved temperature dependency and a reduced action to xylose when compared to pre-modification.
[0168] In addition, one embodiment of the present invention is a modified FADGDH that contains, in the amino acid sequence of the FAD dependent glucose dehydrogenase (FADGDH) shown in SEQ ID NO: 1 or SEQ ID NO: 2, an amino acid substitution at position 58 or at a position equivalent thereto, and that has an improved temperature dependency and a reduced action to xylose when compared to pre-modification.
[0169] Furthermore, one embodiment of the present invention is a modified FADGDH that contains, in the amino acid sequence of the FADGDH shown in SEQ ID NO: 1 or SEQ ID NO: 2, an amino acid substitution at position 59 or a position equivalent thereto, and that has an improved temperature dependency and a reduced action to xylose when compared to pre-modification.
[0170] Still further, one embodiment of the present invention is a modified FADGDH that contains, in the protein having the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 2, any of the amino acid substitutions selected from the group consisting of F58A, F58E, F58H, F58I, F58L, F58M, F58Q, F58S, F58T, and F58Y, or contains an equivalent amino acid substitution at a position equivalent thereto.
[0171] Even further, one embodiment of the present invention is a modified FADGDH that contains, in the protein having the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 2, any of the amino acids substitution selected from the group consisting of G59C, G59D, G59K, G59M, G59Q, G59S, and G59T, or contains an equivalent amino acid substitution at a position equivalent thereto.
[0172] A protein that contains, in the protein having the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 2, a substitution of N at position 504 or an amino acid at a position equivalent thereto with G, has an improved temperature dependency and a reduced action to xylose when compared to pre-modification.
[0173] A protein that contains, in the protein having the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 2, a substitution of G at position 53 or an amino acid at a position equivalent thereto with any of the amino acids selected from the group consisting of F, L, Q, R, S, W, and Y, or a substitution of S at position 60 or an amino acid at a position equivalent thereto with any of the amino acids selected from the group consisting of C, D, G, and N, has an improved temperature dependency and a reduced action to xylose when compared to pre-modification.
[0174] The protein of the present embodiment may have amino acid substitutions at two or more positions selected from the group consisting of position 53 and position 60, as long as the protein has a glucose dehydrogenase activity and an improved temperature dependency and/or a reduced action to xylose when compared to pre-modification.
[0175] The protein of the present embodiment may have an amino acid substitution at one or more positions selected from the group consisting of position 53 and position 60, and may have an amino acid mutation at one or more positions (e.g., at several positions) other than those positions, as long as the protein has a glucose dehydrogenase activity, and has an improved temperature dependency and/or a reduced action to xylose when compared to pre-modification.
[0176] It should be noted that the above described positions that are converted may be an equivalent position in an amino acid sequence of a protein having an activity of an FADGDH derived from an origin (e.g., Aspergillus terreus ) other than that (SEQ ID NO: 1) derived from Aspergillus oryzae , or that (SEQ ID NO: 2) obtained through a modification thereof. The equivalent position can be determined based on knowledge regarding a primary structure (e.g., alignment) or a three-dimensional conformation of the amino acid sequence. The alignment can be compared using GENETYX WIN (sold by GENETYX Corporation).
[0177] A gene of the present invention may include those obtained by changing its codon usage for the purpose of, for example, improving expression of GDH. Specifically, when substituting alanine at position 410 in SEQ ID NOS: 1 and 2 with valine, GCC located at 1228-th to 1230-th in a base sequence shown in SEQ ID NOS: 4 and 5 may be modified to be any of GTG, GTT, GTC, and GTA. When substituting phenylalanine at position 408 in SEQ ID NO: 3 with valine, TTT located at 1222-th to 1224-th in a base sequence shown in SEQ ID NO: 6 may be modified to be any of GTG, GTT, GTC, or GTA.
Method for Producing Protein of Present Invention
[0178] The protein of the present invention can be prepared using various publicly known means. Provided in the following is an example of a method for producing a modified FADGDH obtained by modifying the wild-type FADGDH derived from Aspergillus oryzae shown in SEQ ID NO: 1. Although there is no particular limitation in the production method, the production can be conducted with the steps set forth in the following.
[0179] As a technique for modifying the amino acid sequence forming the FAD dependent glucose dehydrogenase, a method commonly used for modifying genetic information can be employed. More specifically, DNA having genetic information of a modified protein is created, by converting a specific base or inserting or deleting a specific base of DNA having genetic information of a protein. Specific methods for converting base sequences in DNA include, for example, usage of a commercially available kit (Transformer Mutagenesis Kit: product of Clontech Laboratories, Inc., ExoIII/Mung Bean Deletion Kit: product of Stratagene Corp., QuickChange Site Directed Mutagenesis Kit: product of Stratagene Corp., and the like), and utilization of polymerase chain reaction (PCR).
[0180] DNA having the genetic information of the modified. FAD dependent glucose dehydrogenase, which has been created, is ligated with a plasmid and introduced into a host microorganism to obtain a transformant that produces the modified FADGDH. As the plasmid used in such a case, for example, Escherichia coli JM109, Escherichia coli DH5 α, Escherichia coli W3110, Escherichia coli C600, and the like can be used. For example, as a method for introducing a recombinant vector to a host microorganism when the host microorganism is a microorganism that belongs to Escherichia coli, a method of performing the introduction of recombinant DNA in presence of calcium ion can be employed. Furthermore, an electroporation method can also be used. In addition, a commercially available competent cell (e.g., Competent high JM109: product of Toyobo Co., Ltd.) can be used.
[0181] It should be noted that embodiments of the present invention also include a gene (polynucleotide) that encodes the modified FADGDH obtained by these processes, a vector containing the gene, and a transformant transformed with the vector.
[0182] Although a gene that becomes a basis of the modification for the modified FADGDH of the present invention is not particularly limited, the FADGDH derived from the genus Aspergillus is preferably used. Further preferably, the FADGDH derived from Aspergillus oryzae or Aspergillus terreus is used.
[0183] Examples of the FADGDH derived from Aspergillus oryzae include the protein shown in SEQ ID NO: 1 or SEQ ID NO: 2. Examples of the FADGDH derived from Aspergillus terreus include the protein shown in SEQ ID NO: 3.
[0184] One embodiment of the present invention is a gene (polynucleotide) that encodes any of the proteins described above.
[0185] With regard to a gene that encodes a pre-modified protein, a base sequence shown in SEQ ID NO: 4 is an example of a gene encoding the above described protein shown in SEQ ID NO: 1. In addition, a base sequence shown in SEQ ID NO: 5 is an example of a gene encoding the above described protein shown in SEQ ID NO: 2. Furthermore, a base sequence shown in SEQ ID NO: 6 is an example of a gene encoding the above described protein (FADGDH derived from Aspergillus terreus ) shown in SEQ ID NO: 3.
[0186] For example, with regard to the gene (polynucleotide) of the present invention, a part that encodes an amino acid at position 58 or an amino acid at a position equivalent thereto in a sequence of a gene encoding a pre-modified protein described above, is substituted so as to encode another amino acid.
[0187] With regard to the gene (polynucleotide) of the present invention, a part that encodes an amino acid at position 59, position 82, or position 505, or an amino acid at a position equivalent thereto in a sequence of a gene encoding a pre-modified protein described above, is substituted so as to encode another amino acid.
[0188] With regard to the gene (polynucleotide) of the present invention, a part that encodes an amino acid at position 504 or an amino acid at a position equivalent thereto in a sequence of a gene encoding a pre-modified protein described above, is substituted so as to encode another amino acid.
[0189] With regard to the gene (polynucleotide) of present invention, a part that encodes an amino acid at either position 53 or position 60, or an amino acid at a position equivalent thereto in a sequence of a gene encoding a pre-modified protein described above, is substituted so as to encode another amino acid.
[0190] In another embodiment, the gene encoding the modified FADGDH of the present invention is DNA that encodes a protein having an FADGDH activity, and that hybridizes with DNA having a base sequence complementary to the base sequence shown in SEQ ID NO: 4, 5, or 6 under a stringent condition. Here, a stringent condition refers to a condition of hybridization in a temperature range between a Tm for highly homologous nucleic acids, e.g., a completely matched hybrid, and a temperature that is 15° C., preferably 10° C., below the Tm. Specifically, for example, this refers to a condition of hybridization at 68° C. for 20 hours in a commonly used hybridization buffer. In the present invention, a condition is considered stringent when it is for a base sequence encoding an amino acid sequence having a homology not lower than 50% with the amino acid sequence coded by the base sequence shown in SEQ ID NO: 4, 5, or 6; preferably not lower than 80%, further preferably not lower than 90%, and even further preferably not lower than 95%.
[0191] The gene of the present invention may include those obtained by changing its codon usage for the purpose of, for example, improving the expression of the GDH.
[0192] Embodiments of the present invention include: a vector containing the above described gene, a transformant transformed with the vector, and a method for producing a protein that has a glucose dehydrogenase activity by culturing the transformant and collecting the protein having a glucose dehydrogenase activity.
[0193] For example, the above described GDH gene is inserted in an expression vector (many thereof are known in the art, including plasmids), and an appropriate host (many thereof such as Escherichia coli are known in the art) is transformed using the expression vector. An obtained transformant is cultured, and microbial cells are collected from the culture medium by centrifugal separation. Then, the microbial cells are disrupted by a mechanical method or a method using an enzyme such as lysozyme, and, if necessary, a surfactant, a chelating agent such as EDTA, and the like are added for solubilization. As a result, a water soluble fraction containing the GDH can be obtained. Alternatively, the expressed GDH can be directly secreted in the culture medium with a use of an appropriate host-vector system.
[0194] A GDH containing solution obtained as described above can be precipitated by, for example, vacuum concentration, membrane concentration, a salting-out process using ammonium sulfate, sodium sulfate, or the like, a fractional precipitation method using a hydrophilic organic solvent such as methanol, ethanol, acetone, and the like. In addition, heat treatment and isoelectric focusing are also effective purification means. A purified GDH can be obtained by performing gel filtration using an adsorbent or a gel filtering agent, adsorption chromatography, ion exchange chromatography, or affinity chromatography. The purified enzyme preparation is preferably purified to a degree that results in a single band when electrophoresis (SDS-PAGE) is performed using the preparation.
[0195] These techniques can be performed in accordance with, for example, the following literature.
[0196] (a) Tanpakushitsu Jikken Protocol, Vol. 1 Functional Analysis, Vol. 2 Structural Analysis, (Shujunsha) edited by Yoshifumi Nishimura and Shigeo Ohno.
[0197] (b) Revised Tanpakushitsu Jikken Note, Extraction and Separation/Purification, (Yodosha) edited by Masato Okada and Kaori Miyazaki.
[0198] (c) Tanpakushitsu Jikken no Susumekata, (Yodosha) edited by Masato Okada and Kaori Miyazaki.
[0199] Alternatively, the techniques can be performed by the methods exemplified below.
[0200] The created DNA having genetic information of the protein is ligated to a vector, and introduced into a host microorganism.
[0201] Suitable vectors include those constructed for the purpose of genetic transformation from a phage or a plasmid capable of self-replicating in a host microorganism. For example, when Escherichia coli is used as the host microorganism, examples of the phage include Lambda gt10, Lambda gt11, and the like. For example, when Escherichia coli is used as the host microorganism, examples of the plasmid include pBR322, pUC19, pKK223-3, pBluescript, and the like. In particular, pBluescript and the like carrying a promoter capable of being recognized in Escherichia coli upstream of a cloning site are preferable.
[0202] The suitable host microorganism is not particularly limited as long as the host microorganism allows a recombinant vector to self-replicate, be stable, and to express a character of a foreign gene. Escherichia coli that can be used includes Escherichia coli W3110, Escherichia coli C600, Escherichia coli HB101, Escherichia coli J14109, and Escherichia coli DH5α.
[0203] As the method for introducing a recombinant vector to a host microorganism, for example, when the host microorganism is a microorganism that belongs to the genus Escherichia , a method of introducing a recombinant DNA in the presence of calcium ion can be employed. Furthermore, an electroporation method can be employed. Still Further, a commercially available competent cell (e.g., Competent High DH5α; product of Toyobo Co., Ltd.) can be employed. When yeast is used as the host, a lithium method or an electroporation method is employed. When Filamentous fungi are used, a protoplast method is employed.
[0204] In the present invention, the method for obtaining the gene encoding GDH includes the following methods. A predicted GDH gene can be found using genome sequence information of Aspergillus oryzae . Then, mRNA is prepared from microbial cells of Aspergillus oryzae and cDNA is synthesized therefrom. The cDNA obtained in a manner described above is used as a template for amplifying the GDH gene using PCR. Blunt ends or sticky ends of both DNAs of the obtained gene and the vector are ligated and closed using DNA ligase or the like to construct a recombinant vector. The recombinant vector is introduced into the host microorganism that allows the recombinant vector to replicate, and then a recombinant microorganism containing the gene encoding the GDH is obtained by using a marker for the vector.
[0205] The so-obtained microorganism which is the transformant is cultured in a nutrient medium for allowing GDH to be stably produced in large quantities. The transformant can be selected by searching for a microorganism that simultaneously expresses a marker for the vector and a GDH activity. For example, a microorganism that grows in a selection medium based on a drug resistance marker and that also produces GDH may be selected.
[0206] The base sequence of the GDH gene was sequenced by the dideoxy method described in Science, 214: 1205 (1981). Furthermore, the amino acid sequence of the GDH was estimated from the base sequence determined as described above.
[0207] Transferring the GDH gene from the recombinant vector which has been selected once as described above to a recombinant vector capable of replicating in another microorganism can be conducted easily by recovering the DNA for the GDH gene from the recombinant vector carrying the GDH gene using a restriction enzyme or PCR, and ligating the recovered DNA with a fragment of another vector. Transformation of other microorganisms with such vectors can be performed using a competent cell method that utilizes calcium treatment, an electroporation method, a protoplast method, and the like.
[0208] As long as the GDH gene of the present invention has a glucose dehydrogenase activity, the GDH gene may have a DNA sequence resulting in a deletion or substitution in some of the amino acid residues in the amino acid sequence obtained by translating the gene, or a DNA sequence resulting in an addition of or a substitution to other amino acid residues.
[0209] As the method for modifying the gene encoding the wild-type GDH, a technique commonly performed for modifying genetic information may be used. More specifically, DNA having genetic information of the modified protein is created, by converting a specific base, or inserting or deleting a specific base in DNA having genetic information of a protein. The specific methods for converting a base in DNA include, for example, usage of a commercially available kit (TransformerMutagenesis Kit: product of Clontech Laboratories, Inc., ExoIII/Mung Bean Deletion Kit: product of Stratagene Corp., QuickChange Site Directed Mutagenesis Kit: product of Stratagene Corp., and the like), and utilization of polymerase chain reaction (PCR).
[0210] With regard to the mode for culturing the host microorganism that is the transformant, a culturing condition may be selected in consideration of nutritional physiology nature of the host. The culturing is performed in a liquid in many cases, and, industrially, it is advantageous to perform the culturing with aeration and stirring. However, when considering the productivity, there are cases where it is advantageous to use a Filamentous fungus as a host and conduct solid culturing.
[0211] As a source of nutrient for the medium, those commonly used for culturing microorganisms may be widely used. As a carbon source, a carbon compound capable of being assimilated may be used, and, for example, glucose, sucrose, lactose, maltose, molasses, and pyruvic acid are used. Furthermore, as a nitrogen source, any applicable nitrogen compound may be used, and, for example, peptone, meat extract, yeast extract, casein hydrolysate, and alkaline extract of soybean meal are used. In addition, phosphates, carbonates, sulfates, salts of magnesium, calcium, potassium, iron, manganese, and zinc, specific amino acids, specific vitamins, and the like are used in accordance with needs.
[0212] Although the culturing temperature can be changed appropriately in a range in which the microbe grows and produces the GDH, preferably, the culturing temperature is about 20 to 37° C. The culturing time differs to some degree depending on the condition, and the culture may be completed at an appropriate time by judging the right timing at which the yield of the GDH becomes the highest. Typically, the culturing time is about 6 to 48 hours. Although the pH of the medium can be changed appropriately in a range in which the microbe grows and produces the GDH, preferably, the pH is in a range of about 6.0 to 9.0.
[0213] The culture medium that contains microbial cells producing the GDH in the culture can be directly collected and used. However, when the GDH exists in the culture medium, generally, in accordance with a method commonly used in the art, the GDH is utilized after separating a GDH containing solution and the microbial cells by filtration or centrifugal separation. When the GDH exists within the microbial cells, the microbial cells are collected from the obtained culture by means of filtration or centrifugal separation. Then, the collected microbial cells are disrupted by a mechanical method or a method using an enzyme such as lysozyme, and, if necessary, a surfactant and a chelating agent such as EDTA or the like are added to solubilize, isolate, and collect the GDH as a solution.
[0214] The GDH containing solution obtained as described above can be precipitated by, for example, vacuum concentration, membrane concentration, a salting-out process using ammonium sulfate, sodium sulfate, or the like, a fractional precipitation method using a hydrophilic organic solvent such as methanol, ethanol, acetone, and the like. In addition, heat treatment and isoelectric focusing are also effective purification means. Then, a purified GDH can be obtained by performing gel filtration using an adsorbent or a gel filtering agent, adsorption chromatography, ion exchange chromatography, or affinity chromatography.
[0215] For example, a purified enzyme preparation can be obtained through separation and purification by gel filtration using Sephadex gel (product of GE Healthcare Bioscience Corp.), or column chromatography using DEAE Sepharose CL-6B (product of GE Healthcare Bioscience Corp.), Octyl Sepharose CL-6B (product of GE Healthcare Bioscience Corp.), and the like. The purified enzyme preparation is preferably purified to a degree that results in a single band when electrophoresis (SDS-PAGE) is performed using the preparation.
[0216] In the present invention, glucose dehydrogenase activity of a protein is measured using the following conditions.
EXPERIMENTAL EXAMPLE
Reagents
[0000]
50 mM PIPES buffer pH 6.5 (containing 0.1% Triton X-100)
24 mM PMS solution
2.0 mM 2,6-dichlorophenolindophenol (DCPIP) solution
1 M D-glucose solution
[0221] A reaction reagent is obtained by mixing 20.5 ml of the PIPES buffer, 1.0 ml of the DCPIP solution, 2.0 ml of the PMS solution, and 5.9 ml of the D-glucose solution, which are described above.
[0222] Measuring Condition
[0223] 3 ml of the reaction reagent is preheated at 37° C. for 5 minutes. 0.1 ml of a GDH solution is added thereto, the mixture is gently mixed. Then the mixture is placed in a spectrophotometer controlled at 37° C., and a change in absorbance at 600 nm is recorded for 5 minutes. From a linear portion of the record, a per-minute absorbance change (AODTEST) is measured using water as a control. As a blank test, a per-minute absorbance change (LODBLANK) is measured in a similar manner but by adding, to the reagent mixture, a solvent used for dissolving the GDH instead of the GDH solution. A GDH activity is obtained from the following formula using these values. Here, 1 unit (U) of the GDH activity is defined as an amount of enzyme that reduces 1 μmol of DCPIP in 1 minute in the presence of D-glucose at a concentration of 200 mM. When measuring an activity value at 25° C., measurement is performed by changing the temperature to 25° C. for the above described operation for 37° C. When measuring reactivity to xylose, 1 M D-xylose can be used instead of the above described 1 M D-glucose solution.
[0000] Activity (U/ml)={−(ΔODTEST−ΔODBLANK)×3.0×dilution factor)/(16.3×0.1×1.0)
[0224] It should be noted that, in the formula, 3.0 is a liquid amount (ml) of reaction reagent +enzyme solution, and 16.3 is a millimolar molecular absorbance coefficient (cm 2 /μmol) for the present activity measurement condition, 0.1 is a liquid amount (ml) of the enzyme solution, and 1.0 is a length (cm) of a light path in a cell.
[0225] The specific activity of the FADGDH in the present invention is obtained in accordance with the following calculation formula.
[0000] Specific Activity (U/A280)=(Activity)/(Protein Concentration)
[0226] Here, protein concentration can be obtained by measuring absorbance at 280 nm using a molecule absorption photometer. Furthermore, A280 is an absorbance value at a wavelength of 280 nm.
[0227] When absorbance A280 at 280 nm is used, protein concentration <Protein> can be derived as:
[0000] <Protein>= A 280/ εM (mol/dm 3 ).
[0228] Here, the molar absorbance coefficient εM of a protein at 280 nm can be obtained as:
[0000] ε M=Trp× 5500+ Tyr× 1490+Cystine×125.
[0229] Glucose Assay Kit
[0230] Another feature of the present invention is a glucose assay kit including the modified FADGDH according to the present invention. The glucose assay kit of the present invention includes the modified FADGDH according to the present invention by an amount sufficient for at least one assay. Typically, the kit includes, in addition to the modified FADGDH of the present invention, a buffer and mediator necessary for the assay, a glucose standard solution for drawing a calibration curve, and a usage instruction. The modified FADGDH according to the present invention can be provided in various modes such as a lyophilized reagent or a solution in an appropriate preservation solution.
[0231] Glucose Sensor
[0232] Another feature of the present invention is a glucose sensor utilizing the modified FADGDH according to the present invention. As an electrode, a carbon electrode, a gold electrode, a platinum electrode, and the like are used. The enzyme of the present invention is immobilized on this electrode. Immobilization methods that can be used include: a method using a cross-linking reagent; a method of sealing using a polymer matrix; a method of covering using a dialysis membrane, a photocrosslinkable polymer, a conductive polymer, a redox polymer, or the like; immobilizing in a polymer or adsorbing-immobilizing onto the electrode, together with an electronic mediator represented by ferrocene or a derivative thereof; or a combination of those described above. Representatively, the modified FADGDH of the present invention is immobilized onto a carbon electrode using glutaraldehyde, and then, glutaraldehyde is blocked by a treatment using a reagent containing an amine group.
[0233] Measurement of glucose levels can be performed in the following manner. The buffer is poured in a constant temperature cell and maintained at a constant temperature. Potassium ferricyanide, phenazine methosulfate, and the like can be used as the mediator. An electrode having the modified FADGDH of the present invention immobilized thereto is used as a working electrode, and a counter electrode (e.g., platinum electrode) and a reference electrode (e.g., Ag/AgCl electrode) are used. A constant voltage is applied on the carbon electrode, and after the current stabilizes, a sample containing glucose is added and an increase in the current is measured. A glucose level in the sample can be calculated in accordance with a calibration curve drawn using glucose solutions with standard concentrations.
EXAMPLES
[0234] The present invention is described more specifically in the following with reference to Examples.
Example B1
Evaluation of Temperature Dependency of FADGDH
[0235] The FADGDH comprising the amino acid sequence shown in SEQ ID NO: 2 was used. An FADGDH purified preparation was prepared using the above described methods, and an activity thereof was measured in a 38 mM PIPES buffer (pH 6.5) at a predetermined temperature condition. A temperature dependency curve of the enzyme activity is shown in FIG. 1 . The vertical axis represents a relative activity value at each temperature, wherein an activity value at 37° C. was defined as 100%. When the activity value at 37° C. was 100%, the activity value at 25° C. was about 63%, and the activity value at 5° C. was about 40%. Furthermore, the temperature dependency of the FADGDH of SEQ ID NO: 1 was similar to that of the FADGDH of SEQ ID NO: 2.
Example B2
Creating Modified FADGDH Gene
[0236] A commercially available Escherichia coli competent cell ( E. coli DH5α; product of Toyobo Co., Ltd.) was transformed using a recombinant plasmid pAOGDH-M76 that contains the gene (SEQ ID NO: 5) encoding the FADGDH. Transformed cells were applied on an agar medium (1% polypeptone, 0.5% yeast extract, 0.5% NaCl, 1.5% agar; pH 7.3) containing ampicillin, and cultured overnight at 30° C. The obtained transformant was inoculated to a liquid medium (1% polypeptone, 0.5% yeast extract, 0.5% NaCl; pH 7.3) containing ampicillin (50 mg/ml; product of Nacalai Tesque, Inc.), and cultured overnight at 30° C. by shaking. A plasmid was prepared from the obtained microbial cells using a method commonly used in the art.
[0237] Using the plasmid as a template, a modified FADGDH was created using a synthetic oligonucleotide of SEQ ID NO: 8 designed such that phenylalanine at position 58 is substituted with alanine, and a synthetic oligonucleotide complementary thereto, in QuikChange™ Site-Directed Mutagenesis Kit (product of Stratagene Corp.).
Example B3
Preparation of Plasmid with Alanine-Modified FADGDH
[0238] A commercially available Escherichia coli competent cell ( E. coli DH5a; product of Toyobo Co., Ltd.) was transformed using the obtained modified FADGDH, and cultured for 16 hours at 37° C. in an LB agar medium containing ampicillin. Then, a single colony of the modified FADGDH was inoculated to an LB liquid medium containing ampicillin, and cultured overnight at 30° C. by shaking. A plasmid was extracted from the obtained microbial cells using a method commonly used in the art. Relevant positions in the extracted plasmid were identified using a DNA sequencer (ABI Prism™ 3700 DNA Analyzer; product of Perkin-Elmer Inc.), and the modified FADGDH having a substitution with alanine was obtained. The plasmid in which phenylalanine at position 58 was substituted with alanine was named pAOGDH-M76-F58A.
Example B4
Preparation of Crude Enzyme Liquid Containing Modified FADGDH, and Comparison of Temperature Dependencies and Actions to Xylose
[0239] A commercially available Escherichia coli competent cell ( E. coli DH5a; product of Toyobo Co., Ltd.) was transformed using pAOGDH-M76-F58A obtained in Example B3, and cultured for 16 hours at 37° C. in an LB agar medium containing ampicillin. Then, a single colony of the alanine-modified FADGDH was inoculated to an LB liquid medium containing ampicillin, and cultured overnight at 30° C. by shaking. Microbial cells obtained from one portion of the culture medium using centrifugal separation were collected, and the microbial cells were homogenized in 50 mM phosphate buffer (pH 6.0) using glass beads to prepare a crude enzyme liquid.
[0240] By using the prepared crude enzyme liquid, GDH activity was measured at 25° C. and 37° C. using the above described activity measuring method. The results are shown in Table 1.
[0241] Table 1 shows the results of comparison of temperature dependency of F58A when culturing was performed for 24 hours at 30° C. in a 5 ml LB medium/test tube.
[0242] Comparing the modified sites and temperature dependencies, an advantageous effect was confirmed that substituting position 58 had improved temperature dependency when compared to the pre-modified FADGDH (described as Mut1), and thereby, position 58 was used as a candidate.
[0000]
TABLE 1
Comparison of temperature dependency of modified FADGDH
Temperature
dependency
Temperature dependency ratio
Variant
(%)
(taking Mut1 as 1)
Mut1
63.37
1.00
F58A
70.59
1.11
Example B5
Optimization of Amino Acid at Position 58
[0243] Using pAOGDH-M76 used in Example B2 as a template, modified FADGDHs were created using synthetic oligonucleotides of SEQ ID NO: 10 designed such that phenylalanine at position 58 is substituted with other types of amino acids and synthetic oligonucleotides complementary thereto, in QuikChange™ Site-Directed Mutagenesis Kit (product of Stratagene Corp.). A commercially available Escherichia coli competent cell ( E. coli DH5a; product of Toyobo Co., Ltd.) was transformed using the modified FADGDH, and cultured for 16 hours at 37° C. in an LB agar medium containing ampicillin. Then, a single colony having the modified FADGDH was inoculated to an LB liquid medium containing ampicillin, and cultured overnight at 30° C. by shaking. Next, 1 ml of the culture medium was taken and a plasmid was extracted using a method commonly used in the art. Relevant positions in the extracted plasmid were identified using a DNA sequencer (ABI Prise™ 3700 DNA Analyzer; product of Perkin-Elmer Inc.). A plasmid containing a modified FADGDH having a substitution at position 58 to A was named pAOGDH-M76-F58A; a plasmid containing a modified FADGDH having a substitution at position 58 to C was named pAOGDH-M76-F58C; a plasmid containing a modified FADGDH having a substitution at position 58 to D was named pAOGDH-M76-F58D; a plasmid containing a modified FADGDH having a substitution at position 58 to E was named pAOGDH-M76-F58E; a plasmid containing a modified FADGDH having a substitution at position 58 to G was named pAOGDH-M76-F58G; a plasmid containing a modified FADGDH having a substitution at position 58 to H was named pAOGDH-M76-F58H; a plasmid containing a modified FADGDH having a substitution at position 58 to I was named pAOGDH-M76-F58I; a plasmid containing a modified FADGDH having a substitution at position 58 to K was named pAOGDH-M76-F58K; a plasmid containing a modified FADGDH having a substitution at position 58 to L was named pAOGDH-M76-F58L; a plasmid containing a modified FADGDH having a substitution at position 58 to M was named pAOGDH-M76-F58M; a plasmid containing a modified FADGDH having a substitution at position 58 to N was named pAOGDH-M76-F58N; a plasmid containing a modified FADGDH having a substitution at position 58 to P was named pAOGDH-M76-F58P; a plasmid containing a modified FADGDH having a substitution at position 58 to Q was named pAOGDH-M76-F58Q; a plasmid containing a modified FADGDH having a substitution at position 58 to R was named pAOGDH-M76-F58R; a plasmid containing a modified FADGDH having a substitution at position 58 to S was named pAOGDH-M76-F58S; a plasmid containing a modified FADGDH having a substitution at position 58 to T was named pAOGDH-M76-F58T; a plasmid containing a modified FADGDH having a substitution at position 58 to V was named pAOGDH-M76-F58V; a plasmid containing a modified FADGDH having a substitution at position 58 to W was named pAOGDH-M76-F58W; and a plasmid containing a modified FADGDH having a substitution at position 58 to Y was named pAOGDH-M76-F58Y.
Example B6
Comparison of Temperature Dependencies and Actions to Xylose of Modified FADGDHs having Optimized Amino Acids at Position 58
[0244] A commercially available Escherichia coli competent cell ( E. coli DH5a; product of Toyobo Co., Ltd.) was transformed using each of the plasmid obtained in Example B5, and cultured for 24 hours at 30° C. in an LB agar medium containing ampicillin. Then, crude enzyme solutions were prepared in a manner similar to Example B4, and their temperature dependencies were measured. The results of the temperature dependencies for the modified FADGDHs are shown in Table 2.
[0245] Table 2 shows the results of comparison of temperature dependencies and substrate specificities of the modified FADGDHs having a modification at position F58 when culturing was performed for 24 hours at 30° C. in 5 ml LB medium/test tubes. Temperature dependency was improved when compared to the pre-modified FADGDH, in the modified FADGDH having a substitution at position 58 to A, the modified FADGDH having a substitution at position 58 to E, the modified FADGDH having a substitution at position 58 to H, the modified FADGDH having a substitution at position 58 to I, the modified FADGDH having a substitution at position 58 to L, the modified FADGDH having a substitution at position 58 to M, the modified FADGDH having a substitution at position 58 to Q, the modified FADGDH having a substitution at position 58 to S, the modified FADGDH having a substitution at position 58 to T, and in the modified FADGDH having a substitution at position 58 to Y. Furthermore, actions to xylose were reduced in all the modified FADGDHs whose temperature dependencies were improved.
[0000]
TABLE 2
Comparison of temperature dependencies and actions
to xylose of the modified FADGDHs in which F58 is
substituted with 19 types of amino acids
Temperature
Ratio of
dependency
action to
Temperature
ratio
xylose
dependency
(taking
Action to
(taking
Variant
(%)
Mut1 as 1)
xylose (%)
Mut1 as 1)
Mut1
63.70
1.00
10.50
1.00
D
inactivated
—
inactivated
—
E
74.24
1.17
8.77
0.84
H
66.34
1.04
7.35
0.70
K
inactivated
—
inactivated
—
R
inactivated
—
inactivated
—
C
57.63
0.90
13.14
1.25
G
inactivated
—
inactivated
—
N
inactivated
—
inactivated
—
Q
72.85
1.14
7.97
0.76
S
71.40
1.12
8.92
0.85
T
69.98
1.10
8.91
0.85
Y
67.25
1.06
7.56
0.72
A
69.46
1.09
8.57
0.82
I
69.01
1.08
8.65
0.82
L
65.99
1.04
9.82
0.94
M
69.12
1.08
8.58
0.82
P
inactivated
—
inactivated
—
V
inactivated
—
inactivated
—
W
inactivated
—
inactivated
—
Example C1
Creating Modified FADGDH Gene
[0246] A commercially available Escherichia coli competent cell ( E. coli DH5a; product of Toyobo Co., Ltd.) was transformed using a recombinant plasmid pAOGDH-M76 that contains the gene (SEQ ID NO: 5) encoding the FADGDH. Transformed cells were applied on an agar medium (1% polypeptone, 0.5% yeast extract, 0.5% NaCl, 1.5% agar; pH 7.3) containing ampicillin, and cultured overnight at 30° C. The obtained transformant was inoculated to a liquid medium (1% polypeptone, 0.5% yeast extract, 0.5% NaCl; pH 7.3) containing ampicillin (50 mg/ml; Nacalai Tesque, Inc.), and cultured overnight at 30° C. by shaking. A plasmid was prepared from the obtained microbial cells using a method commonly used in the art.
[0247] Using the plasmid as a template, a modified FADGDH was created using a synthetic oligonucleotide of SEQ ID NO: 11 designed such that glycine at position 59 is substituted with alanine and a synthetic oligonucleotide complementary thereto, in QuikChange™ Site-Directed Mutagenesis Kit (product of Stratagene Corp.).
Example C2
Preparation of Plasmid with Alanine-Modified FADGDH
[0248] A commercially available Escherichia coli competent cell ( E. coli DH5a; product of Toyobo Co., Ltd.) was transformed using the obtained modified FADGDH, and cultured for 16 hours at 37° C. in an LB agar medium containing ampicillin. Then, a single colony of the modified FADGDH was inoculated to an LB liquid medium containing ampicillin, and cultured overnight at 30° C. by shaking. A plasmid was extracted from the obtained microbial cells using a method commonly used in the art. Relevant positions in the extracted plasmid were identified using a DNA sequencer (ABI Prism™ 3700 DNA Analyzer; product of Perkin-Elmer Inc.), and the modified FADGDH having a substitution with alanine was obtained. The plasmid in which glycine at position 59 was substituted with alanine was named pAOGDH-M76-G59A.
Example C3
Preparation of Crude Enzyme Liquid Containing Modified FADGDH, and Comparison of Temperature Dependencies and Actions to Xylose
[0249] A commercially available Escherichia coli competent cell ( E. coli DH5a; product of Toyobo Co., Ltd.) was transformed using pAOGDH-M76-G59A obtained in Example C2, and cultured for 16 hours at 37° C. in an LB agar medium containing ampicillin. Then, a single colony of the alanine-modified FADGDH was inoculated to an LB liquid medium containing ampicillin, and cultured overnight at 30° C. by shaking. Microbial cells obtained from one portion of the culture medium using centrifugal separation were collected, and the microbial cells were homogenized in 50 mM phosphate buffer (pH 6.0) using glass beads to prepare a crude enzyme liquid.
[0250] By using the prepared crude enzyme liquid, GDH activity at 25° C. and 37° C., and action to xylose at 37° C. were measured using the above described activity measuring method. The results are shown in Table 3.
[0251] Table 3 shows the results of comparison of temperature dependency of G59A when culturing was performed for 24 hours at 30° C. in a 5 ml LB medium/test tube. Comparing the modified sites and temperature dependencies, an advantageous effect was confirmed that substituting the amino acid at position 59 with alanine had improved temperature dependency when compared to the pre-modified FADGDH, and thereby, position 59 was used as a candidate.
[0000]
TABLE 3
Comparison of temperature dependency of modified FADGDH
Temperature
Temperature dependency ratio
Variant
dependency (%)
(taking Mut1 as 1)
Mut1
62.55
100.00
G59A
66.46
106.25
Example C4
Optimization of Amino Acid at Position 59
[0252] Using pAOGDH-M76 used in Example C1 as a template, modified FADGDHs were created using synthetic oligonucleotides of SEQ ID NO: 15 designed such that tyrosine at position 59 is substituted with the 19 other types of amino acids and synthetic oligonucleotides complementary thereto, in QuikChange™ Site-Directed Mutagenesis Kit (product of Stratagene Corp.). A commercially available Escherichia coli competent cell ( E. coli DH5a; product of Toyobo Co., Ltd.) was transformed using the modified FADGDH, and cultured for 16 hours at 37° C. in an LB agar medium containing ampicillin. Then, a single colony having the modified FADGDH was inoculated to an LB liquid medium containing ampicillin, and cultured overnight at 30° C. by shaking. Next, 1 ml of the culture medium was taken and a plasmid was extracted using a method commonly used in the art. Relevant positions in the extracted plasmid were identified using a DNA sequencer (ABI Prism™ 3700 DNA Analyzer; product of Perkin-Elmer Inc.). A plasmid containing a modified FADGDHRR having a substitution at position 59 to A was named pAOGDH-M76-G59A; a plasmid containing a modified FADGDHRR having a substitution at position 59 to C was named pAOGDH-M76-G59C; a plasmid containing a modified FADGDHRR having a substitution at position 59 to D was named pAOGDH-M76-G59D; a plasmid containing a modified FADGDHRR having a substitution at position 59 to E was named pAOGDH-M76-G59E; a plasmid containing a modified FADGDHRR having a substitution at position 59 to G was named pAOGDH-M76-G59G; a plasmid containing a modified FADGDHRR having a substitution at position 59 to H was named pAOGDH-M76-G59H; a plasmid containing a modified FADGDHRR having a substitution at position 59 to I was named pAOGDH-M76-G59I; a plasmid containing a modified FADGDHRR having a substitution at position 59 to K was named pAOGDH-M76-G59K; a plasmid containing a modified FADGDHRR having a substitution at position 59 to L was named pAOGDH-M76-G59L; a plasmid containing a modified FADGDHRR having a substitution at position 59 to M was named pAOGDH-M76-G59M; a plasmid containing a modified FADGDHRR having a substitution at position 59 to N was named pAOGDH-M76-G59N; a plasmid containing a modified FADGDHRR having a substitution at position 59 to P was named pAOGDH-M76-G59P; a plasmid containing a modified FADGDHRR having a substitution at position 59 to Q was named pAOGDH-M76-G59Q; a plasmid containing a modified FADGDHRR having a substitution at position 59 to R was named pAOGDH-M76-G59R; a plasmid containing a modified FADGDHRR having a substitution at position 59 to S was named pAOGDH-M76-G59S; a plasmid containing a modified FADGDHRR having a substitution at position 59 to T was named pAOGDH-M76-G59T; a plasmid containing a modified FADGDHRR having a substitution at position 59 to V was named pAOGDH-M76-G59V; a plasmid containing a modified FADGDHRR having a substitution at position 59 to W was named pAOGDH-M76-G59W; and a plasmid containing a modified FADGDH having a substitution at position 59 to Y was named pAOGDH-M76-G59Y.
Example C5
Comparison of Temperature Dependencies and Actions to Xylose of Modified FADGDHs having Optimized Amino Acids at Position 59
[0253] Measurements of temperature dependencies and actions to xylose were performed for the modified FADGDHs in which the amino acid at position 59 was substituted with 19 types of amino acids using a method similar to that in Example C3. The results of the temperature dependencies and actions to xylose of the modified FADGDHs are shown in Table 4.
[0254] Table 4 shows the results of comparison of temperature dependencies and actions to xylose of the modified FADGDHs having a modification at position G59 when culturing was performed for 24 hours at 30° C. in 5 ml LB medium/test tubes.
[0255] Temperature dependencies were improved when compared to the pre-modified FADGDH, in the modified FADGDH having a substitution at position 59 to A, the modified FADGDH having a substitution at position 59 to C, the modified FADGDH having a substitution at position 59 to D, the modified FADGDH having a substitution at position 59 to F, the modified FADGDH having a substitution at position 59 to H, the modified FADGDH having a substitution at position 59 to K, the modified FADGDH having a substitution at position 59 to L, the modified FADGDH having a substitution at position 59 to M, the modified FADGDH having a substitution at position 59 to N, the modified FADGDH having a substitution at position 59 to P, the modified FADGDH having a substitution at position 59 to Q, the modified FADGDH having a substitution at position 59 to S, the modified FADGDH having a substitution at position 59 to T, the modified FADGDH having a substitution at position 59 to W, and in the modified FADGDH having a substitution at position 59 to Y. Furthermore, not only the temperature dependencies were improved, but also actions to xylose were reduced when compared to the pre-modified FADGDH, in the modified FADGDH having a substitution at position 59 to C, the modified FADGDH having a substitution at position 59 to D, the modified FADGDH having a substitution at position 59 to K, the modified FADGDH having a substitution at position 59 to M, the modified FADGDH having a substitution at position 59 to Q, the modified FADGDH having a substitution at position 59 to S, and the modified FADGDH having a substitution at position 59 to T.
[0000]
TABLE 4
Comparison of temperature dependencies and actions
to xylose of modified FADGDHs in which G59 is
substituted with 19 types of amino acids
Temperature
Ratio of
dependency
action to
Temperature
ratio
xylose
dependency
(taking
Action to
(taking
Variant
(%)
Mut1 as 1)
xylose (%)
Mut1 as 1)
Mut1
62.55
1.00
10.30
1.00
A
66.46
1.06
10.39
1.01
C
72.88
1.17
9.91
0.96
D
64.23
1.03
9.97
0.97
E
inactivated
—
inactivated
—
F
75.86
1.21
15.80
1.53
H
71.32
1.14
11.58
1.12
I
inactivated
—
inactivated
—
K
70.41
1.13
9.79
0.95
L
71.93
1.15
23.98
2.33
M
75.47
1.21
8.26
0.80
N
70.13
1.12
10.71
1.04
P
68.24
1.09
13.12
1.27
Q
70.67
1.13
8.80
0.85
R
inactivated
—
inactivated
—
S
65.66
1.05
9.87
0.96
T
75.05
1.20
9.60
0.93
V
inactivated
—
inactivated
—
W
70.84
1.13
13.79
1.34
Y
76.86
1.23
17.47
1.70
Example D1
Creating Modified FADGDH Gene
[0256] A commercially available Escherichia coli competent cell ( E. coli DH5a; product of Toyobo Co., Ltd.) was transformed using a recombinant plasmid pAOGDH-M76 that contains the gene (SEQ ID NO: 5) encoding the FADGDH of SEQ ID NO: 2. Transformed cells were applied on an agar medium (1% polypeptone, 0.5% yeast extract, 0.5% NaCl, 1.5% agar; pH 7.3) containing ampicillin, and cultured overnight at 30° C. The obtained transformant was inoculated to a liquid medium (1% polypeptone, 0.5% yeast extract, 0.5% NaCl; pH 7.3) containing ampicillin (50 mg/ml; Nacalai Tesque, Inc.), and cultured overnight at 30° C. by shaking. A plasmid was prepared from the obtained microbial cells using a method commonly used in the art.
[0257] Using the plasmid as a template, a modified FADGDH was created using a synthetic oligonucleotide of SEQ ID NO: 22 designed such that asparagine at position 504 is substituted with serine and a synthetic oligonucleotide complementary thereto, in QuikChange™ Site-Directed Mutagenesis Kit (product of Stratagene Corp.).
Example D2
Preparation of Plasmid with Modified FADGDH
[0258] A commercially available Escherichia coli competent cell ( E. coli DH5a; product of Toyobo Co., Ltd.) was transformed using the obtained modified FADGDH, and cultured for 16 hours at 37° C. in an LB agar medium containing ampicillin. Then, a single colony of the modified FADGDH was inoculated to an LB liquid medium containing ampicillin, and cultured overnight at 30° C. by shaking. A plasmid was extracted from the obtained microbial cells using a method commonly used in the art. Relevant positions in the extracted plasmid were identified using a DNA sequencer (ABI Prism™ 3700 DNA Analyzer; product of Perkin-Elmer Inc.), and the modified FADGDH having a substitution with the amino acid described in Example D1 was obtained. The plasmid in which asparagine at position 504 was substituted with serine was named pAOGDH-M76-N504S.
Example D3
Preparation of Crude Enzyme Liquid Containing Modified FADGDH, and Comparison of Temperature Dependencies and Actions to Xylose
[0259] A commercially available Escherichia coli competent cell ( E. coli DH5a; product of Toyobo Co., Ltd.) was transformed using pAOGDH-M76-N504S obtained in Example D2, and cultured for 16 hours at 37° C. in an LB agar medium containing ampicillin. Then, a single colony of the modified FADGDH was inoculated to an LB liquid medium containing ampicillin, and cultured overnight at 30° C. by shaking. Microbial cells obtained from one portion of the culture medium using centrifugal separation were collected, and the microbial cells were homogenized in 50 mM phosphate buffer (pH 6.0) using glass beads to prepare a crude enzyme liquid.
[0260] By using the prepared crude enzyme liquid, GDH activity at 25° C. and 37° C., and action to xylose at 37° C. were measured using the above described activity measuring method. The results are shown in Table 5.
[0261] Table 5 shows the results of comparison of temperature dependency of N504S when culturing was performed for 24 hours at 30° C. in a 5 ml LB medium/test tube.
[0262] Comparing the modified sites and temperature dependencies, an advantageous effect was confirmed that substituting asparagine at position 504 with serine had improved temperature dependency when compared to the pre-modified FADGDH (hereinafter, also represented as Mut1), and thereby, optimization of amino acid was performed at position 504 and a detailed investigation was conducted.
[0000]
TABLE 5
Comparison of temperature dependency of modified FADGDH
Temperature
Temperature dependency ratio
Variant
dependency (%)
(taking Mut1 as 1)
Mut1
62.55
1.00
N504S
71.50
1.14
Example D4
Optimization of Amino Acid at Position 504
[0263] Using pAOGDH-M76 used in Example C1 as a template, modified FADGDHs were created using synthetic oligonucleotides of SEQ ID NO: 26 designed such that asperagine at position 504 is substituted with the 7 other types of amino acids and synthetic oligonucleotides complementary thereto, in QuikChange™ Site-Directed Mutagenesis Kit (product of Stratagene Corp.). A commercially available Escherichia coli competent cell ( E. coli DH5a; product of Toyobo Co., Ltd.) was transformed using the modified FADGDH, and cultured for 16 hours at 37° C. in an LB agar medium containing ampicillin. Then, a single colony having the modified FADGDH was inoculated to an LB liquid medium containing ampicillin, and cultured overnight at 30° C. by shaking. Next, 1 ml of the culture medium was taken and a plasmid was extracted using a method commonly used in the art. Relevant positions in the extracted plasmid were identified using a DNA sequencer (ABI Prism™ 3700 DNA Analyzer; product of Perkin-Elmer Inc.). A plasmid containing a modified FADGDH having a substitution at position 504 to A was named pAOGDH-M76-N504A; a plasmid containing a modified FADGDH having a substitution at position 504 to D was named pAOGDH-M76-N504D; a plasmid containing a modified FADGDH having a substitution at position 504 to G was named pAOGDH-M76-N504G; a plasmid containing a modified FADGDH having a substitution at position 504 to L was named pAOGDH-M76-N504L; a plasmid containing a modified FADGDH having a substitution at position 504 to R was named pAOGDH-M76-N504R; a plasmid containing a modified FADGDH having a substitution at position 504 to S was named pAOGDH-M76-N504S; and a plasmid containing a modified FADGDH having a substitution at position 504 to T was named pAOGDH-M76-N504T.
Example D5
Comparison of Temperature Dependencies and Actions to Xylose of Modified FADGDHs having Optimized Amino Acids at Position 504
[0264] Measurements of temperature dependencies and actions to xylose were performed for the modified FADGDHs in which the amino acid at position 504 was substituted with 7 types of amino acids using a method similar to that in Example D3. The results of the temperature dependencies and actions to xylose of the modified FADGDHs are shown in Table 6.
[0265] Table 6 shows the results of comparison of temperature dependencies and actions to xylose of the modified FADGDHs having modifications at position N504 when culturing was performed for 24 hours at 30° C. in 5 ml LB medium/test tubes.
[0266] Temperature dependencies were improved when compared to the pre-modified FADGDH (Mut1), in the modified FADGDH having a substitution at position 504 to G and the modified FADGDH having a substitution at position 504 to S. Furthermore, not only the temperature dependencies were improved, but also actions to xylose were reduced when compared to the pre-modified FADGDH (Mut1) in the modified FADGDH having a substitution at position 504 to G.
[0000]
TABLE 6
Comparison of temperature dependencies and actions
to xylose of modified FADGDHs having a substitution
at N504 with 7 types of amino acids
Temperature
Ratio of
dependency
action to
Temperature
ratio
xylose
dependency
(taking
Action to
(taking
Variant
(%)
Mut1 as 1)
xylose (%)
Mut1 as 1)
Mut1
62.55
1.00
10.30
1.00
A
inactivated
—
inactivated
—
D
inactivated
—
inactivated
—
G
78.30
1.25
9.52
0.92
L
inactivated
—
inactivated
—
R
inactivated
—
inactivated
—
S
71.50
1.14
11.61
1.13
T
inactivated
—
inactivated
—
Example E1
Creating Modified FADGDH Gene
[0267] A commercially available Escherichia coli competent cell ( E. coli DH5a; product of Toyobo Co., Ltd.) was transformed using a recombinant plasmid pAOGDH-M76 that contains the gene (SEQ ID NO: 5) encoding the FADGDH of SEQ ID NO: 2. Transformed cells were applied on an LB agar medium (1.0% polypeptone, 0.5% yeast extract, 1.0% NaCl, 1.5% agar; pH 7.3) containing ampicillin, and cultured overnight at 30° C. The obtained transformant was inoculated to an LB liquid medium (1% polypeptone, 0.5% yeast extract, 1.0% NaCl; pH 6.5) containing ampicillin (50 mg/ml; product of Nacalai Tesque, Inc.), and cultured overnight at 30° C. by shaking. A plasmid was prepared from the obtained microbial cells using a method commonly used in the art.
Example E2
Optimization of Amino Acid G53
[0268] Using pAOGDH-M76 used in Example E1 as a template, PCR was performed using synthetic oligonucleotides of SEQ ID NO: 27 designed such that glycine at position 53 is substituted with other amino acids and synthetic oligonucleotides complementary thereto, in QuikChange™ Site-Directed Mutagenesis Kit (product of Stratagene Corp.). Then, a commercially available Escherichia coli competent cell ( E. coli DH5a; product of Toyobo Co., Ltd.) was transformed using the PCR product, and cultured for 16 hours at 37° C. in an LB agar medium containing ampicillin. Next, a single colony having the modified FADGDH was inoculated to an LB liquid medium containing ampicillin, and cultured overnight at 30° C. by shaking. Then, 1 ml of the culture medium was taken, and a plasmid was extracted using a method commonly used in the art. Relevant positions in the extracted plasmid were identified using a DNA sequencer (ABI Prism™ 3700 DNA Analyzer; product of Perkin-Elmer Inc.). A plasmid containing a modified FADGDH having a substitution at position 53 to F was named pAOGDH-M76-G53F; a plasmid containing a modified FADGDH having a substitution at position 53 to I was named pAOGDH-M76-G53I; a plasmid containing a modified FADGDH having a substitution at position 53 to L was named pAOGDH-M76-G53L; a plasmid containing a modified FADGDH having a substitution at position 53 to P was named pAOGDH-M76-G53P; a plasmid containing a modified FADGDH having a substitution at position 53 to Q was named pAOGDH-M76-G53Q; a plasmid containing a modified FADGDH having a substitution at position 53 to R was named pAOGDH-M76-G53R; a plasmid containing a modified FADGDH having a substitution at position 53 to S was named pAOGDH-M76-G53S; a plasmid containing a modified FADGDH having a substitution at position 53 to W was named pAOGDH-M76-G53W; and a plasmid containing a modified FADGDH having a substitution at position 53 to Y was named pAOGDH-M76-G53Y.
Example E3
Evaluation of Temperature Dependencies and Actions to Xylose of Modified FADGDHs having Optimized Amino Acids at Position 53
[0269] Batches of Escherichia coli DH5α were transformed with the respective modified FADGDH plasmids having a substitution at position 53 acquired in Example E2 with other amino acids, and cultured for 16 hours at 37° C. in LB agar media containing ampicillin. Then, a single colony of each of the modified FADGDHs was inoculated to an LB liquid medium containing ampicillin, and cultured overnight at 30° C. by shaking. Microbial cells obtained from one portion of each of the culture media using centrifugal separation were collected, and the microbial cells were homogenized in 50 mM phosphate buffer (pH 6.0) using glass beads to prepare crude enzyme liquids. By using the prepared crude enzyme liquids, GDH activities at 25° C. and 37° C., and actions to xylose at 37° C. were measured using the above described activity measuring method. The results are shown in Table 7.
[0270] Table 7 shows the results of comparison of temperature dependencies and actions to xylose of the modified FADGDHs having modifications at position 53 when culturing was performed for 24 hours at 30° C. in 5 ml LB medium/test tubes.
[0271] The modified FADGDHs having a substitution at position 53 to F, L, Q, R, S, W, and Y not only had improved temperature dependencies, but also had reduced actions to xylose when compared to the pre-modified FADGDH (Mut1).
[0000]
TABLE 7
Comparison of temperature dependencies and actions
to xylose of modified FADGDHs having a substitution
at G53 to other amino acids
Temperature
Ratio of
dependency
action to
Temperature
ratio
xylose
dependency
(taking
Action to
(taking
Variant
(%)
Mut1 as 1)
xylose (%)
Mut1 as 1)
Mut1
62.55
1.00
10.50
1.00
F
69.07
1.10
5.87
0.56
I
N.D.
N.D.
N.D.
N.D.
L
68.51
1.10
3.74
0.36
P
N.D.
N.D.
N.D.
N.D.
Q
67.30
1.08
6.15
0.59
R
73.04
1.17
3.12
0.30
S
69.61
1.11
4.70
0.45
W
68.88
1.10
9.37
0.89
Y
68.77
1.10
7.72
0.74
Example E4
Optimization of Amino Acid at Position 60
[0272] With a method similar to that in Example E2, optimization of amino acid was conducted using synthetic oligonucleotides of SEQ ID NO: 29 designed such that the amino acid at position 60 is substituted with 20 types of amino acids, and synthetic oligonucleotides complementary thereto. A plasmid containing a modified FADGDH having a substitution at position 60 to C was named pAOGDH-M76-S60C; a plasmid containing a modified FADGDH having a substitution at position 60 to D was named pAOGDH-M76-S60D; a plasmid containing a modified FADGDH having a substitution at position 60 to G was named pAOGDH-M76-S60G; a plasmid containing a modified FADGDH having a substitution at position 60 to I was named pAOGDH-M76-S60I; a plasmid containing a modified FADGDH having a substitution at position 60 to K was named pAOGDH-M76-S60K; a plasmid containing a modified FADGDH having a substitution at position 60 to L was named pAOGDH-M76-S60L; a plasmid containing a modified FADGDH having a substitution at position 60 to N was named pAOGDH-M76-S60N; a plasmid containing a modified FADGDH having a substitution at position 60 to T was named pAOGDH-M76-S60T; a plasmid containing a modified FADGDH having a substitution at position 60 to V was named pAOGDH-M76-S60V; and a plasmid containing a modified FADGDH having a substitution at position 60 to Y was named pAOGDH-M76-S60Y.
Example E5
Comparison of Temperature Dependencies and Actions to Xylose of Modified FADGDHs having Optimized Amino Acids at Position 60
[0273] With a method similar to that in Example E3, crude enzyme liquids of the modified FADGDHs were prepared, and temperature dependencies and actions to xylose were measured. The results of the temperature dependencies and actions to xylose of the modified FADGDHs are shown in Table 8.
[0274] Table 8 shows the results of comparison of temperature dependencies and actions to xylose of the modified FADGDHs having modifications at position S60 when culturing was performed for 24 hours at 30° C. in 5 ml LB medium/test tubes.
[0275] The modified FADGDHs, having a substitution at position 60 to C, D, G, and N, not only had reduced temperature dependencies but also had reduced actions to xylose when compared to the pre-modified FADGDH (Mut1). Furthermore, the modified FADGDHs having a substitution at position 60 to L, T, and V had improved temperature dependencies when compared to the pre-modified FADGDH (Mut1).
[0000]
TABLE 8
Comparison of temperature dependencies and actions
to xylose of modified FADGDHs having a substitution
at S60 to 9 types of amino acids
Temperature
Ratio of
dependency
action to
Temperature
ratio
xylose
dependency
(taking
Action to
(taking
Variant
(%)
Mut1 as 1)
xylose (%)
Mut1 as 1)
Mut1
62.55
1.00
10.30
1.00
C
82.36
1.32
5.16
0.50
D
68.93
1.10
9.30
0.90
G
64.74
1.03
9.10
0.88
I
N.D.
N.D.
N.D.
N.D.
K
62.74
1.00
10.23
0.99
L
68.86
1.10
12.74
1.24
N
68.04
1.09
7.79
0.76
T
63.00
1.01
10.14
0.98
V
67.56
1.08
15.06
1.46
Y
62.05
0.99
10.11
0.98
INDUSTRIAL APPLICABILITY
[0276] Usage of an FAD dependent glucose dehydrogenase of the present invention having improved temperature dependency allows improving precision of glucose measurement, and has a large contribution to industries in medical related fields and the like.
|
Provided is an enzyme that is further advantageous in terms of practical aspects when compared to publicly known enzymes for blood sugar sensors, and that can be used in a blood sugar level measuring reagent.
A flavin adenine dinucleotide-dependent glucose dehydrogenase that has amino acid sequence including a specific amino acid in an amino acid sequence shown in SEQ ID NO: 2 or an amino acid sequence that has a 60% homology therewith, and that has an improved temperature dependency.
| 2 |
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] Pursuant to 35 U.S.C. §119 and the Paris Convention Treaty, this application claims priority benefits to Chinese Patent Application No. 200810197315.4 filed on Oct. 21, 2008, the contents of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention relates to a small-molecule nucleotide sequence (DNA aptamer) and a method of preparing the same, and more particularly to a small-molecule nucleotide sequence for hepatitis C virus (HCV), preparation method and method of use thereof.
[0004] 2. Description of the Related Art
[0005] Hepatitis C virus (HCV) was firstly identified in 1989. Nowadays, approximately 170 million people worldwide suffer from this infectious disease. In China, the number is about 3.2% of total population, and 80% of acute infections become persistent. More terribly, the infection rate has been increasing with passing day.
[0006] The hepatitis C virus (HCV) is mainly spread by blood-to-blood contact. The infection is often asymptomatic, but once established, chronic infection can progress to scarring of the liver (fibrosis), and advanced scarring (cirrhosis). In some cases, those with cirrhosis will go on to develop liver cancer. Clinical treatment of hepatitis C basically depends on anti-virus medication such as IFN-α or IFN-α coupling with ribavirin. However, the treatment has some effect only on those in early infection, and no vaccine against hepatitis C is available to date. Therefore, to detect HCV accurately and sensitively in blood source before transfusion is a key step for prevention of HCV infection.
[0007] Now it is clear that HCV is a single-stranded positive RNA-containing member of the flavivirus family, approximately 9.6 kb in length. It contains a single large open reading frame (ORF). The HCV ORF encodes a polypeptide of about 3010 amino acid residues. This polypeptide has been proteolyticaly processed into 9 different structural proteins and non structural proteins by the co-action of proteolytic enzymes of HCV and a host thereof. After the host signal peptide is hydrolyzed, HCV envelope glycoprotein E1 (gp35) and E2 (gp70) come into being. Although the infection and replication mechanism of the virus is not definitely clear from molecular level, the glycoprotein E2 is very important for the virus to adhere to and invade host cells. The glycoprotein E2 adheres to and invades host cells at early infection by recognizing and binding to CD81, a surface receptor of human liver cells.
[0008] Nowadays, clinical methods of detecting and diagnosing HCV infection include: (1) enzyme-linked immunosorbent assay (ELISA) to detect antibody against HCV, such as recombinant immunoblot assay (RIBA); (2) RT-PCR to detect HVC RNA, such as fluorescent PCR, immune-PCR(PCR-ELISA), and branch DNA (bDNA) technology; and (3) biochip detection technology to detect HCV gene.
[0009] ELISA is easy for practice and has been widely used by blood collection and supply agencies, but the method can not detect HCV from blood samples of patients in window phase (in this phase, a patient has been infected but no antibody produced), and a false positive or false negative result may be obtained due to a series of uncertain factors including but not limited to the sensitivity of kit, the technical proficiency of operators, their sense of responsibility, laboratory temperature, and the quality of sample-adding instrument.
[0010] RT-PCR is costly. Although branch DNA (bDNA) technology features high stability, repeatability, and an accurate result, its disadvantages such as low amplification, low sensitivity, narrow detection range, and being not applicable for detecting a low level of HCV RNA are also obvious.
[0011] Biochip detection technology is suitable for study of the HCV epidemiology, mutation trend, transmission mode, disease determination, treatment guidance, efficacy prediction, and prognosis. However, the cost is high and a false negative result occurs easily.
[0012] Due to a variety of disadvantages above-mentioned, a novel clinical method for detection of HCV antigen, particularly HCV envelope antigen, is urgently required. The method should have high specificity, low cost, rapid diagnosis and is easy for practice.
[0013] In recent years, the study of DNA aptamers opens a new channel for treatment of various diseases. As a reagent for early diagnosis and treatment of HCV, HCV-E2 DNA aptamer plays an important role in screening HCV of blood donors, determining an early infection, fighting against HCV infection, and treating hepatitis C. Furthermore, aptamers will replace antibody in some aspects and thereby develop into a novel receptor inhibitor and detection reagent.
[0014] SELEX (Systematic Evolution of Ligands by Exponential Enrichment) technology is a new combinatorial chemistry technology developed in the early 1990s. The principle of the technology is that a large amount of random oligonucleotide library is selected, amplified through PCR, specifically bound to target molecules, and screened repetitively to yield an aptamer having high affinity and specificity. The advantages of the technology include large library capacity, a wide range of target molecules, high affinity, and wide application. The method has been applied to screening of various target molecules including metal ions, organic dyes, proteins, drugs, amino acids, and a variety of cytokines. The method is simple, rapid, and economic. Compared with other combinational chemical libraries such as random peptide libraries, antibody libraries, and phage display libraries, aptamers screened from oligonucleotide libraries have much higher affinity and specificity, with good prospects. Compared with conventional antibody, aptamers have low molecular weight, penetrate into cells more quickly, and can be synthesized stably and removed quickly, and easy for modification. Therefore, it is very promising as a new reagent of prevention, diagnosis and treatment of diseases.
[0015] So, according to the above description, to screen small-molecule nucleotide aptamer against HCV by SELEX technology will lay the foundation for the study of HCV infection mechanism and the development of diagnostic reagents against HCV.
SUMMARY OF THE INVENTION
[0016] In view of the above-described problems, it is one objective of the invention to provide a small-molecule nucleotide aptamer for hepatitis C virus (HCV) which functions as an antagonist for prevention and treatment of hepatitis C.
[0017] It is another objective of the invention to provide a method of preparing a small-molecule nucleotide aptamer against HCV which functions as an antagonist for prevention and treatment of hepatitis C.
[0018] It is still another objective of the invention to provide a pharmaceutical composition for prevention and treatment of hepatitis C.
[0019] It is further an objective of the invention to provide a diagnostic reagent for detection of HCV surface antigen.
[0020] It is still another objective of the invention to provide a method for detection of HCV infection.
[0021] In another aspect, the invention provides a method of prevention and treatment of HCV infection.
[0022] To achieve the above objectives, in accordance with one embodiment of the invention, provided is a DNA aptamer against HCV comprising a nucleotide sequence as shown in SEQIDNO.1, SEQIDNO.2, SEQIDNO.3, SEQIDNO.4, SEQIDNO.5, SEQIDNO.6, SEQIDNO.7, SEQIDNO.8, SEQIDNO.9, SEQIDNO.11, SEQIDNO.12, SEQIDNO.13, SEQIDNO.14, SEQIDNO.15, SEQIDNO.16, SEQIDNO.17, SEQIDNO.18, SEQIDNO.19, SEQIDNO.20, SEQIDNO.21, SEQIDNO.22, SEQIDNO.23, SEQIDNO.24, SEQIDNO.25, SEQIDNO.26, SEQIDNO.27, SEQIDNO.28, and SEQIDNO.29.
[0023] In accordance with another embodiment of the invention, provided is a method of preparing a small-molecule nucleotide aptamer against HCV which functions as an antagonist for prevention and treatment of hepatitis C, the method comprising the steps of:
a) constructing a single-stranded DNA (ssDNA) library (88 base), 5′-GCGGAATTCTAATACGACTCACTATAGGGAACAGTCCGA GCC-N 30 -GGGTCAATGCGTCATA-3′, an upstream primer, 5′-GCGGAATTC TAATACGACTCACTATAGGG AACAGTCCGAGCC-3′, and a downstream primer, 5′-GCGGGATCCTATGACGCATTGACCC-3′, wherein N represents A, G, T, or C, the library capacity is between 10 14 and 10 15 , the underlined part comprises a T7 promoter sequence, the upstream primer comprises an EcoRI restriction site, and the downstream primer comprises an BamHI restriction site; the single-stranded DNA library and primers can be purchased from a primer synthesis company (such as SBS Genetech Co., Ltd.); b) amplifying the single-stranded DNA library into a double-stranded DNA (dsDNA) library (totally 14 cycles), conserving, and amplifying the double-stranded DNA library to yield another single-stranded DNA library for next screening, the reaction program for PCR being 94° C. 4 min, 94° C. 30 s, 56° C. 45 s, 72° C. 90 s, for 18-25 cycles, and then 72° C. 7 min; the best amplification effect being obtained by modifying the cycle number (18-25 cycles); c) electrophoresing a product of PCR amplification from step b) with 2 g/100 mL agarose gel containing 0.5 μg/mL ethidium bromide, placing the resultant product on a 260 nm fluoroscopy board, cutting an orange stripe, and purifying the orange stripe with a DNA purification kit (manufactured by Qiagen Co., Ltd., German); d) placing 8 μg of ssDNA aptamer from step c) in a bath at 85° C. for 15 min and in an ice bath for 5 min respectively, mixing with CT26-HCV-E2 (10 8 ) in a 1× screening buffer, oscillating at 37° C. for 30 min, 2000 rpm for 5 min, removing supernatant, washing with 1× screening eluent for 4-6 times, centrifugating, collecting cells, blowing homogenously with 50 μL of sterile double-distilled water, boiling for 5 min, putting in an ice bath, extracting with phenol:chloroform=25:24, collecting supertanant, amplifying to yield a dsDNA library, performing single-stranded amplification with the dsDNA library as a template, and purifying by the method of step c) to yield ssDNA aptamer for next screening; the screening buffer 2× is 25 mmol/L Tris-HCl buffer, 50 mmol/L KCl, 200 mmol/L NaCl, 0.2 mmol/L EDTA, 5 mL/100 mL of glycerol, or 0.5 mmol/L dithiothreitol (DTT); the screening eluent 2× is 25 mmol/L Tris-HCl buffer, 50 mmol/L KCl, 1 mol/L NaCl, 0.2 mmol/L EDTA, 5% glycerol, or 0.5 mmol/L dithiothreitol (DTT); e) repeating step d) for a second and a third round of screening with 10 8 CT26-HCV-E2 (Li P F, et al., Vaccine, 25: 1544-1551), and the ssDNA ampamer obtained from the previous round is used for next round of screening; f) collecting 8 μg of single-stranded DNA aptamer from the third round of screening, placing in a bath at 85° C. for 15 min and in an ice bath for 5 min respectively, mixing with 10 6 CT26 (Li P F, et al., Vaccine, 25: 1544-1551) in a 1× screening buffer, oscillating at 37° C. for 30 min, 2000 rpm for 5 min, collecting supernatant, mixing with 10 6 CT26-HCV-E2 in a 1× screening buffer, oscillating at 37° C. for 30 min, 2000 rpm for 5 min, washing with 1× screening eluent for 4-6 times, centrifugating, collecting cells, blowing homogenously with 50 μL of sterile double-distilled water, boiling for 5 min, putting in an ice bath, extracting with phenol:chloroform=25:24, collecting supertanant, amplifying to yield dsDNA library, and performing single-stranded amplification with the dsDNA library as a template to yield ssDNA aptamer for next screening; g) repeating step f) for a fifth and a sixth round of screening, and the ssDNA ampamer obtained from the previous round is used for next round of screening; repeating step f) for a seventh, eighth, and ninth round of screening, and the CT26 is 10 7 , the CT26-HCV-E2 is 10 6 , the ssDNA ampamer obtained from the previous round is used for next round of screening; repeating step f) for a tenth to fourteenth round of screening, and the CT26 is 10 8 , the CT26-HCV-E2 is 10 5 , the ssDNA ampamer obtained from the previous round is used for next round of screening; and h) comparing the affinity of each round of ssDNA with CT26-HCV-E2, amplifying an ssDNA aptamer having the highest affinity (the thirteenth round of aptamer) with CT26-HCV-E2 following the method of step b) to yield dsDNA, digesting with DNA endonuclease EcoRI and BamHI, connecting to plasmid pUC19 (Yanisch-Perron, C., et al., 1985), transforming into E. coli DH5α (Hanahan, D., 1983; Tartof, K. D., et al., 1987), screening with ampicillin, and sequencing screened single bacterial colony.
[0034] By the method, the obtained aptamers are SEQIDNO.1, SEQIDNO.2, SEQIDNO.3, SEQIDNO.4, SEQIDNO.5, SEQIDNO.6, SEQIDNO.7, SEQIDNO.8, SEQIDNO.9, SEQIDNO.11, SEQIDNO.12, SEQIDNO.13, SEQIDNO.14, SEQIDNO.15, SEQIDNO.16, SEQIDNO.17, SEQIDNO.18, SEQIDNO.19, SEQIDNO.20, SEQIDNO.21, SEQIDNO.22, SEQIDNO.23, SEQIDNO.24, SEQIDNO.25, SEQIDNO.26, SEQIDNO.27, SEQIDNO.28, and SEQIDNO.29 as shown in Sequence Listing.
[0035] The obtained small-molecule nucleotide aptamer can play the following roles described below for prevention or treatment of HCV infection.
[0036] 1. The small-molecule nucleotide aptamer inhibits competitively the binding of the acceptor CD81 (Cao J, et al., et al., 2007, J Microbiol Methods, 68(3):601-4) to HCV (Zhong J, et al., 2005, Proc Natl Acad Sci USA, 102(26): 9294-9) antigen E2. CD81 is a receptor of HCV envelope glycoprotein E2, and can inhibit the binding of the aptamer to CT26-HCV-E2. 300 ng/100 μL purified CD81 and cells were incubated at 37° C. for 60 min, 2000 rpm, and the precipitated cells were washed with PBS thrice. 4 μg of FITC-labeled aptamer/100 μL was added, incubated, and washed following the method described above. A control group without CD81 was established. The fluorescence intensity was measured with a flow cytometry. The results showed CD81 inhibited the binding of both aptamer library and a single aptamer to HCV antigen E2, which meant CD81 competed with the aptamer to bind to E2. Different single aptamer has different binding site with E2. Therefore, the aptamer can be used as a medication interfering in the binding of HCV to acceptors in vivo.
[0037] 2. Experiments of small-molecule nucleotide aptamer inhibiting the binding of HCV envelop antigen E2 to human liver cells
[0038] Human liver cancer cells Huh 7.5.1 have natural HCV acceptors, following the method described above, the similar results are obtained (the binding rate decreases from 36.7% to 15.4%), which means the aptamer can inhibit the binding of GST-E2 (Li P F, et al., Vaccine, 25: 1544-1551.) to Huh 7.5.1 (Zhong J, et al., 2005, Proc Natl Acad Sci USA, 102(26):9294-9). Further experiment showed that the inhibition exhibited dose-dependent and dose-saturated.
[0039] 3. Application of small-molecule nucleotide aptamer as material for preparation of medication for prevention or treatment of HCV infection, i.e., experiments of small-molecule nucleotide aptamer inhibiting the infection of live HCV on human liver cells
[0040] 1) Immunofluorescence
[0041] a) Huh 7.5.1 cells were cultured in a 96-well plate, 37° C. and 5% CO 2 ;
[0042] b) HCV (3×10 5 , 18 μL)+samples (8 μg and 4 μg of aptamer), 37° C. for an hour (three wells, 180 μL/well);
[0043] c) Huh 7.5.1 cells were washed with PBS, and the incubated virus were added, cultured at 37° C. and 5% CO 2 for 5 hours;
[0044] d) the cells were washed, added to a culture medium, and cultured at 37° C. and 5% CO 2 for 72 hours;
[0045] e) the cells were washed and monoclonal antibody HCV-E2 was added for further culture (Zhong J, et al., 2005, Proc Natl Acad Sci USA, 102(26):9294-9); and
[0046] f) the cells were washed and red fluorescence points of each well were counted under a fluorescence microscope (ffu/well, 580 nm).
[0047] 2) Fluorescent Real-Time Quantitative RT-PCR Method
[0048] QuantiTect SYBR Green PCR Handbook Kit (manufactured by QIAGEN Co., Ltd) was used to quantifying HCV RNA of cells. Huh 7.5.1 cells were cultured in a 6-well plate, 4.5×10 5 /well, and aptamers, mutants thereof having different concentration, or 500 U IFN-α was added. 200 μL of JFH1-HCVcc (the content of virus was 10 7 copies) was further added. The resultant plate was culture overnight at 37° C. The supernatant was removed. The cells were washed with DEPC-treated PBS, and the total RNA was extracted with TRIzol (manufactured by Invitrogen Life Technologies Co., Ltd.). The RNA (the total volume 20 μL) was transcripted reversly with First Strand cDNA synthesis kit (manufactured by Fergment Co., Ltd.), at presence of 0.5 μg oligo(dT)18 as a primer, 1 μL of RNase inhibitor, 1 μL of M-MLV reverse transcriptase, and 2 μL of 10×RT buffer (manufactured by Ambion Co., Ltd.), firstly 42° C. for 45 min, and then 75° C. for 10 min to synthesize cDNA. The upstream and downstream primers for HCV amplification were 5′AATGGCTCGAGGAAACTGTGAAGCGA3′ and 5′TTCATCATGCCAATGGTGTTCGTGGC3′ respectively. The PCR program was: 94° C. for 5 min, 95° C. for 10 s, 58° C. for 20 s, and 72° C. for 30 s, totally 45 cycles. The results were analyzed by Rotogene software.
[0049] 3) Western Blot Method
[0050] Huh 7.5.1 cells were cultured in a 6-well plate, 4.5×10 5 /well, and aptamers, mutants thereof having different concentration, or 500 U IFN-α was added. 200 μL of JFH1-HCVcc (the content of virus was 10 7 copies) was further added. The resultant plate was culture overnight at 37° C. The cells were dissolved in a 200 μL of SDS-loading buffer at 100° C. for 5 min and electrophoresed at 12% SDS-polyacrylamide gel solution. The obtained proteins were transferred to a PVDF membrane. HCV-E2 was measured by anti-E2 antibody. β-actin (internal reference) was measured by anti-β-actin antibody.
[0051] 4. Cytotoxicity Assay of Aptamers
[0052] a) Huh 7.5.1 cells were cultured in a 96-well plate, about 3×10 3 cells/well;
[0053] b) after the cells were attached to the wall, aptamers having different concentration were added, 6 wells for each concentration;
[0054] c) 72 hours later, the supertanant was removed, 80 μL new medium was added, 20 μL of 5 mg/mL MTT was further added to each well and cultured for 4 hours;
[0055] d) the supertanant was removed and 150 μL of DMSO was added, mixing, and shaking for 10 min to make crystal dissolved completely; and
[0056] e) OD 570 was measured by an ELISA reader to calculate IC 50 .
[0057] Inhibition rate=((control−blank)−(sample−blank))/(control−blank)×100%
[0058] 1 gIC50=Xm−I(P−(3−Pm−Pn)/4), wherein Xm represents 1 g(maximum dose), I represents 1 g(maximum dose/adjacent dose), P represents the summation of positive response rate, Pm represents maximum positive response rate, and Pn represents minimum positive response rate.
[0059] The measured IC 50 of single aptamer=3.35×104 μg/100 μL=10.47 mmol/L.
[0060] Advantages of the invention are summarized below:
1) The aptamers of the invention can significantly inhibit HCV infection on cells by binding to HCV envelop glycoprotein E2. The aptamers have low toxicity, can be used directly as an antagonist against HCV for detection, prevention, and treatment of hepatitis C. That the aptamers of the invention is screened with SELEX technology ensures the aptamers can bind to HCV active site, and thereby HCV can not bind to CD81, can not enter a host cell, and can not stay and multiply in vivo, all of which benefit the immune system to eliminate the virus. 2) The aptamers of invention provide effective and powerful means for early and sensitive detection of HCV. HCV is mainly spread by blood-to-blood contact. The infection is often asymptomatic, but once established, chronic infection can progress to scarring of the liver (fibrosis), and advanced scarring (cirrhosis). In some cases, those with cirrhosis will go on to develop liver cancer. No vaccine against hepatitis C is available to date. Therefore, to detect HCV accurately and sensitively in blood source before transfusion is a key step for prevention of HCV infection. ELISA has been widely used for detection HCV antibody to determine whether an infection occurs. However, during the early HCV infection, or for a patient with immunodeficiency syndrome, no antibody produced even there is an HCV infection. Furthermore, by ELISA, a false positive or false negative result may be obtained. As another assistant method for detection of HCV infection, RT-PCR is costly, cause pollution easily, so it is not suitable for clinical application. Therefore, DNA aptamers are a better diagnostic reagent for early detection of HCV than antibody. 3) The aptamers of the invention are small-molecule nucleotide, with different molecular structure compared with any other broad-spectrum antibiotic, so there is no question about its resistance. Additionally, DNA aptamers of the invention are specific to HCV, cause no harm to a variety of beneficial bacteria and cells in vivo. Compared with protein antibody, DNA aptamers have small molecular weight, penetrate into cells quickly, no antigenicity, and cause no side effect. 4) The aptamers (libraries) of the invention have been cloned to plasmid pUC19 which has been transformed to E. Coli DH5α, so the aptamers can be produced in large scale by the bacteria. The aptamers can also be synthesized directly.
BRIEF DESCRIPTION OF THE DRAWINGS
[0065] The invention is described hereinbelow with reference to accompanying drawings, in which:
[0066] FIG. 1 shows an establishment of stable cell line CT26-HCV-E2 which expresses protein HCV-E2 according to one embodiment of the invention; there are more protein E2 at the surface of cells CT26-HCV-E2 than that of CT26, and E2-CT26 can be used as target cells for screening HCV-E2 aptamers; A: protein E2 expressed at the surface of cells CT26-HCV-E2; B: protein E2 expressed in the cytoplasm of cells CT26-HCV-E2;
[0067] FIG. 2 is a flow chart of screening specific aptamers against HCV with CELL-SELEX technology according to one embodiment of the invention; randomly synthesized single-stranded oligonucleotide libraries are mixed with cells CT26-HCV-E2, unbound aptamers are removed, after three rounds of screening, cells CT26 are added for negative screening, there are totally 14 rounds of screening; finally, aptamers which can bind to E2-CT26 and not bind to CT26 are screened by SELEX;
[0068] FIG. 3 is a schematic diagram of amplification of single-stranded and double-stranded DNA according to one embodiment of the invention; before each round of screening, an ssDNA library are amplified into a dsDNA library, conserved, and the obtained dsDNA is further amplified into another ssDNA library for next screening; the figure shows an electrophoretic mobility of ssDNA and dsDNA, and after PCR, the aptamers are used for screening (M: Marker; 1-5: ssDNA; 6-10: dsDNA);
[0069] FIG. 4 shows an binding capacity of ssDNA aptamer library with cells CT26-HCV-E2 according to one embodiment of the invention; each round of screened ssDNA (8 μg) are mixed with 10 6 CT26-HCV-E2 respectively, and the results show the thirteenth round of aptamer library has the strongest binding capacity with the cells, and the binding is dose-dependent; A: the thirteenth round of aptamer library has the strongest binding capacity (89%); B: the binding capacity of a single aptamer cloned from the thirteenth round of aptamer library with E2-CT26 is dose-dependent;
[0070] FIG. 5 shows the receptor CD81 of HCV-E2 can inhibit the binding of the screened aptamer libraries (the thirteenth and the twelfth) and a single aptamer with protein E2 according to one embodiment of the invention; CD81 is a receptor of HCV envelope glycoprotein E2, and can inhibit the binding of the aptamer to CT26-HCV-E2; 300 ng/100 μL purified CD81 and cells are incubated, and then 4 μg of FITC-labeled aptamer/100 μL is added; a control group without CD81 is established; the results showed CD81 inhibits the binding of both aptamer library (for the thirteenth library, the binding rate decreases from 10.2% to 7.6%) and a single aptamer (the binding rate decreases from 14.8% to 5.8%), particularly for a single aptamer; the figure shows the screened aptamer libraries (the thirteenth library and the twelfth library) and the single aptamer can inhibit the binding of HCV-E2 to an acceptor thereof; 4thP: the fourth round of screened library; 12thP: the twelfth round of screened library; 13thP: the thirteenth round of screened library; the single aptamer is cloned from the thirteenth round of screened library;
[0071] FIG. 6 shows aptamers inhibit the binding of HCV-E2 to human liver cells according to one embodiment of the invention; human liver cancer cells Huh 7.5.1 have born HCV acceptors, and the binding rate of the cells to protein GST is 1%, to protein E2 36.7%; after addition of the thirteenth round of aptamer, the binding rate decreases to 23.2%, and after addition of a single aptamer, the binding rate decreases to 15.4%, which means that the aptamer can inhibit the binding of HCV to an acceptor thereof; 1stP: the first round of screened library; 6thP: the sixth round of screened library; 13thP: the thirteenth round of screened library;
[0072] FIG. 7 shows aptamers inhibit the infection of live HCV on liver cells according to one embodiment of the invention, and the inhibition is dose-dependent; 7 A: a single aptamer inhibits the infection of HCV JFH-1 on liver cell Huh 7.5.1, and the infection is dose-dependent, H represents a high dose, L represents a low dose, and the result is obtained by an immunofluorescence microscope; 7 B: an aptamer inhibits the infection of HCVcc on liver cell Huh 7.5.1 by fluorescent real-time quantitative RT-PCR method, and the infection is dose-dependent; 7 C: an aptamer inhibits the infection of HCVcc on liver cell Huh 7.5.1 by Western blot method, and the infection is dose-dependent; 7 D: an aptamer inhibits the infection of HCVcc on liver cell Huh 7.5.1 with an immune confocal microscope, while an mutant of the aptamer has no obvious inhibition capacity; and
[0073] FIG. 8 shows a result of cytotoxic assay of an aptamer according to one embodiment of the invention, and IC 50 =3.35×104 μg/100 μL=10.47 mmol/L.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0074] For further illustrating the invention, embodiments detailing a small-molecule nucleotide sequence for hepatitis C virus (HCV), preparation method and method of use thereof are described below. It should be noted that the following embodiments are intended to describe and not to limit the invention.
[0075] In the invention, a DNA aptamer against HCV comprising a nucleotide sequence as shown in SEQIDNO.1-29 is constructed.
[0076] Secondly, provided is a method of preparing a small-molecule nucleotide aptamer against HCV which functions as an antagonist for prevention and treatment of hepatitis C, the method comprising the steps of:
a) constructing a single-stranded DNA (ssDNA) library (88 base), 5′-GCGGAATTCTAATACGACTCACTATAGGGAACAGTCCGA GCC-N 30 -GGGTCAATGCGTCATA-3′, an upstream primer, 5′-GCGGAATTC TAATACGACTCACTATAGGG AACAGTCCGAGCC-3′, and a downstream primer, 5′-GCGGGATCCTATGACGCATTGACCC-3′, wherein N represents A, G, T, or C, the library capacity is between 10 14 and 10 15 , the underlined part comprises a T7 promoter sequence, the upstream primer comprises an EcoRI restriction site, and the downstream primer comprises an BamHI restriction site; the single-stranded DNA library and primers can be purchased from Shanghai Bioengineering Company; b) amplifying the single-stranded DNA library into a double-stranded DNA (dsDNA) library (totally 14 cycles), conserving, and amplifying the double-stranded DNA library to yield another single-stranded DNA library for next screening, the reaction program for PCR being 94° C. 4 min, 94° C. 30 s, 56° C. 45 s, 72° C. 90 s, for 18-25 cycles, and then 72° C. 7 min; the best amplification effect being obtained by modifying the cycle number (18-25 cycles); c) electrophoresing a product of PCR amplification from step b) with 2 g/100 mL agarose gel containing 0.5 μg/mL ethidium bromide, placing the resultant product on a 260 nm fluoroscopy board, cutting an orange stripe, and purifying the orange stripe with a DNA purification kit; the purification kit being purchased from Qiagen Company, German; d) placing 8 μg of ssDNA aptamer from step c) in a bath at 85° C. for 15 min and in an ice bath for 5 min respectively, mixing with CT26-HCV-E2 (10 8 ) in a 1× screening buffer, oscillating at 37° C. for 30 min, 2000 rpm for 5 min, removing supernatant, washing with 1× screening eluent for 4-6 times, centrifugating, collecting cells, blowing homogenously with 50 μL of sterile double-distilled water, boiling for 5 min, putting in an ice bath, extracting with phenol:chloroform=25:24, collecting supertanant, amplifying to yield a dsDNA library, performing single-stranded amplification with the dsDNA library as a template, and purifying by the method of step c) to yield ssDNA aptamer for next screening; the screening buffer 2× is 25 mmol/L Tris-HCl buffer, 50 mmol/L KCl, 200 mmol/L NaCl, 0.2 mmol/L EDTA, 5 mL/100 mL of glycerol, or 0.5 mmol/L dithiothreitol (DTT); the screening eluent 2× is 25 mmol/L Tris-HCl buffer, 50 mmol/L KCl, 1 mmol/L NaCl, 0.2 mmol/L EDTA, 5% glycerol, or 0.5 mmol/L dithiothreitol (DTT); e) repeating step d) for a second and a third round of screening with 10 8 CT26-HCV-E2, and the ssDNA ampamer obtained from the previous round is used for next round of screening; f) collecting 8 μg of single-stranded DNA aptamer from the third round of screening, placing in a bath at 85° C. for 15 min and in an ice bath for 5 min respectively, mixing with 10 6 CT26 in a 1× screening buffer, oscillating at 37° C. for 30 min, 2000 rpm for 5 min, collecting supernatant, mixing with 10 6 CT26-HCV-E2 in a 1× screening buffer, oscillating at 37° C. for 30 min, 2000 rpm for 5 min, washing with 1× screening eluent for 4-6 times, centrifugating, collecting cells, blowing homogenously with 50 μL of sterile double-distilled water, boiling for 5 min, putting in an ice bath, extracting with phenol: chloroform=25:24, collecting supertanant, amplifying to yield dsDNA library, and performing single-stranded amplification with the dsDNA library as a template to yield ssDNA aptamer for next screening; g) repeating step f) for a fifth and a sixth round of screening, and the ssDNA ampamer obtained from the previous round is used for next round of screening; repeating step f) for a seventh, eighth, and ninth round of screening, and the CT26 is 10 7 , the CT26-HCV-E2 is 10 6 , the ssDNA ampamer obtained from the previous round is used for next round of screening; repeating step f) for a tenth to fourteenth round of screening, and the CT26 is 10 8 , the CT26-HCV-E2 is 10 5 , the ssDNA ampamer obtained from the previous round is used for next round of screening; and h) comparing the affinity of each round of ssDNA with CT26-HCV-E2, amplifying an ssDNA aptamer having the highest affinity (the thirteenth round of aptamer) with CT26-HCV-E2 following the method of step b) to yield dsDNA, digesting with DNA endonuclease EcoRI and BamHI, connecting to plasmid pUC19 (Yanisch-Perron, C., et al., 1985), transforming into E. coli DH 5α(Hanahan, D., 1983; Tartof, K. D., et al., 1987), screening with ampicillin, and sequencing screened single bacterial colony.
[0087] The obtained small-molecule nucleotide aptamer can play the following role described below for prevention or treatment of HCV infection.
[0088] 1. The small-molecule nucleotide aptamer inhibits competitively the binding of the receptor CD81 to HCV antigen E2. CD81 is a receptor of HCV envelope glycoprotein E2, and can inhibit the binding of the aptamer to CT26-HCV-E2. 300 ng/100 μL purified CD81 and cells were incubated at 37° C. for 60 min, 2000 rpm, and the precipitated cells were washed with PBS thrice. 4 μg of FITC-labeled aptamer/100 μL was added, incubated, and washed following the method described above. A control group without CD81 was established. The fluorescence intensity was measured with a flow cytometry. The results showed CD81 inhibited the binding of both aptamer library and a single aptamer (ZE18) to HCV antigen E2, particularly ZE18, but the inhibition on single aptamers ZE14 and ZE25 was not so significant, which meant CD81 competed with the aptamer to bind to E2, and different single aptamer has different binding site with E2. Therefore, the aptamer can be used as a medication interfering in the binding of HCV to acceptors in vivo.
[0089] 2. Experiments of small-molecule nucleotide aptamer inhibiting the binding of HCV envelop antigen E2 to human liver cells
[0090] Human liver cancer cells Huh 7.5.1 have born HCV acceptors, following the method described above, the similar results are obtained (the binding rate decreases from 36.7% to 15.4%), which means the aptamer can inhibit the binding of GST-E2 to Huh 7.5.1. Further experiment showed that the inhibition exhibited dose-dependent and dose-saturated.
[0091] 3. Application of small-molecule nucleotide aptamer as material for preparation of medication for prevention or treatment of HCV infection, i.e., experiments of small-molecule nucleotide aptamer inhibiting the infection of live HCV on human liver cells
[0092] 1) Immunofluorescence
[0093] a) Huh 7.5.1 cells were cultured in a 96-well plate, 37° C. and 5% CO 2 ;
[0094] b) HCV (3×10 5 , 18 μL)+samples (8 μg and 4 μg of aptamer), 37° C. for an hour (three wells, 180 μL/well);
[0095] c) Huh 7.5.1 cells were washed with PBS, and the incubated virus were added, cultured at 37° C. and 5% CO 2 for 5 hours;
[0096] d) the cells were washed, added to a culture medium, and cultured at 37° C. and 5% CO 2 for 72 hours;
[0097] e) the cells were washed and monoclonal antibody PE-E2 was added for further culture (Zhong J, et al., 2005, Proc Natl Acad Sci USA, 102(26):9294-9); and
[0098] f) the cells were washed and red fluorescence points of each well were counted under a fluorescence microscope (ffu/well, 580 nm).
[0099] 2) Fluorescent Real-Time Quantitative RT-PCR Method
[0100] QuantiTect SYBR Green PCR Handbook Kit (manufactured by QIAGEN Co., Ltd.) was used to quantifying HCV RNA of cells. Huh 7.5.1 cells were cultured in a 6-well plate, 4.5×10 5 /well, and aptamers, mutants thereof having different concentration (4 μg/100 μL, 8 μg/100 μL, 16 μg/100 μL, and the mutants mutated by 2 base), or 500 U IFN-α was added. 200 μL of JFH1-HCVcc (the content of virus was 10 7 copies) was further added. The resultant plate was culture overnight at 37° C. The supernatant was removed. The cells were washed with DEPC-treated PBS, and the total RNA was extracted with TRIzol (manufactured by Invitrogen Life Technologies Co., Ltd.). The RNA (the total volume 20 μL) was transcripted reversly with First Strand cDNA synthesis kit (manufactured by Fergment Co., Ltd.), at presence of 0.5 μg oligo(dT)18 as a primer, 1 μL of RNase inhibitor, 1 μL of M-MLV reverse transcriptase, and 2 μL of 10×RT buffer (manufactured by Ambion Co., Ltd.), firstly 42° C. for 45 min, and then 75° C. for 10 min to synthesize cDNA. The upstream and downstream primers for HCV amplification were 5′AATGGCTCGAGGAAACTGTGAAGCGA3′ and 5′TTCATCATGCCAATGGTGTTCGTGGC3′ respectively. The PCR program was: 94° C. for 5 min, 95° C. for 10 s, 58° C. for 20 s, and 72° C. for 30 s, totally 45 cycles. The results were analyzed by Rotogene software.
[0101] 3) Western Blot Method
[0102] Huh 7.5.1 cells were cultured in a 6-well plate, 4.5×10 5 /well, and aptamers, mutants thereof having different concentration, or 500 U IFN-α was added. 200 μL of JFH1-HCVcc (the content of virus was 10 7 copies) was further added. The resultant plate was culture overnight at 37° C. The cells were dissolved in a 200 μL of SDS-loading buffer at 100° C. for 5 min and electrophoresed at 12% SDS-polyacrylamide gel solution. The obtained proteins were transferred to a PVDF membrane. HCV-E2 was measured by anti-E2 antibody. β-actin (internal reference) was measured by anti-β-actin antibody.
[0103] 4. Cytotoxicity Assay of Aptamers
[0104] a) Huh 7.5.1 cells were cultured in a 96-well plate, about 3×10 3 cells/well;
[0105] b) after the cells were attached to the wall, aptamers having 8 different of concentration (0.5-100 μg/100 μL) were added, 6 wells for each concentration;
[0106] c) 72 hours later, 20 μL of 5 mg/mL MTT was further added to each well and cultured for 4 hours;
[0107] d) the supertanant was removed and 100 μL of DMSO was added to terminate the reaction; and
[0108] e) OD 570 was measured by an ELISA reader to calculate IC 50 .
[0109] Inhibition rate=((control−blank)−(sample−blank))/(control−blank)×100%
[0110] 1 gIC50=Xm−I(P−(3−Pm−Pn)/4), wherein Xm represents 1 g(maximum dose), I represents 1 g(maximum dose/adjacent dose), P represents the summation of positive response rate, Pm represents maximum positive response rate, and Pn represents minimum positive response rate.
[0111] The measured IC50 of single aptamer=3.35×104 μg/100 μL=10.47 mmol/L.
[0112] While particular embodiments of the invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications may be made without departing from the invention in its broader aspects, and therefore, the aim in the appended claims is to cover all such changes and modifications as fall within the true spirit and scope of the invention.
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A DNA aptamer specific for HCV having a nucleotide sequence as shown in SEQIDNO.1-29, and a method of preparing the same including the steps of: (1) constructing a single-stranded DNA library; (2) constructing a double-stranded DNA library; (3) screening by SELEX; (4) amplifying by PCR; (5) cloning and sequencing; and (6) testing the effect from cellular level in vitro. The DNA aptamer can be used directly as medication and diagnostic reagent for detection, prevention, and treatment of hepatitis C. A method for detection of HCV infection is also provided.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The invention relates to fabrication of graded-index plastic optical fiber.
[0003] 2. Discussion of the Related Art
[0004] Glass optical fiber has become a significant transmission medium in recent years, particularly for long distance transmission applications. Such optical fiber has not found significant usage, however, in smaller scale applications, such as distribution of fiber to the desk in local area networks. In particular, glass optical fiber has not been as cost effective as, for example, copper wire, and connectorization of glass fiber (which needs well-polished end faces) requires substantial time, skilled personnel, and precise connector components. There has been interest, therefore, in pursuing plastic optical fiber (POF). POF offers many of the benefits of glass optical fiber, but is expected to be more cost effective, and POF also offers a larger core that makes connection easier.
[0005] Initially, step index POF (having a core of one refractive index, surrounded by a cladding of a lower refractive index) was manufactured and used. Unfortunately, the modes propagating in a step index fiber experience an undesirably high level of dispersion, thereby limiting the fiber's capability. In response to this problem, graded index POF (GI-POF) was developed, which possesses a varying refractive index from the core to the cladding layer. GI-POF exhibits a lower level of mode dispersion, thereby providing improved properties. GI-POF, however, was more difficult, and thus more expensive, to manufacture than step index POF. Improved methods for manufacturing GI-POF were therefore sought.
[0006] One method of forming GI-POF is to start with a preform, similar to the preform from which glass optical fiber is generally drawn. See, e.g., U.S. Pat. Nos. 5,639,512 and 5,614,253, which discuss a process for chemical vapor deposition (CVD) formation of a preform for GI-POF. According to the process, a polymer and a refractive index modifier are deposited onto a rod, and the amount of refractive index modifier is varied during the deposition to provide the desired refractive index profile. While such preforms are useful for preparing GI-POF, easier processes are desired.
[0007] One alternative to preform-formation is extrusion, which is commonly used with plastics to form a variety of items. Extrusion was expected to be quicker and cheaper than forming and drawing a preform, but the need for a graded refractive index profile created complications. U.S. Pat. No. 5,593,621 (the '621 patent) discusses an extrusion process for GI-POF. According to the '621 patent, GI-POF is manufactured by extruding one material circumferentially around another material, e.g., by use of a concentric nozzle. At least one of the materials contains a diffusible material having a distinct refractive index, such that the diffusion of the material provides the desired refractive index contrast. The method of the '621 patent appears to offer a functional process, but also appears to exhibit several drawbacks.
[0008] In particular, it is not clear that the process is able to be performed without providing a delay time (stopping the flow of material) or a very slow extrusion speed, to allow the diffusible material sufficient time to diffuse. Specifically, the examples disclose a small distance, 3 cm, between the outlet of concentric nozzle 5 (see FIG. 1) and the outlet of core nozzle 3 . Thus, the two materials are in contact only over this small distance before exiting the apparatus. It is unclear whether this small contact distance allows sufficient diffusion, without requiring either intermittent stoppage or an extremely slow extrusion speed. It appears that either stoppage or low speed was used, because, for example, Embodiment 6 states that diffusion was effected for about 3 minutes within this contact region, and Embodiments 7 , 8 , and 9 all state that diffusion occurred for about 10 minutes in the contact region. Unfortunately, the reference does not disclose an extrusion speed nor make clear whether the process had to be halted intermittently. In addition, there is no information on how to predict the refractive index profile in the resulting fiber, and trial-and-error is apparently required to find appropriate process parameters.
[0009] An improved extrusion technique for plastic optical fiber is reflected in coassigned U.S. patent application 09/321050 filed May. 27, 1999 (our reference Blyler 4318-1-18), the disclosure of which is hereby incorporated by reference. Further improvements in such extrusion methods are desired.
SUMMARY OF THE INVENTION
[0010] The invention provides an improved process for extruding plastic optical fiber without the need to prepare a preform. Specifically, it was discovered that conventional extrusion techniques, e.g., screw extruders, tended to introduce an undesirable amount of particulate contaminants which increased the loss of the drawn fiber. To overcome this problem, the invention substantially reduces the number of mechanical interactions that contribute to such contamination. The process of the invention does so by using fluid (typically gas) pressure, instead of screw extruders, to induce polymer flow. The process also controls the flow characteristics of the polymer, or halts the flow altogether, without mechanical controls. Specifically, the temperature of the sections through which the polymer flows is controlled, such that it is possible to bring the polymer to a desired flow rate, or even to a solid state to provide a plug. Using the process of the invention, high quality graded index plastic optical fiber is possible, e.g., GI-POF that exhibits a relatively low loss of 50 dB/km or better.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] [0011]FIG. 1 is a schematic illustration of an apparatus suitable for practicing an embodiment of the invention.
[0012] [0012]FIG. 2 is a co-extrusion head suitable for use in the process of the invention.
[0013] [0013]FIG. 3 illustrates a technique for continuous extrusion according to an embodiment of the invention.
[0014] [0014]FIG. 4 illustrates a technique for reducing gas adsorption into molten polymer, according to an embodiment of the invention.
[0015] [0015]FIGS. 5A and 5B illustrate the ability of the invention to control refractive index profile by adjusting temperature of the flowing polymer.
DETAILED DESCRIPTION OF THE INVENTION
[0016] An extrusion apparatus 10 suitable for practicing an embodiment of the invention is schematically illustrated in FIG. 1. The apparatus 10 comprises a tank 12 containing a gas that is capable of providing the necessary pressure for extrusion. Typically the gas is nitrogen. The gas flows from the tank 12 into one or more high pressure regulators 13 , 14 . The gas then flows through one or more filters 15 , 16 , 17 to lower particulate contamination in the gas, and is then directed into a cladding reservoir 18 and a core reservoir 22 . The reservoirs 18 , 22 contain molten cladding polymer and core polymer, with one or both of the polymers typically doped to provide a desired refractive index profile in the final fiber. The pressure of the gas forces the polymers out of the reservoirs 18 , 22 toward a first crosshead 25 . Generally, a constant gas pressure is maintained, with the precise flow rate of the polymers controlled by temperature, as discussed below. Multiple gas sources are possible.
[0017] A significant feature of the invention is the treatment of the polymer as it flows from the reservoirs. According to this embodiment, the molten polymer exiting the reservoirs 18 , 22 encounters thermal homogenizer sections 19 , 23 . The thermal homogenizer sections 19 , 23 are designed to bring the molten polymers to a substantially uniform temperature (determined according to guidelines discussed herein), which is often different from the reservoir 18 , 22 temperature. (It is possible, however, to provide the temperature homogenization in the reservoir, instead of using separate thermal homogenizer sections.)
[0018] The molten polymer, having achieved the substantially uniform temperature, then flows into flow restrictor sections 20 , 24 , which are generally maintained at the same temperature as the thermal homogenizer sections 19 , 23 . The flow restrictor sections 20 , 24 act to regulate the polymer flow rates. Specifically, given a flow restrictor section of a particular geometry, it is possible to adjust the temperature to attain a viscosity that provides the desired flow rate. Typically, the flow restrictor sections are of smaller diameter than the thermal homogenizer sections, since the function of the thermal homogenizer sections is to provide polymer with a substantially uniform temperature, while the function of the flow restrictor sections is to control the flow of the polymer. The thermal homogenizer sections 19 , 23 and the flow restrictor sections 20 , 24 are heated by any suitable technique. One useful heating technique is surrounding the sections with an aluminum cylinder having an inner profile that substantially matches the outer profile of the sections, including any fittings that are present, and then surrounding the aluminum cylinder with resistive heating tape. In addition to controlling flow rate by adjusting the temperature of the thermal homogenizer sections and flow restrictor sections, it is also possible to seal the reservoirs, e.g., to allow replenishment of polymer, by cooling these sections such that the polymer becomes non-flowing, and thus essentially plugs the reservoir. Such a step is useful in embodiments of the invention that provide for continuous extrusion, as discussed below.
[0019] The flow restrictor sections 20 , 24 feed the cladding polymer and the core polymer into a first extrusion crosshead 25 . The first extrusion crosshead 25 directs the core polymer into the central section of a diffusion section 26 and distributes the cladding polymer concentrically around the core polymer in the diffusion section 26 . The core polymer and cladding polymer thereby flow together in the diffusion section 26 , advantageously in a smooth laminar flow without disruption of the core/cladding interface. A detailed view of a particular cross head, a co-extrusion head, is shown in FIG. 2. The co-extrusion head is designed to distribute the annular cladding melt stream around the central core melt stream in a smooth, laminar flow with no disruption of the interface between them. The joined streams co-flowed axially into a tubular diffusion section, e.g., of 5 mm inner diameter. The molten core material is introduced into the center of the crosshead assembly via a core tube 40 , which includes a gradually tapered (e.g., 5°) internal cross section followed by a long, straight section of constant cross sectional area. The tapered region provides a transition in cross sectional area for the molten core material to flow from an extruder output nozzle to the smaller diameter required at the point the core and cladding materials are brought together. The inner diameter of the exit end of the core tube 40 is held, for example, at about 40% of the channel diameter in the die holder 44 , just downstream, where the core and cladding materials are joined. The external surface of the exit end of the core tube 40 is also tapered (e.g., 10°) and forms the interior wall of the transition region that directs the cladding material to flow into the channel in the die holder 43 , where the cladding material joins with the core material.
[0020] The cladding material is introduced into the crosshead assembly via a channel in the crosshead housing 42 , from which the cladding material flows into a channel machined in the side of die holder 44 . The material flows upward and exits this channel to flow into distributing channels machined into the lower surface of core tube holder 43 . The distributing channels assure a relatively uniform flow of cladding material around the tapered exterior of the core tube 40 by dividing the flow into four streams and introducing them to the tapered channel 90° apart. With this arrangement the core and cladding melt streams are joined together in a smooth regular manner, with little, if any, disruption of the interface between the two materials or distortion of the concentric circular geometry of the core/cladding cross section. The assembly is held together by a nut 41 , which threads into crosshead housing 42 , and clamps all assembled parts together to prevent leakage. The diffusion section 45 is threaded onto the die holder 44 .
[0021] In the diffusion section 26 , the dopant(s) present in the core and/or cladding undergo molecular diffusion from the cladding polymer into the core polymer and/or vice versa, to form the desired graded refractive index profile. The diffusion section is thus maintained at a particular temperature to promote this diffusion (typically 200 to 270° C.), and is of sufficient length to allow the desired extent of diffusion to occur (typically 33 to 400 cm, typically at least 50 cm, and optionally at least 100 cm). Optionally, the diffusion section comprises one or more lengths capable of being threaded together, and threaded onto the first and/or second extrusion crossheads 25 , 27 , such that length modifications are easily made. By the time the flowing polymer reaches the end of the diffusion section 26 , substantially all of the desired diffusion has generally taken place. It is possible, however, to configure the apparatus to provide some diffusion after a protective cladding layer is deposited.
[0022] The flowing polymer is then typically directed from the diffusion section 26 into a second extrusion crosshead 27 . The second extrusion crosshead coats the core/cladding polymer with a protective cladding, e.g., polycarbonate, fed from a hopper 28 by any suitable extrusion technique, to provide mechanical reinforcement of the fiber. The second crosshead 27 is generally similar to the first crosshead, but may have larger flow channels if a relatively thick protective cladding is desired. The polymer flow is then generally directed into a conditioning section 29 . At least a portion of the conditioning section 29 is optionally kept at a lower temperature than the diffusion section 26 , with this temperature (in combination with the length of the conditioning section 29 ) selected to improve the draw properties of the polymer. The cooler temperature also tends to contribute to locking-in the dopant profile. The conditioned polymer is then directed through an exit die 30 that provides the desired final diameter, and is pulled from the die, using conventional techniques, e.g., a capstan that provides the desired draw rate, a spool to take up the fiber, and a diameter monitor that may be used in a feedback mode with the capstan to improve diameter control. The die generally has a tapered inlet that provides a transition from the cross-section of the conditioning section 26 to a straight land at the end of the die. The land generally has an inner diameter of 1 to 5 mm.
[0023] It is possible to put additional or intermediate layers on the fiber by similar coextrusion techniques.
[0024] The process of the invention is capable, depending on the particular polymers and particular fiber characteristics, of extruding plastic optical fiber at a line speed of at least 0.3 meter/second, advantageously at least 1 meter/second.
[0025] As noted above, particulate contamination from various moving parts tends to contribute to degradation of the properties of the drawn fiber. According to the invention, sources of such contamination are significantly reduced. The elimination of moving parts in the extruder, i.e., a screw, is provided by use of fluid pressure. And flow control of the polymer is provided by temperature adjustment, as opposed to mechanical intervention. To promote further reduction in particulates, for perfluorinated polymers or other corrosive materials, corrosion resistant materials, such as Hastelloy® and other nickel-based materials, are used wherever feasible. In addition, the apparatus is advantageously assembled, and parts cleaned, under clean room conditions.
[0026] A variety of fluids are suitable for providing the extrusion pressure. Typically, the fluid is a gas, but it is also possible to use liquids, e.g., liquids that are immiscible with the polymer and/or that are readily able to be made volatile to ease removal from the reservoirs. Gases used to provide the pressure for extrusion are typically relatively inert, e.g., nitrogen. The gas simply needs to be able to provide the necessary pressure while advantageously causing little or no interference with the overall process, i.e., no chemical interactions with the polymer and no inducement of bubbles (although it is possible to reduce bubble formation by use of particular reservoirs or metal sections, as discussed below). A range of pressures are possible, depending on the particular system. Generally, as noted above, one or more high pressure regulators are provided to regulate the gas pressure, and one or more conventional filters are provided to reduce or substantially eliminate introduction of particulates in the gas stream.
[0027] The reservoirs generally consist of a lid, a body, a funnel attachment to downstream sections, and heaters around the exterior. Where needed, the body is formed of a corrosion-resistant material. The lid attachment is desirably formed to reduce particle generation as much as possible. High temperature seals are formed of suitable materials, e.g., Kalrez™ or bare metal flanges.
[0028] The polymers are typically added to the respective reservoirs in solid form, and melted therein. The invention is capable of producing graded-index plastic optical fibers from a variety of transparent thermoplastic polymers exhibiting useful refractive index, glass transition temperatures and optical transmission characteristics, and for which compatible, refractive index-altering dopants exhibiting sufficient mobility at processing temperatures in the polymer are available. Glass transition temperature typically ranges from about 90° C. to about 260° C., refractive index typically ranges from about 1.3 to about 1.6, and transmission losses typically range from 10 to 1000 dB/km for the bulk polymer. Viscosities (at180 to 260° C.) typically range from 100 to 1,000,00 poise, more typically 1000 to 100,000 poise. Examples of suitable polymers include poly(methyl methacrylate) (PMMA), polycarbonate, polystyrene, styrene-acrylonitride copolymers (SAN), poly(perfluoro-butenyl vinyl ether) (CYTOP™) and copolymers of tetrafluoroethylene and 2,2bistrifluoromethyl-4,5-difluoro-1,3-dioxole (Teflon AF™). Perfluorinated polymers are particularly advantageous.
[0029] The dopant is typically an index-raising substance added to the core polymer. (As used herein, dopant indicates one or more diffusible materials.) Alternatively, the dopant is an index-lowering substance added to the cladding polymer. Useful dopants are relatively low molecular weight compounds which: 1) are soluble in the polymers used or the GI-POF and do not phase-separate or crystallize in the polymers over time; 2) do not significantly increase the transmission loss of the polymers; 3) do not depress the glass transition temperature of the polymers by an unacceptable degree; 4 ) have sufficiently high diffusivities in the polymers at processing temperatures, e.g., 10 −8 to 10 −5 cm 2 /sec; 5) provide large changes in refractive indices at low concentrations in the polymers, e.g., Δn>0.015 for less than 15 wt. % dopant; 6) are chemically stable in the polymers at processing temperatures and in operating environments over the long term; 7 ) have low volatility at processing temperatures; and 8) are substantially immobilized in the glassy polymer in operating environments. Optional dopants for use with PMMA include bromobenzene, benzylbutylphthalate, benzyl benzoate, diphenyl phthalate, and diphenyl sulfide. Suitable dopants for use with CYTOP™ or Teflon AF™ include perhalogenated oligomers and per-halogenated aromatic compounds, which optionally include heteroatoms. It is also possible to make step-index fibers using two different polymers, and no dopants.
[0030] A significant feature of the invention is the ability to control polymer flow, particularly the relative flow of the core and cladding polymers, into the first extrusion crosshead by use of temperature, thereby eliminating the need for mechanical controls and associated contamination. In particular, the temperature to which the polymers are brought prior to introduction into the flow restrictor sections is selected to provide a desired viscosity that provides a desired flow rate through that particular section. Thus, the temperature will vary depending on the properties of an individual polymer (including the effect of dopants present in the polymer), and on any variations in the flow restrictor section itself. To monitor the temperature closely, it has been found to be advantageous to use resistive thermometers, e.g., resistive temperature detectors or RTDs, on the thermal homogenizer sections and flow restrictor sections. Selecting a temperature to provide a particular viscosity, and thus a particular flow rate through a given flow restrictor section is capable of being performed using conventional techniques. Techniques for providing flow rate feedback are typically useful for monitoring the flowing polymers. Such techniques include optical, viscometric, acoustic, or gas flow measurement of polymer displacement.
[0031] It is possible to provide for continuous operation of an extrusion apparatus such as illustrated in FIG. 1, by providing two or more core polymer reservoirs and two or more cladding polymer reservoirs. The apparatus is configured to allow filling of one or more of the reservoirs while maintaining the polymer flow from one or more of the other reservoirs. One embodiment of such a continuous operation is shown, in part, in FIG. 3. FIG. 3 illustrates two feed reservoirs 50 , 60 connected by feed lines 52 , 62 to primary reservoirs 53 , 63 that direct polymer through sections 55 , 65 , and into a manifold 66 that directs the polymer into the remainder of the apparatus. (Thermal homogenization can be done in the manifold 66 or further downstream.) (This pairs of reservoirs provides either the core or the cladding polymer. An additional pair having a similar configuration is required for other polymers.) Relatively low pressure gas lines 51 , 61 , e.g., 100 psi, are connected to the feed reservoirs 50 , 60 , and relatively high pressure gas lines 54 , 64 , e.g., 2000 psi, capable of providing the necessary pressure for extrusion are connected to the primary reservoirs 53 , 63 . Operation of this portion of an extrusion apparatus would typically involve the steps of (with variations being possible):
[0032] (1) cooling the feed line 52 from a first feed reservoir 50 to a first primary reservoir 53 to a temperature that essentially provides a polymer plug, and then filling the first feed reservoir 50 with solid polymer and heating the reservoir 50 to provide a polymer melt;
[0033] (2) while a second primary reservoir 63 is providing sufficient polymer to maintain the extrusion process, halting the gas flow from the high pressure gas line 54 into the first primary reservoir 53 while keeping the temperature of the connection 55 from the first primary reservoir 53 into the manifold 66 low enough to substantially stop or prevent flow of the polymer through that connection 55 ;
[0034] (3) admitting gas from the low pressure gas line 51 into the first feed reservoir 50 while heating the feed line 52 , to promote polymer flow from the first feed reservoir 50 into the first primary reservoir 53 ;
[0035] (4) after the first primary reservoir 53 is sufficiently filled, cooling the feed line 52 from the first feed reservoir 50 to the first primary reservoir 53 to a temperature that halts the polymer flow and essentially plugs the first primary reservoir 53 , while halting the gas flow from the low pressure gas line 51 ; and
[0036] (5) after step (4) is completed, engaging the gas flow through high pressure gas line 54 and heating the connection 55 from the first primary reservoir 53 to the manifold 66 to a desired temperature, to begin flow of the polymer from the first primary reservoir into the remainder of the extrusion apparatus (and adjusting the controls of the second primary reservoir 63 to maintain the desired polymer flow).
[0037] The same process is used to refill the second primary reservoir 63 . By switching back and forth between reservoirs, essentially continuous operation is possible.
[0038] A potential problem with using gas pressure to drive extrusion is the possibility that the gas will be absorbed into the polymer, and thereby induce bubble formation in the drawn fiber. To reduce or avoid such absorption, it is possible to use an arrangement such as illustrated in FIG. 4. According to this arrangement, a reservoir 70 having a molten polymer 71 therein is provided with a pressure transfer element 72 . The element 72 is typically a sphere having a diameter that closely matches the inner diameter of the reservoir 70 , although other shapes are possible. The element 72 is generally formed from a material that is corrosion resistant and that will substantially avoid introducing particulates into the reservoir, with the particular material dependent largely on the corrosiveness of the polymer. Suitable materials include Hastelloy, nickel, and similar corrosion-resistant alloys. (The relatively high viscosity of typical polymers used is generally sufficient to prevent the elements from sinking.) Gas directed into the reservoir through gas line 73 will encounter the pressure transfer element 72 , and the gas pressure will thereby be transferred by the element 72 to the molten polymer 71 . In this way, direct contact between the gas and the molten polymer 71 is reduced.
[0039] It is also possible to remove absorbed gases from the molten polymer by using one or more porous metal elements, e.g., in the diffusion section. The porous metal allows the gas to escape while maintaining the desired polymer flow. For example, it is possible to use a Hastelloy diffusion section formed by sintering metal particles, such that the resulting section has a pore size of about 5 μm, with about 50 vol. % porosity.
[0040] The process of the invention is capable of making plastic optical fiber from a variety of materials, in a variety of diameters, and with a variety of refractive index profiles. Typical outer diameters, including a reinforcing protective cladding, range from 250 to 1000 μm.
[0041] Numerous variations of the above-described apparatus and process steps are possible. For example, it is possible to use additional polymer reservoirs and/or different or additional extrusion crossheads, if such an arrangement contributes to attainment of a particular refractive index profile or other desired fiber characteristics. Additional or different polymer flow and/or feed sections are also possible, e.g., additional flow sections may be present between the reservoirs and the thermal homogenizer sections and/or between the thermal homogenizer sections and the flow restrictor sections.
[0042] The invention will be further clarified by the following example, which is intended to be exemplary.
EXAMPLE
[0043] The apparatus set-up is similar to that illustrated in FIG. 1.
[0044] Gas pressure to the core and cladding reservoirs was provided by nitrogen gas, the nitrogen gas source at a pressure of about 2400 psi. Before reaching the reservoirs, the gas flowed through two high pressure regulators to control the pressure delivered to the reservoirs, and then through three filters—a 1 μm filter, a 0.01 μm filter, and another 1 μm filter.
[0045] The cylindrical core reservoir, 24 inches in length with an inner diameter of 1.374 inches, was connected through a tapered adapter to a flow restrictor assembly, which in turn was connected through an adapter to a crosshead of the design shown in FIG. 2. The flow restrictor assembly consisted of the thermal homogenizer—a 3.97 inches long nickel tube having an inner diameter of 0.245 inches and the flow restrictor—a 5 inches long nickel tube having an inner diameter of 0.055 inches. The connections between the tubes and between the tubes and the adapters were made with Swageloc™ fittings. The entire flow restrictor assembly was encased in a split aluminum cylinder, milled out in the center to fit closely around the enclosed tubing and fittings to promote temperature uniformity. The cylinder was wrapped with heating tape which was controlled via an RTD inserted in a well in the aluminum cylinder, with the RTD connected to an Omega MC572333 temperature controller. Using heating tapes, the core reservoir was configured with three separately controlled heating zones comprising the lower half of the reservoir, the upper half of the reservoir and the reservoir lid. This arrangement allowed higher temperatures to be used in the head space region of the reservoir to prevent any dopant that evaporated from the free surface of the molten core polymer from condensing on the inner wall or lid of the reservoir.
[0046] The cylindrical cladding reservoir had the same dimensions as the core reservoir and was similarly connected to the crosshead via adapters and a flow restrictor assembly. The flow restrictor assembly consisted of the thermal homogenizer—a 12.25 inches long nickel tube having an inner diameter of 0.245 inches and the flow restrictor—a 10 inches long nickel tube having an inner diameter of 0.120 inches. The thermal homogenizer tube had a 90° bend to accommodate entry of the cladding line into the side port of the crosshead. For temperature control and uniformity the flow restrictor assembly was encased by two milled out split aluminum cylinders, one for each leg on either side of the 90° bend. Temperature control of the flow restrictor assembly was effected in the same manner as was done for the core flow restrictor assembly. The cladding reservoir was configured with two separately heated zones, comprising its upper and lower halves. There was no need to control the temperature of the cladding reservoir lid because the vapors in the head space of the undoped cladding polymer did not contain condensable material from the polymer.
[0047] The crosshead to which the core and cladding flow restrictors were attached was independently heated with a band heater controlled by an RTD and an Omega Model CN76000 temperature controller. A diffusion section, having an inner diameter of 0.276 inches and a length of 12.5 inches, was attached to the output of the crosshead through an adapter. The diffusion section was encased with a closely fitting, split aluminum cylinder. The cylinder was wrapped with heating tape and its temperature was independently controlled with a thermocouple and Omega Model CN76000 temperature controller. A die having a land with a diameter of 2 mm and a length of 5 mm was connected through an adapter to the diffusion section. The die and adapter were encased with a split aluminum cylinder, wrapped with heating tape and temperature controlled with a thermocouple and an Omega CN76000 temperature controller.
[0048] Poly perfluorobutenyl vinyl ether) (commercially available as CYTOP™, from Asahi Glass Co., Japan), cast as a clean cylindrical rod, was placed in the cladding reservoir and the reservoir lid which incorporated an O-ring seal was bolted in place. A CYTOP™ rod, uniformly doped with a perfluorinated dopant which raised its refractive index by approximately 1.0%, was placed in the core reservoir and the reservoir lid was similarly bolted in place. Both reservoirs were then heated to melt the polymer rods and allow them to flow under gravity to form melt pools in the bottoms of the reservoirs. Several hours were required to eliminate air bubbles to form consolidated melt pools. The core reservoir temperatures were controlled at 190° C. (bottom zone), 210° C. (top zone) and 220° C. (lid). Consolidation to an acceptable, essentially bubble-free state was accomplished in approximately 18 hours. The cladding reservoir temperatures were controlled at 240° C. (bottom zone) and 220° C. (top zone). Consolidation to an acceptable, essentially bubble-free state was accomplished in approximately 96 hours.
[0049] Two series of runs were carried out to demonstrate how the refractive index profile and diameter of the fiber core is capable of being controllably changed by independently varying the core and cladding flow restrictor assembly temperatures, which in turn control the relative core and cladding polymer flow rates. In these runs, the total polymer throughput, and hence the fiber production rate, was kept approximately constant. The crosshead temperature was controlled at 240° C. and the diffusion section and the die and adapter were controlled at 230° C.
[0050] In the first series of runs the cladding flow restrictor assembly temperature was held constant at 240° C. and the core flow restrictor assembly temperature was varied. The core flow restrictor assembly temperature was first set at 220° C. The nitrogen gas pressure applied to the core and cladding reservoirs was increased gradually stepwise until the total polymer output from the die reached approximately 0.8 g/min. This output was achieved at a gas pressure of 412 psi. The polymer strand extruded from the die was threaded through a glass tube. This tube was placed coaxially around the fiber and against the face of the die in order to provide uniform cooling conditions in the drawdown region to minimize diameter variations of the fiber. Beyond the exit end of the tube the fiber was passed through a LaserMike Model 910 diameter monitor and then into a Heathway Model HTD-209 variable speed capstan. The capstan speed was adjusted to produce a fiber with an outer diameter of approximately 350 microns.
[0051] The process was run for a period of time—about 1.5 hours—to achieve a steady state refractive index profile. A fiber sample was then collected and its refractive index profile determined using a Leitz interference microscope via the transverse interferometric method (see D. Marcuse, Principles of Optical Fiber Measurement, Academic Press, New York, 1981, pp. 150-161). A solution of water and propylene glycol in the weight ratio 92.2 to 7.8 was used to match the refractive index of the CYTOP™ polymer cladding (1.342). The refractive index profile was plotted as the local refractive index change relative to that of the cladding against the radial position, normalized by the fiber radius, as shown in FIG. 5A. To complete the series of runs, the core flow restrictor assembly temperature was changed in 10° C. increments from 220° C. to 180° C., while keeping all other temperatures fixed. After each incremental temperature change of the core restrictor assembly, about 1.5 hours was allowed to achieve steady state conditions and the nitrogen gas pressure was adjusted to keep the total polymer output at approximately 0.8 g/min. Fiber samples were collected for each temperature change, and the refractive index profiles were determined. The results are shown in FIG. 5A.
[0052] It is apparent from FIG. 5A, that when the core flow restrictor assembly temperature is decreased relative to that of the cladding flow restrictor assembly, the fiber core diameter is decreased relative to the constant cladding diameter. This result indicates that the effect of decreasing the core flow restrictor temperature is to decrease the volumetric flow rate of core polymer through the process relative to that of the cladding polymer. Significant changes in the shape of the refractive index profiles are also evident as the core restrictor assembly temperature is decreased relative to that of the cladding flow restrictor. At the highest core flow restrictor temperature, the refractive index profile has a relatively flat central region at the peak. As the core flow restrictor temperature is lowered, the refractive index peak becomes sharper. At the lowest core flow restrictor assembly temperature of 180° C., the refractive index profile is not only sharply peaked, but the refractive index change at the center of the core is reduced from 0.014 to 0.010. At this condition the volumetric flow rate of the core polymer relative to that of the cladding has been reduced to such a degree that dopant at the center of the core is depleted in the diffusion region of the process. This series of runs demonstrates that a high degree of control of the refractive index profile of the fiber can be achieved through control of the relative temperatures of the core and cladding flow restrictors, according to the process of the invention.
[0053] In a second series of runs, the temperature of the core flow restrictor assembly was held constant at 200° C. while the temperature of the cladding flow restrictor assembly was varied stepwise in 10° C. increments from 260° C. to 240° C. As in the previous series of runs, the nitrogen gas pressure was set at a value that produced a total polymer output of approximately 0.8 g/min. The temperatures of the crosshead, diffusion section and die and adapter were the same as those used in the first series. Steady state conditions were achieved at each cladding flow restrictor temperature prior to collecting a sample for measurement of refractive index profile.
[0054] The refractive index profiles from the second series of runs are plotted in FIG. 5B. As the cladding flow restrictor temperature is decreased relative to that of the core flow restrictor, the fiber core diameter increases. At the highest cladding flow restrictor temperature of 260° C., a slight depression of the peak refractive index (relative to the cladding) from 0.14 to 0.12 is apparent. At a cladding flow restrictor temperature of 240° C., the peak refractive index of 0.14, characteristic of the fully doped core, is observed. Overall, the changes in the core diameter and refractive index profile afforded by varying the cladding flow restrictor assembly temperature relative to that of the core are smaller than vice versa. Hence a high degree of fine tuning of the fiber core diameter and refractive index profile are possible by the use of temperature to control the relative volumetric flow rates of the core and cladding polymers through flow restricting capillaries interposed between the reservoirs and crosshead of the gas pressure extrusion system.
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An improved process for extruding plastic optical fiber without the need to prepare a preform is provided. Specifically, it was discovered that conventional extrusion techniques, e.g., screw extruders, tended to introduce an undesirable amount of particulate contaminants which increased the loss of the drawn fiber. To overcome this problem, the invention substantially reduces the number of mechanical interactions that contribute to such contamination. The process of the invention does so by using fluid pressure, instead of, e.g., screw extruders, to induce polymer flow. The process also controls the flow characteristics of the polymer, or halts the flow altogether, without mechanical controls. Specifically, the temperature of the sections through which the polymer flows is controllably adjusted, such that it is possible to bring the polymer to a desired flow rate or even to a solid state to provide a plug.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser. No. 10/557,524, filed Nov. 8, 2006, now U.S. Pat. No. ______, which is the U.S. national phase under 35 U.S.C. §371 of PCT International Application No. PCT/US2004/016260, which has an international filing date of May 20, 2004, designating the United States of America, and which claims the benefit of U.S. Provisional Patent Application Ser. No. 60/472,260, filed May 21, 2003, the disclosures of each of which are hereby expressly incorporated by reference herein.
BACKGROUND AND SUMMARY OF THE INVENTION
[0002] The present invention relates to a hospital bed. More particularly, the present invention relates to a hospital bed having siderails, an articulating deck, and a mattress.
[0003] Hospital bed and other patient supports are known. Typically, such patient supports are used to provide a support surface for patients or other individuals for treatment, recuperation, or rest. Many such patient supports include a frame, a deck supported by the frame, a mattress, siderails configured to block egress of a patient from the mattress, and a controller configured to control one or more features of the bed.
[0004] Additional features of the present invention will become apparent to those skilled in the art upon consideration of the following detailed description of an illustrated embodiment exemplifying the best mode of carrying out the invention as presently perceived.
BRIEF DESCRIPTION OF THE DRAWINGS
[0005] A detailed description particularly refers to the accompanying figures in which:
[0006] FIG. 1 is a perspective view of a patient support according to the present disclosure showing the patient support including a frame, a deck, a mattress supported by the deck, a head board, a foot board, a pair of head end siderails, and a pair of foot end siderail;
[0007] FIG. 2 is a side elevation view showing the mattress supported in a flat and horizontal position;
[0008] FIG. 3 is a view similar to FIG. 2 showing a head section of the deck in a raised position and the head and foot end siderails having complementary profiles;
[0009] FIG. 4 is a view similar to FIG. 3 showing the foot end siderail in a lowered position and the head and foot end siderails having complementary profiles permitting the foot end siderail to be lowered when the head section of the deck is raised;
[0010] FIG. 5 is a diagrammatic view showing an intermediate frame of the patient support in a horizontal position and the deck in an articulated position;
[0011] FIG. 6 is a view similar to FIG. 5 showing the intermediate frame in the Trendelenburg position and the deck in a substantially flat position;
[0012] FIG. 7 is a perspective view of a portion of the patient support of FIG. 1 showing portions of a caster wheel, a brake pedal in a braked position, and a brake position detection switch;
[0013] FIG. 8 is a view similar to FIG. 7 showing the brake pedal in an un-braked position;
[0014] FIG. 9 is a perspective view of a center or fifth wheel assembly showing the fifth wheel assembly coupled to the frame of the patient support of FIG. 1 and a wheel of the patient support facing in a direction parallel with the longitudinal axis of the patient support;
[0015] FIG. 10 is a view similar to FIG. 9 showing the wheel facing in a direction that is neither parallel or perpendicular with the longitudinal axis of the patient support;
[0016] FIG. 11 is a view similar to FIG. 9 showing the wheel facing in a direction that is perpendicular with the longitudinal axis of the patient support;
[0017] FIG. 12 is a cross-section view taken along line 12 - 12 of FIG. 9 showing a ball bearing positioned in a first valley of a wheel position holder;
[0018] FIG. 13 is a cross-sectional view taken along line 13 - 13 of FIG. 10 showing the ball bearing positioned on a first peak of the wheel position holder;
[0019] FIG. 14 is a cross-sectional view taken along line 14 - 14 of FIG. 11 showing the ball bearing positioned in a second valley of the wheel position holder;
[0020] FIG. 15 is an exploded assembly view of the caster wheel assembly;
[0021] FIG. 16 is a perspective view of portions of the deck showing the deck including three removable deck panels;
[0022] FIG. 17 is a view similar to FIG. 16 showing the deck panels removed from the remainder of the deck;
[0023] FIG. 18 is perspective view of the deck showing patient restraint straps coupled to the deck;
[0024] FIG. 19 is a cross-sectional view taken along lines 19 - 19 of FIG. 2 showing one of the removable deck panels including gap fillers positioned adjacent to the head end siderails to partially fill the gap therebetween and the mattress including chamfered corners to receive the gap fillers;
[0025] FIG. 20 is a perspective view of a portion of the patient support of FIG. 1 showing a head end deck panel, the head board, and one of the head end siderails having curved portions that converge to partially fill gaps defined therebetween; and
[0026] FIG. 21 is a top plan view showing the curved portions of the head board and the head end siderail.
DETAILED DESCRIPTION
[0027] A patient support 10 according to the present disclosure is shown in FIG. 1 . Patient support 10 includes a base frame 12 , an intermediate frame 14 supported by base frame 12 , a deck 16 supported by intermediate frame 14 , a mattress 18 supported by deck 16 , a headboard 20 , a footboard 22 , a pair of head end siderails 24 , and a pair of foot end siderails 26 . Footboard 22 is positioned over an extendable foot support. Additional details of a suitable extendable foot support is provided in European Patent Publication No. EP0681799 A1, titled “Blocking device for an extension relative to a piece of furniture, and piece of furniture equipped with it,” filed May 5, 1995, to Pascal Guguin, the disclosure of which is expressly incorporated by reference herein.
[0028] Base frame 12 is supported on the floor by a plurality of caster wheels 28 and a centered or fifth wheel assembly 30 . Intermediate frame 14 is coupled on each end to extendable columns 31 which can be extended or retracted to position intermediate frame 14 and deck 16 in the Trendelenburg or Reverse Trendelenburg positions. Additional details of suitable extendable columns is provided in French Patent Publication No. FR2780638, titled “Hospital bed with telescoping columns,” filed Jul. 1, 1998, to Robic Dominique, the disclosure of which is expressly incorporated by reference herein.
[0029] Deck 16 is configured to articulate between a plurality of positions. Deck 16 includes a head section 32 , a seat section 34 , a thigh section 36 , and a foot section 38 which are pivotably coupled together.
[0030] Head end siderails 24 are coupled to head section 32 and may be moved between raised and lowered positions by siderail linkages 40 . Additional details of suitable siderail linkages are provided in PCT Publication No. WO 02/32271 A 1, titled “Bed with Articulated Barrier Elements,” filed Oct. 18, 2000, to Hensley et al. and U.S. Pat. No. 6,163,903, titled “Chair Bed,” filed Feb. 4, 1998, to Weismiller et al, the disclosures of which are expressly incorporated by reference herein. Foot end siderails 26 are coupled to intermediate frame 14 by siderail linkages 40 between thigh section 36 and foot section 38 and can also be moved between raised and lowered positions.
[0031] A control system is provided to control various functions of patient support 10 . The control system and the remainder of patient support 10 are powered by a building's power supply through an AC plug connector 44 coupled to a building outlet 46 . If AC plug connector 44 is unplugged from building outlet 46 or the building's power is lost, patient support 10 is powered by a battery (not shown) supported by base frame 12 .
[0032] As shown in FIG. 2 , head section siderail 24 include handles 50 , 52 , upper portion 54 , lower portion 56 , and notch 58 . Foot section siderail 26 includes handles 60 , 62 , upper portion 64 , lower portion 66 , and extended portion 68 . Deck 16 can be moved into an articulated position, as shown in FIG. 10 , by moving head section 32 in direction 70 . As shown in FIG. 3 , upper portion 54 of head section siderail 24 complements upper portion 66 of foot section siderail 26 so that head section siderail 24 does not interfere with foot section siderail 26 when deck 16 is in the articulated position.
[0033] Lower portion 56 of head section siderail 24 and lower portion 66 of foot section siderail 26 are also shaped to correspond with one another so that a gap 72 defined between lower portions 56 , 66 remains substantially constant during articulation of deck 16 . During articulation of deck 16 , a gap 74 defined between upper portions 66 , 52 narrows significantly while gap 72 between lower portions 60 , 58 remains substantially constant. In the articulated orientation with both siderails 24 , 26 in the raised position, as shown in FIG. 3 , notch 58 is positioned to receive extended portion 68 of foot section siderail 26 .
[0034] As shown in FIG. 4 , when foot section siderail 26 is moved to the lowered position, the curvature of upper portion 64 of foot section siderail 26 is configured to complement the curvature of lower portion 56 of head section siderail 24 . The radius of curvature of upper portion 64 of foot section siderail 26 is configured to be substantially centered about a pivot axis 76 of head section 32 . This allows foot section siderail 26 to be moved between the raised and lowered positions when the deck is in the articulated position as shown in FIGS. 3 and 4 . A portion of the radius of curvature of lower portion 56 of head section siderail 24 is also substantially centered about pivot axis 76 .
[0035] Head section 32 is pivotably and slidably coupled to a channel or rail 78 at pivot axis 76 (shown in phantom). Rail 78 is coupled to intermediate frame 14 . Rail 78 includes a slot (not shown) that allows pivot axis 76 of head section 32 to slide horizontally as head section 32 is moved between the substantially coplanar position as shown in FIG. 2 and the articulated position as shown in FIG. 3 . A link 80 is pivotably coupled on one end to head section 32 at a pivot axis 82 and coupled to intermediate frame 14 on the other end at a pivot axis 84 .
[0036] Referring now to FIGS. 2 and 3 , as head section 32 rotates in direction 70 into the articulated position, pivot axis 76 slides in the slot in rail 78 towards foot board 22 . Additional details of rail 78 and link 80 are provided in PCT Publication No. WO 02/076266 A1, titled “Bed Equipped with a Back Elevator,” filed Mar. 26, 2002, to Gippert et al., the disclosure of which is expressly incorporated by reference herein.
[0037] Head section siderail 24 also includes angle indicator 88 which, in the preferred embodiment, includes a slot formed in siderail 24 and a ball bearing movable in the slot to indicate the angle of inclination of head section 32 relative to intermediate frame 14 . Head section siderail 24 also includes recessed portions 90 , 92 along lower edge 94 of head section siderail 24 . Recessed portions 90 , 92 allow a caregiver to comfortably stand beside patient support 10 when head section siderail 24 is in the lowered position without interfering with the care givers' feet.
[0038] Foot section siderail 26 also includes an angle indicator 96 which, in the preferred embodiment, includes a slot formed in siderail 26 and a ball bearing movable in the slot to indicate the angle of inclination of intermediate frame 14 relative to the floor. Position indicator 96 can be used to determine the position of deck 16 relative to the floor during movement by columns 31 . Additional description of angle indicators 88 , 96 is provided in U.S. Pat. No. 6,182,310, titled “Bed Side Rails,” filed Jan. 12, 1998, to Weismiller et al., the disclosure of which is expressly incorporated by reference herein.
[0039] Foot section siderail 26 also includes recessed portions 98 on a lower edge 110 . Recessed portions 98 are shaped to allow a caregiver to stand adjacent patient support 10 when siderail 26 is in the lowered position. Recessed portions 98 are shaped to eliminate or minimize contact with the caregivers' feet when he or she is positioned next to patient support 10 .
[0040] As shown in FIG. 1 , the control system of patient support 10 includes siderail controls 112 permanently coupled to head end siderails 24 and pendent controls 113 removably coupled to any of head and foot end siderails 24 , 26 . Additional details of suitable siderail controls and pendant controls is provided in U.S. patent application Ser. No. 09/750,741, titled “Hospital Bed,” filed Dec. 29, 2000, to Osborne et al. and U.S. Patent Application Ser. 60/408,698, titled “Hospital Bed,” filed Sep. 6, 2002, to Menkedick et al., the disclosures of which are expressly incorporated by reference herein.
[0041] Siderail controls 112 are configured to actuate a shock feature of patient support 10 . Referring now to FIGS. 5 and 6 , when the shock feature provide by siderail control 112 is activated, the control system flattens deck 16 to a substantially coplanar orientation, as shown in FIG. 1 , and positions deck 16 in the Trendelenburg position simultaneously. If patient support 10 is in the articulated orientation, as shown in FIG. 5 , when siderail control 112 is activated, sections 34 , 36 , 38 of deck 16 are lowered to the substantially coplanar orientation and extendable column 31 at the head end of patient support 10 is lowered while extendable column 31 at the foot end of patient support 10 is extended to position deck 16 in the Trendelenburg position as shown in FIG. 6 . Siderail control 112 can be a momentary switch or any other suitable user input device. In the preferred embodiment, the control system begins flattening deck 16 and moving deck 16 into the Trendelenburg position only while the siderail control 112 is activated when a button (not shown) is depressed.
[0042] Referring now to FIG. 18 , deck 16 includes a head deck panel 114 , a seat deck panel 116 , a thick deck panel 118 , and a foot deck panel 120 . Head deck panel 114 is rigidly coupled to head section 34 and seat, thigh, and foot deck panels 116 , 118 , 120 are removable from seat and foot sections 36 , 38 of deck 16 . Deck panels 114 , 116 , 118 , 120 , head section siderail 24 , and headboard 20 are preferably formed of blow-molded plastic so that they are hollow. According to alternative embodiments of the present disclosure, other suitable materials such as metal, wood, or composites may also be used.
[0043] As shown in FIG. 20 , corner portions 122 of deck panel 114 is elevated to narrow gaps 124 , 126 defined between head section siderail 24 and deck panel 114 and headboard 20 and deck panel 114 , respectively. Headboard 20 includes curved portions 128 and head section siderail 24 includes curved portions 130 . Curved portions 128 , 130 are configured to narrow gap 132 , as shown in FIG. 21 , defined between headboard 20 and head section siderail 24 .
[0044] Curved portions 128 , 130 and corner portion 122 of head deck panel 114 converge together to narrow gaps 124 , 126 , 132 . In the preferred embodiment, hand holes 134 are provided in corner portions 122 of head deck panel 114 to permit a caregiver to grab head section deck panel 114 to move patent support 10 . In the preferred embodiment, curved portions 128 , 130 , and corner portion 122 are provided at each corner of the longitudinal end of the head end of patient support 10 . According to alternative embodiments of the present disclosure, the converging portions are also provided on the foot end of the patient support.
[0045] Referring now to FIGS. 16 and 17 , deck 16 and deck panels 116 , 118 , 120 are shown that support mattress 18 . Deck panel 116 is removably coupled to seat section 34 of deck 16 by restraint holders 138 . Deck panel 116 includes openings 140 which are sized to fit over restraint holders 138 . Deck panel 116 can be removed from seat section 34 of deck 16 by lifting deck panel 116 above restraint holders 138 . Deck panels 118 , 120 also include openings 140 which receive respective restraint holders 138 in the same fashion.
[0046] Deck panels 116 , 118 , 120 also include gap fillers 142 positioned adjacent the ends of head and foot end siderails 24 , 26 . In the preferred embodiment, gap fillers 142 are semicircular-shaped or half moon-shaped and are integral with deck panels 116 , 118 , 120 . Gap fillers 142 are positioned under mattress 18 when mattress 18 is positioned on deck panels 116 , 118 , 120 . As shown in FIG. 2 , gap fillers 142 are designed to narrow the respective gaps 144 , 146 , 148 defined between deck panels 116 , 118 , 120 and lower edges 76 , 72 of head and foot end siderails 24 , 26 , respectively. Similar gap fillers are also disclosed in PCT Publication No. WO 02/076266 A1, titled “Bed Equipped with a Back Elevator,” filed Mar. 26, 2002, to Gippert et al. and French Patent Application No. FR 01 08540, titled “Lit Medicalise a Plan de Couchage Amovible,” filed Jun. 28, 2001, to Barbu et al., the disclosures of which are expressly incorporated by reference herein.
[0047] Referring now to FIGS. 18 and 19 , mattress 18 includes chamfered lower corner portions 150 that extend along the length of each longitudinal side of mattress 18 . As shown in FIG. 19 , chamfered portions 150 permits mattress 18 to be positioned on deck panels 114 , 116 , 118 , 120 without interference from the gap fillers 142 . As shown in FIG. 19 , gap filler 142 contacts chamfered portions 150 of mattress 18 to prevent mattress 18 from moving laterally when positioned on deck 16 . According to an alternative embodiment of the present disclosure, the chamfered portions are only provided at the locations of the gap fillers.
[0048] As shown in FIG. 18 , restraint holders 138 extend through openings 140 in deck panels 116 , 118 , 120 . Restraint straps 152 are provided that are placed through restraint holders 138 and extended around mattress 18 as shown in FIG. 1 . Restraint straps 152 are placed over a patient to secure the patient to patient support 10 . According to alternative embodiments of the present disclosure, the restraint holders do not extend completely through the openings in the respective deck panels. Additional details of suitable restraint holders and restraint straps are provided in French Patent Application No. FR 01 08540, titled “Lit Medicalise a Plan de Couchage Amovible,” filed Jun. 28, 2001, to Barbu et al., the disclosures of which are expressly incorporated by reference herein.
[0049] As shown in FIG. 1 , the control system includes a battery enable switch 154 , which allows a person, such as a caregiver to operate the electrically controlled functions of patient support 10 using battery power when AC power is not available. In the illustrated embodiment, one battery enable switch 154 is located on head section siderail 24 and another battery enable switch (not shown) is located on pendent controller 113 . According to alternative embodiments of the present disclosure, the battery enable switch is located anywhere on the patient support as necessary or convenient. Battery enable switches 154 are electrically coupled to the battery system (not shown).
[0050] Battery enable switch 154 is a momentary switch such as a push button in the preferred embodiment, although any other suitable switch could be used. In the preferred embodiment, switch 154 includes a light emitting diode (LED) enclosed in a translucent or transparent plastic housing. The LED is “on” (i.e., illuminated) when either AC or battery power is being supplied to patient support 10 . When patient support 10 is disconnected from AC power, such as when a plug 44 is disconnected from wall socket 46 , switch 154 ceases being illuminated.
[0051] When AC power to patient support 10 is cutoff, a timing circuit (not shown) is initiated. In the preferred embodiment, after patient support 10 is disconnected from AC power for twenty minutes and any of the electrically controlled features of patient support 10 have not been actuated for a time period of twenty minutes, patient support 10 is placed in sleep mode. In sleep mode, minimal power is provided to patient support 10 by the battery backup system. During sleep mode, the electrical operable functions of patient support 10 are disabled.
[0052] In the preferred embodiment, when the patient support 10 is running on battery power provided by the battery, activation of one of the battery enable switches 154 causes patient support 10 to switch out of sleep mode and receive sufficient power from the battery so that at least certain electrically operational functions of patient support 10 , such as movement of patient support 10 into emergency Trendelenburg position, can be performed. In the illustrated embodiment, battery enable switch 154 is activated by the application of pressure on one of switches 154 with ones' finger. According to an alternative embodiment, the battery enable switches are not provided and activating any one of the bed function control buttons while patient support 10 is in sleep mode will switch it out of sleep mode.
[0053] In the preferred embodiment, the timing circuit waits for a predetermined time period of twenty minutes so that if no operational activity occurs within the twenty minute period after the battery enable switch 154 has been activated or since the previous operational activity, patient support 10 enters sleep mode. If one of the bed function control buttons is activated within the twenty minute time period, the timing circuit is reset to zero. In this manner, battery power is conserved and a smaller battery can be used to support the battery system.
[0054] Battery enable switches 154 permit patient support 10 to meet regulatory requirements by enabling at least certain of the bed's operational features to be operable on battery backup power only when needed. According to alternative embodiments of the present disclosure, the timing circuit can be set to enter sleep mode after any predetermined time period, such as five minutes, one hour, etc. Details of another suitable battery enable system is provided in U.S. Patent Application Ser. 60/408,698, titled “Hospital Bed,” filed Sep. 6, 2002, to Menkedick et al., the disclosure of which is expressly incorporated by reference herein.
[0055] Referring now to FIGS. 7 and 8 , patient support 10 includes a brake alarm that produces an audible and/or visual alarm signal when a brake 156 that locks caster wheel 28 is moved from the braked position, as shown in FIG. 7 , to the unbraked position as shown in FIG. 8 while patient support 10 is still connected to AC power through wall socket 46 . By activating the alarm, damage to plug 44 and other components of patient support 10 can be avoided.
[0056] Brake 156 includes a brake pedal 160 that rotates an octagonal brake shaft 158 to move brake 156 between the braked and unbraked positions. A lever 161 is coupled to brake shaft 158 so that as brake shaft 158 rotates, lever 161 also rotates. Additional details of a suitable brake is provided in French Patent Application FR02 02510, titled “Cadre de Dispositif a Usage Medical Ou Paramedical de Support Roulant d'une Personne, a Roulettes Facilement Demontables, et Dispositif Ainse Equuipe”, filed Feb. 28, 2002, to Gippert et al., and corresponding PCT Application No. unknown claiming priority, to Gippert et al., which claims priority to French Patent Application FR 02 02510, the disclosures of which are expressly incorporated by disclosure herein.
[0057] A switch 162 is provided that is coupled to a brake alarm controller (not shown) of the control system via wires 164 . Switch 162 includes a spring 166 positioned adjacent to lever 161 . Switch 162 is coupled to frame 24 by another spring 167 . In the preferred embodiment, spring 167 is made of a resilient metallic material to permit some movement of switch 162 .
[0058] When brake 156 is in the braked position, as shown in FIG. 7 , lever 161 depresses spring 166 on switch 162 to complete an electrical circuit. When brake 156 is moved to the unbraked position, as shown in FIG. 8 , lever 161 is rotated away from spring 166 . Spring 166 is then biased away from electrical switch 162 and the electrical circuit is broken. The brake alarm controller detects that the circuit has been broken and determines that brake 156 has moved from the braked position to the unbraked position. According to alternative embodiments of the present disclosure, the braked and unbraked positions of brake 156 are reversed or the brake alarm controller is programmed to activate the brake alarm signal when the circuit is completed rather than broken.
[0059] When the brake alarm controller determines that brake 156 is no longer in the braked position, it determines if patient support 10 is still plugged into an AC power source such as wall socket 46 . If plug 44 of patient support 10 is plugged in to wall socket 46 and receiving AC power while brake 156 is in the unbraked position, an alarm such as an audible alarm and/or a flashing indicator light on control panel 112 will signal to warn the caregiver not to move patient support 10 until plug 44 is removed from wall socket 46 .
[0060] Referring now to FIGS. 9-15 , fifth wheel assembly 30 is coupled to frame 24 of patient support 10 . Fifth wheel assembly 30 is configured to assist a caregiver in steering patient support 10 by providing a central pivot point about which to turn patient support 10 .
[0061] Fifth wheel assembly 30 includes a caster wheel 168 that rolls along the floor and is configured to pivot or swivel about a vertical axis 170 . Fifth wheel assembly 30 further includes a wheel position holder 172 configured to permit such swiveling. However, position holder 172 also encourages or urges caster wheel 168 to remain in predetermined orientation relative to vertical axis 170 .
[0062] As shown in FIG. 9 , caster wheel 168 is positioned in a first parallel position that is parallel to a longitudinal axis 174 of patient support 10 . When in this position, caster wheel 168 is aligned to roll along the floor when patient support 10 is being pushed in direction 176 along longitudinal axis 174 of patient support 10 such as when patient support 10 is being pushed down a hallway. In FIG. 11 , caster wheel 168 is positioned in a second perpendicular position that is perpendicular to longitudinal axis 174 of patient support 10 . When in this position, caster wheel 168 is aligned to roll along the floor when patient support 10 is being pushed in direction 178 perpendicular to longitudinal axis 174 such as when patient support is being positioned in a room.
[0063] Positioning fifth wheel 168 parallel to or perpendicular to longitudinal axis 174 of patient support 10 allows a caregiver to easily steer patient support 10 during movement of patient support 10 in a hallway or in a patient's room. Another suitable fifth wheel assembly is described in French Patent No. 2783463, titled “Rolling support for medical usage, has wheel held by bracket mounted on support shaft, carried in spring loaded sliding housing, which has lower edge profiled to fit on to roller cam fitted to support shaft,” filed Sep. 9, 1998, to Pascal Guguin, the disclosure of which is herein expressly incorporated by reference.
[0064] Position holder 172 is configured to permit movement of wheel 168 to either the first parallel position or the second perpendicular position. However, if wheel 168 is positioned between these two positions, position holder 172 urges wheel 168 back toward either the first parallel position or the second perpendicular position. Thus, if wheel 168 is in an intermediate position as shown in FIG. 10 , position holder 172 urges wheel 168 either toward the first parallel position shown in FIG. 9 or toward the second perpendicular position shown in FIG. 11 .
[0065] Fifth wheel assembly 30 further includes a base 180 coupled to frame 24 as shown in FIG. 9 . In the preferred embodiment, base 180 is positioned in the middle of frame 24 as shown in FIG. 1 . According to alternative embodiments of the present disclosure, base 180 is placed elsewhere on frame 24 such as under the center of gravity of the patient support and/or patient.
[0066] Base 180 is saddle-shaped and includes a pair of side plates 182 and a middle plate 184 extending between side plates 182 . Side plates 182 include openings 185 , 186 , 188 . Position holder 172 includes a saddle-shaped base 190 coupled between side plates 182 . Base 190 includes opening 192 (one not shown) corresponding to openings 185 of side plates 182 and a bearing-receiving opening 192 as shown in FIG. 15 .
[0067] Wheel assembly 30 further includes a post or stem 194 positioned to extend through an opening 196 formed in middle plate 184 of base 180 . A first upper link 198 is rigidly coupled to stem 194 and a second lower link 210 is pivotably coupled to first upper link 198 by a rod 212 . Wheel 168 is rotatably coupled to second lower link 210 by an axle 214 .
[0068] Wheel assembly 30 includes a pair of gas springs or biasers 216 pivotably coupled to upper link 198 by a first coupler 218 and pivotably coupled to lower link 210 by a second coupler 220 . Gas springs 216 urges wheel 168 into contact with the floor surface. Thus, if wheel 168 encounters a pump or depression on the floor, wheel 168 travels up or down and remains in contact with the floor.
[0069] As shown in FIG. 15 , stem 194 includes an upper opening 222 , an annular channel 224 , and a collar 226 . Wheel assembly 30 includes an upper sleeve or bearing 228 positioned between base 190 and an upper portion 230 of stem 194 and a lower sleeve or bearing 232 positioned between collar 226 and middle plate 184 of base 180 when wheel assembly 30 is fully assembled as shown in FIG. 12 . Bearings 228 , 232 reduce the friction and wear between stem 194 and bases 190 , 180 . To retain stem 194 in bases 190 , 180 , a pin 234 is inserted through openings 185 of base 180 and corresponding openings 192 of base 190 and passes through a portion of channel 224 of stem 194 as shown in FIGS. 9-12 . Because channel 224 is annular, stem 194 can rotate while pin 234 is positioned in channel 224 .
[0070] As shown in FIG. 15 , position holder 172 includes a first cam member 236 coupled to side plates 182 , a second cam member 238 positioned to interact with first cam member 236 , and biaser or spring 237 positioned to urge second cam member 238 toward first cam member 236 . First and second cam members 236 , 238 cooperate to urge wheel 168 to either the first parallel or second perpendicular positions.
[0071] First cam member 236 includes three spacers 240 , two ball bearings 242 , and a pin 244 . Pin 244 is inserted through opening 186 in side plates 182 , spacers 240 , and ball bearings 242 to support bearings 242 above second cam member 238 as shown in FIGS. 12-14 .
[0072] Second cam member 238 includes an upper collar 246 having a sinusoidal cam surface 248 , a shoulder 248 , a shaft 250 , and a square keyed portion 252 . When fifth wheel assembly 30 is fully assembled, second cam member 238 is positioned in opening 222 of stem 194 and spring 237 as shown in FIGS. 12-14 . Lower end 256 of passage 254 has a square profile that complements keyed portion 252 of second cam member 238 . Thus, when wheel 168 and stem 194 rotate, second cam member 238 also rotates. However, second cam member 238 can move up and down in passage 254 . Shoulder 248 of second cam member 238 is positioned over spring 237 so that second cam 238 is urged upwardly toward first cam member 236 .
[0073] In the preferred embodiment, cam surface 248 on the upper end of second cam member 238 has a smooth sinusoidal profile that includes a pair of first peaks 258 , a pair of second peaks 260 , a pair of first valleys 262 , and a pair of second valleys 264 . Each respective first peak 258 , second peak, 260 , first valley 262 , and second valley 264 is positioned opposite one another about vertical axis 170 of stem 194 . Peaks 258 , 260 separate valleys 262 , 264 so that valleys 262 , 264 are spaced approximately 90° apart on cam surface 248 about axis 266 .
[0074] Valleys 264 are slightly deeper than valleys 262 in the preferred embodiment. According to alternative embodiments of the present disclosure, the cam surface has fewer or more valleys and peaks, peaks with sharp contours or other contours to provide other suitable profiles.
[0075] When fifth wheel assembly 30 is assembled, cam surface 248 is pushed upward into contact with ball bearings 242 so that ball bearings 242 “roll over” cam surface 248 . Referring now to FIGS. 9-11 , wheel 168 can rotate 360° relative to base 180 . However, because of cam surface 248 , wheel 168 is urged toward one of four positions either parallel or perpendicular to the longitudinal axis of patient support 10 .
[0076] When wheel 168 is in one of the four positions, ball bears 242 are positioned in either first valleys 262 or second valleys 264 as shown in FIGS. 12 and 14 . When wheel 168 is rotated, ball bearings 242 roll up either peaks 258 or peaks 260 and second cam member 238 is pushed down against the bias of spring 237 . When positioned on peaks 258 , 260 , the normal force between ball bearings 242 and cam surface 248 have both axial and radial components. The radial components urge second cam member 238 toward the nearest valley 262 , 264 . Thus, when wheel 168 is not positioned in one of the four positions, it is urged back toward the nearest of the four positions. When ball bearings 242 ride over one of peaks 258 , 260 , they are urged toward the nearest valley 262 , 264 .
[0077] Because valleys 264 are deeper than valleys 262 , the radial components of the normal forces are greater. Thus, it is easier to move from the second perpendicular position to the first parallel position and vice versa. Because cam surface 238 is smooth, the transition of wheel 168 from one position to position is also smooth.
[0078] To move wheel 168 from the first parallel position to the second perpendicular position, a caregiver pushes on patient support 10 in a transverse direction. This force creates torque on wheel 168 and urges ball bearings 242 to ride up one of peaks 258 , 260 . Once wheel 168 has rotated approximately 45°, ball bearings 242 are positioned on top of peaks 258 , 260 . With further movement of wheel 168 about axis 166 , ball bearings 242 and wheels 168 are urged toward the second perpendicular position.
[0079] To move wheel 168 from the second perpendicular position to the first parallel position, a caregiver pushes on patient support 10 in a longitudinal direction. This force creates torque on wheel 168 and urges ball bearings 242 to ride up one of peaks 258 , 260 . Once wheel 168 has rotated approximately 45°, ball bearings 242 are positioned on top of peaks 258 , 260 . With further movement of wheel 168 about axis 166 , ball bearings 242 and wheels 168 are urged toward the first parallel position.
[0080] Fifth wheel 168 is rotated between being parallel to the longitudinal axis of patient support 10 and perpendicular to the longitudinal axis of patient support 10 and vice versa by a caregiver gently pushing patient support 10 from either one of the head or foot end or along one of the longitudinal sides of patient support 10 .
[0081] Preferably, instructions for the assembly, installation, and/or use of patient support 10 are provided with patient support 10 or otherwise communicated to permit a person or machine to assemble, install and/or use patient support 10 . Such instructions may include a description of any or all portions of patient support 10 and/or any or all of the above-described assembly, installation, and use of patient support 10 or components of patient support 10 . The instructions may be provided on separate papers and/or on the packaging in which patient support 10 is sold or shipped. These instructions may also be provided over the Internet or other communication system. Furthermore, the instructions may be embodied as text, pictures, audio, video, or any other medium or method of communicating instructions known to those of ordinary skill in the art.
[0082] The features of the present disclosure have been described with respect to beds, but they can also be used on examination tables, stretchers, gurneys, wheel chairs, chair beds, or any other patient support devices for supporting a person during rest, treatment, or recuperation.
[0083] Unless otherwise stated herein, the figures are proportional. Although the present invention has been described in detail with reference to preferred embodiments, variations and modifications exist within the scope and spirit of the present invention as described and defined in the following claims.
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A patient support is provided for supporting a patient. Patient support includes a frame, a deck, a mattress and siderails. The deck includes a panel having apertures that receive upside down U-shaped wire loops therein to removably couple the panel to the frame. Top portions of the wire loops extend above the panel and serve as restraint strap holders.
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BACKGROUND OF THE INVENTION
This invention relates to electric hammers, in particular rotary hammers, having an air cushion hammering mechanism.
Such hammers will normally have a housing and a hollow cylindrical spindle mounted in the housing. The spindle allows insertion of the shank of a tool or bit, for example a drill bit or a chisel bit, into the front end thereof so that it is retained in the front end of the spindle with a degree of axial movement. The spindle may be a single cylindrical part or may be made of two or more co-axial cylindrical parts, which together form the hammer spindle. For example, a front part of the spindle may be formed as a separate tool holder body for retaining the tool or bit. Such hammers are provided with an impact mechanism which converts the rotational drive from an electric motor to a reciprocating drive causing a piston, which may be a hollow piston, to reciprocate within the spindle. The piston reciprocatingly drives a ram by means of a closed air cushion located between the piston and the ram. The impacts from the ram are transmitted to the tool or bit of the hammer, optionally via a beatpiece.
Such hammers can also be employed in combination impact and drilling mode or in a drilling only mode in which the spindle, or a forwardmost part of the spindle, and hence the bit inserted therein will be caused to rotate. In the combination impact and drilling mode the bit will be caused to rotate at the same time as the bit receives repeated impacts. A rotary drive mechanism transmits rotary drive from the electric motor to the spindle to cause the spindle, or a forwardmost part thereof to rotate.
In smaller hammers, a wobble drive arrangement is generally used to convert a rotary drive from the motor to the reciprocating drive of the piston. In a known arrangement the rotary drive from the motor is transmitted to an intermediate shaft mounted within the hammer housing generally parallel to the axis of the spindle. A wobble sleeve is rotatably mounted on the intermediate shaft. The wobble sleeve is formed with a wobble race which extends around the wobble sleeve at an oblique angle to the axis of the intermediate shaft. Balls are set to run between this inner race and an outer race of a wobble ring, which wobble ring has a wobble pin extending from it to the rearward end of the piston. The wobble pin is pivotally connected to the rearward end of the piston via a trunnion arrangement. Thus, when the wobble sleeve is rotatably driven the wobble pin reciprocates and reciprocatingly drives the piston within the spindle and hammering occurs. In drilling only mode hammering is not required and so a mode change mechanism is required to selectively transmit the rotation of the intermediate shaft to the wobble sleeve.
It is known to have a mode change element moveable along the intermediate shaft in a first direction in order to be engaged with sets of teeth on the wobble sleeve and the intermediate shaft to actuate hammering or in a second opposite direction in order to be disengaged with one of the sets of teeth to disable hammering. The mode change element generally requires some means of determining its end positions on the intermediate shaft. This is generally provided by an axial stop element mounted on the intermediate shaft or the wobble sleeve using a circlip. Such axial stops and circlips are difficult to assemble, if they are not assembled correctly the hammer will not operate correctly and if they become loose, then they can damage other components of the hammer. Alternatively, a mode change linkage, connected to a mode change knob or the mode change knob itself, which act to move the mode change element between its different positions can be used to determine the end positions of the mode change element. However, this may reduce the accuracy with which the end positions can be determined and so may lead to a less compact design.
In smaller hammers, where the compactness of the hammer is a critical design issue, the mode change mechanism must be compact. However, the mode change mechanism must also be robust so that it can operate reliably in the high vibration environment of a hammer.
SUMMARY OF INVENTION
The present invention aims to provide a rotary hammer arrangement with a compact and robust mode change mechanism for selectively actuating hammering.
According to the present invention there is provided an electrically powered hammer comprising:
a hammering mechanism for generating repeated impacts on a tool or bit of the hammer;
a rotatingly driven intermediate shaft;
a wobble drive arrangement for reciprocatingly driving the hammering mechanism, which wobble drive arrangement includes a wobble sleeve mounted on the intermediate shaft; and
a mode change element selectively engageable, by movement along the intermediate shaft, with a set of driving teeth provided on the intermediate shaft and a set of driven teeth provided on the wobble sleeve, such that when the mode change element is engaged with both sets of teeth it transmits rotary drive from the intermediate shaft to the wobble sleeve;
characterized in that the mode change element is formed integrally with at least one axial stop surface and the or each axial stop surface is engageable with a cooperating end stop surface formed integrally with one of the intermediate shaft and the wobble sleeve to limit the movement of the mode change element along the intermediate shaft.
The end stops for the mode change ring are provided by existing components, namely the mode change ring itself and the wobble sleeve and/or the intermediate shaft. This results in a reduction in the number of components required, which improves the compactness and ease of assembly of the hammer. Also, integrating the end stops into pre-existing and themselves robust components leads to a robust design of end stop.
The or each axial stop surface may engage with a cooperating end stop surface when the mode change element engages both sets of teeth. The mode change element may be moved in a first direction along the intermediate shaft to engage both sets of teeth so that the cooperation of the or each axial stop surface and cooperating end stop surface limits the movement of the mode change element further along the intermediate shaft in the first direction. This provides an end stop for the movement of the mode change element into its position where hammering occurs.
In a preferred embodiment the cooperating end stop surfaces are formed by one or more end faces of one of the sets of teeth. This means that additional end stop surfaces need not be provided on the intermediate shaft or the wobble sleeve.
The or each axial stop surface may be formed by an end surface of one or more recesses which recesses extend axially with respect to the longitudinal axis of the intermediate shaft and are formed in a face of the mode change element facing towards the intermediate shaft.
Preferably, the mode change element is non-rotatably and axially slideable mounted on one of the sets of teeth. The mode change element then needs only to be moved axially into engagement with the other of the sets of teeth to engage both sets and transmit rotary drive from the intermediate shaft to the wobble sleeve.
In a preferred embodiment a spring member biases the mode change element into the position in which is engages both sets of teeth. This means that any mode change linkage or mode change knob needs only to move the mode change element in one direction, against the biasing force of the spring. This can simplify the design of mode change linkage or knob, which can increase the compactness of the overall design of mode change mechanism.
The spring member may extend between a flange formed on the mode change element and a bearing ring for rotatably supporting the intermediate shaft in the housing. The bearing ring may form the outer race for a set of balls which run between the outer race and an inner race formed in an external surface of the wobble sleeve. A washer may advantageously by mounted within the bearing ring so that the spring member bears against the washer to prevent wear of the bearing ring. Where a set of balls which run in the bearing ring are held in a cage, the washer may be mounted between the cage and the spring member so that it protects the generally plastic cage from an end of the generally metal helical spring.
For increased compactness and to provide a robust design, the mode change element may be formed as a ring, or alternatively as a part of a ring. The mode change element can then be mounted co-axially with the intermediate shaft.
The mode change element may be non-rotatably and axially slideably mounted on the intermediate shaft drive teeth or it may be non-rotatably and axially slideably mounted on the wobble sleeve driven teeth. Then the or each axial stop surface of the mode change element may engage with a cooperating end stop formed on the wobble sleeve or intermediate shaft, respectively.
Where the mode change element is mounted on the wobble sleeve driven teeth, the mode change element may be biased by a spring member towards engagement with the intermediate shaft drive teeth. Then the mode change element may be formed with one or more engagement surfaces which are engageable with a cooperating engagement surface of a mode change linkage or a mode change knob so as to prevent rotation of the mode change element when the mode change linkage or knob engages the mode change element to draw it out of engagement with the intermediate shaft drive teeth against the biasing force of the spring member. Thus, in drilling only mode when the mode change linkage or knob engages the mode change member, the mode change member is prevented from rotating and slow hammering is prevented from occurring in drilling only mode.
The mode change element may be formed with at least one axially extending recess engageable with both sets of teeth and at least one axially extending recess with an axial stop surface formed in it wherein the axial recesses are formed in a radially inwardly directed surface of the mode change element.
BRIEF DESCRIPTION OF THE DRAWINGS
An embodiment of a hammer according to the present invention will now be described by way of example, with reference to the accompanying drawings in which:
FIG. 1 is a partially cut away side cross-sectional elevation of the forward part of a rotary hammer according to the present invention;
FIG. 2A is a perspective view of the intermediate shaft sub-assembly of FIG. 1 with the mode change element in its forward hammering position with the mode change element shown partially cut away;
FIG. 2B is a longitudinal cross-section through FIG. 2A ;
FIG. 3A is a perspective view of the intermediate shaft sub-assembly of FIG. 1 with the mode change element in its rearward non-hammering position with the mode change element shown partially cut away; and
FIG. 3B is a longitudinal cross-section through FIG. 3A ;
DESCRIPTION OF THE INVENTION
The rotary hammer has a forward portion which is shown in FIG. 1 and a rearward portion incorporating a motor and a rear handle, in the conventional way. The handle may be of the pistol grip or D-handle type. The handle portion incorporates a trigger switch for actuating the electric motor, which motor is formed at the forward end of its armature shaft with a pinion ( 2 ). The pinion ( 2 ) of the motor rotatingly drives an intermediate shaft ( 6 ) via a gear ( 8 ) which gear is press fit onto the rearward end of the intermediate shaft ( 6 ). The intermediate shaft is located within a housing part ( 10 ) of the hammer, so that it can rotate about it longitudinal axis. In the FIG. 1 arrangement the longitudinal axis of the motor is parallel with the longitudinal axis of the hollow cylindrical spindle ( 4 ) of the hammer. Alternatively, the motor could be aligned with its axis, at an angle, for example perpendicular to the axis of the spindle ( 4 ), in which case a bevel pinion would be formed at the end of the armature shaft of the motor, to mesh with a bevel gear press fit on the intermediate shaft ( 6 ) replacing the gear ( 8 ).
A wobble sleeve ( 12 ) is mounted on the intermediate shaft ( 6 ) using needle bearings, so that it can rotate with respect to the intermediate shaft. The wobble sleeve ( 12 ) carries the inner race ( 14 ) for the ball bearings ( 16 ) of a wobble ring ( 18 ) from which extends a wobble pin ( 20 ). The balls are mounted between the inner race ( 14 ) and an outer race ( 22 ) formed in the wobble ring ( 18 ). Thus, as the wobble sleeve ( 12 ) rotates the end of the wobble pin ( 20 ) remote from the wobble ring ( 18 ) is caused to reciprocate, in order to reciprocatingly drive a hollow cylindrical piston ( 24 ). The most rearward position of the wobble pin ( 20 ) is shown cross-hatched in FIG. 1 and the most forward position of the wobble pin ( 20 ) is shown unshaded in FIG. 1 . The end of the wobble pin reciprocatingly drives the piston ( 24 ) via a trunnion pin arrangement ( 26 ), as is well known in the art.
The hollow cylindrical piston ( 24 ) is slideably located within the hollow cylindrical spindle ( 4 ). A ram ( 3 ) is slideably mounted within the hollow cylindrical piston and an O-ring seal is mounted around the ram so as to seal between the periphery of the ram and the internal surface of the piston. During normal operation of the hammer, a closed air cushion is formed between the interior of the piston and the rearward face of the ram and so the ram is reciprocatingly driven by the piston via the closed air cushion. During normal operation of the hammer the ram repeatedly impacts a beatpiece ( 5 ), which beatpiece is mounted within the spindle so as to be able to undergo limited reciprocation. The beatpiece transfers impacts from the ram to a tool or bit ( 34 ) mounted within a forward tool holder portion of the spindle by a tool holder arrangement ( 36 ), for example an SDS-type tool holder. The tool or bit ( 34 ) is releasably locked within the tool holder portion of the spindle so as to be able to reciprocate within the tool holder portion of the spindle by a limited amount. In FIG. 1 , the ram and beatpiece are shown in their idle mode position in the top half of FIG. 1 and in their operating position in the bottom pan of FIG. 1 .
The spindle ( 4 ) which is rotatingly mounted within the hammer housing ( 10 ) can be rotatingly driven by the intermediate shaft ( 6 ), as described below. Thus, as well as or instead of reciprocating, the tool or bit ( 34 ) can be rotatingly driven because it is non-rotatably mounted within the spindle ( 4 ) by the tool holder arrangement ( 36 ). Thus, the hammer may have three modes, a drilling only mode in which no hammering occurs and the spindle is rotatingly driven; a hammer drilling mode in which hammering occurs and the spindle is rotatingly driven and a chisel or hammer only mode in which hammering occurs but there is no rotary drive to the spindle and in which the spindle is generally locked against rotation.
The intermediate shaft ( 6 ) is formed at its forward end with a pinion ( 38 ) which is selectively engageable with a spindle drive gear ( 40 ). The spindle drive gear ( 40 ) rotationally drives the spindle ( 4 ), optionally via a clutch arrangement, as is well known in the art. The spindle drive gear ( 40 ) can be moved axially forwardly on the spindle ( 4 ) in order to disengage the intermediate shaft pinion ( 38 ). Thus, with the spindle drive gear ( 40 ) in a forward position, no rotary drive is transmitted to the spindle ( 4 ) and with the spindle drive gear ( 40 ) in a rearward position rotary drive is transmitted from the intermediate shaft ( 6 ) to the spindle ( 4 ) via the intermediate shaft pinion ( 38 ) and the spindle drive gear ( 40 ).
A mode change element in the form of a ring ( 72 ) is non-rotatably but axially slideably mounted on the forward portion of the wobble sleeve ( 12 ), co-axially with the intermediate shaft ( 6 ). The mode change ring is mounted on the wobble sleeve via driven teeth, which take the form of two opposing splines ( 76 ) formed on the outer surface of the forward end of the wobble sleeve ( 12 ). The driven teeth or splines engage in a pair of cooperating recesses which are formed in the radially inward facing surface of the mode change ring. The recesses extend axially from the forward to the rearward facing face of the mode change ring. The recesses of the mode change ring ( 72 ) are selectively engageable with an opposing pair of a set of drive teeth ( 74 ) formed on an increased outer diameter portion of the intermediate shaft ( 6 ). When the mode change ring ( 72 ) is in a rearward position, as shown in FIGS. 1 , 3 A and 3 B no rotary drive is transmitted from the intermediate shaft ( 6 ) to the wobble sleeve ( 12 ) and so no hammering occurs. When the mode change ring ( 72 ) moves forwardly into a forward position, as shown in FIGS. 2A and 2B , the recesses in the mode change ring ( 72 ) engage an opposing pair of the set of drive teeth ( 74 ) formed on the intermediate shaft ( 6 ). In the forward position of the mode change ring ( 72 ) the recesses in the mode change ring straddle the intermediate shaft drive teeth ( 74 ) and the splines ( 76 ) on the wobble sleeve ( 12 ). Thus, in the forward position of the mode change ring ( 72 ) rotary drive is transmitted from the intermediate shaft ( 6 ) to the wobble sleeve ( 12 ) via the mode change ring ( 72 ) and hammering occurs.
The mode change ring ( 72 ) is biased forwardly, into engagement with the intermediate shaft drive teeth ( 74 ) by a helical spring ( 80 ) which extends around the forward end of the wobble sleeve ( 12 ). The spring ( 80 ) extends between a washer ( 82 ) located in front of a bearing cage ( 56 ) of a support bearing ( 58 ) for the intermediate shaft ( 6 ) and an annular flange ( 84 ) which extends radially outwardly of the forward end of the mode change ring ( 72 ).
The mode change ring ( 72 ) is operated on by a mode change knob ( 21 ). The mode change knob has an eccentric pin ( 23 ) which is engageable with the forward facing face of the mode change ring ( 72 ). The mode change knob ( 21 ) is rotatably mounted in the housing ( 10 ) and can be rotated by a user to change the position of the eccentric pin ( 23 ) to selectively actuate hammering. When a user locates the mode change knob in the drilling only mode position, the eccentric pin ( 23 ) of the mode change knob ( 21 ) engages the mode change ring ( 72 ) to pull the mode change ring rearwardly against the biasing force of the spring ( 80 ) into the rearward position of the mode change ring ( 72 ) shown in FIG. 3A . When a user locates the mode change knob ( 21 ) in a hammering drilling mode position or the chisel mode position the eccentric pin ( 23 ) of the mode change knob ( 21 ) no longer engages the mode change ring ( 72 ) to pull it rearwardly, as shown in FIG. 2A and the biasing force of the spring ( 80 ) biases the mode change ring into its forward position of FIGS. 2A and 2B and hammering occurs. The use of the spring ( 80 ) to bias the mode change ring ( 72 ) into its forward, hammering position, helps to simplify the structure of the mode change knob or other alternative mode change arrangement, as the mode change arrangement or knob has only to engage the mode change ring ( 72 ) in the drilling mode, and need only move the mode change ring ( 72 ) in one direction, ie. rearwardly. Alternatively, a mode change linkage can act between a mode change knob and the mode change ring ( 72 ), as is well known in the art.
On the change from a drilling only mode to a hammer drilling mode or to a chisel mode of the hammer, the mode change sleeve is moved forwardly from the position in FIGS. 1 , 3 A and 3 B by the biasing force of the spring ( 80 ). Sometimes, the recesses in the mode change ring ( 72 ) will not be aligned with the drive teeth ( 74 ) on the intermediate shaft ( 6 ) and so the spring ( 80 ) will not be able to move the mode change ring ( 72 ) into its forward position. However, as soon as the intermediate shaft ( 6 ) is rotatingly driven by the motor, the recesses ( 76 ) in the mode change ring ( 72 ) come into alignment with the intermediate shaft drive teeth ( 74 ) and the spring ( 80 ) moves the mode change ( 72 ) into its forward position of FIGS. 2A and 2B in which the recesses straddle the intermediate shaft drive teeth ( 74 ) and the splines ( 76 ) on the wobble sleeve ( 12 ) and hammering occurs. Thus, the spring ( 80 ) facilitates the synchronization of the teeth ( 76 ) and recesses on the start up of hammering.
During hammering, the wobble sleeve ( 12 ), mode change ring ( 72 ) and spring ( 80 ) rotate with the intermediate shaft ( 6 ). The ball bearing cage ( 56 ) will rotate at a slower speed than the wobble sleeve ( 12 ). The washer ( 82 ) protects the cage ( 56 ), which latter is a plastic part, from the end of the metal spring ( 80 ). In the absence of the washer ( 82 ) the rearward end of the spring ( 80 ) would cause damage to the bearing cage ( 56 ).
Four forwardly facing pockets ( 86 ) are located two between each recess in the mode change ring ( 72 ), on the radially inwardly facing surface of the mode change ring. The pockets are formed as axially extending recesses formed in the radially inward facing face of the mode change ring ( 72 ), which are open at a forward end of the mode change ring and are closed at a rearward end of the recess by an end surface. The intermediate shaft ( 6 ) is formed with six driving teeth ( 74 ) which correspond to the two recesses and the four pockets ( 86 ) of the mode change ring ( 72 ). When the mode change ring ( 72 ) moves to its forward position in which the recesses engage two opposing teeth of the set of driving teeth ( 74 ), the pockets ( 86 ) engage the remaining driving teeth. The rearward end faces of the pockets ( 86 ) abut the rearward facing face of the driving teeth ( 74 ), as shown in FIGS. 2A and 2B , to prevent any further forward movement of the mode change ring ( 72 ). Previously a stop ring would have been provided on the intermediate shaft to limit the forward movement of the mode change ring ( 72 ).
The mode change ring ( 72 ) can also prevent slow hammering from occurring in drilling only mode of the hammer. Due to friction in the needle bearings which are used to rotatably mount the wobble sleeve ( 12 ) on the intermediate shaft ( 6 ), when the hammer is in drilling only mode, the wobble sleeve will rotate slowly, despite the mode change ring ( 72 ) being in its rearward position. This causes slow hammering to occur. To prevent this the mode change ring ( 72 ) is formed on the forward face of its flange with a set of radially extending recesses ( 88 ). In drilling mode, the eccentric pin ( 23 ) of the mode change knob ( 21 ), or a projection on a mode change linkage, engages the forward face of the mode change ring ( 72 ) to pull the mode change ring ( 72 ) rearwardly against the force of the spring ( 80 ). As soon as the wobble sleeve ( 12 ) and thus the mode change ring ( 72 ) start to rotate slowly, the eccentric pin ( 23 ) or other projection engages one of the recesses ( 88 ) in the mode change ring ( 72 ) (as shown in FIG. 3A ) to prevent further rotation of the mode change ring ( 72 ) and thus the wobble sleeve ( 12 ). In this way slow hammering is stopped.
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An electrically hammer comprising a hollow spindle, a piston, and an intermediate shaft. A wobble drive arrangement includes a wobble sleeve rotatably mounted on the intermediate shaft. A mode change element is selectively engageable, by movement along the intermediate shaft, with a set of drive teeth provided on the intermediate shaft and a set of driven teeth provided on the wobble sleeve. When the mode change element is engaged with both sets of teeth it transmits rotary drive from the intermediate shaft to the wobble sleeve so that the wobble sleeve arrangement reciprocatingly drives the piston. A mode change ring is formed integrally with an axial stop surface and the axial stop surface is engageable with a cooperating end stop surface formed integrally with one of the intermediate shaft and the wobble sleeve to limit the movement of the mode change element along the intermediate shaft.
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This is a continuation of application Ser. No. 249,535, filed Sept. 26, 1988, now abandoned.
FIELD OF THE INVENTION
This invention relates to a novel zeolite and to a process for its preparation. In particular, the zeolite, known for convenience as ECR-5, apparently having a cancrinite-like structure, previously prepared using a synthesis solution containing aqueous ammonia, can now be made in the absence of ammonia by using mixed Li-Na and Li-Na-TMA synthesis mixtures.
BACKGROUND OF THE INVENTION
Cancrinite is a well-known natural zeolite having a SiO 2 :Al 2 O 3 ratio of two which is readily synthesized in systems consisting of Na 2 O-SiO 2 -Al 2 O 3 -H 2 O in the presence of a large variety of salts. See, for example, Barrer et al., J. Chem. Soc. A, 1523 (1970). In addition, U.S. Pat. No. 3,433,736 discloses hydroxyparacancrinite of the formula 3(Al 2 O 3 , 2SiO 2 , Na 2 O) 2NaOH from a mixture of silica, aluminum hydroxide and water. The main characterizing feature of cancrinite is a single 12-ring channel parallel to the `c` axis as described by Jarchow, Zeit Krist., 122, 407 (1965) and Pahor et al., Acta Cryst., B38, 893 (1982). Because this channel is invariably faulted or blocked by salt molecules, the structure tends to have very poor sorption properties, even when attempts are made to remove the excess salt molecules (see Barrer and Vaughan, J. Phys. Chem. Solids, 32, 731 (1971)). The synthesis chemistry has been reviewed at great length by Barrer, Hydrothermal Chemistry of Zeolites, Academic Press (1982), Ch. 7.
If the channel of the cancrinite could be unblocked, the cancrinite would be expected to be a highly active catalyst (as are other zeolites having 12-ring channel systems) such as mordenite and offretite for cracking, hydrocracking and hydrodewaxing, and mordenite and zeolite L for hydroisomerization and reforming.
Although the synthetic analog of the zeolite cancrinite is easy to produce and is otherwise well-characterized, it always has an Si/Al ratio at unity, whether in its natural state or synthesized in a wide variety of systems, and such materials have very poor sorption properties and no catalytic activity.
In the present invention, Li-Na and Li-Na-TMA forms of ECR-5 (U.S. Pat. No. 4,717,560) have been made in non-ammonia systems for the first time. ECR-5 is a high silica, porous form of the mineral cancrinite, natural and synthetic forms of which have only previously been made at an Si/Al ratio of unity, and which have no sorption capacity for organic molecules. The main interest of this structure is that it has a structure analogous to those for L, offretite, mordenite and mazzite, which have considerably value as catalysts in reforming, hydrodewaxing and hydroisomerization. This is a new and easier synthesis than that previously used for ECR-5 in that no ammonia is used in the synthesis, and therefore a major pollutant is removed from the process effluent. The product ECR-5 materials have good hydrocarbon sorption properties, ECR-5 is unusual as a 12-ring structure, in that the puckering of the 12-ring causes a narrowing of the channel to make it closer to the diameter of 10-ring structures, such as ZSM-5, ZSM-11, ferrierite, ZSM-23, etc. Such materials are known to have good catalytic properties by virtue of their high degree of shape selectivity for specific substituted aromatics (e.g., para-xylene) and branched paraffins. Therefore the structure of ECR-5 may make it a more selective catalyst than other analogous channel structures, such as mordenite or offretite.
SUMMARY OF THE PRESENT INVENTION
According to the present invention, a zeolite with a cancrinite-like structure is synthesized over a range of SiO:Al 2 O 3 ratios in forms where the twelve ring channel is substantially unblocked and unfaulted, such that the zeolite obtained is a superior sorbent. More particularly, the present invention relates to a method of preparing Li-Na or Li-Na-TMA form of the crystalline zeolite, ECR-5, having a composition, in terms of mole ratios of oxides, in the range:
1.0 to 1.3 (R, Li, Na).sub.2 O Al.sub.2 O.sub.3 :2.0 to 5.0 SiO.sub.2
and having a cancrinite-like structure in which the twelvering channel thereof is substantially unblocked, and therefore sorbs hydrocarbons. The zeolite herein has an x-ray diffraction pattern which identifies it as having a cancrinite-like structure, the pattern being disclosed in Zeit. Krist., 122, 407 (1965), supra, the disclosure of which is incorporated herein by reference. This material may be considered as having a cancrinite-type structure but with higher Si/Al ratios characteristic of the zeolite ECR-5 (U.S. Pat. No. 4,717,560).
The zeolite of this invention is prepared by a process comprising:
(a) preparing a reaction mixture comprising aqueous solution, a source of silica, a source of alumina, said reaction mixture having a composition, in terms of mole ratios of oxides, within the following ranges:
M 2 O:Al 2 O 3 :1.5 to 2.8
SiO 2 :Al 2 O 3 :2 to 5
H 2 O:Al 2 O 3 :50 to 140
wherein
M=(Li+Na±TMA) ##EQU1##
(b) maintaining the reaction mixture at a temperature and for a time sufficient to cause crystallization of the zeolite.
The ECR-5 zeolite may be used as a sorbent or as a catalyst, e.g., as a hydrocarbon conversion catalyst for, e.g., paraffin isomerization, aromatization, reforming, polymerization and alkylation or the cracking, hydrocracking and hydrodewaxing of lube stocks, fuels and crude oils.
It will be understood that the compositions herein as prepared may contain some waters of hydration which may be at least partially removed when the zeolites are employed as sorbents or catalysts. In addition, the sodium and other cations in the original synthesized zeolite may be subsequently exchanged with hydrogen, ammonium cations, metal cations from Groups I through VIII of the Periodic Table, or mixtures thereof, to provide a suitable catalyst material.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The forms of the ECR-5 zeolites of this invention have a cancrinite-like framework as determined by x-ray diffraction analysis and comparison with the x-ray diffraction pattern characteristic of cancrinites. See, Zeit. Krist. supra., U.S. Pat. No. 4,717,560, and Table 1.
In a preferred method for preparing the ECR-5 zeolite forms of the present invention, a reaction mixture is prepared, generally as a slurry. The materials can be made in a limited composition field in the mixed cation system Li + +Na + ), (Li + +Na + +TMA + ) (TMA=tetramethyl ammonium), using aqueous rather than ammonia or ammonia-containing solvents. The elimination ammonia from the synthesis disposes of a major pollution problem, which is costly to recover from effluent waste streams associated with the processing.
In general terms the synthesis composition range for Li-ECR-5 can be stated as follows:
xM.sub.2 O:Al.sub.2 O.sub.3 :ySiO.sub.2 :zH.sub.2 O
where
x=1.5 to 2.8
y=2 to 4
z=50 to 140
M=(Li+Na±TMA) ± means with or without TMA
Li/Na=3 to 9
and TMA/(Li+Na)<0.2:
In the presence of excess Li, Li-ABW is dominant; when K is present, ECR-5 is suppressed; and at high Na levels FAU or MAZ predominate (the latter crystallizes only in the presence of TMA). Temperatures may vary from 80° C. to 200° C. and crystallization times from a few hours to several days.
In the TMA forms of ECR-5 the product is first calcined to remove the organic template (300° C.-500° C. in an air or oxygen atmosphere is sufficient to remove the organic cation), then the template face may be cation exchanged to convert it into the desired cation form using standard ion exchange methods, as described, for instance, in U.S. Pat. No. 3,216,789, and soluble salts fo Groups I through VIII of the Periodic Table of the elements. Such specific cation forms may be used as sorbents or catalysts.
EXAMPLES
The following examples demonstrate the efficiency of the invention.
EXAMPLE 1
A lithium-sodium composition
Li.sub.2 O:Na.sub.2 O:Al.sub.2 O.sub.3 :3SiO.sub.2 :80H.sub.2 O
was made using meta-kaolin as the sole alumina source. 38.9 gms NaOH and 55.4 gms LiOH were dissolved in 500 ml H 2 O, and 126.6 gms sodium silicate (P.Q. N brand) were blended in, followed by 152.9 gms metakaolin. The homogenized sample was divided between three 500 ml teflon jars and reacted in a forced air over at 100° C. The products were sampled at 3, 4 and 5 days. These identical pure products have the x-ray diffraction pattern shown in Table 1. Chemical analysis gave a composition 6.48% Na, 13.90% Al, 20.08% Si, 3.23% Li, representing a stoichiometry:
0.90Li.sub.2 O:0.55Na.sub.2 O:Al.sub.2 O.sub.3 :2.88SiO.sub.2
The capacity of this material for n-hexane at 22° C. and 45 torr was 4.8 wt %. Samples of the product were ion exchanged with delute HCl at pH=6, and 9 and NH 4 Cl at pH=8 (adjusted with dilute HCl), and gave n-hexane sorption value of 3.5 wt %.
These materials clearly have superior porosity to conventional cancrinite and are typical of ECR-5 materials previously reported.
EXAMPLE 2
This sample is made using only metakaolin as the source of silica and alumina from a composition comprising:
0.5Na.sub.2 O:1.5Li.sub.2 O:Al.sub.2 O.sub.3 :2SiO.sub.2 :80H.sub.2 O
18.6 gms LiOH and 6.2 gms NaOH were dissolved in 228 gms H 2 O, to which were added 40 gms metakaolin (derived from Georgia Kaolin Co. U F Kaolin by heating at 600° C. for three hours) and 0.2 gms of a sample of NaA zeolite as seed component. After heating this slurry for three hours at 100° C. in an air oven, the sample was filtered, washed with distilled water and analyzed. The product gave an x-ray diffraction pattern identical to that shown in Table 1, corresponding to the CAN topology, a chemical analysis representing a crystal stoichiometry of:
0.19Na.sub.2 O:0.81Li.sub.2 O:Al.sub.2 O.sub.3 :2SiO.sub.2
A n-hexane sorption capacity at room temperature and 45 torr gave 3.9 wt % sorption.
EXAMPLE 3
A slurry composition:
1.2Li.sub.2 O:0.8Na.sub.2 O:Al.sub.2 O.sub.3 :3SiO.sub.2 :60H.sub.2 O
was synthesized by dissolving 12 gms NaOH and 28.4 gms LiOH in 218 gms H 2 O, adding 36.2 gms HS-40 colloidal silica (DuPont Co.) and 55.3 gms meta-kaolin. This composition was divided and reacted at 100° C. and 150° C. After two days the 100° C. reaction yielded pure ECR-5, having an Si/Al ratio measured by microprobe of 1.31. The reaction at 150° C. yielded only Li-ABW and analcite.
EXAMPLE 4
A similar reaction to example 3 was made, except that the Na content was higher, as shown by the stoichiometry:
1.2Li.sub.2 O: 0.8Na.sub.2 O:Al.sub.2 O.sub.3 :3SiO.sub.2 :60H.sub.2 O
In this case the products of reaction at 100° C. and 150° C. after two days were both good ECR-5 materials. Microprobe analysis of the product from the 150° C. experiment gave an Si/Al=1.30.
EXAMPLE 5
A slurry composition:
1.5Li.sub.2 O:0.5Na.sub.2 O:Al.sub.2 O.sub.3 :4SiO.sub.2 : 80H.sub.2 O
was made by 5.4 gms LiOH in 47.7 gms H 2 O, then adding 17.2 gms sodium silicate (N Brand, PQ Corp.) and 9.95 gms metakaolin. After thoroughly homogenizing, the sample was reacted in a Teflon bottle at 100° C. for three days, after which time the product comprised good ECR-5 plus some chabazite impurity. After seven days reaction the product comprized ECR-5 plus minor zeolite P.
EXAMPLE 6
A slurry composition:
1.0Li.sub.2 O:0.8Na.sub.2 O.sub.2 :0.2(TMA).sub.2 O:Al.sub.2 O.sub.3 :3SiO.sub.2 :80H.sub.2 O
was made using general method of example 5 by mixing together 25.5 g metakaolin, 9.3 g of LiOH(H 2 O), 9.7 g of 25% aqueous of tetra methyl ammonium hydroxide (TMA), 16.7 g of colloidal silica (DuPont Company HF-40), 141 g of H 2 O.
After three days' reaction at 130° C. the sample comprised ECR-5 with minor chabazite impurity as determined by x-ray diffraction.
TABLE 1______________________________________X-Ray Diffraction Pattern For Li--Na ECR-5 (Ex. 1)20° d,Å Intensity______________________________________ 8.22 10.75 w14.10 6.24 s16.25 5.45 w19.38 4.58 vs21.55 4.12 m24.50 3.62 vs25.20 3.53 m27.95 3.19 vs32.90 2.72 s33.05 2.71 s34.60 2.59 m35.60 2.52 w______________________________________ w = weak; m = medium; s = strong; vs = very strong
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ECR-5, a twelve-ring zeolite isostructural with cancrinite, has been synthesized in an ammonia free system for the first time. A range of Li-Na alumino silicate compositions yields porous materials useful as catalysts and sorbents.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a cardiac pacemaker or pacer system, especially of the implantable type including a hermetically sealed case for the pacemaker or pacer electronics and a multielectrode pacer lead. More particularly, the invention relates to methods of and means for electrode selection in a pacing system where two multielectrode leads are installed in the pacer at or prior to the time of implantation and not thereafter disturbed.
2. Description of the Prior Art
Heretofore, multielectrode leads have been proposed for cardiac pacemakers wherein several leads are implanted for sensing and pacing functions. After implantation of the leads, tests, such as threshold, are then used to determine the electrodes that appear to the physician to be most satisfactory for the patient and for dedication to the desired function. Also, it is, at times, desirable that all of the leads remain available for use by the physician, especially if the initially selected electrodes fail to continue to function satisfactorily at a later time.
Bringing each lead conductor, however, through a pacer case to a pacer neck separately through individual feedthroughs is expensive and the individual feedthroughs are bulky. As the number of lead conductors is increased, these problems are exacerbated.
Also, Zener protection diodes have been provided within a pacer case and filters have been provided as a part of a feedthrough structure.
Examples of previously proposed pacing systems using multiple electrode leads and diode protection are disclosed in the patents described below:
The Tatoian et al. U.S. Pat. No. 3,554,198 discloses an isolation circuit for a cardiac pacer which is disposed between the pacer and the patient and which is physically external to the pacer. It does not provide any lead selection means or methods.
The Fontaine et al. U.S. Pat. No. 3,845,773 discloses a cardiac pacer wherein a generator is alternately or sequentially connected first with one electrode lead and then to a second electrode lead. Electronic selection of one or more electrodes or electrode pairs of a multielectrode lead as the active element thereof is not disclosed, suggested or illustrated.
The Chen et al. U.S. Pat. No. 4,099,530 discloses a cardiac pacer whose operation can be altered, as by a physician, from a location external thereto through use of magnetic signals. The magnetic signals are not used to effect lead selection.
The Duncan et al. U.S. Pat. No. 4,152,540 discloses a feedthrough connector for use on an implantable cardiac pacer which includes a filter capacitor within the feedthrough connector.
The Neumann U.S. Pat. No. 4,166,470 discloses a cardiac pacer which is powered and controlled through a single receiving antenna and which includes a multiplexer to enable the single antenna to be used for both purposes. Electrodes of a multielectrode lead are not selected with the multiplexer.
The Allen et al U.S. Pat. No. 4,170,999 discloses a cardiac pacer and illustrates what appears to be a zener diode across the output thereof. The diode is internal to the pacer, is not identified by any reference character and is not described in the patent.
The Hepp et al U.S. Pat. No. 4,187,854 discloses a cardiac pacer which is powered and controlled through a single receiving antenna and which includes a multiplexer to enable the single antenna to be used for both control and power reception. Electrodes of a multielectrode lead are not selected with the multiplexer.
The Walters et al U.S. Pat. No. 4,192,316 discloses a cardiac pacer wherein an externally produced multiple bit data word is used to control the pacer timing and mode of operation. No provision is made for electrode selection in a multielectrode lead.
The Schulman U.S. Pat. No. 4,223,679 discloses an implantable tissue stimulator including telemetry means having a signal selection circuit for selecting one of its input signals to be telemetered in accordance with control signals. The selection circuit is not used for selecting electrodes of a multielectrode lead.
The Mann et al U.S. Pat. No. 4,231,027 discloses an implantable tissue stimulator including telemetry means having a signal selection circuit for selecting one of its input signals to be telemetered in accordance with control signals. The selection circuit is not used for selecting electrodes of a multielectrode lead.
The Schulman U.S. Pat. No. 4,232,679 discloses an implantable tissue stimulator which includes a selector and a transmitter with the selector selectively passing to the transmitter signals from any one of sixteen different sources. The selector is not used for selecting electrodes of a multielectrode lead.
The Gruenewald U.S. Pat. No. 3,236,523 discloses a cardiac telemetry system wherein a bistable signal path selector is provided for alternately selecting between a pair of signal path conditions in response to trigger signals. The selector is not used for selecting electrodes of a multielectrode lead.
The Joseph U.S. Pat. No. 4,248,238 relates to a cardiac pacer wherein magnetically actuated switch means are used to selectively connect an atrial lead to either sensing or pulsing circuitry and to selectively connect the pulse generating circuitry to an atrial or a ventricular lead or both. The leads used may be either unipolar with the other electrode on the pacer casing or bipolar with both electrodes at the end of a catheter lead body. The bipolar lead has only two electrodes and provides only a single electrode pair or circuit path.
The Thompson et al. U.S. Pat. No. 4,275,737 discloses a cardiac pacer including two Zener diodes across the output with anodes of a pacing lead being coupled together and cathodes of the lead coupled each to one of the output terminals to protect the pacer, as from electrocautery currents. The diodes are an integral part of the pacer circuitry, and there is no suggestion that they be other than within the pacer case.
The Monroe U.S. Pat. No. 4,432,372 discloses a two lead power/signal multiplexed transducer system in which a piezoresistive pressure transducer is connected to a power source and to electronic processing circuitry by a single pair of leads. Electronic multiplexing circuitry is provided for selectively switching the single pair of leads back and forth between the power source during a power cycle and the processing circuitry during a sensing cycle. This patent is concerned with reducing the number of conductors in a lead as opposed to the number of conductors and conductor feedthroughs in a pacer can or housing.
As will be described in detail hereinafter, in accordance with the present invention, the number of feedthroughs from a sealed cardiac pacer to a pacer neck is limited by providing only enough feedthroughs to connect the electrodes that will be actively used during pacer operation and to provide an electronic electrode switching/selection circuit external to the sealed pacer case to enable these feedthroughs to be electronically connected with the desired electrode by the physician, either at the time of initial implantation or at any time subsequent thereto, as may be required. The electronic connection may be dedicated to a single feedthrough, to an electrode or electrode pair or the electrodes may be electronically sampled by the pacer circuitry. The electrode switching/selection circuit may be located in the pacer neck, in an adapter between the pacer neck and the multielectrode lead, or in the multielectrode lead. Zener protection diodes are preferably provided connected to the electrode conductors before or after the electronic switching/selection circuit. These Zener protection diodes may be located in the pacer neck, in the adapter, or in the multielectrode lead, according to the location of the electrode switching or selection circuit means.
SUMMARY OF THE INVENTION
According to the invention there is provided a cardiac pacing system including: a cardiac pacer having a sealed case with pacer electronic circuitry therein including a pacer system ground, a neck, and at least one feedthrough passing through the sealed case into the neck a pacing lead having a proximal end portion which is received in said neck, a distal end portion, at least two electrodes in the distal end portion and at least two spaced apart terminal connectors in said proximal end portion, said at least one feedthrough being connectable to said terminal connectors, electrode switching/selection circuit means external to the sealed case and connected to said at least one feedthrough between said pacer electronic circuitry and said at least two electrodes for selectively electrically connecting one or more of the electrodes in the pacing lead through said at least one feedthrough with the pacer electronic circuitry.
Further according to the invention there is provided a method for limiting the number of feedthroughs required, for connection to a pacing lead having two or more distal electrodes, in a cardiac pacer, the pacer having a sealed pacer case with pacer circuitry therein, a pacer neck, and at least one feeedthrough extending therethrough, said method comprising at least the steps of: providing a switching/selection circuit means external to the sealed pacer case for coupling the pacer circuitry with the pacing lead; and selectively electrically operating said switching/selection circuit means for selectively electrically connecting said pacer circuitry through said at least one feedthrOugh with one of the electrodes of the pacing lead.
Still further according to the invention there is provided a cardiac pacer system comprising a cardiac pacer unit having a sealed case containing pacer electronics, a pacer neck, and at least one feedthrough extending through said sealed case into said neck, a permanently implantable multielectrode pacing lead having at least two distal electrodes and being adapted to be connected to and used with said pacer unit, and electronic electrode switching/selection circuit means for selectively electrically coupling one or more of the electrodes of said multielectrode pacing lead with said pacer electronics through said at least one feedthrough.
Modern trends toward use of multielectrode leads in implantable cardiac pacemaker or pacer systems have created a problem in design and manufacture of the pacer. The pacer circuitry is generally hermetically sealed within a metal case, both to protect the pacemaker components from invasion or damage by body fluids and, also, to protect the body tissue from any adverse effects from contact with the components themselves. Generally, a separate feedthrough through the hermetically sealed metal case is provided for each electrode lead conductor of a multielectrode lead if that conductor and its associated electrode is to be available for active use. The cost of additional feedthroughs as well as the amount of space taken up by each feedthrough as the number of electrodes is increased make it desirable to keep the number of feedthroughs to a minimum while still having all the electrodes available for active use at some time.
In accordance with the teachings of the present invention, the number of feedthroughs is limited by providing only enough feedthroughs to connect the electrodes that will be actively used at any one time during pacer operation and to provide electronic electrode switching/selection circuitry external to the hermetically sealed pacer case to enable those feedthroughs to be electronically connected with the desired electrode by the physician as may be required.
If all available electrodes are not intended to be used, as for example where only the electrode exhibiting the best threshold is used; or in the case of redundancy, the selection circuitry of the present invention permits dedicating a feedthrough to each such electrode while still using only a minimum number of feedthroughs. Alternatively, a number of the available electrodes may be used without each requiring a dedicated feedthrough since these may be switched to selected feedthroughs on a sampling basis, or on need, under control of the pacer electronics.
In other words, in accordance with the teachings of the present invention, selection may be made either by programming an electronic switching/selection circuit external to the pacer case by a pacer programmer and/or selection may be made by dynamically switching the electronic electrode switching/selection circuit on a sampling basis by the pacer control electronics. The selection signal may, in the first desired instance, originate in the main pacer programming circuit or the selection circuit may itself be capable of directly receiving programming signals from a programmer.
The selection circuit may be located in the pacer neck, in an adapter between the pacer neck and the multielectrode lead, or in the multielectrode lead itself.
Also one or more zener diodes are preferably provided, such as for defibrillation protection, and coupled to the electronic electrode switching/selection circuit or separately therefrom, either in the pacer neck, an adapter, or in the leads themselves.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a partially schematic, partially mechanical view of a portion of a cardiac pacer and a pair of multielectrode leads connected thereto and shows the electronic electrode switching/selection circuitry of the present invention in the neck of the pacer.
FIG. 2 is a partially schematic, partially mechanical view similar to the view shown in FIG. 1 and shows the electronic electrode switching/selection circuitry in the proximal connector assembly of each lead.
FIG. 3 is a partially schematic, partially mechanical view similar to the view shown in FIG. 1 and shows the location of zener protection diodes ahead of the pacer circuitry before or after the switching/selection circuitry in the pacer or in each proximal connector assembly of each lead.
FIG. 3A is a partially schematic, partially mechanical fragmentary view of a proximal connector and shows another arrangement of zener protection diodes therein.
FIG. 4 is a partially schematic, partially mechanical view similar to the view shown in FIG. 1 and shows a pacer neck having a single lead socket, a plurality of multielectrode leads, an adapter adapted to be received in the pacer neck socket and the electronic electrode switching/selection circuitry built into the adapter.
FIG. 5 is a partially schematic, partially mechanical view similar to the view shown in FIG. 4 and shows the multielectrode leads in the adapter and the adapter in the socket in the pacer neck.
FIG. 6 is a partially schematic, partially mechanical view similar to the view shown in FIG. 4 and shows a pacer neck having two lead sockets, a separate adapter for each of the multielectrode leads adapted to be received in one of the sockets and electronic electrode switching/selection circuits built into each lead.
FIG. 7 is a partially schematic, partially mechanical view similar to the view shown in FIG. 5 and shows the leads in the adapters and the adaptersin the sockets.
FIG. 8 is a schematic circuit diagram of one embodiment of the electronic electrode switching/selection circuitry of the present invention.
FIG. 9 is a schematic circuit diagram of another embodiment of the electronic electrode switching/selection circuitry of the present invention.
FIG. 10 is a schematic circuit diagram of another embodiment of the electronic electrode switching/selection circuitry of the present invention including field effect transistors.
FIG. 11 is a schematic circuit diagram of another embodiment of the electronic electrode switching/selection circuitry of the present invention including an integrated circuit package.
FIG. 12 is a schematic circuit diagram of yet another embodiment of the electronic electrode switching/selection circuitry of the present invention including plural integrated circuit packages enabling selection between plural feedthroughs and the multiple lead conductors.
FIG. 13 is a schematic circuit diagram of the plural integrated circuit packages shown in FIG. 12 in combination with a serial-to-parallel converter.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring now to the drawings, and particularly to FIG. 1, there is shown and illustrated therein a cardiac pacemaker or pacer generally identified by reference numeral 20. The pacer 20 is adapted to be implanted in the body of a patient and to be connected electrically to the patient's heart by one or more, generally two, multielectrode leads 22 and 24 having tip electrode assemblies 26 and 28. The leads 22 and 24 can be sutured in position or, as indicated by the tip electrode assemblies 26 and 28, are pervenous leads which are fed through a vein to the interior of the patient's heart.
One of the leads, for example, the lead 22, may be led to the atrium of the heart and the other, for example, the lead 24, may be led to the ventricle. Then, in accordance with established procedures, electrodes 31-34 in each of the tip electrode assemblies 26 and 28 are tested, as for threshold, whereby the physician may make a determination as to which of the various electrodes 31-34 will be used for which of various pacer functions.
The electrode 34 is a tip electrode and electrodes 31-33 are ring electrodes.
Inasmuch as the spacing, type, and ultimate usage of the various electrodes 31-34 in each of the leads 22 and 24 do not form a part of the present invention, they are not described herein in detail. It will be sufficient to point out that the leads 22 and 24 may be identical, having the same number of sleeve or ring electrodes 31-33 or different, having a different number of sleeve electrodes and may be used for pacing or for sensing, or for both. Further, one or both may be unipolar, that is, where the pulse return path is, for example by way of a pacer case 36, or bipolar, that is, where the pulse path includes a pair of electrodes on the same lead.
Similarly, the pacer 20 may be of substantially any design and have programmable and microprocessor controlled circuitry therein. Accordingly, the pacer 20 will not be described further herein except to point out that such pacer 20 includes the hermetically sealed case 36 having a plurality of feedthroughs (not shown) bringing the pacing and sensing lead conductors through the hermetically sealed case 36 to a pacer neck 38 made of an insulative material. The case 36 is typically made of metal and the feedthroughs for conduction coupled to the pacing and sensing leads 22 and 24 extend through the case 36 and into the neck 38 to sockets 42 and 44 in the pacer neck 38. Each socket 42 and 44 receives a proximal connector 46 on one of the leads 22 or 24.
Each socket 42 or 44 is cylindrical in shape and has a plurality, e.g. three connector rings or sleeves 51, 52 and 53 mounted therein and a pin receiving metal socket connector 54. Each socket 42 or 44 receives one of the connectors 46 which has a plurality, e.g. three, connector sleeves 61, 62 and 63 adapted to contact the rings 51, 52 and 53 and a pin 64 which is received in the metal socket 54.
Each lead 22 and 24 has a tip electrode assembly 26 or 28 at the distal end thereof comprising three sleeve electrodes 31-33 and tip electrode 34, which are connected, respectively, by conductors 65, 66, 67 and 68 to sleeves 61, 62 and 63 and pin 64 as shown.
The neck 38 of the pacer 20 has mounted therein an electronic electrode switching/selection circuit 70 constructed according to the teachings of the present invention and having four output conductors 71-74 which extend through four feedthroughs (not shown) between the neck 28 and the case 36 for connection to pacer circuitry (not shown). Control lines 81-84 also extend through feedthroughs from the pacer circuitry and are connected to the switching/selection circuit 70.
Four input conductors 91-94 are connected, respectively, from each of the contact rings 51-53 and the connector socket 54 of each socket 42 and 44 to the switching/selection circuit 70 as shown.
The control lines 81-84 control the switching/selection circuit 70 for connecting selected "input" conductors 91-94 coupled to each socket 42 and 44 to selected "output" conductors 71-74.
The control lines 81-84 may be controlled by the pacer 20, directly or indirectly, or may be actuated or controlled by a number of other means, including additional programming circuitry. For example, a magnetic reed switch may be used to selectively actuate the control lines 81-84, as may radio-frequency or inductive coupling means. Similarly, if actuated by the pacer electronics, feedthroughs may be used therefor, or inductive or other indirect coupling may be used. The actuating or programming circuitry may be incorporated into the electronic circuitry of the electrode switching/selection circuit 70, if desired.
In accordance with the teachings of the present invention, selection may be made either by programming the electrode switching/selection circuit 70 by a pacer programmer and/or selection may be made by dynamically switching the control lines 81-84 and thereby the electrode switching/selection circuit 70 on a sampling basis by the control electronics of the pacer 20. The selection signal may, in the first stated instance, originate in the main pacer programming circuit or the electrode switching/selection circuit 70 may itself be capable of directly receiving programming signals from a programmer.
In addition, of course, power supply lines for the switches and control circuits, as needed, can also be supplied for the switching/selection circuit 70, but for clarity, these have not been shown. However, it will be apparent that the circuit 70 can be powered separately or by the main pacer power supply including being powered by a capacitor charged by the pacer by a multiplex arrangement through the feedthroughs. Also, as will be apparent hereinafter, zener protection diodes can be provided.
Referring now to FIG. 2, there is shown and illustrated therein another embodiment or modification of a pacer 120 wherein an electrode switching/selection circuit 121 of the present invention is built into proximal connectors 122 and 124 of multielectrode leads 126 and 128 rather than in a pacer neck 130.
The pacer neck 130 has sockets 132 and 134 which have connector contact rings 141-143 and a metal socket 144 therein for making contact with sleeves 151-153 and pin 154 on the connectors 122 or 124. Here all lead conductors 155-158 are connected to the switching/selection circuit 121 in each proximal connector 122, 124; and two input/output conductors 161 and 162 are connected to sleeve 153 and pin 154 while sleeves 151 and 152 provide control line connections to the switching/selection circuit 121.
Control lines 171 and 172 are connected to and extend in the neck 130 from the rings 141 and 142 (in contact with sleeves 151 and 152) through feedthroughs in a pacer case 173 to pacer electronics (not shown). Then, pacer electrode coupling conductors 175 and 176 are connected to and extend in the neck from ring 143 and socket 144 through feedthroughs in the pacer case 173 to pacer electronics.
Multielectrode lead connectors 122 and 124 are plugged into the sockets 132 and 134. An electronic electrode switching/selection circuit 121 is mounted in each connector 122, 124 and has control terminals comprising sleeves 151 and 152 (in contact with rings 141 and 142) and output/input lines defined by conductors 161 and 162 (connected to ring 143 and pin 154). Both ring 143 and pin 154 are in contact with a sleeve 153 or metal socket 144 connected to conductors 175, 176. The electrode switching/selection circuit 21 is effective to selectively connect each conductor 155-158 (connected to one of the four electrodes 181-184) to one of the conductors 175 or 176 with no additional electronics built into the pacer 120.
As stated above, zener protection diodes have heretofore been suggested for use in cardiac pacers to provide protection from potentially damaging high voltages, as may occur during electrosurgery, defibrillation, and the like. Such zener protection diodes, however, are conventionally incorporated into the internal pacer electronic circuitry.
In pacers constructed according to the teachings of the present invention, where additional circuitry is provided external to the hermetically sealed pacer case containing the pacer electronics, such internal zener protection diodes can provide only limited or incomplete protection. Ideally, for complete protection, the zener protection diodes should be coupled between lead conductors ahead of any of the circuitry in the pacer, i.e., closest to the electrodes, including the electrode switching/selection circuits 70 or 121 of the present invention, even though the electrode switching/selection circuits 70 or 121 are external to the pacer case 36 or 173 and even though the electrode switching/selection circuits 70 or 121 may be incorporated in a separate adapter or in the multielectrode leads 22, 24 or 126, 128 themselves. Further, such zener protection diodes may be used whether the leads 22, 24 or 126, 128 are arranged as unipolar, i.e., with the return from an electrode being via the pacer case, or bipolar, utilizing separate lead electrodes 31-34 or 181-184 for the active and return electric current paths.
Referring now to FIG. 3, a zener diode protection arrangement includes zener diodes in a proximal connector 190 or 191 of leads 192 or 194. Three zener diodes are provided connected between each connector sleeve 195, 196 or 197 and a pin 198. However, only one of the diodes, zener diode 199 is shown connected between sleeve 196 and pin 198. Here a pacer 200 has a switching/selection circuit 201 mounted in a pacer neck 202.
Alternatively, zener diodes 204, 205 and 206 shown in phantom can be connected between connector rings 208, 209 and 210 and a metal socket 211 in a socket 212 or 214 in the neck 202 which contact sleeves 195-197 and pin 198. Here the doides 204-206 are embedded in the neck 202. It will be readily apparent that the multielectrode leads 192, 194 are intended to be used in a bipolar mode.
If desired, zener protection diodes may be connected between the electrode lead conductors and ground, to enable the leads to be used in a unipolar mode.
Also shown in phantom in FIG. 3 is an internal zener protection diode 216 which, in the illustrated embodiment, would be redundant but which used alone would provide internal protection. Here the diode 216 is in a pacer case 218 between conductors 220 and 222 from the switching/selection circuit 201.
FIG. 3A is an enlarged, fragmentary view of a proximal lead connector 223 wherein zener diodes 224, 225 and 226 are connected between respective lead conductors 231-233 and lead conductor 234 before these conductors connect with a switching/selection circuit 236 mounted in the connector 223.
Referring now to FIGS. 4-7, there are illustrated therein adapters which have mounted therein switching/selection circuits, which are adapted to receive proximal lead connectors and which have a plug connector adapted to be received in a socket in a pacer neck. In this way, an electrode switching/selection circuit can be provided in the form of a separate component mounted in an adapter which is adapted to be installed between the pacer and a multielectrode lead.
Referring particularly to FIGS. 4 and 5, there is shown and illustrated therein a pacer 240, differing from the pacer 20 of FIG. 2 in that only a single socket 242 is provided in a pacer neck 244 of the pacer 240. A pair of multielectrode pacer leads 252 and 254, identical to the multielectrode leads 22 and 24 of FIG. 1 are adapted to be connected to the pacer 240 through an adapter 260. A plug connector 262 of the adapter 260 is adapted to be received in the pacer socket 242. Further, the adapter 260 has two sockets 272 and 274 which are adapted to receive proximal connectors 276 or 278 of multielectrode leads 252 or 254. The socket 242 and the sockets 272 and 274 can be the same size or different in size.
Within the adapter 260 is a switching/selection circuit 283 for selectively connecting connector rings 284, 285 or 286 or pin socket 287 in socket 242 with the connector rings 291, 292 or 293 or pin socket 294 in socket 272 or 274 in the adapter 260. Once assembled, as shown in FIG. 5, the electrode switching/selection circuit 283 will be interposed and operatively connected between the pacer 240 and the multielectrode leads 252 and 254 and the selection of electrodes 295, 296, 297 or 298 as desired may be carried out as in the previous described embodiments. Also, the adapter 260 can be provided with zener protection diodes similar to the zener protection diodes shown in FIGS. 3-3A.
Referring now particularly to FIGS. 6 and 7, there is shown and illustrated therein another pacer 300, differing from the pacer 240 of FIGS. 4 and 5 in that a pair of single sockets 302 and 304 are provided in a pacer neck 306. A pair of multielectrode pacer leads 312 and 314, identical to the multielectrode leads 252 and 254 shown in FIGS. 4 and 5, are connected by a pair of identical adapters 316, each including a plug connector portion 318 adapted to mate with and be received in one of the two sockets 302 and 304. Each adapter 316 has a socket 321 in a body portion 322 for receiving a proximal connector 324 of each lead 312 or 314. Each socket 321 is adapted to mate with and receive a proximal lead connector 324 of one of the multielectrode leads 312 and 314, as shown in the assembly illustration, FIG. 7.
Within the body portion 322 of each of the adapters 316 is mounted an electronic electrode switching/selection circuit 328 to enable selection of a particular electrode configuration desired for each of the multielectrode leads 312 and 314. Zener diode protection also can be provided as previously described.
The electronic electrode switching/selection circuits 70, 121, 201, 236, 283 or 328 may be implemented in a large number of ways. In view of the fact that they are to be implanted within the patient's body, however, they are preferably at least sealed or encapsulated. For small size, it is preferable that they be implemented in a microcircuit form, such as hybrid integrated circuits enclosed or encapsulated, for example, in electronic flat packs. A number of such implementations are shown and illustrated in FIGS. 8 through 12 and generally, these implementations are shown and illustrated in schematic form only. In the interest of keeping the drawings simple and clear, the power supply lines for the switches and control circuits have not been shown. It is to be expressly understood, however, that such power supply lines will be supplied as necessary. Moreover, it is also to be expressly understood that power may be supplied by any of a number of means and sources, including, by way of example and not by way of limitation, from the pacer directly, as by additional feedthroughs or multiplexing on the electrode feedthroughs, or indirectly, as by induction, or from a separate battery or bio-active generator, or, particularly if the implementation logic is appropriately selected so as to be non-volatile, from an external source, such as a programmer used during setting of the switching/selection circuit means.
With particular reference now to FIGS. 8 and 9, switching circuits for 1 of 4 and 2 of 4 selection, respectively, are schematically illustrated in abstract form. It is to be expressly understood that the switches are only abstractly and schematically illustrated herein and any electric or electronic switches may be used and are intended. Preferably, the switches are electronic or solid state switches and may, for example, comprise bistable or monostable flip-flops, commercially packaged multiplexers, custom circuits, and FET's. Alternatively, and by way of further example and not limitation, the switches may comprise reed switches, particularly bistable magnetic reed switches.
In FIG. 8, there is shown and illustrated in abstract form an electronic electrode switching/selection circuit 348 wherein a single input lead conductor 350 is selectively coupled to any one of four output lead conductors 351-354. As used herein, the terms "input" and "output" are used only in relation to the circuits as shown in the drawings, reading from left to right, with the "input" to the left, and the "output" to the right, and also assuming for descriptive purpose only, that the circuit 348 is to handle a pacing pulse. It is to be expressly understood, however, that the intention is that sensing may also be switched or selected as desired. In this respect, the "input" and "output" would be reversed, when one of the four "sensing" conductors 351-354 is selectively connected with the pacer electronics through the conductor 350.
Accordingly, in either case, the circuit 348 comprises a 1 of 4 selector, selection being controlled by a control circuit or decoder/driver circuit 360 under binary control, for example, of selection or control lines 361 and 362 for driving or controlling four conductor coupling switches 371-374.
In FIG. 9, there is shown and illustrated in abstract form a similar electronic electrode switching/selection circuit means 378 including tandem switching to provide for selective switching of two input conductors 381 and 382 to four output leads 384, 385, 386, 387. Two control circuits or decoder/driver circuits 388, 390 under control of two sets of selection or control lines 391, 392, or 393, 394, respectively, are provided for the two input feedthrough conductors 381 and 382. The sets of selection or control lines 391-394 may, of course, be programmed through additional decoder/driver circuits to further reduce the number of conductors required for operating switches 401-404 or 406-409.
FIGS. 8 and 9, as heretofore pointed out, show, respectively, 1 of 4 and 2 of 4 selection. The switches of FIG. 8 and 9 may conveniently be implemented by MOS-FET switches having low ON and high OFF impedance. Commercial solid state integrated circuit packages are also available which may be used to implement the present invention.
For example, FIG. 10 shows a schematic circuit diagram of one implementation of a switching/selection circuit 420 using a commercially available solid state package. More specifically, FIG. 10 is a schematic circuit diagram of an Intersil G116MOS-FET selection switch package which includes circuitry to define electronic electrode/selection circuit 420. It will be noted that the G116 package contains a zener protection diode 422 and current generating FETS 426-429 which serve as active pullups for the FET switches 431-434 and which are coupled to control lines 436-439, respectively. Since the diode 420 would not provide complete protection, additional zener protection diodes 441-444 can be coupled to "output" conductors 451-454 for complete protection, as shown.
The control lines 436-439 control the connecting of an "input" lead conductor 456 to one of the "output" conductors 451-454.
Alternatively, there is commercially available a large assortment of so-called "analog switches" which may be used or which may be designed on a custom basis.
For example, and with reference to FIG. 11, there is shown and illustrated therein a commercially available device from RCA, RCA CD4052B COS/MOS Analog Multiplexer/Demultiplexer suitable for 1 out of 4 selection. Here a switching/selection circuit 460 defined by the CD4052B device includes eight transmission gates "TG" 461-468 featuring low ON impedance and high OFF impedance. This device 460 can be used to implement the abstract 1 of 4 selection illustrated in FIG. 8 to define an electrode switching/selection circuit 460 in accordance with the present invention. Since this device is designed to switch both wires of a two-wire circuit, and pacer circuits are generally unbalanced to ground, only one channel is generally needed, for example, the Y channel with "input" 470 and "outputs" 471-474 as shown, and the X channel with "input" 480 and "outputs" 481-484 not used. Here three control line inputs 485-487 are provided connected to a Logic Level Conversion circuit 489 which has its output coupled to a Binary to 1 of 4 Decoder circuit 490 that has output control lines 491-494 coupled to the TG's 461-464 and 465-468 for controlling opening or closing of same in response to logic levels on the inputs 485-487.
FIG. 12 is a schematic circuit diagram of two CD4052B devices or switching/selection circuits 460 connected as abstractly schematically illustrated in FIG. 9 to define a 2 out of 4 selection switching/selection circuit 578 constructed according to the teachings of the present invention. Here "input" lead conductor 579 or 580 can be selectively connected to one of four "output" conductors 581-584. Logic levels on control lines 586 and 588 control connection of "input" conductor 579 to "output" conductors 581-584 and logic levels on control lines 590 and 592 control connection of "input" conductor 580 to "output" conductors 581-584. Priority of connections between "output" conductors 581.584 and "input" conductors 579 or 580 can be achieved by conventional "hand-shaking" or other prioritizing techniques via conductors 594 interconnecting the circuits 460. Of course, zener protection diodes may be added to the circuits 460 and 578 of FIGS. 11 and 12, respectively.
It should be recognized that the switching selection circuits disclosed herein will not result in minimization of feedthroughs in all cases. For example, two four electrode leads normally require eight feedthroughs. Selecting two electrodes from each lead, as illustrated above, may require four input/output feedthroughs, four selection/switching circuit control feedthroughs and two selection/switching circuit power feedthroughs, making a total of ten.
However, feedthrough savings will materialize as the number of electrodes increases, if the input/output feedthrough usage is multiplexed, if the switching/selection circuit is controlled or powered by means external to the pacer can or if the switching/selection circuit is controlled by serial sequence. The latter may be accomplished by means of, for example, a pulse-width modulated control sequence which, through a serial-to-parallel converter applies its output to the parallel control inputs of the switching/selection circuit.
In FIG. 13 there is schematically described above the switching/selection circuit 460 shown in FIG. 12 contained within the neck of the pacer along with a serial-to-parallel converter 600, also within the neck of the pacer (or in a lead or an adapter in accordance with the teachings of the present invention). A serial control line 601 with a pulse-width modulated control signal, is the only control line required to originate within the pacer can. Control lines 586, 588, 590 and 592 are generated from this signal.
In the example illustrated in FIG. 13 a signal burst of short, wide, wide, short may represent logic 0, 1, 1, 0 on lines 588, 586, 590 and 592 respectively.
Serial-to-parallel converter 600 may be implemented in various ways. A simple implementation is in the form of a shift register in which, for the example described above, four flip-flops store each serial four bit sequence as determined by a pulse-width demodulator. As a result, the four feedthroughs previously required for control lines 586, 588, 590 and 592 are replaced by a single feedthrough using the method described above.
From the foregoing description, it will be apparent that the switching/selection circuits 70, 121, 201, 236, 283, 328, 348, 378, 420, 460 and 578, the zener protection diode arrangements, and the pacer system in which they are used, of the present invention, provide a number of advantages, some of which have been described above and others of which are inherent in the invention. Most importantly, 1 to 4, 2 to 4 or 2 to 8 lead conductor selection is provided, thereby reducing the number of conductors in a pacer neck and the number of feedthroughs needed from the pacer neck to, through and into a pacer case. Also, various modifications can be made to the pacer system of the present invention without departing from the teachings of the present invention. Accordingly, the scope of the invention is only to be limited as necessitated by the accompanying claims.
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An electronic electrode switching/selection circuit minimizes the number of feedthroughs from a pacer case to a pacer neck needed to connect with pacing lead electrodes that will be actively used during operation of a pacer. These feedthroughs can be electronically connected with the desired electrode by the physician either at the time of initial implantation or at any time subsequent thereto as may be required. The electronic connection to a feedthrough may be dedicated to a single feedthrough/electrode or electrode pair or the electrodes may be electronically sampled by circuitry in the pacer. The electrode switching/selection circuit may be located in the pacer neck, in an adapter between the pacer neck and a multielectrode lead, or in a multielectrode lead.
Preferably, zener protection diodes are also provided which are connected ahead of the pacing circuitry before or after the electrode switching/selection circuit. These zener protection diodes may be located in the pacer neck, in the adapter, or in the multielectrode lead, according to the location of the electrode switching/selection circuit.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The instant application is a continuation-in-part and claims priority to pending U.S. application Ser. No. 13/295193, filed on Nov. 14, 2011. The pending U.S. application Ser. No. 13/295193 is hereby incorporated by reference in its entirety for all of its teachings.
FIELD OF THE INVENTION
[0002] The instant application relates to the production of isopropyl alcohol (IPA) from dimehtyl ketone (DMK) and hydrogen (H 2 ) in gas-phase using ruthenium nanoparticle-supported on activated charcoal/nano-zinc oxide composite catalyst.
BACKGROUND
[0003] The conversion of low-cost commodity chemicals such as DMK to high-value chemicals such as branched monoalchols, diols, α,β-unsaturated aldehydes, and α,β-unsaturated ketones is important for the industry. IPA is used as a solvent and for manufacturing different chemicals such as isopropyl amines and ethers. IPA has also other applications in medicine and industry. Several catalysts have been used for hydrogenation of DMK in the liquid-phase to produce IPA. An activated supported ruthenium catalyst was tested for the production of IPA via direct hydrogenation of aqueous DMK stream in the liquid phase (U.S. Pat. No. 5,495,055). A process and catalyst, which is capable of producing IPA by controlling the reaction conditions to make it economical, would be desirable for industry.
SUMMARY OF THE INVENTION
[0004] The invention discloses a novel composite catalyst and using the composite catalyst for the process of making the IPA in gas-phase from DMK and hydrogen. In one embodiment, process of making IPA using DMK and hydrogen with ruthenium nano-particle supported on activated charcoal with nano zinc oxide (n-ZnO) is disclosed. In another embodiment, catalyst in different ratios for optimizing the production and selectivity of IPA are disclosed.
[0005] In one embodiment, mechanical mixing of the commercially-available ruthenium nano-particle supported on activated charcoal with zinc oxide nano-particle (n-ZnO) for making the composite catalyst is disclosed. In another embodiment, thermal pyrolysis is performed to produce Zinc oxide nanoparticle (n-ZnO). In one embodiment, specific catalyst such as CAT-I, CAT-II, CAT-III, CAT-IV AND CAT-V were made and tested in the process of making IPA. The specific catalyst CAT-IV had the best results.
[0006] In one embodiment, the synthesis and using of five types of composite catalysts, made by the mechanical mixing of ruthenium nanoparticle supported on activated charcoal with zinc oxide nanoparticle in different ratios are disclosed. The ratio is 0-100 by weight percent for Ru/AC and Ru/AC:n-ZnO (wt/wt) is between 0:1 to 3:2 and 1:0.
[0007] The process of making IPA comprises of many conditions. Each condition has its own advantages and disadvantages. The optimum conditions are depicted in the present disclosure to produce the best output of IPA. The variable conditions are temperature, molar ratio of H 2 /DMK, ratio of the composite component and time on stream.
[0008] In one embodiment, the optimal temperature for a reaction between DMK, hydrogen and the composite catalyst is between 75-375° C., more preferably for certain catalyst composite from 75-200° C. In another embodiment, the H 2 /DMK mol ratio is between 1.5 to 6.
[0009] In one embodiment, the process of making the IPA involves making the composite catalyst at a certain ratio to optimize the hydrogenation sites on the catalyst for maximum selectivity of IPA.
[0010] The novel composite catalyst composition, method of synthesizing the novel catalyst and method of utilizing the novel catalyst in chemical reactions disclosed herein may be implemented in any means for achieving various aspects. Other features will be apparent from the accompanying figures and from the detailed description that follows.
BRIEF DESCRIPTION OF DRAWINGS
[0011] Example embodiments are illustrated by way of example and no limitation in the tables and in the accompanying figures, like references indicate similar elements and in which:
[0012] FIG. 1 shows DMK conversion and IPA selectivity over all tested catalysts at different temperatures (H 2 /DMK mol ratio=6, Time on stream (TOS)=1 hr).
[0013] FIG. 2 shows DMK conversion and IPA selectivity vs H 2 /DMK mol ratio for the investigated catalyst (T=250° C.: TOS=1 hr).
[0014] FIG. 3 shows the effect of Ru-loading on DMK conversion and product selectivity (H2/DMK mol ratio=6, temperature=250° C., TOS=1 hr).
[0015] FIG. 4 shows the effect of acidic/basic site concentration ratio on DMK conversion and IPA selectivity (H 2 /DMK mol ratio=6, temperature=250° C., TOS=1 hr).
[0016] Other features of the present embodiments will be apparent from the accompanying figures, tables and from the detailed description that follows.
DETAILED DESCRIPTION
[0017] Several methods of synthesizing a novel ruthenium nano-particle supported on activated charcoal with nano zinc oxide (n-ZnO) as a composite catalyst and utilizing the novel composite catalyst to increase the production of IPA and other by products are disclosed. Although the present embodiments have been described with reference to specific example embodiments, it will be evident that various modifications and changes may be made to these embodiments without departing from the broader spirit and scope of the various embodiments.
[0018] The present composite catalysts comprises of ruthenium nano-particle supported on activated charcoal mixed mechanically with zinc-oxide nano-particle. Ruthenium catalysts are less expensive and can be used for DMK hydrogenation. In addition, the activated charcoal support is superior when compared to other support materials because activated charcoal resists the formation of cock inside the reactor. Zinc oxide nano-particle may be partially reduced to zinc metal, which increases the IPA selectivity in the products.
[0019] The composite catalyst is used for synthesizing IPA by varying the reaction conditions. The catalytic reaction was carried out in the gas-phase. The novel composite catalysts may be used in liquid phase as well, but preferentially in gas-phase wherein the reaction could be carried out at atmospheric pressure. The catalytic performance of the said composite catalysts may be modified by varying the weight ratio of their components, by changing the hydrogen to DMK mole ratio, time on stream, and/or by changing the temperature.
Catalyst Preparation
[0020] Zinc pyruvic acid oxime complex was prepared from reacting zinc sulphate, sodium pyruvate, hydroxyl amine hydrochloride, and sodium bicarbonate. Thermal pyrolysis of zinc pyrovic acid oxime complex was done to produce zinc oxide nanoparticle (n-ZnO). This lab-made n-ZnO was mechanically mixed and ground with the commercially-available ruthenium-supported on activated charcoal (Ru/AC) at different weight ratios. A solid-solid wetting (mechanical mixing) method was adopted to synthesize the composite of Ru/AC/n-ZnO catalysts. Ru/AC and n-ZnO in different ratios were mixed thoroughly using a pestle and mortar then the mixture was pulverized and subsequently calcined at 400° C. for 12 h. The ratios of Ru/AC:n-ZnO used were as follows: 1:2 wt % (CAT-II), 1:1 wt % (CAT-III)and 3:2 wt % (CAT-IV). For comparison the pure n-ZnO (CAT-I) and pure Ru/AC (CAT-V) were also studied. The nominal compositions of the synthesized catalysts are given in Table 1.
[0000]
TABLE 1
Chemical composition of the prepared catalysts:
Ru/AC
Ru/AC:n-ZnO
Catalyst
(wt %)
(wt/wt)
CAT-I
0
0:1
CAT-II
33.33
1:2
CAT-III
50
1:1
CAT-IV
60
3:2
CAT-V
100
1:0
Production of IPA Using Optimal Reaction Conditions and Composite Catalyst
[0021] The effect of temperature on the catalytic performance of the mentioned composite catalysts was investigated in the range between 100° C. and 375° C. at fixed H 2 /DMK mole ratio of 4 or 6. Table 2 shows the variation of DMK conversion % and product selectivity % over the composite catalyst at fixed H 2 /DMK mol ratio of 6, time-on-stream (TOS=1 hour), at 250° C., 300° C., 350° C., and 375° C. As shown in examples, decreasing temperature led to increase in DMK conversion and IPA selectivity. The highest DMK conversion (46.4%) was observed over CAT-IV at 250° C. CAT-IV also showed 87.6% selectivity towards IPA and 10.5% selectivity towards MIBK. However, the highest selectivity towards IPA (95.8%), concomitant with very low selectivity towards MIBK (1%), was observed over CAT-V at 250° C. CAT-V also showed a 15% DMK conversion rate. In contrast, the highest selectivity towards MIBK (69.3%), associated with low selectivity towards IPA (10%), was observed over CAT-III at 375° C. and 13.6% DMK conversion. These observations clearly indicate that addition and condensation reactions are favored over acidic/basic sites with elevating temperature while the direct hydrogenation reaction of DMK is favored with reducing temperature. Moreover, the catalyst identity plays a key role in DMK conversion % and in directing the reaction towards MIBK or IPA. CAT-I and CAT-V gave the lowest DMK conversion % and the lowest selectivity towards MIBK. This can be attributed to the catalyst lack of multifunctionality (balanced acidity/basicity and hydrogenation sites) required for synchronous addition, condensation, and hydrogenation reactions to overcome the reaction thermodynamic equilibrium limitation. For this reason, MO has the highest selectivity among all products at low DMK conversion % over CAT-I, which is acidic. The low selectivity towards IPA over this catalyst could be attributed to the partial reduction of zinc oxide to zinc metal. On the other hand, IPA had the highest selectivity among all products over CAT-V, owing to the predominance of hydrogenation sites on this catalyst.
[0000]
TABLE 2
Gas-phase DMK-self condensation over n-Ru/AC/n-ZnO catalysts*
Temp.,
Conv.,
Selectivity, %
Catalyst
° C.
%
MIBK
DIBK
MO
M
IPA
DA
Others
CAT-I
250
6.7
0.9
0.1
59.4
0.0
19.9
0.0
19.7
300
5.2
trace
0.0
48.9
0.0
31.6
0.0
19.5
350
6.3
trace
0.0
48.7
0.0
32.2
0.0
19.1
375
5.9
0.1
0.0
51.7
0.0
23.7
0.0
24.5
CAT-II
250
27.8
17.4
2.1
2.4
0.2
77.6
0.1
0.2
300
19.4
50.6
7.8
2.2
1.2
36.3
0.5
1.4
350
10.6
54.7
1.9
2.2
1.8
14.9
0.3
24.2
375
9.1
53.5
2.5
5.2
0.5
27.2
1.0
10.1
CAT-III
250
28.2
25.8
4.0
2.9
0.7
64.4
0.2
2.0
300
26.5
53.4
15.2
2.6
0.3
18.6
0.2
9.7
350
22.0
62.8
14.3
1.6
0.4
11.2
trace
9.7
375
13.6
69.3
trace
3.1
trace
10.0
0.1
17.5
CAT-IV
250
46.4
10.5
0.3
1.5
0.0
87.6
0.0
0.1
300
19.1
50.8
8.0
2.0
0.8
34.2
0.0
4.2
350
16.8
48.2
5.3
1.6
0.6
35.9
0.0
8.4
375
15.5
46.2
5.0
1.4
0.6
44.0
0.1
2.7
CAT-V
250
15.6
1.0
trace
trace
trace
95.8
0.0
3.2
300
5.7
0.4
0.0
0.6
0.0
94.9
0.0
4.1
350
0.6
6.7
0.0
10.7
0.0
48.5
0.0
34.1
375
0.9
3.0
0.0
8.6
0.0
19.5
0.0
68.9
*Reaction conditions: 0.25 g catalyst, H 2 /DMK mol ratio = 6, time-on-stream = 1 hour.
[0022] Table 3 displays the variation of DMK conversion and product selectivity % over the composite catalysts at fixed H 2 /DMK mol ratio of 4, time-on-stream (TOS=1 hour), at 250° C., 300° C., 350° C., and 375° C. The impact of temperature under these conditions on the DMK conversion %, IPA selectivity %, and MIBK selectivity % is similar to that observed under the conditions of Table 2. The reduction of H 2 /DMK mol ratio from 6 to 4, however, explicitly has strong influence. It has led to a significant decrease of the highest DMK conversion from 46.4% at H 2 /DMK mol ratio of 6 to 35.0% at H 2 /DMK mol ratio of 4over CAT-IV at 250° C. Such an observation might indicate the importance of hydrogen not only as a reactant but also as an activating agent for the composite catalyst. The highest selectivity towards MIBK (70.5%), associated with low selectivity towards IPA (9.6%) was observed over CAT-III at 350° C. and 19.3% DMK conversion. The highest selectivity towards IPA (95.6%), on contrast, coupled with negligible selectivity towards MIBK (0.4%), was observed over CAT-V at 300° C. and 5% DMK conversion. This low DMK conversion can be attributed to the increase in temperature, which has a negative influence on conversion upon increasing, as shown clearly from the data of Table 3. The lowest conversion of DMK was also observed over CAT-I and CAT-V due to the lack of multifunctionality, reflecting the importance of catalyst identity.
[0000]
TABLE 3
Gas-phase DMK-self condensation over n-Ru/AC/n-ZnO catalysts*
Temp.,
Conv.,
Selectivity, %
Catalyst
° C.
%
MIBK
DIBK
MO
M
IPA
DA
Others
CAT-I
250
1.5
0.3
0.0
65.1
0.0
14.9
0.0
19.7
300
5.1
trace
0.0
55.1
0.0
26.4
0.0
18.5
350
4.9
trace
0.0
50.9
0.0
32.8
0.0
16.3
375
5.8
0.1
0.0
55.2
0.0
21.3
0.0
23.4
CAT-II
250
26.5
22.6
1.8
2.5
0.2
72.1
0.1
0.7
300
13.1
48.9
4.8
1.4
0.5
43.0
0.1
1.3
350
8.3
50.6
4.6
16.1
1.3
15.5
0.6
11.3
375
11.3
40.1
20.7
3.8
0.6
8.4
0.3
26.1
CAT-III
250
33.5
34.8
8.3
3.5
0.9
44.3
0.7
7.5
300
32.2
59.8
11.9
2.2
trace
20.7
0.9
4.5
350
19.3
70.5
10.0
0.7
0.5
9.6
trace
8.7
375
12.5
63.1
8.4
5.6
1.7
10
0.1
11.1
CAT-IV
250
35.0
13.7
1.7
1.8
0.2
80.5
trace
2.3
300
23.09
41.7
9.3
2.6
0.2
40.9
trace
5.3
350
21.9
54.2
8.7
2.3
0.8
31.6
0.3
2.1
375
9.1
52.7
4.1
2.8
0.3
35.5
0.3
4.3
CAT-V
250
15.3
1.7
trace
0.1
0.0
88.3
0.0
9.9
300
5.0
0.4
0.0
0.9
0.0
95.6
0.0
3.1
350
0.8
4.6
0.0
15.1
0.0
58.7
0.0
21.6
375
0.4
14.1
0.0
13.0
0.0
45.4
0.0
27.5
*Reaction conditions: 0.25 g catalyst, H 2 /DMK mol ratio = 4, time-on-stream = 1 hour.
[0023] Table 4 shows the effect of temperature on the DMK conversion % and the selectivity % towards product at H 2 /DMK mol ratio of 6, TOS of 1 hour, over CAT-IV. Reduction of temperature from 200° C. to 100° C. led to tremendous increases in DMK conversion from 56% to ˜82% and IPA selectivity from 89% to ˜100%. On the other hand, a huge reduction in the selectivity towards MIBK from 6% to 0% and MO from ˜3% to ˜0% was observed. These results confirmed the preference of the direct reduction of DMK to IPA over the self-condensation of DMK with reducing temperature. Moreover, these results are in parallel with the exothermic nature of reducing DMK to IPA.
[0000]
TABLE 4
Gas-phase DMK-self condensation over n-Ru/AC/n-ZnO catalysts*
Temp.,
Conv.,
Selectivity, %
Catalyst
° C.
%
MIBK
DIBK
MO
M
IPA
DA
Others
CAT-IV
200
56.1
6.6
trace
2.7
0.0
89.2
0.0
1.5
150
74.3
1.6
trace
0.8
0.0
96.3
trace
1.3
100
81.8
0.0
trace
trace
trace
99.7
trace
0.3
Reaction conditions: 0.25 g catalyst, H 2 /acetone mol ratio = 6, time-on-stream = 1 hour.
[0024] Table 5 shows that reduction of temperature to 75° C. has a strong impact on the DMK conversion and selectivity towards product depending on the H 2 /DMK mol ratio. The highest conversion of DMK was achieved when the H 2 /DMK mol ratio was 1.5. A reduction by ˜2.7% in DMK conversion was observed upon increasing H 2 /DMK mol ratio to 6. This reduction in DMK conversion could be attributed to the reduction in contact time when increasing the H 2 /DMK mol ratio, which increased due to the increase in hydrogen flow rate. However, the selectivity towards IPA increases slightly from 98.7 to 99.8% upon increasing the H 2 /DMK mol ratio from 1.5 to 6.0. This excellent IPA selectivity is due to the reaction low temperature, which is consistent with the exothermic nature of the direct hydrogenation of DMK.
[0000]
TABLE 5
Gas-phase DMK-self condensation over n-Ru/AC/n-ZnO catalysts*
H 2 /DMK
Conv.,
Selectivity, %
Catalyst
mol ratio
%
MIBK
DIBK
MO
M
IPA
DA
Others
CAT-IV
1.5
96.0
0.0
trace
0.0
0.0
98.7
trace
1.14
3.0
93.9
0.0
trace
0.0
0.0
99.8
trace
0.17
4.5
87.0
0.0
trace
0.0
0.0
99.6
trace
0.31
6.0
35.4
0.0
trace
0.0
0.0
99.8
trace
0.13
Reaction conditions: 0.25 g catalyst, Temperature = 75° C., time-on-stream = 1 hour.
[0025] The variation of conversions and selectivity of the reaction at different temperatures over all the investigated catalysts (Table 1) are shown in FIG. 1 . The maximum conversion and the maximum selectivity for IPA were reached at 250° C. CAT-V showed the highest selectivity towards IPA at 250° C. The selectivity towards IPA decreases upon increasing the reaction temperature for all the investigated catalysts. The condensation and dehydrogenation products catalyzed by acidic sites are favored above 250° C., while direct hydrogenation product is favored below this temperature. The effect of variation of H 2 /DMK mol ratio on DMK conversion and IPA selectivity at 250° C. is shown in FIG. 2 . This conversion increased with increasing H 2 /DMK mol ratio up to 3 for CAT-II and CAT-III, while the maximum conversion for CAT-IV and CAT-V was attained at H 2 /DMK mol ratio equivalent to 6. It is noticed that the selectivity towards IPA increased upon increasing H 2 /DMK mol ratio. CAT-V showed the highest selectivity towards IPA at H 2 /DMK ratio equal to 4.5.
The Effect of Ru-Loading
[0026] The conversion and selectivity as a function of Ru-loading are shown in FIG. 3 . DMK conversion increases with increasing Ru-loading up to 3.0 wt % and then decreases when the Ru-loading is increased to 5.0 wt %. The selectivity towards MIBK increases with increasing the Ru-loading up to 2.5 wt % and then decreases with an increased Ru-loading. The observation of the maximum MIBK selectivity at 2.5 wt % Ru-loading can be attributed to the presence of balanced multi-functional sites (hydrogenation and condensation). On the other hand, increasing of Ru-loading results in increasing in IPA selectivity except at Ru-loading of 2.5 wt %. This observation indicates that high Ru-loading favors the direct hydrogenation of DMK carbonyl group. The multifunctional composite catalyst with Ru/AC:n-ZnO equals to 1:0 (wt/wt) (CAT-V) exhibited the highest IPA selectivity. It appears that the metallic sites are very essential for the formation of IPA.
The Effect of Acidic/Basic Sites Concentration
[0027] FIG. 4 shows the comparison between CAT-II, CAT-III, CAT-IV and CAT-V in the effect of their acidic/basic sites concentration on the conversion and IPA selectivity at the best reaction conditions. CAT-IV showed the highest DMK conversion. On the other hand, CAT-V showed the highest selectivity towards IPA, but with a much lower conversion rate. These results show that higher activity, more direct hydrogenation products were obtained over relatively highly acidic catalyst.
[0028] The foregoing examples have been provided for the purpose of explanation and should not be construed as limiting the present disclosure. While the present disclosure has been described with reference to an exemplary embodiment, changes may be made within the perview of the appended claims, without departing from the scope and spirit of the present disclosure in its aspects. Also, although the present disclosure has been described herein with reference to particular materials and embodiments, the present disclosure is not intended to be limited to the particulars disclosed herein; rather, the present disclosure extends to all functionally equivalent structures, methods and uses, such as are within the scope of the instant claims. Accordingly, the specification and drawings are to be regarded in an illustrative rather than in a restrictive sense.
|
Isopropyl alcohol is a very useful chemical that is widely used in the industry as a solvent. Economical and easy process to make ispopropyl alcohol using novel composite catalyst is described in the instant application. Production of isopropyl alcohol (IPA) from dimehtyl ketone (DMK) and hydrogen (H 2 ) in gas-phase using a ruthenium nano-particle-supported on activated charcoal/nano-zinc oxide composite catalyst is described. Gas phase production of isopropyl alcohol using DMK and hydrogen is also described using optimal time on stream, temperature, catalyst ratio and DMK/H 2 ratio. Ruthenium nano-zinc oxide composite catalyst is formulated using different ratios of ruthenium activated charcoal and n-ZnO is described. CAT-IV is shown to be the best performer for the efficient production of isopropyl alcohol.
| 1 |
This application is a Continuation-in-Part of PCT/IL2007/000529, filed 1 May 2007, which claims benefit of U.S. Ser. No. 60/796,561, filed 2 May 2006, and which applications are incorporated herein by reference. To the extent appropriate, a claim of priority is made to each of the above disclosed applications.
FIELD OF INVENTION
The present invention relates to improving the storage stability of cut flowers or other foliage to be marketed long after harvest time or far from harvest site. More particularly, the present invention relates to a protecting composition, and to a method of increasing the storage time of cut flowers by immersing them in said composition.
BACKGROUND OF THE INVENTION
Ornamental cut flowers and foliage are familiar items of commerce being sold world wide. The majority of these is perishable and has short shelf lives. When the growers are situated a long way from their markets, which is true for most of the trade, it is essential to transport the plant product by air freight. However, the low stability of the cut flowers makes many plant products uneconomical in view the high cost of air freight. The plants suffer from dehydration, infection, and aging due to evolution of endogenous ethylene gas. Various techniques have been described for increasing shelf-life of the cut flowers, often comprising toxic materials, or materials difficult to handle. WO 2005/079569 relates to extending the shelf-life of the cut flowers by contacting the plant with a composition comprising nanocrystalline silver; US 2004/0186020 relates to spraying acrylic latex containing a plant nutrient onto cut plants. The intended use of the considered products, namely items of aesthetics serving as gifts, would be contradicted by the presence of harmful or staining, or otherwise unpleasant, materials. So, it is desirable to avoid, for example, dark silver stains, or a release of toxic substances, or the presence of unpleasant odor associated with acrylic emulsions. It is therefore an object of this invention to provide an efficient and simple method for increasing the storage time of the cut flowers, without conferring to the flowers unpleasant odor.
It is another object of this invention to provide a protecting composition for applying onto cut flowers, enabling long-term storage, without conferring to the flowers unpleasant odor or other annoying properties.
Other objects and advantages of present invention will appear as description proceeds.
SUMMARY OF THE INVENTION
The invention provides a method of increasing storage stability of a cut flower, comprising i) providing an odor-free acrylic emulsion comprising at least one acrylic monomer or oligomer, and a nonionic, non-phytotoxic surfactant; ii) applying said emulsion onto the surface of said flower, thereby forming a layer of said emulsion essentially over the whole surface of said flower; and iii) drying said layer, thereby creating a polymer film having a thickness of from about 0.001 to about 0.5 mm; wherein said emulsion comprises from 0.01 to 6 wt % non-aqueous components, preferably from 0.02 to 1 wt %. Said emulsion layer is consequently converted to a relatively stable film which protects the body of the flower against destructive processes; where “essentially the whole surface” is mentioned, the intention is that the most of the surface is protected which is sufficiently achieved when about 90% or more of the surface is protected, preferably 95% or more. Said step of applying said emulsion comprises dipping or coating or spraying. Said surfactant is preferably a non-phytotoxic surfactant, such as, for example, Tween 20, Agral 90 of Zeneca, or Disponil AFX 4060 Said step of drying results in the formation of a transparent or translucent film, that protects the surface of the plant. Said film is in fact formed during a polymerization process. The resulting polymeric layer should preferably have Tg of less than about 15° C. In a preferred embodiment, the method of the invention comprises a stock composition, from which a working composition for applying onto the flowers is diluted, in a preferred embodiment comprising about 30 wt % acrylate-based components, about 5 wt % surfactants, and a cross-linking monomer in an amount of up to 1 or 2 wt % of said total acrylate-based components, preferably between 0.005 and 1.0 wt %. Said acrylate-based components and said cross-linking monomers may comprise, for example, N-methylol acrylamide, methacrylic acid etc. Additional components may be introduced to contribute to the stability of said flower during the storage, for example biocides, such as silver compounds, triazole, kasugamycin, prochloraz, didecyldimethylammonium chloride, etc. Said stabilizing component may also comprise an ethylene deactivator. Said component may be a post-polymerization additive.
The invention also relates to a cut-flower protecting composition comprising from about 0.01 wt % to about 30 wt % acrylic-based monomer, oligomer, or polymer, and further a surfactant. Acrylic-based materials constitute, in one embodiment of the invention, minimally 0.01 wt % of said protection composition, in other embodiment said acrylic-based materials constitute minimally 0.02 wt %, and in still other embodiment it is minimally 0.5 wt %. After eventual dilution from stock solutions, and before applying onto the flowers, said acrylic-based materials constitute preferably up to 5 wt % of said acrylic-based materials. Cross-linking components may constitute from 0.005 to 2 wt % of said acrylic-based materials, for example from 0.005 to 1%. Said surfactant may constitute up to 8 wt % of said composition, usually up to 6 wt %. In a preferred embodiment of a working protecting composition according to the invention, said acrylic-based materials constitute from about 0.01 to about 5 wt % and said surfactant up to 1 wt %. Said composition may, for example, comprise from 0.1 to 1 wt % nonionic surfactant. In one aspect of the invention, a cut-flower protecting composition comprises, after diluting from a stock composition and before applying onto the flower, from about 0.01 to about 0.5 wt % of acrylic-based materials, more preferably from about 0.01 to about 0.2 wt % acrylic-based material. In a preferred embodiment of the invention, the protected flower is a rose, and said cut-flower protecting composition comprises acrylic-based materials in a concentration of from about 0.01 wt % to about 0.03 wt %.
Said composition forms a layer essentially on the whole surface of a cut-flower and preserves the appearance of said flower without conferring to it an unpleasant odor, which typically accompanies low molecular weight acrylic monomer-based materials such as ethyl or butyl acrylate. This is achieved by the use of high molecular weight non-volatile acrylic monomers. A composition according to the invention may comprise about 30 wt % acrylic-based materials, being used as a stock solution to be diluted before applying onto a cut-flower. Said stock further comprises surfactants in a concentration of up to 5 wt %. The composition of the invention enables long-term storage of cut flowers, while preserving their visual appearance without conferring to them an unpleasant odor. In a preferred embodiment of the invention, a protecting composition is prepared by including acrylic monomers lacking unpleasant odor. Such monomers may comprise, for example, CN152 (Sartomer), or SR506 (Sartomer), or 2-(methacryloyloxy)ethylacetoacetate, but a skilled person, being directed by the present invention, will be able to select other suitable components, preparing, for example, a mixture containing from about 10 to about 30 wt % acrylic-based monomer or oligomer, and a nonionic surfactant. The composition according to the invention further comprises polymerization initiators, biocides, cross-linking agents, or other components.
BRIEF DESCRIPTION OF THE DRAWING
The above and other characteristics and advantages of the invention will be more readily apparent through the following examples, and with reference to the appended drawing, wherein:
FIG. 1 is a graph showing the effect of silver thiosulfate concentration in an acrylic emulsion on the quality of cut roses treated according to one embodiment of the invention, after one month of storage, as described in Example 4.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
It has now been found that dipping a cut flower in an acrylic emulsion containing up to 5 wt % of acrylic-based material selected so as not to confer any unpleasant odor to the product, together with suitable surfactants, substantially increases the storage time of the flower product. It turns out that a composition according to the invention solves the above mentioned problems associated with long term storage and long transport, extending the shelf life of the plants by a number of weeks, while keeping the cut flowers attractive, and while avoiding any unpleasant odor due to the used materials.
The invention provides an acrylic emulsion for applying onto the plants by a dipping, coating or spraying process. On drying, a thin film of a few microns thickness is formed, acting as a barrier which slows the rate of water loss. The film further protects the plant surface, and inhibits the development of the various plant pests and diseases. In a preferred embodiment of the invention, specific additives enhancing said protective effect are added to the acrylic emulsion. Such additives may inhibit microbial growth or deactivate ethylene.
Applying said acrylic emulsion on the surface of a plant followed by drying, leads to the formation of a polymeric layer. The polymer preferably has some of the following properties, combined according to specific applications and needs.
a) The polymer is prepared as a water-based acrylic emulsion containing about 30% solids, followed by desired dilutions. On drying, these solids coalesce or react to form a transparent and preferably glossy film on the leaves of the plant. b) The surface tension of the emulsion is below about 30 dyne/cm to ensure good wetting of the leaves and adhesion to the leaves. c) The surface energy of the cured polymer film is preferably similar to that of the plant leaves to ensure good adhesion. d) The polymer film is preferably biodegradable after the plant is discarded. e) The film, formed on the surface of the plant, is flexible under temperatures preferably corresponding to European or US winter conditions, and has limited permeability for gases and water. f) The materials contacting the leaves are preferably non-phytotoxic and do not cause damage to the plant. g) Specifically, a non-phytotoxic surfactant is selected for the emulsion preparation. In general, non ionic surfactants are preferred. h) No harmful materials are emitted from the cured film.
The copolymer emulsions for use according to the invention meet as many as possible of the above requirements simultaneously. Some commercial emulsions are phytotoxic due to the used surfactants. The invention avoids the use of harmful surfactants, employing surfactants used in agricultural applications, such as Tween 20 (see Example 1). Furthermore, relating to the mechanical properties of the film which protects the plant surface in a method of this invention, it was found that the glass transition temperature (Tg) of the copolymer is an important parameter. A suitable Tg value is, for example, around 20° C.
For reasons of mechanical strength, and to prevent polymers from being sticky, in a preferred embodiment of the invention, the polymer that is formed is consequently cross-linked. The levels of cross-linking monomers are up to 2% by weight of the total monomers, preferably between 0.005 and 1.0 wt %. Each cross-linker requires its specific reagent for the cross-linking reaction. These reactions are usually condensation reactions and release a small volatile molecule. Those reactions that release toxic molecules such as formaldehyde will be avoided in favor of safer by-products.
In a preferred method of the invention, the storage stability of the cut flowers is enhanced by including additional agents contributing to the flower stability, for example, antimicrobial or antiaging materials, such an silver thiosulfate which may be added to cut flowers as a pulsing solution, or as part of the film. Biocides may be added to emulsions that are applied according to the invention, such as triazole or kasugamycin or prochloraz or didecyldimethylammonium chloride. Specifically, in a preferred embodiment of the invention, spores and fungi which commonly attack plant tissue during storage are eliminated. Specific target species may include, for example, Botrytis, Alterneria , etc.
The invention, thus, provides a composition and method enabling a long-term storage of cut flowers, while not only preserving their visual appearance, but while also avoiding any unpleasant phenomena, such as staining contacted surfaces. Importantly, any unpleasant odors are avoided, such as odors caused by low molecular weight acrylic monomers. Furthermore, the presence of any plant nutrient is not needed. In a method according to the invention, acrylate monomers or oligomers are used that do not exhibit unpleasant odor, examples being, CN152 (Sartomer), SR506 (Sartomer), 2-(methacryloyloxy) ethylacetoacetate; but the invention is not limited to these examples. The stock composition may comprise, for example, about 30% acrylate monomers and/or oligomers as copolymers; the working emulsion, obtained by diluting said stock may comprise a concentration of from about 0.005 to 5.0%. Said stock composition contains surfactants, preferably nonionic, and an initiator is comprised when the polymerization is desired. The surfactants may have a concentration of from about 1 to about 8 wt %. A typical stock solution contains usually from 27 to 31 wt % acrylate monomers or oligomers as copolymers, and from 3.5 to 6 wt % surfactants.
The invention will be further described and illustrated by the following examples.
EXAMPLES
General
During developing the copolymer emulsion, the synthesis in a reactor produced about liter emulsion by the procedure described below. Emulsion was characterized by the following tests: checking spreading on leaves, measuring glass transition temperature (Tg) by differential scanning calorimeter (DSC), and measuring surface energy using standard solutions for wetting.
The cut flowers were dipped either in water of in the acrylic emulsion, and it was found that the flowers treated according to the invention had a storage life longer by at least four weeks.
Example 1
Phytotoxicity Test of Surfactants on Cut Rose Flowers
Cut flowers of Roses of the Akito variety, an intermediate type of rose, were harvested in a commercial roses green house in Menucha village. The flowers were dipped in different surfactants in several concentration of the surfactant. The highest surfactant concentration was 2% by weight and the lowest concentration was 0.005%. The dilution was with reverse osmosis water.
At each concentration we dipped the flowers in the solution for 20 seconds. Each treatment included 10 flowers. After the dip process we held the flowers with the heads up side down for 15 minutes so that excess solution could drain off. The dry flowers were kept in allocated vases for quality and shelf life test. The quality and appearance of the flowers were checked every day.
The results in the following Table 1 indicate the quality of the flowers after one week in the test room. Positive implies a good appearance, negative implies damage to the flower.
TABLE 1
Surfactant
Surfactant Concentration, %
Name
2
1
0.5
0.20
0.10
0.05
0.02
0.01
0.005
AGRAL 90
NEG
NEG
NEG
POS
POS
POS
POS
POS
POS
TWEEN 20
NEG
NEG
NEG
NEG
NEG
NEG
NEG
POS
POS
Disponil
NEG
POS
POS
POS
POS
POS
POS
POS
POS
AFX 4060
Disponil
NEG
NEG
NEG
POS
POS
POS
POS
POS
POS
AFX 5060
NEG means the test failed.
POS means the test succeeded
Example 2
Procedure:
Pre-Emulsion Preparation:
7.5 g sodium dodecylbenzene sulfonate was completely dissolved in 484g deionized water by mixing with a magnetic stirrer. Then 54 g Disponil AFX 4060 were added to form a transparent viscous surfactant solution. In a 0.5 liter beaker were placed all of the monomers. This monomer solution was poured into the surfactant solution and mixed to give a pre-emulsion. The pre-emulsion was kept for 20 hours in a refrigerator.
Polymerization:
To the pre-emulsion were added 0.6 g ammonium per sulfate and it was stirred with a magnetic stirrer for 0.5 h. 200 ml of water were added to the reactor and the mechanical stirrer was set at 300 rpm. Then 200ml of pre-emulsion were added. Nitrogen gas was purged through the mixture for 30 minutes. Some foam may be formed at this stage. The reactor was then placed in the oil bath and heated to 84° C. and then the remainder of the pre-emulsion was added to the reactor during two hours and 10 minutes using a peristaltic pump. To complete the polymerization, 60 mg of ammonium per sulfate were added and the temperature was raised to 95-97° C. for an additional hour. The heating was shut off and the contents of the reactor were cooled slowly with continuous stirring with the reactor remaining in the oil bath. The emulsion polymer product, a synthetic latex, was removed from the reactor and filtered through a synthetic non-woven cloth. No coagulation product was observed. The pH of the emulsion was 2.7 The pH was raised to 8.0 by carefully adding about twenty two drops of 25% ammonium hydroxide. This was monitored using a pH electrode. The final yield was 1007.4 g
Example 3
Emulsion composition comprised the following materials was prepared as stated in example 2:
Monomers:
45 g CN152 (Sartomer), low viscosity monoacrylate monomer,
82.5 g SR506 (Sartomer), isobornyl monoacrylate,
22.5 g 2-(methacryloyloxy)ethylacetoacetate (AAEM),
Surfactants
3.75 g sodium dodecylbenzene sulfonate, 80%,
18.0 g Shatah 90
Initiator
0.33 g ammonium persulfate;
Water, 350 g
30% ammonia, several drops, to adjust the pH to 8.
Analyses:
T g by DSC=17° C., Total solids=32.8%
The emulsion was used for applying onto flowers, which then exhibited prolonged storage stability, enabling their long-term storage of minimally 4 weeks.
Example 4
The effect of silver thiosulfate (STS) solution in the acrylic emulsion on the quality of cut Rose Flowers (Akito and Red One varieties, an intermediate types of roses, harvested in a commercial roses green house in Menucha village, Israel) was examined after dipping and storing for one month. The flowers were dipped in several emulsions that included several concentration of STS (diluted from 8 g/l by taking from 0.1 to 1.4 ml per liter), ranging from 0.8 to 11.2 ppm. A bunch of roses, flowers and leaves, was dipped in the solution at each concentration for 2 seconds three times. Each treatment included 10 flowers. After the dip process, the flowers were put on a net for 10 minutes, so that an excess solution could drain off. The flowers were kept in an impregnation box at 2° C. for one month, and then they were allocated in vases for quality and shelf life assessments. The quality and appearance of the flowers were checked every day ( FIG. 1 ). It can be seen that the silver salt in a concentration of several ppm improves the quality of the stored roses.
Example 5
The effect of an acrylic emulsion according to the invention (denoted as D60) on the quality of cut roses (the roses of the same type as in Example 4) after dipping and storing for one month was checked. The flowers were dipped in a solution that included:
1. 100-200 ppm of the acrylic polymer (diluted from the emulsion of Example 3); 2. 3 ppm of silver thiosulfate; and 3. 0.02% Prochloraz (diluted from 45%).
The cut flowers were dipped (flowers and leaves) in D60 solution for 2 seconds three times. After the dipping process, the flowers were drained for 10 minutes to get rid of an excess solution. These flowers were kept in a cardboard box in at 2° C. for one month. After one month the flowers were allocated in vases for quality and shelf life assessment. The quality and appearance of the flowers were checked every day. The treated roses were keeping their fresh appearance even after one month, whereas comparison samples of non-treated roses, dipped only in water but kept under the same storage conditions, showed symptoms of advanced withering. The roses in the comparison samples, both white and red samples, exhibited color and shape changes; their petals turned partially brown, and deformed. The treated roses showed no such withering signs in any of the colors.
While the invention has been described using some specific examples, many modifications and variations are possible. It is therefore understood that the invention is not intended to be limited in any way, other than by the scope of the appended claims.
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A composition and method increases storage stability of cut flowers, particularly roses. A liquid composition is applied onto the cut flowers, and then it is converted to a protective polymeric film of a thickness of from about 0.001 to about 0.5 mm.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to animal-stunning tools for use in slaughter houses.
2. Prior Art
Slaughter house techniques have varied over the ages from the crudeness of a sledge-hammer to the sophistication of electrical-shock equipment. The object of all this equipment is to cause unconciousness in the animal during slaughter but not causing the cessation of the pumping action of the heart. The flow of blood through the animal is important to the quality of the meat obtained from the animal.
A search of the Patent Office records has revealed U.S. Pat. No. 4,219,905 (Thacker) which is related to but not anticipative of my invention. In the Thacker patent a piston of low mass and carrying a low-mass needle is moved forward by a blast of compressed air released through a complex combination of valves. Because of the low mass of the piston and needle, the penetrating power of the combination is limited. The combination of valves incorporated in Thacker is expensive, complex, and subject to malfunctioning. Further, the O-rings and seals in Thacker's device cause friction during operation of the piston and are also subject to wear and failure under the air pressure which must be used.
Therefore, it is the general object of this invention to provide an animal stunning gun which is free from the problems associated with prior art devices.
It is further object of this invention to provide a low-cost, highly effective stunning gun with minimal operational problems.
SUMMARY OF THE INVENTION
By providing a relatively massive cylindrical piston with annular recesses in its outer surface, such piston having a diameter such that it forms a slip fit with its containing cylinder so as to eliminate O-rings with their friction, the penetrating bolt carried by said piston having a conically-concave tip, retention of said piston and bolt in the retracted state being by magnetic means, a compressed-air stunning gun with maximum simplicity and effectiveness is realized.
BRIEF DESCRIPTION OF THE DRAWINGS
Those and other features of my invention will be understood from the description which follows taken in connection with the accompanying drawings in which:
The sole FIGURE is a cross-sectional view of an animal stunning gun according to this invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
In the sole FIGURE, stunning gun 10 includes cylindrical, hollow barrel 12 having opposed apertures 14 and 16 therein and having an inside-diameter "D". A cylindrical piston 18, of stainless steel, conventional steel or other material, having an outer-diameter "O" such that a slip-fit exists between piston 18 and the inner wall 19 of diameter "D" in barrel 12, is designed to move within barrel 12 without releasing air around its outer extremity. Piston 18 has annular recesses 20, 22 and 24 which reduce surface friction between inner wall 19 and piston 18 without significantly reducing the mass of piston 18. A coaxial air passage 26 extends from-end 28 of piston 18 to opposite end 30 thereof. The air passage 26 is enlarged at end 30 and internally threaded to permit insertion and retention of bolt or probe 32 therein. Probe 32 has an air passage 34 coaxially therethrough aligned with air passage 26 in piston 18 except that air passage 34 bi-furcates near end 36 of probe 32 into two exhaust ports 38 and 40 having a direction substantially 90° from the axis of passage 34. Annular stop 42 is provided on probe 32 to firmly seat probe 32 in piston 18. Piston 18 and probe 32 may be made of stainless steel to minimize corrosion and contamination. Probe 32, which must be very hard and cannot be made of stainless steel, terminates at its exposed end 36 in a concavity of conical shape. This concentrates penetrating forces in a sharp edge on end 36, enhancing the penetrating powers of probe 32. Air in front of piston 18 as it moves probe 32 into the animal's skull is exhausted through port 31.
Barrel 12 is closed at one end 43 by cap 44 which may be held onto barrel 12 by internal threads 46. A rubber or other shock-absorbing cushion 48, or a coil spring, is held in cap 44. A ring of magnetic material or a ceramic magnet, itself, 50 is secured in piston 18 near end 28.
The opposite end 52 of barrel 12 carries handle 54 by means of threads 56, for example.
Handle 54 contains therein retaining ring magnet 58 polarized to attract and cooperate with ring 50, assuming ring 50 is a magnet. Handle 54 further contains compressed air inlet aperture 60 which selectively communicates through valve assembly 62 with intermediate chamber 64, outlet chamber 66 and the central opening 68 in ring magnet 58 to permit the controlled flow of air therethrough to end 28 of piston 18. Valve assembly 62 includes plug 70 which is secured in handle 54 by means of a threaded region 72. Spool 74 carrying "O"-ring 76 is held captive by plug 70, on one extremity and by shoulder 78 in handle 54 on the opposite extremity. "O"-ring 76 presses against shoulders 78 and forms an air-tight seal therewith under urging from spring 80. Actuating arm 82 on spool 74 extends beyond the surface of handle 54 to permit its actuation by trigger 84 which is pivotally supported at pivot 86 in handle 54.
Upon depression of trigger 84 with piston 18 in a retracted position, compressed air introduced at inlet aperture 60 passes through valve assembly 62, intermediate chamber 64 and outlet chamber 66 and through opening 68 in ring magnet 58 to impress itself on end 28 of piston 18. When the retaining force between magnet 58 and magnetic material or ring magnet 50 is overcome, piston 18, with its considerable mass, is accelerated by the compressed air and attains considerable momentum. Probe 32 moves forward and, with cap 44 resting on or adjacent to an animal's head, probe 32 penetrates the skull and enters the brain. When probe 32 has completed its travel, piston 18 is beyond apertures 14 and 16 and the compressed air escapes through those apertures, terminating the forward thrust on piston 18 and probe 32. A small portion of the compressed air is injected into the brain cavity and the brain of the animal through exhaust ports 38 and 40, causing the animal to become unconscious or comatose. The probe 32 is removed from the animal's skull by pulling back on handle 62. The rebound action produced by the coil or cushion 48 assists the removal of the probe 32 from the skull. The gun is then re-cocked by holding it with probe 32 upright, causing probe 32 to retract into a position with magnetic material 50 in contact with ring magnet 58. The side ports 38 and 40 are relatively free of debris as compared with an end-ported device.
It should be noted that magnet 58 may be an electromagnet, as is indicated by leads 57, 59 in the sole FIGURE. The flux field of magnet 58 is made such that ring 50 and piston 18 are retained in the retracted position until the pressure on piston 18 becomes high so that piston 18 is released in impulse fashion and achieves its operating speed rapidly. Further, the length of barrel 12 is made longer than the combined lengths of piston 18 and the exposed portion of probe 32 so that the combination of piston and probe will achieve a significant forward momentum before probe or bolt 32 strikes the skull of the animal being stunned.
Thus, it can be seen that there has been provided a stunning gun which is simple in construction, subject to little failure in operation and effective in its performance.
While a particular embodiment has been shown and described, it will be apparent to one skilled in the art that variations and modifications thereof may be made without departing from the spirit and scope of my invention. It is the purpose of the appended claims to cover all such variations and modifications.
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By increasing the mass and reducing the surface friction of the piston driving a penetrating bolt in an animal stunning gun and providing that bolt with a conically-shaped recess at its tip, maximum penetrating force with minimum gun complexity is achieved. Further simplification of the gun without the sacrifice of any performance is achieved by utilizing magnetic retention means for the bolt prior to the firing of the gun.
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RELATED APPLICATION
[0001] This application is a Divisional of U.S. patent application Ser. No. 10/223,141, filed Aug. 19, 2002, now allowed.
FIELD OF THE INVENTION
[0002] The present invention relates to lancets which are lancing devices primarily used to obtain capillary blood samples for various testing purposes, not the least of which is blood glucose in the case of diabetics where such testing may be done on a daily basis. The purpose of the lancet is to penetrate the epidermis to a sufficient depth in order to draw the necessary amount of blood needed for the test, and yet hold the penetration, scaring, and injury to the epidermis to the irreducible minimum.
BACKGROUND OF THE INVENTION
[0003] The present invention has, by way of background, various lancing devices which hold the lancet needle, cover, and carrier. One such device is manufactured for ProCare LLC, and is submitted separately in a prior art disclosure. Basically, however, the lancing device contains a sliding barrel with a trigger button and a base support for the lancet. A lancet cover is provided which threadedly surrounds the lancet as it is positioned in the barrel. At the outer end is an adjustable comfort tip with a lancet cover having numerical indicia and an arrow which, by rotation of the cover, determines the empirical depth to which the needle will penetrate.
[0004] Virtually all hypodermic syringes have siliconized needles to aid in insertion to reduce the pain of insertion and further penetration. Therefore, it is desirable to siliconize the lancet needle. This permits the needle to be easily dislodged from the lancet body. In addition, a significant amount of plastic is employed by the prior art for such devices to attempt to secure the needle or blade against dislodgement, and protect against dimensional irregularities.
[0005] Therefore, what is needed is a lancet in which the needle portion is firmly embedded in the plastic body, secured against rotation, secured against linear removal, and yet permits the utilization of a minimal amount of plastic, which plastic may be of an inferior grade and therefore less expensive than most lancet bodies, while still providing the sanitary and dimensional support necessary.
SUMMARY OF THE INVENTION
[0006] The present invention derives from the molding of a lancet body around a needle or blade, in which the inner end of the needle body which is unsharpened has an L-shape bend. As a result of the L-shape bend, when embedded in the plastic which forms the body of the lancet, the needle can neither rotate nor be removed linearly. In short, the needle is permanently immobilized against movement within the body of the lancet, within the X, Y and Z directions. The method of the present invention involves the bending substantially perpendicularly of the unsharpened end of the needle or blade to be substantially perpendicular with the elongate body of the blade. The thus formed needle or blade is placed within a jig interiorly of the plastic mold which is used to form the lancet body and the cover, with the cover surrounding the entirety of the sharpened portion of the needle or blade. The jig includes spaced opposed clamps and a single orienting support to the bent portion of the needle. Also, the body of the lancet is relieved in many areas and has a molded tab cover thereby reducing the plastic used and eliminating a loose part such as a separate cover.
[0007] In view of the foregoing it is a principal object of the present invention to provide an apparatus and method for forming a lancet in which the needle or blade is securely positioned against any dislodgement, whether by rotation, or by linear movement within the lancet body.
[0008] A further object of the present invention is to provide such a lancet in which rotation and longitudinal dislodgement are prevented, which can accommodate a relatively low grade form of plastic and yet present in operation a dimensionally stable lancet, fully sanitary, for use with the typical user's home care kit.
[0009] A further object of the present invention is addressed to a method of forming a lancet body and needle or blade with a cover head on a highly cost effective basis attributable to the lack of necessity for special purpose jigs to control the position of the needle or blade within the lancet body. As a result, a further objective is achieved by providing the bent leg or L-shaped end portion so that it can be precisely positioned interiorly in the mold, and the plastic body of the lancet molded around the needle or blade with the offset anchor resulting in a product which is dimensionally accurate to tolerances which are acceptable and heretofore unknown on the quantities produced for the disposable lancet market.
DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0010] Further objects and advantages of the present invention will become apparent as the following description proceeds, taken in conjunction with the accompanying illustrative drawings in which:
[0011] [0011]FIG. 1 is an exploded partially perspective view of a typical home lancing device showing the lancet in a mid-portion of the figure;
[0012] [0012]FIGS. 2A, 2B, 2 C, 2 D, 2 E, 2 F and 2 G, show the utilization of the device typically by the patient applying the lancet to his/her own finger;
[0013] [0013]FIG. 3 is a perspective partially broken exploded view of the subject lancet showing the needle or blade interiorly thereof in its secured position;
[0014] [0014]FIGS. 4A and 4B are two views of the lancet needle which is molded into the body portion of the lancet;
[0015] [0015]FIG. 5 is a front elevation of the lancet;
[0016] [0016]FIG. 6 is a side elevation of the lancet;
[0017] [0017]FIG. 7 is a transverse sectional view of the lancet taken at 7 - 7 of FIG. 5;
[0018] [0018]FIG. 8 is a plan view, partially diagrammatic and partially broken, of the lower portion of the mold utilized to form the subject lancet;
[0019] [0019]FIG. 9 is a transverse sectional partially diagrammatic view, in enlarged scale, taken along section line 9 - 9 of FIG. 8; and
[0020] [0020]FIG. 10 is yet another transverse sectional view taken from FIG. 8 at section line 10 - 10 showing the support for the angled base anchor 26 of the needle 25 .
DESCRIPTION OF THE PREFERRED EMBODIMENT
[0021] In the preferred embodiment, as illustrated in FIG. 1, the lancing device 10 is used to obtain a capillary blood sample needed for blood glucose monitoring or for other tests requiring one or two drops of blood. The adjustable comfort tip 11 on the lancing device 10 permits choosing the best depth for skin penetration. As shown, there are five discrete positions 12 which can be utilized by the self-user.
[0022] As shown in FIGS. 2A through 2G, the needle cover 21 is twisted off of the lancet device 10 , the new lancet 20 is thereafter inserted into the lancet carrier 15 , the needle cover 21 is removed thereafter revealing the needle 25 , the lancet lancing device then has the comfort tip 11 placed in position. At this point, rotation of the adjustable comfort tip 11 offers a plurality of levels of skin penetration (see FIG. 2E). The user empirically determines which of these is best for his use.
[0023] The lancing device 10 is cocked by slowly pulling the slide barrel 14 away from the lancing device cover. A click indicates audibly when the carrier is locked in position. Thereafter the end of the adjustable comfort tip is pressed against the finger, the trigger button 16 is engaged, and the lancing device needle tip sharpened end 28 penetrates the epidermis to a point where the one or two drops of blood needed can be drawn.
[0024] Turning now to FIG. 3. which is an exploded perspective view, it can be seen that the two principle components of the lancet itself are the body 22 and the needle cover 21 cap which are the molded portions, and the needle or blade 25 which is the metal portion.
[0025] Important to the invention, and particularly shown in FIGS. 3, 5 and 8 , is the configuration of the needle or blade 25 in which the end opposite the sharpened end 28 has been bent at an angle with the needle body 29 . Desirably the bend is perpendicular to the main body 29 . Such a bend to form an anchor 26 critical to the present invention in that, by providing the offset, once the needle is molded into the body of the lancet it cannot be moved longitudinally, nor can it be rotated, nor can it be moved sideways in any direction. By virtue of the angled base anchor 26 , the needle or blade 25 is permanently, dimensionally and sanitarily positioned inside the lancet body with the needle cover in place but removable by twisting to dislodge, basically as described in FIG. 3 above. The method of the present invention will become more apparent as the description of the body 22 of the lancet proceeds. As can be seen in FIGS. 5 and 6, there are four runners 30 which, in cross-section, give a cruciform appearance, as shown in FIG. 7. There are two uninterrupted runners 31 , and two interrupted runners 32 . The interrupted runners 32 are formed when the opposed prongs of a vise are positioned in place interiorly of the mold to securely engage the needle prior to injecting the plastic. In this fashion the position of the needle is ensured and when the vise elements are withdrawn from the body 22 , ports are revealed which reduce the amount of plastic employed, and simultaneously permit the user to see and observe the needle interiorly of the body 22 .
[0026] While dimensions and composition materials do not form a key portion of the invention, those used in a commercial embodiment are illustrative of successful dimensions. All dimensions are in millimeters. As noticed particularly in FIGS. 5 , and 6 the entire lancet is 32 mm in length. The body portion is 20.7 mm, plus or minus 2 mm. The thickness dimension, taken from the tips of the runners, is 6.3 mm.
[0027] The needle, as shown in FIGS. 4A and 4B, is 24.4 mm in length, plus or minus 2 mm. The bent leg is 1.8 mm in length taken from the far side of the body portion. As shown in FIG. 4A, there is double-bevel at the sharpened end 28 of the needle. The material ideally employed is stainless steel 1CR18NI9.
[0028] The material employed for the plastic body is LDPE, better known as “low density polyethylene” blended with HDPE, better known as “high density polyethylene”. Virgin or reground may be used. Runners and flashing are reground and may be used exclusively or blended with virgin material.
[0029] While dimensions are not considered critical, they illustrate the precision involved. The total overall length of the lancet, including the cover, is 32 mm. The diameter at the largest portion of the body across the top of opposed runners is 6 mm. The total diameter of the tip or cap portion is 9.4 mm, and its thickness is 3.5 mm.
THE METHOD
[0030] The method of the present invention involves developing a mold 34 for a plurality of needles 25 in connection with a multiple cavity mold in which the needle or blade are positioned so that the same can be an interior portion of the completed lancet 20 when the plastic is injected into the recess which surrounds the carrying portion of the bent angle needle or blade. In this connection, it will be seen in FIG. 5 that the needle body 22 actually shows interiorly of the lancet body 20 because the support which holds the needle is surrounded by plastic, when the support is removed the needle appears. On the opposite side the needle is similarly viewed through much smaller ports. The reason for the smaller ports is that they contain a pin which clampling engages the needle on the post support of the jig interiorly of the mold to thereby firmly position the needle to be encapsulated in the plastic which is thereafter molded around the needle or blade.
[0031] Specifically as shown in FIG. 8, a multiple cavity mold 34 is intended for forming the lancet 20 . As shown here there are 20 cavities, ten on each side. Specific details of two cavities are shown in the upper right corner of FIG. 8. Turning now to FIG. 9, it will be seen that a clamping assembly 40 is used to engage the main body 29 of the needle 25 . The lower jaw 41 of the clamping assembly 40 is somewhat larger than the upper jaw 42 of the same clamping assembly. The needle 25 is positioned on top of the lower jaw 41 prior to molding. At or about the same time, the angled base anchor 26 of the needle 25 is positioned on top of the anchor support 44 . When the upper portion of the mold is placed over the lower portion, and the plastic is injected, the needle 25 and its components are securely held in place by the clamping assembly 40 . After the plastic has sufficiently cooled, the two mold supports are removed and the lancets 20 removed from the mold. Specifically as shown in FIG. 5, it will be seen that the interrupted runners 32 have ports which remain exposing needle body. The vise ports 35 are large vise ports 36 , and small vise ports 38 . In addition, there is an anchor support port 45 , viewed particularly in FIG. 5, and in which the angled base anchor 26 of the needle 25 is exposed. This results from the withdrawal of the anchor support 44 when the upper and lower portions of the mold are separated.
[0032] Summarizing the above, the method contemplates providing a mold having a plurality of cavities which are the mirror image of the lancet 20 to be molded. The next step in the process relates to providing clamping means, which are opposed, and which clampingly engage the needle body at spaced relationship. Finally, the step includes providing an anchor support at one end whereby the needle is not only supported on the anchor, but the anchor determines the position of the point of the needle within the molded lancet body cover. Thus, the sequencing, once the clamping means are provided within the mold, and the support means exist for the angled base anchor portion 26 of the needle 25 , the needles are inserted in the one portion of the mold on top of their respective supports, shown here as three in number (two for the needle body 25 and one for the angled base anchor 26 ). Thereafter the mold top is placed on the mold bottom, the clamping members engage the needle 25 in fixed relationship to the cavity to be filled with plastic. Once the plastic is within the balance of the cavity, the needle is positively oriented therein in relation to the base of the needle and the runners which, in turn, control the spaced relationship of the sharpened end 28 of the needle or blade 25 when positioned in a typical lancing device 10 , such as shown in FIGS. 1 and 2A through 2 G.
[0033] It will be understood that various changes in the details, materials and arrangements of parts, or method which have been herein described and illustrated in order to explain the nature of the invention, may be made by those skilled in the art within the principle and scope of the invention as expressed in the appended claims.
PARTS LIST 00 34 MULTIPLE CAVITY 68 MOLD 01 35 VISE PORTS 69 02 36 LARGE VISE PORTS (35) 70 03 37 71 04 38 SMALL VISE PORTS (35) 72 05 39 73 06 40 CLAMP ASSEMBLY 74 07 41 LOWER JAW 75 08 42 UPPER JAW 76 09 43 77 10 LANCING DEVICE 44 ANCHOR SUPPORT 78 11 COMFORT TIP 45 ANCHOR SUPPORT PORT 79 12 POSITIONS 46 80 13 47 81 14 SLIDE BARREL 48 82 15 LANCET CARRIER 49 83 16 TRIGGER BUTTON 50 84 17 51 85 18 52 86 19 53 87 20 LANCET 54 88 21 LANCET COVER (20) 55 89 22 NEEDLE BODY 56 90 23 57 91 24 58 92 25 NEEDLE OR BLADE 59 93 26 ANGLED BASE ANCHOR 60 94 27 61 95 28 SHARPENED END 62 96 29 MAIN BODY 63 97 30 RUNNERS (4) 64 98 31 UNINTERRUPTED 65 99 RUNNERS 32 INTERRUPTED RUNNERS 66 100 33 67 101
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A lancet body 15 is molded around a needle or blade, in which the inner end of the needle body which is unsharpened has an L-shape bend at the unsharpened end. The bend, when embedded in the plastic which forms the body of the lancet, secures the needle against removal. The method involves the bending substantially perpendicularly of the unsharpened end of the lancet needle or blade to be substantially perpendicular with the elongate body of the blade. The needle or blade is placed within a jig interiorly of the plastic mold. The jig includes spaced opposed clamps and a single orienting support to the bent portion of the needle. The body of the lancet is relieved in many areas to reduce material cost and has a molded tab cover eliminating a loose part such as a separate cover.
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FIELD OF THE INVENTION
The present invention relates to caddies having sockets for receiving the scrubbing end portions of cleaning implements (e.g., brushes) when the cleaning implement is being stored, particularly including such caddies for storing the types of cleaning implements with long handles used for cleaning toilet bowls or the like that are commonly used and stored in bathrooms.
BACKGROUND
The art is replete with caddies having sockets for receiving the scrubbing end portions of cleaning implements (e.g., brushes) when the cleaning implements are being stored, particularly including such caddies for storing the types of cleaning implements with long handles used for cleaning toilet bowls or the like that are commonly used and stored in bathrooms. U.S. Design Pat. Nos. 345,271; 297,292; 329,775; 276,291; 298,712; 315,269; 400,748; and 291,039; U.S. Pat. No. 4,776,456; and International Publication No. WO 01/60200 A1 provide illustrative examples. Typically, such caddies store the cleaning implement with the handle of the cleaning implement projecting generally vertically upwardly which is convenient for retrieving the cleaning implement when it is to be used, but which, because of the length of the handle and overall length of the cleaning implement (e.g., 16+ inches or 40+ centimeters), makes the caddy and cleaning implement combination inconvenient to store in storage cabinets of the type typically found in bathrooms.
DISCLOSURE OF THE INVENTION
The present invention provides a caddy having a socket for receiving an end portion of a cleaning implement (e.g., a brush) when the cleaning implement is being stored, particularly including the type of cleaning implement or brush having a long handle portion that is used for cleaning toilet bowls or the like and is commonly used and stored in bathrooms. The caddy allows storage of the cleaning implement with the long handle portion of the cleaning implement projecting upwardly in the conventional manner, and also allows the storage of the cleaning implement with its long handle portion extending generally horizontally, thereby facilitating storage of the caddy containing the cleaning implement in cabinets of the types typically found in bathrooms (e.g., a vanity) which may be desirable or necessary, for example, for aesthetic reasons or to keep the cleaning implement away from children.
According to the present invention there is provided a caddy for storing a cleaning implement, which cleaning implement comprises an elongate support member including a generally straight support end portion and a handle end portion. Ends of the support and handle end portions are fixed together with the support end portion and the handle end portion disposed at an obtuse angle with respect to each other (e.g., about 153 degrees). A part of the handle end portion adjacent its end opposite the support end portion is adapted for manual engagement. The cleaning implement includes scrubbing members (e.g., bristles or randomly disposed mineral coated fibers) having inner end parts supported on (e.g., imbedded in) the support end portion. Outer portions of some of the scrubbing members define a convex arcuate end peripheral surface portion (e.g., a convex generally semi-spherical end peripheral surface) extending about 180 degrees around the end of the support end portion opposite the handle end portion. Outer portions of other scrubbing members further define a convex arcuate side peripheral surface (e.g., a convex semi cylindrical side peripheral surface) extending from that convex end peripheral surface toward the handle portion along the side of the support end portion. The caddy comprises walls having a supported surface adapted to be supported on a horizontal surface, and has receiving surfaces defining a socket adapted to receive and support the scrubbing members on the support end portion of the support member. Those receiving surfaces include a concave arcuate side surface (e.g., a concave semi-cylindrical side surface) adapted to support the convex side peripheral surface portion defined by the scrubbing members, which concave arcuate side surface has an axis disposed at an acute angle (e.g., about 55 degrees) with respect to the supported surface, and extends from an inlet end of the socket toward the supported surface. The receiving surfaces further include a concave arcuate end surface (e.g., a generally semi-spherical end surface) at the innermost end of the socket adapted to support the convex arcuate end peripheral surface portion defined by the scrubbing members. The cleaning implement can either be (1) positioned in the socket in a vertical storage position with the portions of the scrubbing members defining the convex end peripheral surface portion resting against the concave arcuate end receiving surface, with the portions of the scrubbing members defining the convex arcuate side peripheral surface portion resting against the concave arcuate side surface, and with the handle portion outside of the socket and projecting generally normally away from the supported surface of the caddy (i.e., projecting generally vertically upwardly if the supported surface is supported on a horizontal surface); or (2) positioned in the socket in a horizontal storage position with the convex end peripheral surface portion defined by the scrubbing members resting against the concave arcuate end surface, with the support portion resting against the caddy at the inlet end of the socket, and with the handle portion outside of the socket and projecting away from the caddy generally parallel to the supported surface.
BRIEF DESCRIPTION OF THE DRAWING
The present invention will be further described with reference to the accompanying drawing wherein like reference numerals refer to like parts in the several views, and wherein:
FIG. 1 is a perspective view of a combination of a cleaning implement or brush and a caddy according to the present invention in which the brush is positioned in the caddy in a vertical storage position with a handle portion of the brush outside of the caddy and projecting generally vertically upwardly away from the caddy;
FIG. 2 is a perspective view of the combination of FIG. 1 in which the brush is positioned in the caddy in a horizontal storage position with a handle portion of the brush outside of the caddy and projecting generally horizontally away from the caddy;
FIG. 3 is an enlarged side view of the brush included in the combination of FIG. 1 ;
FIG. 4 is an enlarged top view of the brush included in the combination of FIG. 1 ;
FIG. 5 is a front view of the caddy according to the present invention included in the combination of FIG. 1 ;
FIG. 6 is a rear view of the caddy included in the combination of FIG. 1 ;
FIG. 7 is a fragmentary sectional view taken approximately along line 7 — 7 of FIG. 5 ;
FIG. 8 is a fragmentary sectional view taken approximately along line 8 — 8 of FIG. 1 ;
FIG. 9 is a fragmentary sectional view taken approximately along line 9 — 9 of FIG. 8 ;
FIG. 10 is a fragmentary sectional view taken approximately along line 10 — 10 of FIG. 2 ;
FIG. 11 is a sectional side view of the brush caddy according to the present invention as shown in FIGS. 1-10 in combination with a second embodiment of a cleaning implement or brush in which the brush is positioned in the caddy in a horizontal storage position with a handle portion of the brush outside of the caddy and projecting generally horizontally away from the caddy;
FIG. 12 is a sectional side view of the caddy according to the present invention as shown in FIGS. 1-10 in combination with a third embodiment of a cleaning implement in which the cleaning implement is positioned in the caddy in a vertical storage position with a handle portion of the cleaning implement outside of the caddy and projecting generally vertically upwardly away from the caddy;
FIG. 13 is a sectional side view of the caddy according to the present invention in combination with the third embodiment of the cleaning implement shown in FIG. 12 in which the cleaning implement is positioned in the caddy in a horizontal storage position with a handle portion of the cleaning implement outside of the caddy and projecting generally horizontally away from the caddy; and
FIG. 14 is a top view of the cleaning implement shown in FIGS. 12 and 13 .
DETAILED DESCRIPTION
Referring now to FIGS. 1 through 10 of the drawing, there is shown a combination 10 according to the present invention including a first embodiment of a cleaning implement or brush 12 and a caddy 14 according to the present invention.
Generally, the brush 12 (best seen in FIGS. 3 and 4 ) comprises a stiff elongate support member 16 of a polymeric material (e.g., polypropylene). The support member 16 includes a generally straight support end portion 18 having opposite first and second ends 19 and 20 , and a handle end portion 22 having opposite first and second ends 23 and 24 . The second ends 20 and 24 of the support and handle end portions 18 and 22 are fixed together (e.g., integrally molded together as illustrated) with the support end portion 18 and the handle end portion 22 disposed at an obtuse angle with respect to each other about a first axis 26 (e.g., as illustrated that obtuse angle is about 153 degrees between the centerline of the support end portion 18 and a straight line extending between the ends 23 and 24 of the handle end portion 22 ). A part of the handle end portion 22 adjacent its first end 23 is adapted for manual engagement and may, as illustrated, have adhered thereto a thin layer 27 of a non-slip material such as a colored thermoplastic rubber having a decorative outline. The brush 12 includes scrubbing members or bristles 28 (e.g., stiff fibers of polypropylene) having inner end parts supported on (e.g., imbedded in) the support end portion 18 . Outer potions or ends of some of the bristles 28 at the first end 19 of the support end portion 18 define a convex arcuate end peripheral surface portion 30 (e.g., a convex semi-spherical end peripheral surface portion 30 as illustrated) extending about 180 degrees around the first end 19 of the support end portion 18 . Outer portions or ends of other bristles 28 along the support end portion 18 further define a convex arcuate side peripheral surface portion 32 (e.g., a convex semi-cylindrical side peripheral surface portion 32 as illustrated) extending from the convex arcuate end peripheral surface portion 30 toward the second end 20 of the support portion 18 about 180 degrees around the side of the support end portion 18 opposite the obtuse angle at which the support end portion 18 and the handle end portion 22 are disposed about the axis 26 . The support end portion 18 is free of bristles along a part 33 of the support end portion 18 opposite the convex arcuate side peripheral surface portion 32 defined by the bristles 28 and adjacent the second end 20 of the support end portion 18 .
The caddy 14 according to the present invention, best seen in FIGS. 5 , 6 , and 7 , is a unitary molding of a polymeric material (e.g., polypropylene) comprising walls having a supported edge surface 40 in a plane adapted to be supported on a horizontal surface. The caddy 14 also has receiving surfaces defining a socket 42 in the caddy 14 adapted to receive and support the bristles 28 and the support end portion 18 of the brush 12 . Those receiving surfaces include a concave arcuate side surface 44 adjacent the edge surface 40 (e.g., a concave semi-cylindrical side surface 44 as illustrated) adapted to conform to and support the convex arcuate side peripheral surface portion 32 defined by the outer ends of the bristles 28 . That concave arcuate side surface 44 has a longitudinal axis (i.e., the longitudinal axis or centerline 43 of the socket 42 ) disposed at an acute angle (e.g., about 55 degrees as illustrated) with respect to the plane of the supported edge surface 40 and extending from an inlet end 45 of the socket 42 toward the plane of the supported edge surface 40 . The receiving surfaces defining the socket 42 further including a concave arcuate end surface 46 (e.g., a concave semi-spherical end surface 46 as illustrated) defining the end of the socket 42 opposite its inlet end 45 adapted to conform to and support the convex arcuate peripheral surface portion 30 defined by the outer ends of the bristles 28 .
The brush 12 can be received and stored in the socket 42 of the caddy 14 in a first or vertical storage position illustrated in FIGS. 1 , 8 , and 9 with the ends of the bristles 28 defining the convex arcuate end peripheral surface portion 30 of the brush 12 resting against the concave arcuate end surface 46 defining the inner end of the socket 42 , with the ends of the bristles defining the convex arcuate side peripheral surface portion 32 of the brush supported against the concave arcuate side surface 32 so that the centerline of the socket 42 is aligned with the centerline of the support end portion 18 , and with the handle portion 22 of the brush 12 outside of the socket 42 in the caddy 14 and projecting generally normally away from the supported edge surface 40 of the caddy 14 so that if the supported edge surface 40 of the caddy 14 is supported on a horizontal surface such as the floor of a bathroom, the handle end portion 22 will project generally vertically upwardly. Alternatively, the brush 12 can be received and stored in the socket 42 in a second or horizontal storage position illustrated in FIGS. 2 and 10 with the ends of the bristles 28 defining the convex arcuate end peripheral surface portion 30 of the brush supported against the concave arcuate end surface 46 defining the inner end of the socket 42 in the caddy 14 , with the bristle free part 33 of the support end portion 18 opposite the convex arcuate side peripheral surface portion 32 supported against the caddy 14 at the inlet end 45 of the socket 42 so that the centerline of the support end portion 18 is at an angle of about 23 degrees with respect to the axis or centerline 43 of the socket 42 , and with the handle end portion 22 outside of the socket 42 and projecting away from the caddy 14 generally parallel to the supported edge surface 40 of the caddy 14 . In this horizontal storage position, the maximum height of the brush 12 above the supported edge surface 40 of the caddy 14 is significantly less than its maximum height in the vertical storage position (e.g., about 4.5 inches or 11.4 cm compared to about 16 inches or 40.6 cm) and less than the height of the caddy 14 (i.e., about 5.8 inches or 14.7 cm) so that the caddy 14 with the brush 12 in it has a height that facilitates storage of the caddy 14 containing the brush 12 in cabinets of the types typically found in bathrooms (e.g., a vanity).
When, as illustrated, the longitudinal central axis 43 of the socket 42 is disposed at an acute angle of about 55 degrees with respect to the plane of the supported edge surface 40 , and the support end portion 18 and the handle end portion 22 of the brush are disposed at an obtuse angle with respect to each other about the first axis 26 of about 153 degrees measured between the centerline of the support end portion 18 and a straight line extending between the ends 23 and 24 of the handle end portion 22 , in the vertical storage position described above the handle portion 22 of the brush 12 projects away from the supported edge surface 40 of the caddy 14 at an angle of about 82 degrees which is considered generally normal with respect to the supported edge surface 40 , as would be considered angles of greater than about 70 degrees. In the horizontal storage position described above in which centerline of the support end portion 18 is at an angle of about 23 degrees with respect to the centerline or axis 43 of the socket 42 or about 32 degrees with respect to the supported edge surface 40 , the handle portion 22 of the brush 12 projects at an angle of about away from the supported edge surface 40 of the caddy 14 at an angle of about 4 degrees which is considered generally parallel with respect to the supported edge surface 40 , as would be considered angles of less than about 15 degrees.
The caddy 14 includes means for restricting rotation of the support end portion 18 about the axis of the socket 42 when the bristles 28 and the support end portion 18 are in the socket 42 in the vertical storage position described above. That means for restricting rotation as illustrated comprises spaced thin locating members or plates 50 having parallel side surfaces parallel to the axis of the socket 42 that project into the socket 42 . The locating plates 50 are received between end portions of the bristles 28 when the bristles 28 and the support end portion 18 are within the socket 42 in the vertical storage position at which, if the supported edge surface 40 of the caddy 14 is supported on a horizontal surface such as the floor of a bathroom, the handle end portion 22 will project generally vertically upwardly. Engagement of end portions of the bristles 28 against the side surfaces of the locating plates 50 will then restrict rotation of the support end portion 18 about the axis of the socket 42 under the influence of the weight of the handle end portion 22 ; which rotation, if it occurred, could cause the handle end portion 22 to move to a lower position out of its upwardly projecting position. The locating members could have shapes other than that illustrated, such as triangular or semi oval cross sections, and should have shapes that easily separate the bristles and allow movement of the separated bristles along opposite sides of the locating members 50 .
As illustrated, the convex end peripheral surface portion 30 defined by the outer ends of the bristles 28 and the concave end surface 46 of the caddy 14 against which that peripheral surface 30 is supported when the brush is in the caddy 14 are both semi-spherical; and the convex side peripheral surface portion 32 defined by the outer ends of the bristles 28 and the concave side surface 44 of the caddy 14 against which that side peripheral surface 32 is supported when the brush is in the caddy 14 in the vertical storage position described above are both semi-cylindrical. Those surfaces 30 , 46 , 32 , and 44 have been described as arcuate to include the possibility that those surfaces 30 , 46 , 32 , and 44 could be other than truly semi-spherical or semi-cylindrical, but could have other regular or irregular curved shapes.
When the surfaces and surface portions 30 , 46 , 32 , and 44 are truly semi-spherical or semi-cylindrical as illustrated, the brush 12 can be received and stored in the socket 42 of the caddy 14 in many optional positions in addition to the first and horizontal storage positions described above with the handle end portion 22 extending over any portion of the inlet end 45 of the socket 42 . With the handle end portion 22 projecting over portions of the inlet end 45 of the socket within about 45 degrees around the inlet end 45 of the socket in either direction from its position in the vertical storage position ( FIGS. 1 , 8 , and 9 ), the ends of the bristles 28 defining the convex arcuate end peripheral surface portion 30 of the brush 12 will rest against the concave arcuate end surface 46 defining the inner end of the socket 42 , and the ends of the bristles defining the convex arcuate side peripheral surface portion 32 of the brush 12 will be at least partially supported against the concave arcuate side surface 32 as in the vertical storage position. With the handle end portion 22 projecting over portions of the inlet end 45 of the socket within about 135 degrees in either direction around the inlet end 45 of the socket from its position in the horizontal storage position ( FIGS. 2 and 10 ) the ends of the bristles 28 defining the convex arcuate end peripheral surface portion 30 of the brush will be supported against the concave arcuate end surface 46 defining the inner end of the socket 42 in the caddy 14 , and the bristle free part 33 of the support end portion 18 opposite the convex arcuate side peripheral surface 32 will be supported against the caddy 14 at the inlet end 45 of the socket 42 as in the horizontal storage position. The handle end portion 22 will be outside of the socket 42 projecting away from the caddy 14 in various directions in those optional positions, one of which directions, under certain circumstances, may provide an advantage for locating or storing the caddy 14 and brush 12 . In any of those optional positions engagement of end portions of the bristles 28 against the side surfaces of the locating members or plates 50 will restrict rotation of the support end portion 18 about the axis of the socket 42 under the influence of the weight of the handle end portion 22 .
As is illustrated in FIG. 11 , the caddy 14 could be used to receive a second embodiment of a cleaning implement or brush 12 a (parts of the brush 12 a that correspond to parts of the brush 12 have been given the same reference numeral to which has been added the suffix “a”) having about the same configuration as the brush 12 except that the support end portion 18 a has bristles supported on or embedded in the part 33 a of the support end portion 18 a opposite the convex arcuate side peripheral surface portion 32 a defined by the bristles 28 a and adjacent the second end 20 a of the support end portion 18 a . A vertical storage position for the brush 12 a (not illustrated) will be essentially the same as the vertical storage position for the brush 12 illustrated in FIGS. 1 , 8 , and 9 at which the ends of the bristles 28 a defining the convex arcuate end peripheral surface portion 30 a of the brush 12 a rest against the concave arcuate end surface 46 defining the inner end of the socket 42 , with the ends of the bristles 28 a defining the convex arcuate side peripheral surface portion 32 a of the brush 12 a supported against the concave arcuate side surface 32 so that the centerline or axis 43 of the socket 42 is about aligned with the centerline of the support end portion 18 a , and the handle portion 22 a of the brush 12 a is outside of the socket 42 a in the caddy 14 and projects generally normally away from the supported edge surface 40 of the caddy 14 so that if the supported edge surface 40 of the caddy 14 is supported on a horizontal surface such as the floor of a bathroom, the handle end portion 22 a will project generally vertically upwardly. Alternatively, the brush 12 a can be received and stored in the socket 42 in a horizontal storage position illustrated in FIG. 11 with the ends of the bristles 28 a defining the convex arcuate end peripheral surface portion 30 a of the brush 12 a supported against the concave arcuate end surface 46 defining the inner end of the socket 42 in the caddy 14 , and with the bristles along the part 33 a of the support end portion 18 a opposite the convex arcuate side peripheral surface portion 32 a supported against the concave arcuate side surface 44 adjacent the edge surface 40 so that the centerline of the support end portion 18 a is about aligned with the centerline of the socket 42 a , and the handle end portion 22 a is outside of the socket 42 a and projecting away from the caddy 14 a at an angle of about 23 degrees with respect to the supported edge surface 40 of the caddy 14 . In this horizontal storage position for the brush 12 a , the maximum height of the brush 12 a above the supported edge surface 40 of the caddy 14 is still significantly less than its maximum height in the vertical storage position (e.g., about 10 inches or 25.4 cm compared to about 16 inches or 40.6 cm) and, while more than the height of the caddy 14 (i.e., about 5.8 inches or 14.7 cm), still may be sufficiently low that it facilitates storage of the caddy 14 containing the brush 12 a in cabinets of the types typically found in bathrooms (e.g., a vanity).
In the horizontal storage position described above in which centerline of the support end portion 18 a is along the centerline of the socket 42 or at about 55 degrees with respect to the supported edge surface portion 40 , the handle portion 22 of the brush 12 projects away from the supported edge surface 40 of the caddy 14 at an angle of about 28 degrees which for such a handle portion 22 , is considered roughly parallel with respect to the supported edge surface 40 as would be considered angles of less than about 30 degrees.
As is illustrated in FIGS. 12 and 13 , the caddy 14 could be used to receive a third embodiment of a cleaning implement 60 (see also FIG. 14 ) such as the cleaning implement 60 commercially designated as a “SCOTCH BRITE” (trade mark) One Scrub, that has been commercially available from 3M Company, St. Paul, Minn., for many years. That cleaning implement 60 comprises an elongate support member 61 including a generally straight support end portion 62 having opposite first and second ends 63 and 64 , and a handle end portion 66 having opposite first and second ends 67 and 68 . The second ends 64 and 68 of the support and handle end portions 61 and 66 are fixed together (e.g., by being integrally molded) with the support end portion 62 and the handle end portion 66 disposed at an obtuse angle with respect to each other about a first axis 70 (e.g., that obtuse angle is about 156 degrees between the centerline of the support end portion 18 and a straight line extending between the ends 67 and 68 of the handle end portion 66 ). A part of the handle end portion 66 adjacent its first end 67 is adapted for manual engagement. The cleaning implement includes a pad 72 of scrubbing members in the form of randomly disposed spaced polymeric fibers (e.g., of polyester) bonded together with a resin (e.g., polyurethane) at points where the fibers contact each other and coated with mineral (e.g., the “SCOTCH BRITE” (trade mark) scrubbing material commercially available from 3M Company, St. Paul, Minn.), which fibers have inner parts supported on the support end portion 61 which has barbs 65 engaged with the fibers to hold the pad 72 on the support end portion 61 . The pad 72 has an outer surface defined by portions of the scrubbing members opposite those inner parts that includes a convex arcuate end peripheral surface portion 76 extending about 180 degrees around the first end 63 of the support end portion 61 , and opposite convex arcuate side peripheral surface portions 78 extending from that convex arcuate end peripheral surface portion 76 toward the second end 64 of the support end portion 62 , which end and side peripheral surface portions 76 and 78 extend between opposite planar parallel top and bottom surface portions 79 and 80 of the pad 72 .
At a vertical storage position for the cleaning implement 60 illustrated in FIG. 12 , the end peripheral surface portion 76 defined by the scrubbing members will rest against the concave arcuate end surface 46 defining the inner end of the socket 42 , and the convex arcuate side peripheral surface portions 78 will engage the concave arcuate side surface 32 and the locating members 50 so that the centerline of the support end portion 18 a is about aligned with the centerline 43 of the socket 42 , and the handle end portion 66 of the cleaning implement 60 is outside of the socket 42 in the caddy 14 and projects generally normally away from the supported edge surface 40 of the caddy 14 so that if the supported edge surface 40 of the caddy 14 is supported on a horizontal surface such as the floor of a bathroom, the handle end portion 22 a will project generally vertically upwardly. Alternatively, the cleaning implement 60 can be received and stored in the socket 42 in a horizontal storage position illustrated in FIG. 13 with the convex arcuate end peripheral surface portion 76 defined by the scrubbing members supported against the concave arcuate end surface 46 defining the inner end of the socket 42 in the caddy 14 , and with the support member 61 supported against the caddy 14 at the inlet end 45 of the socket 42 so that the centerline of the support end portion 62 is at an angle of about 23 degrees with respect to the centerline or axis 43 of the socket 42 , and with the handle end portion 66 outside of the socket 42 and projecting away from the caddy 14 generally parallel to the supported edge surface 40 of the caddy 14 . In this horizontal storage position, the maximum height of the cleaning implement 60 above the supported edge surface 40 of the caddy 14 is significantly less than its maximum height in the vertical storage position (e.g., about 6 inches or 15 cm compared to about 16 inches or 40.6 cm) and about the height of the caddy 14 (i.e., about 5.8 inches or 14.7 cm) so that the caddy 14 with the cleaning implement 60 in it has a height that facilitates storage of the caddy containing the brush in cabinets of the types typically found in bathrooms (e.g., a vanity).
The caddy 14 according to the present invention has now been described with reference to one embodiment and in combination with several cleaning implements 12 , 12 a and 60 together with several possible modifications thereof. It will be apparent to those skilled in the art that many changes can be made in the embodiments and combinations described above without departing from the scope of the present invention. For example, the convex arcuate end peripheral surface portions 30 defined by the outer ends of the bristles 28 of the brush 12 and the arcuate concave end surface 46 of the caddy 14 against which that peripheral surface 30 is supported when the brush 12 is in the caddy 14 instead of being truly semi-spherical could have a central semi-cylindrical portion around an axis parallel to the axis 26 which could limit storage positions of the brush within the caddy 14 to the first and horizontal storage positions described above and could provide the means for restricting rotation of the support end portion 18 about the axis 43 of the socket 42 when the bristles 28 and the support end portion 18 are in the socket 42 in the vertical storage position. Also, to further limit the height between the supported surface 40 and the highest point of the caddy 14 or the brush 12 in the horizontal storage position, an upper part of the caddy 14 above about a horizontal line 52 shown in FIG. 10 could be removed as the portion of the socket 42 defined by surfaces above that line 52 make no contact with the bristles 28 of the brush 12 in either the first or second storage portions. Also, the caddy 14 could be provided with a wall along its side 90 having a planer surface disposed at a right angle with respect to the supporting edge surface 40 , which wall could have an opening for receiving a hook or the like by which the caddy 14 could be hung on a wall. Additionally, a cover could be provided over the inlet end 45 of the socket 42 , which cover could be slotted to facilitate positioning the cleaning implements 12 , 12 a or 60 in either their vertical or horizontal storage positions. Thus, the scope of the present invention should not be limited to the structures described in this application, but only by the structures described by the language of the claims and the equivalents thereof.
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A caddy having a socket shaped to receive the scrubbing end portion of a cleaning implement such as a brush when the implement is being stored, particularly including the type of cleaning implement having a long handle that is used for cleaning toilet bowls or the like that is commonly used and stored in bathrooms. The cooperating shapes of the cleaning and a socket in the caddy allow storage of the cleaning implement or brush either with the long handle of the cleaning implement projecting upwardly in the conventional manner, or with its long handle extending generally horizontally, thereby facilitating storage of the caddy containing the cleaning implement in cabinets of the types typically found in bathrooms.
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This application is a Continuation-in-Part of prior application U.S. Ser. No. 09/141,904 filed Aug. 28, 1998 now U.S. Pat. No. 5,951,965, the disclosure of which is incorporated herein by reference.
BACKGROUND OF THE INVENTION
The washing of human skin with cleansing formulations has been associated with the removal of bacteria for over one hundred years. However, neither the qualitative nor quantitative effectiveness of skin cleanser in bacteria removal has been readily visually demonstrated to the skin cleansing public. Radiolabelling of bacteria and counting amounts of radiolabel left on skin samples is certainly an unacceptable method.
In like manner, there may be a growing interest in preventing attachment of bacteria to various body cells. A document is directed to inhibiting adhesion of a strep pyogenes to specific cells located in the oral cavity, U.S. Pat. No. 5,002,759. Another document, U.S. Pat. No. 5,683,991 is specifically directed to inhibiting E. Coli attachment to epithelial cells of the gastrointestinal tract and urogenital tract through the use of specific galacturonides. EP 806935 A is directed to the use of a carbohydrate or derivative thereof as an antiadhesive against a host of harmful materials including bacteria, parasites and protozoa on cell surfaces such as skin, mucous membranes, body orifices, interiors or hollow body organs, wounds, eyes and hair. U.S. Pat. No. 5,416,075 discloses the use of an oil in water emulsion having an amphipathic molecule including a biospecific moiety at the head end of its hydrophilic part. These compositions are applied to the skin. These headgroups inhibit adhesion of bacteria to the skin.
However, there is no rapid visual demonstration of the efficacy of such a process.
Such a method has now been discovered. It is rapid. It visually demonstrates the efficacy of any such effective or purportedly effective composition. Furthermore, it is effective for a large cross section of bacteria which can be transmitted to the skin.
SUMMARY OF THE INVENTION
In accordance with the invention there is a method for visually demonstrating the effectiveness of an anti-bacteria attachment composition which comprises:
a. treating skin with a potential or known inhibition of bacteria attachment composition;
b. contacting the said skin with a bacteria resulting in the skin having the bacteria attached to it;
c. contacting the skin with a bacteria growth supporting medium having optionally therein or optionally later added a compound or mixture thereof which will assist in visually detecting a bacterial colony.
It should be noted that most people can usually detect a colony of bacteria growing on an agar plate or other supporting media and readily successfully compare a medium with heavy bacterial growth to a medium with light to moderate bacterial growth. Certain bacteria can be visually detectable as a colored grouping without a separate visually detectable medium applied to it. Such bacteria include Serratia marcescens, Straphylococcus aureus, Pseudomonas fluorescens, Pseudomonas aeroginosa, Bacteroides asaccharolyticus and bacteroides melaninogenicus.
However, frequently bacterial growth media have certain component(s) therein which will specifically support the growth of certain bacteria and provide a readily visible color to the bacteria. Furthermore there are certain compound(s) available which when added to the growth media will selectively color certain bacteria, even in the presence of other bacteria.
A further aspect of the invention is a method of visually evaluating the comparable effectiveness of potential or known inhibition of bacteria attachment compositions which comprises steps a, b and c above for each bacteria attachment composition being evaluated and comparing the visual quantities of bacteria colonies on the skin for each said composition
DETAILED DESCRIPTION OF THE INVENTION
Examples of bacteria which are inhibited from attaching to the skin include Staphylococcus aureus, Staphylococcus epidermidis, Corynebacterium minutissimum, Escherichia coli, Salmonella choleraesuis and Serratia marcescens as well as other bacteria mentioned in this application.
The test is simple to run and provides an easy method of assessing visible quantity of bacteria on the skin. A skin part, including but not limited to an ex vivo skin explant or any source from animal and human, synthetic skin and the like, for example the hand, is contacted with a test composition which may inhibit bacteria attachment. On a similar part of the skin, a control composition is applied that does not have the component(s) of the test composition which allegedly bring about the inhibition of bacteria attachment. For example a soap composition having inhibitors of bacteria attachment is applied to the skin (hand). On the other hand the same soap composition without the component(s) responsible for inhibition of bacteria attachment is applied. Each hand is now contacted with a specific bacterium or various bacteria against which the inhibition of bacteria attachment composition is thought to be effective. After a period of time, the hand is contacted with a bacteria growth supporting solid medium which will support bacteria growth or a medium to which the bacterial growth nutrient can be readily added. An example of a growth support medium is agar. Incorporated within the medium or added an appropriate time thereafter is an amount of growth nutrient in sufficient quantity to bring about the growth of the various bacteria transferred from the skin. After an appropriate period of time to allow growth to occur, at least partially dependent on the temperature, particular bacteria, and the like, the medium bearing the bacteria is visually assessed.
As stated previously, individuals with normal vision are able to visualize the bacterial colonies and can distinguish between various levels of growth, such as high and moderate. This is without any additional visual effect that is, bacteria without any natural color. As noted previously, some bacteria do have a natural color. Additionally, color can be imparted to bacterial colonies by the nature of the nutrient growth material employed since many bacteria are capable of producing pigments when grown in medium supplemented with specific nutrients. Such medium can be selective or differential in nature. For example, such nutrient medium will bring about color pigment for the following bacteria:
Escherichia coli will produce colony with a characteristic green metallic sheen on agar containing Eosin Methylene Blue. Such nutrient medium can include such components as peptone, lactose, dipotassium hydrogen phosphate, Eosin Y, Methylene Blue and agar at a pH of 6.8.
Staphylococcus aureus will produce colony with a characteristic yellow color when grown on mannitol salt agar. Such nutrient medium can include the following components per liter of purified water:
______________________________________Pancreatic digest of Casein 5.0 g Peptic digest of animal tissue 5.0 g Beef extract 1.0 g Sodium chloride 75.0 g Phenol red 0.025 g Agar 15.0 g______________________________________
A competent strain of E. coli HB101 produces blue colonies on LB (Luria-Bertani) medium supplemented with X-Gal (5-bromo-4chloro-3-indolyl-β-galactosidase), IPTG (isopropyl β-D-Thiogalacto-pyranoside). LB- medium contains Bacto tryptone, yeast extract, NaCl, agar and water.
Trypticase Soy Agar
Composition: Approximate formula per liter purified water
______________________________________Pancreatic digest of Casein 15.0 g Papaic digest of soybean meal 5.0 g Sodium chloride 5.0 g Agar 15.0 g______________________________________
On this medium Serratia marcescens will produce red colonies.
The following enterobacterial species also produce pigments at a particular incubation temperature*:
______________________________________ Colony color Organism (temp. of incubation ° C.) % pigmented______________________________________Enterobacter agglomerans yellow 76-89 Erwinia stewartii yellow (27) 90-100 Escherichia hermannii yellow 90-100 Xenorhabdus luminescens yellow, orange 90-100 or red (25) Xenorhabdus poinarii Brown (25) 90-100______________________________________ *Manual of Clinical Microbiology, 6th ed. pp. 459
Still further certain medium with specific compounds or mixtures thereof will react or interact with enzyme metabolities elaborated by the growing bacteria and produce a visual color identifying the bacteria. Such compounds are disclosed in WO 97 39103, FR 2708286, FR 2708285 and WO 9409152 all by Alain Rambach. A typical medium having such a chromogen is exemplified below and can be obtained from CHROM agar Company, Paris, France in dehydrated powder form.
Composition:
Peptone
Meat extract
Yeast extract
Agar
Chromogen (a caprylic acid ester, specifically an indolyl caprylate) 40-200 mg/l
On this medium Salmonella will produce blue colonies.
On CHROMagar orientation medium various bacteria will give different color of colonies. For example:
______________________________________E. coli pink-red K. pneumoniae metallic blue Enterobacter species metallic blue Staph. aureus white to yellowish Citrobacter freudii metallic blue Enterococcus species turquoise______________________________________ (Ref. J. Clin. Microbiol. 36(4):990-994, 1998).
The results are assessed on the basis of the quantity of visually detectable bacteria on the medium--the lesser the number of visually detectable bacteria colonies on the medium, the more advantageous the inhibition of bacteria attachment composition while the greater the number of visually detectable bacteria colonies on the skin, the less advantageous the inhibition of bacteria attachment composition.
The term skin as used herein means the top layer of skin (i.e., stratum comeum) and all the components of the stratum, both cellular and acellular (i.e., biomolecules) such as proteins, carbohydrates, lipids and the like.
Any composition which can potentially or is known to inhibit the attachment of bacteria to skin can be evaluated by this method. In addition to the inhibition of bacteria attachment to skin compositions previously discussed are various compositions disclosed in U.S. provisional applications 60/087,533 and 60/087,532, both incorporated by reference. These compositions are directed to combinations including surfactant(s) with either a silicone such as dimethicone or a hydrocarbonaceous component such as petrolatum, minerol oil, paraffin and the like being present in attachment inhibiting amounts or both a silicone and a hydrocarbonaceous component together in attachment inhibiting amounts. A cationic polymer can also be present with either or both the silicone and hydrocarbonaceous component. Various other materials can also be present such as fragrance; antimicrobial materials such as Triclosan or trichlorocarbanilides; and the like. However, an antimicrobial material such as triclosan or triclocarban can be omitted as well.
This method can be used to compare and/or contrast known and unknown antibacteria attachment composition to each other or to a control composition.
The transference of bacteria to the skin can occur through any type of contact, for example skin to skin, or skin surface bearing such bacteria, for example doorknob, faucet, telephone, table top and the like. In sufficient density, bacteria can even be transferred to the skin in an airborne manner.
Transference of bacteria to the growth supporting medium from skin can occur through simple contact of the surface bearing the bacteria to the surface. An example of such a transfer is pressing a hand on the surface of an agar plate.
The bacteria are then allowed to grow into various colonies by incubating at a temperature optimum for bacterial growth and providing nutrients to the growth supporting medium, if not already present. After a period of time necessary to allow such bacteria to grow, at least partially dependent on temperature, pH, type of bacteria and the like, the bacteria are visualized without any assistance with any of the color including media, or compounds previously described. However, these additional method(s) of assisted visualization can be used, if desired.
Below are examples of the invention. These examples are intended to illustrate the broad nature of the invention and not be unduly restrictive thereof.
EXAMPLE 1
Thirty subjects participate in the studies. Subjects undergo a one-week washout period where they refrain from using any products labeled antibacterial such as antibacterial soaps, dishwashing liquids, lotions, creams, talcs, etc. and antidandruff shampoos for one week prior to the beginning of the study and for the duration of the test period.
On the day of the test, the subject's hands are rinsed with 70% ethanol to remove any contaminating bacteria and allowed to air dry. Each of the subject's hands are washed either four times or once by a technician. The washing procedure consists of a 15 second wash with the bar soap, 45 second lather with the gloved hand and 10 second rinse under running warm tap water. For multiple washes, the hands are allowed to air dry before proceeding with the next wash.
The subjects gently place each of their hands on the surface of a plastic plate previously contaminated with 200 μl (approximately 10 6 ) of the marker bacteria, Serratia marcescens (ATCC 14756). Two objects weighing approximately a total of 480 g are placed on top of the hands to help provide even pressure. The hands are left on the plate for 5 seconds. The subjects then, as soon as possible, gently place each of their hands on a pre-poured Microbial Content Agar hand imprint plate to transfer the bacteria. A technician applies gentle pressure to each of the subject's hands and fingers for 10 seconds. The same objects used as weights above are placed on top of the hands to help provide even pressure and the hands are left on the agar plate for 30 seconds. The subjects hands are decontaminated by soaking them in 70% isopropanol for 3 minutes.
The agar plates are incubated overnight at 35-37° C. The plates are evaluated by three judges using the following scale:
0--no bacterial growth
1--very slight bacterial growth
2--slight bacterial growth
3--moderate bacterial growth
4--strong bacterial growth
5--very strong bacterial growth
6--extreme bacterial growth
Only pink colonies were evaluated. Half scores were allowed to delineate between whole unit scores.
The 3 judges scores for each plate are averaged. A paired t-test is employed using the judge average scores to determine whether significant references existed between products at the 5% significance level.
TABLE I______________________________________Bacteria Pick-Up Evaluation: Test Product vs. Placebo Means Judges Score ± S.D. (n = 15 for each study) 4 Washes 1 Wash______________________________________Placebo.sup.a 3.9 ± 1.0 3.5 ± 1.0 Test Product.sup.b 2.8 ± 1.0 2.0 ± 0.8 p-value ≦0.05 ≦0.05______________________________________ .sup.a Soap 77.5 wt %, free fatty acid 9.5 wt %, water 8.4 wt %. .sup.b Soap 74.3 wt %, free fatty acid 9.2 wt %, polyquat 60.12 wt %, triclocarban 0.25 wt %, petrolatum 3.5 wt. %, dimethicone 0.1 wt. %, wate 8.3 wt %.
As shown by the data, the test product has significantly inhibited the attachment of bacteria to the skin.
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A method for visually demonstrating the effectiveness of an anti-bacteria attachment composition which comprises:
a. treating skin with potential or known anti-bacteria attachment composition;
b. contacting the said skin with a bacteria, resulting in the skin having bacteria attached to it;
c. contacting the skin with a bacteria growth supporting medium having optionally therein or later optionally added a compound or mixture thereof which will assist in visually detecting a bacterial colony.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a line-arranging mechanism.
2. Description of the Related Art
One type of a line-arranging mechanism is applied to a fishing pole. Because the diameter of fishing line is very fine, regularity in the arrangement thereof does not affect the volume of the line-arranging mechanism. Another type of line-arranging mechanism is applied to household appliances. The regularity in the arrangement of a power line of a household appliance is of little concern. Referring to FIG. 1 , a conventional line-arranging mechanism 10 demands that the power line be arranged regularly, thus, the conventional line-arranging mechanism 10 comprises a motor 11 to drive a reciprocator for arranging the power line. The conventional line-arranging mechanism 10 comprises a motor 11 , a lead screw 12 , a reciprocator 14 and a bearing (not shown). The motor drives the lead screw 12 and the reciprocator 14 for regularly arranging the power line.
The conventional line-arranging mechanism 10 is complex and large, thus, the conventional line-arranging mechanism 10 is expensive. The volume of an electronic device has gradually decreased. If the line-arranging mechanism 10 is applied to an electronic device, the volume and cost are increased.
BRIEF SUMMARY OF INVENTION
A detailed description is given in the following embodiments with reference to the accompanying drawings. A line-arranging mechanism comprises a cam, an axle connecting to the cam, a sliding element and a transmitting mechanism to drive the cam and the axle. The cam comprises an inclined surface and the sliding element to slide thereon.
The transmitting mechanism comprises a sun gear, a planet pinion and a ring gear. The sun gear is connected to the axle. The planet pinion engages the sun gear and the ring gear. The ring gear is connected to the cam.
BRIEF DESCRIPTION OF DRAWINGS
The present invention can be more fully understood by reading the subsequent detailed description and examples with references made to the accompanying drawings, wherein:
FIG. 1 is a schematic view of a conventional line-arranging mechanism;
FIG. 2 is a schematic view of a line-arranging mechanism of the invention;
FIG. 3 is a schematic view of a transmitting mechanism of the invention; and
FIGS. 4A to 4C are schematic views showing a transmitting mechanism of the invention to arrange a line.
DETAILED DESCRIPTION OF INVENTION
The following description is a best-contemplated mode of carrying out the invention. This description is made for the purpose of illustrating the general principles of the invention and should not be taken in a limiting sense. The scope of the invention is best determined by reference to the appended claims.
Referring to FIGS. 2 and 3 , a line-arranging mechanism 20 comprises a knob 25 , a cam 21 , an axle 22 , a sliding element 23 and a transmitting mechanism 24 (shown by FIG. 3 ). The knob 25 comprises a protrusion 251 and a first engaging portion 252 . A force is exerted on the protrusion 251 for rotating the axle 22 . The axle 22 comprises a second engaging portion 221 which is connected to the first engaging portion 252 , thereby, the knob 25 and the axle 22 rotate together for arranging the line. In this embodiment, the cam 21 is cannular and comprises an inclined surface 211 located in the rim of the cam 21 . The axle is installed in the cam 21 . In this embodiment, the axle 22 is approximately at the center of the cam 21 . A space 28 between the axle 22 and the cam 21 contains the line (not shown). The sliding element 23 is movably installed on the inclined surface 211 and comprises a hole 231 through which the line passes. The transmitting mechanism 24 is installed at the bottom of the line-arranging mechanism 20 and connects to the cam 21 and the axle 22 .
The transmitting mechanism 24 is a planetary gear system which comprises a sun gear 241 , a planet pinion 242 and a ring gear 243 . The sun gear 241 is connected to the axle 22 . The planet pinion 242 engages the sun gear 241 and the ring gear 243 . The ring gear 243 is connected to the cam 21 . The transmission ratio of the sun gear 241 and the ring gear 243 ranges from 3/1 to 20/1. In this embodiment, the transmission ratio of the sun gear 241 and the ring gear 243 is 8/1. When the sun gear 241 turns eight revolutions, the ring gear 243 turns one revolution. When the axle 22 turns eight revolutions, the cam 21 turns a revolution. The inclined surface 211 comprises a high point H and a low point L. When the cam 21 turns one-second revolution (the axle 22 turns four revolutions), the sliding element 23 arrives the high point H. When the cam 21 turns another one-second revolution, the sliding element 23 returns the low point L again.
FIGS. 3 and 4A to 4 C are schematic views showing a transmitting mechanism of the invention to arrange a line. Referring to FIG. 4A , the line-arranging mechanism 20 further comprises a shell 26 for covering the cam 21 , the axle 22 , the sliding element 23 and the transmitting mechanism 24 . The line (not shown) enters the cam 21 from the shell 26 . The shell 26 comprises a groove 261 on the side of the shell. The sliding element 23 is installed on the inclined surface 211 and moves at an incline along the groove 261 .
Referring to FIGS. 3 and 4A , the power line 27 enters the line-arranging mechanism 20 and then passes through the hole 231 . The power line 27 is arranged by the user to turn the protrusion 251 of the knob 25 along an arrow a. The knob 25 links the axle 22 to rotate the axle 22 . The axle 22 links the sun gear 241 of the transmitting mechanism 24 to rotate the sun gear 241 along the arrow a. The sun gear 241 links the planet pinion 242 to rotate the ring gear 243 along an arrow b, thus the cam rotates along the arrow b.
Referring to FIG. 4B , when the knob 25 rotates a revolution along the arrow a, the cam 21 rotates one-eighth revolution. The sliding element 23 in the grove 261 is pushed upward along the inclined surface 211 by rotating the cam 21 . In this embodiment, when the knob 25 rotates a revolution (the cam 21 rotates one-eighth of a revolution), the sliding element 23 rises a height H equal to a diameter of the power line 27 . Referring to FIG. 4C , when the knob 25 rotates four revolutions, the cam rotates one-second revolution, thus, the sliding element 23 moves at the high point H and the power line 27 is wound four revolutions on the axle 22 . When the knob 25 proceeds to rotate four revolutions, the knob 25 moves downward along the inclined surface 211 . The power line 27 is arranged to cover the last wound power line 27 in order. The power line 27 is wound four revolutions per a layer on the axle 22 . The space 28 contains the wound power line 27 .
The invention arranges the power line 27 in order without a complex mechanism, for example, a motor, a lead screw, and a bearing.
While the invention has been described by way of example and in terms of the preferred embodiments, it is to be understood that the invention is not limited to the disclosed embodiments. To the contrary, it is intended to cover various modifications and similar arrangements (as would be apparent to those skilled in the art). Therefore, the scope of the appended claims should be accorded the broadest interpretation so as to encompass all such modifications and similar arrangements.
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An arranging-line mechanism comprises a cam, an axle connecting to the cam, a sliding element and a transmitting mechanism to drive the cam and the axle. The cam comprises an inclined surface and the sliding element to slide thereon. When the axle revolves, the transmitting mechanism drives the cam to revolve. A power line is wound regularly via the sliding element to slide on the inclined surface.
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FIELD OF THE INVENTION
This invention relates to a vectorable nozzle for aircraft possessing vertical lift capability.
BACKGROUND OF THE INVENTION
In particular, the invention concerns aircraft possessing full or partial vertical lift capability in which a ducted gas stream is guided by means of a vectorable nozzle. A number of aircraft having this type of system have been built or proposed. Most notable of these is the British Aerospace HARRIER powered by a Rolls-Royce PEGASUS engine which has four swivellable nozzles to vector hot and cold engine gas streams to generate thrust vectorable between vertical and horizontal directions. The engine exhaust streams are permanently ducted through the four nozzles which contain fixed guide vanes and are disposed in pairs on opposite sides of the aircraft fuselage. A penalty of the nozzle arrangement is a relatively high level of drag since they protrude permanently into airflow over the fuselage.
A development of the vectorable gas stream concept has the main propulsion engine driving one or more lift fans which exhaust selectively through stowable nozzles. These nozzles are deployed when vectored thrust is required but are otherwise stowed behind covers to avoid parasitic drag during a normal flight mode. One of the nozzle designs for this concept has retractable nozzle ducting terminated by a cascade of movable parallel vanes which are turned each about its own longitudinal axis to achieve the vectoring range. A drawback with this type of arrangement remains aerodynamic drag caused by a deployed nozzle. In the proposed arrangement the nozzle is deployed to its fullest extent and the vanes are turned to achieve downwardly directed vertical thrust and to vector the thrust rearwardly in transition to horizontal flight. As a consequence drag forces created by the nozzle increase as forward speed builds-up until such times as the gas stream supply to the nozzle can be terminated and the nozzle retracted. The present invention has for one of its objectives to avoid this drag. For another object it seeks to reduce the weight of the nozzle by avoiding the use of vectorable guide vanes.
SUMMARY OF THE INVENTION
According to one aspect of the invention there is provided a vectoring nozzle comprising a telescoping duct arrangement having at its terminal end thrust deflecting means disposed to vector gas issuing from the duct in a substantially downward direction for vertical lift when the nozzle is extended and in a substantially rearward direction for forward thrust when the nozzle is retracted.
Preferably, the thrust deflecting vanes comprises a cascade of parallel guide vanes carried in a frame pivotally mounted towards its forward side.
According to another aspect of the invention the vectorable nozzle comprises a plurality of generally U-shaped shroud members interlocked one with another in telescoping manner, the U-shaped members being pivoted towards their open sides to a base member whereby said plurality of shroud members may fit one within another so as to telescope together to a stowed position for one mode of operation and to extend to a deployed position for a second mode of operation. The nozzle may be provided with actuation means whereby said plurality of shroud members may be telescoped together or extended.
Each of said plurality of shroud members may be provided with interlocking means whereby adjacent shroud members interlock together when said plurality of shroud members are extended.
The terminal shroud member may support the cascade array of guide vanes each of which vanes may be of the fixed or variable angle kind.
BRIEF DESCRIPTION OF THE DRAWINGS
For a better understanding of the invention a specific embodiment of the invention will now be described by way of example with reference to the accompanying drawings in which:
FIG. 1 is a schematic perspective view of a vectorable nozzle comprising a plurality of shroud members according to the invention, the nozzle being shown in the extended, or deployed, position,
FIG. 2 is a perspective view of one of the shroud members of FIG. 1,
FIG. 3 is a cross-sectional view of the vectorable nozzle shown in FIG. 1 taken along the plane of section line III--III of FIG. 1,
FIG. 4 is a cross-sectional view through three of the shroud members of FIG. 1 taken along the plane of section line IV--IV of FIG. 3,
FIG. 5 is a cross-sectional view of the vectorable nozzle shown in FIG. 1 taken along the plane of section line V--V of FIG. 1 but with the nozzle in the stowed position, and
FIGS. 6a and 6b show side view of an aircraft propulsion engine and lift fan installation illustrating the lift fan deflection nozzle in vertical lift and forward transition deployments respectively.
DETAILED DESCRIPTION OF THE INVENTION
Referring to the drawings a telescopic vectoring nozzle generally indicated at 1 comprises eight shroud members 2-9 each formed from a plurality of sheet metal sections as shown in FIG. 2. Each section consists of a pair of U-shaped side wall members 11,12 of wedge shape spaced apart by an end wall member 13. The upper edges 14,15 of side wall members 11,12 are rolled over to form outwardly directed elongated hook portions 16,17. The lower edges 18,19 are rolled over to form inwardly directed elongated hook portions 21,22. As can be seen in FIG. 4 the outwardly directed portion 16,17 on the upper edge of one side wall member 11,12 interlockingly engage the inwardly directed hook portion 21,22 on the lower edge of the adjacent side wall member when the nozzle is deployed. When the nozzle is in its stowed position the hook portions 16,17 of one side wall member are disengaged from the hook portions 21,22 of the adjacent side wall member and merely make sliding contact with the surface of the adjacent side wall member. A similar interlocking arrangement is provided on the end wall members 13 where outwardly directed elongated hook portions 23 on the upper edges of the end wall members 13 engage inwardly directed elongated hook portions 24 on the lower edges of the end wall members 13.
An aperture 25 is provided in each side wall member 11,12 adjacent the tip 26 of the wedge shape, in order that a pin 27 may be extended through the apertures. The pin 27 is secured at its ends 28,29 to the surrounding airframe 31 and acts as a hinge pin about which the shroud members 2-9 rotate.
The innermost shroud member 9 supports a frame 32 which is apertured at 33 to receive the pin 27 so that the frame 32 may also rotate with the shroud members 2-9. The frame 32 is provided with a hook portion 34 extending along its upper edge for engagement with the lower hook portion 21 on the side wall member 11. An array of guide vanes 35 is carried in the frame 32. The guide vanes 35 are fixed transversely in the frame 32 at an angle which ensures that when the nozzle is deployed, ie the shroud members 2-9 occupy the positions shown in FIG. 3 (and in FIG. 6a), air issuing through the nozzle is directed vertically downwards to develop vertical lift. When the nozzle is in the stowed position as shown in FIGS. 5 and 6b, ie the frame is flush with the airframe, the air stream is vectored rearwardly by the nozzle to generate forward transition.
Each shroud member 2-9 may be provided with a pair of inwardly directed pins 36,37 one in each side wall member 11,12. These are engaged on their undersides by the upper edges of the adjacent lower shroud member or, in the case of the lowest shroud member 9, by the upper edge of the frame 32, when the nozzle is being retracted from the extended position shown in FIG. 3 to the stowed position shown in FIG. 5.
The sides of the frame 32 are each provided with an upwardly directed bracket 38,39 to each of which is connected the end of an actuator rod 41,42 extending from the body 43,44 of a nozzle actuator jack which is extendable to displace the nozzle from the stowed position into the deployed position.
In operation, in order to deploy the nozzle from the stowed position shown in FIG. 5 the actuator rods 41,42 are extended. The frame 32 rotates until the hook portions 16,17 on the top edges of the frame engage the hook portions 21,22 on the bottom edges of the shroud member 9 interlock. Continued extension of the piston rods causes the hook portions 16,17 on the top edge of the shroud member to engage the hook portions 21,22 on the bottom edges of the shroud member 8, and so on until all of the shroud members have been extended to the deployed position shown in FIG. 3. The hook portions 23,24 on the upper and lower edges of the end walls 13 engage one another and interlock in a similar manner as nozzle deployment takes place.
When the actuator rods 41,42 are retracted into actuator housings 43,44 the frame 32 is drawn upwardly disengaging the interlocking hook portions of the frame and shroud members. Engagement of the pins 36,37 by the upper edge of the ascending lower shroud member or frame ensures that the members and frame retract telescopically as shown in FIG. 5.
The frame carrying the array of guide vanes is hinged to the airframe at the forward end of the frame and may be of any shape to match the ducting within the airframe which supplies the exhaust gas or air to the nozzle. The frame must however, be capable of interfacing with the innermost of the shroud members.
The interlocking of the shrouds prevents the gas or air stream spilling over the sides of the frame, and being lost when the frame is moving to the interlocked deployed position. The depth of each shroud member is dictated by the space available in the airframe.
FIGS. 6a and 6b show a possible disposition of propulsion engine 50, lift fan module 52, drive shaft 54 and lift fan deflection nozzle 1. The propulsion engine 50 may exhaust into a jet pipe 56 provided at its downstream end with a further deflection nozzle 58. This second deflection nozzle is not a concern of the present invention. The drive shaft 54 may include a clutch mechanism (not shown) for selectively transmitting drive from propulsion engine 50 to lift fan 52. Air is drawn into fan 52 through an intake aperture 60 in the upper surface of the aircraft fuselage 62 and exhausted generally downwardly through an exit aperture 64 in the underside of the fuselage. Exit aperture 64 may be closed by doors 66.
The vectoring deflection nozzle 1 is mounted below fan 52 adjacent exit aperture 64 and when deployed, as shown in FIG. 6a, extends through the aperture. When the nozzle 1 is telescopically retracted and the fan stopped the upper and lower doors 66,68 may be closed to lie flush with the fuselage skin.
The deflection nozzle 1 has two operating positions shown in FIGS. 6a and 6b respectively. In the first in FIG. 6a the telescoping part of the nozzle is fully extended and the angle guide vanes deliver the lift fan exhaust substantially undeflected in a downward direction. Although the guide vanes frame is deployed at an angle relative to the fan axis the guide vanes themselves are angularly disposed relative to the frame such that downwardly directed fan air continues in the same direction. Although in this fully deployed position the nozzle aerodynamic drag factor is at a maximum value, the vertical lift operational mode means that aircraft forward speed is low or tending towards zero. Thus, drag forces generated by the fully deployed nozzle are correspondingly low or inconsequential.
For the transition to forward flight thrust from the lift fan 52 is vectored rearwardly. To do this the telescoping members of nozzle 1 are retracted so that the guide vane frame 32 lies within the exit aperture in the underside of fuselage 62. In this position the fixed disposition of the guide vanes themselves alter the direction of the fan exhaust air in a rearward direction as shown by the arrows in FIG. 6b. The rearwardly vectored air generates forward thrust (towards the left in the plane of the drawings) and accelerates the aircraft in a forward direction. However, as aircraft speed increase nozzle drag is virtually absent because no part of the nozzle (closure doors 66 excepted) extend into the airstream. Once sufficient forward speed is achieved the fan drive shaft 54 is declutched, the fan runs down and the closure doors 66,68 are closed. The present nozzle arrangement possess a further inherent advantage of minimum weight because the nozzle guide vanes are fixed and need no variable camber or variable angle-of-incidence mechanism to achieve vectoring.
It will be appreciated that the deflecting nozzle of the present invention may be used to vector a gas stream however the flow in that stream is produced. Thus, although in the example described the flow is produced by a shaft drive lift fan, the fan could be gas driven in another example. The flow might also be produced by a gas turbine engine directly either by in the form of a direct lift engine or by a conventional propulsive engine with ducted gas streams.
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A vectorable nozzle for a vertical lift aircraft comprising an array of lift flow deflecting vanes mounted in a frame hinged to an undersurface of the aircraft. The nozzle is formed by a plurality of telescopic shroud members which together with the vane frame are mounted at their forwardmost ends. The disposition of the vanes is such that the lift flow is directed downwards when the nozzle is extended. When the nozzle is retracted the flow is vectored rearwards to provide forward thrust. In this position the nozzle generates minimum aerodynamic drag from forward movement of the aircraft. The nozzle preferably is fully stowed within the aircraft, and concealed by surface doors when not in use.
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BACKGROUND OF THE INVENTION
The present invention relates to a loop lifter, and more particularly to a loop lifter for continuous strip rolling mills.
In continuous strip rolling mills the rolled strip forms pendant loops between successive roll stands. For manufacturing reasons it is necessary to maintain these loops at a certain height and to maintain the strip tension as low and as constant as possible. For this purpose it is known to provide so-called loop lifters which engage the pendant loops from below and exert upwardly directed support for them. Such loop lifters have a pivotable arm provided at one end portion thereof with a so-called loop-lifting table in which a roll is journalled for free pivotable turning about a horizontal axis; it is this roll which engages the loop from below. The arm is made to pivot upwardly so that the roll engages the loop from below, by means of a drive. The construction of the drive is determined by three factors, namely the moment required for compensating the inherent weight of the loop lifter itself, the moment required for compensating the weight of the loop as it is pendant between two successive roll stands, and the moment required for compensating the strip tension. It is readily appreciable that the moment required to compensate the inherent weight of the loop lifter amounts to a substantial portion of the drive moment required for effecting the upward pivoting of the arm.
One known construction of a loop lifter utilizes a lever or arm which is pivotable in a fixed pivot point and which carries the aforementioned roller for engaging the loops from below. It is also known to provide a loop lifter in which an attempt has been made to reduce the swing moment of the loop lifter by mounting the roll not in a pivotable arm, but instead in a carriage which can be moved in vertical guides. In all prior-art loop lifters the engagement of the roll with the respective loops is effected either by means of hydraulic cylinders, pneumatic cylinders for electric motors which pivot the arm or move the carriage. To avoid fluctuations in the strip tension, which causes variations in the thickness and width of the strip being formed, the swing moments of the loop lifter itself, and the drive for the loop lifter, must be maintained as small as possible. Small swing moments for the drives can be obtained if hydraulic or pneumatic drives are used, but the exact regulation of the drive torque is possible in these types of drives. If an electric motor is used to drive the loop lifter, then the drive torque can be regulated very exactly but, on the other hand, the swing moments of the drive, particularly if a transmission is arranged between the motor and the loop lifter, are very substantial.
Another proposal that has been made in the art is to reduce the motor torque in loop lifters which utilize electric motors for their drive, by compensating for the weight of the roll and the arm carrying the same via a counterweight. Although this does not reduce the motor torque, it does not reduce the total swing moment and this measure is therefore also not fully satisfactory.
SUMMARY OF THE INVENTION
It is, accordingly, a general object of this invention to avoid the disadvantages of the prior art.
A more particular object of the invention is to provide a loop lifter for use in strip-rolling mills in which the torque of the loop lifter drive is reduced.
Still more particularly, an object of the invention is to provide a loop lifter of the type mentioned above in which the reduction of the loop lifter drive torque does not result in an increase of the swing moment of the loop lifter components.
Still a further object of the invention is to provide a loop lifter of the type outlined above which permits the use of smaller drive motors which, in turn, leads to a reduction in the cost of manufacture and sale of such equipment and in a concomitant reduction in the energy requirements for operating this equipment.
Pursuant to the above objects, and to others which will become apparent hereafter, one aspect of the invention resides in a loop lifter for continuous strip rolling mills in which the strip forms pendant loops, such loop lifter comprising, briefly stated, a support, an elongated arm, and a shaft journalling the arm in the support for pivotal movement about a substantially horizontal first axis so that one end portion of the arm can bear from below against a respective loop and lift the same. Further, there is provided counter balance means including a spring reacting between the one end portion of the arm and a stationary abutment. This counter balance means counter balances the weight acting upon the one end portion, such that during pivoting of the one end portion between 0° and 90° of arc no free torque is present at and acts upon the shaft.
It is advantageous if the spring is connected to a lever which is mounted on the shaft outside the confines of the support and which can turn with but not relative to the shaft. A particularly advantageous construction is obtained if the spring constitutes part of a separate unit or aggregate which is mounted adjacent to the loop lifter in a separate frame and which is connected with the loop lifter via an appropriate coupling.
It has also been found to be advantageous if the distance of the fixed pivot for the spring from the axis of rotation of the shaft journalling the arm equals the length of the lever which is mounted outside the confines of the support and to which the spring is connected.
A currently preferred embodiment of the invention proposes for the spring to be mounted in a hollow cylinder through one end of which a slidable rod extends which carries at its inner end an abutment, the spring surrounding the rod within the cylindrical housing and bearing with its opposite ends against the abutment and the aforementioned one end of the housing. This one end, incidently, is advantageously of bifurcated configuration.
A loop lifter constructed in accordance with the present invention reduces the torque of the loop lifter drive and permits the use of smaller drive motors. This, in turn, results in a not insignificant reduction of the costs for constructing the loop lifter and also in a corresponding advantageous reduction in the energy costs required for operating the loop lifter. In addition, it should be noted that the prior-art loop lifters can be readily converted to the construction according to the present invention if it is desired to save energy, since the spring respectively the spring unit can be readily installed in such existing devices. There is also the fact that the spring respectively the spring unit is located outside the immediate surroundings of the strip passage, i.e. the path in which the strip travels, so that it can be readily serviced.
Embodiments of the invention will hereafter be described with reference to the appended drawings. It should be understood, however, that these are merely exemplary in nature and that the inventive scope for which protection is being sought is defined exclusively in the appended claims.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a somewhat diagrammatic top-plan view illustrating a loop lifter according to the invention;
FIG. 2 is a side view of the loop lifter of FIG. 1;
FIG. 3 is a section taken on line III--III of FIG. 1;
FIG. 4 shows the same section as in FIG. 3, but with the roll of the loop lifter pivoted through 90° in upward direction; and
FIG. 5 is a top-plan view illustrating another embodiment of the invention.
DESCRIPTION OF PREFERRED EMBODIMENTS
A first embodiment of the invention is illustrated in FIGS. 1-4, wherein the loop lifter is identified with reference numeral 1. It is composed of two laterally spaced supports 2, 3 in which a shaft 4 is journalled which constitutes a fixed pivot for the arm carrying the so-called lifting table 5 which is pivotally mounted on the shaft 4 and which is provided, at a free end remote from the shaft 4, with a roll 6 that is turnably journalled in the table 5 for free turning movement about a diagrammatically illustrated axis 6a that extends parallel to the axis 4a of the shaft 4. The spacing of the supports 2, 3 substantially to the width of the table 5. The drive for pivoting the table 5 about the axis 4a into and out of engagement of the roll 6 with the not illustrated pendant loops of roll strip, is not illustrated because it forms no part of the invention and is known per se in the art.
A plate 7 is secured to the support 3, spaced therefrom in the direction of the axis 4a and the shaft 4 extends not only to the support 3 but also to the plate 7 and in fact outwardly beyond the same. Pivots 8 and 9 are mounted in the support 3 and the plate 7, in axial alignment with one another and in parallelism to the axis 4a of the shaft 4. These pivots or pins 8 and 9 serve as the journals and fixed pivot point in the support 3 and plate 7 for the bifurcated end portion 10 of a spring cylinder unit 11 (see particularly FIG. 3) having a slidable rod 12 which extends into the interior of the unit 11 through the end portion having the end 10 and which is provided in the interior with an abutment 12a. The spring 19 surrounds the rod 12 within the unit 11 and bears upon the abutment 12a and the end portion 10, respectively.
A lever 13 of bifurcated configuration (see particularly FIG. 1) is mounted on that portion of the shaft 4 which extends outwardly beyond the support 3, i.e. it is mounted intermediate the support 3 and the plate 7. The bifurcated lever 13 is connected to the shaft 4 (in a manner known per se from the prior art) so that it can turn with but not relative to the shaft 4. The outer end portion of the rod 12, i.e. the one which projects outwardly of the unit 11 past the end 10 thereof, is identified with reference numeral 14 and is configurated as an eye so that it can be turnably connected to the free end of the lever 13 by means of a bolt or a similar element 15.
The embodiment in FIG. 5 differs from the one in FIGS. 1-4 only in that the spring unit 11 is not mounted to the support 3 and the plate 7, but instead in a separate frame 16 which is located laterally of the supports 2, 3 and table 5. This frame 16 is provided with a shaft 17 on which the lever 13 is mounted in the same manner as it was connected to the shaft 4 in FIGS. 1-4, i.e. so that it can turn with but not relative to the shaft 17. The shaft 17 is in axial alignment with the shaft 4 and a coupling 18 (known per se in the art) is provided by means of which the two shafts 4 and 17 can be coupled for joint rotation or can be disengaged from one another. All other components are the same in FIG. 5 as in FIGS. 1-4 and therefore have the same reference numerals and the same functions.
In FIG. 2 the table 5 is shown in its inoperative horizontal position, as it is in FIG. 3 in broken lines, and in FIG. 4 it is shown in its vertically pivoted position; it is this position in which the roll 6 is displaced through 90° relative to the position in FIGS. 2 and 3, or any position intermediate the position of FIG. 4 and the positions of FIGS. 2 and 3, in which the roll 6 engages a respective loop from below and lifts it upwardly.
The spacing of the axis 8a-9a on which the two pivots 8 and 9 are aligned (both in the embodiment of FIGS. 1-4 and the embodiment of FIG. 5) from the axis 4a of the shaft 4 or, in FIG. 5, the axis 17a of the shaft 17, is equal to the distance from the pivot point of the end portion 14 at the lever 13 to the axis 4a of the shaft 4 respectively the axis 17a of the shaft 17. Due to this choice of distances, and the fact that the end portion 10 of the unit 11 is bifurcated, the free end of the lever 13 can, in response to a turning movement of the lever 13 through 90° in the direction towards the unit 11, enter with the bolt 13 and the end portion 14 of the rod 12, far enough into the bifurcated end portion 10 of the unit 11 that the pivots 8 and 9 move into axial alignment with the bolt 15. This assures that in case of the relaxation of the compensating spring 19 in the unit 11 from a maximum spring force (required for balancing the weight of the table 5 and roll 6 in the horizontal position of FIGS. 2 and 3) to the value 0 when the table 5 and roll 6 are pivoted through 90° upwardly to the position of FIG. 4, the weight of the table 5 and the roll 6 is fully compensated in any position which these two components can assume intermediate a zero degree of arc position (FIGS. 2 and 3) and the 90° of arc position (FIG. 4).
Although the invention has been described with reference to two exemplary embodiments it is to be understood that this is only for purposes of explanation and that the scope of protection sought for the invention is determined exclusively by the appended claims following hereafter.
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A loop lifter for continuous strip rolling mills has an arm which is journalled in a support for pivotal movement about a horizontal axis. An end portion of the arm carries a freely turnable roll which can engage a loop from below and lift it upwardly. A counter balancing spring reacts between a fixed pivot and the arm and assures that the pivot shaft for the arm is not subject to any free torque during pivoting movement of the arm between 0° and 90° of arc.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to stoves and furnaces, and more particularly to portable heating apparatus that include in combination knockdown and separable cooking and warming racks.
2. Description of the Related Art
Humans have several basic needs, including food, water, and a suitable environment. All three of those basic needs become much more difficult to find during winter months in areas outside of the tropics. With that in mind, humanity has found and created various forms of radiant heat, fueled by gas, electricity, wood, coal, and other sources of energy. The radiant heat has been used to warm a living space, food, water and for many other purposes.
Apparatus for producing heat include but are not limited to fires, furnaces, heaters, radiators, stoves, microwaves, ovens, grills, and the like. Many of the structures are large and bulky, and require large amounts of set-up. While this is of less concern with permanent structures such as a residence or home, such apparatus are poorly suited for temporary use and outdoor activities such as ice fishing or camping that would require transporting and setting up the heat apparatus. In such instances, it is far more desirable to have a relatively compact and readily transportable apparatus, such as a camp stove, space heater, recreational fireplace, and the like. Countless examples of such apparatus are found in the prior art.
Since fishermen, campers and other outdoor enthusiasts have to transport gear to and from each temporary location where they will spend time, the size, weight, and number of functions that a single apparatus can reliably perform are each very important. As a result, and whenever possible, any gear or apparatus will desirably serve as many purposes as possible, to decrease the amount of gear necessary to be transported.
One way this may be achieved is by using a heat source such as a campfire or portable heater to also warm or cook food or water. Common apparatus suspend food or a cooking mechanism over or adjacent to a heat source. For less portable devices, pots and pans have been suspended on burners, racks, grills, and the like. One method of cooking has involved using racks or girds over a heat source, such as a stove or in an oven. For example, U.S. Pat. No. 6,945,245 to Wilson, entitled “Trivet Oven Rack”, discloses an oven rack which is self-supporting on the bottom of an oven. Similarly, U.S. Pat. No. 2,376,640 to Wall et al, entitled “Combined Oven Tray and Cooking Rack”, discloses a tray for use in an oven. The Wall et al tray has a cooking rack incorporated with it, allowing for cooking on the rack while catching any drippings. The cooking rack has the additional feature of an adjustable portion which forms a “V” shape ideal for roasting a chicken. Though ideal for use in combination with a fixed stove or oven, these apparatus have not been designed to operate with a more lightweight and portable heat source.
For more portable cooking, a different design of rack is necessary. One such example is U.S. Pat. No. 3,416,510 to Paulson, entitled “Camp Stove Toaster”. The camp stove toaster disclosed is a rack which supports a piece of bread for toasting suspended over a cylindrical member which directs the heat from a camp stove to toast the bread. Similarly, U.S. Pat. No. 7,445,004 to Milner et al., entitled “Campfire Grill Assembly”, is a grill designed for use in combination with a campfire. Another approach to campfire cooking is seen in U.S. Pat. No. 3,067,737 to Brown, entitled “Reflector Oven”, which discloses a rack for cooking next to a campfire, which has radiant heat focused onto it by reflector panels. U.S. Pat. No. 1,999,515 to Muenzer, entitled “Camp Stove”, also discloses a cooking device for combination with a campfire. This device uses the fire as the heat source for a combination stove and garbage disposal system, with grill racks along the top and a portion adjacent to the fire ideal for warming food or baking food, such as potatoes. Another rack is illustrated in U.S. Pat. No. 2,597,127 to Rahr, entitled “Toaster”. Rahr's toaster focuses heat through a series of slits toward racks, which are angled inward. Such racks hold pieces of bread and provide for even toasting of several pieces of bread at once. While all are effective, they are not ideal in all environments and surroundings. Campfires do not work when there is a higher risk of fire spreading, when there is a potential for there not being available firewood or that the firewood is wet, when in an enclosed shelter, or in other instances.
Other devices have been designed with the intention of making portable heating apparatus dual purpose. One exemplary approach to creating a dual-purpose radiant heat and cooking apparatus is found in U.S. Pat. No. 3,280,813 to Schaenzer, entitled “Space Heater Converter for Cooking Stove”, which illustrates a cover for a typical camp stove. The cover has a “multiplicity of small, spaced apertures or perforations which are designed to disperse the heat of the stove laterally outwardly and more or less uniformly throughout a room, in contrast to the straight-upwardly path followed by the heat normally emitted by the stove.” In other words, the cover converts a typical camp stove into a space heater. While functional, the camp stove can only be used in one function at a time, making it less convenient and less efficient.
A similar concept is found in a combination space heater and grill. U.S. Pat. No. 2,422,450 to Van Daam, entitled “Combined Space Heater and Grill” discloses an electric heater which heats air drawn in through an inlet on the bottom and expels the warm air out a vent along the top edge. The directionality of the vent causes the warm air to move outward across a space in such a manner as to warm an entire room. The heater additionally has a door along the front side which, when opened, pulls the heating element into a horizontal position which allows for its use as a grill. Such an embodiment poses the distinct problem that any food drippings land on the heating element. During later use as a space heater, the odor of the further cooking or burning of the drippings would spread throughout the space being heated. Additionally, such a design limits the structure to one function at a time, decreasing the usefulness of the apparatus.
Additional combination grilling apparatuses and space heaters are illustrated in the patents. One such apparatus is found in U.S. Pat. No. 3,935,809 to Bauer, entitled “Grilling Apparatus Usable as a Space Heating Means”. Bauer's patent discloses “a grilling apparatus with a heating arrangement . . . [which] has a vertically a vertically arranged heating plane.” With the grill closed, the vertically arranged heating plane warms the entire interior, allowing for cooking food. However, with the grill hood open and the front wall swung open, the vertically arranged heating plane projects the heat towards the space in front of the grill, much like a traditional space heater. Another example is seen in U.S. Pat. No. 3,547,097 to Rice et al., entitled “Gas Infra-Red Burner Construction”. The burner construction has “ceramic plate material on one face . . . [with] a large number of small perforations throughout its thickness.” The ceramic plate is heated by a fuel-air mixture which moves through the perforations and burns at the surface of the plate. The heat from the ceramic plate emanates as infrared radiation, allowing for heating the air or grilling food, depending upon the angle at which the burner structure is angled. Unfortunately, both such structures are similarly only functional in one capacity at a time and lack true compact portability. In addition, while the drippings do not land on the heating elements, the grill portion is necessarily combined in the same space as the heater, posing a similar issue with odors at later points in time.
Some have designed heaters with exterior racks for cooking. For example, U.S. Pat. No. 3,139,879 to Bauer et al., entitled “Gas Burning Heaters”, illustrates a design similar to a camp stove which emits radiant energy and can be oriented to provide a rack across the top for supporting the object to be heated or cooked. Similarly, U.S. Pat. No. 3,326,265 to Paulin, entitled “Radiant Heating Means”, provides a heating design with a grill structure across the top. Paulin's radiant heating device has rotating braces which can be used to suspend the heating device, brace it at such an angle as to send the heat upward and outward throughout a space, or place the grid facing upward as necessary for cooking. This ideal structure would be difficult to adjust during use due to the temperature of the surfaces, making it difficult to transition from using it suspended or braced at an angle to using it for cooking.
Portable heaters with more focused heat which could be used for cooking are also illustrated in the prior art, including U.S. published patent application 2007/0269758 to Hofbauer et al., entitled “Radiant Burner”; and U.S. Pat. No. 3,513,822 to Korngold, entitled “Space Heaters”.
Heaters with racks that rotate into place are also illustrated in the prior art. U.S. Pat. No. 3,085,350 to Waters, entitled “Portable Heater”, works with a portable heater and a rack structure, which allows for heating objects which can be draped over the bars, such as socks for warming or drying. U.S. Pat. No. 3,199,504 to Morin, Jr. et al, entitled “Dual Purpose Space Heater”, illustrates a wall-mounted space heater with a tray that flips open, allowing for a stand or tray to be placed directly under a heat vent, allowing for the warming of food or beverage. Unfortunately, the device is not transportable, limiting its application in outdoor activities.
U.S. Pat. No. 2,332,117 by Shepherd, entitled “Cooking grid or shelf”, is exemplary of racks that have been designed to be suspended from pans or other cooking utensils.
Each of the patents referenced herein above is expressly incorporated herein by reference for the teachings that they individually and collectively provide relevant to the present invention. Webster's New Universal Unabridged Dictionary, Second Edition copyright 1983, is also incorporated herein by reference in entirety for the definitions of words and terms used herein.
SUMMARY OF THE INVENTION
In a first manifestation, the invention is, in combination, a portable space heater and a compact and collapsible rack. The combination heater and rack has a first operative position providing a support surface on said rack for warming and heating articles placed thereon, and a second stowed position for transport. The portable space heater comprises a body, a heating element supported within the body, and a protective grid shielding the heating element from accidental contact. The protective grid defines a first surface and a second surface, with the first surface relatively more adjacent to the heating element than the second surface, and the second surface of the protective grid relatively more distal to the heating element than the first surface of the protective grid. The rack comprises a main support surface and a leg assembly coupled with and moveable relative to the main support surface. The leg assembly has at least one leg member. In the second stowed position, the leg assembly is folded adjacent to the main support surface, and in the first operative position extends generally perpendicular thereto. A bifurcation on the leg member is located distal to the main support surface. The rack in first operative position is coupled to the protective grid, with the main support surface suspended and engaging therewith. The leg member, at a transition location intermediate the bifurcation and main support surface, passes through the protective grid. The bifurcation is also coupled to the protective grid, and has a first bifurcation member extensive on the first surface of the protective grid and a second bifurcation member extensive on the second surface of the protective grid, the first and second bifurcations capturing the protective grid therebetween.
In a second manifestation, the invention is a method of stowing, transporting, and assembling a rack with a portable space heater.
OBJECTS OF THE INVENTION
Exemplary embodiments of the present invention solve inadequacies of the prior art by providing a compact and collapsible rack that may be folded, stored and transported adjacent with, in the outline of, and supported by a portable space heater. When at a location where food warming or cooking is desired, the rack may be removed from the storage position, unfolded, and coupled to a wire grid found on the face of the portable space heater. The wire grid is commonplace in the art of portable heaters, and serves to protect against accidental contact with the heating element. The rack positively engages with this wire grid in such a way as to prevent the rack from collapsing, even when impacted with substantial force. As a result, the rack will safely support food or beverage. Owing to the placement, food or beverage is much less likely to contaminate the heating element.
A first object of the invention is to expand the utility of portable heaters having protective grids to facilitate warming or cooking foods and beverages. A second object of the invention is to provide this expanded utility with a relatively low cost rack. Another object of the present invention is to maintain the safety features of the portable heater and avoid contamination of the heating element. A further object of the invention is the provision of a rack that will couple with many diverse protective grids, allowing the rack to couple with different models and sizes of heaters without requiring change. Yet another object of the present invention is to facilitate the stowing and transport of the rack within the confines and preferably outline of the portable heater. An additional object of the invention is the provision of a rack geometry which is simple in construction, and also simple and apparent in the coupling to portable heaters.
BRIEF DESCRIPTION OF THE DRAWINGS
The foregoing and other objects, advantages, and novel features of the present invention can be understood and appreciated by reference to the following detailed description of the invention, taken in conjunction with the accompanying drawings, in which:
FIGS. 1-3 illustrate an exemplary prior art portable gas heater suitable for use in the present invention from front side and back views, respectively.
FIGS. 4 and 5 illustrate a first preferred embodiment rack designed in accord with the teachings of the present invention from top and side views, respectively.
FIG. 6 illustrates the first preferred embodiment rack of FIGS. 4 and 5 in operative combination with the portable gas heater of FIGS. 1-3 from side plan view.
FIG. 7 illustrates the first preferred embodiment rack and protective grid of FIG. 6 by enlarged side view.
FIG. 8 illustrates an alternative embodiment rack designed in accord with the teachings of the present invention from view.
FIGS. 9 and 10 illustrate a second alternative embodiment rack designed in accord with the teachings of the present invention from side and top views, respectively.
FIGS. 11 and 12 illustrate the first preferred embodiment rack of FIGS. 4 and 5 in stored combination with the portable gas heater of FIGS. 1-3 from side plan view.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Manifested in the preferred embodiment, the present invention provides a warming rack 10 for use in combination with a prior art portable gas heater 1 , such as may typically be used by outdoors enthusiasts. The specific style of space heater 1 may vary, though the most preferred prior art portable gas heater 1 is illustrated in FIGS. 1-3 . Portable gas heater 1 has an upright body 2 which is readily transported by grasping handle 3 , found along the top edge of body 2 , and lifting. In the most preferred embodiment, portable gas heater 1 is an upright device, with heater 4 centrally located in the body 2 of the gas heater 1 . As can be seen, heater 4 releases warm air and radiates heat out of the portable gas heater 1 through the side of the upright body, with a protective grid 5 preventing contact with and burns from heater 4 . Protective grid 5 further prevents accidental damage to heater 4 , and greatly reduces the risk of catastrophic fire.
For storage purposes or for improved heating in a specific loci, the portable gas heater body 2 also has raised, hollow securing tabs 6 with a cut-out 7 sized to allow a screw, nail, hook, or other protruding fastener to be inserted. Most preferably, cut-out 7 is larger at the bottom, allowing for a fastener with a larger head to be inserted and secured below the head by the smaller design of the top portion of the cut-out 7 .
FIGS. 4 and 5 illustrate a preferred embodiment rack 10 , separated from portable space heater 1 , and laid flat for illustrative purposes. Rack 10 has two main members, main support surface 15 and a leg assembly having individual legs 11 and cross-members 14 . These two members are pivotally coupled together, allowing the leg assembly to rotate relative to main support surface 15 . While main support surface 15 and the leg assembly are each illustrated herein as a wire rack forming a generally rectangular grid, for the purposes of the present invention this will be understood to be merely illustrative. Any suitable materials may be used in the fabrication thereof, and the selection thereof may substantially alter the visual appearance. Exemplary constructions, though not limiting only thereto, include expanded metal, sheet stock that may be solid or perforated, wire rack as illustrated, and any other suitable constructions that will be apparent to those of skill in this art upon a reading of the present disclosure. Wire has been illustrated for preferred embodiment rack 10 , owing to the combination of low weight, low cost, ease of fabrication, visual appearance, and ready passage of heat. However, other materials and techniques may be used and are encompassed by the present invention.
Since individual legs 11 are separated by less than the width of main support surface 15 , stops 16 may be provided to keep legs 11 located properly relative thereto. These stops 16 may simply be enlarged regions, or may be any other suitable structure or hardware which will prevent legs 11 from moving beyond the stops.
Main support surface 15 may optionally be provided with vertical extensions 18 that, in this preferred embodiment rack 15 , are simply folds in the body of the wire rack that extend out of the plane defined generally by main support surface 15 . Optional protrusions 19 may also be provided, which facilitate even resting and stabilize rack 10 by providing two spaced points of contact with heater 1 . In the event that heater 10 is rounded, a straight rack will only contact at one point, and will seem wobbly. These protrusions will ensure two spaced points, and will not wobble so much.
Most preferably, vertical extensions 18 will engage with heater 1 , and more specifically or additionally may engage with protective grid 5 . In the case that vertical extensions 18 do engage with heater 1 , additional support and stabilization is provided to rack 10 by pins 17 , which are positioned in such a manner as to engage with the protective grid 5 . However, there are many different styles of portable heaters, and in some instances vertical extensions 18 of the preferred embodiment rack 10 might not couple with such a heater. In such instances, pins 17 are the main method of coupling. Consequently, any number of pins 17 may be used along cross-members 14 and the main support surface 15 in a pattern desirable for to couple with a wide array of portable space heaters.
Main support surface 15 in the preferred embodiment runs parallel to the earth, pivoting at legs 11 . The pivot of legs 11 allows legs 11 to swing down toward protective grid 5 for engagement therewith. Bifurcated legs 11 are unfolded and coupled to protective grid 5 by intertwining the bifurcation members 12 , 13 with protective grid 5 in such a way as to prevent the rack 10 from collapsing, even when impacted with substantial force.
This engagement is illustrated in FIGS. 6 and 7 , with legs 11 wrapping behind a crossbar of protective grid 5 and arcing away from heater 4 to enable the longer first bifurcation member 12 to connect with the side of protective grid 5 closest to heater 4 and the shorter second bifurcation member 13 to engage with the opposing side of protective grid 5 . Such a design allows for relatively secure connection between legs 11 and protective grid 5 . If force is applied to the preferred embodiment rack 10 towards heater 1 , the shorter second bifurcation member 13 and the weaving of legs 11 into the protective grid will brace rack 10 against protective grid 5 , preventing dislocation. Force applied away from heater 1 will be offset by the first, longer bifurcation member 12 and the weaving of legs 11 through protective grid 5 . Upward force alone likewise cannot displace legs 11 due to the interlacing of legs 11 through protective grid 5 , created by the arcing of legs 11 . Furthermore, downward pressure only further secures the preferred embodiment rack 10 against protective grid 5 , with more pressure being applied at the mating of bifurcated legs 11 and protective grid 5 . Moreover, legs 11 fit within the confines of the vertical bars of protective grid 5 , preventing warming rack 10 from sliding on the horizontal plane as well.
Alternatives to the preferred embodiment warming rack 10 are illustrated in FIGS. 8 and 9 . The first preferred alternative embodiment warming rack 20 of FIG. 8 illustrates a slightly convex main support surface 25 , providing an alternative support for heating individual food items, such as burritos, hot dogs, tacos, or any other variety of food. Additionally, first preferred alternative embodiment warming rack 20 illustrates a hooked longer bifurcation member 23 for more secure engagement with the protective grid 5 . The trade-off, as may be apparent, is more difficult initial engagement of legs 21 .
The second preferred alternative embodiment warming rack 30 of FIG. 9 is very similar to the preferred embodiment warming rack 10 of the present invention. The second preferred alternative embodiment warming rack 30 varies in that it does not have vertical extensions 18 . Rather, the warming rack 30 of FIG. 9 engages with the heater 1 and the protective grid 5 solely using pins 37 to mate with protective grid 5 .
Moreover, the second preferred alternative embodiment warming rack 30 has legs 31 which are pivotally attached to the cross-members 34 at a span equal to that of the cross-members 34 , eliminating the need for stops 16 . The preferred embodiment legs 31 angle inward as one gets more distal to main support surface 35 , with the end result being a narrower span that enables legs 31 to mate with the protective grid 5 within the confines of the vertical bars of protective grid 5 .
As may be apparent, a number of different embodiment racks have been illustrated herein. These illustrate the desired functional characteristics that are most preferred in the present invention. However, upon review, those skilled in the art will recognize that other geometries may be used to attain the same functional results. For exemplary purposes, the legs 11 , 21 , and 31 are illustrated as terminating in bifurcations 12 , 13 , 22 , 23 , and 32 , 33 . However, the bifurcation members 12 , 22 , and 32 could optionally be removed and the embodiments would still function. Since these bifurcation members provide stability when a rack is accidentally bumped or jostled, legs 11 , 21 , and 31 would preferably be redesigned to have a hairpin-type bend or other bends that would engage with and help prevent motion relative to protective grid 5 , such as at the transition point where the legs pass through grid 5 or at other suitable location. Such alterations are considered to be incorporated herein, though somewhat less preferred.
FIGS. 11 and 12 illustrate preferred embodiment rack 10 in a second stowed position in combination with portable space heater 1 . As may be seen from the illustrations, rack 10 is preferably designed and dimensioned to hang from securing tabs 6 , and is secured therewith using hook fastener 41 and strap 42 that has loops to engage with hook fastener 41 . While a hook and loop fastening system is illustrated, it will be apparent that any other type of hardware may be utilized as known from the art of hardware, buckles and fasteners. In this stowed position, rack 10 fits either primarily or alternatively entirely within the outer profile of heater 1 , which adjacent is defined by securing tabs 6 . While as illustrated rack 10 is only primarily within the outer profile, the dimension of members 18 may be decreased and sufficient gap provided between wires on main support surface 15 to permit securing tabs 16 to pass through main support surface 15 . This way, when stowed, securing tabs 6 would protrude farther than rack 10 .
While the foregoing details what is felt to be the preferred embodiment of the invention, no material limitations to the scope of the claimed invention are intended. Further, features and design alternatives that would be obvious to one of ordinary skill in the art are considered to be incorporated herein. The scope of the invention is set forth and particularly described in the claims herein below.
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A portable space heater is combined with a compact and collapsible rack that may be folded, stored and transported adjacent with, in the outline of, and supported by the portable space heater. The rack may be removed from the storage position, unfolded, and coupled to a protective grid found on the face of the portable space heater. The rack positively engages with this grid using bifurcated legs that swivel about a main support surface. The bifurcated legs intertwine with the protective grid in such a way as to prevent the rack from collapsing, even when impacted with substantial force. The main support surface of the rack is vertically displaced from the space heater heating element, so that food or beverage is much less likely to contaminate the heating element.
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BACKGROUND OF THE INVENTION
This invention relates to the synthesis of mesoporous catalytic materials, generally known as molecular sieves.
Porous inorganic solids with molecular sieving properties, such as zeoiites, have been extensively used as heterogeneous catalysts and absorbants. This is because these materials have very large internal surface area, good thermal stability and, most importantly for catalytic applications, shape-selective and acidic properties. In many applications, particularly in the petroleum and petrochemical industries, molecular sieve zeolites totally dominate many established and most new processing technologies. However, most commercial zeolites are microporous with channel or cavity dimensions in the range of 5 to 14 Å. This limits their application in processes dealing with larger molecules. Considerable effort has been devoted to develop a framework with pore diameters greater than 10 Å. Recently, Mobil Oil Corporation has developed a family of mesoporous molecular sieve materials designated as M41S. This is a crystalline molecular sieve material with large pore diameters in the range of 15 to 100 Å. The synthesis methods that are used are similar to those used in traditional zeolite synthesis except that large quaternary ammonium surfactant components were used. These new mesoporous products are typically prepared at temperatures in the range of 90° to 150° C. The production of such mesoporous catalysts is described, for instance, in Kresge et al U.S. Pat. No. 5,250,282, issued Oct. 5, 1993, Beck et al U.S. Pat. No. 5,108,725, issued Apr. 28, 1992 and Beck U.S. Pat. No. 5,057,296, issued Oct. 15, 1991.
It is believed that, like many thousand organic substances with an elongated, narrow molecular framework, the large organic ammonium surfactant molecules form a liquid crystal phase in its aqueous solution. Cationic surfactants are composed of groups of opposing solubility tendencies, typically an oil-soluble hydrocarbon chain and a water-soluble ionic group. Typically, the cationic surfactants have a hydrophilic head group, e.g. an ammonium group, with a positive charge and a long hydrophobic hydrocarbon chain or tail group. It is the hydrophilic portion of the molecule that enables the surfactant molecules to be miscible with water. However, at a given condition, the critical micelle concentration or "CMC" is relatively small. Therefore, as the concentration of the surfactant exceeds its CMC, the surfactant molecules tend to form miceiles. A minimum energy results when the surfactant molecules arrange themselves in such a way that there is a minimum contact between their hydrocarbon tails and surrounding water molecules. Thus, for cationic surfactants in water, micelles of different shapes may be formed. The hydrophilic heads of the surfactant molecules contact surrounding water molecules and the hydrocarbon chains or tails are hidden inside. Thus, as the surfactant concentration in the acueous solution exceeds its CMC, the cationic surfactant molecules form a liquid crystal phase. Such liquid crystal phase serves as a template as well as a catalyst for the formation of a regular aluminosilicate structure. When an as-synthesized product is calcined at high temperature, the surfactant molecules are decomposed and escape from the crystalline structure, creating the desired highly porous silica alumina molecular sieve framework.
Liquid crystals are materials which exhibit aspects of both the crystalline solid and the amorphous liquid state. They resemble liquids in their ability to flow, and solids in the degree of order within their structure. In many systems, this order is established spontaneously. In other cases, it can be brought about, or controlled, by electric, magnetic or hydrodynamic fields.
It is a primary object of the present invention to provide an improved process for producing mesoporous catalytic materials.
SUMMARY OF THE INVENTION
According to the present invention, it has surprisingly been discovered that it is possible to make mesoporous catalytic materials at room temperature with very short preparation times, provided that an appropriate thermal treatment is performed.
Thus, the process of the present invention is for synthesizing a mesoporous molecular sieve material comprising an inorganic, porous material having, after calcination, an arrangement of uniformly-sized mesopores having diameters of at least about 20 Å, preferably 20 to 80 Å, more preferably 30 to 40 Å, an internal area greater than 200 m 2 /g and preferably greater than 800 m 2 /g and a thermal stability of up to 800° C. The steps of the process comprise beginning by preparing two reaction solutions. The first solution contains a source of silica, while the second solution contains a quaternary ammonium surfactant having a hydrophilic ammonium group and a linear hydrophobic hydrocarbon chain. The two solutions are combined and mixing is carried out at a pH in the range of 8 to 13. The mixing is then stopped and the product is allowed to form. Thereafter the solid product is separated and is subjected to a two stage heat treatment including calcinization. The two stage heat treatment includes a first stage in which the temperature of the crystallized product is slowly increased, e.g. at a rate of about 2° to 4° C. per minute, from room temperature to a temperature of about 100° to 150° C., preferably about 110° to 130° C., and the product is held at this temperature for a time of about 0.5 to 24 hours, preferably about 1 to 10 hours. The temperature of the product is then again raised steadily, e.g at a rate of about 4° to 6° C. per minute, up to a calcining temperature of about 300° to 600° C., preferably about 500° to 600° C., and is held at that temperature for a period of about 2 to 24 hours, preferably about 1 to 10 hours.
It has also been found through careful N 2 and Ar adsorption measurements of the products of this invention that there exist actually two types of pores with different pore openings. Thus, in addition to the uniformly-sized mesopores of diameters of at least 20 Å stated above, the products also contain micropores having diameters in the range of about 5 to 12 Å, preferably about 6 to 8 Å. Accordingly, the products of this invention are not typical molecular sieves in the conventional sense. This bimodal pore size distribution of the present invention is potentially important for petroleum processing reactions, particularly hydrocracking. This is because the mesopores can be accessed easily by the heavy molecules, and these large molecules could be cracked to a certain extent in the mesopores. The cracked smaller molecules can then diffuse into and react in the micropores. Since the micropores have a diameter very close to that of zeolite Y, the molecules emerging from their micropores are typically in the gasoline range, as a result of shape-selective effect.
The ammonium ion of the surfactant is preferably of the formula: ##STR1##
wherein at least one of R 1 , R 2 , R 3 and R 4 is aryl or alkyl of from 6 to about 36 carbon atoms, especially from 8 to 36 carbon atoms, e. g. --C 10 H 21 , --C 16 H 33 and --C 18 H 37 , or combinations thereof, the remainder of R 1 , R 2 , R 3 and R 4 being selected from the group consisting of hydrogen, alkyl of from 1 to 5 carbon atoms and combinations thereof. The compound from which the above ammonium ion is derived may be, for example, the hydroxide, halide, silicate, or mixtures thereof.
Among suitable ammonium groups within the above definition there may be mentioned cetyltrimethylammonium, cetyltrimethylphosphonium, octadecyltrimethylphosphonium, cetylpyridinium, myristyltrimethylammonium, decyltrimethylammonium dodecyltrimethylammonium and dimethyldidodecylammonium.
Preferably, the second solution contains also an alumina source. Although this alumina is not essential to the preparation of the solid structure, the alumina incorporated makes the solid much more useful as a catalytic material because of the ion exchange capacity and specific surface site introduced by the alumina. The alumina is typically in the form of aluminum sulphate or sodium aluminate.
It is also possible to add various additional transition metal components to the product and this is preferably done by adding metal salts of transition metals to the second solution. A variety of these may be used including iron sulphate, cobaltous sulphate, cupric sulphate, magnesium sulphate, titanium sulphate, nickel nitrate, ammonium paramolybdate, etc.
Experimental results show that everything else being the same, no mesoporous molecular sieve phase is formed under the following conditions:
1) no surfactant components are added.
2) the surfactant is replaced by a long chain hydrocarbon (i.e., hexanedecane).
3) the linear surfactant is replaced by a non-linear surfactant, bis(hydrogenated tallow alkyl) dimethyl quaternary ammonium chloride.
4) the surfactant is added after silica sources and aluminum sources have mixed.
These results indicate that 1) the critical role played by the linear surfactant molecules is not purely a result of their geometric shape but their ability to form liquid crystal in aqueous solution; 2) a non-linear surfactant usually loses liquid crystal-forming capability and therefore is unable to play the role of templating and catalyzing aluminosilicate formation; and 3) the surfactant molecules are required to be in the mixture before any molecular sieve precursor formation occurs.
Since the orientational association of the surfactant molecules is only partial and, as the nature of intermolecular forces is delicate, liquid crystals are extraordinarily sensitive to external perturbation, e.g. electric or magnetic fields, temperature and pressure. This has been supported by experimental observations. For instance, when only a small amount of additional cations such as F - and NH 4 + were introduced to the system through adding NH 4 F, no crystal phase can be detected in the final product. It is likely that F - or NH 4 + affected the electric valance in the reaction system and no liquid crystal phase can be formed although F - ion has long been considered a crystal stabilizing species in the synthesis of many microporous zeolites. However, to some other species, the liquid crystal phase show little sensitivity. This makes the substitution of aluminum by other metals through the addition of different metal components possible and successful.
A distinctive feature of the process of this invention is that mesoporous structures are formed at standard conditions of temperature and pressure, i.e. about 20° C. at a pressure of one atmosphere. However, the process can be carried out at temperatures generally in the range of about 0° to 25° C. Under these conditions, the time for the mesoporous precursor phase to form can be as little as several minutes, and generally within a time of about 5 minutes to about 4 hours. Such phenomenon has not previously been noted. This suggests that the forming process of this invention is not the same as that of traditional zeolite synthesis for which an induction period, a nucleation step and a silica condensation step are presumed to be the necessary steps. In this mesoporous solid preparation process using linear surfactants, the energy requirement for the formation of a mesoporous structure is substantially reduced. It appears to be more akin to a chemical reaction than to a slow crystallization process. It is believed that this may be the result of the presence of electric charges at the liquid crystals and water interfaces. Thus, it is believed that the ionic silicate and aluminate species present in the solution may rapidly approach these interfaces to balance the electric charges and at the same time form inorganic walls ground the micelies. As indicated above, poor mesoporous solid phase is formed if the surfactant component is added to the system after silica and aluminum sources have mixed. This is probably because certain inorganic polymerization occurs when silica and alumina meet, losing their ability to move freely in the mixture.
This phenomenon opens a wide range of possibilities to create new inorganic structures because thousands of organic molecules have the property of forming liquid crystals under suitable conditions. By changing solvent type, solvent concentration and electric field in a surfactant-solvent-silicate system, it is possible to create liquid crystals of different shapes and sizes, creating the necessary templates and condition for the formation of different inorganic structures.
It is known that liquid crystal phases are capable of solubilization of organic molecules with the hydrophilic interiors. Based on this, different organic molecules, typically mesitylene, have been used by previous researchers to enlarge the pore size of molecular sieves. However, at room temperature, these small organic molecules lose their ability to increase the pore size of molecular sieve materials. On the other hand, it has been found that decalin as an auxiliary component is successful in increasing the molecular sieve pore size.
The thermal treatment of the product is essential to the production of high surface areas, mesoporous molecular sieve material. The preferred thermal treatment is to first raise the temperature of the product at a rate of about 3° C. per minute from room temperature to about 120° C., and hold the temperature for about 2 to 5 hours. The temperature is then again raised at a rate of about 5° C. per hour to about 540° C. and held at that temperature for about 2 to 5 hours. The calcined product exhibits a major XRD peak at 1.5 to 2.5 degrees 2-theta, a surface area greater than 800 m 2 /g, a pore volume greater than 0.6 cm 3 /g and thermal stability up to 800° C. When heated to 900° C. in air, the mesoporous structures of the samples collapsed as indicated by the absence of XRD peaks.
The products of this invention are believed to be somewhat less than true crystalline material and are believed to fall somewhere between conventional definitions of amorphous and crystalline solids.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings which illustrate certain preferred embodiments of this invention.
FIGS. 1, 3, 5, 7, 8, 10, 12 and 14 are X-ray diffraction patterns of products of Examples 1, 3, 4, 5, 6, 7, 8 and 9, respectively, hereinafter preferred.
FIGS. 2, 4, 6, 9, 13 and 15 are pore size distributions obtained by N 2 adsorption for products of Examples 1, 3, 4, 6 and 8, respectively.
FIG. 11 is a pore size distribution obtained by Ar adsorption.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Certain preferred embodiments of this invention are illustrated by the following non-limiting examples.
The surface area, pore size and pore size distribution were measured using a Quantachrome Autosorb I N 2 adsorption instrument. The crystallille phase identification of the solid products was conducted on a SIEMENS DIFFRAL 500 diffractometer with theta-theta geometry and Cu-alpha radiation.
EXAMPLE 1
Two solutions were prepared as follows:
Solution 1: 56.6 grams of sodium silicate solution was mixed with 80 grams of water. 2.4 grams of sulfuric acid was then added with stirring.
Solution 2: 5.2 grams of aluminum sulfate was dissolved in 208 grams of water. 35.8 grams of cetyltrimethyl ammonium bromide (CTMABr) was then added with stirring.
As both solutions are homogeneous, Solution 2 was added to Solution 1 with vigorous stirring for 3 minutes. 46 grams of water was then added. After another 5 minutes of stirring, the mixture was placed in a sealed glass bottle at room temperature for 5 hours. A solid product was recovered by filtration using a Buchner funnel, washed with water, and dried in air at room temperature. The as-synthesized product was dried at 120° C. for 4 hours and then calcined at 540° C. for 1 hour in flowing N 2 /air and 5 hours in air. The X-ray diffraction pattern as shown in FIG. 1 exhibited a high intensity peak having a d-spacing of 46 Å at 2 degrees 2-theta. The pore size distribution obtained by N 2 adsorption had a range of 25 to 35 Å as shown in FIG. 2. The solid product had a BET surface area of 884 m 2 /g.
EXAMPLE 2
Several runs similar to Example 1 were carried out to study the effect of CTMA + /SiO 2 and H 2 O/SiO 2 ratios on product quality. With the same Solution 1 described above, the composition of Solution 2 was changed by varying the amount of CTMABr or water added. Four different CTMA + /SiO 2 ratios, 0.1, 0.2, 0.51 and 0.7, were used. Two H 2 O/SiO 2 ratios, 41.4 and 75.8 were applied. At room temperature and four hours of reaction, all runs produced similar mesoporous solids after calcination. However, it was evident that CTMA + /SiO 2 ratio of 0.51 and H 2 O/SiO 2 ratio of 75.8 produced the best results in terms of strength of the XRD peaks.
EXAMPLE 3
Two solutions were prepared as follows:
Solution 1: 9.4 grams of sodium silicate solution was mixed with 20 grams of water. 0.6 grams of sulfuric acid was then added with stirring.
Solution 2: 8.4 grams of CTMABr was mixed with 25.2 grams of water with stirring.
As both solutions are homogeneous, Solution 2 was added to Solution 1 with vigorous stirring for 3 minutes. 10 grams of water was then added. After another 5 minutes of stirring, the mixture was placed in a sealed glass bottle at room temperature for 10 minutes. A solid product is recovered and calcined using the procedure described in Example 1. The X-ray diffraction pattern in FIG. 3 exhibited a high intensity peak having a d-spacing of 41 Å at 2.135 degrees 2-theta. The pore size distribution obtained by N 2 adsorption was in the range 26 to 36 Å as shown in FIG. 4. The solid product had a BET surface area of 1100 m 2 /g.
EXAMPLE 4
Two solutions were prepared as follows:
Solution 1: 14.5 grams of N-brand sodium silicate was mixed with 20 grams of water under stirring, 0.6 gram of sulfuric acid was then added. The mixture was stirred for 5 minutes.
Solution 2: 1.2 grams iron sulfate was added to 25.2 grams of water under stirring. After the iron sulfate was completely dissolved, 9.0 grams of CTMABr was added. The mixture was stirred for 5 minutes.
Solution 2 was mixed with Solution 1 and the resulting mixture was stirred using a glass rod for 3 minutes. 11.5 grams of water was then added with stirring. The final mixture had a pH value of about 10. The mixture was placed in a sealed glass bottle at room temperature (˜20° C.) for 24 hours. A solid product was obtained using the same procedure described in Example 1. The solid product had a BET surface area of 886 m 2 /g. The X-ray diffraction pattern of the calcined product as shown in FIG. 5 exhibited a high intensity peak having a d-spacing of 42 Å at 2.5 degrees 2-theta. Its pore distribution had a range of 22 to 32 Å as shown in FIG. 6.
EXAMPLE 5
Similar to Example 4, four different runs were made to replace iron sulfate in Solution 2 of Example 4 by cobaltous sulfate (1.2 grams), cupric sulfate (1.1 grams), magnesium sulfate (0.8 gram) and titanium sulfate (1.7 grams) respectively. The resulting mixtures were placed in different glass bottles for 24 hours. The solid products were recovered and treated using the same procedure in Example 1. The XRD patterns of the products given in FIG. 7 showed high intensity peaks having d-spacings in the range of 38 to 43 Å at the range 1.5 to 2.5 degrees 2-theta,
EXAMPLE 6
Two solutions were prepared as follows:
Solution 1: 14.5 grams of sodium silicate solution was mixed with 20 grams of water, 0.6 grams of sulfuric acid was then added with stirring.
Solution 2: 1.3 grams of aluminum sulfate was dissolved in 25.2 grams of water, 9.0 grams of cetyltrimethyl ammonium bromide (CTMABr) was then added with stirring. As the solution became homogeneous, 5.2 grams of decalin liquid was added and the mixture was stirred for 5 minutes.
Solution 2 was added to Solution 1 with vigorous stirring for 3 minutes. 12 grams of water was then added. After another 5 minutes of stirring, the mixture was placed in a sealed glass bottle at room temperature for 1 hour. A solid product was recovered and treated using the same procedure described in Example 1. The product exhibited a d-spacing of 56 Å. BET surface area of the product was 956 m 2 /g. The X-ray diffraction pattern shown in FIG. 8 exhibited a high intensity peak having a d-spacing of 56 Å at 1.58 degrees 2-theta. The pore size distribution obtained by N 2 adsorption showed a range of 25 to 60 Å in FIG. 9.
EXAMPLE 7
Two solutions were prepared as follows:
Solution 1: 14.2 grams of N-brand silica was mixed with 20 g of distilled water. 0.6 grams of sulfuric acid was added with stirring.
Solution 2: 8.94 grams of cetyltrimethyl ammonium bromide was mixed with 25.2 grams of water and 1.3 grams of aluminum sulfate with stirring.
Solution 2 was added to Solution 1 with vigorous stirring and an additional 11.5 grams of water was added. After 5 minutes of stirring, the mixture was placed in a sealed glass bottle at room temperature for 48 hours. A solid product was recovered and treated using the same procedure described in Example 1. The X-ray diffraction pattern of FIG. 10 exhibited a high-intensity peak at 2.1 degrees 2-theta having a d-spacing of 41 Å. The pore volume distribution of the aluminosilicate molecular sieve material was measured by Argon adsorption and a Horvath-Kawozoe differential pore volume plot is shown in FIG. 11. This clearly illustrates two groups of pore diameter, one group having diameters of about 7 Å and a second group having diameters of about 43 Å.
EXAMPLE 8
Two solutions were prepared as follows:
Solution 1: 283 grams of sodium silicate was mixed with 400 grams of water, 12 grams of sulfuric acid was added.
Solution 2: 6 grams of sodium aluminate was dissolved in 1150 grams of water, 178 grams of cetyltrimethyl ammonium bromide (CTMABr) was added.
Both solutions were stirred until homogeneous and then the two solutions were mixed with vigorous stirring. The pH value of the mixture was 11 to 12.
The mixture was placed in a sealed glass (or HDPE) bottle at room temperature for 16 hours. A solid product was recovered by filtration using a Buchner funnel. The solid was washed with water, dried at in air at room temperature. The as-synthesized product was: then placed in a programmable furnace for thermal treatment using the following procedure:
(a) raise temperature from room temperature to 120° C. at a rate of 2°/min;
(b) hold at 120° C. for 3 hr.;
(c) raise temperature from 120° C. to 540° C. at a rate of 5°/min.;
(d) hold at 540° C. for 3 hr.
The X-ray diffraction pattern of the product as shown in FIG. 12 exhibited a high intensity peak with a d-spacing of 40 Å. The pore size distribution of the sample is given in FIG. 13. The specific surface area of the product is 1022 m 2 /g.
EXAMPLE 9
113.2 grams of N-brand sodium silicate is mixed with 160 grams of water and 4.8 grams of sulfuric acid, resulting in a mixture of pH 11.5
4 grams of sodium aluminate, 4.4 grams of nickel nitrate and 7.2 grams of ammonium paramolybdate were dissolved in 464 grams of deionized water. 71.2 grams of cetyltrimethyl ammonium bromide was then added. The solution pH was 8.0.
The two solutions were mixed with vigorous stirring for 10 minutes. The pH of the final mixture was 11.0.
The mixture was placed in a sealed HDPE bottle at room temperature. After 20 hours, a solid product was recovered using the same procedure described in Example 1. The solid was then dried at 120° C. for 4 hours and calcined at 540° C. in air for 4 hours. The X-ray diffraction pattern of the calcined sample is shown in FIG. 14. The pore volume distribution of the material is shown in FIG. 15. The material has a surface area of 1105 m 2 /g.
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A novel siliceous molecular sieve material is described for use as catalyst, along with a process for its production. The sieve material is unique in having a bimodal pore size distribution with micropores having diameters in the range from 5 to 12 Å and uniformly sized mesopores having diameters in the range from 20 to 80 Å. It is prepared by first preparing two reaction solutions, the first solution containing a source of silica and the second solution containing a quaternary ammonium surfactant having a hydrophilic ammonium group and a linear hydrophobic hydrocarbon chain. The two solutions are combined and the solid product obtained at room temperature is subjected to a two-stage heat treatment.
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CROSS-REFERENCE TO RELATED APPLICATIONS
The present application is a Continuation-in-Part of U.S. patent application Ser. No. 09/657,276 filed on Sep. 7, 2000, which claims priority to U.S. Provisional Patent Application No. 60/153,406 filed on Sep. 10, 1999, and to U.S. Provisional Patent Application No. 60/159,783 filed on Oct. 15, 1999. This application is also a Continuation-in-Part Application of U.S. patent application Ser. No. 11/040,810 filed Jan. 21, 2005, which is a Continuation Application of U.S. patent application Ser. No. 10/471,348 filed on Sep. 8, 2003, which is a National Stage of International Patent Application No. PCT/CA03/01097 filed on Jul. 29, 2003, which claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application Ser. No. 60/400,199 filed on Jul. 31, 2002, and U.S. Provisional Patent Application Ser. No. 60/400,413 filed on Jul. 31, 2002. U.S. patent application Ser. No. 11/040,810 is also a Continuation-in-Part Application of U.S. patent application Ser. No. 09/623,548 filed on May 17, 2000, now U.S. Pat. No. 6,849,714, which was a National Stage of International Application No. PCT/US00/13576, filed on May 17, 2000, which claims priority to U.S. Provisional Patent Application No. 60/134,406 filed on May 17, 1999, U.S. Provisional Patent Application No. 60/153,406 filed on Sep. 10, 1999, and to U.S. Provisional Patent Application No. 60/159,783 filed on Oct. 15, 1999. The above-mentioned applications are incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
The present invention relates to compounds and methods for treating eating disorders or metabolic syndromes. More particularly, the present relates to peptides, conjugates and methods for treating obesity.
BACKGROUND OF THE INVENTION
A number of postprandial endocrine, paracrine or autocrine messenger products involved in the signaling of hunger and satiety that are present in circulation such as hormones or peptides. The results from an elevated or reduced plasma concentration of one or more of these products will have either global orexigenic or anorexigenic effects.
Examples of peptides associated with anorexigenic effects are pancreatic polyeptide (PP), neuropeptide Y (NPY) and peptide YY (PYY).
These peptides act through Y receptors for which five are known, Y1, Y2, Y3, Y4 and Y5 and regulate pancreatic secretion, gastric emptying and gastric motility. The Y receptors are found throughout the peripheral and central nervous systems as well as on various gastrointestinal organ cells.
Pancreatic polypeptide is secreted in the pancreas and helps control energy homeostasis through inhibition of pancreatic secretions such as for example insulin thus leading to an increased blood glucose level and signaling a need for reduced feeding.
Hypothalamic secreted neuropeptide Y participates in the control of food intake through binding and activation Y1 and possibly Y2 and Y5 receptors.
One of the most discussed examples in recent times is PYY 1-36 . It is produced in endocrine L cells lining the distal small bowel and colon. The prepro PYY is clipped by signal peptidases to give proPYY 1-70 . This peptide is further modified by prohormone dibasic convertase leading to PYY-Gly-Lys-Arg followed by Carboxypeptidase B to give PYY-Gly and finally to PYY 1-36 by amidation enzyme. It is then released from the cell where a metabolic derivative obtained through DPP-IV cleavage of the two N-terminal amino acids give circulating PYY 3-36 .
PYY 1-36 binds and activates Y1, Y2 and Y5 receptors found on a variety of cells surfaces as for NPY. The cells are found peripherally in the gastrointestinal tract as well as on the arcuate nucleus. The result of interaction with the Y2 found on the arcuate is thought to lead to a central nervous system response. Alternatively the Y2 receptors found peripherally on the surface of cell within the gastrointestinal tract have been shown to have an effect on gastric motility, gastric acid secretion and intestinal motility. The result of these interactions lead to reduced food and caloric intake.
Unlike PYY 1-36 which interacts equally with the Y1 and Y2 receptors, PYY 3-36 is selective to the Y2 receptor. A selective agonist of the Y2 receptor has been demonstrated to be beneficial as compared to a broad agonist. In fact, the Y1 receptor has been associated with hypertension (A. Balasubramaniam et al. J. Med. Chem. 2000, 43, 3420-27, Balasubramaniam A et al. Pept Res. 1988 1, 32-5). PYY 3-36 has been demonstrated to reduce food intake in vivo (Nature, 2002, 418, 650-4).
The advantage of using PYY 3-36 is that it is a natural appetite controlling hormone. There will not psychological side effect from the central nervous system such as when norepinephrine and serotonin reuptake inhibitor or other stimulants are used. Another advantage is that this class of therapeutic agent does not interfere with the absorption of certain nutritional or fat containing elements such as gastrointestinal lipase inhibitor that cause uncomfortable side effects. An inconvenience of using PYY 3-36 is need for multiple daily administrations.
A new anti-obesity agent that has an enhanced activity and which would permit to avoid the above-mentioned drawbacks would therefore be highly desired. A method for enhancing the anti-obesity activity of a PYY peptide or a functional derivative thereof would also be desired.
SUMMARY OF THE INVENTION
According to one aspect of the invention, there is provided a compound comprising a PYY peptide or a functional derivative thereof which is coupled to a reactive group, the reactive group being capable of reacting with an amino group, a hydroxyl group or a thiol group on a blood component so as to form a stable covalent bond therewith, thereby substantially preventing the PYY peptide or functional derivative thereof from crossing the blood brain barrier.
According to another aspect of the invention, there is provided a conjugate comprising
a blood component; and a PYY peptide or a functional derivative thereof which is coupled to a reactive group,
wherein the reactive group is coupled with at least an amino group, a hydroxyl group or a thiol group on the blood component so as to form a stable covalent bond therewith, thereby substantially preventing the PYY peptide or derivative thereof from crossing the blood brain barrier.
It should be understood that, in the compounds and conjugates of the present invention, the stable covalent bond between the PYY peptide or functional derivative thereof and the blood component can be formed in vivo or ex vivo.
According to another aspect of the invention, there is provided a method of enhancing, in a patient, the anti-obesity activity of a PYY peptide or functional derivative thereof comprising the step of covalently bonding the PYY peptide or functional derivative thereof to a blood component, thereby preventing the PYY peptide or functional derivative thereof from crossing the blood brain barrier when administered to the patient, wherein preventing the PYY peptide or functional derivative thereof from crossing the blood brain barrier results in an enhanced anti-obesity activity of the PYY peptide or functional derivative thereof.
According to another aspect of the invention, there is provided in a method for treating obesity by administering a PYY peptide or a functional derivative thereof to a patient, the improvement wherein the PYY peptide or functional derivative thereof is covalently bonded to a blood component so as to prevent the PYY peptide or functional derivative thereof from crossing the blood brain barrier, thereby enhancing its anti-obesity activity.
It should also be understood that, in the methods of the present invention, the covalent bonding between the PYY peptide or the functional derivative thereof and the blood component can be formed in vivo or ex vivo.
According to another aspect of the invention, there is provided a compound comprising a peptide of formula:
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -
(SEQ ID NO: 1)
X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -X 19 -X 20 -
X 21 -X 22 -X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 -
X 30 -X 31 -X 32 -X 33 -X 34 -X 35 -X 36 -A
wherein
X 1 is absent, tyr or ala;
X 2 is absent or pro;
X 3 is absent, lys or an analog thereof, ile, leu, or ala;
X 4 is absent, lys or an analog thereof, or glu;
X 5 is absent or pro;
X 6 is absent, glu, val or asp;
X 7 is absent, ala, tyr or asn;
X 8 is absent or pro;
X 9 is absent or gly;
X 10 is absent, glu or asp;
X 11 is absent, asp or asn;
X 12 is absent, lys or an analog thereof, or ala;
X 13 is absent, lys or an analog thereof, ser, thr, or pro;
X 14 is absent, lys or an analog thereof, ala, or pro;
X 15 is absent, lys or an analog thereof, or glu;
X 16 is absent, glu, gln or asp;
X 17 is absent, leu or met;
X 18 is absent, lys or an analog thereof, ser, ala, or asn;
X 19 is absent, arg or gln;
X 20 is absent or tyr;
X 21 is absent, tyr or ala;
X 22 is ala or ser;
X 23 is ser, asp or ala;
X 24 is leu;
X 25 is arg or lys;
X 26 is his, arg or lys;
X 27 is tyr;
X 28 is leu or ile;
X 29 is asn
X 30 is leu or met;
X 31 is val, leu or ile;
X 32 is thr;
X 33 is arg or lys;
X 34 is gln or pro;
X 35 is arg or lys;
X 36 is tyr or a derivative thereof; and
A is absent lys or a derivative thereof, and
at least one reactive group coupled to any one of X 1 to X 36 and A, directly or via a linking group.
According to another aspect of the invention, there is provided a conjugate comprising a blood component and a compound having a peptide of formula:
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 - (SEQ ID NO: 1) X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -X 19 -X 20 - X 21 -X 22 -X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 - X 30 -X 31 -X 32 -X 33 -X 34 -X 35 -X 36 -A
wherein X 1 -X 36 and A are as previously defined, and
a reactive group coupled to any one of X 1 -X 36 and A, directly or via a linking group, and wherein the reactive group is coupled with at least an amino group, a hydroxyl group or a thiol group on the blood component so as to form a stable covalent bond therewith.
It has been found that the compounds and conjugates of the present invention demonstrated an enhanced anti-obesity activity with respect to PYY peptides such as PYY 1-36 and PYY 3-36 . It also has been found that these compounds and conjugates are efficient for reducing the food consumption of a subject, thereby treating or preventing obesity.
It has been found that the methods of the present invention are effective for enhancing the anti-obesity activity of PYY peptide or a derivative thereof and/or for treating obesity. It also has been found that by preventing the compounds or conjugates from crossing the blood brain barrier, an enhanced anti-obesity activity of the PYY peptides or derivative thereof was observed.
The expression “a PYY peptide or a functional derivative thereof” as used herein refers to a PYY peptide such as PYY 1-36 or PYY 3-36 or to a functional derivative of the PYY peptide. Such a functional derivative would be understood by a person skilled in the art as a derivative which substantially maintains the activity of the PYY peptide. Preferably, such a functional derivative has an in vitro NPY Y2 receptor binding activity which is at least 1/100 of the in vitro NPY Y2 receptor binding activity of PYY 3-36 . More preferably, the functional derivative has an in vitro NPY Y2 receptor binding activity which is equal or superior to the in vitro NPY Y2 receptor binding activity of PYY 3-36 . In a non-limitative manner, the functional derivative can comprise a peptide of the following formula: X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -X 19 -X 20 -X 21 -X 22 -X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 -X 30 -X 31 -X 32 -X 33 -X 34 -X 35 -X 36 -A (SEQ ID NO: 1) or Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -Z 7 -Z 8 -Z 9 -Z 10 -Z 11 -Z 12 (SEQ ID NO: 2) wherein X 1 to X 36 , and A are as previously defined, and wherein Z 1 is ala, Z 4 is arg, Z 8 is asn, Z 12 is arg, and Z 2 , Z 3 , Z 5 to Z 7 and Z 9 to Z 11 are selected from the group consisting of the natural amino acids.
The expression “lys or an analog thereof” refers to a lysine or an analog thereof that will substantially maintains the activity of the peptide. In a non-limitative manner, the lys analog can be of formula:
where n is an integer having a value of 0, 1, 2, 3 or 4.
The expression “tyr or a derivative thereof” refers to a tyrosine or a derivative thereof that will substantially maintains the activity of the peptide. In a non-limitative manner, the tyr derivative can be of formula:
where
R 1 is H, a protecting group (PG), a C 1 -C 10 branched, linear or cyclic alkyl, a phosphate or a sulfate; R 2 and R 3 are same or different and selected from the group consisting of H, D and I; and R 4 is OH, OPG, OR 5 , SH, SPG, SR 5 , NH 2 , NHPG, N(PG) 2 , N(R 5 ) 2 , NR 5 PG, or NHR 6 , where R 5 is a C 1 -C 10 branched, linear or cyclic alkyl, and R 6 is a solid phase support.
The expression “protecting group (PG)” as used herein refers to suitable protecting groups as defined in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, (1999) John Wiley & Sons, which is hereby incorporated by reference. The person skilled in the art will understand that nature of the protecting group will vary according to the functionality that has to be protected. Greene et al. discloses, as example, various protecting groups for carboxylic acids, alcohols, thiols, amines, amides etc.
The expression “lys or a derivative thereof” refers to a lysine or a derivative thereof that will substantially maintains the activity of the peptide. In a non-limitative manner, the lys derivative can be of formula:
where
R 4 is OH, OPG, OR 5 , SH, SPG, SR 5 , NH 2 , NHPG, N(PG) 2 , N(R 5 ) 2 , NR 5 PG, or NHR 6 , where R 5 is a C 1 -C 10 branched, linear or cyclic alkyl, and R 6 is a solid phase support; and n is an integer having a value of 0, 1, 2, 3 or 4.
The PYY peptide or functional derivative thereof can be selected from SEQ IDS NO: 1 to 15, preferably from SEQ IDS NO: 2 to 13, and more preferably from SEQ ID NO: 4.
In the compounds and conjugates of present invention, there is preferably only one reactive group. Advantageously, the reactive group is coupled to any one of X 1 to X 21 , X 23 , X 24 , X 26 to X 28 , X 30 to X 32 , X 34 to X 36 , and A. Alternatively, the reactive group can be coupled to any one of Z 1 to Z 12 and preferably to any one of Z 2 , Z 3 , Z 5 to Z 7 and Z 9 to Z 11 . The reactive group can also be connected to the peptide or the PYY functional derivative by means of a linking group.
According to preferred embodiments, in the compounds and conjugates of the invention which comprise a peptide of formula: X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -X 19 -X 20 -X 21 -X 22 -X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 -X 30 -X 31 -X 32 -X 33 -X 34 -X 35 -X 36 -A (SEQ ID NO: 1):
X 1 can be absent, the reactive group, linking group-(reactive group), tyr or ala, the tyr or ala being optionally coupled to the reactive group or to the linking group-(reactive group). Preferably, X 1 is absent. X 2 can be absent, pro, the reactive group or the linking group-(reactive group). Preferably, X 2 is absent. X 3 can be absent, lys or an analog thereof, (reactive group)-lys, (reactive group)-linking group-lys, (reactive group)-lys analog, (reactive group)-linking group-lys analog, ile, leu, or ala, wherein the reactive group is coupled to the free amine of lys or lys analog. Preferably, X 3 is leu. X 4 can be absent, lys or an analog thereof, (reactive group)-lys, (reactive group)-linking group-lys, (reactive group)-lys analog, (reactive group)-linking group-lys analog, or glu, wherein the reactive group is coupled to the free amine of lys or lys analog. Preferably, X 4 is lys (reactive group)-lys or (reactive group)-linking group-lys. X 5 is preferably pro. X 6 is preferably glu. X 7 is preferably ala. X 8 is preferably pro. X 9 is preferably gly. X 10 is preferably glu. X 11 is preferably asp. X 12 can be absent, lys or an analog thereof, (reactive group)-lys, (reactive group)-linking group-lys, (reactive group)-lys analog, (reactive group)-linking group-lys analog, or ala, wherein the reactive group is coupled to the free amine of lys or lys analog. Preferably, X 12 is ala. X 13 can be absent, lys or an analog thereof, (reactive group)-lys, (reactive group)-linking group-lys, (reactive group)-lys analog, (reactive group)-linking group-lys analog, ser, thr, or pro, wherein the reactive group is coupled to the free amine of lys or lys analog. Preferably, X 13 is ser. X 14 can be absent, lys or an analog thereof, (reactive group)-lys, (reactive group)-linking group-lys, (reactive group)-lys analog, (reactive group)-linking group-lys analog, ala or pro, wherein the reactive group is coupled to the free amine of lys or lys analog. X 14 is preferably pro. X 15 can be absent, lys or an analog thereof, (reactive group)-lys, (reactive group)-linking group-lys, (reactive group)-lys analog, (reactive group)-linking group-lys analog, or glu, wherein the reactive group is coupled to the free amine of lys or lys analog. X 15 is preferably glu. X 16 is preferably glu. X 17 is preferably leu. X 18 can be absent, lys or an analog thereof, (reactive group)-lys, (reactive group)-linking group-lys, (reactive group)-lys analog, (reactive group)-linking group-lys analog, ser, ala, or asn, wherein the reactive group is coupled to the free amine of lys or lys analog. X 18 is preferably asn. X 19 is preferably arg. X 20 is preferably tyr. X 21 can be absent, tyr, ala, a reactive group, or linking group-(reactive group), wherein the linking group is coupled to X 20 and X 22 . X 21 is preferably tyr. X 22 is preferably ala. X 23 is preferably ser. X 25 is preferably arg. X 26 is preferably his. X 28 is preferably leu. X 30 is preferably leu. X 31 is preferably val. X 33 is preferably arg. X 34 is preferably gln. X 35 is preferably arg.
In a preferred embodiment of the present invention, the reactive group can be selected from the group consisting of Michael acceptors (preferably an unsaturated carbonyl such as a vinyl carbonyl or a vinyl sulfone moiety), succinimidyl-containing groups (such as, N-hydroxysuccinimide (NHS), N-hydroxy-sulfosuccinimide (sulfo-NHS) etc.), an electrophilic thiol acceptor (such as pyridyldithio (Pyr-S—S), an alpha halogenated alkyl carbonyl (such as an alpha halogenated alkyl carbonyl where the alkyl, further to the halogen substituent, may contains or not a substituent such as a C 1 -C 8 alkyl or phenyl), and maleimido-containing groups (such as gamma-maleimide-butyralamide (GMBA), beta-maleimidopropionic acid (MPA), alpha-maleimidoacetic acid (MAA) etc.). Advantageously, the reactive group is a maleimido-containing group. Alternatively, the reactive group is advantageously an alpha halogenated alkyl carbonyl and preferably alpha iodo acetyl. Preferably, the reactive group is a reactive group, which is capable of reacting with an amino group, a hydroxyl group or a thiol group on a blood component so as to form a stable covalent bond.
As example, the maleimido group is most selective for sulfhydryl groups on peptides when the pH of the reaction mixture is kept between 6.5 and 7.4. At pH 7.0, the rate of reaction of maleimido groups with sulfhydryls is 1000-fold faster than with amines. A stable thioether linkage between the maleimido group and the sulfhydryl is formed which cannot be cleaved under physiological conditions. Primary amines can be the principal targets for NHS esters. Accessible α-amine groups present on the N-termini of proteins can react with NHS esters. However, α-amino groups on a protein may not be desirable or available for the NHS coupling. While five amino acids have nitrogen in their side chains, only the ε-amine of lysine reacts significantly with NHS esters. An amide bond can be formed when the NHS ester conjugation reaction reacts with primary amines releasing N-hydroxysuccinimide.
In a preferred embodiment of the present invention, the reactive group is coupled to an amino acid of the peptide via a linking group (or linker), such as, but not limited to (2-amino) ethoxy acetic acid (AEA), ethylenediamine (EDA), amino ethoxy ethoxy succinimic acid (AEES), AEES-AEES, 2-[2-(2-amino)ethoxy)] ethoxy acetic acid (AEEA), AEEA-AEEA, —NH 2 —(CH 2 ) n —COOH where n is an integer between 1 and 20 and alkyl chain (C 1 -C 10 ) motif saturated or unsaturated in which could be incorporated oxygen nitrogen or sulfur atoms, such as, but not limited to glycine, 3-aminopropionic acid (APA), 8-aminooctanoic acid (OA) and 4-aminobenzoic acid (APhA) and combinations thereof.
In a preferred embodiment of the present invention, the blood component is a blood protein, more preferably is albumin (such as human serum albumin (HSA)).
Preferably, the invention relates to anti-obesity agents such as PYY 3-36 or derivatives thereof, which can be shortened versions of the latter. The new bioconjugates formed by the ex vivo, in vivo or in vitro covalent bonding between the peptides of the present invention and a blood component have been found to be very selective to the neuropeptide Y2 receptor.
PP and NPY peptides could also be suitable as an alternative to PYY or its functional derivatives in the various embodiments of the present invention.
The methods of the present invention include extending the effective therapeutic life of the conjugated anti-obesity peptide derivatives as compared to administration of the unconjugated peptide to a patient. Moreover, the anti-obesity activity of the conjugated anti-obesity peptide derivatives of the present invention is considerably enhanced as compared the unconjugated peptide to a patient peptides of the present invention. The derivatives or modified peptides can be of a type designated as a DAC™ (Drug Affinity Complex), which comprises the anti-obesity peptide molecule and a linking group together with a chemically reactive group capable of reaction with a reactive functionality of a mobile blood protein. By reaction with the blood component or protein the modified peptide, or DAC, may be delivered via the blood to appropriate sites or receptors. Moreover, conjugating the peptides to a blood component provides a protection against the degradation of enzymes.
A. Specific Labeling.
Preferably, the compounds, derivatives or modified peptides of this invention are designed to specifically react with thiol groups on mobile blood proteins. Such a reaction is preferably established by covalent bonding of the peptide modified with a maleimido-containing group linked to a thiol group on a mobile blood protein such as serum albumin or IgG.
Under certain circumstances, specific labeling with maleimido-containing group offers several advantages over non-specific labeling of mobile proteins with groups such as NHS and sulfo-NHS. Thiol groups are less abundant in vivo than amino groups. Therefore, the compounds of the present invention such as maleimido-modified peptides, can covalently bond to fewer proteins. For example, in albumin (an abundant blood protein) there is only a single thiol group. Thus, peptide-(maleimido-containing group)-albumin conjugates can tend to comprise a 1:1 molar ratio of peptide to albumin. In addition to albumin, IgG molecules (class II) also have free thiols. Since IgG molecules and serum albumin make up the majority of the soluble protein in blood they also make up the majority of the free thiol groups in blood that are available to covalently bond to maleimide-modified peptides.
Further, even among free thiol-containing blood proteins, including IgGs, specific labeling with a maleimido-containing group leads to the preferential formation of peptide-(maleimido-containing group)-albumin conjugates, due to the unique characteristics of albumin itself. The single free thiol group of albumin, highly conserved among species, is located at amino acid residue 34 (Cys34). It has been demonstrated recently that the Cys34 of albumin has increased reactivity relative to free thiols on other free thiol-containing proteins. This is due in part to the very low pK value of 5.5 for the Cys34 of albumin. This is much lower than typical pK values for cysteine residues in general, which are typically about 8. Due to this low pK, under normal physiological conditions Cys34 of albumin is predominantly in the anionic form, which dramatically increases its reactivity. In addition to the low pK value of Cys34, another factor, which enhances the reactivity of Cys34 is its location in a crevice close to the surface of one loop of region V of albumin. This location makes Cys34 very available to ligands of all kinds, and is an important factor in Cys34's biological role as a free radical trap and a free thiol scavenger. These properties make Cys34 highly reactive toward maleimide-peptides, and the reaction rate acceleration can be as much as 1000-fold relative to rates of reaction of maleimide-peptides with other free-thiol containing proteins.
Another advantage of peptide-(maleimido-containing group)-albumin conjugates is the reproducibility associated with the 1:1 loading of peptide to albumin specifically at Cys34. Other techniques, such as glutaraldehyde, DCC, EDC and other chemical activations of, e.g, free amines, lack this selectivity. For example, albumin contains 52 lysine residues, 25 to 30 of which are located on the surface of albumin and therefore accessible for conjugation. Activating these lysine residues, or alternatively modifying peptides to couple through these lysine residues, results in a heterogenous population of conjugates. Even if statistical 1:1 molar ratios of peptide to albumin are employed, the yield will consist of multiple conjugation products, some containing 0, 1, 2 or more peptides per albumin, and each having peptides randomly coupled at any one or more of the 25 to 30 available lysine sites. Given the numerous possible combinations, characterization of the exact composition and nature of each conjugate batch becomes difficult, and batch-to-batch reproducibility is all but impossible, making such conjugates less desirable as a therapeutic. Additionally, while it would seem that conjugation through lysine residues of albumin would at least have the advantage of delivering more therapeutic agent per albumin molecule, studies have shown that a 1:1 ratio of therapeutic agent to albumin is preferred. In an article by Stehle, et al., “The Loading Rate Determines Tumor Targeting properties of Methotrexate-Albumin Conjugates in Rats,” Anti-Cancer Drugs, Vol. 8, pp. 677-685 (1988), the authors report that a 1:1 ratio of the anti-cancer methotrexate to albumin conjugated via amide coupling of one of the available carboxylic acids on methotrexate to any lysine on albumin gave the most promising results. The conjugates describe therein were preferentially taken up by tumor cells, whereas the conjugates bearing 5:1 to 20:1 methotrexate molecules to albumin had altered HPLC profiles and were quickly taken up by the liver in vivo. It is postulated that at these higher ratios, confer conformational changes to albumin diminishing its effectiveness as a therapeutic carrier.
Through controlled administration of maleimido-peptides in vivo, one can control the specific labeling of albumin and IgG in vivo. In typical administrations, 80-90% of the administered maleimido-peptides will label albumin and less than 5% will label IgG. Trace labeling of free thiols such as glutathione, cysteine or Cys-Gly will also occur. Such specific labeling is preferred for in vivo use as it permits an accurate calculation of the estimated half-life of the administered agent.
In addition to providing controlled specific in vivo labeling, maleimide-peptides can provide specific labeling of serum albumin and IgG ex vivo. Such ex vivo labeling involves the addition of maleimide-peptides to blood, serum or saline solution containing serum albumin and/or IgG. Once conjugation has occurred ex vivo with the maleimido-peptides, the blood, serum or saline solution can be readministered to the patient's blood for in vivo treatment.
In contrast to NHS-peptides, maleimido-peptides are generally quite stable in the presence of aqueous solutions and in the presence of free amines. Since maleimido-peptides will only react with free thiols, protective groups are generally not necessary to prevent the maleimido-peptides from reacting with itself. In addition, the increased stability of the modified peptide permits the use of further purification steps such as HPLC to prepare highly purified products suitable for in vivo use. Lastly, the increased chemical stability provides a product with a longer shelf life.
B. Non-Specific Labeling.
The anti-obesity peptides of the invention may also be modified for non-specific labeling of blood components. Bonds to amino groups will also be employed, particularly with the formation of amide bonds for non-specific labeling. To form such bonds, one may use as a chemically reactive group a wide variety of active carboxyl groups, particularly esters, where the hydroxyl moiety is physiologically acceptable at the levels required. While a number of different hydroxyl groups may be employed in these linking agents, the most convenient would be N-hydroxysuccinimide (NHS) and N-hydroxy-sulfosuccinimide (sulfo-NHS).
Other linking agents that may be utilized are described in U.S. Pat. No. 5,612,034, which is hereby incorporated by reference. The various sites with which the chemically reactive group of the modified peptides may react in vivo include cells, particularly red blood cells (erythrocytes) and platelets, and proteins, such as immunoglobulins, including IgG and IgM, serum albumin, ferritin, steroid binding proteins, transferrin, thyroxin binding protein, α-2-macroglobulin, and the like. Those receptors with which the modified peptides react, which are not long-lived, will generally be eliminated from the human host within about three days. The proteins indicated above (including the proteins of the cells) will remain at least three days, and may remain five days or more (usually not exceeding 60 days, more usually not exceeding 30 days) particularly as to the half life, based on the concentration in the blood.
For the most part, reaction can be with mobile components in the blood, particularly blood proteins and cells, more particularly blood proteins and erythrocytes. By “mobile” is intended that the component does not have a fixed situs for any extended period of time, generally not exceeding 5 minutes, more usually one minute, although some of the blood component may be relatively stationary for extended periods of time.
Initially, there will be a relatively heterogeneous population of functionalized proteins and cells. However, for the most part, the population within a few days will vary substantially from the initial population, depending upon the half-life of the functionalized proteins in the blood stream. Therefore, usually within about three days or more, IgG will become the predominant functionalized protein in the blood stream.
Usually, by day 5 post-administration, IgG, serum albumin and erythrocytes will be at least about 60 mole %, usually at least about 75 mole %, of the conjugated components in blood, with IgG, IgM (to a substantially lesser extent) and serum albumin being at least about 50 mole %, usually at least about 75 mole %, more usually at least about 80 mole %, of the non-cellular conjugated components.
The desired conjugates of non-specific modified peptides to blood components may be prepared in vivo by administration of the modified peptides to the patient, which may be a human or other mammal. The administration may be done in the form of a bolus or introduced slowly over time by infusion using metered flow or the like.
If desired, the subject conjugates may also be prepared ex vivo by combining blood with modified peptides of the present invention, allowing covalent bonding of the modified peptides to reactive functionalities on blood components and then returning or administering the conjugated blood to the host. Moreover, the above may also be accomplished by first purifying an individual blood component or limited number of components, such as red blood cells, immunoglobulins, serum albumin, or the like, and combining the component or components ex vivo with the chemically reactive modified peptides. The functionalized blood or blood component may then be returned to the host to provide in vivo the subject therapeutically effective conjugates. The blood also may be treated to prevent coagulation during handling ex vivo. Other sources of blood components, such as recombinant proteins are also suitable for the preparation of the conjugates of the present invention.
Some of the preferred compounds of the invention are derivatives of PYY 1-36 and PYY 3-36 . These derivatives comprise a strategically placed maleimido-containing group as described above. PYY 1-36 and PYY 3-36 have the following structures:
These peptides have an alpha helical structure starting at position 18 running through to position 36 (example on PYY in Biochemistry, 2000, 39, 9935). The amino acids at positions 22, 25, 29 and 33 can be considered as relatively important for the activity. All derivatives of these peptides can be truncated, modified, mutated or intact peptides. Preferably, they are able to expose side chains found on these four amino acid residues. These residues are conserved in PYY 1-36 (SEQ ID NO: 3), PYY 3-36 (SEQ ID NO: 4), pancreatic polypeptide and neuropeptide Y. Secondary conserved amino acids of potential importance can be those at positions 5, 8, 9, 12, 15, 20, 24, 27, 32, 35 and 36.
Another aspect of the invention is to reduce excess intestinal water and decreasing excess electrolyte secretion.
Another aspect of the invention is to relieve tumor necrosis factor (TNF)-induced acute pancreatitis through the inhibition of NF-B translocation to acinar nuclei (Vona-Davis L. et al., J. Am. Coll. Surg., 2004, 199, 87-95) using the DAC PYY 1-36 series of derivatives.
BRIEF DESCRIPTION OF DRAWINGS
Further features and advantages of the invention will become more readily apparent from the following description of preferred embodiments as illustrated by way of examples in the appended drawings wherein:
FIG. 1 is a diagram showing a comparison between the anti-obesity activity of PYY 3-36 and the anti-obesity activity a compound according to a preferred embodiment of the invention, wherein the anti-obesity activity of these compounds has been determined in an experiment by administering them, at various doses, to Sprague-Dawley rats and by measuring the food consumption of these rats before and after administration of these compounds;
FIG. 2 is another diagram as in FIG. 1 , wherein the PYY peptide and the compound according to a preferred embodiment of the invention have been administered to the rats according to other dosages;
FIG. 3 is a diagram showing the reduction in food intake after 24 hours, which has been generated by the administration of the PYY peptide and the compound of the invention, during the experiment described in FIG. 1 ;
FIG. 4 is a diagram showing the reduction in food intake after 24 hours, which has been generated by the administration of the PYY peptide and the compound of the invention, during the experiment described in FIG. 2 ; and
FIG. 5 is a plot showing the influence of the dosage of another compound according to a preferred embodiment of the invention on the total food intake of Sprague-Dawley rats over time.
DESCRIPTION OF PREFERRED EMBODIMENTS
The following non-limiting examples further illustrate the invention.
EXAMPLES
1. Synthetic Scheme
General
The synthesis of the PYY peptides and functional derivatives thereof was performed using an automated solid-phase procedure on a Symphony Peptide Synthesizer with manual intervention during the generation of the DAC peptide. The synthesis was performed on Fmoc-protected Ramage amide linker resin, using Fmoc-protected amino acids. Coupling was achieved by using O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (HBTU) and diisopropylethylamine (DIEA) as the activator cocktail in N,N-dimethylformamide (DMF) solution. The Fmoc protective group was removed using 20% piperidine/DMF. When needed, a Boc-protected amino acid was used at the N-terminus in order to generate the free N α -terminus after the peptide was cleaved from resin. All amino acids used during the synthesis possessed the L-stereochemistry unless otherwise stated. Sigmacoted glass reaction vessels were used during the synthesis.
Compound I (PYY 3-36 )
Ile-Lys-Pro-Glu-Ala-Pro-Gly-Glu-Asp-
(SEQ ID NO: 4)
Ala-Ser-Pro-Glu-Glu-Leu-Asn-Arg-Tyr-
Tyr-Ala-Ser-Leu-Arg-His-Tyr-Leu-Asn-
Leu-Val-Thr-Arg-Gln-Arg-Tyr-CONH 2
Step 1: Solid phase peptide synthesis of the DAC™ peptide on a 100 μmole scale was performed using manual and automated solid-phase synthesis, a Symphony Peptide Synthesizer and Ramage resin. The following protected amino acids were sequentially added to resin: Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Leu-OH, Fmoc-Asn(Trt)-OH, Fmoc-Leu-OH, Fmoc-Tyr(tBu)-OH, Fmoc-His(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Leu-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ala-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Leu-OH, Fmoc-Glu(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ala-OH, Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Gly-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Glu(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, Boc-Ile-OH. They were dissolved in N,N-dimethylformamide (DMF) and, according to the sequence, activated using O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (HBTU) and Diisopropylethylamine (DIEA). Removal of the Fmoc protecting group was achieved using a solution of 20% (V/V) piperidine in N,N-dimethylformamide (DMF) for 20 minutes (step 1).
Step 2: The peptide was cleaved from the resin using 85% TFA/5% TIS/5% thioanisole and 5% phenol, followed by precipitation by dry-ice cold (0-4° C.) Et 2 O. The crude peptide was collected on a polypropylene sintered funnel, dried, redissolved in a 40% mixture of acetonitrile in water (0.1% TFA) and lyophilized to generate the corresponding crude material used in the purification process.
Compound II
Ile-Lys-Pro-Glu-Ala-Pro-Gly-Glu-Asp-
(SEQ ID NO: 5)
Ala-Ser-Pro-Glu-Glu-Leu-Asn-Arg-Tyr-
Tyr-Ala-Ser-Leu-Arg-His-Tyr-Leu-Asn-
Leu-Val-Thr-Arg-Gln-Arg-Tyr-
Lys(MPA)-CONH 2
Step 1: Solid phase peptide synthesis of the DAC derivative on a 100 μmole scale was performed using manual solid-phase synthesis, a Symphony Peptide Synthesizer and Fmoc protected Ramage resin. The following protected amino acids were sequentially added to resin: Fmoc-Lys(Aloc)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Leu-OH, Fmoc-Asn(Trt)-OH, Fmoc-Leu-OH, Fmoc-Tyr(tBu)-OH, Fmoc-His(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Leu-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ala-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Leu-OH, Fmoc-Glu(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ala-OH, Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Gly-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Glu(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, Boc-Ile-OH. The following protected amino acids were sequentially added to resin. They were dissolved in N,N-dimethylformamide (DMF) and, according to the sequence, activated using O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (HBTU) and Diisopropylethylamine (DIEA). Removal of the Fmoc protecting group was achieved using a solution of 20% (V/V) piperidine in N,N-dimethylformamide (DMF) for 20 minutes (step 1).
Step 2: The selective deprotection of the Lys (Aloc) group was performed manually and accomplished by treating the resin with a solution of 3 eq of Pd(PPh 3 ) 4 dissolved in 5 mL of C 6 H 6 :CHCl 3 (1:1): 2.5% NMM (v:v): 5% AcOH (v:v) for 2 h (Step 2). The resin is then washed with CHCl 3 (6×5 mL), 20% AcOH in DCM (6×5 mL), DCM (6×5 mL), and DMF (6×5 mL).
Step 3: The synthesis was then re-automated for the addition of the 3-maleimidopropionic acid (Step 3). Between every coupling, the resin was washed 3 times with N,N-dimethylformamide (DMF) and 3 times with isopropanol.
Step 4: The peptide was cleaved from the resin using 85% TFA/5% TIS/5% thioanisole and 5% phenol, followed by precipitation by dry-ice cold (0-4° C.) Et 2 O (Step 4). The crude peptide was collected on a polypropylene sintered funnel, dried, redissolved in a 40% mixture of acetonitrile in water (0.1% TFA) and lyophilized to generate the corresponding crude material used in the purification process.
Compound III
MPA-Ile-Lys-Pro-Glu-Ala-Pro-Gly-Glu-
(SEQ ID NO: 16)
Asp-Ala-Ser-Pro-Glu-Glu-Leu-Asn-Arg-
Tyr-Tyr-Ala-Ser-Leu-Arg-His-Tyr-Leu-
Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-
CONH 2
Step 1: Solid phase peptide synthesis of the DAC derivative on a 100 μmole scale was performed using manual solid-phase synthesis, a Symphony Peptide Synthesizer and Fmoc protected Ramage resin. The following protected amino acids were sequentially added to resin: Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Leu-OH, Fmoc-Asn(Trt)-OH, Fmoc-Leu-OH, Fmoc-Tyr(tBu)-OH, Fmoc-His(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Leu-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ala-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Leu-OH, Fmoc-Glu(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ala-OH, Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Gly-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Glu(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, Fmoc-Ile-OH MPA-OH. They were dissolved in N,N-dimethylformamide (DMF) and, according to the sequence, activated using O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (HBTU) and Diisopropylethylamine (DIEA). Removal of the Fmoc protecting group was achieved using a solution of 20% (V/V) piperidine in N,N-dimethylformamide (DMF) for 20 minutes (step 1).
Step 2: The peptide was cleaved from the resin using 85% TFA/5% TIS/5% thioanisole and 5% phenol, followed by precipitation by dry-ice cold (0-4° C.) Et 2 O (Step 4). The crude peptide was collected on a polypropylene sintered funnel, dried, redissolved in a 40% mixture of acetonitrile in water (0.1% TFA) and lyophilized to generate the corresponding crude material used in the purification process.
Compound IV
Ile-Lys-Pro-Glu-Ala-Pro-Gly-Glu-Asp-
(SEQ ID NO: 6)
Ala-Ser-Pro-Glu-Glu-Leu-Asn-Arg-Tyr-
Tyr-Ala-Ser-Lys(MPA)-Arg-His-Tyr-
Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-
CONH 2
Step 1: Solid phase peptide synthesis of the DAC derivative on a 100 μmole scale was performed using manual solid-phase synthesis, a Symphony Peptide Synthesizer and Fmoc protected Ramage resin. The following protected amino acids were sequentially added to resin: Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Leu-OH, Fmoc-Asn(Trt)-OH, Fmoc-Leu-OH, Fmoc-Tyr(tBu)-OH, Fmoc-His(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Lys(Aloc)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ala-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Leu-OH, Fmoc-Glu(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ala-OH, Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Gly-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Glu(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, Boc-Ile-OH. They were dissolved in N,N-dimethylformamide (DMF) and, according to the sequence, activated using O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (HBTU) and Diisopropylethylamine (DIEA). Removal of the Fmoc protecting group was achieved using a solution of 20% (V/V) piperidine in N,N-dimethylformamide (DMF) for 20 minutes (step 1).
Step 2: The selective deprotection of the Lys (Aloc) group was performed manually and accomplished by treating the resin with a solution of 3 eq of Pd(PPh 3 ) 4 dissolved in 5 mL of C 6 H 6 :CHCl 3 (1:1): 2.5% NMM (v:v): 5% AcOH (v:v) for 2 h (Step 2). The resin is then washed with CHCl 3 (6×5 mL), 20% AcOH in DCM (6×5 mL), DCM (6×5 mL), and DMF (6×5 mL).
Step 3: The synthesis was then re-automated for the addition of the 3-maleimidopropionic acid (Step 3). Between every coupling, the resin was washed 3 times with N,N-dimethylformamide (DMF) and 3 times with isopropanol.
Step 4: The peptide was cleaved from the resin using 85% TFA/5% TIS/5% thioanisole and 5% phenol, followed by precipitation by dry-ice cold Et 2 O (0-4° C.) (Step 4). The crude peptide was collected on a polypropylene sintered funnel, dried, redissolved in a 40% mixture of acetonitrile in water (0.1% TFA) and lyophilized to generate the corresponding crude material used in the purification process.
Compound V
Ile-Lys-Pro-Glu-Ala-Pro-Gly-Glu-Asp-
(SEQ ID NO: 7)
Ala-Ser-Pro-Glu-Glu-Leu-Asn-Arg-
Lys(MPA)-Tyr-Ala-Ser-Leu-Arg-His-
Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-
Tyr-CONH 2
Step 1: Solid phase peptide synthesis of the DAC derivative on a 100 μmole scale was performed using manual solid-phase synthesis, a Symphony Peptide Synthesizer and Fmoc protected Ramage resin. The following protected amino acids were sequentially added to resin: Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Leu-OH, Fmoc-Asn(Trt)-OH, Fmoc-Leu-OH, Fmoc-Tyr(tBu)-OH, Fmoc-His(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Leu-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ala-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Lys(Aloc)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Leu-OH, Fmoc-Glu(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ala-OH, Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Gly-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Glu(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, Boc-Ile-OH They were dissolved in N,N-dimethylformamide (DMF) and, according to the sequence, activated using O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (HBTU) and Diisopropylethylamine (DIEA). Removal of the Fmoc protecting group was achieved using a solution of 20% (V/V) piperidine in N,N-dimethylformamide (DMF) for 20 minutes (step 1).
Step 2: The selective deprotection of the Lys (Aloc) group was performed manually and accomplished by treating the resin with a solution of 3 eq of Pd(PPh 3 ) 4 dissolved in 5 mL of C 6 H 6 :CHCl 3 (1:1): 2.5% NMM (v:v): 5% AcOH (v:v) for 2 h (Step 2). The resin is then washed with CHCl 3 (6×5 mL), 20% AcOH in DCM (6×5 mL), DCM (6×5 mL), and DMF (6×5 mL).
Step 3: The synthesis was then re-automated for the addition of the 3-maleimidopropionic acid (Step 3). Between every coupling, the resin was washed 3 times with N,N-dimethylformamide (DMF) and 3 times with isopropanol.
Step 4: The peptide was cleaved from the resin using 85% TFA/5% TIS/5% thioanisole and 5% phenol, followed by precipitation by dry-ice cold Et 2 O (0-4° C.) (Step 4). The crude peptide was collected on a polypropylene sintered funnel, dried, redissolved in a 40% mixture of acetonitrile in water (0.1% TFA) and lyophilized to generate the corresponding crude material used in the purification process.
Compound VI
Ile-Lys-Pro-Glu-Ala-Pro-Gly-Glu-Asp-
(SEQ ID NO: 8)
Ala-Ser-Pro-Glu-Glu-Lys(MPA)-Asn-
Arg-Tyr-Tyr-Ala-Ser-Leu-Arg-His-Tyr-
Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-
CONH 2
Step 1: Solid phase peptide synthesis of the DAC derivative on a 100 μmole scale was performed using manual solid-phase synthesis, a Symphony Peptide Synthesizer and Fmoc protected Ramage resin. The following protected amino acids were sequentially added to resin: Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Leu-OH, Fmoc-Asn(Trt)-OH, Fmoc-Leu-OH, Fmoc-Tyr(tBu)-OH, Fmoc-His(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Leu-OH, Fmoc-Ser(tBu)-OH, Fmoc-Al a-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Lys(Aloc)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ala-OH, Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Gly-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Glu(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, Boc-Ile-OH They were dissolved in N,N-dimethylformamide (DMF) and, according to the sequence, activated using O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (HBTU) and Diisopropylethylamine (DIEA). Removal of the Fmoc protecting group was achieved using a solution of 20% (V/V) piperidine in N,N-dimethylformamide (DMF) for 20 minutes (step 1).
Step 2: The selective deprotection of the Lys (Aloc) group was performed manually and accomplished by treating the resin with a solution of 3 eq of Pd(PPh 3 ) 4 dissolved in 5 mL of C 6 H 6 :CHCl 3 (1:1): 2.5% NMM (v:v): 5% AcOH (v:v) for 2 h (Step 2). The resin is then washed with CHCl 3 (6×5 mL), 20% AcOH in DCM (6×5 mL), DCM (6×5 mL), and DMF (6×5 mL).
Step 3: The synthesis was then re-automated for the addition of the 3-maleimidopropionic acid (Step 3). Between every coupling, the resin was washed 3 times with N,N-dimethylformamide (DMF) and 3 times with isopropanol.
Step 4: The peptide was cleaved from the resin using 85% TFA/5% TIS/5% thioanisole and 5% phenol, followed by precipitation by dry-ice cold Et 2 O (0-4° C.) (Step 4). The crude peptide was collected on a polypropylene sintered funnel, dried, redissolved in a 40% mixture of acetonitrile in water (0.1% TFA) and lyophilized to generate the corresponding crude material used in the purification process.
Compound VII
Ile-Lys-Pro-Glu-Ala-Pro-Gly-Glu-Asp-
(SEQ ID NO: 9)
Ala-Ser-Pro-Glu-Lys(MPA)-Leu-Asn-
Arg-Tyr-Tyr-Ala-Ser-Leu-Arg-His-Tyr-
Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-
CONH 2
Step 1: Solid phase peptide synthesis of the DAC derivative on a 100 μmole scale was performed using manual solid-phase synthesis, a Symphony Peptide Synthesizer and Fmoc protected Ramage resin. The following protected amino acids were sequentially added to resin: Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Leu-OH, Fmoc-Asn(Trt)-OH, Fmoc-Leu-OH, Fmoc-Tyr(tBu)-OH, Fmoc-His(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Leu-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ala-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Leu-OH, Fmoc-Lys(Aloc)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ala-OH, Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Gly-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Glu(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, Boc-Ile-OH They were dissolved in N,N-dimethylformamide (DMF) and, according to the sequence, activated using O-benzotriazol-1-yl-N, N,N′,N′-tetramethyl-uronium hexafluorophosphate (HBTU) and Diisopropylethylamine (DIEA). Removal of the Fmoc protecting group was achieved using a solution of 20% (V/V) piperidine in N,N-dimethylformamide (DMF) for 20 minutes (step 1).
Step 2: The selective deprotection of the Lys (Aloc) group was performed manually and accomplished by treating the resin with a solution of 3 eq of Pd(PPh 3 ) 4 dissolved in 5 mL of C 6 H 6 :CHCl 3 (1:1): 2.5% NMM (v:v): 5% AcOH (v:v) for 2 h (Step 2). The resin is then washed with CHCl 3 (6×5 mL), 20% AcOH in DCM (6×5 mL), DCM (6×5 mL), and DMF (6×5 mL).
Step 3: The synthesis was then re-automated for the addition of the 3-maleimidopropionic acid (Step 3). Between every coupling, the resin was washed 3 times with N,N-dimethylformamide (DMF) and 3 times with isopropanol.
Step 4: The peptide was cleaved from the resin using 85% TFA/5% TIS/5% thioanisole and 5% phenol, followed by precipitation by dry-ice cold Et 2 O (0-4° C.) (Step 4). The crude peptide was collected on a polypropylene sintered funnel, dried, redissolved in a 40% mixture of acetonitrile in water (0.1% TFA) and lyophilized to generate the corresponding crude material used in the purification process.
Compound VIII
Ile-Lys-Pro-Glu-Ala-Pro-Gly-Glu-
(SEQ ID NO: 10)
Asp-Ala-Ser-Pro-Lys(MPA)-Glu-Leu-
Asn-Arg-Tyr-Tyr-Ala-Ser-Leu-Arg-
His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-
Gln-Arg-Tyr-CONH 2
Step 1: Solid phase peptide synthesis of the DAC derivative on a 100 μmole scale was performed using manual solid-phase synthesis, a Symphony Peptide Synthesizer and Fmoc protected Ramage resin. The following protected amino acids were sequentially added to resin: Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Leu-OH, Fmoc-Asn(Trt)-OH, Fmoc-Leu-OH, Fmoc-Tyr(tBu)-OH, Fmoc-His(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Leu-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ala-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Leu-OH, Fmoc-Glu(tBu)-OH, Fmoc-Lys(Aloc)-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ala-OH, Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Gly-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Glu(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, Boc-Ile-OH They were dissolved in N,N-dimethylformamide (DMF) and, according to the sequence, activated using O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (HBTU) and Diisopropylethylamine (DIEA). Removal of the Fmoc protecting group was achieved using a solution of 20% (V/V) piperidine in N,N-dimethylformamide (DMF) for 20 minutes (step 1).
Step 2: The selective deprotection of the Lys (Aloc) group was performed manually and accomplished by treating the resin with a solution of 3 eq of Pd(PPh 3 ) 4 dissolved in 5 mL of C 6 H 6 :CHCl 3 (1:1): 2.5% NMM (v:v): 5% AcOH (v:v) for 2 h (Step 2). The resin is then washed with CHCl 3 (6×5 mL), 20% AcOH in DCM (6×5 mL), DCM (6×5 mL), and DMF (6×5 mL).
Step 3: The synthesis was then re-automated for the addition of the 3-maleimidopropionic acid (Step 3). Between every coupling, the resin was washed 3 times with N,N-dimethylformamide (DMF) and 3 times with isopropanol.
Step 4: The peptide was cleaved from the resin using 85% TFA/5% TIS/5% thioanisole and 5% phenol, followed by precipitation by dry-ice cold Et 2 O (0-4° C.) (Step 4). The crude peptide was collected on a polypropylene sintered funnel, dried, redissolved in a 40% mixture of acetonitrile in water (0.1% TFA) and lyophilized to generate the corresponding crude material used in the purification process.
Compound IX
Ile-Lys-Pro-Glu-Ala-Pro-Gly-Glu-
(SEQ ID NO: 11)
Asp-Ala-Ser-Lys(MPA)-Glu-Glu-Leu-
Asn-Arg-Tyr-Tyr-Ala-Ser-Leu-Arg-
His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-
Gln-Arg-Tyr-CONH 2
Step 1: Solid phase peptide synthesis of the DAC derivative on a 100 μmole scale was performed using manual solid-phase synthesis, a Symphony Peptide Synthesizer and Fmoc protected Ramage resin. The following protected amino acids were sequentially added to resin: Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Leu-OH, Fmoc-Asn(Trt)-OH, Fmoc-Leu-OH, Fmoc-Tyr(tBu)-OH, Fmoc-His(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Leu-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ala-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Leu-OH, Fmoc-Glu(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Lys(Aloc)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ala-OH, Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Gly-OH, Fmoc-Pro-OH, Fmoc-Ala-OH, Fmoc-Glu(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, Boc-Ile-OH They were dissolved in N,N-dimethylformamide (DMF) and, according to the sequence, activated using O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (HBTU) and Diisopropylethylamine (DIEA). Removal of the Fmoc protecting group was achieved using a solution of 20% (V/V) piperidine in N,N-dimethylformamide (DMF) for 20 minutes (step 1).
Step 2: The selective deprotection of the Lys (Aloc) group was performed manually and accomplished by treating the resin with a solution of 3 eq of Pd(PPh 3 ) 4 dissolved in 5 mL of C 6 H 6 :CHCl 3 (1:1): 2.5% NMM (v:v): 5% AcOH (v:v) for 2 h (Step 2). The resin is then washed with CHCl 3 (6×5 mL), 20% AcOH in DCM (6×5 mL), DCM (6×5 mL), and DMF (6×5 mL).
Step 3: The synthesis was then re-automated for the addition of the 3-maleimidopropionic acid (Step 3). Between every coupling, the resin was washed 3 times with N,N-dimethylformamide (DMF) and 3 times with isopropanol.
Step 4: The peptide was cleaved from the resin using 85% TFA/5% TIS/5% thioanisole and 5% phenol, followed by precipitation by dry-ice cold Et 2 O (0-4° C.) (Step 4). The crude peptide was collected on a polypropylene sintered funnel, dried, redissolved in a 40% mixture of acetonitrile in water (0.1% TFA) and lyophilized to generate the corresponding crude material used in the purification process.
Compound X
Ac-Ala-Ser-Leu-Arg-His-Tyr-Leu-
(SEQ ID NO: 12)
Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-
CONH 2
Step 1: Solid phase peptide synthesis of the DAC derivative on a 100 μmole scale was performed using manual solid-phase synthesis, a Symphony Peptide Synthesizer and Fmoc protected Ramage resin. The following protected amino acids were sequentially added to resin: Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Leu-OH, Fmoc-Asn(Trt)-OH, Fmoc-Leu-OH, Fmoc-Tyr(tBu)-OH, Fmoc-His(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Leu-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ala-OH, Acetic Acid. They were dissolved in N,N-dimethylformamide (DMF) and, according to the sequence, activated using O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (HBTU) and Diisopropylethylamine (DIEA). Removal of the Fmoc protecting group was achieved using a solution of 20% (V/V) piperidine in N,N-dimethylformamide (DMF) for 20 minutes (step 1).
Step 2: The peptide was cleaved from the resin using 85% TFA/5% TIS/5% thioanisole and 5% phenol, followed by precipitation by dry-ice cold Et 2 O (0-4° C.) (Step 4). The crude peptide was collected on a polypropylene sintered funnel, dried, redissolved in a 40% mixture of acetonitrile in water (0.1% TFA) and lyophilized to generate the corresponding crude material used in the purification process.
Compound XI
MPA-Ala-Ser-Leu-Arg-His-Tyr-Leu-
(SEQ ID NO: 12)
Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-
CONH 2
Step 1: Solid phase peptide synthesis of the DAC derivative on a 100 μmole scale was performed using manual solid-phase synthesis, a Symphony Peptide Synthesizer and Fmoc protected Ramage resin. The following protected amino acids were sequentially added to resin: Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Leu-OH, Fmoc-Asn(Trt)-OH, Fmoc-Leu-OH, Fmoc-Tyr(tBu)-OH, Fmoc-His(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Leu-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ala-OH, MPA-OH. They were dissolved in N,N-dimethylformamide (DMF) and, according to the sequence, activated using O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (HBTU) and Diisopropylethylamine (DIEA). Removal of the Fmoc protecting group was achieved using a solution of 20% (V/V) piperidine in N,N-dimethylformamide (DMF) for 20 minutes (step 1).
Step 2: The peptide was cleaved from the resin using 85% TFA/5% TIS/5% thioanisole and 5% phenol, followed by precipitation by dry-ice cold Et 2 O (0-4° C.) (Step 4). The crude peptide was collected on a polypropylene sintered funnel, dried, redissolved in a 40% mixture of acetonitrile in water (0.1% TFA) and lyophilized to generate the corresponding crude material used in the purification process.
Compound XII
Ac-Ala-Ser-Leu-Arg-His-Tyr-Leu-
(SEQ ID NO: 13)
Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-
Lys(MPA)-CONH 2
Step 1: Solid phase peptide synthesis of the DAC derivative on a 100 μmole scale was performed using manual solid-phase synthesis, a Symphony Peptide Synthesizer and Fmoc protected Ramage resin. The following protected amino acids were sequentially added to resin: Fmoc-Lys(Aloc)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Leu-OH, Fmoc-Asn(Trt)-OH, Fmoc-Leu-OH, Fmoc-Tyr(tBu)-OH, Fmoc-His(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Leu-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ala-OH, Acetic Acid. They were dissolved in N,N-dimethylformamide (DMF) and, according to the sequence, activated using O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (HBTU) and Diisopropylethylamine (DIEA). Removal of the Fmoc protecting group was achieved using a solution of 20% (V/V) piperidine in N,N-dimethylformamide (DMF) for 20 minutes (step 1).
Step 2: The selective deprotection of the Lys (Aloc) group was performed manually and accomplished by treating the resin with a solution of 3 eq of Pd(PPh 3 ) 4 dissolved in 5 mL of C 6 H 6 :CHCl 3 (1:1): 2.5% NMM (v:v): 5% AcOH (v:v) for 2 h (Step 2). The resin is then washed with CHCl 3 (6×5 mL), 20% AcOH in DCM (6×5 mL), DCM (6×5 mL), and DMF (6×5 mL).
Step 3: The synthesis was then re-automated for the addition of the 3-maleimidopropionic acid (Step 3). Between every coupling, the resin was washed 3 times with N,N-dimethylformamide (DMF) and 3 times with isopropanol.
Step 4: The peptide was cleaved from the resin using 85% TFA/5% TIS/5% thioanisole and 5% phenol, followed by precipitation by dry-ice cold Et 2 O (0-4° C.)
2. Purification procedure:
Each product was purified by preparative reversed phase HPLC, using a Varian (Dynamax) preparative binary HPLC system.
Purification of all the above compounds were performed using a Phenomenex Luna 10μ phenyl-hexyl, 50 mm×250 mm column (particules 10μ) equilibrated with a water/TFA mixture (0.1% TFA in H 2 O; Solvent A) and acetonitrile/TFA (0.1% TFA in CH 3 CN; Solvent B). Elution was achieved at 50 mL/min by running various gradients of % B gradient over 180 min. Fractions containing peptide were detected by UV absorbance (Varian Dynamax UVD II) at 214 and 254 nm.
Fractions were collected in 25 mL aliquots. Fractions containing the desired product were identified by mass detection after direct injection onto LC/MS. The selected fractions were subsequently analyzed by analytical HPLC (20-60% B over 20 min; Phenomenex Luna 5μ phenyl-hexyl, 10 mm×250 mm column, 0.5 mL/min) to identify fractions with ≧90% purity for pooling. The pool was freeze-dried using liquid nitrogen and subsequently lyophilized for at least 2 days to yield a white powder.
Other suitable peptides are represented in the following sequences:
Tyr-Pro-Ala-Lys-Pro-Glu-Ala-Pro- (SEQ ID NO: 14) Gly-Glu-Asp-Ala-Ser-Pro-Glu-Glu- Leu-Ser-Arg-Tyr-Tyr-Ala-Ser-Leu- Arg-His-Tyr-Leu-Asn-Leu-Val-Thr- Arg-Gln-Arg-Tyr; and Tyr-Pro-Ile-Lys-Pro-Glu-Ala-Pro- (SEQ ID NO: 15) Gly-Glu-Asp-Ala-Ser-Pro-Glu-Glu- Leu-Asn-Arg-Tyr-Tyr-Ala-Ser-Leu- Arg-His-Tyr-Leu-Asn-Leu-Leu-Thr- Arg-Pro-Arg-Tyr.
3. Table of Products
TABLE 1 List of the various peptides prepared together with their molecular weight Compound no: Theoretical M.W. Actual M.W. I 4049.5 4049.5 II 4328.8 4328.6 III 4200.6 4200.0 IV 4255.5 4257.1 V 4212.2 4214.1 VI 4197.2 4199.0 VII 4229.1 4231.5 VIII 4239.2 4241.6 IX 4255.2 4257.5 X 1931.2 1930.7 XI 2185.5 2185.0 XII 2210.5 2210.1
4. Flow Diagram for Each Compound:
A) Identical synthetic schemes, as exemplified in the flow diagram below, were employed for all stabilized DAC™. Of course, for the natives the Aloc removal step along with the addition step of AEEA and\or MPA were omitted.
Direct Synthesis
Alternative Synthesis of Compound III and Isolation of Compound XIII
PYY 3-36 (human) is a 34 amino acids peptide. From the sequence the N-terminal and lysine residue (in position 2) can be modified by direct attachment of the DAC group. Since the peptide is not very soluble in DMF, it has to be treated with TFA to be dissolved and then neutralized by NMM. Thus the reaction has to be in the TFA/NMM buffer system. However, both amino groups in N-terminal and lysine show the same reactivity towards MPA-OSu under the buffer system. With 1 equivalent of MPA-OSu in the TFA/NMM system, the reaction produced four different products. The differences between these products are the position of the MPA on the sequence and the number of MPA attached to the sequence. Two positional isomers of having a single MPA group (MPA-PYY) have been obtained as major products and two positional isomers having two MPA groups ((MPA) 2 -PYY and cyclization)) have been minor products. These four products were separated by HPLC. The positional isomers bearing a single MPA have been isolated to give MPA-PYY positional isomer-1 (Compound XIII) and positional isomer-2 (Compound III) in 27.8 and 15.2% yield respectively (see the following scheme). The starting material PYY was also recovered (37.6% recovery).
Compounds XIV and XV
In the same way, PYY can react with excess MPA-OA-OpNP for overnight to give two positional isomers having a single MPA group: MPA-OA-PYY isomer-1 (Compound XIV, 19% yield) and MPA-OA-PYY isomer-2 (Compound XV, 17.2% yield). In this case, MPA-OA-OpNP ester is less reactive and thus a large excess reagent is required for the reaction to occur. The minor products are still cyclization and (MPA-OA) 2 -PYY.
PYY (100 mg) was dissolved in DMF (5 mL) in the presence of TFA (25 μL) with the help of sonication. Then NMM (100 μL) was added followed by addition of MPA-OSu (5.6 mg). The reaction was stirred at room temperature for 2.5 h. The reaction was quenched by addition of AcOH (1 mL). The DMF solution was diluted with water to 20 mL. The products were separated by semi-preparative HPLC column (3 injections) to give PYY (37.6 mg), MPA-PYY isomer-1 (Compound XII, 27.8 mg) and PMA-PYY isomer-2 (Compound XIII, 15.2 mg).
PYY (50 mg) was dissolved in DMF (5 mL) in the presence of TFA (25 μL). NMM (100 μL) was then added followed by MPA-OA-OpNP (50 mg). The reaction was stirred for 16 h at room temperature. The linker was removed by addition of ether and the solution removed after centrifugation. The precipitate was dissolved in water and injected to semi-preparative HPLC to give MPA-OA-PYY isomer-1 (Compound XIV, 9.5 mg) and MPA-OA-PYY isomer-2 (Compound XV, 8.6 mg).
Compound XVI
Compound III was solubilized in nanopure water at a concentration of 10 mM then diluted to 1 mM into a solution of HSA (25%, Cortex-Biochem, San Leandro, Calif.). The sample were then incubated at 37° C. for 30 min. Prior to purification, the conjugate solution was diluted to 5% HSA in 20 mM sodium phosphate buffer (pH 7) composed of 5 mM sodium octanoate and 750 mM (NH 4 ) 2 SO 4 .
Using an ÄKTA purifier (Amersham Biosciences, Uppsala, Sweden), the conjugate was loaded at a flow rate of 2.5 ml/min onto a 50 ml column of butyl sepharose 4 fast flow resin (Amersham Biosciences, Uppsala, Sweden) equilibrated in 20 mM sodium phosphate buffer (pH 7) composed of 5 mM sodium octanoate and 750 mM (NH 4 ) 2 SO 4 . Under these conditions, Compound XVI adsorbed onto the hydrophobic resin whereas essentially all non-conjugated (unreacted) HSA eluted within the void volume of the column. The conjugate was further purified from any free (unreacted) maleimido PYY 3-36 derivative by applying a linear gradient of decreasing (NH 4 ) 2 SO 4 concentration (750 to 0 mM) over 4 column volumes. The purified conjugate was then desalted and concentrated using Amicon® ultra centrifugal (30 kDa) filter devices (Millipore Corporation, Bedford, Mass.). Finally, the conjugate solution was immersed into liquid nitrogen, lyophilized and stored at −80° C.
Compounds XVII to XXII
Compounds XVII to XXII are all conjugates having in form of a white solid and they have been prepared according to the same manner than Compound XVI. The table below indicates from which peptides these conjugates have been prepared. Moreover, the molecular weight of each conjugate is given.
TABLE 2
Conjugates obtained from various peptides.
M r (conjugates)
Peptides
Conjugate
Predicted
Measured
Compound III
Compound XVI
70643
70639
Compound XIII
Compound XXI
70645
70640
Compound XI
Compound XXII
68629
68626
Compound II
Compound XIX
70771
70668
Compound XII
Compound XVIII
68654
68651
Compound XV
Compound XVII
70787
70785
Compound XIV
Compound XX
70787
70785
Example I
In vitro Binding Assay: Selectivity Toward the NPY Y2 Receptor
Serially diluted test compounds (10 −13 M to 10 −5 M) were incubated for 60 minutes at 37° C. in the presence of 4.09 μg of human neuropeptide Y2 receptor expressing human KAN-TS cells and 50000 CPM of 125 I-PYY 3-36 . The individual solutions were filtered (Whatman 934 A/H filters) and washed with ice-cold buffer. The filters were then placed in a gamma counter and the values reported as the percent relative to the maximum gamma emission at the zero concentration as a function of test compound concentration as shown on Table 3.
TABLE 3
Comparison of the NPY Y2 Receptor
binding of the PYY derivatives
Peptide
Sequence
IC 50 (nM)
Compound I
PYY 3–36
1.17
NPY( 13–36 ) control
—
2.48
Compound XVI
N-term SL PYY 3–36 -HSA
35.2
conjugate
Compound XVII
N-term LL PYY 3–36 -HSA
52.4
conjugate
Compound XX
N-K5 LL PYY 3–36 -HSA
40.2
conjugate
Compound XIX
C-term SL PYY 3–36 -HSA
>10 3
conjugate
Compound XVIII
C-term SL PYY 22–36 -HSA
>10 3
conjugate
Example II
In vitro Binding Assay: Loss of Selectivity Toward the NPY Y1 Receptor
Compound I (PYY 3-36 ) and Compound XVI were tested so as to evaluate the preferential binding of the Y2 receptor relative to the Y1 receptor. A selective binding to the Y2 receptor ensures reduced (unwanted) side effects such as for example hypertension.
TABLE 4
Comparison of the NPY Y1 Receptor
binding of the PYY derivatives
Peptide
Sequence
IC 50 (nM)
Compound I
PYY 3–36
83.2
NPY(human, rat) control
—
1.09
Compound XVI
N-term SL PYY 3–36 -HSA
875.9
conjugate
Example III
Food Intake in Rats Following IV Administration of DAC
Compound I (PYY 3-36 ) and Compound III were injected into the tail vein of fully grown Sprague-Dawley rats. Two experiments were carried out so as to verify the influence of the concentration on Compound III of the food consumption of the animal. The food intake was measured pre and post administration (see FIGS. 1 and 2 ). In experiment 1 on FIG. 1 , 4-500 g rats were used and in experiment 2 on FIG. 2 , 2-300 g rats were used.
As it can be seen from FIGS. 1 and 2 , the results shown a significant reduction in food intake over the 0-12 hour and 12-24 hour periods. The overall effect is very significant over the 0-24 hour period at the highest dose tested (375 nM/kg).
A comparison of reduction in food intake in the two experiments can easily be made by using FIGS. 3 and 4 . It can be seen from FIGS. 3 and 4 that PYY 3-36 does not show reduction in food after 24 hrs at a dose of 25 nmol/kg or at a dose of 375 nmol/kg, while Compound III, at a dose of 375 nmol/kg, shows a strong effect by reducing food intake by 50% after 24 hrs. This comparison demonstrates the long lasting effect of Compound III as compared to the free peptide PYY 3-36 in vivo.
Example IV
Peripheral vs. Central Action of Compound III
A publication by Batterham ( Nature, 2002, 418, 650-654) demonstrated the strong effect of PYY 3-36 administration into the arcuate nucleus to rats on overall food intake. The arcuate nucleus does possess a blood brain barrier and therefore no evidence was ever shown in the literature that peripheral neuropeptide Y2 receptors would have and influence on food intake. Applicant has shown that Compound XVI cannot cross the blood brain barrier (molecular weight >70 000 Da). It is known that PYY 3-36 interacts with the Y2 receptor found in the arcuate nucleus of the hypothalamus. This receptor is found behind the blood brain barrier (BBB). Nonaka et al., in an article entitled “Characterization of blood-brain barrier permeability to PYY 3-36 in the mouse” and published in J. Pharmacol. Exp. Ther. 2003, 306, 948-53, have hypothesized that the PYY must “cross the BBB” in order to be responsible for the appetite regulating activity.
The injection of Compound XVI i.p. into acclimatized Sprague-Dawley rats in a repeat of the Batterham experiment showed the results shown in FIG. 5 .
According to FIG. 5 , the 375 nmol/kg dose showed significant reduction in food intake at the 4 hour time point in the experiment. The results are comparable to PYY3-36 25 nmol/kg. Even though there is 15 fold more Compound XVI, pharmacokinetics of absorption will play a role in this head to head comparison. Compound XVI will peak in plasma at a later time than the short peptide. This experiment was done to compare the HSA conjugate directly to the peptide.
It has thus been demonstrated from FIGS. 3 and 4 that the compounds of the invention are very effective for treating food disorders such as obesity. In fact the peptide (Compound III) demonstrated an activity which clearly superior than the activity of PYY 3-36 . It can also be inferred from the results shown in FIG. 5 that the conjugate (Compound XVI) is prevented from crossing the blood brain barrier. In fact reduction in food intake via the PYY receptors (Y1 and Y2, which are thought to have an important role in appetite reduction) is thought to be found on the arcuate nucleus. There is a blood brain barrier separating the arcuate nucleus from plasma. The importance of this experiment is that the conjugate (Compound XVI) has a molecular mass >70 kDA. Therefore, this compound does not cross the blood brain barrier. It can thus be assumed that the PYY receptors involved in the reduction of food intake are found peripherally.
As demonstrated in Kratz et al. J. Med. Chem. 2002, 45, 5523-33, when a compound containing a reactive maleimide group such as compound III is injected in a patient, this compound will be eventually covalently bonded to albumin, thereby being converted into Compound XVI. It can thus be said from FIGS. 1 to 5 that the enhanced activity of Compound III with respect to the activity of PYY 3-36 is due to the fact that Compound III is prevented from crossing the blood brain barrier when the latter is covalently bonded to HSA (converted into Compound XVI).
It has thus been surprisingly noted that by preventing a PYY peptides or derivative thereof from crossing the blood brain barrier, an enhanced anti-obesity activity of this peptide is observed as compared to the peptide alone.
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The present invention relates to a compound comprising a PYY peptide or a functional derivative thereof, which is coupled to a reactive group. Such a reactive group is capable of reacting on a blood component so as to form a stable covalent bond therewith. The present invention also relates to a conjugate comprising such a compound which is covalently bonded to a blood component. Moreover, the invention also relates to a method of enhancing, in a patient, the anti-obesity activity of a PYY peptide or functional derivative thereof.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to an oral care composition which contains a bis-biguanide compound effective in the retardation of bacterial plaque accumulation on the teeth and gum diseases such as gingivitis and periodontitis. More particularly, the present invention relates to a dual component dentifrice composition of improved shelf-stability containing a bis-biguanide compound which achieves plaque and gimgivitis reduction with substantially less staining of teeth than normally occurs with bis-biguanide compound containing dentifrices and rinses.
2. The Prior Art
Dental plaque is a soft deposit which forms on teeth and is comprised of an accumulation of bacteria and bacterial by-products. Plaque adheres tenaciously at the points of irregularity or discontinuity, e.g., on rough calculus surfaces, at the gum line and the like. Besides being unsightly, plaque is implicated in the occurrence of gingivitis and other forms of periodontal disease.
A wide variety of antibacterial agents have been suggested in the art to retard plaque formation and the oral infection and dental disease associated with plaque formation. For example, bis-biguanide compounds such as chlorhexidine are well known to the art for their antibacterial activity and have been used in oral compositions to counter plaque formation by bacterial accumulation in the oral cavity. However, it is also well known that bis-biguanide compounds, when used as dental antiplaque agents cause unsightly staining of teeth. Many procedures have been proposed by the art to reduce such tooth staining: U.S. Pat. Nos. 3,925,543, 3,934,002, 3,937,807, 4,051,234, 4,080,441, 4,256,931, 4,273,759 and 4,886,658. However, the presence of bis-biguanide compounds in dentifrice compositions containing conventional ingredients such as abrasives, anionic surfactants and flavorants which are necessary for adequate cleaning and palatability of the dentifrice, these ingredients are normally incompatible with bis-biguanide compounds, and tend to diminish the bioavailability of such compounds necessary for antiplaque efficacy.
U.S. Pat. No. 5,958,381 discloses a dentifrice product capable of delivering a bis-biguanide antibacterial agent without bioavailability limitation and with limited tooth staining. U.S. Pat. No. 5,958,381 discloses a dual component bis-biguanide containing dentifrice composition in which the first component contains a bis-biguanide antibacterial agent and the second component contains an abrasive such as silica or alumina normally incompatible with the bis-biguanide. Undiminished antibacterial efficacy with minimal staining is achieved when the components which are physically separated prior to use are mixed upon tooth brushing application. However, subsequently a problem has been found to exist with the dual component composition in that the packaged dentifrice has been found to lack sufficient shelf stability for commercial acceptance.
SUMMARY OF THE INVENTION
The present invention encompasses a dual component dental composition having improved shelf stability which when applied to teeth contains a combination of a bis-biguanide compound, an abrasive and other ingredients normally incompatible with the bis-biguanide compound whereby reduction of plaque is accomplished during tooth brushing with substantially less staining of teeth that normally accompanies the use of dental compositions containing bis-biguanide compounds.
The present invention is based upon the discovery that when the separately maintained bis-biguanide compound containing dental gel component of U.S. Pat. No. 5,958,381 is prepared with a cellulose polymer thickener instead of polyoxyethylene/polyoxypropylene block copolymer as disclosed in U.S. Pat. No. 5,958,381, improved shelf stability is attained with undiminished antiplaque efficacy and limited staining when the teeth are brushed with the combined components.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the practice of the present invention the dental gel component containing the bis-biguanide ingredient is prepared using a vehicle containing a safe and effective amount of the bis-biguanide compound such as chlorhexidine in a suitable pharmaceutically acceptable vehicle in which a cellulose polymer is used as the thickening agent.
The bis-biguanide compounds useful in the practice of the present invention are known to the art and a disclosure of such compounds may be found in U.S. Pat. No. 4,886,650 (columns 2-3) which disclosure is herewith incorporated by reference. A bis-biguanide compound preferred for use in the present invention is di(N 1 ,N 1 ′-p-chlorophenyldiguanido-N 5 ,N 5 ′)hexane (chlorhexidine) and water soluble salts thereof, including the digluconate and the diacetate salts, especially the digluconate salts. Other salts include the diproponate, the diformate, the dilactate, the dihydrochloride, the dihydrofluoride, the dihydrobromide, the sulfate, the phosphate, the succinate, the pivalate, the citrate, the tartrate and the maleate. Other suitable bis-biguanide compounds include hexetidine, octenidine and alexidine.
The bis-biguanide compounds are incorporated in gel component of the present invention at about 0.001% to about 4% by weight of the gel and preferably about 2%.
The gel component prepared is using a vehicle which contains water, humectant, nonionic surfactant and thickener. The humectant is generally a mixture of humectants, such as glycerin, sorbitol and a polyethylene glycol of a molecular weight in the range of 200-1000, but other mixtures of humectants and single humectants may also be employed. The humectant content is in the range of about 10% to about 50% by weight and preferably about 10-30% by weight. The water content is in the range of about 10 to about 80% by weight.
Cellulose polymer thickeners useful in preparing a stable vehicle for the bis-biguanide containing gel component of the present invention includes hydroxyethylpropylcellulose, hydroxybutyl methyl cellulose, hydroxypropyl methyl cellulose, and hydroxyethyl cellulose sodium carboxymethyl cellulose. The cellulose polymer thickener may be incorporated in the gel component of the present invention at a concentration of about 1.0 to about 6% by weight and preferably about 3 to about 5% by weight.
A surfactant is incorporated in the gel component to provide foaming properties. The surfactant is preferably nonionic and is included in the gel component in amounts up to about 3% and preferably from about 0.05% to about 2% by weight of the composition.
Examples of suitable nonionic surfactants for use in the present invention include condensates of sorbitan esters of fatty acids with ehtylene oxide (polysorbates) such as sorbitan mono-oleate with from about 20 to about 60 moles of ethylene oxide. A particularly preferred polysorbate is Polysorbate 20, polyoxyethylene 20 sorbitan monolaurate.
Additional suitable nonionic surfactants useful in the present invention are the condensation products of an alpha-olefin oxide containing 10 to 20 carbon atoms, a polyhydric alcohol containing 2 to 10 carbon atoms and 2 to 6 hydroxyl groups, and either ethylene oxide or a mixture of ethylene oxide and peropylene oxide. The resultant surfactants are polymers which have a molecular weight in the range from about 400 to about 160, contain from about 40% to about 80% ethylene oxide by weight and have an alpha-olefin oxide to polyhydric alcohol mole ratio in the range from about 1:1 to about 1:3, respectively. Other nonionic surfactants useful in the present invention include condensates of sorbitan esters of fatty acids with polyethylene glycol such as sorbitan isostearate condensed with polyethylene glycol.
The paste component of the present invention in which an abrasive material is included, is generally a paste prepared using a vehicle which contains water, humectant, nonionic surfactant and thickener. The humectant is generally a mixture of humectants, such as glycerin, sorbitol and a polyethylene glycol of a molecular weight in the range of 200-1000, but other mixtures of humectants and single humectants may also be employed. The humectant content is in the range of about 10% to about 80% by weight and preferably about 10-30% by weight. The water content is in the range of about 10 to about 30% by weight.
Thickeners which may be used in the preparation of the abrasive paste component include natural and synthetic gums such as carrageenan (Irish moss), xanthan gum and sodium carboxymethyl cellulose, starch, polyvinylpyrrolidone, hydroxyethylpropylcellulose, hydroxybutyl methyl cellulose, hydroxypropyl methyl cellulose, and hydroxyethyl cellulose. Hydroxyethyl cellulose is the preferred thickener for use in preparing the paste component. The thickener may be incorporated in the abrasive containing dentifrice component of the present invention at a concentration of about 0.1 to about 3% by weight and preferably about 0.3 to about 1.5% by weight.
By using a cellulose polymer thickener in the gel and synthetic gum in the paste component it has been determined that the force required to actuate the dual gel and paste components is substantially reduced as compared to similar dual component compositions in which thickeners of different compositions were used to prepare the individual components.
A surfactant is incorporated in the abrasive paste component to provide foaming properties. The surfactant is preferably nonionic, and is included in the abrasive dentifrice component in amounts up to about 3%, and preferably from about 0.05% to about 2% by weight of the composition.
Examples of suitable nonionic surfactants for use in the present invention include condensates of sorbitan esters of fatty acids with ethylene oxide (polysorbates) such as sorbitan mono-oleate with from about 20 to about 60 moles of ethylene oxide. A particularly preferred polysorbate is Polysorbate 20, polyoxyethylene 20 sorbitan monolaurate.
Additional suitable nonionic surfactants useful in the present invention are the condensation products of an alpha-olefin oxide containing 10 to 20 carbon atoms, a polyhydric alcohol containing 2 to 10 carbon atoms and 2 to 6 hydroxyl groups, and either ethylene oxide or a mixture of ethylene oxide and propylene oxide. The resultant surfactants are polymers which have a molecular weight in the range from about 400 to about 1600, contain from about 40% to about 80% ethylene oxide, by weight, and have an alpha-olefin oxide to polyhydric alcohol mole ratio in the range from about 1:1 to abut 1:3, respectively. Other nonionic surfactants useful in the present invention include condensates of sorbitan esters of fatty acids with polyethylene glycol such as sorbitan diisostearate condensed with polyethylene glycol.
Silica abrasives are the preferred abrasive for preparing the paste component of the present invention. Examples of such silica abrasives include precipitated silicas having a mean particle size of up to about 20 microns, such as Zeodent 115, marketed by J. M. Huber Chemicals Division, Havre de Grace, Maryland 21078, or Sylodent 783 marketed by Davison Chemical Division of W. R. Grace & Company.
Particularly preferred abrasive materials useful in the practice of the preparation of dentifrice compositions in accordance with the present invention include silica gels and precipitated amorphous silica having an oil absorption value as measured by ASTM Rub-Out Method D281 of less than 100 cc/100 g silica and preferably in the range of from about 45 cc/100 g to less than about 70 cc/100 g silica. These silicas are colloidal particles having an average particle size ranging from about 3 microns to about 12 microns, and more preferably between about 5 to about 10 microns and a pH range from 4 to 10 preferably 6 to 9 when measured as a 5% by weight slurry.
Commercially available low oil absorption silica abrasives are marketed under the trade designation Sylodent XWA by Davison Chemical Division of W. R. Grace & Co., Baltimore, Md. 21203. Sylodent 650 XWA, a silica hydrogel composed of particles of colloidal silica having a water content of 29% by weight averaging from about 7 to about 10 microns in diameter, and an oil absorption of less than 70 cc/100 g of silica.
The silica abrasive is present in the oral are compositions of the present invention at a concentration of about 5 to about 50% by weight and preferably about 10 to about 40% by weight.
Fluorine-providing salts having anti-caries efficacy may also be incorporated in the abrasive dentifrice component of the present invention and are characterized by their ability to release fluoride ions in water. Among these materials are alkali metal salts, for example, sodium fluoride, potassium fluoride, sodium fluorosilicate, and sodium monofluorophosphate. It is preferable to employ a fluoride salt to release about 10 to 1500 ppm of fluoride ion in the product mixture.
Any suitable flavoring or sweetening material may also be incorporated in the abrasive containing dentifrice component of the present invention. Examples of suitable flavoring constituents are flavoring oils, e.g., oils 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 and sodium saccharin. Suitably, flavor and sweetening agents may together comprise from 0.01% to 5% by weight or more of the abrasive containing dentifrice and at such concentrations render the combined gel and dentifrice components with a palatability acceptable to the user.
A striped dentifrice product is obtained in accordance with the practice of the present invention wherein colorants of contrasting colors are incorporated in each of the dentifrice components used in the practice of the present invention, the colorants being pharmacologically and physiologically nontoxic when used in the suggested amounts. Colorants used in the practice of the present invention include pigments and dyes.
Pigments used in the practice of the present invention include non-toxic, water insoluble inorganic pigments such as titanium dioxide and chromium oxide greens, ultramarine blues and pinks and ferric oxides as well as water insoluble dye lakes prepared by extending calcium or aluminum salts of FD&C # Yellow 15 lake. The pigments have a particle size in the range of 5-1000 microns, preferably 250-500 microns, and are present at a concentration of 0.5 to 3% by weight.
The dyes used in the practice of the present invention are generally food color additive presently certified under the Food Drug & Cosmetic Act for use in food and ingested drugs, including dyes such as FD&C Red #3 (sodium salts of tetraiodofluorescein), FD&C Yellow #5 (sodium slat of 4-p-sulfophenylaxo-B-naphtol-6-monosulfonate), FD&C Green #3 (disodium salt of 4-{[4-(n-ethyl-p-sulfobenzylamino)-phenyl ]-4-hydroxy-2-sulfoniumphenyl)-methylene}-[1-(N-ethyl-N-p-sulfobenzyl)-3,5-cyclohexadienimine], FD&C Blue #1 (disodium salt of disulfonic acid of indigotin) and mixtures thereof in various proportions. The concentration of the dye for the most effective result in the present invention is present in the abrasive containing dentifrice composition in an amount from about 0.0005% to about 2% by weight.
It is preferred that the colorant included in the gel component be a dye and that the colorant included in the abrasive containing dentifrice component be a pigment such as TiO 2 and that the pigment be of a different color than the dye included in the gel component.
To prepare the bis-biguanide compound containing gel component of the present invention, the cellulose polymer and humectant are dispersed in a conventional mixer. The bis-biguanide compound, water and color are mixed separately for 10 minutes. The polymer/humectant mixture is then added to the water mixture in a vacuum mixer and mixed for 20-40 minutes under a vacuum mixer in the range of 5 to 100 millimeter of mercury pressure, preferably 15 to 30 mm Hg, providing a homogeneous mixture. The nonionic surfactant is then added to the mixture which is followed by mixing another 10 to 20 minutes under vacuum of 5 to 50 mm Hg. The resultant product is a non-fluid gel.
To prepare the abrasive containing dentifrice component of the present invention, the humectant and the synthetic gum material are dispersed in a conventional mixer until the mixture becomes a slurry which is smooth in appearance, after which water is added. This mixture is heated to 100-150° F. and mixed for 10 to 30 minutes producing a homogeneous gel phase. Sweetener and color are added and mixed for 20 minutes. The mixture is transferred to a vacuum mixer and the abrasive such as a silica abrasive is added and mixed for 10 to 30 minutes at high speed under a vacuum in the range of 5 to 100 millimeter of mercury pressure, preferably 5 to 50 mm Hg, providing a homogeneous mixture. The surfactant and flavor are then added to the mixture which is followed by mixing another 10 to 20 minutes under vacuum of 5 to 50 mm Hg. The resultant product is an abrasive dentifrice paste of a texture like that of normal toothpastes having a pH in the range of 5 to 8, preferably 5.5 to 6.5, e.g., 6, and of satisfactory flavor.
The dual component composition of the present invention is packaged in a suitable dispensing container such as a tube or pump in which the components are maintained physically separated and from which the separated components may be dispensed synchronously. Such containers are known to the art. Examples of suitable pump devices are disclosed in U.S. Pat. No. 4,528,180 and U.S. Pat. No. 5,332,124. Examples of a suitable dispensing tube are disclosed in U.S. Pat. No. 4,487,757 and 4,687,663 wherein the tube is formed from a collapsible plastic web and is provided with a partition within the tube defining separate compartments in which the physically separated components are stored and from which they are dispersed through a suitable dispensing outlet.
The following specific Example illustrates the present invention. The individual gel and paste components described below were prepared by following the procedure described above. The amounts of the various ingredients are by weight unless otherwise indicated. The resultant components were packaged in tubes or other containers provided with means for physical separation of the individual dentifrice components.
EXAMPLE
A gel component designated “Component A” of a dual component bis-biguanide dentifrice composition of the present invention was prepared with the following ingredients.
Ingredient
Wt. %
Chlorhexidine digluconate (20%)
10.0
Hydroxyethyl cellulose
4.0
Deionized H 2 O
64.50
Glycerin
20.0
Polysorbate 20
1.20
FD&C Blue #1 1% soln.
0.30
Abrasive Dentifrice Component
An abrasive containing component of the dual component dentifrice composition of the present invention was prepared with the following ingredients:
Ingredients
Wt. %
Deionized water
22.714
Glycerin
21.00
Sorbitol (70% solution)
20.00
Xanthan gum
0.60
Sodium Saccharin
0.80
Polysorbate 20
0.80
Sodium fluoride
0.486
Zeodent 115
20.00
Zeodent 165
1.50
Sylodent XWA
10.00
Titanium Dioxide
0.50
Flavor
1.60
The gel and abrasive paste components prepared above were of extrudable consistency. The pump force required to actuate extrusion of the combined components was 30 lbs as determined by a Force to Actuate test methodology. Ribbons of the two components were extruded synchronously and combined.
By way of contrast when a dual component composition similar to that of the Example was prepared except that 15% by weight Pluronic F127 was used as the thickening agent, the force required to pump actuate dual extrusion of the separated components was found to be 37 lbs or greater.
A simulated shelf-life test was performed by exposing the gel component to a temperature of 60° C. for 3 weeks and then measuring the retention of chlorhexidine levels at the beginning and end of the test. The gel component used in the dual component composition of the Example designated Gel Component A as indicated in Table II below, was found to retain more than 90% of the original Chlorhexidine incorporated in the gel whereas the comparative gel component designated Gel Component B prepared with Pluronic F127, as the thickener in place of hydroxyethyl cellulose, exhibited a retention level of chlorhexidine substantially less than 90% , a retention level of 90% or more being a proxy for acceptable 2-year shelf stability.
TABLE II
Gel Component Shelf Stability at 3 weeks at 60° C.
Initial Chlorhexidine
After 3 weeks
Gel Component
(%)
(%)
% Recovery
A
2.03
1.92
94.58
B
2.07
1.78
85.99
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A dual component chlorhexidine dentifrice composition of improved shelf stability in which the first component is a gel containing a bis-biguanide antibacterial agent in which the gel vehicle is thickened with a cellulose polymer and the second component is a paste containing a silica abrasive wherein the bis-biguanide antibacterial agent provides undiminished antiplaque and antigingivitis effect with reduced staining when the physically separated components are combined and mixed upon application to dental tissue.
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TECHNICAL FIELD
[0001] The present invention relates to an ultrasonic diagnostic system, and more particularly to an ultrasonic diagnostic system composed of a plurality of devices connected wirelessly and through wire.
BACKGROUND
[0002] Ultrasonic diagnostic systems are apparatuses that form an ultrasound image based on received signals obtained by transmitting and receiving ultrasound waves with respect to a living body. When an ultrasonic diagnostic system is composed of a plurality of independent devices (a plurality of units or modules), these devices are generally used in a separated state or in a docking state. In the separated state, the plurality of devices are connected with each other according to a wireless communication mode. In the docking state, the plurality of devices are connected with each other according to a wire communication mode. The docking state can include a state in which two devices are connected through a cable.
[0003] Patent Document 1 discloses an ultrasonic diagnostic system including a first casing and a second casing that are always coupled with each other physically. Patent Document 2 discloses an ultrasonic diagnostic system composed of a front-end device and a back-end device. These devices cannot be separated from each other and connected with each other according to a wire communication mode. Patent Document 3 discloses an ultrasonic diagnostic system including a device main body and an ultrasound probe which are connected wirelessly to preform wireless communication for transmission and wireless communication for reception between the devices. This configuration prohibits wire communication between the devices. Patent Document 4 discloses an ultrasonic diagnostic system capable of using both a wireless probe and a wire probe. Patent Document 4 does not disclose a probe adaptable for both a wireless mode and a wire mode.
CITATION LIST
Patent Literature
[0004] Patent Document 1: JP 2011-5241 A
[0005] Patent Document 2: JP 2008-114065 A
[0006] Patent Document 3: JP 2011-87841 A
[0007] Patent Document 4: JP 2008-406 A
SUMMARY
Technical Problem
[0008] For an ultrasonic diagnostic system including a plurality of individual devices that can be separated from each other, the following needs exist in accordance with diagnosis situations or the examiner's preferences: the examiner wishes to use these devices in a separated state in which the devices are physically separated from each other or in a docking state in which the devices are physically coupled with each other. Ultrasonic diagnostic systems that can satisfy both needs are expected.
[0009] In such an ultrasonic diagnostic system, it is necessary to ensure proper operations or operation stability of each device during a shift from the separated state to the docking state and a shift from the docking state to the separated state. Because a change in the state generally involves a change in data processing conditions and control conditions, it is desirable to avoid problems of unstable data processing and display of improper images. In the change of state from the separated state to the docking state, as the distance between the two units becomes shorter, saturation is more likely to occur at the time of receiving radio waves (which appears as an increased error rate, for example), which may cause a problem that proper wireless communication cannot be performed.
[0010] An advantage of the invention is to avoid an unstable or improper operation in an ultrasonic diagnostic system including a plurality of separate devices, even when a physical relationship of these devices or a communication mode among the plurality of devices is changed. An alternative advantage of the invention is to avoid any operational problems during transition of a state from a separated state to a docking state. Another alternative advantage of the invention is to provide an ultrasonic diagnostic system with good usability, for which a separated state or a docking state is selectable.
Solution to Problem
[0011] In accordance with one aspect, an ultrasonic diagnostic system includes a first device configured to function for ultrasonic diagnosis, and a second device configured to function, with the first device, for the ultrasonic diagnosis. In a separated state in which the first device and the second device are separated from each other, the first device and the second device communicate with each other according to a wireless communication mode. In a docking state in which the first device and the second device are coupled to each other, the first device and the second device communicate with each other according to a wire communication mode. The ultrasonic diagnostic system further includes an immediately-before determining unit configured to determine immediately-before state of docking during a course of a change of state from the separated state to the docking state. The first device includes a first controller configured to cause an operation state of the first device to transition from a normal operation state to an operation limited state when the immediately-before state of docking is determined. The second device includes a second controller configured to cause an operation state of the second device to transition from a normal operation state to an operation limited state when the immediately-before state of docking is determined.
[0012] The above ultrasonic diagnostic system can operate in both the separated state and the docking state. This mechanism allows selection of an appropriate usage mode in accordance with diagnosis situations, examiner's preference, and other conditions. In the course of a change of state from the separated state to the docking state, the immediately-before determining unit determines immediately-before state of docking. Based on this determination, prior to docking of the first device and the second device, each device can execute control to avoid problems associated with the change of state. Although a simple change of the communication mode at the time of docking would result in unstable synchronization and unnatural images, for example, determining the immediately-before state of docking and setting the operation state of each device to a fixed state based on the determination should be able to prevent the above problems. More specifically, the system operation can be restricted so as to avoid the problems. In general, an ultrasonic examination is not actually performed with respect to an examinee in the course of a change of state from the separated state to the docking state. It is therefore desirable to restrict the operation in consideration of this situation. For example, it is desirable that, on determining immediately-before state of docking, wireless communication is stopped and the operation of each of the first and second devices is caused to transit from a real-time operation state to a freeze state. In this state, the operation of the transmitting circuit (and the receiving circuit), for example, is stopped, and the operation of the booster circuit is also stopped. Further, moving image display is changed to still image display.
[0013] The separated state generally refers to a state in which two devices are physically or mechanically separated from each other, and the docking state generally refers to a state in which two devices are physically or mechanically coupled to each other. In the docking state, a plurality of communication lines are connected according to connector connection, which practically corresponds to cable connection. In preferred embodiments, the first device is a front-end device closer to a living body, and the second device is a back-end device distant from the living body. The first device may be formed of a probe, and the second device may be formed of an ultrasonic diagnostic device main body.
[0014] The immediately-before determining unit determines a state immediately before the docking state, and this state (immediately before the docking) is practically a state in which two devices are spatially proximate to each other. The immediately-before state of docking can be determined based on the intensity of transmission radio waves (if a distance-linked transmitting circuit is adopted), the intensity of received electric field, a received error rate, and other parameters, or determined using various sensors such as a proximity sensor. Prior to formation of the docking state, operation conditions may be switched in three or more stages, rather than in two stages.
[0015] In preferred embodiments, the first device includes a transmitting circuit, and the first controller is configured to stop operation of the transmitting circuit at the time of transition to the operation limited state. This mechanism saves power. In preferred embodiments, the first device includes a power source circuit including a booster converter, and the first controller is configured to stop operation of the booster converter at the time of transition to the operation limited state. This mechanism not only saves power but also enhances safety. In preferred embodiments, the second controller is configured to change moving image display to still image display at the time of transition to the operation limited state. This mechanism can avoid display of unnatural images, thereby preventing the examiner or the examinee from feeling uneasy.
[0016] In preferred embodiments, the immediately-before state determining unit is configured to determine the immediately-before state of docking when the first device and the second device are in a proximity relationship. In preferred embodiments, the immediately-before state determining unit is configured to determine the immediately-before state of docking based on a wireless communication state between the first device and the second device. Determination of the immediately-before state of docking using information generally obtainable in wireless communication simplifies a system configuration.
[0017] In preferred embodiments, the immediately-before state determining unit includes a first immediately-before state determining unit disposed in the first device and configured to determine the immediately-before state of docking based on the wireless communication state; and a second immediately-before state determining unit disposed in the second device and configured to determine the immediately-before state of docking based on the wireless communication state. The first controller is configured to cause the operation state of the first device to transition to the operation limited state when the first immediately-before state determining unit determines the immediately-before state of docking, and the second controller is configured to cause the operation state of the second device to transition to the operation limited state when the second immediately-before state determining unit determines the immediately-before state of docking. When the first device and the second device are in extremely proximity, wireless communication may be unstable or may fail to be established due to a phenomenon of saturation of a received signal. It is therefore desirable that each of the first device and the second device includes an immediately-before state determining unit to reliably determine the immediately-before state of docking in each device.
[0018] In preferred embodiments, the first controller and the second controller are configured to resume communication using the wire communication mode after transition to the operation limited state and formation of the docking state. The timing for resuming the operation can advanced by starting control for establishment of wire communication between the devices from when the docking state is formed. While automatic return to the normal operation state immediately after establishment of the docking state is possible, as it can be assumed that use of the system is terminated after establishment of the docking state, it is desirable that return to the normal operation state is performed after user input for confirmation.
[0019] In preferred embodiments, the system further include a separation determining unit configured to determine a change of state from the docking state to the separated state as separation. The first controller is configured to cause the operation state of the first device to transition from the normal operation state to the operation limited state when the separation is determined, and the second controller is configured to cause the operation state of the second device to transition from the normal operation state to the operation limited state when the separation is determined. This mechanism recognizes a state transition from the docking state to the separated state as separation (disconnection), which can then be used as a trigger to change the operation states of both devices to the operation limited state. In preferred embodiments, thereafter, the operation state is returned to the normal operation state upon input of confirmation by the user.
[0020] In preferred embodiments, the first device and the second device are configured to communicate with each other using a first wireless communication mode and a second wireless communication mode in the separated state. In preferred embodiments, the first wireless communication mode is a higher speed mode than the second wireless communication mode, the first device is a front-end device including a transmitting circuit and a receiving circuit, and the second device is a back-end device including an input device and a display device. The first wireless communication mode is used to transmit data from the front-end device to the back-end device, and the second wireless communication mode is used to transmit a control signal from the back-end device to the front-end device.
[0021] In preferred embodiments, the display device is configured to display a single communication establishment symbol when communication is established using both the first wireless communication mode and the second wireless communication mode. The communication establishment symbol is not displayed when communication is established using one of the first wireless communication mode and the second wireless communication mode and when neither the first wireless communication mode nor the second wireless communication mode establishes communication. When two wireless communication modes are used, in general, the system operation is not available until wireless communication using both wireless communication modes is established, and the system cannot be operated when only one of the wireless communication modes is established. The examiner normally would like to know whether or not the system can be operated and need not recognize each wireless communication state individually. Therefore, display of a single symbol (a communication indicator or a communication icon) indicating that communication is established with both of the two wireless communication modes is adequate for the examiner. The examiner rather prefers such a symbol so as to avoid confusion.
[0022] In accordance with another aspect, in a method of controlling an ultrasonic diagnostic system including a first device and a second device, the first device and the second device communicate with each other through a wireless communication mode in a separated state in which the first device and the second device are separated from each other, and the first device and the second device communicate with each other through a wire communication mode in a docking state in which the first device and the second device are coupled with each other. The method includes determining immediately-before state of docking during a course of a change of state from the separated state to the docking state; and, when the immediately-before state of docking is determined, causing operation states of the first device and the second device to transition to a freeze state. This method can be implemented by a control program which can be stored in a storage medium within the device or a portable storage medium, or can be transferred via the network.
BRIEF DESCRIPTION OF DRAWINGS
[0023] [ FIG. 1 ]
[0024] FIG. 1 is a conceptual view illustrating an ultrasonic diagnostic system according to a preferred embodiment of the invention.
[0025] [ FIG. 2 ]
[0026] FIG. 2 is a perspective view of an ultrasonic diagnostic system in a separated state.
[0027] [ FIG. 3 ]
[0028] FIG. 3 is a perspective view of an ultrasonic diagnostic system in a docking state.
[0029] [ FIG. 4 ]
[0030] FIG. 4 is a block diagram of a front-end device.
[0031] [ FIG. 5 ]
[0032] FIG. 5 is a block diagram of a back-end device.
[0033] [ FIG. 6 ]
[0034] FIG. 6 shows communication modes in a docking state and communication modes in a separated state.
[0035] [ FIG. 7 ]
[0036] FIG. 7 is a flowchart illustrating an example operation executed immediately before docking.
[0037] [ FIG. 8 ]
[0038] FIG. 8 is a diagram showing a first example proximity decision.
[0039] [ FIG. 9 ]
[0040] FIG. 9 is a diagram showing a second example proximity decision.
[0041] [ FIG. 10 ]
[0042] FIG. 10 is a flowchart illustrating another example operation executed immediately before docking.
[0043] [ FIG. 11 ]
[0044] FIG. 11 is a flowchart illustrating a first example operation when the separated state is established.
[0045] [ FIG. 12 ]
[0046] FIG. 12 is a flowchart illustrating a second example operation when the separated state is established.
[0047] [ FIG. 13 ]
[0048] FIG. 13 is a block diagram for explaining symbol display processing.
[0049] [ FIG. 14 ]
[0050] FIG. 14 is a diagram illustrating example display of a symbol.
[0051] [ FIG. 15 ]
[0052] FIG. 15 is a conceptual view illustrating a system including a wireless probe.
DESCRIPTION OF EMBODIMENTS
[0053] Preferred embodiments of the invention will be described hereinafter with reference to the drawings.
(1) Ultrasonic Diagnostic System
[0054] FIG. 1 schematically illustrates a structure of an ultrasonic diagnostic system according to the invention. An ultrasonic diagnostic system 10 is a medical apparatus for use in medical facilities such as hospitals and is used to perform ultrasonic diagnosis with respect to an examinee (living body). The ultrasonic diagnostic system 10 is composed mainly of a front-end device (hereinafter referred to as an “FE device”) 12 , a back-end device (hereinafter referred to as a “BE device) 14 , and a probe 16 . The FE device 12 is closer to a living body than the BE device 14 and the BE device 14 is more distant from the living body than the FE device is. The FE device 12 and the BE device 14 are discrete devices, each forming a portable device. The FE device 12 and the BE device 14 can operate in a separated state in which the devices are separated from each other and can also operate in a docking state in which these devices are coupled with each other. FIG. 1 shows the separated state.
[0055] The probe 16 is a transmitter/receiver designed for transmitting and receiving ultrasound waves in contact with a surface of a living body. The probe 16 includes a 1D array transducer formed of a plurality of transducer elements arranged in a linear or arc shape. The array transducer forms ultrasound beams, which are electronically scanned repeatedly. For each electronic scanning, a beam scanning plane is formed within the living body. Known electronic scanning methods include, for example, an electronic linear scanning method and an electronic sector scanning method. In place of a 1D array transducer, a 2D array transducer capable of forming a three-dimensional echo data capturing space can be provided. In an example structure illustrated in FIG. 1 , the probe 16 is connected to the FE device 12 via a cable 28 . The probe 16 may be connected to the FE device 12 through wireless communication. In this case, a wireless probe is used. The probe 16 which is to be actually used may be selected from among a plurality of probes connected to the FE device 12 . The probe 16 which is to be inserted into a body cavity may be connected to the FE device 12 .
[0056] The FE device 12 and the BE device 14 are electrically connected to each other according to a wireless communication mode in the separated state illustrated in FIG. 1 . In the present embodiment, these devices are connected to each other according to a first wireless communication mode and a second wireless communication mode. FIG. 1 clearly shows a wireless communication path 18 according to the first wireless communication mode and a wireless communication path 20 according to the second wireless communication mode. The first wireless communication mode is a higher speed mode than the second wireless communication mode, and is used in the present embodiment to transmit ultrasound received data from the FE device 12 to the BE device 14 . In other words, the first wireless communication mode is used for data transmission. The second wireless communication mode is a mode of lower speed and simpler communication than the first wireless transmission mode and is used in the present embodiment to transmit a control signal from the BE device 14 to the FE device 12 . In other words, the second wireless communication mode is used for control.
[0057] In the docking state in which the FE device 12 and the BE device 14 are physically coupled with each other, the FE device 12 and the BE device 14 are electrically connected with each other according to the wire communication mode. When compared to the above two wireless communication modes, the wire communication has a much higher speed. FIG. 1 illustrates a wire communication path 22 between the two devices. A power source line 26 supplies direct current power from the FE device 12 to the BE device 14 in the docking state. The power is used for operating the BE device 14 and used for charging a battery within the BE device 14 .
[0058] Reference numeral 24 denotes a receiving line for DC power supplied from an AC adaptor (AC/DC converter). The AC adaptor is connected to the FE device 12 as required. The FE device 12 , which also includes a built-in battery, can be operated using the battery as a power source. The FE device 12 has a box shape as will be described below. The structure and operation of the FE device 12 will be detailed below.
[0059] The BE device 14 has a tablet form or a flat board shape in the present embodiment, and basically has a structure similar to the structure of a general tablet computer. The BE device 14 , however, includes various kinds of software dedicated to ultrasonic diagnosis installed therein, including an operation control program, an image processing program, and other programs. The BE device 14 includes a display panel 30 with a touch sensor, which functions as a user interface serving both as an input device and a display device. In FIG. 1 , the display panel 30 indicates a B-mode tomographic image as an ultrasound image. A user enters various inputs using icons indicated on the display panel 30 . A sliding operation and an enlarging operation can also be performed on the display panel 30 .
[0060] In accordance with the purpose of diagnosis, preferences of the examiner, and other conditions, the ultrasonic diagnostic system 10 can be operated with a usage mode selected from the separated state and the docking state. Consequently, an ultrasonic diagnostic system with improved usability can be provided.
[0061] In order to avoid the ultrasonic diagnostic system 10 from operating unstably or improperly during a change of state, in the present embodiment, control is executed to forcibly place the ultrasonic diagnostic system 10 in a freeze state prior to the change of state. Specifically, in the course of a transition from the separated state to the docking state, immediately-before state of docking is determined in each of the FE device 12 and the BE device 14 based on the intensity of radio waves indicating a distance between the devices or a receiving state, and, based on the determination, control is executed to cause the operation state of each of the devices 12 and 14 to transition to the freeze state. After formation of the docking state and an unfreezing operation by the examiner, the freeze states of these devices 12 and 14 are actually cancelled. In the course of a transition from the docking state to the separated state, the separated state is detected individually in the FE device 12 and the BE device 14 using detection of disconnection and other methods, and then these devices 12 and 14 are placed in the freeze state. Then, after the unfreezing operation, the freeze states of the devices 12 and 14 are actually cancelled.
[0062] The BE device 14 may also be connected to a hospital LAN using a wireless communication mode and a wire communication mode. Communication paths for these modes are not shown in the drawings. The BE device 14 (or the FE device 12 ) may also be connected to other dedicated devices which function for ultrasonic diagnosis (e.g., a remote controller) according to the wireless communication mode or the wire communication mode.
[0063] FIG. 2 illustrates the separated state. The FE device 12 is placed on a desk, for example. The FE device 12 includes a holder 34 having an insertion opening (slot). The holder 34 has a hinged mechanism and is pivotable about a horizontal axis. The FE device 12 includes a predetermined side surface on which a connector disposed on an end portion of a probe cable is mounted. The FE device 12 may have a chamber formed therein for accommodating a probe and other components. Such a structure is convenient for transportation of the ultrasonic diagnostic system and can also protect the probe. In FIG. 2 , the BE device 14 is separated from the FE device 12 . The BE device 14 can be further distant from the FE device 12 , as long as wireless communication is available between the FE device 12 and the BE device 14 .
[0064] FIG. 3 illustrates the docking state. A lower end of the BE device 14 is inserted in the insertion opening of the holder 34 . In this inserted state, wire connection is established between the FE device 12 and the BE device 14 . More specifically, the devices are connected with each other via wire LAN and are also connected with each other with a wire power source line. In the docking state, an inclination angle of the BE device 14 can be varied as desired to alter the position of the BE device 14 . The BE device 14 can be tilted completely on the back surface side thereof (on the top surface of the FE device 12 ) to obtain a horizontally flat position.
(2) Front-End Device
[0065] FIG. 4 is a block diagram of the FE device 12 . Individual blocks in the drawing are formed by hardware such as processors and electronic circuits. A transmitting signal generating circuit 38 supplies a plurality of transmitting signals to a plurality of transducer elements within the probe in parallel, via a probe connecting circuit 40 . Upon receiving the signals, the probe forms a transmitting beam. A plurality of transducer elements, receiving reflected waves from within a living body, output a plurality of received signals, which are then input to a received signal processing circuit 42 via the probe connecting circuit 40 . The received signal processing circuit 42 includes a plurality of preamplifiers, a plurality of amplifiers, a plurality of A/D converts, and other components. A plurality of digital received signals output from the received signal processing circuit 42 are fed to a received beam former 46 . The received beam former 46 applies phase alignment and summation processing to the plurality of digital received signals and outputs beam data as a signal after the phase alignment and summation. The beam data is composed of a plurality of echo data items arranged in the depth direction corresponding to the received beams. A plurality of beam data items obtained by single electronic scanning form received frame data.
[0066] A transmission/reception controller 44 , based on transmission/reception control data transmitted from the BE device, controls transmitting signal generation and received signal processing. A beam processor 50 is a circuit that applies various data processing, such as detection processing, logarithmic transformation processing, and correlation processing, to the individual beam data input thereto in a time sequence order. A control unit 52 controls the operation of the FE device 12 as a whole. The control unit 52 further executes control for transmitting the beam data sequentially fed from the beam processor 50 using wire transmission or wireless transmission. In the present embodiment, the control unit 52 also functions as a wire communication device. A wireless communication device 54 is a module for performing communication according to the first wireless communication mode, and a wireless communication device 56 is a module for performing communication according to the second wireless communication mode.
[0067] Reference numeral 18 denotes a wireless communication path according to the first wireless communication mode and reference numeral 20 denotes a wireless communication path according to the second wireless communication mode. Although each of the wireless communication paths 18 and 20 is a two-way transmission path, in the present embodiment, the former is used to transmit a great amount of data from the FE device 12 to the BE device and the latter is used to transmit a control signal from the BE device to the FE device 12 . Reference numeral 64 denotes a terminal for wire communication, to which a wire communication path 22 is connected. Reference numeral 66 denotes a terminal for power source, to which a power source line 26 is connected. The power source line 26 supplies direct current power from the FE device 12 to the BE device, as described above.
[0068] A battery 60 is a lithium ion battery, for example, and a power source controller (power source circuit) 58 controls charging and discharging of the battery 60 . During use of the battery, electric power is supplied from the battery 60 to each circuit within the FE device 12 via the power source controller 58 . The power source controller 58 includes a booster converter. Reference numeral 62 denotes a power source line when an AC adaptor is connected. When an AC adaptor is connected, external electric power is supplied to each circuit within the FE device 12 with the operation of the power source controller 58 . At this time, if the charging amount of the battery 60 is less than 100%, the external power is used to charge the battery 60 .
[0069] During an ultrasonic diagnostic operation (during transmission and reception), the FE device 12 , in accordance with control on the BE device side, executes supply of a plurality of transmitting signals to the probe and processing of a plurality of received signals obtained thereafter in a repeated manner. A plurality of beam data items in time sequence order thus obtained are sequentially transmitted to the BE device through wireless communication in the separated state and through wire communication in the docking state. At this time, the individual beam data items are converted to a plurality of packets and transmitted according to a so-called packet transmission mode.
[0070] Known operation modes include, in addition to the B-mode, various modes including a CFM mode, an M mode, and a D mode (PW mode and CW mode), for example. Transmission and reception processing for harmonics imaging and elastic information imaging may also be executed. Circuits such as a living body signal input circuit, for example, are omitted in FIG. 1 .
(3) Back-End Device
[0071] FIG. 5 is a block diagram illustrating the BE device 14 . In FIG. 5 , individual blocks show hardware such as a processor, a circuit, memory, and other components. A CPU block 68 includes a CPU 70 and an internal memory 72 , for example. The internal memory 72 functions as a working memory or a cache memory. An external memory 80 connected to the CPU block 68 stores an OS, various control programs, and various processing programs, for example. The various processing programs include a scan convert processing program. The external memory 80 also functions as a cine memory having a ring buffer structure. A cine memory may be formed on the internal memory 72 .
[0072] The CPU block 68 performs scan convert processing with respect to a plurality of beam data items forming received frame data to thereby generate display frame data. The display frame data constitute an ultrasound image (a tomographic image, for example). This processing is repeated to generate a moving image. The CPU block 68 applies various processing for displaying an ultrasound image to the beam data or an image. The CPU block 68 also controls the operation of the BE device 14 and further controls the whole ultrasonic diagnostic system.
[0073] A touch panel monitor (display panel) 78 functions as an input device and a display device. Specifically, the touch panel monitor 78 includes a liquid display device and a touch sensor and functions as a user interface. The touch panel monitor 78 shows display images including an ultrasound image, and also shows various buttons (icons) for operation.
[0074] A wireless communication device 74 is a module for performing wireless communication according to the first wireless communication mode. A wireless communication path for this wireless communication is denoted with reference numeral 18 . A wireless communication device 76 is a module for performing wireless communication according to the second wireless communication mode. A wireless communication path for this wireless communication is denoted with reference numeral 20 . The CPU block 68 also has a function to perform wire communication according to the wire communication mode. In the docking state, the wire communication line is connected to a wire communication terminal 92 , and the power source line 26 is connected to a power source terminal 94 .
[0075] A plurality of detectors 84 to 90 are connected to the CPU block 68 via an I/F circuit 82 . The detectors may include a photosensor, a proximity sensor, a temperature sensor, and other sensors. A module such as a GPS may also be connected to the CPU block 68 . The I/F circuit 82 functions as a sensor controller.
[0076] A battery 102 is a lithium ceramic battery, and a power source controller (power source circuit) 100 controls charging and discharging of the battery. During operation of the battery, the power source controller 100 supplies electric power from the battery 102 to each circuit within the BE device 14 . When the battery is not in operation, the power source controller 100 supplies the electric power from the FE device or the electric power from the AC adaptor to each circuit within the BE device 14 . Reference numeral 104 denotes a power source line from the AC adaptor.
[0077] The BE device 14 controls the FE device and simultaneously sequentially processes the plurality of beam data items transmitted from the FE device to generate an ultrasound image, which is then displayed on the touch panel monitor 78 . At this time, a graphic image for operation is also displayed with the ultrasound image. In a normal real time operation, the BE device 14 and the FE device are electrically connected with each other by wire or wirelessly, and an operation for ultrasound diagnosis is continuously executed while the operations of these devices are synchronized. In the freeze state, in the BE device 14 , the operations of the transmitting signal generating circuit and the received signal generating circuit are stopped, and the operation of the booster circuit within the power source controller 100 is also stopped. The BE device displays a still image when frozen and retains the content of the still image. The BE device may be configured to be connected to an external display device.
(4) Communication Mode
[0078] FIG. 6 summarizes communication modes used in the docking state 118 and the separated state 120 . Reference numeral 110 denotes the first wireless communication mode and reference numeral 112 denotes the second wireless communication mode. Reference numeral 114 denotes the wire communication mode. Reference numeral 116 denotes the content of the wireless communication modes. In the docking state 118 , wire communication is selected; in the FE device and the BE device, the operations of the first wireless communication device and the second wireless communication device are stopped, and power saving is achieved. In the separated state 120 , on the other hand, wireless communication is selected, and in the FE device and the BE device, the first wireless communication device and the second wireless communication device work. At this time, the operation of the wire communication system is stopped. The first wireless communication mode 110 has a higher speed than the second wireless communication mode 112 . In other words, while the second wireless communication mode 112 has a lower speed than the first wireless communication mode 110 , the second wireless communication mode 112 is simpler and less expensive, and consumes less power. The wire communication mode includes TCP/IP protocol on the Ethernet (registered mark).
[0079] The first wireless communication mode includes IEEE802.11 and the second wireless communication mode includes IEEE802.15.1. These are only examples, and other communication modes may be used. In any case, it is desirable to use secure communication modes.
[0080] In the present embodiment, the wireless communication device in accordance with the second wireless communication mode 112 has a function to automatically vary the transmission power in accordance with the receiving intensity (that is, a distance). More specifically, the wireless communication device automatically executes control to lower the transmission power of the BE device and the FE device when the BE device is in proximity to the FE device. It is therefore possible to determine that both devices are in proximity to each other based on a change in the transmission power which is set. Alternatively, the proximity of the two devices may also be determined based on the receiving intensity, the receiving error rate, and other parameters. Further, a proximity sensor may also be used.
(5) Description of Operation
[0081] FIG. 7 illustrates an example basic operation performed in the course of a shift from the separated state to the docking state. In step S 10 , immediately-before state of docking; that is, proximity, is determined. In the present embodiment, the second wireless communication device within the FE device and the second wireless communication device within the BE device each performs control for varying the transmission power based on the intensity of an electric field. In step S 10 , referring to the operation conditions of the respective second wireless communication devices, and more specifically, referring to the transmission power (electric power value) in a predetermined register of each wireless communication device, proximity is determined simultaneously in both devices based on a change in the transmission power. While in the present embodiment, proximity is determined simultaneously in both devices, proximity may be determined in one of the devices and the result may be transferred to the other device. In an extremely proximate state, however, as the wireless communication may not be performed correctly due to saturation of the receive signals, it is reliable that proximity is determined individually in the FE device and the BE device.
[0082] Steps S 12 and S 14 are executed in parallel. In step S 12 , the FE device is placed in a freeze state, and simultaneously the wireless communication is stopped. The freeze state is an operation limited state or a partially non-operating state. Specifically, the operations of the transmitting circuit and the booster circuit (booster converter) are stopped. The interruption control for the wireless communication results in stop of the operation of the two wireless communication devices within the FE device. This interruption control reduces a waste of power, leading to power saving. In step S 12 , other control for establishing the freeze state is executed, as required. At this time, operations necessary for the future docking state (e.g., wire communication) may be prepared. In step S 14 , on the other hand, the BE device is placed in the freeze state, and simultaneously, the wireless communication is stopped. Specifically, upon freeze of the BE device, storage of a new image in a cine memory and further image processing are stopped. As a result, an image displayed at the time of freeze remains as a still image until an examiner performs any operation or input. Upon the freeze, the operations of the two wireless communication devices within the BE device are also stopped, which achieves power saving. In step S 14 , other control for establishing the freeze state is executed as required. Further, operations necessary for the future docking state (e.g., wire communication) may be prepared, as required.
[0083] In step S 16 , whether or not the docking state is established is determined. The docking state is individually determined in each device by detecting connection of the connectors in each device, for example. After establishment of the docking state, in step S 18 , the wire communication is automatically established between the FE device and the BE device. These devices are already paired, and therefore the wire communication is automatically established without input for authentication being requested. In other words, mutual device authentication is automatically completed. However, certain user authentication may be performed at this time. Also, an operation for unfreezing may be awaited to establish the wire communication.
[0084] After step S 18 or in parallel to step S 18 , in step S 20 , whether or not the examiner has performed an operation for unfreezing is determined. If yes, in steps S 22 and S 24 , the freeze states of the FE device and the BE device are cancelled. In other words, these devices return to a normal real-time operation state. Steps S 22 and S 24 are executed in parallel. Specifically, in step S 22 , transmission of ultrasound waves is resumed in the FE device. In other words, the operations of the booster circuit and the transmitting circuit are resumed. In addition, control operations necessary in association with the unfreezing are executed. In step S 24 , scan convert processing, storage of an image in the cine memory, processing of an image read from the cine memory, and other processing operations are resumed in the BE device, and display of a moving image is also resumed accordingly. In addition, control operations necessary in association with the unfreezing are executed.
[0085] When the FE device and the BE device are connected by wire, wireless communication is not performed between these devices. In other words, the respective wireless communication devices are placed in a non-operating state, resulting in power consumption. Once input of unfreezing is enabled, a message to encourage such input is displayed on the display screen of the BE device. The icons displayed on the display screen include an icon for unfreezing.
[0086] As described above, according to the present embodiment, in the course of a shift from the separated state to the docking state, prior to docking, more specifically, immediately before docking, proximity between the FE device and the BE device is determined as a spatial relationship between these devices. Using this determination as a trigger, each device then automatically transitions to the freeze state. This mechanism can be used to prevent problems caused by wireless communication errors occurring in the proximity state, problems of the system operation being unstable due to the change in the state, and other problems. Further, stop of the operation of the booster circuit (booster converter) at the time of proximity increases safety. In general, the examiner, when wishing for a docking state, is not executing an ultrasonic test itself with respect to the examinee even if transmission and reception of ultrasound waves is actually performed. Therefore, the examiner would not feel that the above-described control is burdensome or inconvenient. The examiner would rather feel convenience because an operation for freezing can be omitted.
[0087] If the freeze state has been already established between the two devices before determination of proximity, the freeze state would be maintained when determining proximity. Even in this case, at the time of proximity determination, wireless communication is stopped and other necessary control operations are executed.
[0088] FIG. 8 illustrates a first example proximity determining method. A second wireless communication module 122 (wireless communication devices 56 and 76 ) in the FE device and the BE device has a function to detect the intensity of an electric field, a function to automatically reduce the transmission power in accordance with an increase in the intensity of the electric field, a function to detect an error rate, and other functions. A register 124 stores therein status data indicating communication states such as the intensity of a received electric field, the transmission power, and the error rate. A determining unit 128 refers to the data stored in the register 124 as a communication state signal 126 , and determines proximity based on the communication state signal 126 . A method for determining proximity can be selectively adopted from among a method for determining proximity when the transmission power is equal to or less than a threshold value, a method for determining proximity when the intensity of a receive electric field is equal to or greater than a threshold value, a method for determining proximity when the error rate is equal to or greater than a threshold value, and other methods, for example. In preferred embodiments, each of the FE device and the BE device individually determines proximity. The determining unit 128 is implemented as a function of the control unit, for example, in the FE device and is implemented as a function of the CPU block, for example, in the BE device.
[0089] FIG. 9 illustrates a second example proximity determining method. Each of the FE device and the BE device includes a distance sensor 130 which detects a distance between the devices. The distance sensor is disposed close to a docking connector, for example. When an output signal from the distance sensor 130 is equal to or less than a predetermined value (when the distance between the devices is equal or less than a fixed value), a determining unit 132 determines proximity. Similar to the first example described above, the determining unit 132 is implemented as a function of the control unit, for example, in the FE device and is implemented as a function of the CPU block, for example, in the BE device. An optical sensor, an ultrasonic sensor, a magnetic sensor, and other sensors may be used as the distance sensor 130 .
[0090] FIG. 10 illustrates another example operation performed in the course of a shift from the separated state to the docking state. In FIG. 10 , steps similar to those shown in FIG. 7 are designated by corresponding reference numerals and will not be described. In the basic operation example shown in FIG. 7 , a situation in which the FE device and the BE device are relatively withdrawn from each other (a situation in which proximity is cancelled) after the proximity is determined but before the docking is determined. However, in the example operation illustrated in FIG. 10 , such a situation is fully considered.
[0091] In step S 26 in FIG. 10 , when, prior to the docking determination, separation is determined; that is, when cancellation of the proximity state is determined, whether or not the examiner has performed an unfreezing operation is determined in step S 28 . If yes is determined, in step S 30 , wireless communication is automatically established between the FE device and the BE device, and wireless communication is resumed. Thereafter or simultaneously, the freeze state is cancelled in both devices, and a normal operation state is placed. Then, the process returns to step S 10 . If, in step S 28 , the proximity state is determined once again before the unfreezing operation is determined, the processes in step S 10 and the subsequent steps are to be executed. To perform the control operation illustrated in FIG. 10 , the proximity determining method based on a result of detection of the distance between the devices, rather than the proximity determining method based on a change in the wireless communication state, is preferably used.
[0092] FIG. 11 illustrates an example operation performed when shifting from the docking state to the separated state. In step S 40 , disconnection (separated state) is determined. Disconnection is determined based on physical and electrical separation between the connector of the FE device and the connector of the BE device. Based on this determination, in steps S 42 and S 44 , wire communication is stopped in the FE device and the BE device, and simultaneously, these devices are placed in a freeze state. In step S 46 , whether or not an unfreezing operation has been performed is determined, and if the unfreezing operation is confirmed, in steps S 48 and S 50 , wireless communication is established between the two devices, so that wireless communication is resumed. Thereafter or simultaneously, the freeze state is cancelled in the FE device and the BE device, and the normal real-time operation state is resumed.
[0093] With the example operation illustrated in FIG. 11 , while it is not possible to detect a separated state in advance to prepare for a change of state, it is possible to detect disconnection to reliably place the individual devices in a freeze state. As, in general, an ultrasonic test is not actually being performed with respect to an examinee during such transition, no special problems would arise by automatically establishing the freeze state. Rather, this mechanism is convenient and safe for a user. Alternatively, the processes in steps S 42 and S 44 may be executed prior to formation of the separated state, by using, as a trigger, an output from a sensor disposed for detecting immediately-before separation.
[0094] FIG. 12 illustrates another example operation performed when shifting from the docking state to the separated state. In FIG. 12 , the process steps similar to those illustrated in FIG. 11 are designated by the corresponding reference numerals and will not be described. In this example operation, after both devices are placed in the freeze state, in step S 52 , wireless communication is automatically established. In preferred embodiments, the process in step S 52 is executed upon detection of separation of the devices from each other by a predetermined distance, for example. Alternatively, establishment of wireless communication may be started from immediately after disconnection. After establishment of wireless communication, in steps S 54 and S 56 , the freeze state is cancelled in the both devices. In other words, after disconnection, the devices are automatically return to the normal operation state. This control process eliminates the need for an unfreezing operation by the examiner. However, as it is sometimes more appropriate to cause the devices to return to the normal operation state after confirmation by the examiner, the system may be configured to enable the examiner to preset a desired method from among manual return and automatic return.
[0095] In an ultrasonic diagnostic system formed of a portable FE device and a portable BE device, in accordance with a diagnosis situation and other status, there can occur a transition of state from the separated state to the docking state and a transition of state from the docking state to the separated state. In such a transition of state, the operation according to the above embodiment can avoid problems such as examiner's confusion and unstable system operation, thereby providing an ultrasonic diagnostic system with good usability.
(6) Other Configurations
[0096] According to the present embodiment, in the separated state, the FE device and the BE device are connected with each other with two types of wireless communication paths. The system cannot operate until both of these two types of wireless communications are established. Therefore, when displaying the wireless state, it is preferable, from a viewpoint of whether or not the system operation is available, to display the wireless state with AND conditions, rather than to display the states of the two types of wireless communication individually. As illustrated in FIG. 13 , for example, it is preferable to cause a symbol display controller 138 receiving two wireless state signals from the two wireless communication devices to display a symbol indicating that the wireless state is OK only when both of the two wireless state signals show that communication is available. An example is shown in FIG. 14 . Specifically, the display panel 30 of the BE device 14 shows a symbol 140 indicating a wireless state near an ultrasound image. This symbol 140 is displayed only when both of the two types of wireless communications are established and is not displayed when at least one of the wireless communications is not established. While the symbol 140 which can indicate the magnitude of the electric field may be displayed, in the present system, as the examiner is interested in whether or not the system can operate, the symbol is displayed to indicate that wireless communication is available (OK) without using such a stepwise indication. However, other display modes may be adopted.
[0097] FIG. 15 illustrates another embodiment. An ultrasonic diagnostic system includes an FE device 142 , a BE device 144 , and a probe 146 . In the illustrated example, the FE device 142 and the BE device 144 are connected with each other by two types of wireless communications (see reference numeral 148 ). The probe 146 and the FE device 142 are connected with each other through wireless communication 150 . In this case, two types of wireless communications may be used. When this configuration is adopted, as the probe 146 , a wireless probe including a transmitting and receiving circuit is used. The probe 146 and the FE device 142 may be configured to be connected through a cable (electrical docking), in addition to wireless connection. In this case, the technique described in the above embodiment may be applied between the probe 146 and the FE device 142 .
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In the present invention, an FE device and a BE device communicate using two wireless communication routes in a separate state. Approaching of each device is determined in both devices immediately prior to a docking state by monitoring of a wireless communication state. Wireless communication between the two devices is then stopped, and both devices enter a freeze state (operation-limited state). When the docking state is then formed, wired communication is established between both devices. Then, when an unfreeze input occurs, both devices return to a normal operation state. Both devices temporarily enter the freeze state also when a state change from the docking state to the separate state occurs.
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FIELD OF THE INVENTION
The present invention claims priority to U.S. provisional patent application No. 61/267,784 filed on Dec. 8, 2009 and to U.S. nonprovisional patent application No. 12/963,562 filed on Dec. 8, 2010.
The present invention relates to a specially weighted ball used to train hitters or hitters for softball, baseball, cricket, over-the-line ball, t-ball, golf or any other ball sport that involves striking a ball with a bat, club or any other hitting object.
BACKGROUND OF THE INVENTION
Softball and baseball hitters develop their skills by participating in batting practice. There are several major obstacles and problems associated with using a regulation ball for batting practice. One major problem with using a regulation ball for batting practice is that the ball typically travels great distances when hit by hitters. This means that, to avoid property damage or personal injury to other players in the near vicinity, large spaces are required for batting practice, such as an outside practice area. Alternatively, the use of safety nets, screens or specially designed batting cages can be implemented; however, it is more costly, time consuming and difficult to set up all the nets or screens in addition to the fact that there is still the possibility that the ball will get past the nets or screens. A weighted ball that is energy absorbing, nonburstable and soft, so as to travel shorter distances when hit, is highly beneficial.
Also, it is known that dynamic training with weighted objects enhances strength, speed and conditioning. In addition, the hitter or the instructor wishes to know immediately whether or not the hitter hit the ball properly, that is, on the center line or off-center of the ball. Furthermore, it is desirable to control the size of the practice ball so as to develop hand/eye coordination. There is an unfulfilled need in the market for a ball that meets all of the above requirements.
One art of which applicant is aware is the Muhl Ball™. Although the Muhl Ball™ is designed for batting, it is different from the present invention in that it weighs one pound, has a foam core and is 20 inches in circumference. The Muhl Ball™ has several disadvantages. First, the Muhl Ball™ is too big to toss underhanded (as required by softball rules) or overhand and because of this size problem the ball is typically placed on a t-stand for practice purposes. Thus, it does not allow for an effective simulation of regulation game play. Next, because the ball is filled with a spongy type material it absorbs some bat impact but does not deform to instantly show the hitter if she hit the ball properly or not. Because of this configuration and composition the ball travels very far. Additionally, the Muhl Ball™ is expensive.
Another related art is seen in the Power Systems™ training balls. These balls come in three different weights, 7 ounce, 14 ounce and 21 ounce and even though they have differing weights they are all dimensionally at least 9 inches in diameter. These balls are designed specifically for pitching training and specifically to strengthen and rehabilitate the shoulder. They help to develop dynamic strength through the throwing motion. They are made of a thin vinyl shell and are filled with some sort of material. These are not designed to be used for batting practice as the ball structure simply will not withstand the continual strikes from a bat. This is due in large part to their construction, that is, they are made from a thin outer shell and they have a weak valve structure. A simple plug is inserted into the filler valve of these balls. This plug is sufficient for throwing, however, when struck with a bat the valve becomes a weak spot and is susceptible to damage or breakage making the ball useless.
Basketballs, deflated basketballs or volleyballs and 16 inch softballs are also used as practice balls but again, they all have limitations that are similar to the above referenced limitations that do not make the balls practical or desirable options for batting practice. These options do not offer all of the benefits of the present invention.
There is also a withdrawn Japanese patent application for a weighted golf ball that is filled with a granular material. The shell is made of a resilient material and the ball can be filled with sand, metal particles, water, or any other filler that will add weight to the ball. This application does not teach or give any indication of how the ball is filled or how the material stays inside the ball. It simply teaches a weighted golf ball.
SUMMARY OF THE INVENTION
The present invention is a durable and environmentally friendly batting practice ball that can be used without a safety net and is designed to be tossed directly from in front of the hitter or from the side of the hitter. The ball is designed to develop strength, a proper swing with extension through the hitting zone, and to allow the hitter to perform full hitting with the ability to instantly see if proper contact has been made between the bat and the ball, all within a limited space. Because of the unique design, the ball will retain its spherical shape before hitting and after hitting if the ball is hit properly, that is, at the center line of the ball. If hit other than at the center line, for example, above or below the center line, the ball spin generated by the off center contact of the bat against the ball and the resultant centrifugal forces will cause the ball to donut perpendicular to the horizon (flatten out and look like a donut due to the filler material). Additionally, the ball reacts differently when struck with an inside out or open swing. This swing is the type where the hitter's hands travel through the hitting zone ahead of the barrel of the bat and the ball is driven to the opposing direction or field. In this scenario, the ball will donut horizontal to the ground, thus again letting the hitter know that she has hit the ball incorrectly.
In any situation where the ball is hit incorrectly, the ball will remain in the donut shape until the centrifugal force acting on the ball is reduced enough to allow the filler to come to rest in its natural form; or the ball comes to a stop. Because of this ball mutation, it is easy for the hitter and/or the instructor to know immediately if proper contact is or is not made during each hit. If proper contact is not made then the instructor (or hitter) will know immediately what the hitter is doing wrong, that is, hitting too high, too low, inside, outside, etc. and will be able to provide instantaneous feedback based on the immediately known information. Additionally, based on the amount of spin and the resultant donuting it is also possible to ascertain just how badly the ball has been hit and thus provides the trainer with continued information on whether or not the hitter is actually improving her swing.
The ball's exterior or skin is constructed from a special blend of materials that are nonburstable. The ball is filled with natural materials, synthetic materials, or a mixture of synthetic and natural materials. Preferably this mixture has a 1.3 to 2.2 weight to volume ration difference. The compound of the filler material may have differing granular configurations and screen mesh sizes that will allow the proper weight and ball reactions. The ball can be made in multiple sizes and may be used for a variety of sports, including softball, baseball, cricket, stickball, over-the-line ball, t-ball, golf or any other ball sport that involves striking a ball with a bat, club or any other hitting/batting object.
In general, the ball of the present invention has numerous advantages over prior balls, including but not limited to developing dynamic strength, giving instant feedback to the hitter, it has no seams, it has a floating filler or core of ball, it develops eye-hand coordination, it requires drive and extension thru the hitting zone to hit the ball correctly, it is water, weather and temperature resistant, it is soft enough to catch with the bare hand and it is designed to collapse around a bat and absorb energy from the bat. Because the ball filler is composed of different sized particles the particles absorb substantially more energy than a solid ball or a singled sized filler ball and the variously sized material allows the smaller particles to move into the spaces between the larger particles allowing greater compressibility and thus a less jarring effect on the hitter.
The ball is not designed to be thrown overhand as it is developed specifically for hitting but is not designed to be used in a pitching machine. Finally, the ball is longer lasting because there is no seam. The ball may also be designed such that it does not have a plug, which also makes it easier to use.
BRIEF DESCRIPTION OF THE DRAWINGS
The above and other objects of the present invention will become readily apparent by reference to the following detailed description when considered in conjunction with the accompanying drawing wherein:
FIG. 1 is a sectional view of the batting practice ball.
FIG. 2 is an elevated view of the ball showing the resemblance to a regular softball; also showing the present invention baseball.
FIG. 3 is an outside cover comparison of a standard softball and the present invention.
FIG. 4 is a graphical representation of distances traveled by a regular softball versus the ball of the present application.
FIGS. 5 a through 5 c are a series of figures showing how the ball reacts when hit properly.
FIGS. 6 a through 6 c are a series of figures showing how the ball reacts when hit badly from above.
FIGS. 7 a through 7 c are a series of figures showing how the ball reacts when hit badly from below.
FIGS. 8 a through 8 c are a series of figures showing how the ball reacts when hit badly from the inside out.
FIG. 9A is a sectional, elevated view showing a standard valve embodiment.
FIG. 9B is an elevated view showing the standard valve from the inside of the ball.
FIG. 9C is a view of a standard plug.
FIG. 9D is a sectional view of the ball prior to plug insertion.
FIG. 9E is a sectional view of the ball after plug insertion.
FIG. 9F is a sectional view of the ball after plug insertion and after the sealant is added.
FIG. 10A is a sectional view showing another embodiment with a stem flap.
FIG. 10B is a section view showing the same embodiment with the flap closed and after the filler material has been added.
DETAILED DESCRIPTION OF THE INVENTION
Currently there exist numerous types of practice batting balls and hitting balls for the sports listed above. However, none of these balls are structurally the same, are used the same or provide all the advantages of the present invention. One embodiment for the present invention is a weighted softball designed to change shape when hit improperly. The following description and explanation relates mainly to softballs but it should be noted that it can apply to any other ball as well, such as golf balls, baseballs, cricket balls, and any other balls used in a batting sport or hitting sport.
When playing baseball or softball it is extremely important to practice batting, or hitting, and through practice it is important to learn the proper way to hit a ball 1 . In baseball and softball the hitter 9 strives to obtain a level swing. In other words, the hitter wants to bring the bat 10 around and swing level through the hitting zone and then extend through the ball 1 and ultimately finish with her hands high. This is often difficult to teach because it is not always obvious to the hitter 9 or trainer when she has hit the ball 1 incorrectly.
Batting practice is designed to develop hitter mechanics. However, by using the ball of the present invention batting practice also will build hitters strength. During a game a hitter may only hit several times. However, during batting practice the hitter may hit numerous times. This practice is designed to build muscle memory and thus improve the player's batting strength.
Level Swing. Presently, there are several methods used to both teach hitters how to hit properly and to develop muscle memory. As noted, a level swing is extremely important. One method of training a hitter to develop a level swing is to use a T-stand. A T-stand is simply a batting stand and the ball 1 is placed on top of the stand, that is approximately waist height in relation to the hitter, but is typically also adjustable. Obviously this does not sufficiently replicate real life pitching and hitting and as such has limitations.
One training method currently available that uses the T-stand is The Muhl™ ball. This ball is designed to provide batting training. The Muhl™ ball weighs one pound, has a foam core and is 20 inches in circumference. Due to its large diameter and weight, it is not designed to be pitched and thus is typically used on a T stand, as was explained above. This is a good training method to develop a level swing but it does not replicate real pitching. Because of its weight the Muhl™ Ball typically cannot be pitched and thus must be used only on a T-stand. Also, because of its large diameter, it does not adequately replicate hitting a real softball. Finally, because the ball has a solid, foam core it does not change shape when it is hit so the hitter cannot really know if she is hitting the ball on the center or not.
Strength Training. A level swing is important but so is strength training. The Muhl™ ball is a heavy ball and thus can provide strength training. However, the ball diameter is so large that it does not adequately represent hitting a regulation size ball. It is also quite solid and resilient so the balls fly further and not much energy is actually absorbed by the ball.
Another commonly used method to develop strength is to hit deflated basketballs or volleyballs. These were commonly used because they stop the bat motion when struck and the hitter must muscle through the ball. However, when struck they cause a jarring effect and can possibly injure the hitter because they quickly reach a compression point where the air inside can be compressed no more. This is potentially dangerous for hitters and not truly beneficial for developing strength. Also, they are difficult to pitch and they do not provide the real life feel of hitting a baseball or softball, mostly due to the size and to their deformed shape. Also, when struck they travel in a peculiar or strange flight pattern due to their deformed shape, making them difficult to retrieve and to use for long periods of time.
Another method used for strength training is to strike a stationary weighted bag of some sort. This supposedly develops hand, wrist and forearm strength at contact. Again, this bag again does not replicate actual hitting as the bag is stationary and when it is hit it is pushed forward and then it swings back into place. It also can be somewhat dangerous and could cause injury to the hitter.
Muscle Memory. As can be understood from above, it is extremely desirable to have a weighted ball. Using a heavier ball requires the hitter to use more energy when hitting the ball and as a result helps to greatly improve the hitter's batting strength. Additionally, this same weighted ball and motion creates increased muscle memory. Because the ball is generally the same size as a regulation ball the hitter swings as if hitting a regulation ball, thus practicing proper form. The hitter's swing goes through the hitting zone. The hitting zone is the horizontal plane of the ball, from just before and until just after the ball passes the back edge of home plate. The hitter begins her swing, makes contact and follows through the hitting zone of the ball as if hitting a regular ball but because of the design and weight the ball does not travel as far. However, hitting the ball of the present invention requires greater bodily muscle use. Hitting this weighted ball causes the hitter to gain muscle strength and dramatically increases her hitting ability. Because the same muscles are used to hit a regular ball the hitter additionally builds muscle memory. Due to the increased muscle memory regular balls are struck with more force and thus have improved exit speeds when hit.
When an active person repeatedly trains movement, that is, muscle activity of the same muscle through the same activity, in an effort to stimulate the mind's adaptation process, the outcome is to induce physiological changes which attain increased levels of accuracy through repetition. Even though the process is really brain-muscle memory or motor memory, the colloquial expression “muscle memory” is commonly used. Individuals rely upon the mind's ability to assimilate a given activity and adapt to the training. As the brain and muscle adapts to training, the subsequent changes are a form or representation of its muscle memory. In other words, the hitter is able to build up the muscles used in hitting using the weighted ball and then when batting with a regular sized and weighted ball the muscles remember the action and thus transfer the muscle strength into batting the un-weighted ball, thus providing the hitter with increased batting strength. As is known, repetitive muscle use increases muscle mass, strength and memory.
To explain further, there are two broad types of voluntary muscle fibers: slow twitch and fast twitch. Slow twitch fibers contract for long periods of time but with little force while fast twitch fibers contract quickly and powerfully but fatigue very rapidly. For example, when a runner is running the fast twitch muscles are used in pulling up and putting down the runner's foot. The slow twitch muscles are used to pull the ground underneath the runner as she runs. When hitting, the fast twitch muscles are used in bringing the bat around from the raised position to the ball contact position, and slow twitch muscles are used to push through the ball. In other words, the raw strength part of the swing. Using the ball of the present invention develops both fast twitch muscle fiber and slow twitch muscle fiber.
Thus, it is extremely desirable to have a ball 1 that is substantially the same size as a regulation ball of any sport but weighs more. Obviously, if the ball is the same size or smaller than a regulation ball the hitter will see the ball as the same size and will not be trained to hit a larger ball or a bag. This is advantageous due to the fact that during games the player will be playing with a regulation size and weight ball. It is also important to have a ball that is similar in size or smaller than a regulation ball that can be pitched from in front of the hitter or tossed to the hitter from directly in front of the hitter or from the side. Additionally it is desirable to have a safe, nonburstable, economical ball. The ball of the present invention provides all of these advantages.
Flexible Ball and deformable. The present invention uses a flexible, pliable PVC, preferably non-phthalate material, as the external skin, or outer shell 3 . Its non-breakability is important for many reasons. First, this material is strong enough to withstand multiple batting strikes thus giving the ball longevity. This longevity is important because the balls are somewhat expensive to manufacture and of course these costs ultimately pass through to the consumer. Having a ball that does not break benefits the consumer because she does not have to continually purchase replacement balls.
Next, the flexibility and durability allows for utilizing a variety of ball filler materials 4 . Although the present invention utilizes specific materials it should be noted that a variety of different fillers could be used. Additionally, this flexibility and non-burstability of the ball outer shell 3 allows greater weight to be added to the ball, depending on the material filler 4 .
Safety. Additionally, this flexibility makes the ball much safer than other practice balls. This occurs for a number of reasons. First, the flexibility allows the weighted filler to disburse across a greater area than the area of a ball at rest, greatly decreasing the per square inch pressure when hit, thus removing any incurring damage or breakage to the bat or the object used to hit the ball. Also, due to the energy absorption the ball does not travel as far or as fast as a standard ball when hit, making it safer and easier to catch.
Visual feedback. Most important however, is the fact that the flexibility and deformability of the ball provides the hitter with instant, visual feedback. The ball reacts differently when it is struck properly as to when it is struck improperly. This is more fully described below.
Composition. The practice batting ball of an embodiment of the present invention is generally the same size or smaller than a regulation size softball. However, the structure, design and components are entirely different. FIG. 1 shows a ball of the present invention properly filled to the proper percentages. Ideally, the ball face accounts for approximately 20% of the weight. In one embodiment the ball is filled with either natural materials, synthetic materials, or a mixture of synthetic and natural materials. Preferably this mixture has a 1.3 to 2.2 weight to volume ration difference. The compound of the filler material may have differing granular configurations and screen mesh sizes that will allow the proper weight and ball reactions.
In a second embodiment the ball is filled with a ferrous material and sand, preferable proportions of filler material are approximately 50% ferrous material and 30% sand. Preferably, the sand is river sand rather than regular sand as river sand is smoother and does not have sharp edges that are present in regular sand. This prevents the skin from ripping because of the sand impregnating itself into the skin. Note that these amounts are not exact numbers and may vary.
The practice ball of the present invention has an outer, spherical, flexible external shell 3 designed to withstand contact from bats 10 over numerous strikes without bursting. This shell is then filled through hole 6 with a combination of multiple sized fillers 4 , such as a synthetic material, sand, iron particles and or other small particles so that when a hitter 9 hits the ball 1 the energy from the hitter's swing propagates throughout the ball 1 and the filler 4 so the hitter's energy is maximally absorbed. A small percentage of ultra fine powder may also be added to fill micro-voids and help cushion and lubricate the inner shell surface 2 of the ball.
In an embodiment for a softball, the practice ball is an approximately 5 to 13.5 cm in outer diameter. The hollow ball shell is made of pliable, flexible, durable environmentally safe PVC, non-phthalate material with at least a 3 mm wall thickness. This outer shell is molded, or blow formed into a ball shape, creating a hollow inner cavity. After molding the shell is then filled through an aperture, valve or filler hole 6 with a mixture of special compounds, where the special compound can be either a synthetic material, silica sand, river sand or other natural sands, iron or iron based materials. The filler compound could also be a mixture of any of the above, as long as the appropriate weight is reached. These filler materials 4 are injected into the ball 1 through the filler hole 6 . Additionally, a small percentage of an ultra fine powder, typically less than 1%, may be inserted and combined with the other materials. The ultra fine powder is used to help fill voids between the different sized sand, synthetic material and/or ferrous particles in order to help provide a lubricating effect between the sands and the inner shell 2 PVC, non-phthalate material, thus providing a longer life span for the shell material.
After the ball is filled with the weighted material through the filler hole a self-sealing plug (number) is inserted into the filler hole. This self sealing plug also acts as a valve such that when an air needle is inserted into the ball through the plug to add or remove air, when the needle is removed the plug self-seals, thus keeping the air in the ball. In the present invention, any additional air is removed after filling through the self-sealing plug, like a basketball air filler, such that the outside air pressure and the internal air pressure are equal. Ambient or slightly negative pressure levels of air are slight and allow the shell strength to return the ball to its spherical size without deforming the ball when at rest.
Filler Hole and Plug Sealant Description
The filler hole 6 of the present invention as shown in FIG. 9 can be a standard type valve used in typical basketballs, volleyballs, or any other ball that must be filled with material or air. However, it is preferred that the valve be of a type that is completely sealed within the ball after filling, as shown in FIG. 9F . The problem with the standard valve, as shown in FIG. 9 , is that it is generally used on balls that are bounced or rolled, but not struck. When they are used on a ball that is continually struck they cause a weak spot in the ball. For example, if the hitter strikes the valve stem directly it is forced into the center of the ball. This also occurs when the ball is struck directly on the opposite side. Either event causes the valve stem to become weak and eventually it will leak and may even be forced out of the ball, causing the filler release prematurely. It is preferred to have a valve that is protected. For example, it is possible to add protection to the valve stem.
One method of protecting the filler hole is after filling the ball with the filler and adjusting the air pressure within the ball, the filler hole stem can be sealed with a sealant 15 to protect the stem from the outside. This hole plug sealant 15 is a solvent based PVC, non-phthalate material. This sealant is poured into and over the filler hole and the hole plug, filling all vacant air space and sealing the plug securely and firmly into place
Alternatively, a self-sealing, filler hole 13 , as shown in FIGS. 10A and 10B , can be used. In this self-sealing system, the ball is filled with the weighted filler material 4 through a filler hole. The filler hole 13 has a hole flap 16 at the tip of the filler hole. This flap 16 is forced back and out of the way during the filling process and then after filling is complete the flap flaps back into place, thus closing the filler hole and preventing the filler material 4 from escaping. Then, after filling, the filler hole stem can be externally sealed using the sealing material and the method described above.
The ball described has a variety of unique features not found in presently available practice balls. FIGS. 5 through 8 shows the unique aspect of the ball of the present invention in its ability to absorb energy and to deform so as to not harm bats during practice. The ball can be pitched similar to a standard ball, it can be drop pitched or it can be placed on a T-stand. If a T-stand is used the ball is simply placed on top of the T-stand and hit from there. If the ball is pitched hitter swings at the ball as if she were hitting a standard ball. However, in either situation and upon contact it can be seen that the ball acts entirely different from a standard ball.
Upon contact the ball 1 flexes and conforms to the bat 10 , as can be seen in FIGS. 5 through 8 . As described above, this provides several advantages over other balls. First, it does not harm the bat during batting practice. Other weighted balls are hard and tend to harm, damage and even destroy bats during practice. The ball of the present invention does not cause injury to the bat.
Next, the ball absorbs a large majority of the energy transferred from the hitter to the ball. Because of this absorption the ball does not travel as far. Also, because of the energy absorption the hitter must strike the ball harder in order to get the ball to carry at all.
As the hitter practices with the ball she trains her muscles to react to the heavier weight and thus learns from the heavier weight how to hit the ball with more strength. As the hitter practices with the ball she builds muscles and muscle memory and thus when hitting a lighter ball she is able to drive through the ball more easily as she has been practicing with a much heavier ball.
Next, the flexible outer shell 3 and unique filler provides for a flexible ball. As noted, this flexibility protects bats from damage, the weight builds muscle memory, and the flexibility causes the ball to deform differently when it is hit properly and improperly. This resultant deformation provides significant training advantages. FIGS. 5 a through 5 c shows a hitter striking a ball properly. As can be seen in the figures the ball forms to the bat, is released from the bat and then projects forward in a relatively straight path. However, if the hitter hits the ball improperly it causes the ball to donut. Donuting occurs when the ball is struck improperly because the improper strike causes the ball to spin irregularly thus causing the granular filler to be forced to the outside of the inside of the shell. This internal force on the shell causes the shell to deform and donut.
FIGS. 6 a through 6 c shows a ball donuting due to a hitter hitting the ball high. FIGS. 7 a through 7 c show a ball donuting after a hitter hits the ball low. FIGS. 8 a through 8 c shows a ball donuting after a hitter strikes the ball inside out. As can be seen from the figures, if the ball is struck improperly it is immediately apparent to the hitter or trainer as the ball displays the donuting properties. Thus, the ball is an exceptional training tool due to this visual output.
Finally, the thicker outer shell, the outer shell material and the valve reinforcement technology used in the present ball allows for repeated striking and hitting the ball without the ball bursting apart. This provides a ball that may be used for batting practice over an extended period of time. Because the hitter can repeatedly hit the ball the hitter does not need to continually purchase new balls, thus making it more cost effective.
The above description can be used with a softball, baseball, cricket, stickball, over-the-line ball, t-ball, golf or any other ball that may be struck with a bat or club. Further, it is readily apparent that the features described above have the advantage of wide commercial utility. It should be understood that the specific features described are intended to be representative only, as certain modifications within the scope of these teachings will be apparent to those skilled in the art. For example, alternative fillers could be used and/or the dimensions could be varied.
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The invention is for a method of training and evaluating a hitter using a weighted ball where the hitter hits the weighted ball with a bat and where the weighted ball wraps around the bat and thereby the ball absorbs some of the energy from the batter and whereafter striking the weighted ball the ball leaves the bat in a substantially horizontal plane if it is hit correctly and where the weighted ball donuts substantially vertical to the ground if hit incorrectly or lifts up if hit too low or dives downward if hit to high or donuts horizontally if hit in an inside out manner with the bat.
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BACKGROUND OF THE INVENTION
This invention relates to a novel, crystalline, ethercarboxylate monohydrate particularly suited for processing into detergent formulations and to processes for preparation of such monohydrate. It has been discovered that a compound represented by the formula: ##STR1## EXHIBITS EXCELLENT FUNCTIONALITY AS A DETERGENCY BUILDER. This compound and its use as a detergency builder is described in U.S. Pat. No. 3,865,755, the disclosure of said patent being incorporated herein by reference. Under conditions of high relative humidity, the amorphous form of this compound tends to be hygroscopic and water uptake can result in problems of agglomeration of the compound per se or the detergent formulations in which it is employed. A higher hydrate (tri or tetra) of the compound, which is substantially non-hygroscopic, can be prepared by evaporating a solution of the compound at ambient temperatures. However, the trihydrate loses water of hydration at relatively low temperatures (around 100° C.) and if rapidly dried, as in spray-drying processes for the preparation of detergent formulations, is converted to amorphous form.
It is apparent, therefore, that provision of a form of the above-discussed compound which is relatively non-hygroscopic and thermally stable would constitute an advance in the art.
SUMMARY OF THE INVENTION
It is an object of this invention to provide a relatively non-hygroscopic, thermally stable, crystalline hydrate of the compound: ##STR2## AND PROCESSES FOR PREPARING SUCH CRYSTALLINE HYDRATE. The compound of this invention fulfilling these objectives is a crystalline monohydrate represented by the formula: ##STR3## and whose preparation and properties will be understood from the following description of the preferred embodiments.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The compound of the present invention is a novel crystalline monohydrate represented by the formula: ##STR4## and characterized by an X-ray diffraction pattern exhibiting strong diffraction lines corresponding to approximate values of interplanar spacing d: 8.14 A, 5.65 A, 5.45 A, 5.24 A, 4.50 A, 4.35 A, 3.42 A, 2.77 A, 2.59 A, and 2.38 A. The term "approximate" is used to indicate that the interplanar spacings recited may vary by as much as 1% due to factors such as variations in analytical techniques, co-crystallization of minor amounts of other materials, etc.
This novel crystal hydrate has desirable handling properties generally associated with crystalline materials, and is substantially less hygroscopic than anhydrous crystalline or amorphous forms of the compound. Further, the novel crystalline hydrate of this invention has excellent thermal stability and does not lose water of hydration readily at temperatures below 220° C. as contrasted to the trihydrate which loses water at about 100° C. and the dihydrate which loses water at about 135° C. In addition, the monohydrate is more readily separated from slurries than other hydrates due to its more controllable crystallization characteristics.
The crystalline monohydrate of this invention is prepared by crystallization from an aqueous solution of: ##STR5## If the ##STR6## is prepared by neutralization or saponification of acids or esters thereof with sodium hydroxide, care must be taken to ensure that excess sodium hydroxide is neutralized or removed so that the total amount of sodium hydroxide in the solution is less than 5% of the weight of ##STR7## in the solution. Otherwise, unduly large amounts of what appears to be a dihydrate rather than the desired monohydrate will be crystallized from the solution in the process hereinafter described. Neutralization of excess sodium hydroxide to form sodium carbonate can be conveniently accomplished by bubbling carbon dioxide into the solution until the pH is below 11.5.
It is further necessary that crystallization and separation of monohydrate from the solution be effected at temperatures between 50° C. and 220° C., with the use of temperatures near the boiling point (110°-115° C.) being preferred.
Further, heat input to the solution should be controlled to prevent formation of a solution which is more than about 5% super-saturated. If heat input is unduly high (e.g., if the solution is vigorously boiled), excess super-saturation may cause the solution to become highly viscous and, on further heating, lead to the formation of amorphous solids rather than the desired crystalline monohydrate.
The precipitation of the crystalline monohydrate can be promoted by addition of seed crystals of the monohydrate and/or addition of an organic liquid which is miscible with water but which exhibits relatively low solvation of the monohydrate, for example, methanol. The precipitated, crystalline monohydrate can be separated by conventional mechanical procedures, and heating continued to remove any free water or organic solvent.
The practice of the invention is further illustrated by the following Examples wherein all parts and percentages are by weight unless otherwise indicated.
EXAMPLE I
A solution of 1 part ##STR8## substantially free of sodium hydroxide in 1 part water is formed and admixed with 1 part methanol. The mixture is refluxed at atmospheric pressure for about 2 hours and a crystalline solid precipitate forms which is separated from the heated mixture. This crystalline solid is identified by thermogravimetric and differential thermal analyses as the monohydrate: ##STR9## and exhibits an X-ray diffraction pattern characterized by the following interplanar spacings d: 8.14 A, 5.65 A, 5.45 A, 5.24 A, 4.50 A, 4.35 A, 3.42 A, 2.77 A, 2.59 A, and 2.38 A.
EXAMPLE II
About 1,000 grams of a 40% aqueous solution of: ##STR10## substantially free of sodium hydroxide is heated to boiling. As evaporation of water raises the solids concentration of the solution to 57%, 581/2%, 60%, 611/2%, 1 gram of monohydrate prepared according to Example I is added as "seed material". Upon the last seeding, the solution becomes and remains turbid. Seeding is discontinued and boiling is continued with heat input being controlled so that the boiling point does not exceed 113° C. (if unduly high heat input were employed a more highly super-saturated solution having a boiling point in excess of 113° C. would be formed). The boiling is continued until a slurry containing substantial amounts of solids are present at which point the solids are separated and identified as the monohydrate: ##STR11## by the procedures set forth in Example I above.
The novel, crystalline monohydrate of the present invention can be employed in detergent formulations as described, for example, in previously referenced United States Patent 3,865,755. The use of the novel, crystalline monohydrate is particularly advantageous for use in preparing detergent formulations by well-understood spray-drying techniques in view of the high thermal stability of the monohydrate.
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A novel, crystalline, ethercarboxylate monohydrate useful as a detergency builder exhibits excellent handling and thermal stability properties and is particularly suited for use in preparing detergent formulations.
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CROSS-REFERENCE TO RELATED APPLICATIONS
The present application is a continuation of U.S. patent application Ser. No. 12/716,523, filed on Mar. 3, 2010. The previous application is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
The present invention is directed to a bone fixation assembly and, in particular, to a low profile fastening assembly for securing an orthopedic device to bone tissue
BACKGROUND OF THE INVENTION
As is known in the field of orthopedic surgery, and more specifically spinal surgery, orthopedic fasteners may be used for fixation or for the anchoring of orthopedic devices or instruments to bone tissue. An exemplary use of fasteners may include using the fastener to anchor an orthopedic device, such as a bone plate, a spinal rod or a spinal spacer to a vertebral body for the treatment of a deformity or defect in a patient's spine. Focusing on the bone plate example, fasteners can be secured to a number of vertebral bodies and a bone plate can be connected to the vertebral bodies via the bone anchors to fuse a segment of the spine. In another example, orthopedic fasteners can be used to fix the location of a spinal spacer once the spacer is implanted between adjacent vertebral bodies. In yet another example, fasteners can be anchored to a number of vertebral bodies to fasten a spinal rod in place along a spinal column to treat a spinal deformity.
However, the structure of spinal elements presents unique challenges to the use of orthopedic implants for supporting or immobilizing vertebral bodies. Among the challenges involved in supporting or fusing vertebral bodies is the effective installation of an orthopedic implant that will resist migration despite the rotational and translational forces placed upon the plate resulting from spinal loading and movement. Also, for certain implants, having low profile characteristics is beneficial in terms of patient comfort as well as anatomic compatibility.
Furthermore, over time, it has been found that as a result of the forces placed upon the orthopedic implants and fasteners resulting from the movement of the spine and/or bone deterioration, the orthopedic fasteners can begin to “back out” from their installed position eventually resulting in the fasteners disconnecting from the implant and the implant migrating from the area of treatment.
As such, there exists a need for a fastening system that provides for low profile placement of the bone anchor or screws and provides a mechanism where the fasteners are blocked to prevent the anchors from “backing out” of their installed position.
SUMMARY OF THE INVENTION
In a preferred embodiment, the present invention provides an anchor assembly that can be used for the fixation or fastening of orthopedic implants to bone tissue. In particular, the present invention preferably provides a low profile variable angle or fixed angle fastener assembly that is able to securely connect the orthopedic device to bone tissue. Furthermore, in a preferred embodiment, the present invention further provides a fastener assembly having a locking mechanism that will quickly and easily lock the anchor assembly with respect to the orthopedic device.
Further areas of applicability of the present invention will become apparent from the detailed description provided hereinafter. It should be understood that the detailed description and specific examples, while indicating the preferred or exemplary embodiments of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention will become more fully understood from the detailed description and the accompanying drawings, wherein:
FIG. 1 is an exploded perspective view of one embodiment of an fastening assembly;
FIG. 2 is a cross sectional side view of the fastening assembly shown in FIG. 1 ; and
FIG. 3 is schematic cross sectional side view of a prior art anchor system.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following description of the preferred embodiment(s) is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses.
With reference to FIGS. 1 and 2 , a preferred embodiment of a fastening assembly 10 is illustrated. The fastening assembly 10 preferably includes a fastener 12 , a polyaxial locking head 24 and a locking mechanism 14 . The fastening assembly 10 is preferably constructed from any biocompatible material including, but not limited to, stainless steel alloys, titanium, titanium based alloys, or polymeric materials. Although the fastener 12 will be discussed in the context of an orthopedic screw, it is contemplated that the fastener 12 can be any type of fastening element including, but not limited to, a hook, a pin, or a nail.
In a preferred embodiment, the fastener 12 includes, concentric to a longitudinal axis 16 , a head portion 18 , a neck portion 20 and a shank portion 22 . The head portion 18 connects to the shank portion 22 through the neck portion 20 . The neck portion 20 of the fastener 12 , preferably, integrally connects the head portion 18 with the shank portion 22 . The diameter of the neck portion 20 is preferably dimensioned to match a minor diameter of the fastener 12 . By having the diameter of the neck portion 20 dimensioned at least as large as the minor diameter of the fastener 12 , the overall rigidity and strength of the fastener 12 is increased.
In a preferred embodiment, the shank portion 22 of the fastener 12 includes a shaft 23 surrounded at least in part by a thread portion 25 . The diameter of the shaft 23 is the minor diameter of the fastener 12 . In a preferred embodiment, the diameter of the shaft 23 remains generally constant from a proximal end of the shaft 23 toward a distal end of the shaft 23 . The constant diameter of a majority portion of the shaft 23 allows for optimal fastener positioning when the fastener 12 is inserted into a predetermined area in the bone tissue. The constant diameter also allows for varying the depth positioning of the fastener 12 in the bone. For example, if a surgeon places the fastener 12 into bone tissue at a first depth and decides the placement is more optimal at a second, shallower depth, the fastener 12 can be backed out to the second depth and still remain fixed in the bone. In another embodiment, the diameter of the shaft 23 may vary along its length, including increasing in diameter from the proximal end to the distal end or decreasing in diameter from the proximal end to the distal end.
With continued reference to FIGS. 1-2 , the thread portion 25 surrounding the shaft 23 extends, in a preferred embodiment, from the distal end of the shaft 23 to the neck portion 20 . In another preferred embodiment, the thread portion 25 may extend along only a portion of shaft 23 . The thread portion 25 is preferably a Modified Buttress thread but the thread can be any other type of threading that is anatomically conforming, including, but not limited to Buttress, Acme, Unified, Whitworth and B&S Worm threads.
In a preferred embodiment, the diameter of the thread portion 25 decreases towards the distal end of the fastener 12 . By having a decreased diameter thread portion 25 near the distal end of the fastener 12 , the fastener 12 can be self-starting. In another preferred embodiment, fastener 12 may also include at least one flute to clear any chips, dust, or debris generated when the fastener 12 is implanted into bone tissue.
As best seen in FIG. 1 , in a preferred embodiment, at least a portion of the head portion 18 of the fastener 12 has a generally spherical shape and is preferably surrounded by the polyaxial locking head 24 . In another preferred embodiment, the polyaxial locking head 24 includes at least one extension 26 , but, preferably includes two extensions 26 ; each extension 26 being located diametrically opposite to the other on the polyaxial locking head 24 . Preferably, also located on polyaxial locking head 24 is at least one, but preferably two, notches or openings 28 . The notches 28 are configured and dimensioned to correspond with the end of a driving instrument (not shown) designed to engage the polyaxial locking head 24 . This engagement allows a user to manipulate the polyaxial locking head 24 through the driving instrument. Similarly, the head portion 18 of the fastener 12 also preferably includes a cavity or opening 30 configured and dimensioned to correspond with the end of the same driving instrument or a separate driving instrument (not shown) designed to engage the fastener 12 . This engagement allows a user to drive the fastener 12 into bone tissue and otherwise manipulate the fastener 12 .
Turning back to FIGS. 1 and 2 , the generally spherical shape of the head portion 18 is configured and dimensioned to be received within a correspondingly shaped cavity 32 in the polyaxial locking head 24 . The shape of the head portion 18 and the correspondingly shaped cavity 32 allows the fastener 12 to pivot, rotate and/or move with respect to the polyaxial locking head 24 . It should be noted that the head portion 18 and the cavity 32 are dimensioned such that the head portion 18 cannot be removed or otherwise disengaged from the cavity 32 of the polyaxial locking head 24 . In another embodiment, instead of allowing the fastener 12 to pivot, rotate and/or move with respect to the polyaxial locking head 24 , the head portion 18 and the correspondingly shaped cavity 32 may be configured and dimensioned to keep the fastener 12 in a fixed position. In a preferred embodiment, the head portion 18 may include texturing 35 that extends along at least a portion of the head portion 18 . The texturing 35 on the head portion 18 provides additional frictional surfaces which aid in gripping the fastener 12 and holding the fastener 12 in place with respect to the polyaxial locking head 24 .
In an exemplary use with an orthopedic device, the fastener 12 with the polyaxial locking head 24 is received in an opening 34 in an orthopedic device 36 . The opening is appropriately configured and dimensioned to receive the fastener 12 and the polyaxial locking head 24 such that the polyaxial locking head 24 can be rotated with respect to the device 36 and the fastener 12 can be pivoted, rotated or moved until the desired orientation is met with respect to the polyaxial locking head 24 and/or the device 36 . In a preferred embodiment, the opening 34 includes an upper opening 37 which receives the polyaxial locking head 24 and the head portion 18 of the fastener 12 and a lower opening 39 which receives the shank portion 22 . In a preferred embodiment, the upper opening 37 also includes extensions 38 which are configured and dimensioned to receive the extensions 26 .
As mentioned above, in a preferred embodiment, the fastener assembly 10 includes the locking mechanism 14 . The locking mechanism 14 will lock the fastener assembly 10 with respect to the orthopedic device 36 thereby preventing the fastener assembly 10 from disengaging or “backing out” from the orthopedic device 36 . The locking mechanism 14 further assists in engaging the fastener 12 and the polyaxial locking head 24 with the opening 34 in the orthopedic device 36 in a low-profile arrangement. In a preferred embodiment, the locking mechanism 14 includes extensions 26 of the polyaxial locking head 24 , corresponding extensions 38 in the opening 34 , and grooves 40 . In a preferred embodiment, the grooves 40 extend from one extension 38 to the other extension 38 and are generally radial. Preferably, the grooves 40 are located between the upper surface 42 and a lower surface 46 of the device 36 .
In an exemplary use of the fastener assembly 10 with the orthopedic device 36 , the orthopedic device 36 is first oriented and placed in the area of treatment. The orthopedic device 36 is then fastened to the bone tissue via at least one fastener assembly 10 which is received in at least one opening 34 of the orthopedic device 36 . More specifically, looking at FIGS. 1-2 , in a preferred embodiment, the fastener 12 and the polyaxial locking head 24 are received in opening 34 such that the shank portion 22 passes through the lower opening 39 and the polyaxial locking head 24 and head portion 18 are receiving and seated in the upper opening 37 . The fastener 12 via notch 30 can then be driven into the bony tissue. As best seen in FIG. 2 , when received in the opening 34 , the polyaxial locking head 24 and the fastener 12 are received in a low profile manner. In other words, regardless of the position of fastener 12 , even when the fastener 12 is rotated, pivoted, or otherwise moved, the head portion 18 of the fastener 12 will not breach the plane defined by an upper surface 42 of the device 36 . This is in contrast to prior art systems, one of which is shown in FIG. 3 , where the head of a fastener will breach the plane defined by the upper surface of the orthopedic implant. This is particularly true when the fastener is installed at a steep or sharp angle.
Once the fastener assembly 10 is seated in the cavity 34 , the fastener assembly 10 can be locked in the opening 34 by actuating the locking mechanism 14 . In a preferred embodiment, a user actuates locking mechanism 14 by rotating the polyaxial locking head 24 via notches 28 in a first direction. The rotational movement causes the extensions 26 which are seated in the extensions 38 to rotate into the grooves 40 . Although only one groove is shown in broken lines in FIG. 1 , it should be understood that there are two sets of diametrically opposed grooves 40 which extend in an annular fashion between the extensions 38 . In a preferred embodiment, the grooves 40 include a stop to provide feedback to the user that the polyaxial locking head 24 has been fully rotated and the locking assembly 14 is engaged. In another preferred embodiment, the grooves 40 change in dimension so that the protrusions 26 can be captured in grooves 40 in an interference manner as the polyaxial locking head 24 is rotated. In yet another preferred embodiment, the grooves 40 include protrusions that provide audible and tactile feedback to the user as the user locks the fastening assembly 10 .
With the polyaxial locking head 24 rotated, the fastener assembly 10 is locked in the opening 34 since the protrusion 26 in the grooves 40 prevents the polyaxial locking head 24 and fastener 12 from disengaging or “backing out” from the opening 34 . If a user wants to unlock the locking mechanism 14 and remove fastener assembly 10 from the opening 34 of device 36 , the user would simply rotate the polyaxial locking cap 24 via notches 28 in a second direction thereby rotating the protrusions 28 out of grooves 40 and into extensions 38 . At that point the locking mechanism 14 is disengaged and the fastener assembly 10 can be removed from the opening 34 of the orthopedic device 36 .
The invention being thus described, it will be obvious 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 obvious to one skilled in the art are intended to be included within the scope of the following claims.
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In an exemplary embodiment, the present invention provides a fastener assembly that can be used for the fixation or anchoring of orthopedic devices or instruments to bone tissue. In particular, the present invention preferably provides a low profile variable angle or fixed angle fastener assembly that is able to securely connect the orthopedic device to bone tissue. Furthermore, in an exemplary embodiment, the present invention provides a fastener assembly having a locking mechanism that will quickly and easily lock the fastener assembly with respect to the orthopedic device.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation in part of Ser. No. 12/005,554, filed on Dec. 27, 2007 by the present inventor.
[0002] This application claims the benefit of provisional patent application Ser. No. 61/271,605, filed on Jul. 23, 2009 by the present inventor, which is incorporated by reference.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0003] Not applicable.
BACKGROUND
[0004] 1. Technical Field
[0005] This disclosure relates to using electric fields to cause levitation of a vehicle. More specifically, it relates to levitation and horizontal motion of a vehicle, which operates on an uncharged and non-magnetized arbitrary surface by using electric fields.
[0006] 2. Background
[0007] Since several decades, levitation systems have been used in a variety of industrial and other applications. For example, magnetic levitation systems have been used for railroad trains, steel structures etc.
[0008] There are several issued patents and published application. For example, a published application No. US 2001/0045311 A1 describes a control levitation vehicle, which uses rope shuttles where the vehicle is towed by a rope, and a linear shuttle where the vehicle is driven by a linear motor.
[0009] U.S. Pat. No. 5,319,336 issued to Andrew R. Alcon, discloses a magnetic levitation system for a stable or rigid levitation of a body. The object to be levitated is maintained in an equilibrium position above a flat guideway or plurality of continuous guideways.
[0010] The prior art indicates that no levitation system has been developed with the capability to levitate on an uncharged and non-magnetized or arbitrary surface with the capability of horizontal motion.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 a show a schematic of an embodiment of the levitation vehicle.
[0012] FIG. 1 b is a schematic of another embodiment of the levitation vehicle.
[0013] FIG. 2 a shows a schematic of a simple field plate assembly.
[0014] FIG. 2 b is a schematic of a compound field plate assembly.
[0015] FIG. 2 c is a sketch of a Halbach array field plate assembly.
[0016] FIG. 3 a is a schematic of the simple feedback signal control.
[0017] FIG. 3 b is a schematic of a compound feedback signal control.
[0018] FIG. 3 c is a schematic of an alternate embodiment of the simple feedback signal control.
[0019] FIG. 3 d is a schematic of an alternate embodiment of the compound feedback signal control.
[0020] FIG. 4 is a schematic of a high voltage transformer drive.
[0021] FIG. 5 is a schematic of a levitator drive unit.
[0022] FIG. 6 is a schematic of a circuit that the user controls in order to control the levitation vehicle.
[0023] FIG. A shows a block diagram of another embodiment of the levitation vehicle
[0024] FIG. B shows a schematic for the force feedback step-up transformer (FFST).
[0025] FIG. C 1 shows a stack-up of conducting power plates for the levitation vehicle.
[0026] FIG. C 2 illustrates a charging scheme for the conducting power plates.
[0027] FIG. D shows an alternate arrangement of a stack-up of conducting power plates.
[0028] FIG. E shows an alternate arrangement for the force feedback step-up transformer (FFST).
[0029] FIG. A 0 ( a, b, c ) is a set of drawings that is used to illustrate the physics involved in dielectric polarization and its use to cause repulsion.
[0030] FIG. A 1 is a schematic to illustrate the physical picture of a source of electric field that is causing dielectric polarization of the surface of levitation
[0031] FIG. A 2 is a schematic to illustrate the physical picture involved in levitation through the use of dielectric polarization
DETAILED DESCRIPTION OF THE DRAWINGS
[0032] Referring now to FIG. 1 a , FIG. 1 a show a schematic of the levitation vehicle. The levitation vehicle comprises a chassis assembly (A 0003 a , A 0003 b , A 0003 c , A 0003 d ). A 0003 a is the part of the chassis on which the user controls is placed. The user may also be positioned on top of A 0003 a to control the levitation vehicle through the use of the user control (A 0002 ). A 0003 c is the part of the chassis that is inclined at an angle θ R to (A 0003 a ) as shown in FIG. 1 a . (A 0003 d ) is the part of the chassis that is inclined at an angle θ L to (A 0003 a ) as shown in FIG. 1 a . A 0003 b is the part of the chassis that is closest to the surface (C 0405 ) and joins (A 0003 c ) and (A 0003 d ) as shown in FIG. 1 a. θ R =(A 0004 a , A 0004 b , A 0004 c ) are each levitator drive units as sketched in FIG. 5 . A 0004 a is assembled on the part of the chassis (A 0003 c ). The levitator drive unit is what causes repulsive forces between the surface (C 0405 ) and the levitation vehicle. By positioning some of the levitation drive units at the depicted angles of θ L , θ R as shown in FIG. 1 a , horizontal forces can also produced since it is inclined at an angle to the surface and thereby enables horizontal motion. (A 0004 c ) and (A 0004 a ) are positioned at such an incline to the surface as can be seen in FIG. 1 a , thus horizontal motion is possible in different directions due to (A 0004 c ) and (A 0004 a ). More levitation drive units may also be attached to the levitation vehicle on different sides of the levitation vehicle depending on the desired direction of horizontal motion needed. For example, levitator drive units may also be placed at inclines of about 45° at two other sides to enable sideways motion, thus enabling the levitation vehicle to move in four different horizontal directions. (A 0004 b ) is parallel to the surface and is responsible for most of the force that lifts the levitation vehicle. (A 0001 c , A 0001 b , A 0001 a ) are conductive wire leads. Each of these wires is connected to a user control input like (C 0301 ) in FIG. 5 where FIG. 5 is a more detailed schematic of a levitation drive unit. Each levitation drive unit should have a dedicated user control circuit. The user control circuit is depicted in FIG. 6 . (A 0002 ) is the user control station. The user control station is a unit that controls the output delivered to leads (A 0001 a , A 0001 b , A 0001 c ). Each of the leads (A 0001 a , A 0001 b , A 0001 c ) are connected to a dedicated user control output (C 0402 ) of FIG. 6 . For example, lead A 0001 a will be connected to a separate user control output (C 0402 ) of a separate user control circuit. The user can then operate the vehicle by manipulating R U2 in the user control circuit shown in FIG. 6 of each of the corresponding leads (A 0001 a , A 0001 b , A 0001 c ).
[0033] Referring now to FIG. 1 b , FIG. 1 b is an alternate embodiment of the levitation vehicle. The embodiment of the levitation vehicle depicted in FIG. 1 b comprises a platform of chassis (B 0007 ). (B 0007 ) is a rigid, flat and non-metallic or is constituted of a material of low electric permittivity. (B 0006 ) is a levitator drive unit. The levitator drive unit is depicted in detail in FIG. 5 (B 0008 ) is the user control lead of the levitator drive unit (B 0006 ). (B 0008 ) can be passed through the chassis (B 0007 ) as shown in the figure, comes out of the chassis (B 0002 ) and is fed into the user control unit (B 0001 ). (B 0001 ) is the user control unit. Here the user can control the vehicle. (B 0004 , B 0005 ) are propellers. These are also controlled from the user control unit. (B 0004 , B 0005 ) can be used to propel the levitation unit in different directions by changing the direction of the propeller thrust.
[0034] Referring now to FIG. 2 a , FIG. 2 a shows a schematic of a simple field plate assembly. A simple field plate assembly comprises conductive power plates (C 0007 ). (C 0007 ) is one of the array of conductive power plates that are shown in FIG. 2 a . A conductive power plate is a flat metallic plate or foil that is about 20 square feet in area and is about 10 μm thick. The conductive power plate should be made as thin as possible so that is weighs as little as possible and as large in area as practical because wider conductive power plates will cause dielectric polarization in a larger area of the surface and therefore will cause the electric fields due to the dielectric polarization of the surface to reach up further away from the surface and therefore will enable greater levitation force on the levitation vehicle. About 100 of these conductive power plates are stacked one on top of the other with electrically insulating material (C 0006 ) separating them. The insulating material like (C 0006 ) can be made of a plastic sheet or a spray of electrically insulating coating like enamel. The insulating material (C 0006 ) is any electrically non-conductive material. The thickness of the insulating material should be just thick enough to provide electric insulation between the area of the conductive power plates where the insulating material is placed but should not surpass such thickness in order to keep the weight of the levitation vehicle low. The insulating material should not extend over the entire area of a conductive power plate as shown in FIG. 2 a . At an edge of the conductive power plates, metallic supports (C 0016 ) are used to separate the power plates. These metallic supports (C 0016 ) are used to electrically connect all of the conductive power plates together. Alternatively, the conductive power plates can be separated entirely by insulating material (C 0006 ) and the conductive power plates (C 0007 ) can be electrically connected together with electrical wires. (C 0001 ) is the field plate assembly chassis. (C 0001 ) is made of a rigid body which the assembly of the conductive power plates (C 0007 ) and insulating material (C 0006 ) is attached to. (C 0002 ) are attachments screws that are used to attach the simple field plate assembly to external bodies. (C 0004 ) is the top electrometer and (C 0009 ) is the bottom electrometer. The bottom electrometer is attached to the side of the simple field plate assembly that is closest to the surface on which the levitation vehicle of FIG. 1 a and FIG. 1 b are levitated on. (C 0004 ) and (C 0009 ) are electrometers that are used to measure the magnitude of the electric fields in the region that the electrometer is located. (C 0003 a , C 0003 b , C 0003 c , C 0003 d ) are supports for the electrometers (C 0004 , C 0009 ). X T is the clearance of the top electrometer from the top most conductive power plate while K B is the clearance of the bottom electrometer from the bottom most conductive power plate. If the material between the top electrometer and the topmost conductive power plate is of the same dimensions and the same constitution as the material between the bottom electrometer and the bottom most conductive power plate then X T =X B . More generally, the bottom electrometer and the top electrometer should be adjusted in such a way that when the simple field plate assembly is very far away from any material body or when the field plate assembly is enclosed in a closed metallic enclosure where there are no sources of electric fields other than the conductive power plates, then the output from the top electrometer should be equal to or very close to the output from the bottom electrometer if the conductive power plates are charged by the high voltage transformer (Vx) that is shown in FIG. 4 . A simple way to achieve this requirement is that X T =X B in addition to requiring any material between the top electrometer and the top most conductive power plate and the any material between the bottom electrometer and the bottom most conductive power plate to be of the same physical dimensions and the same constitution. This is necessary because the top electrometer reads the magnitude of the electric field at the top of the simple field plate assembly and the bottom electrometer reads the magnitude of the electric field at the bottom of the simple field plate assembly. (C 0012 ) is the simple field plate assembly power lead made of electrical wire that is connected to one of the metallic supports, for example (C 0016 ) and therefore is electrically connected to all the conductive power plates in the simple field plate assembly. The simple field plate assembly power lead (C 0012 ) is connected to one output wire of the high voltage transformer (Vx) shown in FIG. 4 for example (C 0204 ) or (C 0205 ) shown in FIG. 4 , thus enabling the assembly of conductive power plates to produce high electric fields from their surfaces. (C 0014 ) is the output of the top electrometer. It goes into the input (C 0105 ) of the comparator (C 0106 ) shown in FIG. 3 a or the input (CE 0105 ) of the comparator (CE 0106 ) shown in FIG. 3 c while (C 0013 ) is the output from the bottom electrometer (C 0009 ). Output (C 0013 ) of the bottom electrometer (C 0009 ) goes into the input (C 0104 ) of the comparator (C 0106 ) shown in FIG. 3 a or the input (CE 0104 ) of the comparator (CE 0106 ) shown in FIG. 3 c . The top electrometer and the bottom electrometer are used to measure the force on the simple field plate assembly due to the dielectric polarization that was induced on the surface by the simple field plate assembly by measuring the magnitude of the electric field in the vicinity of the top electrometer and the bottom electrometer. The bottom electrometer (C 0009 ) is closest to the surface of levitation, so if a repulsive force acts between the surface of levitation and the simple field plate assembly due to the induced dielectric polarization of the surface on which the simple field plate assembly is levitated on, then the magnitude of the electric field in the vicinity of the bottom electrometer (C 0009 ) will be less than the magnitude of the electric field in the vicinity of the top electrometer (C 0004 ). If an attractive force acts on the simple field plate assembly due to the induced dielectric polarization on which the simple field plate assembly is levitated on, then the magnitude of the electric field in the vicinity of the bottom electrometer (C 0009 ) will be greater than the magnitude of the electric field in the vicinity of the top electrometer (C 0004 ).
[0035] Referring now to FIG. 2 b , FIG. 2 b is a schematic of a compound field plate assembly. A compound field plate assembly comprises simple field plates (CC 0003 , CC 0004 ). The simple field plate assembly power lead (CC 0005 ) of simple field plate assembly (CC 0003 ) is connected to one lead of transformer Vx shown in FIG. 4 , for example (CC 0005 ) may be connected to the lead (C 0204 ) of the transformer Vx which is depicted in FIG. 4 and the simple field plate assembly power lead (CC 0006 ) of simple field plate assembly (CC 0004 ) is connected to the other lead of transformer Vx shown in FIG. 4 , for example if simple field plate assembly power lead (CC 0005 ) is connected to (C 0204 ) then (CC 0006 ) should be connected to (C 0205 ). (CC 0007 ) is the output from the bottom electrometer of simple field plate assembly (CC 0003 ). (CC 0008 ) is the output from the top electrometer of simple field plate assembly (CC 0003 ). Bottom electrometer output (CC 0007 ) is connected to input (CD 0108 ) of subtractor (CD 0109 ) in FIG. 3 b . Top electrometer output (CC 0008 ) is connected to input (CD 0107 ) of subtractor (CD 0109 ) in FIG. 3 b . (CC 0009 ) is the output from the bottom electrometer of simple field plate assembly (CC 0004 ). (CC 0010 ) is the output from the top electrometer of simple field plate assembly (CC 0004 ). Bottom electrometer output (CC 0009 ) is connected to input (CD 0105 ) of subtractor (CD 0106 ) shown in FIG. 3 b . Top electrometer output (CC 0010 ) is connected to the input (CD 0104 ) of subtractor (CD 0106 ) shown in FIG. 3 b . The subtractor (CD 0109 ) subtracts the output of bottom electrometer of (CC 0003 ) from the output of the top electrometer of (CC 0003 ). The subtractor (CD 0106 ) subtracts the output of the bottom electrometer of (CC 0004 ) from the output of the top electrometer of (CC 0004 ). The output of (CD 0109 ) and (CD 0106 ) is added by adder (CD 0112 ) and thus the output of adder (CD 0112 ) indicates the nature of the force that is acting on the compound field plate assembly due to the induced dipole polarization of the surface on which the levitation vehicle is being levitated on. X CP is the physical separation of the simple field plate assembly (CC 0003 ) and (CC 0004 ). X CP should be about 6 feet, more generally X CP should be about the same as the dimensions of the simple field plate assembly. (CC 0001 ) is the metallic shield plate. The purpose of (CC 0001 ) is to minimize the appearance of electric fields above the metallic shield plate. The metallic shield plate can be a simple aluminum foil that spans the area of the compound field plate assembly. (CC 0002 a , CC 0002 b , CC 0002 c , CC 0002 d ) are physical supports that position the metallic shield plate (CC 0001 ) at a clearance Y CPA , Y CPB from the simple field plate assembly (CC 0003 , CC 0004 ) as shown in FIG. 2 b . Y CPA =Y CPB and they should be about 5 feet, more generally Y CPA , Y CPB should be about the same as the dimensions of the simple field plate assembly.
[0036] Referring now to FIG. 2 c , FIG. 2 c is a sketch of a Halbach array field plate assembly. The Halbach array field plate assembly is the electrostatic version of the popular magnetic Halbach array. (CC 0207 ) is one of an array of horizontal metal field plates as shown in FIG. 2 c . These horizontal metal field plates are arranged as shown in the figure. The surface area of (CC 0207 ) is about 25 square inches. (CC 0208 ) one of the electrical connections between the vertical metal field plates, for example (CC 0213 ) and the horizontal metal field plates for example (CC 0207 ) and electrical wires for example (CC 0209 ). The vertical metal field plates and the horizontal metal field plates are connected as shown in FIG. 2 c . (CC 0211 ) is one of the physical supports to attach the horizontal metal field plates to the chassis (CC 0210 ). (CC 0211 ) are made out of electrical insulators. (CC 0210 ) is a physically rigid enclosure that is made out of an electrical insulator material or a material of low electrical permeability. (CC 0209 ) is one of the electrical wires shown in FIG. 2 c . Electrical wires like (CC 0209 ) are used to connect the vertical metal field plates and the horizontal metal field plates in such a way that they form the electric analogue of a Halbach array. (CC 0213 ) is one of an array of vertical metal field plates as shown in FIG. 2 c . These are metal plates of about 25 square inches in area. (CC 0212 ) are one of an array of physical supports for the vertical metallic field plates as shown in FIG. 2 c . (CC 0212 ) are made out of an electrical insulator. The supports for the vertical metal field plates like (CC 0212 ) are used to attach the vertical metal field plates to the horizontal metal field plates. (CC 0206 ) is one power input into the Halbach array field plate assembly. (CC 0206 ) should be connected to one output of the transformer Vx shown in FIG. 4 . For example (CC 0206 ) in FIG. 2 c can be connected to (C 0204 ) in FIG. 4 (CC 0205 ) is one power input into the Halbach array field plate assembly. (CC 0205 ) should be connected to the output of the transformer (Vx) shown in FIG. 4 that (CC 0206 ) of FIG. 2 c is not connected to. For example if (CC 0206 ) in FIG. 2 c is connected to (C 0204 ) in FIG. 4 , then (CC 0205 ) in FIG. 2 c should be connected to (C 0205 ) in FIG. 4 . (CC 0201 ) is the top electrometer of the Halbach array field plate assembly and (CC 0203 ) is the bottom electrometer of the Halbach array field plate assembly. (CC 0202 ) is the output from the top electrometer (CC 0201 ). (CC 0202 ) is connected to (C 0105 ) of FIG. 3 a or (CE 0105 ) of FIG. 3 c . (CC 0204 ) is the output of the bottom electrometer (CC 0203 ). (CC 0204 ) is connected to (C 0104 ) of FIG. 3 a or (CE 0104 ) of FIG. 3 c . The electrometers (CC 0201 , CC 0203 ) are used to measure the magnitude of the electric field in their respective vicinities. The electrometers should be adjusted in such a way that when the Halbach array field plate assembly is far from a material body and (CC 0205 ,CC 0206 ) is charged by transformer (Vx) that is depicted in FIG. 4 that the output of both the bottom electrometer and the top electrometer of the Halbach array field plate assembly should be close. A plurality of Halbach array field plate assembly should be placed side by side so that the total area that is covered by the assembly of Halbach array field plate assemblies should be around 25 square feet and additionally, the arrangement of these Halbach array field plate assembly should be stacked one on top of the other if more repulsive force is desired. The Halbach array field plate assembly enables higher electric fields at the bottom of the Halbach array field plate assembly and lower electric fields at the top of the Halbach array field plate assembly.
[0037] Referring now to FIG. 3 a , FIG. 3 a is a schematic of the simple feedback signal control. The simple feedback signal control comprises a comparator (C 0106 ) with inputs (C 0105 ) and (C 0104 ) as shown in FIG. 3 a . (C 0106 ) can be an operational amplifier. The simple feedback signal control can either be used with the simple field plate assembly or with the Halbach array field plate assembly. The output from the top electrometer of either the simple field plate assembly of FIG. 2 a or the Halbach array field plate assembly of FIG. 2 c is connected to (C 0105 ) of FIG. 3 a . The output from the bottom electrometer of either the simple field plate assembly of FIG. 2 a or of the Halbach array field plate assembly of FIG. 2 c is connected to (C 0104 ) of FIG. 3 a . Thus if the magnitude of the electric field in the vicinity of the top electrometer is higher than the magnitude of the electric field in the vicinity of the bottom electrometer of either the simple field plate assembly of FIG. 2 a or the Halbach array field plate of FIG. 2 c , then the comparator (C 0106 ) registers a high voltage at its output (OC). If the magnitude of the electric field in the vicinity of the top electrometer is lower than or equal to the magnitude of the electric field in the vicinity of the bottom electrometer of either the simple field plate assembly of FIG. 2 a or the Halbach array field plate of FIG. 2 c , then the comparator (C 0106 ) registers a low voltage at its output (OC). If a repulsive force acts on the simple field plate assembly or the Halbach array field plate assembly due to the induced dipole polarization of the surface, then the magnitude of the electric field in the vicinity of the top electrometer will be higher than the magnitude of the electric field in the vicinity of the bottom electrometer and the comparator will indicate this with an output of high voltage. If an attractive or a neutral force acts on the simple field plate assembly or Halbach array field plate assembly due to the induced dielectric polarization of the surface, then the magnitude of the electric field in the vicinity of the top electrometer will be lower than or equal to the magnitude of the electric field in the vicinity of the bottom electrometer and the comparator will indicate this as a low voltage at its output (OC). The output from the comparator is fed into the voltage controlled oscillator (C 0101 ). The voltage controlled oscillator should be of such a type that if the input to the frequency control of the voltage controlled oscillator (C 0101 ) is high that the frequency of the output of the voltage controlled oscillator should be low and if the input to the frequency control of the voltage controlled oscillator (C 0101 ) is low that the frequency of the output of the voltage controlled oscillator should be high. Note that if a voltage controlled oscillator which outputs high frequency if the input to the frequency control is high and outputs a low frequency if the input to its frequency control is low, then a signal inverter should be placed between the output of (C 0106 ) and the input to the frequency control of the voltage controlled oscillator. Alternatively (C 0104 ) should be fed into the input that is depicted to be fed by (C 0105 ) and (C 0105 ) should be fed into the input that is depicted to be fed by (C 0104 ) in FIG. 3 a . The voltage controlled oscillator must also be the type that outputs sinusoidal signals. Such voltage controlled oscillators are readily available in the market. The value of the low frequency output of the voltage controlled oscillator (C 0101 ) should be adjusted to produce maximum levitation force on the levitation vehicle. This can be done by adjusting the voltage of the low output of the comparator (C 0106 ). Also the value of the high frequency output of the voltage controlled oscillator (C 0101 ) should be adjusted to such a value as to give the maximum levitation force on the levitation vehicle. This can be done by adjusting the voltage of the high output of the comparator (C 0106 ). The output of the voltage controlled oscillator has to be fed into the high voltage transformer drive of FIG. 4 , but it needs to be processed so that the output from the transformer Vx in FIG. 4 has the same magnitude regardless of the frequency of the output of the voltage controlled oscillator (C 0101 ) or the output (OVa) may be processed so that the magnitude of the output of the transformer is lower when the frequency of the output (Ova) is high. The circuit composed of (R 04 ,RP,RQ,R 06 ,R 00 ,R 07 ,T 01 a ,T 01 b ,R 03 ,R 01 ) is the electronic system that provides the necessary processing of the output (Ova). When the frequency of the output Ova is high, transistor T 01 a is turned on and the magnitude of the output Ovb is lowered by the voltage divider formed by R 04 and R 03 . When the frequency of the output Ova is low, transistor T 01 a is turned off and the magnitude of the output OVb is held equal to the output Ova. The output Ovb is connected to the input 10201 of FIG. 4 . (C 0102 ) is a lead to allow the user to control the simple feedback signal control and thus the levitation vehicle. Alternatively the entire simple feedback signal control of FIG. 3 a may be programmed on a microcontroller. The reason why the voltage controlled oscillator should output low frequency when the levitation vehicle is being acted on by a repulsive force and a high frequency when the levitation vehicle is being acted on by an attractive or neutral force is the following: The polarity of output of transformer Vx in FIG. 4 will depend on whether the output (OVb) is rising or falling henceforth referred to the changing state of (OVb). If repulsive force is acting on the levitation vehicle, then it means that the dielectric polarization of the surface on which the levitation vehicle is being levitated on and the changing state of (OVb) are such that they cause repulsive force on the levitation vehicle. In this case, the frequency of the voltage controlled oscillator should remain low if it was initially low or should be made low if it was initially at high in order to maintain the changing state of (OVb) which causes levitation. If attractive or neutral force is acting on the levitation vehicle, then it means that the dielectric polarization of the surface on which the levitation vehicle is being levitated on and the changing state of (OVb) are such that they cause attractive force or no force on the levitation vehicle. In this case, the frequency of the voltage controlled oscillator should remain high if it was initially high or should be made high if it was initially low in order to change the changing state of (OVb) to a state that will cause repulsion on the levitation vehicle. Thus the levitation vehicle spends much more time for any given time interval in a state of repulsion between the levitation vehicle and the surface and thus the levitation vehicle stays levitated. Possible values for the resistors are (R 01 =1k, R 04 =1k, R 03 =100, R 00 =1k, R 07 =10k, R 05 =10k, RP=10k, RQ=1k, R 06 =10k) but a variety of different values of the resistors are possible.
[0038] Referring now to FIG. 3 b , FIG. 3 b is a schematic of a compound feedback signal control which is to be used for the compound field plate assembly shown in FIG. 2 b . (CD 0109 , CD 0106 ) are subtractors. (CD 0109 ) subtracts the output of the bottom electrometer from the output of the top electrometer of one of the simple field plates in the compound field plate and (CD 0106 ) subtracts the output of the bottom electrometer from the output of the top electrometer of the other simple field plate in the compound field plate assembly. The output of (CD 0109 ) and (CD 0106 ) are fed into an adder (CD 0112 ) which adds the output of the two subtractors (CD 0109 , CD 0106 ). Thus if a repulsive force acts on the compound field plate assembly due to the induced dielectric polarization on the surface then the output from the adder (CD 0113 ) registers a high voltage and if an attractive force or no force acts on the compound field plate assembly due to the induced dielectric polarization on the surface then the output from the adder (CD 0113 ) registers a low voltage. The output from the adder (CD 0112 ) is fed into the voltage controlled oscillator (C 0101 ). The voltage controlled oscillator should be of such a type that if the input to the frequency control of the voltage controlled oscillator (C 0101 ) is high that the frequency of the output of the voltage controlled oscillator should be low and if the input to the frequency control of the voltage controlled oscillator (C 0101 ) is low that the frequency of the output of the voltage controlled oscillator should be high. The voltage controlled oscillator must also be the type that outputs sinusoidal signals. Such voltage controlled oscillators are readily available in the market. The value of the low frequency output of the voltage controlled oscillator (C 0101 ) should be adjusted to produce maximum levitation force on the levitation vehicle. This can be done by adjusting the voltage of the high output of the comparator (C 0106 ). Also the value of the high frequency output of the voltage controlled oscillator (C 0101 ) should be adjusted to such a value as to give the maximum levitation force on the levitation vehicle. This can be done by adjusting the voltage of the high output of the comparator (C 0106 ). The output of the voltage controlled oscillator has to be fed into the high voltage transformer drive of FIG. 4 , but it needs to be processed so that the output from the transformer Vx in FIG. 4 has the same magnitude regardless of the frequency of the output of the voltage controlled oscillator (C 0101 ) or the output (OVa) may be processed so that the magnitude of the output of the transformer is lower when the frequency of the output (Ova) is high. The circuit composed of (R 04 ,RP,RQ,R 06 ,R 00 ,R 07 ,T 01 a ,T 01 b ,R 03 ,R 01 ) is the electronic system that provides the necessary processing of the output (Ova). When the frequency of the output Ova is high, transistor T 01 a is turned on and the magnitude of the output Ovb is lowered by the voltage divider formed by R 04 and R 03 . When the frequency of the output Ova is low, transistor T 01 a is turned off and the magnitude of the output OVb is held equal to the output Ova. The output Ovb is connected to the input 10201 of FIG. 4 . (C 0102 ) is a lead to allow the user to control the simple feedback signal control and thus the levitation vehicle. Alternatively the entire compound feedback signal control of FIG. 3 b may be programmed on a microcontroller. The reason why the voltage controlled oscillator should output low frequency when the levitation vehicle is being acted on by a repulsive force and a high frequency when the levitation vehicle is being acted on by an attractive or neutral force is the following: The polarity of output of transformer Vx in FIG. 4 will depend on whether the output (OVb) is rising or falling henceforth referred to the changing state of (OVb). If repulsive force is acting on the levitation vehicle, then it means that the dielectric polarization of the surface on which the levitation vehicle is being levitated on and the changing state of (OVb) are such that they cause repulsive force on the levitation vehicle. In this case, the frequency of the voltage controlled oscillator should remain low if it was initially low or should be made low if it was initially at high in order to maintain the changing state of (OVb) which causes levitation. If attractive or neutral force is acting on the levitation vehicle, then it means that the dielectric polarization of the surface on which the levitation vehicle is being levitated on and the changing state of (OVb) are such that they cause attractive force or no force on the levitation vehicle. In this case, the frequency of the voltage controlled oscillator should remain high if it was initially high or should be made high if it was initially low in order to change the changing state of (OVb) to a state that will cause repulsion on the levitation vehicle. Thus the levitation vehicle spends much more time for a given time interval in a state of repulsion between the levitation vehicle and the surface and thus the levitation vehicle stays levitated. Possible values for the resistors are (R 01 =1k, R 04 =1k, R 03 =100, R 00 =1k, R 07 =10k, R 05 =10k, RP=10k, RQ=1k, R 06 =10k) but a variety of different values of the resistors are possible.
[0039] Referring now to FIG. 3 c , FIG. 3 c is a schematic of an alternate embodiment of the simple feedback signal control. The alternate embodiment of the simple feedback signal control comprises a comparator (CE 0106 ). The comparator (CE 0106 ) indicates whether the magnitude of the electric field in the vicinity of the top electrometer is higher than the magnitude of the electric field in the vicinity of the bottom electrometer with an output of high which is delivered to lead (CE 0113 b ). The output of the top electrometer of either the simple field plate assembly or the Halbach array field plate assembly is connected to (CE 0105 ). The output of the bottom electrometer of either the simple field plate assembly or the Halbach array field plate assembly is connected to (CE 0104 ). The output of the comparator (CE 0106 ) is connected to the input of the voltage controlled oscillator (CE 0101 ) that controls the frequency of the output of the voltage controlled oscillator. The voltage controlled oscillator is the type that outputs sinusoidal signals. The voltage controlled oscillator (CE 0101 ) is the type that outputs a low frequency when the input to its frequency control is high and a high frequency when the input to its frequency control is low. (LS) is an inductor. The impedance of (LS) is high when the frequency of the output of the voltage controlled oscillator is high and the impedance of (LS) is low when the frequency of the output of the voltage controlled oscillator is low. Thus the voltage divider that is formed by (LS, R 03 ) makes the magnitude of the output from the transformer Vx in FIG. 4 to have less dependence on the frequency of the output of the voltage controlled oscillator (OVa). (CE 0112 ) is a subtractor. (CE 0112 ) subtracts the output of the bottom electrometer from the output of the top electrometer. The output of (CE 0112 ) is fed into the base of transistor (T 01 ) through capacitor (CS). If the dielectric polarization of the surface is increasing and the dielectric polarization of the surface has the polarity that repels the levitation vehicle from the surface, then the output of (CE 0112 ) will be increasing and thus a current will be able to pass out of (CE 0112 ) through the capacitor (CS) and into the base of transistor (T 01 ). This will make the magnitude of output (OVb) lower. If the dielectric polarization of the surface is decreasing and the dielectric polarization of the surface has the polarity that repels the levitation vehicle from the surface, then the output of (CE 0112 ) will be decreasing and thus a current will be going into (CE 0112 ) through capacitor (CS) and thus the transistor (T 01 ) will act as an open switch and the magnitude of output OVb will be higher. Thus the action of (CE 0112 , CS, T 01 ) is seen to produce higher magnitude of electric field from either the simple field plate assembly or the Halbach field plate assembly when the dielectric polarization of the surface is decreasing. In this method, the magnitude of the dielectric polarization of the surface can be increased and thus giving rise to greater repulsive force on the levitation vehicle, in particular the action of (CE 0112 , CS, T 01 ) implements the resonance delivery algorithm. The reason why the voltage controlled oscillator should output low frequency when the levitation vehicle is being acted on by a repulsive force and a high frequency when the levitation vehicle is being acted on by an attractive or neutral force is the following: The polarity of output of transformer (Vx) in FIG. 4 will depend on whether the output (OVb) is rising or falling henceforth referred to the changing state of (OVb). If repulsive force is acting on the levitation vehicle, then it means that the dielectric polarization of the surface on which the levitation vehicle is being levitated on and the changing state of (OVb) are such that they cause repulsive force on the levitation vehicle. In this case, the frequency of the voltage controlled oscillator should remain low if it was initially low or should be made low if it was initially at high in order to maintain the changing state of (OVb) which causes levitation. If attractive or neutral force is acting on the levitation vehicle, then it means that the dielectric polarization of the surface on which the levitation vehicle is being levitated on and the changing state of (OVb) are such that they cause attractive force or no force on the levitation vehicle. In this case, the frequency of the voltage controlled oscillator should remain high if it was initially high or should be made high if it was initially low in order to change the changing state of (OVb) to a state that will cause repulsion on the levitation vehicle. Thus the levitation vehicle spends much more time for a given time interval in a state of repulsion between the levitation vehicle and the surface and thus the levitation vehicle stays levitated.
[0040] Referring now to FIG. 3 d , FIG. 3 d is a schematic of an alternate embodiment of the compound feedback signal control. The alternate embodiment of the compound feedback signal control comprises subtractors (CD 0109 , CD 0106 ). (CD 0109 ) subtracts the output of the bottom electrometer from the output of the top electrometer of one of the simple field plates in the compound field plate and (CD 0106 ) subtracts the output of the bottom electrometer from the output of the top electrometer of the other simple field plate in the compound field plate assembly. The output of (CD 0109 ) and (CD 0106 ) are fed into an adder (CD 0112 ) which adds the output of the two subtractors (CD 0109 , CD 0106 ). Thus if a repulsive force acts on the compound field plate assembly due to the induced dielectric polarization on the surface then the output from the adder (CD 0113 b ) registers a high voltage and if an attractive force or no force acts on the compound field plate assembly due to the induced dielectric polarization on the surface then the output from the adder (CD 0113 b ) registers a low voltage. The output from the adder (CD 0112 ) is fed into the voltage controlled oscillator (CE 0101 ). The voltage controlled oscillator should be of such a type that if the input to the frequency control of the voltage controlled oscillator (CE 0101 ) is high that the frequency of the output of the voltage controlled oscillator should be low and if the input to the frequency control of the voltage controlled oscillator (C 0101 ) is low that the frequency of the output of the voltage controlled oscillator should be high. The voltage controlled oscillator (CE 0101 ) should also be the type that outputs sinusoidal signals. (LS) is an inductor. The impedance of (LS) is high when the frequency of the output of the voltage controlled oscillator is high and the impedance of (LS) is low when the frequency of the output of the voltage controlled oscillator is low. Thus the voltage divider that is formed by (LS, R 03 ) makes the magnitude of the output from the transformer Vx in FIG. 4 to have less dependence on the frequency of the output of the voltage controlled oscillator (OVa). The output of (CD 0112 ) is fed into the base of transistor (T 01 ) through capacitor (CS). If the dielectric polarization of the surface is increasing and the dielectric polarization of the surface has the polarity that repels the levitation vehicle from the surface, then the output of (CD 0112 ) will be increasing and thus a current will be able to pass out of (CD 0112 ) through the capacitor (CS) and into the base of transistor (T 01 ). This will make the magnitude of output (OVb) lower. If the dielectric polarization of the surface is decreasing and the dielectric polarization of the surface has the polarity that repels the levitation vehicle from the surface, then the output of (CD 0112 ) will be decreasing and thus a current will be going into (CE 0112 ) through capacitor (CS) and thus the transistor (T 01 ) will act as an open switch and the magnitude of output OVb will be higher. Thus the action of (CD 0112 , CS, T 01 ) is seen to produce higher magnitude of electric field from either the simple field plate assembly or the Halbach field plate assembly when the dielectric polarization of the surface is decreasing. In this method, the magnitude of the dielectric polarization of the surface can be increased and thus giving rise to greater repulsive force on the levitation vehicle, in particular the action of (CD 0112 , CS, T 01 ) implements the resonance delivery algorithm.
[0041] Referring now to FIG. 4 , FIG. 4 is a schematic of a high voltage transformer drive. This is used to drive a high voltage step-up transformer (Vx). A simple example of a high voltage transformer drive is a H-bridge. A H-bridge driver is a common electronic device and comes in wide variety. FIG. 4 is an illustration of how to use the H-bridge driver in the levitation vehicle disclosed in this patent application. (I 0201 ) is the input to the H-bridge which receives the output of either the simple feedback signal control (OVb) or the output of the compound feedback signal control OVb. Circuit components (R 16 ,T 06 ,R 15 ) is used to control transistors (T 03 ,T 04 ) while input (C 0203 ) is used to control transistors (T 02 ,T 05 ). In the usual H-bridge configuration, a sinusoidal current is developed in the primary coil of the high voltage step-up transformer (Vx). The voltage of the sinusoidal signal from the output of the simple feedback signal control or the compound feedback signal control is thus multiplied by the transformer (Vx). The voltage output from the transformer (Vx) should be high enough to cause levitation of the levitation vehicle but should not be higher than the voltage required to cause the levitation vehicle to produce electric fields of more than 3MV/m although in some environments this limit can be relaxed.
[0042] Referring now to FIG. 5 , FIG. 5 is a schematic of a levitator drive unit. The levitator drive unit comprises of a unit (C 0306 ). (C 0306 ) can either be a simple field plate assembly, a compound field plate assembly or a Halbach array field plate assembly. (C 0304 ) is the high voltage transformer drive. (C 0305 ) connects the transformer (Vx) shown in FIG. 4 to unit (C 0306 ). If (C 0306 ) is a compound field plate assembly or a Halbach array field plate assembly, then (C 0305 ) comprises two leads that are connected to the two leads of the output (C 0204 , C 0205 ) of transformer (Vx). If (C 0306 ) is a simple field plate assembly, then (C 0305 ) comprises a single lead that is connected to one of the leads of the output of transformer (Vx). (C 0305 ) is connected to (C 0012 ) of FIG. 2 a if unit (C 0306 ) is a simple field plate assembly. (C 0305 ) comprises 2 leads that are connected to (CC 0005 , CC 0006 ) of FIG. 2 b if unit (C 0306 ) is a compound field plate assembly. (C 0305 ) comprises 2 leads that are connected to (CC 0206 , CC 0205 ) of FIG. 2 c if unit (C 0306 ) is a Halbach array field plate assembly. (C 0303 ) is a lead that is connected to (I 0201 ) of the high voltage transformer drive shown in FIG. 4 . (C 0303 ) is also connected to (OVb) in either the simple feedback signal control of FIG. 3 a or FIG. 3 c or (OVb) of the compound feedback signal control of FIG. 3 b depending on which embodiment of unit (C 0306 ) is used and which embodiment of the simple feedback signal control ( FIG. 3 a , FIG. 3 c ) is used. (C 0302 ) is either the simple feedback signal control of ( FIG. 3 a , FIG. 3 c ) or (C 0302 ) is the compound feedback control of FIG. 3 b . (C 0301 ) is the user control signal. (C 0301 ) is connected to (C 0402 ) of FIG. 6 . (C 0308 , C 0307 ) are the outputs of the top electrometer and bottom electrometer of unit (C 0306 ). If unit (C 0306 ) is a simple field plate assembly or a Halbach array field plate assembly then (C 0308 , C 0307 ) each comprise single wires where one of (C 0307 ,C 0308 ) is the output of the top electrometer and the other of (C 0307 , C 0308 ) is the output of the bottom electrometer. If unit (C 0306 ) is a compound field plate assembly then (C 0308 ) is composed of 2 leads and (C 0307 ) is composed of 2 leads where (C 0308 ) can be the outputs of the 2 top electrometers and (C 0307 ) can be the outputs of the 2 bottom electrometers.
[0043] Referring now to FIG. 6 , FIG. 6 is a schematic of a circuit that the user controls in order to control the levitation vehicle. The user input is made through the manipulation of a variable resistor (Ru 2 ). Thus the voltage divider formed by resistors (Ru 1 ,Ru 2 ) divides the voltage of the voltage source (C 0401 ). The output (C 0402 ) is fed into either input (C 0102 ) of FIG. 3 b or (C 0102 ) of FIG. 3 a or (CE 0102 ) of FIG. 3 c depending on which embodiment of the simple field plate assembly, the compound field plate assembly or the Halbach array field plate assembly is used and which embodiment of the simple feedback signal control ( FIG. 3 a , FIG. 3 c ) is used.
[0044] Referring now to FIG. A, FIG. A shows a block diagram of an electromagnetic levitation device 100 . The device 100 comprises a chassis 102 , which houses the device 100 . A force feedback step-up transformer (FFST) 104 . The FFST 104 controls a high frequency high voltage power source (HFHV) 106 , a stack of power plates 108 . The HFHV has frequency, which is controlled by the FFST 106 . The HFHV 106 transmits power to the stack of power plates 108 . The stack of power plates 108 generates an electric field. The FFST 104 controls the frequency of the electric field from the stack of conductive power plates 108 in such a manner that the device 100 remains levitated from the uncharged and non-magnetized arbitrary surface 110 . The levitation height between the chassis 102 and the uncharged and non-magnetized arbitrary surface can be about 5 feet. The lead to primary coil in from HFHV 106 to FFST 104 is shown by a connection lead 114 . The secondary coils from FFST 104 to the conductive power plates 108 is shown by the leads 116 . The operation of device 100 can be controlled by signals from 118 to HFHV 106 by control box 120 . The levitation is achieved by controlling the electric field in the stack of conductive power plates 108 by the FFST 104 depending upon the induced polarization of the uncharged and non-magnetized arbitrary surface 110 .
[0045] Referring now to FIG. B, FIG. B shows a schematic 200 , which shows details for the force feedback step-up transformer (FFST) as described in FIG. A. The FFST comprises a frequency control 202 . The frequency control 202 regulates frequency at which high voltage oscillates by transmitting signals that change the permeability of a variable permeability transformer (VPST) 204 . The signals sent to VPST 204 depend on the output of a force sensor 206 . When a repulsive force is sensed by the force sensor, the frequency of VPST 204 decreases so as to maintain the charge polarity on the power plate, which will generate repulsion from the uncharged and non-magnetized arbitrary surface 110 (FIG. A). When attractive or neutral force are sensed by the force sensor 206 , it prompts the frequency control 202 to increase the frequency of VPST 204 and thereby to rapidly switch the charge polarity of the conductive power plates 108 (FIG. A). The input leads 208 to VPST 204 are from HFHV 106 (FIG. A), and frequency control 202 feeds signals 210 to VPST 204 . The leads 212 are from secondary coil of VPST 204 to stack up of conductive power plates 108 (FIG. A). The force sensor feed forward signal 214 determines the nature of the force, which can be attractive, repulsive or neutral.
[0046] Referring now to FIG. C 1 , FIG. C 1 shows a cross sectional view 300 for a stack-up of conducting power plates for the levitation vehicle. The cross sectional view comprises an engine chassis 302 , a stack-up of conductive power plates 308 , and conductors 304 , 306 for the electromagnetic levitation vehicle. The number of conductive power plates 308 can be about 20. The gap 306 between the power plates is about 1.0 inch. The stack of conductive power plates 308 care connected to conductors 304 , 306 through electrical connections ( 308 ) (n=20) and the corresponding connecting leads (n=20) for each conductor. The conductor 304 and 306 are of opposite polarity depending on the output from the FFST 104 (FIG. A). The polarity of stack of conductive power plates 308 is changed in such a controlled manner that a repulsive force between the uncharged and non-magnetized arbitrary surface 110 (FIG. A) and the stack of conductive power plates initiates levitation of the conductive power plates and the chassis 102 (FIG. A) to which it is attached. This embodiment will have fields only from the parts facing towards the uncharged and non-magnetized arbitrary surface 110 (FIG. A).
[0047] Referring now to FIG. C 2 , FIG. C 2 illustrates a schematic 300 , which comprises single power plate 308 (FIG. C 1 ), thin metal foils 310 - 326 , the corresponding leads that connect thin metal foils arranged in Halbach configuration, connecting leads 330 (with negative charge) and 332 (with positive charge) from the secondary coils from VPST 204 (FIG. B). The thin metal plates 310 - 328 can be Aluminum with a thickness of about 0.5 inch and length of about 15 feet. The schematic 300 illustrates the charge mechanism for the single power plate 308 . The charge is switched between positive to negative charge at a rate, which initiates levitation.
[0048] Referring now to FIG. D, FIG. D shows an alternate arrangement 400 of a stack-up of conducting power plate 400 . The alternate arrangement comprises the chassis 402 , a set of about twenty conducting power plates 404 . The conductor 606 and the lead (−q) 408 connect to the secondary coil of VPST 204 (FIG. B). The chassis 402 supports the conducting power plates 404 . The conducting power plate 404 material can be Aluminum. This embodiment, unlike FIG. C 1 can have the electric field generated both from the top and the bottom of stack up of conducting power plates.
[0049] Referring now to FIG. E, FIG. E shows an alternate arrangement 500 for the force feedback step-up transformer (FFST). The arrangement 500 comprises a chassis 502 , force feedback step-up transformer 504 , force sensor 506 , control capacitor 508 , connecting leads 510 , 512 from HFHV generator (not shown in FIG. E) to FFST 504 and 514 . The connecting lead 516 to control capacitor 508 , leads 518 and 520 from secondary coil of FFST 504 to HFHV generator and lead 522 to the force sensor 506 . In this embodiment, output from secondary coil of FFST 504 is controlled by the control capacitor 508 . The force sensor 506 controls the capacitor 508 . When there is no repulsion, the capacitance is reduced by the force sensor, thereby increasing the frequency and rapidly switching the conducting power plate (not shown in FIG. E) polarity that will generate repulsion. If there is repulsion, the capacitance is increased, thereby decreasing the frequency of the secondary output, and thus maintaining the desired repulsion.
DESCRIPTION OF EMBODIMENTS
[0050] If an electric field is applied to an insulator, for example a cement or wooden wall, such an insulator will undergo dielectric polarization in that given that electric field E is applied, charges of opposite sign to E will be pulled towards the surface while charges of like sign will be repelled. A common example of this effect is that which can be brought about by charging a balloon by rubbing it against hair or another material suitably positioned in the tribo-electric series and allowing it to stick against the wall. Forces due to such elementary demonstrations can be quite significant, for example it is worth noting that the electrostatic force between a balloon and the wall is typically more than enough to carry the weight of the balloon. A much more visceral example can be had through the use of Van Der Graff generators. If the electric charges could somehow be switched in polarity while maintaining the same charge magnitude, then it would be possible to levitate objects from arbitrary surfaces since all material surfaces contain dipoles and are therefore electrically polarizable. In the embodiments disclosed in this patent application, method and apparatus are disclosed which accomplishes just this switching of charge polarity in order to cause the levitation of objects.
[0051] To motivate the idea behind the physics of the embodiments disclosed in this patent application, FIG. A 0 is referred to where a charged balloon and a wall is used for illustration. The series of figures in FIG. A 0 illustrates what happens when a positively charged balloon is first brought close to a wall, removed and replaced by a negatively charged balloon within the time when the initially induced negative charges on the wall retreat from the surface of the wall. In the configuration of part (c) of FIG. A 0 , it can be seen that the balloon will be repelled from the wall during the time τ when the negative charges are still on the wall. By automatically responding for of any given surface, the embodiments disclosed in this patent application basically does this task automatically in such a way that it is repelled and thus levitated away from an arbitrary surface.
[0052] In order to shed light on the possibility of using dipole polarization of insulators for the purpose of levitation, we reduce the physical picture as so depicted in FIG. A 1 . For conductors, the situation is a bit different because all the charges are free but the levitation vehicle disclosed in embodiments in this patent application is designed in such a way that this does not present a problem to the levitation process as will soon be described.
[0053] In FIG. A 1 , a positive electric field due to the metal sheet of the levitator E>0 is defined as electric field directed out of the metal plate and of course is defined opposite for negative electric field E<0. Here ( 1 ) in FIG. A 1 is the surface which the vehicle is levitated on. It is represented as having a distribution of dipoles which are polarizable depending on the electric field E, which are represented by dashed lines, coming from the vehicle ( 2 ). The levitation height is represented by y and xz is the surface area of one of the conducting sheets of the vehicle. When −E 0 is applied from ( 2 ) and held for a while, where E 0 >0, positive charges are pulled to the surface of ( 1 ) and when E 0 is applied for a while, negative charges are pulled to the surface. Note that this is not what is depicted in FIG. A 1 which is a depiction of the vehicle ( 1 ) in a given instant in the act of levitation.
[0054] Referring to FIG. A 1 , suppose that an electric field −E 0 is initially applied to ( 1 ) from ( 2 ), then positive charges of amount Q will be pulled to the surface. Now if the electric field is abruptly removed, the positive charges induced on the surface will be removed after some characteristic time τ as in the case of the balloon of FIG. A 0 . So if during that time τ the −E 0 is replaced by E 0 , the positive charges will be forced away by the electric field and negative charges will then be brought up to the surface. During the time in which positive charges are still on the surface, when the field is replaced by E 0 a repulsive force will act between ( 1 ) and ( 2 ). The repulsive force will continue to be active until the positive charges are removed from the surface. Now if at this time the electric field E 0 is removed, negative charges will still appear on the surface even without the application of any electric field because the previous application of E 0 on ( 1 ) gave momentum to those negative charges and the momentum that is contained by the negative charges will draw the negative charges up to the surface while the momentum that is still contained by the positive charges will move the positive charges away from the surface, although more momentum is clearly delivered to the positive charges at this instant, and in the case when negative charges are on the surface and the applied electric field is switched in sign, more momentum will be given to the negative charges. If it is arranged that close to the time that negative charges eventually appear in ( 1 ) that an electric field of −E 0 is then applied, then there will be repulsive force acting between ( 1 ) and ( 2 ) because the newly produced negative charges on the surface will cause the repulsion. If this process is continually repeated, then the source of the electric field ( 2 ) which is the vehicle will remain levitated above the surface. Embodiments disclosed in this patent application are methods and apparatus that performs precisely the described switching of electric fields in order to induce and maintain levitation. Since we are dealing with an insulator, the charges are firmly attached in the material and the system can be roughly approximated as an elastic oscillator with the appropriate Young's modulus, some mass M and being excited by force QE where Q is the charge induced on the surface of levitation ( 1 ) and E is the electric field emanating from ( 2 ) in FIG. A 1 . Here, the equations of motion for the surface material on which the vehicle is levitated will be obtained.
[0055] Doing this will allow for the demonstration of the functional dependence of the frequency of oscillation of the electric field E and also of the oscillations of ( 2 ) as well as help to more clearly demonstrate the workings of the invention. The amount of displacement that the surface material ( 2 ) is displaced by must be proportional to the amount of charge that is brought up to the surface since a stronger electric field will displace more material and also draw up more charge. Even if no fields are applied after a period of electric field application, charges will still be oscillating back and forth for a while in the surface material, being brought in and out of the surface in the surface material because of the inertia and mechanical energy still present as delivered to the charges by the previously applied electric fields (although a part of this energy will be transferred to heat as well as non-polarizing vibrations of the material, the charges will still be oscillating into and out of the surface material for a while). This phenomena is then guided roughly by equation of the form
[0000]
δ
¨
=
-
ω
2
δ
+
F
M
equation
(
1
)
[0000] where δ is the displacement of the material which makes up ( 2 ) and F is the force applied on ( 2 ) due to the electric field E from ( 1 ) and ω is a natural frequency of the material. So since F=QE, if a relation can be found for Q to δ then it can be used in equation (1). For a displacement δ, we have a restoring force F 0 =−Mω 2 δ, assuming that in the absence of applied electric field E, that the restoring force is caused by the dipole polarization and also assuming that the area of the surface that is affected by the dipole polarization (and also the metal sheet) is large enough that the electric field can be considered parallel up to an appreciable depth into the surface material gives
[0000]
Q
2
ɛ
=
M
ω
2
δ
equation
(
2
)
[0000] where ∈ is the dielectric constant of the surface material. Thus
[0000] Q =±√{square root over (∈ Mω 2 δ)} equation (3)
[0056] Since in the surface material, we have both positive and negative charges, we must define 2 equations
[0000]
δ
¨
+
=
-
ω
2
δ
+
-
Q
+
E
+
M
+
equation
(
4
)
[0000] for the positive charge, and
[0000]
δ
¨
-
=
-
ω
2
δ
-
-
Q
-
E
-
M
-
equation
(
5
)
[0000] for the negative charge where Q + is for the positive charges and Q − is for the negative charge and M + , M − are the masses of the positive and negative charges respectively. The negative sign in front of the 2 nd term on the right hand side of equation (4) and equation (5) comes from the fact that a positive/negative electric field according to the metal plate is a negative/positive electric field according to the surface. Embodiments that are disclosed in this patent application generate electric fields in order to cause and maintain levitation by using the following prescription referred to in this patent application as the E-field switching algorithm.
E-Field Switching Algorithm:
[0057] 1) If Q + rises to the surface, that E + >0 (that is according to the convention of the sign of the electric field that positive electric field is directed away from the surface of the source of the electric field). This means that a repulsive force is acting between the vehicle and the surface and a restoring force is acting on the surface charges Q + because the electric field lines from the surface due to the charges Q + (which is directed out of the surface) and that of E + (which is directed out of the metal sheet(vehicle)) are in opposite directions.
2) If Q − rises to the surface, that E − <0 (that is according to the sign convention that negative electric field is directed toward the surface of the source of the electric field). This means that a repulsive force is acting between the vehicle and the surface and a restoring force is acting on the surface charges Q − because the electric field lines from the surface due to the charges Q − (which is directed into the surface) and that of E − (which is directed into the metal sheet(vehicle)) are in opposite directions.
Essentially, this means that the electric field from the metal plate will always act as a restoring force to the charges regardless of the displacement δ, coupled with the condition of E + =−E − , and using the assumption that δ + δ − =δ, |Q + |=|Q − |=|Q|, and M + =M − and adding up equation (4) and equation (5), there is obtained
[0000]
δ
¨
=
-
(
ω
2
+
2
M
M
ω
2
ɛ
δ
E
0
)
δ
equation
(
6
)
[0060] This opportunity will be used to point out that this system is a parametric oscillator which is a well known system with applications in a wide variety of fields.
[0061] In order to increase the magnitude of the oscillations on the surface of levitation, embodiments disclosed in this patent application are disclosed which use the following prescription that is referred to in this patent application as the resonance delivery algorithm:
[0062] Resonance Delivery Algorithm:
1) If Q + is on the surface and Q + is a decreasing function of time, that E + >0 (that is according to my convention of the sign of the electric field), if Q + is on the surface and Q + is an increasing function of time, that E + =0. This means that a repulsive force is acting between the vehicle and the surface and a restoring force is acting on the surface charges Q + only when Q + is traveling down into the surface. This has the effect of delivering a non-zero net kinetic energy to the surface material when Q + is on the surface. 2) If Q − is on the surface and Q − is a decreasing function of time, that E − <0 (that is according to my convention of the sign of the electric field), if Q − is on the surface and Q − is an increasing function of time, that E − =0. This means that a repulsive force is acting between the vehicle and the surface and a restoring force is acting on the surface charges Q − only when Q − is traveling down into the surface. This has the effect of delivering a non-zero net kinetic energy to the surface material when Q − is on the surface
For the case where the surface is a conductor, the charges are not fixed in the surface material so the situation cannot simply be modeled as a spring system like an insulator. Instead, the surface then has capacitance C s , resistance R s and inductance L s . Referring to FIG. A 2 , if E=−E 0 is initially applied, positive charges are attracted to the surface (note that the picture depicted in FIG. A 2 is the vehicle in a momentary act of levitation not what has just been described), and when the electric field is removed, the surface is neutralized in a characteristic time
[0000]
τ
=
L
s
C
s
4
.
Now if during this time, the field is replaced with E=E 0 , then for the duration of the time when the surface charge is positive, there will be repulsive forces acting between ( 1 ) and ( 2 ) until the surface becomes neutral. Now just after or just before the surface becomes occupied by negative charges (which will eventually be the case since this is essentially an LCR system) a field of E=−E 0 can then be applied at this time in order to maintain a repulsive force between ( 1 ) and ( 2 ).
[0066] We can get a rough estimate of the repulsive force that can act on a metal foil of unit surface area on a typical surface like concrete. We can limit the field of the foil to about 3Mv/m. The charge on the surface is approximately
[0000]
ɛ
surface
-
ɛ
0
ɛ
surface
+
ɛ
0
ɛ
0
E
0
equation
(
7
)
[0000] where ∈ surface , ∈ 0 are the dielectric constants of the surface material and the medium between ( 1 ) and ( 2 ) respectively (Note that ∈ 0 is the symbol used for the dielectric constant of a vacuum but in FIG. A 2 the medium between ( 1 ) and ( 2 ) will almost invariably be air, but the difference is negligible since the dielectric constant for air and vacuum are very close). The force acting between ( 1 ) and ( 2 ) is then
[0000]
ɛ
surface
-
ɛ
0
ɛ
surface
+
ɛ
0
ɛ
0
E
0
2
equation
(
8
)
[0067] A survey of insulator dielectric constants reveal the following:
Concrete: ∈ surface =45∈ 0 Paper: ∈ surface =3.5∈ 0 Silicon dioxide (A.K.A. Sand): ∈ surface =4.5∈ 0 Conductors ∈ surface →∞ Where ∈ 0 =8.854×10 −12 F/M
[0073] For insulators, we take a typical ∈ surface =4.56∈ 0 , so that
F insulator ≈51.0 Newtons
[0075] For conductors, that figure becomes
F conductor ≈72.0 Newtons
[0077] The frequency of the oscillations is automatically controlled by the mechanisms in the levitation vehicle such that a repulsive force is generated between the surface and the levitation vehicle. It is expected that the frequency of oscillation that is necessary to induce and maintain levitation will vary with different surface material. It is also expected that the frequency of oscillation that is necessary to induce and maintain levitation will be time dependent.
[0078] In FIG. 2 a and FIG. 2 b , the conductive power plates that are inside the simple field plate assembly is the source of the electric fields. For FIG. 2 c , the vertical and horizontal metal field plates are the source of the electric fields. Its function is to spread electric field over a large area on the surface and thus polarize that large area, thus making large the area of the surface in which charge is induced by the electric field from the metal plates so that the force on the levitating system can be large enough to levitate the vehicle without exceeding the breakdown voltage of the surrounding media (i.e. air) and also producing the effect that due to the fact that a large area of the surface contains charge, the electric field due to that area of surface charge can reach a considerable distance from the surface on which the levitation vehicle is being levitated to the vicinity of the levitation vehicle since as is well known in electrostatics, the electric field at a distance from a large sheet of charge of uniform charge density is approximately σ/∈ where σ is the charge density on the sheet. The important point is that for an appreciable distance from the sheet of charge induced on the surface on which the vehicle is being levitated the electric field is only weakly dependent on the distance away from that sheet of charge. The electric field will eventually be strongly dependent on the distance away from the surface (since the area of the charge on the surface is not actually infinite) but the point is that for a large distance from the surface, this dependence on distance will be weak. The advantage of this weak dependence on the distance away from the surface of the electric field is that the repulsive force on the vehicle can then be increased by simply stacking more conductive power plates, one atop another since with a large area of charge on the surface, the fields due to these charges on the surface reach further out into the air so that extra metal sheets higher up can feel roughly the same repulsive force as lower ones. This is the reason for the stacking of the conductive power plates one on top of the other.
[0079] The E-Field switching algorithm is implemented with the top electrometer and bottom electrometer as shown in ( FIG. 2 a , FIG. 2 b , FIG. 2 c ) and the simple feedback control ( FIG. 3 a , FIG. 3 c ) or the compound feedback signal control ( FIG. 3 b ).
[0080] The way that force detection is achieved by the top electrometer and the bottom electrometer is as follows:
If the magnitude of the electric field measured by the top electrometer is higher than the magnitude of the electric field measured by the bottom electrometer, then this means that a repulsive force is acting between the system and the surface but if the magnitude of the electric field measured by the top electrometer is lower than the magnitude of the electric field measured by the bottom electrometer, then this means that an attractive force is acting between the levitation vehicle and the surface. The top electrometer and the bottom electrometer ( FIG. 2 a , FIG. 2 b , FIG. 2 c ) measures the magnitude of the electric field in their vicinities and feeds it to comparators ( FIG. 3 a , FIG. 3 c ) or subtractors ( FIG. 3 b ). Thus the output of the comparator ( FIG. 3 a , FIG. 3 c ) or the adder ( FIG. 3 b ) provides information on the nature of the force that is acting on the levitation vehicle due to the induced dielectric polarization of the surface on which the levitation vehicle is being levitated. In ( FIG. 3 a , FIG. 3 b , FIG. 3 c ) the voltage controlled oscillator implements the E-Field switching algorithm by changing its frequency in response to the output of the comparator ( FIG. 3 a , FIG. 3 c ) or the adder ( FIG. 3 b ) as follows:
The voltage controlled oscillator should output low frequency when the levitation vehicle is being acted on by a repulsive force and a high frequency when the levitation vehicle is being acted on by an attractive or neutral force is the following: The polarity of output of transformer Vx in FIG. 4 will depend on whether the output (OVb) is rising or falling henceforth referred to the changing state of (OVb). Here (OVb) refers to the output that is depicted in ( FIG. 3 a , FIG. 3 b , FIG. 3 c ). If repulsive force is acting on the levitation vehicle, then it means that the dielectric polarization of the surface on which the levitation vehicle is being levitated on and the changing state of (OVb) are such that they cause repulsive force on the levitation vehicle. In this case, the frequency of the voltage controlled oscillator should remain low if it was initially low or should be made low if it was initially at high in order to maintain the changing state of (OVb) which causes levitation. If attractive or neutral force is acting on the levitation vehicle, then it means that the dielectric polarization of the surface on which the levitation vehicle is being levitated on and the changing state of (OVb) are such that they cause attractive force or no force on the levitation vehicle. In this case, the frequency of the voltage controlled oscillator should remain high if it was initially high or should be made high if it was initially low in order to change the changing state of (OVb) to a state that will cause repulsion on the levitation vehicle. Thus the levitation vehicle spends much more time for a given time interval in a state of repulsion between the levitation vehicle and the surface and thus the levitation vehicle stays levitated.
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Methods and systems for levitation on uncharged and non-magnetized arbitrary surface are disclosed. The levitation system generates electric fields in order to cause dielectric polarization on the surface on which levitation is to be caused. Methods and systems are disclosed in which the polarity of the electric field that is produced by the system is switched in a controlled manner. Due to kinetic inertia of the effective dipole moment of the uncharged and non-magnetized arbitrary surface, the dipole moment cannot maintain the changes in response to the changes in polarity of the electric field that is produced by the levitation system and thus, a repulsive force is generated between the levitation system and the non-magnetized arbitrary surface. The controlled repulsive force initiates and maintains the desired level of levitation with respect to the uncharged and non-magnetized arbitrary surface. Additionally the source of electric fields is made to have a large area in order to increase the repulsive force on the levitation system.
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BACKGROUND
1. Technical Field
The present disclosure generally relates to a lid for a reservoir to be connected to a liquid spraying device, in particular a lid with a ventilation system for venting the reservoir.
2. Description of the Related Art
Today, different kinds of liquid spraying devices are known. These kinds of liquid spraying devices use different techniques to transport liquid from a reservoir to a spraying mechanism. In general, suction feed liquid spraying devices and gravity feed liquid spraying devices are known. In the case of the suction feed liquid spraying devices, the reservoir is generally located below the spraying mechanism and the liquid is sucked from the reservoir by negative pressure. In the case of the gravity feed liquid spraying devices, the reservoir is generally located above the spraying mechanism and the liquid can flow from the reservoir towards the spraying mechanism according to the principle of gravity.
Independent from these different techniques, it is desirable to have an undisturbed flow of the liquid from the reservoir to the spraying mechanism in order to achieve a uniform application of the liquid onto a surface which has to be treated.
WO 2005/077543 A1 describes a reservoir for a gravity feed liquid spraying device with a vent opening at the bottom of the reservoir, wherein the vent opening is closed when the reservoir is filled with liquid and is opened after the complete spraying device is turned upside down so that the reservoir is positioned above the spraying mechanism for spraying. However, opening and closing the vent opening at the correct point in time is cumbersome and may cause problems, such as liquid leaving the reservoir, if the vent opening is not closed correctly.
WO 2009/046806 A1 describes a lid for a reservoir of a gravity feed liquid spraying device. The lid is provided with a vent opening constructed as a labyrinth seal formed by three cylinders being plugged into each other. The labyrinth seal is intended to prevent liquid from flowing out of the reservoir both when the reservoir is in its upright position and when the reservoir is inverted during the liquid spraying process. However, the labyrinth seal cannot always prevent liquid from flowing past the labyrinth seal. This is in particular the case when the reservoir is inverted. Moreover, the labyrinth seal protrudes from the lid, such that the lid cannot be stored in a space-saving manner.
SUMMARY OF THE DISCLOSURE
The embodiments disclosed herein provide a reservoir with a vent opening for venting the reservoir which reliably prevents liquid from flowing out of the reservoir during use. In addition, these embodiments provide individual components of the reservoir that are storable in a space-saving manner as well as easily and securely transportable.
The lid for a reservoir to be connected to a liquid spraying device according to the disclosure comprises a ventilation hole, a flexible tube, and a valve, wherein the combination of the ventilation hole, the flexible tube, and the valve forms a ventilation system which allows an air movement from the outside of the reservoir via the ventilation system to the inside of the reservoir while it blocks the movement of a liquid from the inside of the reservoir via the ventilation system to the outside of the reservoir.
This new ventilation system provides a reliable venting of the reservoir, i.e. without risk of liquid flowing into the venting system. This is the case, since the ventilation hole does not require opening or closing during use of the liquid spraying device. The flexible tube serves as an extension of the ventilation hole into the inside of the reservoir and is sealed at its distal end by the valve in a liquid tight manner. The valve prevents liquid from flowing out of the reservoir into the ventilation system during use, i.e. during the refilling process, as the spraying device is inverted from the filling position to the spraying position, and during the spraying process. In addition, it is possible to easily refill the reservoir by removing the lid from the reservoir together with the ventilation system.
Due to the new ventilation system, the lid according to the present disclosure could be easily stored and transported. This is the case, since the tube is flexible. While the prior art lid has a protruding labyrinth seal formed by three rigid cylinders, the flexible tube according to the present disclosure enables the tube, and therefore the ventilation system, to be placed in a position in which it does not disturb during storing and transporting. In accordance with the present disclosure, a flexible tube is a tube which could be bent at at least one point of the length of the tube. However, in a preferred embodiment, the flexible tube could be bent at several points, i.e. at at least two points. In a further preferred embodiment, the flexible tube could be bent at any point of the length, which is identified herein as a “completely flexible” tube.
Basically, the liquid used for the spraying process may be any flowable material, but preferably one of color, paint, glue, or garden chemicals.
In a preferred embodiment, the flexible tube is made at least in part of a flexible material having at the same time a sufficient stiffness in order to prevent collapse due to liquid pressure. Preferably, the flexible tube is made at least in part of rubber, silicone, or plastic, wherein plastic is preferably polyethylene or polyprophylene.
In a further preferred embodiment, the flexible tube is adapted for allowing the valve to be located above a liquid level in the reservoir during operation by means of a gravity feed liquid spraying device. This may be achieved, for example, by using a tube having a suitable length. In general, the reservoir may be formed by a lid and a container. For filling the reservoir, the container is placed on its bottom and the liquid to be sprayed is filled in the container through an opening at the opposite side of the container, i.e. opposite to the bottom. In subsequent steps, the opening is closed by the lid to form the reservoir and the reservoir is connected to the spraying device. When the reservoir and the spraying device are turned, some liquid flows into the lid and in the spraying device. As a consequence, in this upside down position, the reservoir is not completely filled with the liquid. Therefore, a tube with a suitable length will cause that at least the valve connected to the tubes is located above the liquid level when the reservoir is upside down and the spraying device is in operation. Preferably, the tube has also a sufficient stiffness to locate the valve above the liquid level.
In general, the lid with the ventilation system may consist of one, two, three or more pieces. The lid, the flexible tube, and the valve can be formed in one piece. This does not necessarily mean that the ventilation system is produced in one piece. The components of the ventilation system such as the flexible tube and the valve may be produced separately but permanently put together, e.g. glued to form one piece. However, it is also possible that at least some of the components are removable connected to each other and therefore form several pieces.
In a further preferred embodiment, at least portions of the ventilation system have a buoyancy that is high enough to enable the valve to float on the liquid. For example, the shape and/or the material of the valve may be chosen so that the valve floats on the liquid. This may be supported by the shape and/or the material of the flexible tube.
In a further preferred embodiment, portions of the lid form a cavity, wherein the flexible tube and the valve are adapted for being arranged at least in part in the cavity. In particular, the flexible tube and the valve could be stored at least in part in the cavity during transport of the lid. This substantially reduces the space needed by the lid as compared to some lids known in the prior art. Additionally, the lid can be easily sealed with a material that can be removed before using the lid, such that the lid is protected from dust and dirt during transport and storing. However, when the lid is connected to a container of a reservoir, the flexible tube and the valve could be taken out of the cavity so that the valve is located above the liquid level in the reservoir during operation by means of a gravity liquid spraying device. As described above, the flexible tube could be realized in different ways. For example, the flexible tube could be a completely flexible tube which is flexible enough to be arranged circular or serpentine in the cavity. Since the valve is preferably small and compact, it either marginally protrudes beyond the dimensions of the lid itself or does not protrude beyond the dimensions of the lid itself at all when arranged in the cavity. Preferably, the cavity is a groove nearby the edge of the lid.
In a further preferred embodiment, the flexible tube comprises nearby the ventilation hole a hinge that allows an orientation of the flexible tube in various directions. Preferably, the hinge is a section of the flexible tube comparable with the bellows-shaped section of a straw. Nevertheless, other implementations of the hinge are conceivable so long as an air movement through the hinge as well as an airtight sealing of the hinge against the inside of the reservoir are ensured.
In a further preferred embodiment, the lid further comprises means for detachably connecting the flexible tube and/or the valve to the lid at a location apart from the ventilation hole. This means for detachably connecting enables that the flexible tube and the valve stay at least partially in the cavity during transport of the lid.
In a further preferred embodiment, the means for detachably connecting the flexible tube and/or the valve to the lid comprises at least one clamp. Preferably, the at least one clamp is a horseshoe-shaped tube clamp comprising a central, preferably circular, opening for the flexible tube and two slightly movable wing portions forming an inlet opening to the central opening. Thereby, the width of the inlet opening is smaller than the smallest diameter of the central opening, such that the wing portions have to be moved away from each other in order to insert the flexible tube into the central opening. Such a horseshoe-shaped tube clamp is advantageous since the connection of the flexible tube with the lid can be easily detached by simply pulling out the flexible tube of the horseshoe-shaped tube clamp. However, the person skilled in the art knows several alternatives, how the flexible tube could be connected to the lid.
In a further preferred embodiment, the valve comprises a valve body forming a first opening and a second opening, wherein the first opening is adapted to be connected to the flexible tube in such a way that the flexible tube generally extends in a layer parallel to the second opening. Thereby, air can enter the inside of the reservoir via the second opening of the valve body. The flexible tube extending in a layer parallel to the second opening is advantageous since herewith the flexible tube and the valve can be arranged in a cavity formed by portions of the lid in an even more space-saving manner. In particular, it can be avoided that the valve protrudes beyond the dimensions of the lid itself.
In a further preferred embodiment, the valve body further comprises a valve seat having a sealable valve opening. The sealable valve opening blocks movement of liquid from the second opening to the first opening, while permitting movement of air from the first opening to the second opening. Preferably, the sealable valve opening is arranged in a layer which is parallel to the second opening, but which is substantially perpendicular to the layer of the first opening. This is advantageous since herewith the flexible tube does not have to be connected directly to the sealable valve opening in order to allow an air movement from the outside of the reservoir to the inside of the reservoir. Instead, the flexible tube can be connected to the valve at the most technically appropriate position with regards to storing the lid as space-saving as possible, namely at the first opening.
In a further preferred embodiment, the valve comprises venting means arranged at the side of the sealable valve opening facing the second opening, wherein the venting means prevents liquid from the inside of the reservoir from entering the flexible tube and allows air movement from the outside of the reservoir into the reservoir.
Suitable venting means may be formed by an air-permeable but liquid-tight body. Such a body which is air-permeable and liquid-tight may prevent liquid drops from entering the flexible tube and at the same time may allow an air pressure compensation between the outside of the reservoir and the inside of the reservoir. An example for a suitable air-permeable but liquid-tight body is a fine grid that is air-permeable all the time. However, it is also possible to use an air-permeable but liquid-tight body that becomes only air-permeable when the air pressure in the inside of the reservoir decreases.
In a preferred embodiment, the venting means comprises an elastically deformable membrane. On the one hand, this elastically deformable membrane can be arranged in a closed position, where it lies on the valve seat and seals the sealable valve opening by covering the sealable valve opening. In such an arrangement, it is advantageously prevented that liquid drops get into the flexible tube as well as that air moves from the outside of the reservoir via the ventilation system to the inside of the reservoir when there is no need for an air pressure compensation between the inside of the reservoir and the outside of the reservoir. When the air pressure inside of the reservoir decreases, at least a portion of the elastically deformable membrane curves away from the valve seat. Hence, on the other hand, the elastically deformable membrane can be arranged in an open position, where it is at least partially lifted from the valve seat and thus forms a certain air passage. Such an arrangement is advantageous since air can flow from the outside of the reservoir via the ventilation hole, the flexible tube, the first opening of the valve body, the sealable valve opening, the air passage, and finally the second opening of the valve body to the inside of the reservoir and thus an air pressure compensation between the outside of the reservoir and the inside of the reservoir can take place. Upon completion of such an air pressure compensation, the elastically deformable membrane moves back to its closed position. The elastically deformable membrane may be made at least in part of any elastic material, but preferably it is made at least in part of rubber, silicone, or plastic, wherein plastic is preferably polyethylene or polyprophylene. Advantageously, when the deformable membrane is in the open position, liquid drops may be prevented from entering the flexible tube. This is, since the air passage is only present if air flows from the outside of the reservoir to the inside of the reservoir in order to compensate air pressure and as long as air flows, liquid cannot flow in the opposite direction into the valve.
In a further preferred embodiment, the venting means further comprise a seal liquid for enhancing the sealing, wherein the seal liquid is located in at least one area between the valve seat and the elastically deformable membrane. Preferably, the seal liquid is a silicone oil which is located in concentric channels surrounding the sealable valve opening. Such a seal liquid is advantageous since it enables an even better liquid tightness as well as air tightness when the elastically deformable membrane is arranged in the closed position.
By the lid for a reservoir described above, for the first time a lid for a reservoir with a vent opening which reliably prevents that liquid could flow out of the reservoir during use is provided. In addition, the lid is designed in such a way that it is storable in a space-saving manner as well as easily and securely transportable.
BRIEF DESCRIPTION OF THE DRAWINGS
In the following, the disclosure is further described by reference to the schematic illustrations shown in the figures, wherein:
FIG. 1 shows a cross section of an embodiment of a lid for a reservoir according to the disclosure;
FIG. 2 shows a side view of a ventilation system arranged in a cavity formed by portions of an embodiment of a lid for a reservoir according to the disclosure; and
FIG. 3 shows a cross section of an embodiment of a valve for a lid according to the disclosure.
It should be understood that the drawings are not necessarily to scale and that the disclosed embodiments are sometimes illustrated diagrammatically and in partial views. In certain instances, details which are not necessary for an understanding of the disclosed methods and apparatus or which render other details difficult to perceive may have been omitted. It should be understood, of course, that this disclosure is not limited to the particular embodiments illustrated herein.
DETAILED DESCRIPTION
FIG. 1 shows a cross section of an embodiment of a lid 2 according to the present disclosure connected to a container 18 to form a reservoir 1 , with the lid 2 in an inverted position to facilitate use with a gravity feed spraying device. The lid 2 comprises a ventilation hole 3 , a flexible tube 4 , and a valve 5 . In the following, the combination of the ventilation hole 3 , the flexible tube 4 , and the valve 5 is referred to as the ventilation system. As shown in FIG. 1 , the ventilation system, in particular the flexible tube 4 , is adapted to allow the valve 5 to be located above a level 7 of a liquid 6 in the reservoir 1 during operation by means of a gravity feed liquid spraying device. Among others, this could be achieved due to a sufficient length and a sufficient stiffness of the flexible tube 4 .
FIG. 2 shows a side view of a lid 2 according to the disclosure as it may be transported. The flexible tube 4 and the valve 5 are arranged in a cavity formed by portions of the lid 2 . In the embodiment shown in FIG. 2 , the flexible tube 4 and the valve 5 are completely arranged in the cavity. Nevertheless, according to this disclosure it is sufficient if portions of the flexible tube 4 and the valve 5 are arranged in the cavity. For arranging the flexible tube 4 and the valve 5 in the cavity, in the present embodiment the flexible tube 4 comprises nearby the ventilation hole 3 a bellows-shaped section 8 which allows the flexible tube 4 to be bent so that it may be arranged easily in the cavity of the lid 2 . However, the bend of the flexible tube 4 can also be achieved by any kind of hinge or by simply utilizing the elasticity of the flexible tube itself. Furthermore, for arranging the ventilation system in the cavity, in the present embodiment the flexible tube 4 is bent in a circular shape. In order to prevent the flexible tube 4 from returning from its circular bent position to its original position due to forces resulting from its elasticity, the lid 2 further comprises a horseshoe-shaped tube clamp 9 in whose central opening the flexible tube 4 is inserted. Nevertheless, any kind of clamp and any kind of easily removable adhesive tapes or adhesive points may be used for detachably connecting the flexible tube 4 and/or the valve 5 to the lid 2 .
FIG. 3 shows a cross section of a valve 5 of an exemplary embodiment ventilation system according to the disclosure. In the illustrated embodiment, the valve 5 comprises a valve body 10 forming a first opening 11 and a second opening 12 . The flexible tube 4 is connected to the first opening 11 and generally extends in a layer parallel to the second opening 12 . The valve body 10 also comprises a valve seat 13 having a sealable valve opening 14 . Venting means are arranged at the side of the sealable valve opening 14 facing the second opening 12 in order to prevent liquid 6 from inside the reservoir 1 from entering the flexible tube 4 , and to permit air from outside the reservoir 1 to communicate with an interior of the reservoir 1 . For this purpose, the venting means in this embodiment comprises an elastically deformable membrane 15 as well as a sealing liquid 16 located between the valve seat 13 and the elastically deformable membrane 15 .
FIG. 3 illustrates the sealable valve opening 14 in both a closed state as well as in an open state. In the case of the sealable valve opening 14 being in its closed state as shown on the left-hand side of FIG. 3 , the elastically deformable membrane 15 is arranged in a closed position. In this closed position, the elastically deformable membrane 15 completely covers the sealable valve opening 14 by lying on the valve seat 13 . Sealing between the membrane 15 and the valve seat 13 is further improved by the sealing liquid 16 . Due to this combination, an outstanding liquid tightness as well as air tightness is ensured in the closed position. In the illustrated embodiment, the sealable valve opening 14 changes from closed to open state when the air pressure in the inside of the reservoir 1 decreases during the spraying process, as shown on the right-hand side of FIG. 3 . During the change from the closed state to the open state, a portion of the elastically deformable membrane 15 curves away from the valve seat 13 in the direction of the second opening 12 of the valve body 10 . At the same time, other portions of the elastically deformable membrane 15 are forced not to curve away from the valve seat 13 and instead to remain laying on the valve seat 13 , such as by means of a stop element 17 . Such a stop element 17 prevents the elastically deformable membrane 15 from too extensively lifting from the valve seat 13 and thus prevents an air passage formed thereby getting too large. Hence, in the case of the sealable valve opening 14 being in its open state, the elastically deformable membrane 15 is arranged in an open position forming an air passage for allowing air pressure compensation. Thereby, air flows from the outside of the reservoir 1 via the flexible tube 4 and the valve 5 to the inside of the reservoir 1 and at the same time the elastically deformable membrane 15 steadily moves back to its closed position up to the completion of the air pressure compensation.
All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference. The description of certain embodiments as “preferred” embodiments, and other recitation of embodiments, features, or ranges as being preferred, is not deemed to be limiting, and the claims are deemed to encompass embodiments that may presently be considered to be less preferred. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended to illuminate the disclosed subject matter and does not pose a limitation on the scope of the claims. Any statement herein as to the nature or benefits of the exemplary embodiments is not intended to be limiting, and the appended claims should not be deemed to be limited by such statements. More generally, no language in the specification should be construed as indicating any non-claimed element as being essential to the practice of the claimed subject matter. The scope of the claims includes all modifications and equivalents of the subject matter recited therein as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the claims unless otherwise indicated herein or otherwise clearly contradicted by context. The description herein of any reference or patent, even if identified as “prior,” is not intended to constitute a concession that such reference or patent is available as prior art against the present disclosure.
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A lid ( 2 ) for a reservoir ( 1 ) to be connected to a liquid spraying device, comprising a ventilation hole ( 3 ); a flexible tube ( 4 ); and a valve ( 5 ), wherein the combination of the ventilation hole ( 3 ), the flexible tube ( 4 ), and the valve ( 5 ) forms a ventilation system which allows an air movement from the outside of the reservoir ( 1 ) via the ventilation system to the inside of the reservoir ( 1 ) while it blocks the movement of a liquid ( 6 ) from the inside of the reservoir ( 1 ) via the ventilation system to the outside of the reservoir ( 1 ).
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to a cooking apparatus with a charcoal starting device and more specifically, a charcoal preparation system for a cooking apparatus, and the system comprises: a firebowl having an open topside and a bottomside, the bottomside comprises at least one aperture; and the charcoal starting device comprises a charcoal grate and a chimney, the charcoal grate is moveable to a first position below the firebowl during a charcoal igniting stage and to a second position within the firebowl during a cooking stage, and at least a portion of the charcoal starting device designed to fit within the chimney, and the chimney is movable through said aperture of the bottomside of the firebowl, and at least a portion of the chimney is situated within the firebowl during a usage position and is moveable to a position below the firebowl during a stowage position.
[0003] 2. Description of the Related Art
[0004] It is known in the art to use charcoal as a source for cooking heat in barbecues. In order to start the charcoal barbecues, the charcoals must be burned quickly to commence the cooking process without substantial delay. Chimneys have been used with charcoal barbecues in preparation of the charcoals.
[0005] The present invention provides for a charcoal preparation system using a moveable chimney and moveable charcoal grate.
SUMMARY OF THE INVENTION
[0006] In one embodiment, the present invention provides for a barbecue cooking system with moveable charcoal chimney device, the system comprises: a firebowl having an open topside and a bottomside, and the bottomside comprising at least one aperture; and a chimney movable through the aperture of the bottomside of the firebowl, and at least a portion of the chimney is situated within the firebowl during a usage position and at least a portion of the chimney is moveable to a position below the firebowl during a stowage position.
[0007] In another embodiment, the system further comprises a base having top and bottom portions, and the bottomside of the firebowl is situated upon the top portion of the base. In yet another embodiment, the system further comprises an actuator for moving the chimney.
[0008] In still another embodiment, the base comprises an internal cavity and at least one aperture, and at least a portion of the chimney is situated within the internal cavity of the base during the stowage position. In still yet another embodiment, at least a portion of the actuator is situated within the internal cavity of the base, and the actuator comprises a handle protruding through the aperture of the base.
[0009] In a further embodiment, the system further comprises a charcoal grate. In another further embodiment, at least a portion of the charcoal grate is designed to collapse within the chimney during a charcoal igniting stage. In yet a further embodiment, at least a portion of the chimney is situated within the firebowl during the charcoal igniting stage. In still a further embodiment, the charcoal grate is expanded during a cooking stage. In still yet a further embodiment, at least a portion of the chimney is moveable to a position below the firebowl during the cooking stage.
[0010] In another embodiment, the system further comprises a charcoal grate actuator designed to move the charcoal grate between the charcoal igniting stage and cooking stage.
[0011] In yet another embodiment, the system further comprises a housing, and at least a portion of the chimney is designed to fit within the housing, and the housing is situated below the firebowl.
[0012] In still another embodiment, the charcoal grate has an external portion and an internal portion. In still yet another embodiment, the internal portion of the charcoal grate is situated within the internal cavity of the chimney and is moveable with the chimney. In a further embodiment, the internal portion of the charcoal grate and at least a portion of the internal cavity of the chimney forms a basket for holding charcoal. In another further embodiment, the charcoal grate comprises a central hub grate and a multiplicity of extensions pivotally attached to said hub grate at its periphery enabling a basket configuration and a flat configuration to be formed. In yet another further embodiment, the hub grate is moveable vertically relative to the firebowl between a lower and an upper position. In still another further embodiment, the charcoal grate is in its basket configuration while the hub grate is in its lower position. In still yet another further embodiment, the charcoal grate is in its flat configuration while the hub grate is in the upper position.
[0013] In another embodiment, the charcoal grate comprises an inner grate, an outer grate surrounding the inner grate and a gap between the inner and outer grates through which the chimney may move between the usage and stowage positions.
[0014] In still another embodiment, the system further comprises a cooking grate situated above the charcoal grate. In yet another embodiment, the system further comprises a heat source situated below the firebowl. In still yet another embodiment, the heat source is a flammable gas torch.
[0015] In another further embodiment, the base is an elongated tube. In still a further embodiment, the system further comprises an elongated column situated below the firebowl and a platform situated below the column.
[0016] In another embodiment, the present invention provides for a charcoal preparation system for a cooking apparatus, and the system comprises: a firebowl having an open topside and a bottomside, and the bottomside comprises at least one aperture; and a charcoal starting device comprising at least one charcoal grate and at least one chimney, and at least a portion of the charcoal grate is moveable to a first position below the firebowl during a charcoal igniting stage and to a second position within the firebowl during a cooking stage, and at least a portion of the charcoal grate is designed to fit within the chimney, and the chimney is movable through the aperture of the bottomside of the firebowl, and at least a portion of the chimney is situated within the firebowl during a usage position and is moveable to a position below the firebowl during a stowage position.
[0017] In another further embodiment, the system further comprises a base, and the base is attached to the bottomside of the firebowl. In yet a further embodiment, the system further comprises an elongated housing situated on an external surface of the bottomside of the firebowl, and the housing comprises an internal cavity, an external surface and at least two apertures, and at least a portion of the charcoal starting device being situated with the internal cavity of the housing of the base during the charcoal igniting stage, and at least a portion of the chimney is situated within the internal cavity of the housing of the base during the stowage position.
[0018] In still a further embodiment, the system further comprises a first actuator for moving the charcoal grate and a second actuator for moving the chimney, and at least a portion of the first and second actuators are situated within the internal cavity of the housing of the base, and each of the actuators comprises a handle protruding through the apertures of said housing.
[0019] In still yet a further embodiment, the system comprises a heat source situated below the firebowl. In another further embodiment, the heat source is a flammable gas torch. In yet another further embodiment, the heat source comprises a tank, and an extended portion and a nozzle portion from which the flame originates, and the tank is situated external of the base, and at least a portion of the extended portion and the nozzle portion is situated within the internal cavity of the base.
[0020] In still another embodiment, the system further comprises a column connected to the bottomside of the firebowl. In still yet another embodiment, the column comprises an internal cavity and the aperture of the firebowl leads to the internal cavity of the column. In a further embodiment, the column comprises top and bottom portions, the top portion of the column is connected to the bottomside of the column and the bottom portion of the column being connected to the base.
[0021] In still another embodiment, the charcoal grate is a foldable grate which is moveable between the charcoal igniting stage wherein the charcoal grate is folded to form a basket for holding the charcoal and the cooking stage wherein the charcoal grate is unfolded to form a generally flat grate for holding burning charcoal. In yet another embodiment, the charcoal grate comprises a central hub and a plurality of petal-like structures pivotally attached to the hub and extending outwardly from the hub to thereby form a circular array, and the structures are designed to pivot upwardly to form the basket and designed to pivot downwardly to form the generally flat grate.
[0022] In still yet another embodiment, the system further comprises a grate situated above the charcoal grate.
[0023] In a further embodiment, the chimney has an internal cavity, and the charcoal grate collapses within the cavity of the chimney during the charcoal igniting stage, and at least a portion of the chimney is situated within the firebowl during the charcoal igniting stage. In another further embodiment, the charcoal grate is expanded and within the firebowl during the cooking stage, and at least a portion of the chimney is moveable to a position below the firebowl during the cooking stage. In yet a further embodiment, the charcoal grate has an external portion and an internal portion. In still a further embodiment, the internal portion of the charcoal grate is situated within the internal cavity of the chimney and is moveable within the chimney. In still yet a further embodiment, the internal portion of the charcoal grate and at least a portion of the internal cavity of the chimney forms a basket for holding charcoal.
[0024] In another embodiment, the present invention provides for a barbecue cooking system with moveable charcoal chimney device, and the system comprises: a firebowl having an open topside and a bottomside; a moveable chimney, and at least a portion of the chimney is situated within the firebowl during a usage position and at least a portion of the chimney is moveable to a position below the bottomside of the firebowl during a stowage position; and an actuator designed to move the chimney between the use and non-use positions.
[0025] In another further embodiment, the system further comprises an elongated column attached to the bottomside of the firebowl and a stand attached to the column, and the column comprising an internal cavity, and the chimney is designed to fit within the internal cavity of the column.
[0026] In another embodiment, the charcoal igniting stage is performed as follows: the actuator is moved in a position that allows the charcoal grate to form a basket and at least a portion of the basket is situated below the firebowl; the actuator of the chimney is positioned so that the chimney is still situated below the firebowl; charcoal briquettes are poured then poured into the charcoal grate basket and slightly heaped (in other embodiments, the charcoal briquettes are placed on the expanded charcoal grate and then, the basket is formed); the chimney is then raised by moving the actuator (in some embodiments, the actuator is moved in an upwardly direction to raise the chimney and moved in a downwardly direction to lower the chimney and in some other embodiments, the actuator is moved in a downwardly direction to raise the chimney and moved in an upwardly direction to lower the chimney; the access door is opened and paper is crumbled and inserted under the basket; and the paper is ignited and access door closed allowing the smoke to vent through the chimney and allow the charcoal to be ignited.
[0027] In another further embodiment, the cooking stage is performed as follows: after the charcoal has been ignited (usually 15 to 20 minutes), the chimney is lowered and the basket is raised by moving the respective actuators; the basket actuator may be moved side to side to redistribute the ignited charcoal on the charcoal grate; the cooking grate is placed above the charcoal grate with the charcoal and the foodstuff to be cooked is placed on the cooking grate and the cover is placed over the firebowl and airflow may be controlled by adjusting a vent on the lid cover.
[0028] In still another further embodiment, the cleanup stage is performed as follows: make sure the ash bin is situated adjacent the aperture at the bottomside of the firebowl and use the actuator to encourage the ash to fall through the aperture and into the ash bin; and the ash bin may then be removed and emptied (at times, every one to three uses).
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] The accompanying drawings are included to provide a further understanding of the present invention. These drawings are incorporated in and constitute a part of this specification, illustrate one or more embodiments of the present invention, and together with the description, serve to explain the principles of the present invention.
[0030] FIG. 1 is a front perspective view of one of the embodiments of the barbecue cooking systems of the present invention;
[0031] FIG. 2 a is a side view of FIG. 1 showing the chimney in a usage position;
[0032] FIG. 2 b is a cross-sectional view of FIG. 2 a;
[0033] FIG. 3 a is a side view of FIG. 1 of the present invention;
[0034] FIG. 3 b is a cross-sectional view of FIG. 3 a showing a first actuator moving the charcoal grate from the charcoal igniting stage to the cooking stage;
[0035] FIG. 3 c is a cross-sectional view of the cooking system of the present invention showing the second actuator moving the chimney from the usage position to the stowage position;
[0036] FIG. 4 a is a side view of FIG. 1 showing the chimney in the stowage position;
[0037] FIG. 4 b is a cross-sectional view of FIG. 4 a showing the charcoal grate in the cooking stage;
[0038] FIG. 5 is a top perspective view of one of the embodiments of the present invention, in particular, the cooking apparatus with the moveable chimney;
[0039] FIG. 6 is a top perspective view of the charcoal grate of the present invention being filled with charcoal;
[0040] FIG. 7 is a top perspective side view of FIG. 6 showing the formation of the “basket” and descent of the collapsed charcoal grate;
[0041] FIG. 8 is a top perspective view of FIG. 7 showing a heat source being applied to the charcoal in the charcoal grate;
[0042] FIG. 9 is a perspective view of FIG. 8 showing the ignited charcoal and the charcoal grate in the cooking stage; and
[0043] FIG. 10 is a top perspective view of FIG. 9 showing the cooking grate being situated above the ignited charcoal and the charcoal grate in the cooking stage.
[0044] Among those benefits and improvements that have been disclosed, other objects and advantages of this invention will become apparent from the following description taken in conjunction with the accompanying drawings. The drawings constitute a part of this specification and include exemplary embodiments of the present invention and illustrate various objects and features thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0045] As required, detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the invention that may be embodied in various forms. The figures are not necessarily to scale, some features may be exaggerated to show details of particular components. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present invention.
[0046] Referring now to FIGS. 1-4 , the present invention provides for a cooking apparatus 1 comprising a firebowl 2 , a column 3 and a base 4 . The top portion of the column 3 is attached to a bottomside of the firebowl 2 and the bottom portion of the column 3 is attached to a base 4 . There is a moveable charcoal grate 5 situated within the firebowl and a cooking grate 7 adapted to be situated above the charcoal grate 5 during a cooking stage. There is a moveable chimney 6 (not shown in FIG. 1 ). There are two actuators, 9 a and 9 b respectively, which are connected to and designed to move the charcoal grate 5 and the chimney 6 . There are at least two handles 8 situated on an external surface of the firebowl 2 .
[0047] FIGS. 2 a and 2 b show the chimney 6 in the usage position and the charcoal grate 5 in the charcoal igniting stage. There is a heat source 10 attached to the column and situated adjacent to the charcoal grate during the charcoal igniting stage. The heat source 10 may be a flammable gas torch. FIG. 2 b shows a cross-sectional view of the cooking apparatus 1 . During its charcoal igniting stage, the charcoal grate 5 is collapsed into a “basket” form for holding the charcoals 11 which are being ignited by the heat source 10 . In one embodiment, at least a portion of the charcoal grate 5 is situated within an internal cavity of the chimney 6 during the charcoal igniting stage.
[0048] FIGS. 3 a , 3 b and 3 c illustrate the transition of the chimney 6 from the usage position to the stowage position and the charcoal grate 5 from the charcoal igniting stage to the cooking stage. Once the charcoals 11 have been ignited, the actuator 9 a is activated to allow the ascent of the charcoal grate 5 from the internal cavity of the column 3 to the internal cavity of the firebowl 2 . The actuator 9 b is also activated to allow the descent of the chimney 6 from the internal cavity of the firebowl 2 into the internal cavity of the column 3 .
[0049] FIGS. 4 a and 4 b show the chimney 6 in its stowage position and the charcoal grate 5 with the ignited charcoals 11 in its cooking stage. During its stowage position, the chimney 6 is situated within the internal cavity of the column 3 . During its cooking stage, the charcoal grate 5 is expanded to allow the exposure of the ignited charcoals 11 and situated within the internal cavity of the firebowl 2 .
[0050] FIG. 5 shows another embodiment of the present invention showing the cooking system 100 with its moveable chimney 16 . The cooking system 100 comprises a firebowl 12 with an aperture 21 on its bottomside, a column 13 having top and bottom portions, 13 a and 13 b respectively, and a base 14 . The top portion 13 a of the column 13 is attached to the bottomside of the firebowl 12 and the bottom portion 13 b of the column 13 is attached to the base 14 . The column 13 has an internal cavity (not shown) and the aperture 21 of the firebowl 12 leads to the internal cavity of the column 13 . There are handles 18 which are situated on opposing sides of the external surface of the firebowl 12 . There are also supports 20 for a cooking grate (not shown) situated within the firebowl 12 . There is also an access door 23 with a handle 22 for accessing the internal cavity of the column 13 . There are two actuators, 19 a and 19 b respectively, protruding from apertures on the external surface of the column 13 . The actuator 19 b activates the movement of the chimney 16 from the usage position to stowage position and back to the usage position. The chimney 16 moves downwardly through the aperture 21 of the firebowl 12 into the internal cavity of the column 13 for storage. The chimney 16 moves upwardly from the internal cavity of the column 13 through the aperture 21 and into the internal cavity of the firebowl 12 to achieve the usage position. At least the top portion of the chimney is situated above the topside opening of the firebowl 12 during the usage position.
[0051] FIGS. 6-10 demonstrate another embodiment of the present invention, in particular, the cooking system 30 with the moveable charcoal grate 35 . The cooking system comprises a firebowl 32 with a bottomside attached to a column 33 and the column 33 is attached to a stand or base 34 . The external surface of the firebowl 32 comprises handles 38 . The external surface of the column 33 shows an access door 43 with its handle 42 and apertures which allow for the protrusion of at least two actuators, 39 a and 39 b respectively.
[0052] FIG. 6 shows the first stage of the charcoal igniting process of the present invention. A bag 41 of charcoals 11 are poured into the expanded charcoal grate 35 or charcoal grate basket. FIG. 7 shows the second stage wherein the actuator 39 a is activated to allow the charcoal grate 35 begins to collapse to create the “basket” form and allow for the descent of the charcoal grate from the internal cavity of the firebowl, through the aperture of the firebowl 32 and into the internal cavity of the column 33 . FIG. 8 shows how a heat source 50 is applied to the charcoal grate 35 to ignite the charcoal 11 . In one embodiment, the access door 43 with its handle 42 is used to access the charcoal grate 35 and apply the heat source to ignite the charcoal 11 . In this one embodiment, the heat source is paper or other flammable materials. FIG. 9 shows that once the charcoals 11 are ignited, the actuator 39 a is activated to raise the charcoal grate 35 with the ignited charcoals 11 from the internal cavity of the column 33 to the internal cavity of the firebowl 32 . The charcoal grate 35 goes from the “basket” form to its expanded form to expose the ignited charcoals 11 . In another embodiment, the actuator 39 a may be moved side to side or up and down to distribute the ignited charcoals 11 evenly across the charcoal grate 35 . FIG. 10 shows how the cooking grate 37 is situated upon the supports 60 and positioned above the ignited charcoals 11 on the charcoal grate 35 .
[0053] Numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the attendant claims attached hereto, this invention may be practiced otherwise than as specifically disclosed herein.
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A barbecue cooking system with moveable charcoal chimney device is provided, the system comprises: a firebowl having an open topside and a bottomside, and the bottomside comprising at least one aperture; and a chimney movable through the aperture of the bottomside of the firebowl, and at least a portion of the chimney is situated within the firebowl during a usage position and at least a portion of the chimney is moveable to a position below the firebowl during a stowage position.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit of U.S. Provisional Patent Application No. 60/821,877 filed on Aug. 9, 2006.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not Applicable
BACKGROUND OF THE INVENTION
[0003] 1. Field of the Invention
[0004] The present invention relates to hydraulic power systems with electrically operated valves that control fluid flow to hydraulically drive actuators, and more particularly to mechanisms that detect faults occurring in such systems.
[0005] 2. Description of the Related Art
[0006] A wide variety of machines have moveable elements that are driven by a hydraulic actuator, such as a cylinder and piston arrangement. For example, a telehandler has a tractor on which a telescopic boom is mounted with a load carrier pivotally attached to the remote end of the boom. The telescopic boom and the load carrier are moved with respect to the tractor by hydraulic actuators. The flow of fluid to and from each hydraulic actuator is governed by a valve assembly controlled by the machine operator.
[0007] There is a present trend away from manually operated hydraulic valves toward electrical controls and the use of solenoid valves. For example, the operator sitting in a cab of the telehandler manipulates a joystick that produces an electrical signal designating a velocity desired for an associated element, such as the boom or load carrier. An electronic controller responds to the joystick signal by applying electric current to the valve assembly so that the proper amount of fluid is supplied to the respective hydraulic actuator to move the machine component at the desired velocity.
[0008] It is important to detect velocity faults or errors between the actual velocity of a machine component and the desired velocity. Such errors may result in an unsafe operation of the machine and thus require corrective action. On a telehandler, for example, it is desirable to detect a sudden drop of the boom which could occur due to a burst hose or other event. Upon detection of a velocity error, corrective action, such as operating a secondary isolation valve, can be performed.
[0009] Therefore, it is desirable to detect a velocity error of a machine component in order to take proper corrective action. However, such detection must be sufficiently robust to avoid erroneously declaring a fault condition because taking corrective action during normal machine action also may have adverse consequences.
SUMMARY OF THE INVENTION
[0010] A method is provided for detecting a velocity fault of a machine component that is hydraulically driven. This method comprises receiving a velocity command that indicates a desired velocity for the machine component and determining an actual velocity at which the machine component is moving. A velocity error value is produced based on a difference between the velocity command and the actual velocity and the velocity error value is integrated to produce an integrated value. Then the integrated value is analyzed to determine whether a velocity fault has occurred.
[0011] Integrating the velocity error value ensures that an over speed or an under speed condition must persist for a defined period of time before a velocity fault is declared. In a preferred implementation, the integrating is accomplished by a biquadratic filter function which decreases the integrated value for error frequencies that are below a cutoff frequency.
[0012] To determine whether a velocity fault has occurred, the integrated value preferably is analyzed by a threshold operation. The preferred threshold operation compares the integrated value to an over speed threshold and an under speed threshold. An over speed fault is declared when the integrated value is greater than the over speed threshold, and an under speed fault is declared when the integrated value is less than the under speed threshold.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1 shows a telehandler that incorporates a hydraulic system which employs the present invention;
[0014] FIG. 2 is a schematic diagram of the hydraulic system; and
[0015] FIG. 3 is a control diagram depicting a velocity fault detection mechanism.
DETAILED DESCRIPTION OF THE INVENTION
[0016] With initial reference to FIG. 1 , a telehandler 10 is an example of a machine on which the present invention can be used, with the understanding that the invention has application to a wide variety of machines. The telehandler 10 has a carriage 11 with an operator cab. The carriage 11 supports an engine or battery powered motors (not shown) for driving the wheels across the ground and for powering a hydraulic system. A boom assembly 12 comprises a boom 14 , an arm 15 , and a load carrier 16 . The boom 14 is pivotally attached to the rear of the carriage 11 and is raised and lowered by a boom hydraulic actuator 21 , in this case a pair of boom cylinders 22 each having a piston rod 24 (only one cylinder/piston rod arrangement is visible in FIG. 1 ). An arm hydraulic actuator 26 causes the arm 15 to slide telescopically within the boom 14 thereby extending and retracting the length of the boom assembly 12 . The load carrier 16 is pivotally mounted at the remote end of the arm 15 and may comprise any one of several structures for carrying a load 20 . The load carrier 16 is tilted up and down by a load carrier hydraulic actuator 28 .
[0017] The present hydraulic system controls boom motion in terms of the boom hydraulic actuator 21 . For that purpose, a conventional sensor produces an electrical signal in response to motion of the boom assembly with respect to the carriage 11 in order to provide an indication of the actual velocity of the boom hydraulic actuator 21 . For example, a linear transducer 18 indicates the extension distance of a piston rod 24 from one of the boom cylinders 22 wherein that position signal is differentiated to derive the boom velocity. Alternatively, a velocity sensor could directly sense the boom hydraulic actuator velocity. The boom velocity also could be calculated from sensing the fluid flow to or from the boom cylinders. As an alternative sensor, an accelerometer 17 may be mounted on the boom 14 with its signal being integrated to produce a boom velocity signal, which then is converted trigonometrically into the corresponding boom hydraulic actuator velocity. Similarly, a resolver or encoder 19 can be attached to the pivot shaft 13 of the boom with its position signal being differentiated into a boom velocity value that then is converted into the velocity of the boom hydraulic actuator 21 . The velocity of the boom hydraulic actuator is arbitrarily defined as being positive when the boom is being raised and being negative when lowering the boom. As a further alternative, the hydraulic system 30 could control the motion in terms of velocity of the boom 14 thereby enabling velocity values from sensors on the boom assembly to be used without conversion. Thus the component of the telehandler 10 , the velocity of which is being controlled, may be the actuator or the element that is moved by the actuator, e.g. the boom 14 .
[0018] With additional reference to FIG. 2 , the telehandler 10 has a hydraulic system 30 that controls movement of the boom 14 , the arm 15 , and the load carrier 16 . Hydraulic fluid is held in a reservoir, or tank, 32 from which the fluid is drawn by a conventional variable displacement pump 34 and fed through a check valve 36 into a supply line 38 . Alternatively, a fixed displacement pump may be utilized with an unloader valve at its outlet to control the supply line pressure. A tank return line 40 also runs through the telehandler 10 and provides a conduit for the hydraulic fluid to flow back to the tank 32 . A pair of pressure sensors 42 and 44 provide electrical signals that indicate the pressure in the supply line 38 and the tank return line 40 , respectively.
[0019] The supply line 38 furnishes hydraulic fluid to a first control valve assembly 50 comprising a Wheatstone bridge configuration of four electrohydraulic proportional (EHP) valves 51 , 52 , 53 and 54 which control the flow of fluid to and from the two boom hydraulic cylinders 22 . A separate EHP isolation valve 60 or 62 is located immediately adjacent each boom cylinder 22 and connect the first control valve assembly 50 to the respective cylinder's head chamber 57 . Each of these EHP valves 51 - 54 , 60 , 62 and other electrohydraulic proportional valves in the system 30 preferably are bidirectional poppet valves, thereby controlling flow of hydraulic fluid flowing in either direction through the valve. These EHP valves may be the type described in U.S. Pat. No. 6,328,275, for example, however other types of control valves, including an electrically operated spool valve, can be used.
[0020] A first pair of the EHP valves 51 and 52 governs the fluid flow from the supply line 38 into the head chamber 57 on one side of the piston in the boom cylinder 22 and from a rod chamber 55 , on the opposite side of the piston, to the tank return line 40 . This action extends the piston rod 24 from the boom cylinder 22 which raises the boom 14 . A second pair of EHP valves 53 and 54 controls the fluid flow from the supply line into the rod chamber 55 and from the head chamber 57 to the tank return line, which retracts the piston rod into the cylinder 22 thereby lowering the boom 14 . By controlling the rate at which pressurized fluid is sent into one cylinder chamber and drained from the other chamber, the boom 14 can be raised and lowered in a controlled manner. A first pair of pressure sensors 58 and 59 provide electrical signals indicating the pressure in the two chambers of the boom cylinder 22 .
[0021] A second control valve assembly 66 , similar to the first control valve assembly 50 , controls the flow of hydraulic fluid into and out of the arm hydraulic cylinder 26 . Operation of the second control valve assembly 66 extends and retracts the arm 15 with respect to the boom 14 . A third control valve assembly 68 controls fluid flow to and from a load carrier cylinder 28 that tilts the load carrier 16 up and down with respect to the remote end of the arm 15 .
[0022] With continuing reference to FIG. 2 , operation of the hydraulic system 30 is governed by a system controller 70 that includes a microcomputer 71 connected by conventional signal busses 72 to a memory 73 in which software programs and data are stored. The set of signal busses 72 also connects input circuits 74 , output circuits 76 and valve drivers 78 to the microcomputer 71 . The input circuits 74 interface a joystick 79 , the boom motion sensor, and the pressure sensors and other devices to the system controller. The output circuits 76 provide signals to devices that indicate the status of the hydraulic system 30 and the functions being controlled.
[0023] A set of valve drivers 78 in the system controller 70 responds to commands from the microcomputer 71 by generating pulse width modulated (PWM) signals that are applied to the EHP valve assemblies 50 , 66 and 68 . Each PWM signal is generated in a conventional manner by switching a DC voltage at a given frequency. When the hydraulic system is on a vehicle, such as a telehandler, the DC voltage is supplied from a battery and an alternator. By controlling the duty cycle of the PWM signal, the magnitude of electric current applied to a given valve can be varied, thus altering the degree to which that valve opens. This proportionally controls the fluid flowing through the valve to or from the associated hydraulic actuator.
[0024] To raise or lower the boom 14 , the machine operator moves the joystick 79 in the appropriate direction to produce an electrical signal indicating the desired velocity for the boom cylinder 22 , and indirectly the boom assembly 12 . The system controller 70 responds to the joystick signal by generating a velocity command and from that command derives current commands that designate electric current magnitudes for driving selected EHP valves 51 - 54 in order to apply fluid to the two boom cylinders 22 and produce the desired motion. Those current commands are sent to the valve drivers 78 which apply the appropriate electric current magnitudes to the selected EHP valves 51 - 54 . Thus, the hydraulic valves in assembly 50 are opened and closed to various degrees by varying the electric currents applied to those valves. Current commands also are sent to the valve drivers 78 to open fully the two isolation valves 60 and 62 . The control technique described in U.S. Pat. No. 6,775,974 may be used by the controller.
[0025] For example, when the machine operator desires to extend the rods 24 from the boom cylinders 22 and raise the boom assembly 12 , the electric current commands open the first and second EHP valves 51 and 52 by amounts that enable the proper level of fluid flow. Opening the first EHP valve 51 sends pressurized hydraulic fluid from the supply line 38 into the boom cylinder head chambers 57 and opening the second EHP valve 52 allows fluid from the rod chambers 55 to flow to the tank 32 . The system controller 70 monitors the pressure in the various hydraulic lines to properly operate the valves. To retract the rods 24 into the boom cylinders 22 and lower the boom assembly, the system controller 70 opens the third and fourth EHP valves 53 and 54 , which sends pressurized hydraulic fluid from the supply line 38 into the boom cylinder rod chambers 55 and exhausts fluid from the head chambers 57 to tank 32 . The force of gravity aids in lowering the boom assembly 12 .
[0026] With reference to FIG. 3 , the system controller 70 continuously executes a velocity fault detection routine 80 as part of the software for controlling the telehandler 10 . That routine receives the velocity command produced in response to the signal from the joystick 79 and also receives the signal from the sensor 17 , 18 or 19 which indicates the actual velocity of the boom assembly 12 . Those signals are applied to an arithmetic function 81 which produces a velocity ERROR value by calculating the difference between the velocity command (a desired velocity) and the actual boom velocity. The velocity ERROR, or difference, value is applied to two branches 82 and 83 of the velocity fault detection routine 80 . The first branch 82 is active when a positive velocity of the boom is commanded, whereas the second branch 83 is active for negative velocity commands. Two branches are provided so that an over speed or an under speed condition in one direction does not affect operation in the other direction. Note that the velocity of the boom has been arbitrarily defined as being positive when the boom is being raised.
[0027] The first branch 82 commences at a first selection function 84 where a determination is made whether the velocity command is positive, i.e. to raise the boom. If so, the velocity ERROR value is passed to the output of the first selection function 84 , otherwise the output is set to zero, thereby effectively disabling the first branch 82 . Assuming that the velocity command is positive, the velocity ERROR value is adjusted by a first multiplier function 85 which multiplies the velocity ERROR by minus one (−1), so that a positive velocity ERROR value represents an over speed condition. The adjusted velocity ERROR value from the first multiplier function 85 is applied to the input of a first dead band function 86 , so that relatively small velocity errors will be ignored and a fault condition will not be declared as a result. The first dead band function 86 produces a zero output when the adjusted velocity ERROR value is within a predefined range of values centered about zero, otherwise the adjusted velocity ERROR value is passed after being offset by an amount equal to the upper or lower limit of the dead band.
[0028] Simply determining when the adjusted velocity ERROR value exceeds a given threshold is not robust enough to avoid erroneously declaring a velocity fault condition. Large velocity errors typically occur for short durations when the boom-arm assembly strikes an object. A sizeable momentary over speed condition also exists immediately after the operator commands the boom motion to stop and a momentary under speed condition also occurs immediately after the operator commands the boom motion to commence from a stop. Therefore, the two branches 82 and 83 of the fault detection routine employ integration so that an over speed or under speed condition must persist for a period of time before declaring a fault condition.
[0029] Therefore, the output of the first dead band function 86 is applied to a first integration function 87 which forms a leaky integrator that is functionally equivalent to low pass filter with a very low cutoff frequency (e.g. 0.05 Hz) and high gain. The first integration function 87 preferably is implemented by a biquadratic filter having a filter function given by the expression:
[0000]
y
(
n
)
=
B
0
*
x
(
n
)
+
B
1
*
x
(
n
-
1
)
+
B
2
*
x
(
n
-
2
)
A
1
*
y
(
n
-
1
)
+
A
2
*
y
(
n
-
2
)
[0000] where y(n) is the filter function output referred to as an integrated value, A 1 , A 2 , B 0 , B 1 and B 2 are filter coefficients, x(n) is the present output value from the dead band function 86 , x(n−1) and x(n−2) are the previous two dead band function output values, and y(n−1) and y(n−2) are the last two integrated values from the filter. At low frequencies, below a cutoff frequency defined by the filter coefficients, the filter leaks (i.e. decays) which drives the integrated value to zero over time, whereas above the cutoff frequency the filter act as an integrator. That integration converts error indication from a velocity value to a position value.
[0030] That position value is applied to a first unit conversion function 88 where it is multiplied by a conversion factor 89 to convert the position error into the desired units of distance. The resultant position value then is applied to a first threshold operation 90 to an over speed threshold and an under speed threshold. Specifically the first threshold operation 90 comprises a first threshold function 91 that compares the position value to a positive over speed threshold, and a second threshold function 92 that compares the position value to a positive under speed threshold. When the positive over speed threshold is exceeded, a positive over speed fault is declared by first over speed function 91 . Similarly, if the speed is below the positive under speed fault threshold, a positive under speed fault is declared by a first under speed function 92 . These fault signals are binary thereby indicating whether a fault is or is not occurring.
[0031] If the first dead band function 86 was eliminated and a true integrator used in the first integration function 87 , small errors continue to accumulate over time until an error threshold eventually is reached. However, when determining the fault thresholds for functions 91 and 92 , it is helpful to consider the leaky first integration function 87 as a true integrator over a relatively small time period. In this way, the thresholds can be considered as a maximum allowable distance error after the velocity error is integrated. The dead band limits, cutoff frequency and gain of the first integration function 87 , and the fault detection thresholds are parameters that are determined and adjusted for the particular type of machine in order to ensure proper operation.
[0032] A clear ERROR command can be produced by the system controller 70 and applied to reset the first integration function 87 to zero. This avoids the accumulation of errors over a prolonged period of machine operation from producing continuous speed fault declarations.
[0033] The second branch 83 is similar to the first branch 82 , except the second selection function 93 renders the second branch active only when the velocity command is negative (i.e. a boom lower command). In other words, the velocity ERROR value is passed into the second branch 83 only upon occurrence of a negative velocity command, otherwise a zero value is applied to the downstream components in the second branch which thereby is disabled from indicating a fault condition. The output of the second selection function 93 is applied unadjusted to a second dead band function 94 which produces an output that is applied to a leaky second integration function 95 . The results of that latter function are then applied to a second units converter 96 to generate a signal representing the error in terms of a position. That position error then is compared by third and fourth threshold functions 97 and 98 of a second threshold operation 99 to a negative over speed threshold and a negative under speed threshold, respectively. When one of those negative thresholds is exceeded, a negative over speed fault indication or a negative under speed fault indication is generated.
[0034] It also should be understood that a particular machine may not require all the positive and negative over speed and under speed fault indications, as one or more of them may not correspond to a potentially hazardous condition.
[0035] The system controller 70 responds to the fault indications from the velocity fault detection routine 80 by taking the appropriate corrective action. For example, in response to an over speed fault condition, the system controller 70 operates the two isolation valves 60 and 62 for the boom cylinders 22 , thereby stopping any motion of the boom assembly 12 . As noted, these isolation valves are located in close proximity to the respective boom cylinders 22 and thus prevent fluid from exiting the head chambers 57 should the hose connecting those cylinders to the valve assembly 50 burst. A similar safeguard occurs if the first or fourth valve 51 or 54 fails in the open position. In place of the isolation valves, a mechanical stop on the load holding side of the actuator could be activated to arrest motion of the boom assembly 12 .
[0036] The foregoing description was primarily directed to a preferred embodiment of the invention. Although some attention was given to various alternatives within the scope of the invention, it is anticipated that one skilled in the art will likely realize additional alternatives that are now apparent from disclosure of embodiments of the invention.
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Motion of a hydraulically driven machine component is controlled in response to a velocity command that indicates a desired velocity for the machine component. A method for detecting a velocity fault involves determining an actual velocity at which the machine component is moving, and producing a velocity error value based on a difference between the velocity command and the actual velocity. The velocity error value is integrated, such as by a low pass, biquadratic filter function, to produce an integrated value. The integrated value is compared to one or more thresholds to determine whether a velocity fault has occurred.
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BACKGROUND OF THE INVENTION
The present invention relates to the general art of containers, and to the particular field of container and lid combinations.
It is quite common for people to store food in plastic containers. This food is stored in the refrigerator or in the freezer or in a cabinet, as suitable. These containers may simply store the food or, as is often the case, provide a convenient vessel in which the food can be cooked or heated. This type of container has been very convenient.
However, one drawback to such containers it that the lids therefor may, and often do, become separated from the container. Thus, when one wishes to use a container, a search must be conducted for the lid. If one owns several containers, there may be many lids, all of different sizes, through which the search must be conducted. This can be time consuming and annoying. Lids often become lost, and this exacerbates the annoyance.
Therefore, there is a need for a means for storing a lid for a container in an efficient manner.
Sometimes, lids are stored in a location that differs from the storage location of the container. Therefore, even if the lid can be found, a user must move between two locations to form a single container. Again, this can be time consuming and annoying.
Therefore, there is a need for a means for storing a lid for a container in a location that is convenient to the container.
It is often difficult to properly seal a container. Air becomes trapped in the container and it must be “burped” in order to remove excess air so the container can be properly sealed. This may be difficult if a person's dexterity is limited.
Therefore, there is a need for a container from which air can be easily removed.
PRINCIPAL OBJECTS OF THE INVENTION
It is a main object of the present invention to provide a means for storing a lid for a container in an efficient manner.
It is another object of the present invention to provide a means for storing a lid for a container in a location that is convenient to the container.
It is another object of the present invention to provide a container from which air can be easily removed.
SUMMARY OF THE INVENTION
These, and other, objects are achieved by a container having a ledge unit on the bottom into which a lid can be slidably stored. The lid remains with the container during storage and is easily removed by sliding it out of the ledge unit for use.
Using the combination embodying the present invention will permit a lid for a container to be efficiently stored in a convenient location, to wit: directly on the container.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
FIG. 1 is a perspective view of a container and lid combination embodying the present invention.
FIG. 2 is a bottom perspective view of a container and lid combination embodying the present invention.
FIG. 3 is an elevational view of a portion of the container and lid combination shown in FIG. 1 showing the vent slots defined in the container adjacent to the lip of the container and which will be covered and closed by the lid when the lid is in place on the container.
FIG. 4 is a plan view of the lid.
FIG. 5 is a schematic representation showing movement of the lid in the lid storage area on the container.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Other objects, features and advantages of the invention will become apparent from a consideration of the following detailed description and the accompanying drawings.
Referring to the Figures, it can be understood that the present invention is embodied in a container unit 10 that achieves the above-stated objectives.
Container unit 10 comprises a body 12 which includes a planar element 14 which is a bottom when body 12 is in use. Planar element 14 includes a first end 16 , a second end 18 , and a longitudinal axis 20 which extends between first end 16 and second end 18 . Planar element 14 also includes a first side 22 , a second side 24 , and a transverse axis 26 which extends between first side 22 and second side 24 . As is best seen in FIG. 3 , a first surface 30 is a top surface when body 12 is in use and a second surface 32 is a bottom surface when body 12 is in use.
Referring back to FIG. 1 , it can be seen that body 12 further includes a first end wall 40 on first end 16 of body 12 , a second end wall 42 on second end 18 of planar element 14 , a first side wall 44 on first side 22 of planar element 14 , and a second side wall 46 on second side 24 of planar element 14 .
The walls extend in a plane that is perpendicular to a plane containing planar element 14 and define with the planar element 14 a storage volume 48 in which food or the like can be stored in the manner known to those skilled in the art.
Each wall has a rim, such as rim 50 on first side wall 44 , that is spaced apart from planar element 14 and which is a top rim when body 12 is in use. The top rims of the walls are all co-planar with each other.
Each side wall has an air vent, such as air vent 52 in first side wall 44 , defined therein adjacent to the top rim 50 thereof. It is noted that, if desired, the end walls can also have air vents, such as air vent 52 ′, defined therein as well.
Each wall has a shoulder element, such as shoulder element 54 on first side wall 44 , thereon. The shoulder elements on the side walls are located adjacent to the air vent 52 defined therein.
Each wall has a base portion, such as base portion 56 of first end wall 40 , located between the shoulder element 54 thereon and planar element 14 .
Each wall further includes a locking portion, such as locking portion 58 on first side wall 44 as shown in FIG. 3 , located between the shoulder element 54 thereon and the rim 50 thereof. Each locking portion 58 is planar and oriented at an oblique angle to the base portion 56 thereof. The locking portion 58 of each wall extends outwardly with respect to storage volume 48 and the air vents 52 are located in the locking portion 58 of each side wall.
A lid storage section 60 is located on body 12 and includes a first L-shaped bracket 62 which has a first leg 64 , which includes a proximal end 66 that is fixedly secured to second surface 32 of planar element 14 adjacent to first side 22 of the planar element 14 and a distal end 68 that is spaced apart from second surface 32 of planar element 14 . Bracket 62 further includes a second leg 70 , which includes a proximal end 72 that is unitary with distal end 68 of first leg 64 and which extends from first leg 64 toward second side 24 of planar element 14 . Second leg 70 is oriented in a plane that is parallel with planar element 14 and has a distal end 74 that is spaced apart from proximal end 72 and which is located between first side 22 of the planar element 14 and second side 24 of the planar element 14 .
First L-shaped bracket 62 extends from first end 16 of planar element 14 to second end 18 of the planar element 14 in the direction of the longitudinal axis 20 of the planar element 14 .
Lid storage section 60 further includes a second L-shaped bracket 80 which is similar to the first L-shaped bracket 62 and has a first leg 82 which includes a proximal end 84 fixedly secured to second surface 32 of planar element 14 adjacent to second side 24 of the planar element 14 and a distal end 86 that is spaced apart from second surface 32 of the planar element 14 .
Second L-shaped bracket 80 further includes a second leg 90 which includes a proximal end 92 that is unitary with distal end 86 of first leg 82 of the second L-shaped bracket 80 and which extends from first leg 82 toward first side 22 of planar element 14 . Second leg 90 is oriented in a plane that is parallel with planar element 14 and has a distal end 94 that is spaced apart from proximal end 92 of second leg 90 and is located between second side 24 of planar element 14 and first side 22 of the planar element 14 .
Second leg 90 is co-planar with second leg 70 of first L-shaped bracket 62 and distal end 94 of second leg 90 is spaced apart from distal end 74 of second leg 70 of first L-shaped bracket 62 and defines a gap 98 therebetween.
Second L-shaped bracket 80 extends from first end 16 of planar element 14 to second end 18 of the planar element 14 in the direction of longitudinal axis 20 .
As best seen in FIG. 2 , lid storage section 60 further includes a third L-shaped bracket 100 which has a first leg 102 which includes a proximal end 103 , that is fixedly secured to second surface 32 of planar element 14 adjacent to second end 18 of the planar element 14 , and a distal end 104 , that is spaced apart from second surface 32 of the planar element 14 .
A second leg 106 of bracket 100 includes a proximal end 108 that is unitary with distal end 104 of first leg 102 of third L-shaped bracket 100 and extends from first leg 102 toward first end 16 of planar element 14 . Second leg 106 is oriented in a plane that is parallel with planar element 14 and has a distal end 110 that is spaced apart from proximal end 108 and is located between second end 18 of planar element 14 and first end 16 of the planar element 14 .
Second leg 106 is co-planar with the second legs 70 , 90 of the first and second L-shaped brackets 62 , 80 and distal end 110 is spaced apart from the distal ends 74 , 94 of the second legs 70 , 90 of the first and second L-shaped brackets 62 , 80 and defines a gap 112 with the distal ends 74 , 94 of the second legs 70 , 90 of the first and second L-shaped brackets 62 , 80 .
The second legs 70 , 90 , 106 of the first, second and third L-shaped brackets 62 , 80 , 100 define a lid-supporting ledge 120 adjacent to second surface 32 of planar element 14 of body 12 .
A lid 130 includes a planar portion 131 which includes a first end 132 , a second end 134 , and a longitudinal axis 136 which extends between first end 132 and second end 134 , a first side 138 , a second side 140 , and a transverse axis 142 which extends between first side 138 and second side 140 . Lid 130 further includes a first surface 148 , which is a top surface when lid 130 is in use, and a second surface 150 , which is a bottom surface when lid 130 is in use. A first end groove 152 is defined in planar portion 131 adjacent to first end 132 of planar portion 131 , a second end groove 154 is defined in planar portion 131 adjacent to second end 134 of the planar portion 131 , a first side groove 156 is defined in planar portion 131 adjacent to first side 138 of planar portion 131 , and a second side groove 158 is defined in planar portion 131 adjacent to second side 140 of planar portion 131 . The grooves of lid 130 are sized and adapted to frictionally accommodate the locking portions 58 of the walls of body 12 when lid 130 is in place on body 12 . The lid 130 further includes portions, such as portion 160 and 162 , which are located to cover the air vents 52 defined in the side walls of body 12 when the lid 130 is in place on the body 12 .
Lid 130 also has a projection 166 on the first end 132 of the lid 130 . Projection 166 is grasped by a user when the lid 130 is to be moved or manipulated.
The lid 130 is sized and adapted to be slidably accommodated in the lid-supporting ledge 120 of the lid storage section 60 between the lid-supporting ledge 120 and the second surface 32 of the planar element 14 of body 12 with projection 166 extending beyond first end 16 of planar element 14 during storage of the lid 130 .
Use and operation of container unit 10 can be understood by those skilled in the art based on the teaching of the foregoing disclosure and therefore such use and operation will only be briefly described. When unit 10 is stored, the lid 130 is stored in lid storage section 60 by being supported on the ledge 120 of the lid storage section 60 beneath planar element 14 after being slidingly placed on the ledge 120 in direction 170 . When the container is to be closed, the lid 130 is removed from the lid storage section 60 by grasping projection 166 and sliding the lid 130 out of the lid storage section 60 and placing the lid 130 on body 12 . While the lid 130 is being moved onto the body 12 , air will be forced out of storage volume 48 through the air vents 52 . After the lid 130 is seated on the body 12 , the lid 130 will cover the air vents 52 thereby sealing storage volume 48 .
Additionally, the lid 130 may rest without being moved onto the body 12 to allow hot air to be forced out of storage volume 48 through the air vents 52 when container unit 10 is used to cook or heat food.
It is to be understood that while certain forms of the present invention have been illustrated and described herein, it is not to be limited to the specific forms or arrangements of parts described and shown.
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A container unit includes a container body having a ledge unit on the bottom thereof. A lid is slidably stored on the ledge unit and is thus stored with the container body and is readily available for use when needed. The container body also has air vent slits defined therein near the top rim thereof and the lid covers these vents when in place.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a permanent magnet material or a hard magnetic material and more particularly to a rare earth alloy permanent magnet material.
2. Description of the Prior Art
Rare earth alloy permanent magnet materials fit a wide range of applications to magnetic recording materials such as magnetic tapes, magnetic recording devices, and motors and have been finding utility in various technical fields.
There is known that nitrogen is incorporated into rare earth element-transition element type matrix alloys, particularly Sm-Fe matrix alloys, to improve the magnetic properties thereof. These permanent magnet materials are produced by pulverizing a Sm-Fe matrix alloy into minute particles not exceeding several μm in diameter and subjecting the minute particles to a nitriding treatment in an atmosphere of N 2 gas at a temperature in the range of from 400° to 650° C.
The conventional rare earth alloy permanent magnetic material, however, undergoes decomposition at temperatures exceeding 650° C. While a compressed piece of pulverized particles obtained by compression molding the particles in a magnetic field is sintered to produce a permanent magnet for practical use, the retention of nitrogen and the magnetic properties of magnet are appreciably degraded. It is, therefore, impossible to form a permanent magnet for practical use by the sintering method without any sacrifice of the outstanding magnetic properties produced by the nitriding treatment.
SUMMARY OF THE INVENTION
An object of this invention, therefore, is to provide a permanent magnet material possessing excellent magnetic properties such that a rare earth element-transition element type matric alloy is enabled to assimilate nitrogen positively during the process of manufacture of a magnet and, at the same time, is allowed to be shaped while the nitride consequently formed is restrained from thermal decomposition.
Another object of this invention is to provide a permanent magnet material which, in the process of manufacture of a permanent magnet for practical use by the sintering method, experiences only a sparing degradation in the retention of nitrogen and the magnetic properties of magnet and permits safe retention of excellent magnetic properties.
To accomplish the objects described above, according to this invention, there is provided a permanent magnet material which has as main components thereof a rare earth element, a transition element (except for rare earth elements, Cu, and Ag), and nitrogen and contains as an additive component thereof at least one element selected from the group consisting of Cu, Ag, Al, Ga, Zn, Sn, In, Bi, and Pb.
Desirably, the content of the rare earth element is set in the range of from 6 to 30 atomic %, the content of the transition element in the range of from 60 to 91 atomic %, and the content of nitrogen in the range of from 3 to 15 atomic %. Meanwhile, the content of the additive component ought to be set in a range in which the magnetic properties of a magnet material formed solely of the main components will not be degraded owing to the use of the additive component therein. Generally in the case of a Sm-Fe-N type alloy, the content of the additive component is desirably set at a level below 4.5 atomic %, though variable with the composition of the matrix alloy and the kind of the additive component.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic diagram illustrating a first example of the apparatus for the production of a permanent magnet material according to the present invention.
FIG. 2 is a graph showing the relation of the Ga content in an alloy of Sm 11 Fe 77-X N 12 Ga X and the intrinsic magnetic coercive force of the alloy.
FIG. 3 is a graph showing the relation of the Cu content in an alloy of Sm 11 Fe 77-X N 12 Cu X and the intrinsic magnetic coercive force of the alloy.
FIG. 4 is a graph showing-the relation of the Ag content in an alloy of Sm 11 Fe 77-X N 12 Ag X and the intrinsic magnetic coercive force of the alloy.
FIG. 5 is a graph showing the relation of the Al content in an alloy of Sm 11 Fe 77-X N 12 Al X and the intrinsic magnetic coercive force of the alloy.
FIG. 6 is a graph showing the relation of the Al content in an alloy of Sm 11 Fe 76-X N 12 Cu 1 .0 Al X and the intrinsic magnetic coercive force of the alloy.
FIG. 7 is a graph showing the relation of the Ga content in an alloy of Sm 11 Fe 76-X N 12 Cu 1 .0 Ga X and the intrinsic magnetic coercive force of the alloy.
FIG. 8 is a graph showing the relation of the Zn content in an alloy of Sm 11 Fe 77-X N 12 Zn X and the intrinsic magnetic coercive force of the alloy.
FIG. 9 is a graph showing the relation of the Sn content in an alloy of Sm 11 Fe 77-X N 12 Sn X and the intrinsic magnetic coercive force of the alloy.
FIG. 10 is a graph showing the relation of the Pb content in an alloy of Sm 11 Fe 77-X N 12 Pb X and the intrinsic magnetic coercive force of the alloy.
FIG. 11 is a graph showing the relation of the In content in an alloy of Sm 11 Fe 77-X N 12 In X and the intrinsic magnetic coercive force of the alloy.
FIG. 12 is a schematic diagram illustrating a second example of the apparatus for the production of a permanent magnet material according to the present invention.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The permanent magnet material of this invention is composed of main components and an additive component. The main components include a rare earth element, a transition element (with the exception of rare earth elements and Cu and Ag), and nitrogen and the additive component is at least one element selected from the group consisting of Cu, Ag, Al, Ga, Zn. Sn, In, Bi, and Pb.
In the main components, Sm, for example, is used as a rare earth element. The content of this element is set at a level of not less than 6 atomic % and not more than 30 atomic %. Any deviation of the content of this rare earth element from this range is undesirable because the intrinsic magnetic coercive force is unduly low if the content is less than 6 atomic %, whereas the saturated magnetization is notably low if the content exceeds 30 atomic %.
Fe or Co, for example, is used as a transition element. The content of the transition element is set at a level of not less than 60 atomic % and not more than 91 atomic %. Any deviation of the content of this transition element from the range is undesirable because the saturated magnetization is degraded if the content is less than 60 atomic %, whereas the intrinsic magnetic coercive force is unduly low if the content exceeds 91 atomic %.
The content of N is set at a level of not less than 3 atomic % and not more than 15 atomic %. Any deviation of the content of nitrogen from this range is undesirable because the rare earth element-transition element alloy fails to manifest uniaxial magnetic anisotropy if the N content is less than 3 atomic %, whereas the alloy undergoes phase separation and loses magnetic coercive force if the content exceeds 15 atomic %.
The additive component, in the process of manufacture of a permanent magnet, functions to curb possible thermal decomposition of the nitride of the main components described above. The content of the additive component is set in a range in which the magnetic properties of the nitride are not degraded owing to the use of this additive component.
Among other elements usable for the additive component as mentioned above, Cu, Ag, Al, and Ga are capable of further improving the magnetic properties of the nitride, depending on the content thereof. On the other hand, Zn, Sn, In, and Bi are sparingly effective in enhancing the magnetic properties of the nitride. The content of the additive component will be described more specifically herein below.
Now, this invention will be described more specifically below with reference to working examples. As a matter of course, this invention is not limited to the following examples. It ought to be easily understood by any person of ordinary skill in the art that this invention allows various modifications within the scope of the spirit of this invention.
FIG. 1 illustrates an apparatus to be used for the production of a permanent magnet material contemplated by this invention.
This apparatus is provided with a main chamber 1 and a sub-chamber 2 disposed below the main chamber 1. These two chambers 1 and 2 intercommunicate via a duct 3 of which upper opening part 4 is directed toward a hearth 8 made of copper disposed inside the main chamber 1. In the main chamber 1, a W electrode 6 is inserted and set in place so that the leading terminal part 7 thereof is positioned above the hearth 8 of Cu. The W electrode 6 and the Cu hearth 8 are connected to a power source 9. Inside the sub-chamber 2, a substrate 11 provided with a built-in heater 10 is disposed below the lower opening part 5 of the duct 3.
The main chamber 1 is connected via a first valve 12 to a first vacuum pump 13, whereas the sub-chamber 2 is connected via a second valve 14 to a second vacuum pump 15. The main chamber 1 is further connected via a third valve 16 to a processing gas supply source 17 for handling N 2 gas, for example.
For the production of the permanent magnet material, the following procedure may be adopted.
(1) A matrix alloy A is placed in the hearth 8 and the substrate 11 is heated to a prescribed temperature.
(2) With the second and third valves 14 and 16 kept closed and the first valve 12 opened, the first vacuum pump 13 is set into operation to evacuate the interior of the main chamber 1 and the interior of the sub-chamber 2 each to the order of about 10 -5 Torr.
(3) With the first and second valves 12 and 14 kept closed and the third valve 16 opened, the processing gas supply source 17 is set into operation to supply such processing gas as N 2 gas into the main chamber 1 and the sub-chamber 2. The amounts of the processing gas so supplied are controlled so that the inner pressure of the main chamber 1 falls in the neighborhood of 50 cmHg.
(4) A voltage of 20 V is applied between the W electrode 6 and the hearth 8 to induce arc discharge and vaporize the matrix alloy A.
(5) The inner pressure of the sub-chamber 2 is decreased by opening the second valve 14 and setting the second vacuum pump 15 into operation and, at the same time, the amount of the processing gas being supplied is controlled so that the processing gas flows out of the main chamber 1 into the sub-chamber 2 via the duct
The vapor of the matrix alloy reacts with the processing gas. The product of this reaction is carried on the current of the processing gas and then accumulated on the substrate 11 inside the sub-chamber 2, to give rise to a film of permanent magnet M.
Besides the N 2 gas, HCN gas, NH 3 gas, and B 3 N 3 H 6 gas, etc. are available as the processing gas.
EXAMPLE 1
By using the apparatus described adore and following the procedure described above, a permanent magnet material, Sm 11 Fe 75 N 12 Ga 2 (wherein the numerals represent the relevant proportions in atomic %; similarly applicable hereinafter), of this invention about 3 μm in thickness was produced.
The conditions for the production were as follows:
Matrix alloy: Sm 17 Fe 81 Ga 2 , weight 150 g
Substrate: heat resistant glass sheet, temperature 460° C.
Processing gas: N 2 gas (purity not lower than 99.99%)
Duration of accumulation: 20 minutes
COMPARATIVE EXAMPLE 1
A permanent magnet material for comparison, Sm 11 Fe 78 N 11 , was produced by following the procedure described above, excepting Sm 17 Fe 83 was used as a matrix alloy.
Table 1 shows the magnetic properties of the permanent magnet material of this invention and the comparative experiment.
TABLE 1______________________________________ Intrinsic magnetic Saturated coercive force magnetizationNo. iHc (KOe) Ms (emu/g)______________________________________Example 1 23 120Comparative 20 123Experiment 1______________________________________
It is clearly noted from Table 1 that the permanent magnet material of this invention, owing to the incorporation of Ga, possesses better intrinsic magnetic coercive force than the permanent magnet material of the comparative experiment.
To study the permanent magnet materials of this invention and the comparative experiment as to susceptibility to thermal decomposition, the two permanent magnet materials were subjected to a heating test performed at 650° C., the temperature at which the materials were shaped during their manufacture, for five hours and then tested for magnetic properties and residual ratio of N. The results are shown in Table 2. The residual ratio of N was calculated by the following formula: ##EQU1##
TABLE 2______________________________________ Intrinsic magnetic Residual coercive force ratioNo. iHc (KOe) of N (%)______________________________________Example 1 21 90Comparative 13 40Experiment 1______________________________________
It is clearly noted from Table 2 that the permanent magnet material of this invention gave rise to the decomposition product only in a small amount in the heating test and retained its excellent magnetic properties even after the heating test, whereas the permanent magnet material of the comparative experiment succumbed to decomposition in the heating test and consequently suffered from notable degradation of the magnetic properties. Example 2:
Various permanent magnet materials were produced by following the procedure of Example 1, excepting various additive components were used.
FIG. 2 shows the relation between the Ga content in the permanent magnet material of this invention, Sm 11 Fe 77-X N 12 Ga X (inclusive of the aforementioned Sm 11 Fe 75 N 12 Ga 2 ), and the intrinsic magnetic coercive force thereof. It is noted from FIG. 2 that the content of Ga was set at a level of not more than 4 atomic % under the conditions such that the intrinsic magnetic coercive force of Sm 11 Fe 77-X N 12 Ga X would not fall below that of Sm 11 Fe 78 N 11 .
FIG. 3 shows the relation between the Cu content in the permanent magnet material of this invention, Sm 11 Fe 77-X N 12 Cu X and the intrinsic magnetic coercive force thereof. It is noted from FIG. 3 that the content of Cu should be set at a level of not more than 4.5 atomic % under the conditions such that the intrinsic magnetic coercive force of Sm 11 Fe 77-X N 12 Cu X would not fall below that of Sm 11 Fe 78 N 11 .
FIG. 4 shows the relation between the Ag content in the permanent magnet material of this invention, Sm 11 Fe 77-X N 12 Ag X and the intrinsic magnetic coercive force thereof. It is noted from FIG. 4 that the content of Ag should be set at a level of not more than 4 atomic % under the conditions such that the intrinsic magnetic coercive force of Sm 11 Fe 77-X N 12 Ag X would not fall below that of Sm 11 Fe 78 N 11 .
FIG. 5 shows the relation between the Al content in the permanent magnet material of this invention, Sm 11 Fe 77-X N 12 Al X and the intrinsic magnetic coercive force thereof. It is noted from FIG. 5 that the content of Al should be set at a level of not more than 4.5 atomic % under the conditions such that the intrinsic magnetic coercive force of Sm 11 Fe 77-X N 12 Al X would not fall below that of Sm 11 Fe 78 N 11 .
FIG. 6 shows the relation between the Al content in the permanent magnet material of this invention, Sm 11 Fe 76-X N 12 Cu 1 .0 Al X and the intrinsic magnetic coercive force thereof. It is noted from FIG. 6 that the content of Al should be set at a level of not more than 3.5 atomic % under the conditions such that the intrinsic magnetic coercive force of Sm 11 Fe 76-X N 12 Cu 1 .0 Al X would not fall below that of Sm 11 Fe 78 N 11 and the content of Cu is kept at 1 atomic % (constant).
FIG. 7 shows the relation between the Ga content in the permanent magnet material of this invention, Sm 11 Fe 76-X N 12 Cu 1 .0 Ga X and the intrinsic magnetic coercive force thereof. It is noted from FIG. 7 that the content of Ga should be set at a level of not more than 3 atomic % under the conditions such that the intrinsic magnetic coercive force of Sm 11 Fe 76-X N 12 Cu 1 .0 Ga X would not fall below that of Sm 11 Fe 78 N 11 and the content of Cu is kept at 1 atomic % (constant).
FIG. 8 shows the relation between the Zn content in the permanent magnet material of this invention, Sm 11 Fe 77-X N 12 Zn X and the intrinsic magnetic coercive force thereof. It is noted from FIG. 8 that the content of Zn should be set at a level of not more than 2.5 atomic % under the conditions such that the intrinsic magnetic coercive force of Sm 11 Fe 77-X N 12 Zn X would not fall below that of Sm 11 Fe 78 N 11 .
FIG. 9 shows the relation between the Sn content in the permanent magnet material of this invention, Sm 11 Fe 77-X N 12 Sn X and the intrinsic magnetic coercive force thereof. It is noted from FIG. 9 that the content of Sn should be set at a level of not more than 2.5 atomic % under the conditions such that the intrinsic magnetic coercive force of Sm 11 Fe 77-X N 12 Sn X would not fall below that of Sm 11 Fe 78 N 11 .
FIG. 10 shows the relation between the Pb content in the permanent magnet material of this invention, Sm 11 Fe 77-X N 12 Pb X and the intrinsic magnetic coercive force thereof. It is noted from FIG. 10 that the content of Pb should be set at a level of not more than 2 atomic % under the conditions such that the intrinsic magnetic coercive force of Sm 11 Fe 77-X N 12 Pb X would not fall below that of Sm 11 Fe 78 N 11 .
FIG. 11 shows the relation between the In content in the permanent magnet material of this invention, Sm 11 Fe 77-X N 12 In X and the intrinsic magnetic coercive force thereof. It is noted from FIG. 11 that the content of In should be set at a level of not more than 2.5 atomic % under the conditions such that the intrinsic magnetic coercive force of Sm 11 Fe 77-X N 12 In X would not fall below that of Sm 11 Fe 78 N 11 .
Various permanent magnet materials shown in FIG. 3 to FIG. 11 were severally subjected to the same heating test at 650° C. for five hours as described above. The results were as shown in Table 3. The chemical formulas in the table represent the compositions of the permanent magnets of this invention prior to the heating test.
TABLE 3______________________________________ Intrinsic magnetic coercive force iHc (KOe) Residual Before After ratio ofPermanent magnet heating heating N (%)______________________________________Sm.sub.11 Fe.sub.75 N.sub.12 Cu.sub.2 24.5 21.0 90Sm.sub.11 Fe.sub.75.2 N.sub.12 Ag.sub.1.8 24.5 20.5 85Sm.sub.11 Fe.sub.75.8 N.sub.12 Al.sub.1.2 24 19.5 85Sm.sub.11 Fe.sub.75 N.sub.12 Cu.sub.1.0 Al.sub.1.0 24 20.0 83Sm.sub.11 Fe.sub.74.8 N.sub.12 Cu.sub.1.0 Ga.sub.1.2 24.8 21.5 88Sm.sub.11 Fe.sub.76 N.sub.12 Zn.sub.1.0 21 16.0 80Sm.sub.11 Fe.sub.76 N.sub.12 Sn.sub.1.0 20.5 16.0 78Sm.sub.11 Fe.sub.76 N.sub.12 Pb.sub.1.0 20.5 15.0 78Sm.sub.11 Fe.sub.75.5 N.sub.12 In.sub.1.5 20.7 16.0 80______________________________________
It is clearly noted from Table 3 that the permanent magnet materials of this invention retained excellent magnetic properties even after the heating test.
The method of production depicted in FIG. 1 is advantageous in that the speed of accumulation of the product is high, the increase of surface area is easy to obtain, the pulverization of the product into minute particles is realized because the melting point of the matrix alloy is lowered by the addition such as of Cu, and the permanent magnet of uniform high-density texture is obtained.
FIG. 12 illustrates another apparatus to be used for the production of a permanent magnet conforming to this invention.
In this apparatus, a water-cooled crucible 22 is disposed in a chamber 21 and a pair of discharge electrodes 24 and 25 connected to a power source 23 are disposed as opposed to each other above the crucible 22. A heating plate 26 is set in place above the two discharge electrodes 24 and 25. A substrate 27 formed of quartz glass or strontium titanate, for example, is attached to the lower surface of the heating plate 26. A laser oscillator 28 is installed in the ceiling part of the chamber 21 and adapted so that a pulse laser emanating from this oscillator 28 advances through a perforation 29 formed in the heating plate 26 and the substrate 27 and impinges on the water-cooled crucible 22. The chamber 21 is connected via first and second valves 30 and 32 respectively to a vacuum pump 31 and a processing gas supply source 33.
For the production of a permanent magnet, the following procedure may be adopted.
(1) A matrix alloy A is placed in the water-cooled crucible 22 and the substrate 27 is heated to a temperature in the range of from 400° to 800°.
(2) With the second valve 32 kept closed and the first valve 30 opened, the vacuum pump 31 is set into operation to decrease the inner pressure of the chamber 21 to a level of about 5×10 -5 Torr.
(3) With the first valve 30 kept closed and the second valve 32 opened, the processing gas supply source 33 is set into operation to supply the processing gas such as N 2 into the chamber 21. The amount of supply of the processing gas is regulated so that the inner pressure of the chamber 21 reaches a level in the range of from about 10 to about 70 cmHg.
(4) A voltage of 2 kV is applied between the two discharge electrodes 24 and 25 to induce generation of plasma. The matrix alloy A is vaporized by projecting the pulse laser from the laser oscillator 28 onto the matrix alloy A.
The resultant vapor of the matrix alloy reacts with the plasma of the processing gas and the product of this reaction is deposited on the substrate 27, to give rise to a permanent magnet M.
The method of production depicted in FIG. 12 is advantageous in respect that the vapor of the matrix alloy is easily combined with N because the treatment proceeds under the reactive plasma, the defilement of the product with the dirt from the atmosphere occurs only sparingly, and the adjustment of the composition of the final product and that of the matrix alloy due to the addition such as of Cu is easy to effect (since the matrix alloy is fused with the pulse laser, local processing is easy to accomplish).
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A permanent magnet material having as main components thereof a rare earth element, a transition element (except for rare earth elements and Cu and Ag), and nitrogen and containing as an additive component thereof at least one element selected from the group consisting of Cu, Ag, Al, Ga, Zn, Sn, In, Bi, and Pb. It finds extensive utility in magnetic recording materials such as magnetic tapes, magnetic recording devices, and motors, for example.
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BACKGROUND OF THE INVENTION
This invention relates to dispensers for fluids, typically for soaps, lotions and detergents, and in particular, to a new and improved fluid dispenser valve which requires lower operating forces than conventional dispenser valves. Dispensers of this nature are sometimes referred to as valves and sometimes as pumps, and "dispenser valve" or "valve" will be used herein as meaning a valve or a pump.
The conventional soap and lotion dispenser utilizes O-rings for seals, and a typical device is Bobrick Model B-111, produced by Bobrick Washroom Equipment, Inc. In this type of device, a piston is mounted in a valve body of a fluid storage container, with the piston sliding in the valve body and having O-rings for sealing purposes. The piston is pushed inward to force fluid out from the valve chamber, typically manually, mechanically or electrically, and is pushed outward by a spring to return the piston to the rest position and to suck fluid into the valve body. While this type of design has been satisfactory for many purposes, a relatively high force is required for operation, typically requiring a manual push in the order of six to eight pounds. While satisfactory for many installations, a dispenser with a lower operating force is desired for environments where the valve will be utilized by handicapped individuals.
Accordingly, it is an object of the present invention to provide a new and improved fluid dispenser valve which will have the desirable operating characteristics of conventional valves, while being operable with substantially less force, typically in the range of three to four pounds maximum. It is a further object of the invention to provide such a new and improved valve which will operate with a source of supply having a substantial negative pressure head or a substantial positive pressure head and at the same time not be subject to dripping or leaking of fluid.
These and other objects, advantages, features and results will more fully appear in the course of the following description.
SUMMARY OF THE INVENTION
The preferred embodiment of the invention comprises a valve for dispensing a material such as soap or detergent or hand lotion, from a fluid dispenser. The valve body is designed for mounting in a fluid container and includes a valve chamber with a rolling diaphragm dividing the chamber into a piston section and a fluid flow section. A piston having no O-rings or other seals is slidingly positioned in the piston section, and a flow restrictor is slidingly positioned in the fluid flow section, with a spring urging the restrictor into engagement with the piston with the diaphragm therebetween, for moving the piston to the out or rest, position. Conventional fluid inlet and fluid outlet valves are provided in the fluid flow section so that an inward movement of the piston dispenses fluid and an outward or return motion of the piston draws or sucks a new charge of fluid into the valve. The restrictor functions to provide pressure on the fluid section side of the rolling diaphragm during the return or suction stroke to prevent collapse of the diaphragm and reduce the friction in the device.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a side view of a fluid dispenser with a dispenser valve mounted on a fluid container;
FIG. 2 is an enlarged sectional view showing an embodiment of the dispenser valve;
FIG. 3 is an isometric view of a rolling diaphragm;
FIG. 4 is a sectional view showing an alternative embodiment for the restrictor of the valve of FIG. 2; and
FIG. 5 is a view similar to that of FIG. 2 showing an alternative and presently preferred embodiment of the dispenser valve.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The illustration of FIG. 1 shows a container 10 suitable for mounting against a vertical surface 11 of a wall or cabinet or the like. A dispenser valve 12 is mounted in the container near the bottom, and a sight glass 1 is mounted in the container above the valve to provide an indication of when the container requires refilling. This is a conventional dispenser valve installation, and a wide range of similar installations are known and utilized.
One embodiment of the valve is shown in detail in FIG. 2, with the valve piston in the in or compressed position in the upper half of the Figure, and in the out or rest position in the lower half.
The valve includes a valve body having a base 15 and a cap 16, with pins 17 for aligning the base and cap and preventing rotation of the cap relative to the base. The cap is clamped to the base by a clamp ring 18 which threadedly engages the base 15, with a washer 19 therebetween. The valve is mounted on the container 10 by a nut 20 which threadedly engages a boss 21 of the base 15 projecting through an opening in the container 10, with an 0-ring 22 providing a seal.
A rolling diaphragm 25 is clamped in the valve body between the base 15 and cap 16. The rolling diaphragm is a conventional device, such as that provided by Bellofram Corporation, and a typical rolling diaphragm is shown in FIG. 3. The rolling diaphragm has a cup shaped body 26 with a flange 27 and mounting rim 28. When installed as shown in FIG. 2, the mounting rim 28 is positioned in an annular groove 29 in the body cap 16, and the clamping action provided by the threaded clamp ring 18 compresses the rim in the groove to provide a seal.
The rolling diaphragm 25 divides the valve chamber within the valve body into a piston section 32 and a fluid flow section 33. A piston 34 is slideably positioned within the piston section 32, and preferably has a truncated conical shape at its inner end 35. A screw 36 is threadedly mounted in the body cap 16 and rides in a groove 37 in the piston 34, for limiting axial movement and preventing rotation of the piston in the valve body.
A valve 40, a spring ring 41, a spring 42, and a restrictor 43 are mounted in the fluid flow section 33. The valve 40 is positioned at the fluid inlet passage 45 in the body base 15, and is held in place by the force exerted by the spring 42 which urges the spring ring 41 against the valve 40 and urges the restrictor 43 against the diaphragm 25 to move the piston 34 to the out or ready position. Preferably, the restrictor has a concave shape at its inner end 46 mating with the end 35 of the piston and clamping the diaphragm therebetween.
In the embodiment illustrated, the bore of the body base 15 in which the restrictor 43 moves, is cylindrical, and the restrictor has a first cylindrical section 50 adjacent the diaphragm and a second cylindrical section 51 spaced from the diaphragm by the first section 50, with the diameter of the second section 51 greater than that of the first section 50, thereby providing a flow restriction between the body base 15 and the restrictor 43 at the section 51.
An outlet nozzle 55 is threadedly mounted in the body base 15, with an umbrella valve 56 positioned therein on a gasket 57 and held in place by a spring 58. The section 33 is in communication with the nozzle 55 through an opening 59 in the body 15. The inlet valve 40 and the outlet valve 56 may be conventional in design, and a variety of such valve constructions are available.
In operation, the valve is normally in the rest or out position as shown in the lower half of FIG. 2. A quantity of the fluid from the container 10 is in the fluid flow section 33. The user pushes inward on the piston, compressing the spring 42 and reducing the volume of the section 33 which results in expulsion of fluid past the valve 56 and out through the nozzle 55. The piston is released and the spring 42 moves the piston from the position of the upper half of FIG. 2 back to the position of the lower half of FIG. 2. This motion enlarges the volume of the section 33 producing a lower pressure, which permits opening of the valve 40 and fluid flow from the container 10 through the passage 45 into the section 33.
In the conventional rolling diaphragm pump, there is no restrictor in the valve chamber and the reduced pressure produced in the fluid flow section 33 during the return stroke appears at the fluid flow section face of the rolling diaphragm. This reduction in pressure usually results in a collapse of the rolling diaphragm onto itself, with the sliding of the collapsed diaphragm along itself producing friction and wear of the diaphragm material with a reduction in operating life of the diaphragm.
This problem is overcome by the use of the restrictor in the fluid flow section. The restrictor functions to restrict the fluid flow from the zone at the face of the diaphragm to the zone at the inlet and outlet valves, so that while a suction is produced in the latter zone, pressure is maintained at the former zone sufficient to prevent collapse of the rolling diaphragm during the return stroke.
During the return stroke, while fluid is being drawn into the fluid flow section 33 from outside the dispenser valve, the portion of the fluid flow section around the restrictor section 50 becomes smaller in volume which causes an increase in pressure of the fluid contained in this section facing the diaphragm 25. Due to the resulting pressure differential over the restrictor, there is fluid flow past the restrictor section 51 from the diaphragm face to the main portion of the fluid flow section 33. The lesser diameter of the restrictor at section 00 permits the restrictor to move into the cap 16 without touching the inner wall of the diaphragm, as shown in the lower half of FIG. 2.
In making certain that the inner surfaces of the rolling diaphragm, i.e., the surfaces facing the section 33, are always under positive pressure during periods of motion, these surfaces are always kept apart. Since these surfaces are moving in relation to each other, this separation precludes any rubbing action of the surfaces and eliminates abrasive wear which can cause failure.
The conventional valve presently on the market requires in the order of six to eight pounds pushing force to operate the valve. In contrast, the valve of the present application which is designed as a direct substitute for the conventional valve, requires a maximum of three to four pounds for operation. Also, the valve of the invention will operate with a negative head at the inlet passage 45 and with a positive head at this passage, typically with a negative head or positive head in the order of thirty inches or greater. The specific inlet valve 40 and outlet valve 56 may be selected as desired, with the choice depending in part on the pressure head of the fluid source.
The amount of flow restriction provided by the restrictor 43 can be varied by varying the size and/or shape of the restrictor. In an alternative arrangement, a bypass flow path can be provided around the restrictor, such as a path through the body base 15 or a path through the restrictor itself. One such arrangement is shown in FIG. 4, with a flow path 60, 60a through the restrictor 43, with a check valve mounted in the flow path. A check ball 61 is held in position against a tapered shoulder by a spring 62, with the spring being held in position by a threaded plug 63. With this configuration, there is fluid flow from right to left through the restrictor during the dispensing or compression stroke. However during the return stroke, the passage 60 is closed, and the restrictor functions to maintain the pressure at the diaphragm face.
An alternative and presently preferred embodiment of the dispenser valve of the invention is shown in FIG. 5, wherein elements corresponding to those of FIG. 2 are identified by the same reference numbers.
The illustration of FIG. 5 shows a container 10A with a passage 60 for slidingly receiving a dispenser valve. As in the embodiment of FIG. 2, the valve includes a valve body having a base 15 and a cap 16, with the cap being a snap fit into the base. The valve is mounted on the container 10A by a snap ring 61 with the boss 21 of the base 15 projecting through an opening in the container. O rings 62, 63 provide seals between the valve body and the passage 60.
The rolling diaphragm 25 is clamped in the valve body between the base 15 and cap 16. When installed as shown in FIG. 5, the mounting rim 28 is positioned around an annular shoulder 64 of the body cap 16, and the clamping action provided by the interengaged base and cap compresses the rim to provide a seal.
A valve 40A, the spring ring 41, the spring 42, and the restrictor 43 are mounted in the fluid flow section 33. The valve 40A functions as an inlet valve in the same manner as the valve 40 of FIG. 2.
An outlet nozzle 55 is mounted in the container 10A in alignment with an opening 66 in the container with the umbrella valve 56 positioned therein between gaskets 57A and 57B. As with the embodiment of FIG. 2, the inlet valve 40 and the outlet valve 56 may be conventional in design, and a variety of such valve constructions are available.
A fluid flow path is provided from the fluid flow section 33 to the outlet valve 56 by way of an opening 67 in the side wall of the base 15, an annular groove 68 in the exterior of the base 15, and a passage 69 along the exterior of the base 15, to the opening 66. A shoulder or key 72 of the piston 34 rides in a grove 73 in the cap 16 to limit movement of the piston.
The operation of the dispenser valve of FIG. 5 is the same as that of the dispenser valve of FIG. 2, and a bypass flow path may be used in the FIG. 5 valve as in the FIG. 2 valve.
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A valve for dispensing a liquid such as soap or hand lotion, from a fluid dispenser. A valve body for mounting in the fluid dispenser and having a valve chamber with a rolling diaphragm carried in the body dividing the chamber into a piston section and a fluid flow section. A piston is slidingly positioned in the piston section and a flow restrictor is slidingly positioned in the fluid flow section, with a spring in the fluid flow section urging the restrictor into engagement with the diaphragm for moving the piston to the out position. A fluid inlet and a fluid outlet are provided in the fluid flow section so that an inward movement of the piston dispenses fluid and an outward or return motion of the piston draws a new charge of fluid into the valve.
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PRIORITY CLAIMS AND RELATED PATENT APPLICATIONS
This application claims the benefit of priority from U.S. Provisional Application Ser. No. 61/649,766, filed on May 21, 2012, the entire content of which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
The present application relates generally to the field of reagents, synthesis and purification of oligonucleotides. More particularly, the invention relates to compositions of oligonucleotide derivatives and methods for conjugating oligonucleotides.
BACKGROUND OF THE INVENTION
Many methods are available for conjugating oligonucleotides with other molecules. These methods typically involve attachment of a reactive moiety on the target entity to be coupled with the oligonucleotide. The target entities with the reactive moieties are often made separately, usually by organic synthesis methods, and purified before use.
In each case the oligonucleotides are modified with appropriate functional groups for reacting with the reactive moieties on the target entities. Modifications of oligonucleotides are often accomplished by making special phosphoramidites and/or modified bases, and incorporating them into the oligonucleotide sequences at the desired points. Many of these amidite reagents contain functional groups that require protecting groups for the coupling of these reagents to the oligonucleotides. These protecting groups must be removed before the subsequent conjugation reaction occurs. Alternatively, the reactive moieties on the target entities may be created before the conjugation to the oligonucleotides.
Most of current coupling chemistries involve the use or creation of hydrolytically and/or oxidatively unstable species of at least one of the conjugation partners. This is a problem under conditions (typically in aqueous solutions) needed for conjugation with the oligonucleotides (or protein, or any organic insoluble/water soluble species). Newer conjugation chemistries may generate a novel structure upon reaction. For example, U.S. Pat. No. 6,737,236, issued to Pieken et al., discloses cycloaddition reactions for the conjugations of biomolecules. One example, a 1,3-dipolar cycloaddition conjugation between an alkyne and an azide (later labeled under the general term “Click” chemistry by Sharpless et. al. Angew. Chem. Int. Ed. 40: 2004 (2001) produces a substituted triazine as part of the conjugation product. These new chemical entities can be a problem if the oligonucleotide conjugates are used in humans because these new chemical entities may cause toxicity unrelated to the oligonucleotide products.
SUMMARY OF THE INVENTION
One aspect of the invention relates to oligonucleotide derivatives having the structure of formula (A):
wherein R 3 is a first oligonucleotide; R 1 is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, a polyethylene glycol, a peptide, a protein, a polysaccharide, and a second oligonucleotide; R 2 is a linker or a direct bond; Z 1 is NR 4 , S, or O, and Z 2 is NR 4 or S, wherein R 4 is selected from H, alkyl, aryl, heterocyclyl, or heteroaryl.
In some embodiments of the invention, R 2 is a (C 1 -C 12 ) linker attached to a 5′ hydroxy group, a 3′ hydroxy group, or an exocyclic amino group on a nucleobase of the first oligonucleotide. In some embodiments of the invention, Z 2 is NH. In some embodiments of the invention, R 1 is a (C 1 -C 12 ) alkyl and Z 1 is O.
In some embodiments of the invention, R 1 is a 1K-40K polyethylene glycol and Z 1 is NH. In some embodiments of the invention, R 1 is a second oligonucleotide and Z 1 is NH, wherein the second oligonucleotide may be complementary to the first oligonucleotide.
Another aspect of the invention relates to methods for conjugating oligonucleotides. A method in accordance with one embodiment of the invention includes: synthesizing an oligonucleotide derivative comprising an amino or thiol group; and reacting a 3,4-dialkoxycyclobutene-1,2-dione with the oligonucleotide derivative to produce an oligonucleotide-squarate mono-conjugate.
In some embodiments of the invention, a method further comprises reacting the oligonucleotide-squarate mono-conjugate with a target entity selected from a polyethylene glycol, a peptide, a protein, a polysaccharide, or a second oligonucleotide.
In some embodiments of the invention, the oligonucleotide comprises a second amino or thiol group at a second location in the oligonucleotide derivative, the method further comprising forming an intra-oligonucleotide crosslink creating a cyclic structure.
Other aspects and advantages of the invention will be apparent from the following description and the appended claims.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 shows squaric acid and various reactions with the squaric acid.
FIG. 2 shows a reaction between a modified oligonucleotide and a squaric acid diester in accordance with one embodiment of the invention.
FIG. 3 shows conjugation of an oligonucleotide-squarate mono-adduct with a target entity (e.g., R—NH 2 ) in accordance with one embodiment of the invention.
FIG. 4 shows conjugation of an oligonucleotide-squarate mono-adduct with various target entities in accordance with embodiments of the invention.
FIG. 5 shows conjugation of two complimentary RNA stands, one with a 5′ amine, the other with a 3′ amine using the described squarate coupling procedure
FIG. 6 shows conjugation of an oligonucleotide-squarate mono-adduct with various secondary amine target entities in accordance with embodiments of the invention.
DEFINITIONS
Unless defined otherwise, 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. Terms and symbols of nucleic acid chemistry, biochemistry, genetics, and molecular biology used herein follow those of standard treatises and texts in the field, e.g. Kornberg and Baker, DNA Replication, Second Edition (W.H. Freeman, New York, 1992); Lehninger, Biochemistry, Second Edition (Worth Publishers, New York, 1975); Strachan and Read, Human Molecular Genetics, Second Edition (Wiley-Liss, New York, 1999); Eckstein, editor, Oligonucleotides and Analogs: A Practical Approach (Oxford University Press, New York, 1991); Gait, editor, Oligonucleotide Synthesis: A Practical Approach (IRL Press, Oxford, 1984); Sambrook et al., Molecular Cloning: A Laboratory Manual, 2.sup.nd Edition (Cold Spring Harbor Laboratory, 1989); and the like. Still, certain terms are defined below for the sake of clarity and ease of reference.
The term “nucleoside”, as used herein, refers a modified or naturally occurring deoxyribonucleoside or ribonucleoside or any chemical modifications thereof. Modifications of the nucleosides include, but are not limited to, 2′-, 3′- and 5′-position sugar modifications, 5- and 6-position pyrimidine modifications, 2-, 6- and 8-position purine modifications, modifications at exocyclic amines, substitution of 5-bromo-uracil, and the like. Nucleosides can be suitably protected and derivatized to enable oligonucleotide synthesis by methods known in the field, such as solid phase automated synthesis using nucleoside phosphoramidite monomers, H-phosphonate coupling or phosphate triester coupling.
The term “nucleotide”, as used herein, refers to a modified or naturally occurring deoxyribonucleotide or ribonucleotide. Nucleotide is a nucleoside as defined above having one or several phosphates or substituted phosphates attached at the 5′-, 2′- or 3′-positions. Nucleotides typically include purines and pyrimidines, which include thymidine, cytidine, guanosine, adenine and uridine.
The term “oligonucleotide”, as used herein, refers to a polynucleotide formed from a plurality of linked nucleotide units as defined above. The nucleotide units each include a nucleoside unit linked together via a phosphate linking group. The term oligonucleotide also refers to a plurality of nucleotides that are linked together via linkages other than phosphate linkages such as phosphorothioate linkages. The oligonucleotide may be naturally occurring or non-naturally occurring. In a preferred embodiment the oligonucleotides of this invention have between 1-1,000 nucleotides. Oligonucleotides may be synthetic or may be made enzymatically, and, in some embodiments, are 10 to 50 nucleotides in length. Oligonucleotides may include ribonucleotide monomers (i.e., may be oligoribonucleotides) or deoxyribonucleotide monomers. Oligonucleotides may be 10 to 20, 21 to 30, 31 to 40, 41 to 50, 51-60, 61 to 70, 71 to 80, 80 to 100, 100 to 150, 150 to 200, 200 to 500, or greater than 500 nucleotides in length, for example.
The term “alkyl”, as used herein, refers to a saturated straight chain, branched or cyclic hydrocarbon group of 1 to 24 (i.e., (C 1 -C 24 )alkyl), typically 1-12 (i.e., (C 1 -C 12 )alkyl) carbon atoms, more typically 1-6 carbon atoms (i.e., (C 1 -C 6 )alkyl), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. The term “lower alkyl” intends an alkyl group of one to six carbon atoms, and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. The term “cycloalkyl” refers to cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
“Alkylene” and “alkylene chain”, as used herein, refer to a straight or branched divalent hydrocarbon chain, linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, preferably having from one to eight carbons, e.g., methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain may be attached to the rest of the molecule and to the radical group through one carbon within the chain or through any two carbons within the chain.
Moreover, the term “alkyl” includes “modified alkyl”, which references an alkyl group having from one to twenty-four (C1-C20) carbon atoms, and further having additional groups, such as one or more linkages selected from ether-, thio-, amino-, phospho-, oxo-, ester-, and amido-, and/or being substituted with one or more additional groups including lower alkyl, aryl, alkoxy, thioalkyl, hydroxyl, amino, sulfonyl, thio, mercapto, imino, halo, cyano, nitro, nitroso, azide, carboxy, sulfide, sulfone, sulfoxy, phosphoryl, silyl, silyloxy, and boronyl.
Similarly, the term “lower alkyl” includes “modified lower alkyl”, which references a group having from one to eight carbon atoms and further having additional groups, such as one or more linkages selected from ether-, thio-, amino-, phospho-, keto-, ester-, and amido-, and/or being substituted with one or more groups including lower alkyl; aryl, alkoxy, thioalkyl, hydroxyl, amino, sulfonyl, thio, mercapto, imino, halo, cyano, nitro, nitroso, azide, carboxy, sulfide, sulfone, sulfoxy, phosphoryl, silyl, silyloxy, and boronyl. The term “alkoxy” as used herein refers to a substituent —O—R wherein R is alkyl as defined above. The term “lower alkoxy” refers to such a group wherein R is lower alkyl. The term “thioalkyl” as used herein refers to a substituent —S—R wherein R is alkyl as defined above.
The term “aryl”, as used herein, refers to aromatic monocyclic or multicyclic, some of which may be fused together, hydrocarbon ring system consisting only of hydrogen and carbon and containing from 6 to 19 carbon atoms (represented as (C 6 -C 19 )aryl), preferably 6 to 10 carbon atoms (represented as (C 6 -C 10 )aryl), where the ring system may be partially or fully saturated. Aryl groups include, but are not limited to groups such as fluorenyl, phenyl and naphthyl. Unless stated otherwise specifically in the specification, the term “aryl” is meant to include aryl radicals optionally substituted by one or more substituents selected from (C 1 -C 12 )hydrocarbyl, —O—R″, —O—CO—R″, —CO—O—R″, —NR′—R″, —NR′—CO—R″, —CO—NR′—R″, —CO—R″, —R—O—R″, —R—O—CO—R″, —R—CO—O—R″, —R—NR′—R″, —R—NR′—CO—R″, —R—CO—NR′—R″, —R—CO—R″, —CN, halogen, or a combination thereof, wherein R′ and R″ are independently H or (C 1 -C 12 )hydrocarbyl, and R is (C 1 -C 12 )hydrocarbyl.
The term “heteroaryl”, as used herein, refers to a 5- to 18-membered monocyclic- or bicyclic- or fused polycyclic-ring system which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Preferably heteroaryl is a 5- to 12- or 5- to 9-membered ring system. For purposes of this invention, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl. Unless stated otherwise specifically in the specification, the term “heteroaryl” is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from (C 1 -C 12 )hydrocarbyl, —O—R″, —O—CO—R″, —CO—O—R″, —NR′—R″, —NR′—CO—R″, —CO—NR′—R″, —CO—R″, —R—O—R″, —R—O—CO—R″, —R—CO—O—R″, —R—NR′—R″, —R—NR′—CO—R″, —R—CO—NR′—R″, —R—CO—R″, —CN, halogen, or a combination thereof, wherein R′ and R″ are independently H or (C 1 -C 12 )hydrocarbyl, and R is (C 1 -C 12 )hydrocarbyl.
The term “heteroaryl” also refers to a group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include but are not limited to 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinoliyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinoliyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-, 3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-4aH carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-carbzaolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenathrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenoxazinyl, 2-, 3-, 4-, 5-, 6-, or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-benzisoqinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6-, or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or 8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or 5-1H-pyrazolo[4,3-d]-oxazolyl, 2-, 4-, or 54H-imidazo[4,5-d]thiazolyl, 3-, 5-, or 8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10, or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-, or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-1H-pyrrolo[1,2-b][2]benzazapinyl. Typical fused heteroary groups include, but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or 7-benzothiazolyl.
The term “cycloalkyl”, as used herein, refers to a stable non-aromatic monocyclic or bicyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having from three to fifteen carbon atoms, preferably having from three to twelve carbon atoms, (C 3 -C 12 )cycloalkyl, and which is saturated or unsaturated and attached to the rest of the molecule by a single bond, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl and the like. Unless otherwise stated specifically in the specification, the term “cycloalkyl” is meant to include cycloalkyl radicals which are optionally substituted by one or more substituents selected from —O—R″, —O—CO—R″, —CO—O—R″, —NR′—R″, —NR′—CO—R″, —CO—NR′—R″, —CO—R″, —CN, halogen, or a combination thereof, wherein R′ and R″ are independently H or (C 1 -C 12 )hydrocarbyl.
The terms “heterocyclyl” or “heterocycle”, as used herein, refer to an optionally substituted, saturated or partially unsaturated, nonaromatic cyclic group, e.g., which is a 4- to 7-membered monocyclic, 7- to 12-membered bicyclic or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, wherein the nitrogen and sulfur heteroatoms may also optionally be oxidized. The heterocyclic group may be attached at a heteroatom or a carbon atom. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. The bicyciic and tricyclic heterocyclyl groups can be fused or spiro rings or ring groups. Preferably heterocyclyl is a 4- to 12-membered ring system. Also preferably heteocyclyl is a 4- to 9-membered ring system.
Exemplary monocyclic heterocyclic groups include oxetanyl, thiatanyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, pyrrolidinyl, dihydropyrazolyl, tetrahydropyrazolyl, dihydropyridinyl, tetrahydropyridinyl, dihydrothiopyranyl, tetrahydrothipyranyl, pyranyl, dihydropyranyl, tetrahydropyranyl, thiopyranyl, dihydrothiopyranyl, tetrahydrothiopyranyl, ptperidinyl, piperazinyl, morphoiinyl, azepinyl, dihydroazepinyl, tetrahydroazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, oxepanyl, thiepanyl, dihyrothiepinyl, tetrahydrothiepinyl, dihydrooxepinyl, tetrahydrooxepinyl, 1,4-dioxanyl, 1,4-oxathianyl, morphoiinyl, oxazolyl, oxazolidinyl, isoxazolinyi, A-ptperidony!, isoxazoiinyi, isoxazolyl, 1,4-azathianyl, 1,4-oxathiepanyl, 1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thieaxepanyl, 1,4-diazepanyl, tropanyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorphoiinyl suifone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, 1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl, pyrazolinyl, and the like.
Exemplary bicyclic heterocyclic groups include but are not limited to, dihydroindolyl, quinuctidinyl, tetrahydroquinolinyl, decahydroquinolinyl, 2-oxa-6-azaspiro[3,3]heptan-6-yl, tetrahydroisoquinoiinyl, decahydroisoquinoiinyl, dihydroisoindolyl, indoiinyl, norboranyl, adamantanyl, and the like.
Unless stated otherwise specifically in the specification, the term “heterocyclyl” is meant to include heterocyclyl radicals as defined above which are optionally substituted by one or more substituents selected from —O—R″, —O—CO—R″, —CO—O—R″, —NR′—R″, —NR′—CO—R″, —CO—NR′—R″, —CO—R″, —CN, halogen, or a combination thereof, wherein R′ and R″ are independently H or (C 1 -C 12 )hydrocarbyl.
The term “direct bond”, as used herein, means that the two entities linked by the “direct bond” are connected to each other directly. The direct bond may be a single bond or a double bond, for example.
The term “DNA”, or “deoxyribonucleic acid”, as used herein, refers to a polynucleotide or oligonucleotide that comprises at least one deoxyribonucleotide residue.
The term “RNA”, or “ribonucleic acid”, as used herein, refers to a polynucleotide or oligonucleotide that comprises at least one ribonucleotide residue.
As used herein, a “linker” bridges two moieties in a molecule. A “linker” may be a hydrocarbyl chain (e.g., (C 1 -C 12 )alkylene, (C 2 -C 12 )alkenylene), optionally substituted with a substituent group, or a linker may be a hydrocarbyl chain interspersed with other atoms, as represented by —(CHR′) a —W b —(CHR′) c —V d —(CHR′) e —, wherein W and V are independently —O—, —S—, or —NR—; R′ is H or (C 1 -C 6 )alkyl; and a, b, c, d, and e are independently an integer from 0 to 10, preferably from 0 to 6, or preferably from 0 to 3, and the sum of a, b, c, d, and e is preferably an integer from 2 to 6. The optional substituent group may be —O—R″, —O—CO—R″, —NR′—R″, —NR′—CO—R″, —CO—NR′—R″, —CO—R″, —CN, halogen, or a combination thereof, wherein R′ and R″ are independently H or (C 1 -C 6 ) hydrocarbyl.
The term “polyethylene glycol”, as used herein, refers to polyether compounds having a formula R—(O—CH 2 —CH 2 ) n —O—R′, wherein R and R′ are independently H or an alkyl. “Polyethylene glycol derivative” refers to polyether compounds having a formula R—(O—CH 2 —CH 2 ) n —X—R′, wherein R and R′ are independently H or an alkyl, and X is O or NH.
The term “polypeptide”, as used herein, refers a molecule containing a plurality of amino acids linked by peptide bonds. A polypeptide may be generated from a natural protein or chemically synthesized.
The term “protein”, as used herein, refers to a molecule containing one or more polypeptides. A protein is often of natural origin, but may include those modified from a natural protein.
The terms “polysaccharide” or “polycarbohydrate”, as used herein, refer to a carbohydrate molecule having a plurality of sugar moieties linked by glycosidic bonds.
“Optional” or “optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not. For example, the phrase “optionally substituted” means that a non-hydrogen substituent may or may not be present, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present.
DETAILED DESCRIPTION OF THE INVENTION
Embodiments of the invention relate to methods for conjugating oligonucleotides with other molecules or target entities. The oligonucleotides may include DNA, RNA, or a chimeric DNA/RNA. The target entities may be any desired targets, such as other oligonucleotides, proteins/peptides, carbohydrates, or supports (which may include soluble polymers or solid supports, such as resins, glass beads, magnetic beads, matrix surfaces, etc.).
Embodiments of the invention are based on the fact that squaric acid and derivatives thereof can be readily coupled with amino groups under mild conditions. These conjugation processes provide simple aqueous based methods for producing oligonucleotide conjugates. The products from these reactions are stable and can be readily isolated and stored. In addition, squaric acid derivatives have been used in modifications of pharmaceuticals and are found to be nontoxic.
FIG. 1 shows the structure of squaric acid (i.e., cyclobutene 3,4 dione), which can be reacted with alcohols to give squaric diesters. The esterification can easily occur in the presence of an acid catalyst, as in the usual esterification of carboxylic acids. Nucleophilic substitution of the squaric acid esters can readily occur, e.g., with amines as nucleophiles to give the corresponding monoamides or diamides. These properties can be used in many applications, including modification of biological molecules to change their properties.
In addition to the esters, other squaric acid derivatives that can also be used to react with nucleophiles (e.g., amino groups or thiol groups) include squaric halides, squaric ester halide, and squaric imidazoles. All these squaric acid derivatives may be used with embodiments of the invention, and all these reagents can react with oligonucleotides having amino or thiol functional groups. Embodiments of the invention preferably use squaric acid diesters as the reagents.
The use of squaric acid derivatives has been described for conjugations with small molecules, and for conjugation of small molecules to proteins or carbohydrates. It has also been used to couple large molecules, such as a 20K polysaccharide to a protein. In addition, U.S. Pat. No. 6,602,692, issued to Gliisenkamp et al., discloses the use of squaric acid derivatives to conjugate peptides to solid support that has been modified with a squaric derivative. The disclosure of the '692 patent is incorporated by reference in its entirety.
Embodiments of the invention may use any of the above squaric acid derivatives. Preferred embodiments of the invention use squaric acid esters, which may be referred generally as squarate. The squaric acid esters are diesters, wherein the two ester groups (—OR groups) maybe the same or different.
While the uses of squarate to conjugate various molecules are known, no applications using this technology for conjugations to DNA or RNA have been reported. Considerable efforts have been directed to the application of oligonucleotides and oligonucleotide analogs as diagnostic/research reagents or as potential therapeutics. Examples of potential applications of oligonucleotides as pharmaceutics may include antisense oligonucleotides that can bind to certain coding regions to prevent the expression of proteins or to block various cell functions. Furthermore, the development of SELEX techniques (Systematic Evolution of Ligands by Exponential Enrichment) (Tuerk and Gold, Science, 249:505 (1990)) makes it possible to identify oligonucleotides that will bind to almost any biologically interesting targets.
The potential uses of oligonucleotides as pharmaceutical agents have led to further development of various chemical modifications aiming to increase their therapeutic activities and stabilities. Such modifications may increase cell penetration of the oligonucleotides or their resistance to nucleases. In addition, these modifications may enhance the bindings of oligonucleotides to their targets or may improve the pharmacokinetic properties of the oligonucleotides. Therefore, methods that can easily modify oligonucleotides for various applications are desirable.
Embodiments of the invention provide methods for the modifications of oligonucleotides under very mild conditions and they methods are suitable for applications in the modifications of oligonucleotide pharmaceuticals. In accordance with embodiments of the invention, oligonucleotide derivatives (containing reactive functional groups for coupling with squaric acid derivatives) may be prepared with any suitable methods. For example, the oligonucleotides may be synthesized with a reactive functional group (e.g., an amino group) for coupling with a squaric acid derivative. The reactive functional groups, for example, may be an amino group or a thiol group.
Various methods for attaching functional groups to oligonucleotides are known. (For a review, see Goodchild, Bioconjugate Chemistry, 1:165-187 (1990)). Once the chemically reactive functional groups are attached to oligonucleotides (e.g., at the 5′- and or 3′terminus), these reactive functional groups can be used to couple with various conjugates. For example, a primary aliphatic amino group may be incorporated at the 5′-terminus of the oligonucleotide in the final step of the synthesis of an oligonucleotide. Reagents for linking to the 5′ terminus of an oligonucleotide are commercially available. For example, various linkers having different lengths of —(CH 2 ) n — connectors for linking to the 5′ terminus of an oligonucleotide are available. One example is 5′-Amino-Modifier C6 is available from Glen Research Corp. (Sterling, Va.). Amino modifiers for the 3′ end of oligonucleotides are also readily available, either as phosphoramidites or already attached to the synthesis solid support.
The reagents used to modify the oligonucleotides to provide reactive functional groups may be in the form of phosphoramidites, which may be coupled to the free 5′-hydroxyl group of the full length oligonucleotide while it is attached to a solid support. This coupling would be like attaching another nucleotide monomer. (See, e.g., Theison et al., Tetrahedron Lett., 33:5033-5036 (1992).)
In accordance with some embodiments of the invention, the reactive groups (e.g., amino or thiol groups) may be attached to the oligonucleotides using modified nucleotides. In this case, the reactive groups need not be attached to the 5′ or 3′ end. Instead, one can use these modified nucleotide analogs to incorporate the reactive groups at the internal positions. Some examples of such modified nucleotides are shown below:
In the above examples, R 1 is H or OH. Formula (I) represents a natural nucleoside or deoxynucleoside (R is H or OH), and formulae (II)-(IV) (wherein n is an integer greater than 0) represent various analogs having reactive amino groups modifications on the sugar rings. These amino groups will be protected during incorporation of these analogs into oligonucleotides. Some of these reagents are commercially available or may be prepared according to procedures known in the art.
Other modified nucleotide analogs may have modifications on the purine or pyrimidine rings, such as those shown below:
The above formulae (V)-(X) (wherein n is an integer greater than 0) show examples of nucleotide analogs that contain reactive amino groups. These analogs may be used to incorporate into oligonucleotides after these amino groups have been protected. Some of these reagents are commercially available or may be prepared according to procedures known in the art.
Once the oligonucleotides are derivatized with reactive functional groups (e.g., amino or thiol groups), they may be used to couple with squaric acid derivatives. The following examples illustrate some embodiments of the invention.
In accordance with some embodiments of the invention, the oligonucleotide-squarate mono conjugates could be used to attach oligonucleotides to other target entities, such as peptides, proteins, oligosaccharides, solid surfaces, polymeric materials, nanoparticles, hydrogels, and small molecules.
In accordance with some embodiments of the invention, these mono conjugates can be used to couple with other handles that may be selected for particular purposes. One example of such application is to attach a diene moiety (e.g., a furan) to a oligonucleotide-squarate mono adduct in order for this to participate in a Diels Alder reaction with a dienophile-linked molecule (e.g., N-ethyl maleimide), which is disclosed in a co-pending application filed on the same day.
It should be noted that while examples described herein use amino groups to conjugate with a squarate, other nucleophilic groups (e.g., thiol) may also be used.
Treatment of the oligonucleotide mono squarate with limited amounts of species containing more than one amine (eq. di amines, tri amines, to polyamines) would provide a means to make mutimeric oligonucleotide structures.
Another application of this conjugation may be the coupling of two amino labeled oligonucleotides together to form cyclical or hairpin-type oligonucleotide structures. The oligonucleotides could be complimentary sequences, with a 3′ amino label on one strand and a 5′ amino label on the other. This would form a hairpin like dimer.
Advantages of the invention may include one or more of the following. Embodiments of the invention provide easy and efficient methods for the conjugation of oligonucleotides to various target entities. The reactions with squarates can be conducted in aqueous solutions with high yields and the products can be easily purified (e.g., by ultra filtration or by size exclusion chromatography). The mono-squarate adducts are stable and can be purified and stored for later uses.
The stability of the mono conjugate with DNA/RNA might allow coupling of a second amino labeled oligonucleotide that is not complementary to the sequence of the oligonucleotide-mono squarate species. The coupling of two non-complimentary oligonucleotides is very difficult to do non-enzymatically. Methods of the invention would provide access to these molecules. The squaric acid derivatives are small and would not illicit immunogenic responses, resulting in fewer adverse reactions when incorporating the functionality into pharmaceuticals.
EXAMPLES
Synthesis of Oligonucleotide-Squarate Mono Conjugate
An oligonucleotide is synthesized with an amino linker attached, using any method know in the art (see the above discussion). The example shown in FIG. 2 uses a TFA-protected amine C6 linker phosphoramidite (i.e., CF 3 —CO—NH—(CH 2 ) 6 —O—P((O—CH(CH 3 ) 2 ) 2 (O—CH 2 —CH 2 —CN), which is coupled to the 5′-OH end of the oligonucleotide on solid support using the appropriate synthesis conditions. This coupling may be carried out under conditions similar to the coupling of a nucleotide monomer and can be performed while the oligonucleotide is still attached to a solid support. After the synthesis and deprotection as usual (standard ammonia and TEA 3HF for RNA), the mixture may be ultrafiltered against NaCl to remove all ammonia and ammonium salts. Finally, the retentate is washed with water to remove all excess salts. The oligonucleotide solution may then be concentrated down. The concentrate may be lyophilized or used as is.
Once the amino-labeled oligonucleotide is available, it can be coupled to a squaric acid derivative. For example, a solution of amino-labeled oligonucleotide, approximately 10 mg in 500 μL of 300 mM sodium phosphate, pH 7-8 was prepared. To this was added an excess of dimethyl ester of squaric acid (dimethyoxy cyclobutene 1,2 dione; approx. 0.75 mg to each mg of oligonucleotide), as shown in FIG. 2 . Excess squaric ester is used to favor the formation of mono-substituted squarate derivative and to suppress the formation of di-substituted squarate derivatives.
The reaction mixture was kept at 25° C. and the pH of the solution was adjusted with dibasic phosphate to maintain the reaction pH between 7 and 7.8, as the pH tends to drop during conjugation. After about 4 hours, the reaction solution was filtered and washed with water in a 3K ultrafiltration (UF) spin cartridge to remove remaining small molecules. (e.g., excess squaric ester and salts). The UF retentate was lyophilized and analyzed by LCMS, which confirmed the formation of the desired product—i.e., an oligonucleotide-squarate mono adduct. Such adducts are very stable. For example, these mono substituted squarates are found to be stable for at least two days in aqueous solutions at pH=7, and for over 1 year at 4° C. as a lyophilized solid.
Alternatively, the reaction solution may be filtered and washed with water, followed by washing with a borate buffer, which may be used as the buffer for the next reaction and used directly in the next conjugation step (e.g., conjugation to a target entity shown below).
The above described coupling reaction is very efficient. The reactions have been run many times and these reactions are found to proceed to 90-99% completion, as judged by the amount of starting amino labeled oligonucleotides remaining after the conjugation. The reactions can be easily monitored by LCMS analysis.
Reaction of Oligonucleotide-Squarate Mono Conjugate with a Target Entity
The lyophilized squarate mono conjugate was taken up in a 25 mM sodium borate buffer, pH=9.2, and treated with an excess (e.g., 10-40 folds) of a target entity containing an amino group (e.g., NH 2 —R) dissolved in a small amount of DMSO, as shown in FIG. 3 . The mono conjugate pre-ultrafiltered in 25 mM borate buffer (see above) could be treated directly with the amine/DMSO mixture, without lyophilization and re-dissolution.
In this particular example, the target entity is a 5-methyl furfuryl amine (i.e., R=5-methyl-furfuryl). The reaction was run at room temperature for 2 hours. The reaction mixture was again concentrated and washed in the 3K UF spin cartridges to remove excess amine and salts. The retentate was lyophilized and a portion of the solid analyzed by LCMS, which showed the desired conjugate was formed in approximately 95% yield, based on starting mono conjugate.
Based on these protocols, various target entities have been conjugated with oligonucleotides. Some examples of these conjugations are shown in FIG. 4 . The preparations of PEG-oligonucleotide conjugates are known, see e.g., Goodchild et al., Bioconjugate Chem., 1:165 (1990); and Zalipsky et al., Bioconjugate Chem., 6:150 (1995). The PEG conjugates can be used to improve the in vivo stabilities of the oligonucleotides and/or to reduce the immunogeneities of the oligonucleotides.
Formation of Oligonucleotide Duplex with Two Complimentary Oligonucleotides
An RNA 20 mer that contained a 5′ Hexaethylene glycol (HEG) spacer linker followed by the standard six carbon amino linker was made using standard oligonucleotide solid phase synthesis techniques. The HEG and C6 amino linkers (both are commercially available) were added as phosphoramidites using standard oligonucleotide synthesis/deprotection protocols, see example 1 above. The crude RNA was purified by anion exchange chromatography and ultrafiltered on a 2K Hydrosart membrane prior to lyophilization. LCMS analysis of the lyophilized material gave the expected molecular weight of the modified oligonucleotide. 150 mg of this lyophilized amino modified RNA was taken up in 3.0 mL of sodium phosphate giving a solution with a pH range of 7-8. To this solution was added 100 mg of dimethoxy squarate dissolved in 300 uL of DMSO. LCMS analysis after 1 hour showed that the amino labeled RNA had been converted completely over to the desired mono squarate, as shown in FIG. 5 .
The complimentary sequence to the one mentioned in the above section (0074) was made using the same standard synthesis protocols used, in this case with a 3′ amino linker attached, see FIG. 5 . The modified RNA was deprotected, purified, ultrafiltered and lyophilized using the same procedures as used in the preparation of the 5′ amino labeled RNA. 10 mg of the lyophilized 5′amino RNA was dissolved in 400 uL of water. 11 mg (approx. 1.2 fold excess) of the lyophilized 3′ amino RNA compliment was dissolved in a separate 400 uL of water. The two solutions were combined and warmed to 50-60° C. for approximately 5 minutes, the solution was allowed to cool to room temperature over 30 minutes. To this solution was then added 300 uL of 150 mM sodium borate which brought the solution pH to approximately 9 (by pH paper). This mixture was allowed to stand at room temperature for 3 hours. LCMS analysis of a sample of this reaction showed that the dimer had been cleanly formed, with no hydrolyzed mono RNA squarate observed.
Conjugates of Two Oligonucleotides
In addition, the stability of mono conjugates of squarate with oligonucleotides (e.g., DNA or RNA) permits one to isolate the mono-conjugate intermediates and use them to couple with a second oligonucleotide, even if the second amino-labeled oligonucleotide is not complementary to the sequence of the oligonucleotide-squarate mono adduct. The coupling of two non-complimentary oligonucleotides (particularly when one oligonucleotide is DNA and the other is RNA) is very difficult to do non-enzymatically. Methods of the invention would provide access to these molecules.
Formation of Cyclic Oligonucleotides
As noted above, the stability of mono conjugates of squarate with oligonucleotides (e.g., DNA or RNA) permits one to isolate the mono-conjugate intermediates and use them to couple with a second oligonucleotide later. One may take advantage of this property and use these mono-conjugates to conjugate with second amino groups (which may be temporarily protected during the first stage of the conjugation) present at the other terminus of the oligonucleotides to form cyclic oligonucleotides.
Conjugation with Secondary Amines
Oligonucleotide Mono Squarate Conjugation with Peptides
To 100 μL of a 100 mM sodium borate buffered solution (pH=9.2) of the mono methoxy squarate labeled RNA 20 mer, approximately 1 μM, was added and excess of the tripeptide, Leu-Gly-Gly, dissolved 100 μL of 100 mM sodium borate buffered solution (pH=9.2). This mixture left at 25° C. for 1.5 hours. LCMS analysis of the reaction mixtures showed that the peptide conjugate was produced in approximately 85% yield, also see FIG. 6 .
Oligonucleotide Mono Squarate Conjugation with Lipids
To 75 μL of 100 mM sodium borate buffered solution (pH=9.2) of the mono methoxy squarate labeled RNA 20 mer, at approximately 1 μM, was added a small excess of shpingosine dissolved 75 μL of isopropanol. This mixture left at 25° C. for 30 minutes. LCMS analysis of the reaction mixtures showed that the lipid conjugate was produced in approximately 60% yield, also see FIG. 6 .
Oligonucleotide Mono Squarate Conjugation with Isopropyl Amine
To 150 μL of a 100 mM sodium borate buffered solution (pH=9.2) of the mono methoxy squarate labeled RNA 20 mer, approximately 1 μM, was added and excess of isopropyl amine dissolved 20 μL of DMSO. After 4 hours at 25° C. LCMS analysis of the reaction mixtures showed that the isopropyl amine derivative was formed in over 95% yield, also shown in FIG. 6 .
It is noted that the amino/thio labeled oligonucleotide can be added to an already derivatized mono squarate, inverting the order of addition. The mono squarate of a small molecule amine/thio, or peptide, protein, etc. can be made first and then treated with an amino/thio labeled oligonucleotide to form the squarate oligonucleotide conjugate.
In this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural reference, unless the context clearly dictates otherwise.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Methods recited herein may be carried out in any order that is logically possible, in addition to a particular order disclosed.
While the invention has been described with respect to a limited number of embodiments, those skilled in the art, having benefit of this disclosure, will appreciate that other embodiments can be devised which do not depart from the scope of the invention as disclosed herein. Accordingly, the scope of the invention should be limited only by the attached claims.
INCORPORATION BY REFERENCE
References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made in this disclosure.
All such documents are hereby incorporated herein by reference in their entirety for all purposes. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material explicitly set forth herein is only incorporated to the extent that no conflict arises between that incorporated material and the present disclosure material. In the event of a conflict, the conflict is to be resolved in favor of the present disclosure as the preferred disclosure.
EQUIVALENTS
The representative examples disclosed herein are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples which follow and the references to the scientific and patent literature cited herein. The following examples contain important additional information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.
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An oligonucleotide derivative having the structure of formula (A) and methods for preparing the oligonucleotide derivative are disclosed. wherein R 3 is a first oligonucleotide; R 1 is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, a polyethylene glycol, a peptide, a protein, a polysaccharide, and a second oligonucleotide; R 2 is a linker or a direct bond; Z 1 is NR 4 , S, or O, and Z 2 is NR 4 or S, wherein R 4 is selected from H, alkyl, aryl, heterocyclyl, or heteroaryl. A method includes: synthesizing an oligonucleotide derivative comprising an amino or thiol group; and reacting a 3,4-dialkoxycyclobutene-1,2-dione with the oligonucleotide derivative to produce an oligonucleotide-squarate mono-conjugate.
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BACKGROUND
[0001] The present invention claims priority on PCT Application Ser. No. PCT/U.S. 2007/079119 filed Sep. 21, 2007, which in turn claims priority on U.S. Provisional Application Ser. No. 60/846,154 filed Sep. 21, 2006. The various embodiments of the present invention relate generally to medical devices, and particularly to an implant for use within a body to repair various types of body passageways, and even more particularly to an expandable graph which is useful in repairing blood vessels narrowed or occluded by disease. The medical device at least partially includes novel refractoty metals that have specific design features that accommodate the intrinsic properties of the metal.
[0002] Medical treatment of various illnesses or diseases commonly includes the use of one or more medical devices. Two types of medical devices that are commonly used to repair various types of body passageways are an expandable graft or stent, or a surgical graft. These devices have been implanted in various areas of the mammalian anatomy. One purpose of a stent is to open a blocked or partially blocked body passageway. When a stent is used in a blood vessel, the stent is used to open the occluded vessel to achieve improved blood flow which is necessary to provide for the anatomical function of an organ. The procedure of opening a blocked or partially blocked body passageway commonly includes the use of one or more stents in combination with other medical devices such as, but not limited to, an introducer sheath, a guiding catheter, a guide wire, an angioplasty balloon, etc.
[0003] Various physical attributes of a stent can contribute directly to the success rate of the device. These physical attributes include radiopacity, hoop strength, radial force, thickness of the metal, dimensions of the metal and the like. Cobalt and chromium and stainless steel are commonly used to form stents and have physical characteristics that are common throughout the design and functional phase. These materials are commonly used since such materials having a known history of safety, effectiveness, ease of manufacturing and biocompatibility.
[0004] The materials commonly used to form prior stents are biostable materials that remain in the blood vessel long after the stent has achieved its function. As such, the continued presence of the stent in the blood vessel can increase the risks associated with thrombosis, in-stent restenosis, vascular narrowing and/or restenosis in the blood vessel at the location of the stent. The presence of the stent in the blood vessel also can create a potential obstruction to later medical procedures that attempt to correct problems in a body passageway upstream from the stent. The stent can also be prone to fracturing overtime, especially when the stent is located in regions exposed to bending (e.g., leg, aims, neck, etc.). The repeated bending of the stent can eventually fatigue the stent, thereby resulting in one or more portions of the stent fracturing and/or becoming loose from the stent. These fractures (e.g., strut fractures, etc.) and/or loose portions of the stent can result in damage to the blood vessel and/or one or more regions of the vascular system down stream of the stent. The over all strut thickness also has the ability to hinder blood flow and thus remains a hindrance to healing within the mammalian anatomy.
SUMMARY OF THE INVENTION
[0005] The current invention is generally directed to a medical device that is at least partially formed of tantalum, zirconium, niobium, and/or tungsten material and a method of making the same. The medical device can also incorporate one or more specific design features and/or surface modifications that enhance one or more of the physical properties of a medical device so as to improved the success rate of such medical device and to overcome the several of the past problems associated with such medical devices.
DESCRIPTION OF DRAWINGS
[0006] Reference may now be made to the drawings which illustrate various preferred embodiments that the invention may take in physical form and in certain parts and arrangement of parts wherein:
[0007] FIG. 1 is an front elevation view of a stent in accordance with the present invention;
[0008] FIG. 2 is an enlarged sectional view of a strut of the stent illustrated in FIG. 1 ;
[0009] FIG. 3 is a side view of a portion of a stent body in accordance with one aspect of the invention;
[0010] FIG. 4 is a side view of another configuration of a stent;
[0011] FIG. 5 is a side view of yet another configuration of a stent;
[0012] FIG. 6 is yet another stent configuration according to the present invention;
[0013] FIG. 7A-K are various possible configurations for support portions of a stent in accordance with another embodiment;
[0014] FIG. 8 is a stent having a cavity in accordance with one embodiment;
[0015] FIG. 9A-9B show the stent cavity filled with various coatings;
[0016] FIG. 10 is a stent portion showing variations in thickness over its length in accordance with another embodiment;
[0017] FIG. 11A-11F show various coating combinations that can be used on the stents of the present invention;
[0018] FIG. 12 shows yet another possible stent configuration according to another embodiment.
DETAILED DESCRIPTION OF INVENTION
[0019] The previously mentioned shortcomings of prior art medical devices are addressed by the novel medical device of the present invention. The medical device in accordance with one present embodiment can be in the form of many different medical devices such as, but are not limited to, stents, grafts, surgical grafts (e.g., vascular grafts, etc.), orthopedic implants, staples, sheaths, guide wires, balloon catheters, hypotubes, catheters, electrophysiology catheters, cutting devices, etc.
[0020] In one non-limiting aspect, the medical device is directed for use in a body passageway. As used herein, the term “body passageway” is defined to be any passageway or cavity in a living organism (e.g., bile duct, bronchiole tubes, nasal cavity, blood vessels, heart, esophagus, trachea, stomach, fallopian tube, uterus, ureter, urethra, the intestines, lymphatic vessels, nasal passageways, eustachian tube, acoustic meatus, etc.). The techniques employed to deliver the medical device to a treatment area include, but are not limited to, angioplasty, vascular anastomoses, transplantation, implantation, subcutaneous introduction, minimally invasive surgical procedures, interventional procedures, and any combinations thereof For vascular applications, the term “body passageway” primarily refers to blood vessels and chambers in the heart. The blood vessels can be located in any portion of the body (e.g., legs, arms, brain, body organs, etc.).
[0021] In one non-limiting embodiment, the medical device is in the form of a stent. The stent can be an expandable stent that is expandable by a balloon and/or other means. The stent can have many shapes and forms. Such shapes can include, but are not limited to, stents disclosed in U.S. Pat. Nos. 6,206,916 and 6,436,133; and all the prior art cited in these patents. These various designs and configurations of stents in such patents are incorporated herein by reference. When the medical device is in the form of a stent, the stent is designed to be insertable into a treatment area (e.g., body passageway, etc.) and be expanded in the treatment area to enable better or proper fluid flow through the body passageway.
[0022] In most cases, such as intraluminal endoprostheses, a durable support function afforded by the endoprosthesis is required. In some situations, the body tissue can recover in a more efficient manner in the presence of the support prosthesis that has a specific design feature and is comprised of a refractory metal that has minimized content of metal and still exemplifies the mechanical characteristics required for the advanced healing of such mammalian anatomy. In view of this realization, the present invention is directed to a medical device that is at least partially form of a zirconium, tantalum, niobium and/or tungsten material. The present embodiments are in part directed to the formation of medical devices for use in such situations.
[0023] Traditional metals have a finite thickness that makes them functional. If the thickness is reduced below a certain point, the medical devices become unstable and incapable of functioning without fracturing. The converse is also true, especially with drug and polymer coatings over the metal adding to the thickness of the stent or other medical device. That is, the device may become too bulky due to the thickness of the metal and any coatings, thus limiting its expandability and profile, resulting in undue blockages in the blood vessel. With new manufacturing techniques and new metals, the device can be reduced in thickness without the threat of fracturing, compared to traditional metals. A drug and/or polymer coating can then be applied to the device at even greater thicknesses than previously, while still not approaching the upper limit of thickness that would cause device failure as described above.
[0024] Thus, in one non-limiting embodiment, the medical device can be formed of a material that is considered a refractory metal and at least partially includes zirconium, tantalum, tungsten and/or niobium. By utilizing the intrinsic properties of one or more of these materials, a medical device such as, but not limited to a stent, can be manufactured in such a way that has not been previously produced, and which can at least partially overcome potential problems with thrombosis, in-stent restenosis, vascular narrowing and/or restenosis in the body passageway in and/or around at the treatment location of the stent. In order to achieve the desired mechanical properties of one or more of these metals, the medical device typically should include one or more specific design features. Stainless steel and cobalt and chromium have only a limited potential when used in medical device and such limited potential cannot be enhanced due to their physical properties.
[0025] In another and/or additional non-limiting aspect, the medical device that is at least partially made of zirconium, tantalum, niobium and/or tungsten has improved physical properties as compared to past medical devices. The metal used to at least partially form the medical device can be radiopaque; however, this is not required. In another and/or additional one non-limiting embodiment, the metal used to at least partially form the medical device can improve one or more physical properties of such medical device (strength, durability, hardness, biostability, bendability, coefficient of friction, radial strength, flexibility.tensile strength, tensile elongation, longitudinal lengthening, stress-strain properties, improved recoil properties, radiopacity, heat sensitivity, biocompatibility, etc.); however, this is not required. These one or more improved physical properties of the metal used in the medical device can be achieved in the medical device without having to increase the bulk, volume and/or weight of the medical device, and in some instances these improved physical properties can be obtained even when the volume, bulk and/or weight of the medical device is reduced as compared to medical devices that are at least partially formed from traditional stainless steel or cobalt and chromium alloy materials; however, this is not required.
[0026] In still another and/or additional one non-limiting embodiment, the medical device comprises a metal or alloy, that, compared to traditional stainless steel or cobalt chromium alloy materials, can 1) increase the radiopacity of the medical device, 2) increase the radial strength of the medical device, 3) increase the yield strength and/or ultimate tensile strength of the medical device, 4) improve the stress-strain properties of the medical device, 5) improve the crimping and/or expansion properties of the medical device, 6) improve the bendability and/or flexibility of the medical device, 7) improve the strength and/or durability of the medical device, 8) increase the hardness of the medical device, 9) improve the longitudinal lengthening properties of the medical device, 10) improved the recoil properties of the medical device, 11) improve the friction coefficient of the medical device, 12) improve the heat sensitivity properties of the medical device, 13) improve the biostability and/or biocompatibility properties of the medical device, and/or 14) enable smaller, thinner and/or lighter weight medical devices to be made.
[0027] In still another and/or additional non-limiting aspect, the present medical device generally includes one or more materials that impart the desired properties to the medical device so as to withstand the manufacturing processes that is needed to produce the medical device. These manufacturing processes can include, but are not limited to, laser cutting, etching, crimping, annealing, drawing, pilgering, electroplating, electro-polishing, chemical polishing, cleaning, pickling, ion beam deposition or implantation, sputter coating, vacuum deposition, etc.
[0028] In yet another and/or additional non-limiting aspect, the design characteristics of the medical device are developed into an array of configurations that do not adversely affect the function of such medical device. That is, besides the desired mechanical properties of the medical device (e.g., stent, etc.), the medical device is designed to interact with the body tissue at the implantation location in a manner such that renewed vessel constrictions do not occur, in particular vessel constrictions caused by the medical device itself. Re-stenosis (re-constriction of the vessel) should be avoided as much as possible. It is also desirable that the medical device, as far as possible, is responsible for little or no inflammatory effect at the implantation site. In regard to a metal medical device, it is moreover desirable if the composition products of the medical device have little or no negative physiological effects. As can be appreciated, the composition of the products of the medical device can have positive physiological effects; however, this is not required.
[0029] In still yet another and/or additional non-limiting aspect, the design of the medical device can take any number of different structures. Thus, with reference to FIG. 1 , there is shown an exemplary embodiment endoluminal prosthesis in the form of a stent 10 having a carrier structure. As can be appreciated, the stent can have many other or additional configurations. As illustrated in FIG. 1 , the stent 10 and its carrier structure are in the form of a hollow body which is open at its ends and the peripheral wall of which is formed by the carrier structure which in turn is formed by partially folded legs 12 . The legs 12 form support portions 14 which are each formed by a leg 12 which is closed in an annular configuration in the longitudinal direction and which is folded in a zig-zag or meander-shaped configuration. The stent is suitable for coronary use or other types of use.
[0030] The carrier structure of the stent 10 is formed by a plurality of such support portions 12 which occur in succession in the longitudinal direction. The support portions 12 are connected together by way of one or more connecting legs 16 . As illustrated in FIG. 1 , each two connecting legs 16 are mutually adjacent in the peripheral direction and the parts of the support portions 12 , which are in mutually opposite relationship between those connecting legs 16 , define a mesh 18 of the stent 10 . As can be appreciated, the legs can be oriented in many different configurations. Each mesh 18 encloses a radial opening in the peripheral wall or the carrier structure of the stent 10 .
[0031] The stent 10 is expandable in the peripheral direction by virtue of the folding of the support portions 12 . That is affected for example, by means of a per se known balloon catheter which at its distal end, has a balloon which is expandable by means of a fluid. The stent 10 is crimped onto the deflated balloon, in the compressed condition. Upon expansion of the balloon, both the balloon and also the stent 10 are enlarged. The balloon can then be deflated again and the stent 10 is released from the balloon. In that way, the catheter can serve simultaneously for introducing the stent 10 into a blood vessel and in particular into a constricted coronary vessel and also for expanding the stent 10 at that location.
[0032] The geometry of the peripheral wall and legs of the stent will be described by using the co-ordinates shown in FIG. 1 , more specifically x as the longitudinal axis of the stent, y as coordinates extending radially in the peripheral direction of the stent with respect to the longitudinal direction x, and z as coordinates extending along the width or thickness of the stent. It can be seen from the view in cross-section through a support portion as illustrated in FIG. 2 that the geometry can be described by a length a, a width b, and a thickness c. In this case, the length a is the dimension of a bar in the longitudinal direction x with respect to the stent while the width b represents the dimension of a bar in the direction of a peripheral surface formed by the peripheral wall of the stent, and the thickness c is the dimension extending into the interior volume of the stent.
[0033] In another and/or additional non-limiting aspect of the present invention, the wall thickness of at least a portion of the support portions and/or connecting legs of the stent vary over the length and/or over the periphery of the stent along at least one of the axes x, y, and z. The varying of the thickness of the support portions and/or connecting legs enables the stent to be controllably expanded in a body passageway. The stent can be designed so that the entire stent expands uniformly, or be designed such that one or more portions of the stent expands at differing times and/or rates from one or more other portions of the stent. That is, at least one of the dimensions a, b and c of at least some of the support portions and/or connecting legs in the stent can be varied.
[0034] In still another and/or additional non-limiting aspect of the present invention, the stent is designed such that the first and last thirds of the stent with support portion and/or connecting legs wall have thicknesses a and/or widths b that are slightly greater than the thicknesses of the configurations in the middle third of the stent. In this non-limiting configuration, the stent design accounts for the first and last thirds being subjected to more turbulence and other degrading influences than the middle third. Alternately, the wall thickness of one or more portions of the stent can be steadily varied over the length of a support portion and/or a connecting leg as shown in FIG. 10 . In FIG. 10 , the wall thickness is at a minimum in the middle of the support portion and/or a connecting leg and at a maximum on the two ends. As can be appreciated, other non-limiting examples of varying wall thickness configurations can be used on the legs and/or support portions (e.g., notches in the legs/support portion, ribs in the legs/support portion, etc.).
[0035] In yet another and/or additional non-limiting aspect, the exact thickness and/or width variations along the longitudinal axis of the stent will in part depend on the material used to construct the stent as well as the design of the support portions and/or connecting legs of the stent. In addition, the use of polymer coatings (as detailed below) as well as other layers added to the stent surface can be used to affect one or more properties of the stent. These properties of the stent can thus be used to control the degradation rate and/or release rate of one or more of the polymer and/or drugs on the stent. In one non-limiting one embodiment, the thickness of the support portions and/or connecting legs of the stent is generally about 0.002-0.006 inch. As can be appreciated, one or more portions of the support portion and/or connecting leg can have greater or small thickness. For example, the average thickness of one or more legs can be about 0.0042 inch; however, the thinnest portion of the one or more legs could be about 0.0012-0.0035 inch and/or the thickest portion of the one or more legs could be about 0.0045-0.007 inch.
[0036] As discussed above, the thickness of the material in one portion of the stent can be different from the thickness of another material in another portion of the stent, so as to achieve the desired rate of structural success of the stent in one or more portions of the stent.
[0037] In still yet another and/or additional non-limiting aspect, the shape of the support portions and/or connecting legs of the stent can be selected to increase or decrease the strength of one or more portions of the support portions and/or connecting legs. As such pits, jagged surfaces, sharp angles, etc. can be incorporated into the stent design to alter the strength and/or flexibility of one or more portions of the stent. As can also be appreciated, smooth surfaces, curved surfaces, etc. can be used. As such, the structural configuration of the stent can also or alternatively be used to achieve the desired rate of success of the stent.
[0038] In another and/or additional non-limiting aspect, many configurations for the support portions and/or connecting legs of the stent lattice are possible. In various possible non-limiting embodiments, the configurations for the support portions can take multiple forms, including, e.g., the shape of a “W” ,“Y” ,“Z” , “X”, “U”, “V” and/or “S”. Stent structures showing these configurations are shown in FIGS. 7A-7G . These configurations also can have straight line or other structured connecting legs that connect the previously mentioned configurations, such as seen in FIG. 7E showing straight line connecting legs between “S” configurations. In addition, an almost limitless variety of other configurations can be achieved by combining one or more of the above basic configurations. Some non-limiting examples of configurations using two combined basic configurations are shown in FIGS. 7H-7K , which show “XZ”, “VU”, “XS”, and “YU” configurations. Many more such combinations are possible. Still additional configurations can be seen in FIGS. 3-6 and 12 . All of these connectors and configurations can have multiple thicknesses along its axis and have different angles or degrees of separation. This is utilized to accommodate the different stress points that occur so as not to weaken the device prior to achieving its' goal of repairing or supporting a mammalian organ or vessel.
[0039] In still another and/or additional non-limiting aspect, the medical device such as a stent can be fully or partially formed of a metal or a metal alloy. Hereinafter, descriptions using the term “alloy” may be used to generally describe embodiments using both a pure metal as well as an alloy of different metals. In one non-limiting embodiment, the medical device is generally designed to include at least about 25 weight percent of the metal alloy; however, this is not required. In one non-limiting embodiment, the medical device includes at least about 40 weight percent of the metal alloy. In another and/or additional non-limiting embodiment, the medical device includes at least about 50 weight percent of the metal alloy. In still another and/or additional non-limiting embodiment, the medical device includes at least about 60 weight percent of the metal alloy. In yet another and/or additional non-limiting embodiment, the medical includes at least about 70 weight percent of the metal alloy. In still yet another and/or additional non-limiting embodiment, the medical includes at least about 85 weight percent of the metal alloy. In another and/or additional non-limiting embodiment, the medical device includes at least about 90 weight percent of the metal alloy. In still another and/or additional non-limiting embodiment, the medical device includes at least about 95 weight percent of the metal alloy. In yet another and/or additional non-limiting embodiment, the medical device includes about 100 weight percent of the metal alloy.
[0040] In another and/or additional non-limiting aspect, the metal alloy that is used to form all or part of the medical device 1) is not clad, metal sprayed, plated and/or formed (e.g., cold worked, hot worked, etc.) onto another metal, or 2) does not have another metal or metal alloy metal sprayed, plated, clad and/or formed onto the novel metal alloy. It will be appreciated that in some applications, the metal alloy for use in the present devices may be clad, metal sprayed, plated and/or formed onto another metal, or another metal or metal alloy may be plated, metal sprayed, clad and/or formed onto the metal alloy when forming all or a portion of the medical device.
[0041] In yet another and/or additional non-limiting aspect, the metal alloy that is used to form all or a portion of the medical device includes a majority weight percent of tantalum. A minority weight percent of tungsten may form part of the alloy. In one non-limiting embodiment, the metal alloy comprises about 7.0-10.0% by weight tungsten and 90.0-93.0% tantalum. Specific non-limiting contemplated metal alloys in accordance with the present invention comprise 1) 92.5% tantalum with 7.5% tungsten, 2) 90% tantalum with 10% tungsten, and 3) 90-97.5% tantalum and 2.5-10% tungsten. Other non-limiting contemplated metal alloys in accordance with the present invention can include niobium and/or zirconium. In yet another and/or additional non-limiting embodiment, the metal comprises niobium. In one embodiment, the metal comprises at least about 95% niobium, and more particularly about 99.5-100% niobium. In a second embodiment, the metal comprises an alloy of niobium and zirconium wherein niobium has a larger weight percent than zirconium.
[0042] In still yet another and/or additional non-limiting aspect of the present invention, the medical device that is at least partially formed from the metal alloy can be formed by a variety of manufacturing techniques. In one non-limiting embodiment of the invention, the medical device can be formed from a rod or tube of the metal alloy. If a solid rod of the metal alloy is formed, the rod can be drilled (e.g., gun drilled, EDM, etc.) to form a cavity or passageway partially or fully through the rod; however, this is not required. The rod or tube can be cleaned, polished, annealed, drawn, etc. to obtain the desired diameter and/or wall thickness of the metal rod or tube. After the metal rod or tube has been formed to the desired diameter and wall thickness, the metal tube can further processed by one or more processing techniques such as, but not limited to, laser cutting, etching, etc. After the medical device has been fog wed, the medical device can be cleaned, polished, sterilized, etc.
[0043] In another and/or additional non-limiting aspect of the present embodiments, the medical device can be in the form of a stent. The stent can have a variety of applications such as, but not limited to placement into the vascular system, esophagus, trachea, colon, biliary tract, or urinary tract; however, the stent can have other applications. The stent can have one or more body members, wherein each body member includes first and second ends and a wall surface disposed between the first and second ends. Each body member can have a first cross-sectional area which permits delivery of the body member into a body passageway, and a second, expanded cross-sectional area.
[0044] The expansion of the stent body member can be accomplished in a variety of manners. Typically, the body member is expanded to its second cross-sectional area by a radially, outwardly extending force applied at least partially from the interior region of the body member (e.g., by use of a balloon, etc.); however, this is not required. When the second cross-sectional area is variable, the second cross-sectional area is typically dependent upon the amount of radially outward force applied to the body member. The stent can be designed such that the body member expands while retaining the original length of the body member; however, this is not required. The body member can have a first cross-sectional shape that is generally circular so as to form a substantially tubular body member; however, the body member can have other cross-sectional shapes. When the stent includes two of more body members, the two of more body members can be connected together by at least one connector member.
[0045] The stent can include rounded, smooth and/or blunt surfaces to minimize and/or prevent damage to a body passageway as the stent is inserted into a body passageway and/or expanded in a body passageway; however, this is not required. The stent can also have its subsurface treated in such a way that it forms gaps below the surface that are sponge-like; however, this is not required. The stent can be treated with gamma, beta and/or e-beam radiation, and/or otherwise sterilized; however, this is not required. The stent can have multiple sections; however, this is not required. The sections of the stent can have a uniform architectural configuration, or can have differing architectural configurations. Each of the sections of the stent can be formed of a single part or formed of multiple parts which have been attached. When a section is formed of multiple parts, typically the section is formed into one continuous piece; however, this is not required.
[0046] In still another and/or additional non-limiting aspect of the present invention, one or more portions of the medical device can include, contain and/or be coated with one or more biological agents that are used to facilitate in the success of the medical device and/or treated area. The medical device can include, contain and/or be coated with one or more biological agents. The term “biological agent” includes, but is not limited to, a substance, drug or otherwise formulated and/or designed to prevent, inhibit and/or treat one or more biological problems, and/or to promote the healing in a treated area. Non-limiting examples of biological problems that can be addressed by one or more biological agents include, but are not limited to, viral, fungus and/or bacteria infection; vascular diseases and/or disorders; digestive diseases and/or disorders; reproductive diseases and/or disorders; lymphatic diseases and/or disorders; cancer; implant rejection; pain; nausea; swelling; arthritis; bone diseases and/or disorders; organ failure; immunity diseases and/or disorders; cholesterol problems; blood diseases and/or disorders; lung diseases and/or disorders; heart diseases and/or disorders; brain diseases and/or disorders; neuralgia diseases and/or disorders; kidney diseases and/or disorders; ulcers; liver diseases and/or disorders; intestinal diseases and/or disorders; gallbladder diseases and/or disorders; pancreatic diseases and/or disorders; psychological disorders; respiratory diseases and/or disorders; gland diseases and/or disorders; skin diseases and/or disorders; hearing diseases and/or disorders; oral diseases and/or disorders; nasal diseases and/or disorders; eye diseases and/or disorders; fatigue; genetic diseases and/or disorders; burns; scarring and/or scars; trauma; weight diseases and/or disorders; addiction diseases and/or disorders; hair loss; cramps; muscle spasms; tissue repair; and/or the like.
[0047] Non-limiting examples of biological agents that can be used include, but are not limited to, 5-Fluorouracil and/or derivatives thereof; 5-Phenylmethimazole and/or derivatives thereof; ACE inhibitors and/or derivatives thereof; acenocoumarol and/or derivatives thereof; acyclovir and/or derivatives thereof; actilyse and/or derivatives thereof; adrenocorticotropic hormone and/or derivatives thereof; adriamycin and/or derivatives thereof; agents that modulate intracellular Ca 2+ transport such as L-type (e.g., diltiazem, nifedipine, verapamil, etc.) or T-type Ca 2+ channel blockers (e.g., amiloride, etc.); alpha-adrenergic blocking agents and/or derivatives thereof; alteplase and/or derivatives thereof; amino glycosides and/or derivatives thereof (e.g., gentamycin, tobramycin, etc.); angiopeptin and/or derivatives thereof; angiostatic steroid and/or derivatives thereof; angiotensin II receptor antagonists and/or derivatives thereof; anistreplase and/or derivatives thereof; antagonists of vascular epithelial growth factor and/or derivatives thereof; anti-biotics; anti-coagulant compounds and/or derivatives thereof; anti-fibrosis compounds and/or derivatives thereof; anti-fungal compounds and/or derivatives thereof; anti-inflammatory compounds and/or derivatives thereof; Anti-Invasive Factor and/or derivatives thereof; anti-metabolite compounds and/or derivatives thereof (e.g., staurosporin, trichothecenes, and modified diphtheria and ricin toxins, Pseudomonas exotoxin, etc.); anti-matrix compounds and/or derivatives thereof (e.g., colchicine, tamoxifen, etc.); antimicrobial agents and/or derivatives thereof; anti-migratory agents and/or derivatives thereof (e.g., caffeic acid derivatives, nilvadipine, etc.); anti-mitotic compounds and/or derivatives thereof; anti-neoplastic compounds and/or derivatives thereof; anti-oxidants and/or derivatives thereof; anti-platelet compounds and/or derivatives thereof; anti-proliferative and/or derivatives thereof; anti-thrombogenic agents and/or derivatives thereof; argatroban and/or derivatives thereof; ap-1 inhibitors and/or derivatives thereof (e.g., for tyrosine kinase, protein kinase C, myosin light chain kinase, Ca, 2 /calmodulin kinase II, casein kinase II, etc.); aspirin and/or derivatives thereof; azathioprine and/or derivatives thereof; i-Estradiol and/or derivatives thereof; α-i-anticollagenase and/or derivatives thereof; calcium channel blockers and/or derivatives thereof; calmodulin antagonists and/or derivatives thereof (e.g., H7, etc.) ; CAPTOPRIL and/or derivatives thereof; cartilage-derived inhibitor and/or derivatives thereof; CHlMP-3 and/or derivatives thereof; cephalosporin and/or derivatives thereof (e.g., cefadroxil, cefazolin, cefaclor, etc.); chloroquine and/or derivatives thereof; chemotherapeutic compounds and/or derivatives thereof (e.g., 5-fluorouracil, vincristine, vinblastine, cisplatin, doxyrubicin, adriamycin, tamocifen, etc.); chymostatin and/or derivatives thereof; CILAZAPRIL and/or derivatives thereof; clopidigrel and/or derivatives thereof; clotrimazole and/or derivatives thereof; colchicine and/or derivatives thereof; cortisone and/or derivatives thereof; Coumadin and/or derivatives thereof; curacin-A and/or derivatives thereof; cyclosporine and/or derivatives thereof; cytochalasin and/or derivatives thereof (e.g., cytochalasin A, cytochalasin B, cytochalasin C, cytochalasin D, cytochalasin E, cytochalasin F, cytochalasin G, cytochalasin H, cytochalasin J, cytochalasin K, cytochalasin L, cytochalasin M, cytochalasin N, cytochalasin 0 , cytochalasin P, cytochalasin Q, cytochalasin R, cytochalasin S, chaetoglobosin A, chaetoglobosin B, chaetoglobosin C, chaetoglobosin D, chaetoglobosin E, chaetoglobosin F, chaetoglobosin G, chaetoglobosin J, chaetoglobosin K, deoxaphomin, proxiphomin, protophomin, zygosporin D, zygosporin E, zygosporin F, zygosporin G, aspochalasin B, aspochalasin C, aspochalasin D, etc.); cytokines and/or derivatives thereof; desirudin and/or derivatives thereof; dexamethazone and/or derivatives thereof; dipyridamole and/or derivatives thereof; eminase and/or derivatives thereof; endothelin and/or derivatives thereof; endothelial growth factor and/or derivatives thereof; epidermal growth factor and/or derivatives thereof; epothilone and/or derivatives thereof; estramustine and/or derivatives thereof; estrogen and/or derivatives thereof; fenoprofen and/or derivatives thereof; fluorouracil and/or derivatives thereof; flucytosine and/or derivatives thereof; forskolin and/or derivatives thereof; ganciclovir and/or derivatives thereof; glucocorticoids and/or derivatives thereof (e.g., dexamethasone, betamethasone, etc.); glycoprotein 11 b / 111 a platelet membrane receptor antibody and/or derivatives thereof; GM-CSF and/or derivatives thereof; griseofulvin and/or derivatives thereof; growth factors and/or derivatives thereof (e.g., VEGF; TGF; IGF; PDGF; FGF, etc.); growth hormone and/or derivatives thereof; heparin and/or derivatives thereof; hirudin and/or derivatives thereof; hyaluronate and/or derivatives thereof; hydrocortisone and/or derivatives thereof; ibuprofen and/or derivatives thereof; immunosuppressive agents and/or derivatives thereof (e.g., adrenocorticosteroids, cyclosporine, etc.); indomethacin and/or derivatives thereof; inhibitors of the sodium/calcium antiporter and/or derivatives thereof (e.g., amiloride, etc.); inhibitors of the IP 3 receptor and/or derivatives thereof; inhibitors of the sodium/hydrogen antiporter and/or derivatives thereof (e.g., amiloride and derivatives thereof, etc.); insulin and/or derivatives thereof; Interferon alpha 2 Macroglobulin and/or derivatives thereof; ketoconazole and/or derivatives thereof; Lepirudin and/or derivatives thereof; LISINOPRIL and/or derivatives thereof; LOVASTATIN and/or derivatives thereof; marevan and/or derivatives thereof; mefloquine and/or derivatives thereof; metalloproteinase inhibitors and/or derivatives thereof; methotrexate and/or derivatives thereof; metronidazole and/or derivatives thereof; miconazole and/or derivatives thereof; monoclonal antibodies and/or derivatives thereof; mutamycin and/or derivatives thereof; naproxen and/or derivatives thereof; nitric oxide and/or derivatives thereof; nitroprusside and/or derivatives thereof; nucleic acid analogues and/or derivatives thereof (e.g., peptide nucleic acids, etc.); nystatin and/or derivatives thereof; oligonucleotides and/or derivatives thereof; paclitaxel and/or derivatives thereof; penicillin and/or derivatives thereof; pentamidine isethionate and/or derivatives thereof; phenindione and/or derivatives thereof; phenylbutazone and/or derivatives thereof; phosphodiesterase inhibitors and/or derivatives thereof; Plasminogen Activator Inhibitor-1 and/or derivatives thereof; Plasminogen Activator Inhibitor- 2 and/or derivatives thereof; Platelet Factor 4 and/or derivatives thereof; platelet derived growth factor and/or derivatives thereof; plavix and/or derivatives thereof; POSTMI 75 and/or derivatives thereof; prednisone and/or derivatives thereof; prednisolone and/or derivatives thereof; probucol and/or derivatives thereof; progesterone and/or derivatives thereof; prostacyclin and/or derivatives thereof; prostaglandin inhibitors and/or derivatives thereof; protamine and/or derivatives thereof; protease and/or derivatives thereof; protein kinase inhibitors and/or derivatives thereof (e.g., staurosporin, etc.); quinine and/or derivatives thereof; radioactive agents and/or derivatives thereof (e.g., Cu-64, Ca-67, Cs-131, Ga-68, Zr-89, Ku-97, Tc-99 m, Rh-105, Pd-103, Pd-109, in-111 ,1-123, 1-125,1-131 , Re-186, Re-188, Au-198, Au-199, Pb-203, At-211, Pb-212, Bi-212,H 3 P 32 O 4 , etc.); rapamycin and/or derivatives thereof; receptor antagonists for histamine and/or derivatives thereof; refludan and/or derivatives thereof; retinoic acids and/or derivatives thereof; revasc and/or derivatives thereof; rifamycin and/or derivatives thereof; sense or anti-sense oligonucleotides and/or derivatives thereof (e.g., DNA, RNA, plasmid DNA, plasmid RNA, etc.); seramin and/or derivatives thereof; steroids; seramin and/or derivatives thereof; serotonin and/or derivatives thereof; serotonin blockers and/or derivatives thereof; streptokinase and/or derivatives thereof; sulfasalazine and/or derivatives thereof; sulfonamides and/or derivatives thereof (e.g., sulfamethoxazole, etc.); sulphated chitin derivatives; Sulphated Polysaccharide Peptidoglycan Complex and/or derivatives thereof; THi and/or derivatives thereof (e.g., Interleukins-2, -12, and -15, gamma interferon, etc.); thioprotese inhibitors and/or derivatives thereof; taxol and/or derivatives thereof (e.g., taxotere, baccatin, 10-deacetyltaxol, 7-xylosyl-10-deacetyltaxol, cephalomannine, 10-deacetyl-7-epitaxol, 7 epitaxol, 10-deacetylbaccatin III, 10-deacetylcephaolmannine, etc.); ticlid and/or derivatives thereof; ticlopidine and/or derivatives thereof; tick anti-coagulant peptide and/or derivatives thereof; thioprotese inhibitors and/or derivatives thereof; thyroid hormone and/or derivatives thereof; Tissue Inhibitor of Metalloproteinase-1 and/or derivatives thereof; Tissue Inhibitor of Metalloproteinase-2 and/or derivatives thereof; tissue plasma activators; TNF and/or derivatives thereof; tocopherol and/or derivatives thereof; toxins and/or derivatives thereof; tranilast and/or derivatives thereof; transforming growth factors alpha and beta and/or derivatives thereof; trapidil and/or derivatives thereof; triazolopyrimidine and/or derivatives thereof; vapiprost and/or derivatives thereof; vinblastine and/or derivatives thereof; vincristine and/or derivatives thereof; zidovudine and/or derivatives thereof. As can be appreciated, the biological agent can include one or more derivatives of the above listed compounds and/or other compounds.
[0048] In one non-limiting example, the medical device can be coated with and/or includes one or more biological agents such as, but not limited to, trapidil and/or trapidil derivatives, taxol, taxol derivatives (e.g., taxotere, baccatin, 10-deacetyltaxol, 7-xylosyl-IO-deacetyltaxol, cephalomannine, 10-deacetyl-7-epitaxol, 7 epitaxol, 10-deaeetylbaccatin III, 10-deaeetyleephaolmannine, etc.), cytochalasin, cytochalasin derivatives (e.g., cytochalasin A, cytochalasin B, cytochalasin C, cytochalasin D, cytochalasin E, cytochalasin F, cytochalasin G, cytochalasin H, cytochalasin J, cytochalasin K, cytochalasin L, cytochalasin M, cytochalasin N, cytochalasin 0 , cytochalasin P, cytochalasin Q, cytochalasin R, cytochalasin S, chaetoglobosin A, chaetoglobosin B, chaetoglobosin C, chaetoglobosin D, chaetoglobosin E, chaetoglobosin F, chaetoglobosin G, chaetoglobosin J, chaetoglobosin K, deoxaphomin, proxiphomin, protophomin, zygosporin D, zygosporin E, zygosporin F, zygosporin G, aspochalasin B, aspochalasin C, aspochalasin D, etc.), paclitaxel, paclitaxel derivatives, rapamycin, rapamycin derivatives, 5-Phenylmethimazole, 5-Phenylmethimazole derivatives, GM-CSF (granulo-cyte-macrophage colony-stimulating-factor), GM-CSF derivatives, or combinations thereof. In one non-limiting embodiment of the invention, the medical device can be partially of fully coated with one or more biological agents, impregnated with one or more biological agents to facilitate in the success of a particular medical procedure.
[0049] In another and/or additional non-limiting aspect of the present invention, the one or more biological agents can be coated on the medical device by a variety of mechanisms such as, but not limited to, spraying (e.g., atomizing spray techniques, etc.), dip coating, roll coating, sonication, brushing, plasma deposition, depositing by vapor deposition. In another and/or alternative non-limiting embodiment of the invention, the type and/or amount of biological agent included on, in and/or in conjunction with the medical device is generally selected for the treatment of one or more medical treatments. Typically the amount of biological agent included on, in and/or used in conjunction with the medical device is about 0.01-100 μg per mm 2 . However, other amounts can be used.
[0050] In still another and/or additional non-limiting aspect of the present invention, the amount of two of more biological agents on, in and/or used in conjunction with the medical device can be the same or different. For instance, one or more biological agents can be coated on one or more portions of the medical device to provide local and/or systemic delivery of one or more biological agents in and/or to a body passageway to a) inhibit or prevent thrombosis, in-stent restenosis, vascular narrowing and/or restenosis after the medical device has been inserted in and/or connected to a body passageway, b) at least partially passivate, remove and/or dissolve lipids, fibroblast, fibrin, etc. in a body passageway so as to at least partially remove such materials and/or to passivate such vulnerable materials (e.g., vulnerable plaque, etc.) in the body passageway in the region of the medical device and/or down stream of the medical device. As can be appreciated, the one or more biological agents can have many other or additional uses.
[0051] In yet another and/or additional non-limiting example, the medical device is coated with and/or includes one or more biological agents such as, but not limited to trapidil, trapidil derivatives, taxol, taxol derivatives, cytochalasin, cytochalasin derivatives, paclitaxel, paclitaxel derivatives, rapamycin, rapamycin derivatives, 5-Phenylmethimazole, 5-Phenylmethimazole derivatives, GM-CSF, GM-CSF derivatives, or combinations thereof, and one or more additional biological agents, such as, but not limited to, biological agents associated with thrombolytics, vasodilators, anti-hypertensive agents, anti-microbial or anti-biotic, anti-mitotic, anti-proliferative, anti-secretory agents, non-steroidal antiinflammatory drugs, immunosuppressive agents, growth factors and growth factor antagonists, antitumor and/or chemotherapeutic agents, anti-polymerases, antiviral agents, anti-body targeted therapy agents, hormones, anti-oxidants, biologic components, radio-therapeutic agents, radiopaque agents and/or radio-labeled agents. In addition to these biological agents, the medical device can be coated with and/or include one or more biological agents that are capable of inhibiting or preventing any adverse biological response by and/or to the medical device that could possibly lead to device failure and/or an adverse reaction by human or animal tissue. A wide range of biological agents thus can be used.
[0052] In another and/or additional non-limiting aspect of the present invention, the one or more biological agents on and/or in the medical device, when used on the medical device, can be released in a controlled manner so the area in question to be treated is provided with the desired dosage of biological agent over a sustained period of time. As can be appreciated, controlled release of one or more biological agents on the medical device is not always required and/or desirable. As such, one or more of the biological agents on and/or in the medical device can be uncontrollably released from the medical device during and/or after insertion of the medical device in the treatment area.
[0053] It can also be appreciated that one or more biological agents on and/or in the medical device can be controllably released from the medical device and one or more biological agents on and/or in the medical device can be uncontrollably released from the medical device. As such, the medical device can be designed such that 1) all the biological agent on and/or in the medical device is controllably released, 2) some of the biological agent on and/or in the medical device is controllably released and some of the biological agent on the medical device is non-control lably released, or 3) none of the biological agent on and/or in the medical device is controllably released. The medical device can also be designed such that the rate of release of the one or more biological agents from the medical device is the same or different. The medical device can also be designed such that the rate of release of the one or more biological agents from one or more regions on the medical device is the same or different.
[0054] In still another and/or additional non-limiting aspect of the present invention, non-limiting arrangements that can be used to control the release of one or more biological agent from the medical device, when such controlled release is desired, include a) at least partially coat one or more biological agents with one or more polymers, b) at least partially incorporate and/or at least partially encapsulate one or more biological agents into and/or with one or more polymers, and/or c) insert one or more biological agents in pores, passageway, cavities, etc. in the medical device and at least partially coat or cover such pores, passageway, cavities, etc. with one or more polymers. As can be appreciated, other or additional arrangements can be used to control the release of one or more biological agent from the medical device.
[0055] In yet another and/or additional non-limiting aspect of the present invention, one or more polymers can be used to at least partially control the release of one or more biological agent from the medical device. The one or more polymers, when used, can be porous or non-porous. As such, the one or more biological agents on the medical device can be 1) coated on one or more surface regions of the medical device, and/or 2) form at least a portion or be included in at least a portion of the structure of the medical device. When the one or more biological agents are coated on the medical device, the one or more biological agents can 1) be directly coated on one or more surfaces of the medical device, 2) be mixed with one or more coating polymers or other coating materials and then at least partially coated on one or more surfaces of the medical device, 3) be at least partially coated on the surface of another coating material that has been at least partially coated on the medical device, and/or 4) be at least partially encapsulated between a) a surface or region of the medical device and one or more other coating materials and/or b) two or more other coating materials.
[0056] With reference to FIGS. 11 A- 11 F, various non-limiting arrangements for the coating of polymer and/or biological agents on the surfaces of the medical device are shown. As can be appreciated, many other coating combinations and configurations can be used. FIG. 11A shows a non-coated body portion. FIG. 11B shows a body portion coated on all sides with a biological agent. FIG. 11C shows a body portion coated with a polymer, which is then coated with a biological agent. FIG. 11D shows a body portion coated with an intimate mixture of biological agent and polymer. FIG. 11E shows a body portion coated with biological agent, which is then coated with a polymer. FIG. 11F shows a body portion with a sandwich layer coating of biological agent between two layers of polymer.
[0057] In still yet another and/or additional non-limiting aspect of the present invention, one or more portions of a support portion and/or a connecting leg of the stent can include one or more passageways. These one or more passageways can be used to alter one or more physical properties of the support portion and/or a connecting leg (e.g., strength, bendability, etc.) and/or be used to contain one or more polymers and/or biological agents. FIG. 8 shows a stent leg or body portion having a cavity or internal passageway formed in it. Such passageways can be formed using the same various methods used to form the main body of the medical device, such as laser etching, etc. The internal passageways can be coated with polymer along with the surface of the medical device, as shown in FIG. 9A . In addition, the interior of the passageway can also or alternately be filled with a biological agent, as shown in FIG. 9B . These passageways can be filled in various ways. One non-limiting method is to place the medical device in a vacuum chamber and create a vacuum around the device. Biological agent or polymer is then introduced onto the medical device. The reduced pressure will draw the biological agent or polymer into the internal passageways. As can be appreciated, other methods can be used to incorporate polymer and/or biological agent in the cavity or internal passageway.
[0058] In another and/or additional non-limiting aspect of the present invention, many coating arrangements can be used on the medical device. When the one or more biological agents are inserted and/or impregnated in one or more internal structures, surface structures and/or micro-structures of the medical device, 1) one or more other coating materials can be applied at least partially over the one or more internal structures, surface structures and/or micro-structures of the medical device, and/or 2) one or more polymers can be combined with one or more biological agents. As such, the one or more biological agents can be 1) embedded in the structure of the medical device; 2) positioned in one or more internal structures of the medical device; 3) encapsulated between two polymer coatings; 4) encapsulated between the base structure and a polymer coating; 5) mixed in the base structure of the medical device that includes at least one polymer coating; or 6) one or more combinations of 1 , 2, 3, 4 and/or 5.
[0059] In addition or alternatively, the one or more coating of the one or more polymers on the medical device can include 1) one or more coatings of non-porous polymers; 2) one or more coatings of a combination of one or more porous polymers and one or more non-porous polymers; 3) one or more coatings of one or more porous polymers and one or more coatings of one or more non-porous polymers; 4) one or more coating of porous polymer, or 5) one or more combinations of options 1 , 2, 3 and 4. As can be appreciated different biological agents can be located in and/or between different polymer coating layers and/or on and/or the structure of the medical device, as described above. As can also be appreciated, many other and/or additional coating combinations and/or configurations can be used. The concentration of one or more biological agents, the type of polymer, the type and/or shape of internal structures in the medical device and/or the coating thickness of one or more biological agents can be used to control the release time, the release rate and/or the dosage amount of one or more biological agents; however, other or additional combinations can be used. As such, the biological agent and polymer system combination and location on the medical device can be numerous.
[0060] As can also be appreciated, one or more biological agents can be deposited on the top surface of the medical device to provide an initial uncontrolled burst effect of the one or more biological agents prior to 1) the control release of the one or more biological agents through one or more layers of polymer system that include one or more non-porous polymers and/or 2) the uncontrolled release of the one or more biological agents through one or more layers of polymer system. The one or more biological agents and/or polymers can be coated on the medical device by a variety of mechanisms such as, but not limited to, spraying (e.g., atomizing spray techniques, etc.), dip coating, roll coating, sonication, brushing, plasma deposition, and/or depositing by vapor deposition. The thickness of each polymer layer and/or layer of biological agent is generally at least about 0.01 μm and is generally less than about 150 μm. In one non-limiting embodiment, the thickness of a polymer layer and/or layer of biological agent is about 0.02-75 μm, more particularly about 0.05-50 μm, and even more particularly about 1-30 μm.
[0061] When the medical device includes and/or is coated with one or more biological agents such that at least one of the biological agents is at least partially controllably released from the medical device, the need or use of body-wide therapy for extended periods of time can be reduced or eliminated. In the past, the use of body-wide therapy was used by the patient long after the patient left the hospital or other type of medical facility. This body-wide therapy could last days, weeks, months or sometimes over a year after surgery.
[0062] In still another and/or additional non-limiting aspect of the present invention, the medical device of the present invention can be applied or inserted into a treatment area and 1) reduced use and/or extended use of body wide therapy after application or insertion of the medical device can be used or 2) no use and/or extended use of body wide therapy after application or insertion of the medical device is used. As can be appreciated, use and/or extended use of body wide therapy can be used after application or insertion of the medical device at the treatment area, in one non-limiting example, no body-wide therapy is needed after the insertion of the medical device into a patient.
[0063] In another and/or alternative non-limiting example, when short term use of body-wide therapy is needed or used after the insertion of the medical device into a patient, such short term use can be terminated after the release of the patient from the hospital or other type of medical facility, or one to two days or weeks after the release of the patient from the hospital or other type of medical facility; however, it will be appreciated that other time periods of body-wide therapy can be used. As a result of the use of the medical device of the present invention, the use of body-wide therapy after a medical procedure involving the insertion of a medical device into a treatment area can be significantly reduced or eliminated.
[0064] In another and/or additional non-limiting aspect of the present invention, controlled release of one or more biological agents from the medical device, when controlled release is desired, can be accomplished by using one or more non-porous polymer layers; however, other and/or additional mechanisms can be used to controllably release the one or more biological agents. The one or more biological agents are at least partially controllably released by molecular diffusion through the one or more non-porous polymer layers. When one or more non-porous polymer layers are used, the one or more polymer layers are typically biocompatible polymers; however, this is not required. The one or more non-porous polymers can be applied to the medical device without the use of chemical, solvents, and/or catalysts; however, this is not required. In one non-limiting example, the non-porous polymer can be at least partially applied by, but not limited to, vapor deposition and/or plasma deposition. The non-porous polymer can be selected so as to polymerize and cure merely upon condensation from the vapor phase; however, this is not required.
[0065] The non-porous polymer system can be mixed with one or more biological agents prior to being coated on the medical device and/or be coated on a medical device that previously included one or more biological agents; however, this is not required. The use or one or more non-porous polymer layers allow for accurate controlled release of the biological agent from the medical device. The controlled release of one or more biological agents through the non-porous polymer is at least partially controlled on a molecular level utilizing the motility of diffusion of the biological agent through the non-porous polymer. In one non-limiting example, the one or more non-porous polymer layers can include, but are not limited to, polyamide, parylene (e.g., parylene C, parylene N) and/or a parylene derivative.
[0066] In still another and/or additional non-limiting aspect of the present invention, controlled release of one or more biological agents from the medical device, when controlled release is desired, can be accomplished by using one or more polymers that form a chemical bond with one or more biological agents. In one non-limiting example, at least one biological agent includes trapidil, trapidil derivative or a salt thereof. The amount of biological agent that can be loaded with one or more polymers may be a function of the concentration of anionic groups and/or cationic groups in the one or more polymer.
[0067] For biological agents that are anionic, the concentration of biological agent that can be loaded on the one or more polymers is generally a function of the concentration of cationic groups (e.g., amine groups and the like) in the one or more polymer and the fraction of these cationic groups that can ionically bind to the anionic form of the one or more biological agents.
[0068] For biological agents that are cationic (e.g., trapidil, etc.), the concentration of biological agent that can be loaded on the one or more polymers is generally a function of the concentration of anionic groups in the one or more polymers, and the fraction of these anionic groups that can ionically bind to the cationic form of the one or more biological agents. As such, the concentration of one or more biological agent that can be bound to the one or more polymers can be varied by controlling the amount of hydrophobic and hydrophilic monomer in the one or more polymers, by controlling the efficiency of salt formation between the biological agent, and/or the anionic/cationic groups in the one or more polymers.
[0069] In still another and/or additional aspect of the present invention, a variety of polymers can be coated on the medical device and/or be used to form at least a portion of the medical device. The one or more polymers can be used on the medical for a variety of reasons such as, but not limited to, 1) forming a portion of the medical device, 2) improving a physical property of the medical device (e.g., improve strength, improve durability, improve biocompatibility, reduce friction, etc.), 3) forming a protective coating on one or more surface structures on the medical device, 4) at least partially forming one or more surface structures on the medical device, and/or 5) at least partially controlling a release rate of one or more biological agents from the medical device. As can be appreciated, the one or more polymers can have other or additional uses on the medical device. The one or more polymers can be porous, non-porous, biostable, biodegradable (i.e., dissolves, degrades, is absorbed, or any combination thereof in the body), and/or biocompatible.
[0070] Non-limiting examples of polymers that are considered to be biodegradable, bioresorbable, or bioerodable include, but are not limited to, aliphatic polyesters; poly(glycolic acid) and/or copolymers thereof (e.g., poly(glycolide trimethylene carbonate); poly(caprolactone glycolide)); poly(lactic acid) and/or isomers thereof (e.g., poly-L(lactic acid) and/or poly-D Lactic acid) and/or copolymers thereof (e.g., DL-PLA), with and without additives (e.g., calcium phosphate glass), and/or other copolymers (e.g., poly(caprolactone lactide), poly(lactide glycolide), poly(lactic acid ethylene glycol)); poly(ethylene glycol); poly(ethylene glycol) diacrylate; poly(lactide); polyalkylene succinate; polybutylene diglycolate; polyhydroxybutyrate (PHB); polyhydroxyvalerate (PHV); polyhydroxybutyrate/polyhydroxyvalerate copolymer (PHB/PHV); poly(hydroxybutyrate-co-valerate); polyhydroxyalkaoates (PHA); polycaprolactone; poly(caprolactone-polyethylene glycol) copolymer; poly(valerolactone); polyanhydrides; poly(orthoesters) and/or blends with polyanhydrides; poly(anhydride-co-imide); polycarbonates (aliphatic); poly(hydroxyl-esters); polydioxanone; polyanhydrides; polyanhydride esters; polycyanoacrylates; poly(alkyl 2-cyanoacrylates); poly(amino acids); poly(phosphazenes); poly(propylene fumarate); polypropylene fumarate-co-ethylene glycol); poly(fumarate anhydrides); fibrinogen; fibrin; gelatin; cellulose and/or cellulose derivatives and/or cellulosic polymers (e.g., cellulose acetate, cellulose acetate butyrate, cellulose butyrate, cellulose ethers, cellulose nitrate, cellulose propionate, cellophane); chitosan and/or chitosan derivatives (e.g., chitosan NOCC, chitosan NOOC-G); alginate; polysaccharides; starch; amylase; collagen; polycarboxylic acids; polyethyl ester-co-carboxylate carbonate) (and/or other tyrosine derived polycarbonates); poly(iminocarbonate); poly(BPA-iminocarbonate); poly(trimethylene carbonate); poly(iminocarbonate-amide) copolymers and/or other pseudo-poly(amino acids); poly(ethylene glycol); poly(ethylene oxide); poly(ethylene oxide)/poly(butylene terephthalate) copolymer; polyCepsilon-caprolactone-dimethyltrimethylene carbonate); poly(ester amide); poly(amino acids) and conventional synthetic polymers thereof; poly(alkylene oxalates); poly(alkylcarbonate); poly(adipic anhydride); nylon copolyamides; NO-carboxymethyl chitosan NOCC); carboxymethyl cellulose; copoly(ether-esters) (e.g., PEO/PLA dextrans); polyketals; biodegradable polyethers; biodegradable polyesters; polydihydropyrans; polydepsipeptides; polyarylates (L-tyrosine-derived) and/or free acid polyarylates; polyamides (e.g., Nylon 66, polycaprolactam); polypropylene fumarate-co-ethylene glycol) (e.g., fumarate anhydrides); hyaluronates; poly-p-dioxanone; polypeptides and proteins; polyphosphoester; polyphosphoester urethane; polysaccharides; pseudo-poly(amino acids); starch; terpolymer; (copolymers ofglycolide, lactide, or dimethyltrimethylene carbonate); rayon; rayon triacetate; latex; and/pr copolymers, blends, and/or composites of above. Non-limiting examples of polymers that considered to be biostable include, but are not limited to, parylene; parylene c; parylene f; parylene n; parylene derivatives; maleic anyhydride polymers; phosphorylcholine; poly n-butyl methacrylate (PBMA); polyethylene-co-vinyl acetate (PEVA); PBMA/PEVA blend or copolymer; polytetrafluoroethene (Teflon®) and derivatives; poly-paraphenylene terephthalamide (Kevlar®); poly(ether ether ketone) (PEEK); poly(styrene-b-isobutylene-b-styrene) (Translute™); tetramethyldisiloxane (side chain or copolymer); polyimides polysulfides; poly(ethylene terephthalate); poly(methyl methacrylate); poly(ethylene-co-methyl methacrylate); styrene-ethylene/butylene-styrene block copolymers; ABS; SAN; acrylic polymers and/or copolymers (e.g., n-butyl-acrylate, n-butyl methacrylate, 2-ethylhexyl acrylate, lauryl-acrylate, 2-hydroxy-propyl acrylate, polyhydroxyethyl, methacrylate/methylmethacrylate copolymers); glycosaminoglycans; alkyd resins; elastin; polyether sulfones; epoxy resin; poly(oxymethylene); polyolefins; polymers of silicone; polymers of methane; polyisobutylene; ethylene-alphaolefin copolymers; polyethylene; polyacrylonitrile; fluorosilicones; poly(propylene oxide); polyvinyl aromatics (e.g., polystyrene); polyvinyl ethers) (e.g., polyvinyl methyl ether); polyvinyl ketones); poly(vinylidene halides) (e.g., polyvinylidene fluoride, polyvinylidene chloride); poly(vinylpyrolidone); poly(vinylpyrolidone)/vinyl acetate copolymer; polyvinylpridine prolastin or silk-elastin polymers (SELP); silicone; silicone rubber; polyurethanes (polycarbonate polyurethanes, silicone urethane polymer) (e.g., chronoflex varieties, bionate varieties); vinyl halide polymers and/or copolymers (e.g., polyvinyl chloride); polyacrylic acid; ethylene acrylic acid copolymer; ethylene vinyl acetate copolymer; polyvinyl alcohol; poly(hydroxyl alkylmethacrylate); Polyvinyl esters (e.g., polyvinyl acetate); and/or copolymers, blends, and/or composites of above. Non-limiting examples of polymers that can be made to be biodegradable and/or bioresorbable with modification include, but are not limited to, hyaluronic acid (hyanluron); polycarbonates; polyorthocarbonates; copolymers of vinyl monomers; polyacetals; biodegradable polyurethanes; polyacrylamide; polyisocyanates; polyamide; and/or copolymers, blends, and/or composites of above. As can be appreciated, other and/or additional polymers and/or derivatives of one or more of the above listed polymers can be used. The thickness of each polymer layer is generally at least about 0.01 μm and is generally less than about 150 μm; however, other thicknesses can be used. In one non-limiting embodiment, the thickness of a polymer layer and/or layer of biological agent is about 0.02-75 μm, more particularly about 0.05-50 μm, and even more particularly about 1-30 μm. As can be appreciated, other thicknesses can be used. In one non-limiting embodiment, the medical device includes and/or is coated with parylene, PLGA, POE, PGA, PLLA, PAA, PEG, chitosan and/or derivatives of one or more of these polymers.
[0071] In another and/or alternative non-limiting embodiment, the medical device includes and/or is coated with a non-porous polymer that includes, but is not limited to, polyamide, parylene c, parylene n and/or a parylene derivative. In still another and/or alternative non-limiting embodiment, the medical device includes and/or is coated with poly(ethylene oxide), poly(ethylene glycol), and poly(propylene oxide), polymers of silicone, methane, tetrafluoroethylene (including TEFLON brand polymers), tetramethyldisiloxane, and the like.
[0072] In another and/or additional non-limiting aspect of the present invention, the medical device, when including and/or is coated with one or more biological agents, can include and/or can be coated with one or more biological agents that are the same or different in different regions of the medical device and/or have differing amounts and/or concentrations in differing regions of the medical device. For instance, the medical device can a) be coated with and/or include one or more biologicals on at least one portion of the medical device and at least another portion of the medical device is not coated with and/or includes biological agent; b) be coated with and/or include one or more biologicals on at least one portion of the medical device that is different from one or more biologicals on at least another portion of the medical device; c) be coated with and/or include one or more biologicals at a concentration on at least one portion of the medical device that is different from the concentration of one or more biologicals on at least another portion of the medical device; etc.
[0073] In still another and/or additional non-limiting aspect of the present invention, one or more surfaces of the medical device can be treated to achieve the desired coating properties of the one or more biological agents and one or more polymers coated on the medical device. Such surface treatment techniques include, but are not limited to, cleaning, buffing, smoothing, etching (chemical etching, plasma etching, etc.), etc. When an etching process is used, various gasses can be used for such a surface treatment process such as, but not limited to, carbon dioxide, nitrogen, oxygen, freon, helium, hydrogen, etc. The plasma etching process can be used to clean the surface of the medical device, change the surface properties of the medical device so as to affect the adhesion properties, lubricity properties, etc. of the surface of the medical device. As can be appreciated, other or additional surface treatment processes can be used prior to the coating of one or more biological agents and/or polymers on the surface of the medical device.
[0074] In one non-limiting manufacturing process, one or more portions of the medical device are cleaned and/or plasma etched; however, this is not required. Plasma etching can be used to clean the surface of the medical device, and/or to form one or more non-smooth surfaces on the medical device to facilitate in the adhesion of one or more coatings of biological agents and/or one or more coatings of polymer on the medical device. The gas for the plasma etching can include carbon dioxide and/or other gasses. Once one or more surface regions of the medical device have been treated, one or more coatings of polymer and/or biological agent can be applied to one or more regions of the medical device. For instance, 1) one or more layers of porous or non-porous polymer can be coated on the medical device, 2) one or more layers of biological agent can be coated on the medical device, or 3) one or more layers of porous or non-porous polymer that includes one or more biological agents can be coated on the medical device. The one or more layers of biological agent can be applied to the medical device by a variety of techniques (e.g., dipping, rolling, brushing, spraying, particle atomization, etc.). One non-limiting coating technique is by an ultrasonic mist coating process wherein ultrasonic waves are used to break up the droplet of biological agent and form in a mist of very fine droplets. These fine droplets have an average droplet diameter of about 0.1-3 microns. The fine droplet mist facilitates in the formation of a uniform coating thickness and can increase the coverage area on the medical device.
[0075] In still yet another and/or additional non-limiting aspect of the present invention, one or more portions of the medical device can 1) include the same or different biological agents, 2) include the same or different amount of one or more biological agents, 3) include the same or different polymer coatings, 4) include the same or different coating thicknesses of one or more polymer coatings, 5) have one or more portions of the medical device controllably release and/or uncontrollably release one or more biological agents, and/or 6) have one or more portions of the medical device controllably release one or more biological agents and one or more portions of the medical device uncontrollably release one or more biological agents.
[0076] In still yet another and/or alternative non-limiting aspect of the present invention, the polymeric covering, the biological agent or any combination thereof can be biodegradable and has degradable properties. Suitable polymeric or other materials can have a certain tensile strength and/or other mechanical properties to enhance the physical properties of the stent; however, this is not required. Non-limiting examples of the properties of the polymeric coatings include, but are not limited to, 1) a polymer having sufficient mechanical properties that match the application, remaining sufficiently strong until the surrounding tissue has healed, 2) a polymer that does not invoke an inflammatory or toxic response, 3) a polymer that is metabolized in the body after fulfilling its purpose, leaving little no trace, 4) a polymer that is easily processable into the final product form, 5) a polymer that demonstrates acceptable shelf life, and/or 6) a polymer that is easily sterilized. As can be appreciated, when one or more biological agents are included on the medical device, the one or more biological agents can be used to at least partially control the rate of degradation of the biodegradable polymer when a biodegradable polymer is used; however, this is not required.
[0077] Suitable non-limiting examples of acceptable biodegradable polymers include: polyglycolide (PGA), polylactide (PLA), poly([epsilon]-caprolactone), poly(dioxanone) (a polyether-ester), poly(lactide-co-glycolide), as well as other homopolymers or copolymers of glycolide, lactide, caprolactone, p-dioxanone, and tri methylene carbonate.
[0078] In yet another and/or additional non-limiting aspect of the invention, the medical device can include a marker material that facilitates enabling the medical device to be properly positioned in a body passageway. The marker material is typically designed to be visible to electromagnetic waves (e.g., x-rays, microwaves, visible light, inferred waves, ultraviolet waves, etc.); sound waves (e.g., ultrasound waves, etc.); magnetic waves (e.g., MRI, etc.); and/or other types of electromagnetic waves (e.g., microwaves, visible light, inferred waves, ultraviolet waves, etc.). In one non-limiting embodiment, the marker material is visible to x-rays (i.e., radiopaque). The marker material can form all or a portion of the medical device and/or be coated on one or more portions (flaring portion and/or body portion; at ends of medical device; at or near transition of body portion and flaring section; etc.) of the medical device.
[0079] The location of the marker material can be on one or multiple locations on the medical device. The size of the one or more regions that include the marker material can be the same or different. The marker material can be spaced at defined distances from one another so as to form ruler like markings on the medical device to facilitate in the positioning of the medical device in a body passageway. The marker material can be a rigid or flexible material. The marker material can be a biostable or biodegradable material. When the marker material is a rigid material, the marker material is typically formed of a metal material (e.g., metal band, metal plating, etc.); however, other or additional materials can be used. The metal which at least partially forms the medical device can function as a marker material; however, this is not required.
[0080] The marker material can be coated with a polymer protective material; however, this is not required. When the marker material is coated with a polymer protective material, the polymer coating can be used to 1) at least partially insulate the marker material from body fluids, 2) facilitate in retaining the marker material on the medical device, 3) at least partially shielding the marker material from damage during a medical procedure and/or 4) provide a desired surface profile on the medical device. As can be appreciated, the polymer coating can have other or additional uses. The polymer protective coating can be a biostable polymer or a biodegradable polymer (e.g., degrades and/or is absorbed). The coating thickness of the protective coating polymer material, when used, is typically less than about 300 microns; however, other thickness can be used. In one non-limiting embodiment, the protective coating materials include parylene, PLGA, POE, PGA, PLLA, PAA, PEG, chitosan and/or derivatives of one or more of these polymers.
[0081] In another and/or additional non-limiting aspect of the present invention, other or additional manufacturing techniques can be used. The medical device can include one or more surface structures (e.g., pore, channel, pit, rib, slot, notch, bump, teeth, well, hole, groove, etc.). These structures can be at least partially formed by other types of technology.
[0082] In still another and/or additional non-limiting aspect of the invention, the medical device can be used in conjunction with one or more other biological agents that are not on the medical device. For instance, the success of the medical device can be improved by infusing, injecting or consuming orally one or more biological agents. Such biological agents can be the same and/or different from the one or more biological agents on and/or in the medical device. Such use of one or more biological agents are commonly used in systemic treatment of a patient after a medical procedure such as body wide after the medical device has been inserted in the treatment area can be reduced or eliminated by use of the novel alloy.
[0083] Although the medical device of the present invention can be designed to reduce or eliminate the need for long periods of body wide therapy after the medical device has been inserted in the treatment area, the use of one or more biological agents can be used in conjunction with the medical device to enhance the success of the medical device and/or reduce or prevent the occurrence of in-stent restenosis, vascular narrowing, and/or thrombosis. For instance, solid dosage forms of biological agents for oral administration, and/or for other types of administration (e.g., suppositories, etc.) can be used. Such solid forms can include, but are not limited to, capsules, tablets, effervescent tablets, chewable tablets, pills, powders, sachets, granules and gels. The solid form of the capsules, tablets, effervescent tablets, chewable tablets, pills, etc. can have a variety of shapes such as, but not limited to, spherical, cubical, cylindrical, pyramidal, and the like. In such solid dosage form, one or more biological agents can be admixed with at least one filler material such as, but not limited to, sucrose, lactose or starch; however, this is not required. Such dosage forms can include additional substances such as, but not limited to, inert diluents (e.g., lubricating agents, etc.).
[0084] When capsules, tablets, effervescent tablets or pills are used, the dosage form can also include buffering agents; however, this is not required. Soft gelatin capsules can be prepared to contain a mixture of the one or more biological agents in combination with vegetable oil or other types of oil; however, this is not required. Hard gelatin capsules can contain granules of the one or more biological agents in combination with a solid carrier such as, but not limited to, lactose, potato starch, corn starch, cellulose derivatives of gelatin, etc; however, this is not required. Tablets and pills can be prepared with enteric coatings for additional time release characteristics; however, this is not required. Liquid dosage forms of the one or more biological agents for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc.; however, this is not required. In one non-limiting embodiment, when at least a portion of one or more biological agents is inserted into a treatment area (e.g., gel form, paste form, etc.) and/or provided orally (e.g., pill, capsule, etc.) and/or anally (suppository, etc.), one or more of the biological agents can be controllably released; however, this is not required. In one non-limiting example, one or more biological agents can be given to a patient in solid dosage form and one or more of such biological agents can be controllably released from such solid dosage forms. In another and/or alternative non-limiting example trapidil, trapidil derivatives, taxol, taxol derivatives, cytochalasin, cytochalasin derivatives, paclitaxel, paclitaxel derivatives, rapamycin, rapamycin derivatives, 5-Phenylmethimazole, 5-Phenylmethimazole derivatives, GM-CSF, GM-CSF derivatives, or combinations thereof are given to a patient prior to, during and/or after the insertion of the medical device in a treatment area.
[0085] Certain types of biological agents may be desirable to be present in a treated area for an extended period of time in order to utilize the full or nearly full clinical potential the biological agent. For instance, trapidil and/or trapidil derivatives is a compound that has many clinical attributes including, but not limited to, anti-platelet effects, inhibition of smooth muscle cells and monocytes, fibroblast proliferation and increased MAPK- 1 which in turn deactivates kinase, a vasodilator, etc. These attributes can be effective in improving the success of a medical device that has been inserted at a treatment area. In some situations, these positive effects of trapidil and/or trapidil derivatives need to be prolonged in a treatment area in order to achieve complete clinical competency. Trapidil and/or trapidil derivatives has a half life in vivo of about 2-4 hours with hepatic clearance of 48 hours. In order to utilize the full clinical potential of trapidil and/or trapidil derivatives, trapidil and/or trapidil derivatives should be metabolized over an extended period of time without interruption; however, this is not required.
[0086] By inserting trapidil and/or trapidil derivatives in a solid dosage form, the trapidil and/or trapidil derivatives could be released in a patient over extended periods of time in a controlled manner to achieve complete or nearly complete clinical competency of the trapidil and/or trapidil derivatives. These biological agents can be at least partially encapsulated in one or more polymers, as with the biological agents on the medical device described above. The rate of degradation of the polymer is principally a function of 1) the water permeability and solubility of the polymer, 2) chemical composition of the polymer and/or biological agent, 3) mechanism of hydrolysis of the polymer, 4) the biological agent encapsulated in the polymer, 5) the size, shape and surface volume of the polymer, 6) porosity of the polymer, 7) the molecular weight of the polymer, 8) the degree of cross-linking in the polymer, 9) the degree of chemical bonding between the polymer and biological agent, and/or 10) the structure of the polymer and/or biological agent. As can be appreciated, other factors may also affect the rate of degradation of the polymer.
[0087] When the one or more polymers are biostable, the rate at when the one or more biological agents are released from the biostable polymer is a function of 1) the porosity of the polymer, 2) the molecular diffusion rate of the biological agent through the polymer, 3) the degree of cross-linking in the polymer, 4) the degree of chemical bonding between the polymer and biological agent, 5) chemical composition of the polymer and/or biological agent, 6) the biological agent encapsulated in the polymer, 7) the size, shape and surface volume of the polymer, and/or 8) the structure of the polymer and/or biological agent. As can be appreciated, other factors may also affect the rate of release of the one or more biological agents from the biostable polymer. Similar or different polymers than those described above for use with the medical device can be used. As can be appreciated, the at least partially encapsulated biological agent can be introduced into a patient by means other than by oral introduction, such as, but not limited to, injection, topical applications, intravenously, eye drops, nasal spray, surgical insertion, suppositories, intrarticularly, intraocularly, intranasally, intradermally, sublingually, intravesical̂, intrathecal ly, intraperitoneally, intracranially, intramuscularly, subcutaneously, directly at a particular site, and the like.
[0088] One or more biological agents, when used, can be released from the medical device for at least about one week after the medical device is inserted in the body of a patient, more typically at least about two weeks after the medical device is inserted in the body of a patient, and even more typically about one week to one year after the medical device is inserted in the body of a patient. As can be appreciated, the time frame that one or more of the biological agents can be released from the medical device can be longer or shorter. The time period for the release of two or more biological agents from the medical device can be the same or different.
[0089] The type of the one or more biological agents used on the medical device, the release rate of the one or more biological agents from the medical device, and/or the concentration of the one or more biological agents being released from the medical device during a certain time period is typically selected to deliver one or more biological agents directly to the area of disease after the medical device has been implanted; however, this is not required. In one non-limiting design of medical device, the medical device releases one or more biological agents over a period of time after being inserted in the body after the medical device has been implanted. In another non-limiting design of medical device, the medical device releases one or more biological agents over a period of time after being inserted in the body so that no further drug therapy is required about two weeks to one month after the medical device has been implanted.
[0090] In one non-limiting design of medical device, the medical device releases one or more biological agents over a period of up to one day after the medical device has been implanted. In still yet another non-limiting design of medical device, the medical device releases one or more biological agents over a period of up to one week after the medical device has been implanted. In further another non-limiting design of medical device, the medical device releases one or more biological agents over a period of up to two weeks after the medical device has been implanted. In still a further non-limiting design of medical device, the medical device releases one or more biological agents over a period of up to one month after the medical device has been implanted. In yet a further non-limiting design of medical device, the medical device releases one or more biological agents over a period of up to one year after the medical device has been implanted. As can be appreciated, the time or release of one or more biological agents from the medical device can be more than one year after the medical device has been implanted.
[0091] Typically the introduction of one or more biological agents used for anti-platelet and/or anti-coagulation therapy from a source other than the medical device is about one day after the medical device has been implanted in a patent, and typically up to about one week after the medical device has been implanted in a patent, and more typically up to about one month after the medical device has been implanted in a patent; however, it can be appreciated that periods of up to 2-3 months or more can be used.
[0092] The stent is at least partially formed of an alloy that includes a majority of Ta and W. For example, the metal alloy can include about 90-97.5 weight percent Ta and 2.5-10 weight percent W (i.e., 92.5% Ta-7.5% W). The stent can be formed by use of several processes. For instance, a tube of TaW alloy can be formed by a vacuum arc melting process in which the formed alloy extruded and processed into a rod, or metal power can be consolidated into the alloy isostatic pressing and sintering at high temperatures under a vacuum. The formed rod cut into lengths of about 20-48 inches (i.e., 36 inches). The diameter of the rod may be up to about 0.1 inches (e.g., 0.0625 inches). The solid rod can be drilled to form a tube having the desired inner and outer diameters and wall thickness. The tube can be chemically cleaned (e.g., 2-98% nitric acid and 2-98% hydrochloric acid, 50% nitric acid and 50% hydrochloric acid). Generally, the cut tube is wrapped in niobium foil to reduce contamination if shipped to another location for annealing. The TaW alloy is annealed at about 2600-2800° F. under a vacuum of no greater that about 5-10 Torr.
[0093] Horizontal or vertical furnaces can be used for the annealing process, for a period of about 60 minutes. The annealed tube is processed to a final diameter (e.g., pilgering and drawing of no more than about 60% working reduction between annealing processes, etc.). The drawing of the tube can be at room or ambient temperature (i.e., 60-90° F.). The tube may be processed until the wall thickness of the tube up to about 0.0025 inches (i.e., 0.0018-0.002 inches). For example, the original tube diameter may be about 0.003-0.008 inches, and is preferably processed to a thickness of no more than about 0.0025 inches, although the original diameter of the tube can of course be greater than this.
[0094] Once the tube has been processed to its final or near final diameter, the tube is cleaned and polished by an electro-polishing process using sulfuric acid and hydrofluoric acid (i.e., 60-95% sulfuric and 5-40 hydrofluoric, 85% sulfuric and 15% hydrofluoric at 60-100° F. and at a current of 15-30 milliamps). After the tube is polished, the medical device can be formed by cutting the tube (e.g., laser cutting at about 2800-32000° C. in a helium and/or argon containing environment) As can be appreciated, other or additional manufacturing processes can be used to form the stent. The grain size of the metal alloy is about 8-14 ASTM. The stent can include one or more coating and/or one or more surface structures and/or micro-structures. Other processing steps for the TaW alloy that can be used in the present invention are disclosed in U.S. Pat. Publ. No. 2006/0264914, which is incorporated herein.
[0095] One non-limiting object of the present invention is the provision of a medical device that is formed of a metal alloy that includes zirconium, tantalum, niobium and/or tungsten.
[0096] Still another and/or additional non-limiting object of the present invention is the provision of a medical device having improved procedural success rates.
[0097] Yet another and/or additional non-limiting object of the present invention is the provision of a medical device that is simple and cost effective to manufacture.
[0098] Another and/or additional non-limiting object of the present invention is the provision of a medical device that is at least partially formed of, contains, and/or is coated one or more biological agents.
[0099] Still yet another and/or additional non-limiting object of the present invention is the provision of a medical device that controllably releases one or more biological agents.
[0100] A further and/or additional non-limiting object of the present invention is the provision of a medical device that is at least partially coated with one or more polymer coatings.
[0101] Yet a further and/or additional non-limiting object of the present invention is the provision of a medical device that has one or more polymer coatings to at least partially control the release rate of one or more biological agents.
[0102] Still a further and/or additional non-limiting object of the present invention is the provision of a medical device that at least partially control the release rate of one or more biological agents by molecular diffusion.
[0103] A further and/or additional non-limiting object of the present invention is the provision of a medical device that has one or more polymer coatings and/or one or more coating or biological agent that is used to at least partially control the rate of degradation of a biodegradable material on the medical device.
[0104] Another and/or additional non-limiting object of the present invention is the provision of a medical device that is in the form of a stent.
[0105] Yet another and/or additional non-limiting object of the present invention is the provision of a medical device that includes one or more markers.
[0106] Still yet another and/or additional non-limiting object of the present invention is the provision of a medical device that includes and/or is used with one or more physical hindrances.
[0107] Still a further and/or additional non-limiting object of the present invention is the provision of a medical device that can be used in conjunction with one or more biological agents not on or in the medical device.
[0108] Still yet another and/or additional non-limiting object of the present invention is the provision of a medical device that includes one or more structural component having varying thicknesses, configurations, and/or surface features so as to affect rate and/or degree at which the medical expands and/or retains its shape in a body passageway.
[0109] These and other advantages will become apparent to those skilled in the art upon the reading and following of this description taken together with the accompanying drawings.
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Medical devices having special geometrical design features and possible surface modifications and can be comprised of niobium, tantalum, zirconium and/or tungsten alloy which is useful in treating a body passageway.
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FIELD
[0001] This disclosure relates to a filter element, in particular a fuel filter element, configured with automatic air bleeding features.
BACKGROUND
[0002] For heavy-duty diesel engines where achieving maximum fuel pressure is desired, any trapped air within large fuel housings can pose a great engineering challenge. Air can become trapped within the fuel housing in a number of ways, including as a result of a new filter element being installed in the housing and air entrained in fuel entering the fuel filter housing.
[0003] Manual external or internal air-bleed valves have been developed to purge air outside of the filter housing. Various automatic air bleeding fuel filter designs are also known. The use of external air-bleed valves can present additional possibilities of functional failure where fuel-leaks could occur. Moreover, to manually bleed air out, some amount of fuel can spill out of the housing posing safety risks to the operator. The same safety risks apply to draining the fuel manually out of the housing during filter replacement.
[0004] In addition, fuel supply to a high pressure fuel pump typically utilizes part of the returned fuel from an in-built reservoir of the fuel filter housing which could contain air that's already vented out from the fuel filter housing. Some of this air can make it back into the Stage-1 filter through the standpipe which is on the upstream or dirty side of the filter media. If the media air-vent is located on the downstream or “clean-side” of the filter media, then the air-vent functionality will be reduced or eliminated altogether and air from the fuel supply could cause engine performance issues if it does not get vented out.
SUMMARY
[0005] A filter element is described that is provided with automatic air bleeding features to efficiently bleed air from a filter housing containing the filter element. The described filter element and filter housing requires no manual air-bleeding from the fuel module during its service. To facilitate the description, the filter element will be specifically described as being a fuel filter element. However, the concepts described herein are applicable to any type of filter element/filter housing application where air needs to be bled from the filter housing.
[0006] Both stage-1 and stage-2 fuel filters will be described herein. The stage-1 filter element is described as having a first or upper end cap with two air vents, an inner air vent and a media air vent. The media air vent provides a bypass for air through wet filter media through which air from the fuel supply may not be able to pass through easily. The inner air vent is provided on both the stage-1 and the stage-2 fuel filters. In each case, the inner air vent is located on the inside of a circle formed by attachment clips that attach the respective filter element to a removable receptacle cover. The inner air vent allows for air inside the filter housing to be easily purged out via a drain hole on the fuel filter housing, while providing resistance to fuel. The drain hole is provided on the filter housing which is internally connected to the fuel outlet and therefore to the fuel tank. The removable filter element therefore needs to provide a hermetic passage from the upper end cap, through a center tube of the filter element, and through a bottom end cap.
[0007] In one embodiment, the stage-1 fuel filter can also use locating features to help locate the media air vent on the upstream or dirty side of the filter media. In particular, the center tube of the stage 1 filter element includes a pleat separation element, for example a wedge-shaped feature, that helps to separate two adjacent pleats between which the media air vent will be located. In addition, the center tube will include an alignment element that interacts with a corresponding alignment element on the upper end cap to help appropriately locate the media air vent on the upstream or dirty side of the filter element between the two adjacent pleats.
[0008] In one example, a filter element comprises a ring of filtration media having a first end and a second end and circumscribing a central cavity. A first end cap is sealingly attached to the first end of the filtration media, with the first end cap including a vent passageway. In addition, a second end cap is sealingly attached to the second end of the filtration media, with the second end cap including a plurality of vent openings extending therethrough. A center tube is disposed within the central cavity, with the center tube having a first end connected to the first end cap and a second end connected to the second end cap. The center tube further includes a fuel passageway and an air vent passageway, with the air vent passageway being fluidly separated from the fuel passageway and the air vent passageway being in fluid communication with the vent passage in the first end cap and with the vent openings in the second end cap. Also, first and second seals are attached to the second end cap, with the first seal being located radially inward of the second seal, the first seal being disposed within an opening formed in the second end cap, the second seal being disposed in a second opening formed by the second end cap, and the vent openings in the second end cap being between the first seal and the second seal.
[0009] When the filtration media is pleated, the filtration media has an unfiltered fluid side and a filtered fluid side, and the first end cap further includes a media vent passage radially outward from the vent passage. The media vent passage is disposed on the unfiltered side of the media between two of the pleats. To facilitate proper positioning of the vent passage, a pleat separation element can be formed on the center tube adjacent to the first end thereof and adjacent to the media vent passage on the first end cap, with the pleat separation element being disposed between the two pleats. The pleat separation element helps to separate the two pleats so that the media vent passage is properly located on the dirty or unfiltered fluid side of the filtration media between the two pleats.
[0010] In addition, an alignment element can be provided at the first end of the center tube that is engaged with a corresponding alignment element on the first end cap. The alignment elements help to ensure proper orientation of the center tube, to help properly position the pleat separation element relative to the media vent passage.
[0011] The filter element can include other elements as well, such as an outer coalescing element surrounding the filtration media. The outer coalescing element has a first end connected to the first end cap and a second end connected to the second end cap.
DRAWINGS
[0012] FIG. 1 illustrates a fuel filter described herein removably installed within a respective receptacle in a fuel filter module.
[0013] FIG. 2 is a cross-sectional view of the fuel filter element of FIG. 1 .
[0014] FIG. 3 is an exploded view of the components of the fuel filter element of FIG. 1 .
[0015] FIG. 4 is a detailed view illustrating the air bleed path near the base of the fuel filter.
[0016] FIG. 5 is a partially exploded view of the fuel filter element illustrating a pleat spacer on the center tube of the fuel filter element.
[0017] FIG. 6 is a side view of the center tube of the fuel filter element of FIG. 5 .
[0018] FIG. 7 is an end view of the center tube of the fuel filter element of FIG. 5 illustrating alignment features on the end of the center tube.
[0019] FIG. 8 is a close-up view of the engagement between the center tube and the upper end plate of the fuel filter element of FIG. 5 .
[0020] FIG. 9 illustrates another embodiment of a fuel filter element described herein removably installed within a respective receptacle in the fuel filter module.
[0021] FIG. 10 is a cross-sectional view of the fuel filter element of FIG. 9 .
[0022] FIG. 11 is an exploded view of the components of the fuel filter element of FIG. 9 .
[0023] FIG. 12 is a view similar to FIG. 9 but showing partial removal of the fuel filter element from its receptacle in the fuel filter module.
[0024] FIG. 13 is a cross-sectional view of another embodiment of a stage 1 fuel filter element disposed on a standpipe.
[0025] FIG. 14 is a cross-sectional view of the fuel filter element in FIG. 13 .
[0026] FIG. 15 is a view of the upper end of the center tube of the fuel filter element of FIG. 13 .
[0027] FIG. 16 illustrates an alignment feature and vent passageway formed in the upper end cap of the fuel filter element of FIG. 13 .
[0028] FIG. 17 illustrates the venting of air from the filtration media through the end cap of the fuel filter element of FIG. 13 .
[0029] FIG. 18 illustrates the flow of vented air through the base end of the fuel filter element of FIG. 13 .
[0030] FIG. 19 illustrates another embodiment similar to FIG. 18 .
[0031] FIG. 20 is a cross-sectional view of another embodiment of a stage 2 fuel filter element disposed on a standpipe.
[0032] FIG. 21 is a cross-sectional view of the fuel filter element of FIG. 20 .
DESCRIPTION
[0033] FIGS. 1-8 illustrate a stage 1 fuel filter assembly 10 that includes a fuel filter element 12 removably installed within a receptacle 14 of a fuel filter module. A stage 2 fuel filter assembly 200 is illustrated in FIGS. 9-12 . The stage 1 filter element 12 is an inside-out flowing filter, while a stage 2 filter element 208 , discussed further below, is an outside-in flowing filter. The stage 1 filter element 12 and the stage 2 filter element 208 are mounted within respective receptacles of a filter module in a side-by-side relationship and work in series. The receptacles for the filter elements are in communication with one another and effectively form a single larger cavity.
[0034] In operation, fuel that is filtered by the stage 1 filter element 12 flows from the receptacle for the stage 1 filter element into the receptacle for the stage 2 filter element 208 . Fuel exiting out a lift pump (for example, a gear pump) has finely dispersed water droplets that the stage 1 filter's media material coalesces from smaller droplets into bigger drops which finally sink to the lower-most portion of the filter module. The stage 2 filter media removes finer hard particles. The stage 2 filter also strips out water droplets that make it through from the stage 1 filter. Filtered fuel exiting out of the stage 2 filter is then routed to a high pressure pump.
[0035] With reference to FIG. 1 , the receptacle 14 includes a fixed housing 16 and a removable cover 18 that is removably attached to the fixed housing, for example using threads. In use, the cover 18 is attached to the fixed housing 16 so that the two define an interior volume sufficient to receive the fuel filter element 12 . The cover 18 is sealed with the fixed housing 16 to prevent fuel leaks from the interior thereof. The cover 18 can be removed from the fixed housing to access the interior volume for removal of the filter element.
[0036] As shown in FIGS. 1 and 4 , the fixed housing 16 includes a base end 20 and a standpipe 22 extends upwardly from the base end 20 into the interior of the fixed housing. In this embodiment, the standpipe 22 forms an inlet for fuel to be introduced into the fuel filter assembly 10 . The base 20 also includes a drain hole(s) 24 that is in fluid communication with the fuel tank or other fuel storage location through which air and/or fuel mixed with air is returned to the fuel tank after being vented from the fuel filter.
[0037] The cover 18 also includes attachment structure 26 defined on the interior thereof that detachably engages with corresponding structure formed at the upper end of the filter element 12 so that when the cover 18 is removed, the filter element 12 is removed with the cover 18 . The filter element 12 can then be removed from the cover for replacement. Attachment structures between a removable cover and a filter element for removing the filter element when the cover is removed are known in the art.
[0038] Turning now to the filter element 12 , the filter element is designed to filter the incoming fuel entering through the standpipe 22 prior to the fuel flowing to the stage 2 filter 200 . In the illustrated embodiment, the filter element is designed for inside-out flow with the fuel entering through the standpipe 22 , flowing generally radially outward through the filter element which filters the fuel, and then flowing to and through the stage 2 filter element before exiting out through a fuel outlet.
[0039] With reference to FIGS. 1-3 , the filter element 12 includes a ring of filtration media 30 , a first or upper end cap 32 , a second or lower end cap 34 , and a center tube 76 . The filtration media 30 has a first or upper end 40 and a second or lower end 42 and circumscribes a central cavity 44 . In the illustrated embodiment, the filtration media 30 is pleated and is generally cylindrical in construction, although other forms and shapes of filtration media can be used.
[0040] The first end cap 32 is sealingly attached to the first end 40 of the filtration media using any suitable attachment method, for example using an adhesive or embedding the end 40 into the end cap 32 which can be made of plastic or metal. The first end cap 32 is a closed end cap in that fuel is not intended to flow through the end cap 32 . However, as described further below, the end cap 32 includes an air vent passageway 46 and a media air vent 48 which permit venting of air through the end cap 32 .
[0041] As best seen in FIGS. 2 and 3 , the end cap 32 includes a plate section 50 that is attached to the first end 40 of the filtration media 30 . The plate section 50 surrounds a skirt 52 that includes a portion 54 extending downwardly into the central cavity 44 and a portion 56 that extends upwardly. A plate 58 extends across the skirt portion 56 to close the skirt 52 . A plurality of resilient fingers 60 extend upwardly from the plate 58 for engagement with the attachment structure 26 on the cover 18 to connect the filter element 12 to the cover 18 .
[0042] As shown in FIG. 2 , the air vent passageway 46 is formed in and extends through the plate 58 . This provides fluid communication between the upper end of the interior of the fuel filter assembly 10 and the central cavity 44 so that air from the upper end of the fuel filter can vent into the central cavity 44 .
[0043] In addition, the media air vent 48 is formed in the plate section 50 so that it is located radially outward from the air vent passageway 46 . As will be discussed further below, the media air vent 48 is disposed on the unfiltered side of the filtration media 30 between two of the pleats.
[0044] The second end cap 34 is sealingly attached to the second end 42 of the filtration media using any suitable attachment method, for example using an adhesive or embedding the end 42 into the end cap 34 which can be made of plastic or metal.
[0045] With reference to FIGS. 2-4 , the second end cap 34 includes a plate section 62 that is attached to the second end 42 of the filtration media 30 . The plate section 62 surrounds a skirt 64 that includes a portion 66 extending downwardly and a portion 68 that extends upwardly. A circumferential wall 70 extends radially inwardly from the skirt 64 , and a second skirt portion 72 extends upwardly from the inner edge of the circumferential wall 70 spaced from and substantially parallel to the skirt portion 68 . As best seen in FIG. 4 , a plurality of vent openings 74 are formed in and extend through the wall 70 to place the space between the skirt portions 68 , 72 in fluid communication with the opposite side of the end cap 34 .
[0046] Returning to FIGS. 2 and 3 , a center tube 76 is disposed within the central cavity 44 . The center tube 76 has a first end 78 sealingly connected to the first end cap 32 and a second end 80 sealingly connected to the second end cap 34 . In particular, the first end 78 is attached to the skirt portion 54 of the end cap 32 and the second end 80 is attached to the skirt portion 68 (see FIG. 4 ). The attachment between the end 78 and the skirt portion 54 , and between the end 80 and the skirt portion 68 , can be accomplished in any suitable manner so long as fluid leakage between the surfaces is prevented, for example a friction fit, using adhesive, welding or combinations thereof.
[0047] The center tube 76 further includes a fuel passageway 82 and one or more air vent passageways 84 . The passageways 82 , 84 are defined by a wall 86 within the center tube 76 that defines an opening 87 that extends from one side of the center tube to the other for fuel to be filtered to enter into the central cavity 44 of the filter media 30 . At the base of the wall 86 a cylindrical tube 88 is formed through which the standpipe 22 can extend as shown in FIG. 4 .
[0048] As best seen in FIG. 4 , a first cylindrical gasket 90 is disposed between the tube 88 and the skirt portion 72 to seal between the tube 88 and the skirt portion 72 . The gasket 90 also includes a cylindrical portion 92 that projects radially inward beyond the tube 88 for sealing with the outer surface of the standpipe 22 . The base of the gasket 90 is supported by a small rib 94 that projects radially inwardly from the skirt portion 72 .
[0049] A second cylindrical gasket 96 is attached to the inner surface of the skirt portion 66 for sealing between the second end cap 34 and the base end 20 of the fixed housing 16 when the filter element is installed.
[0050] The first and second gaskets 90 , 96 can be secured in any suitable manner, for example using snap features, using an adhesive, or being overmolded onto the respective skirt portions.
[0051] Returning to FIGS. 2 and 3 , the filter element 12 can also include a coalescing element 98 surrounding the filtration media 30 and an outer support wrap 100 . The coalescing element 98 is designed to coalesce water from the fuel. The outer coalescing element 98 has a first end connected to the plate section 50 of the first end cap 32 and a second end connected to the plate section 62 of the second end cap 34 . However, use of the coalescing element is optional. The support wrap 100 helps to support the filtration media 30 and, if present, the coalescing element 98 .
[0052] As indicated above, the media air vent 48 is disposed on the unfiltered side of the filtration media 30 between two of the pleats. With reference to FIGS. 5-8 , to facilitate proper positioning of the media air vent 48 , a pleat separation element 102 is formed on the outer surface of the center tube 76 adjacent to the first end 78 thereof. When the center tube 76 is assembled into the filter element, the pleat separation element 102 is also adjacent to the media air vent 48 on the first end cap 32 as best seen in FIG. 8 .
[0053] As best seen in FIG. 6 , the pleat separation element 102 is a wedge-shaped element that projects from the outer surface of the center tube. As the center tube 76 is being installed into the filtration media 30 , the pleat separation element 102 fits between two adjacent pleats and separates those two pleats to create a larger space between the two pleats so that the media air vent 48 can more easily be positioned between the two pleats on the unfiltered or dirty side thereof.
[0054] In addition, alignment elements 104 a, 104 b are formed at the first end 78 of the center tube 76 and corresponding alignment elements 106 are formed on the skirt portion 54 . The alignment elements 104 a, 104 b, 106 help to ensure proper orientation of the center tube 76 , to help properly position the pleat separation element 102 relative to the media air vent 48 . In the illustrated embodiment, the alignment elements 104 a, 104 b comprise radially outward protruding channels formed on diametrically opposite sides of the center tube 76 , and the alignment elements 106 comprise correspondingly shaped protrusions formed on the skirt portion 54 that fit into the channels. As shown in FIG. 7 , the alignment elements 104 a, 104 b are of different size with the alignment element 104 a being larger than the alignment element 104 b. The alignment elements 106 would also have corresponding different sizes. Therefore, the center tube 76 can only be attached to the skirt portion 54 in the correct orientation.
[0055] Operation of the fuel filter assembly 10 will now be described with reference to FIG. 1 . Unwanted air can enter the receptacle 14 as a result of a new filter element 12 being installed and/or as a result of air entrained in fuel entering through the standpipe 22 . During operation, fuel to be filtered enters via the standpipe 22 , into the fuel passageway 82 , and through opening 87 into the central cavity of the filtration media. The fuel then flows radially outward through the filtration media which filters the fuel. If the coalescing element is present, the fuel flows through the coalescing element, and then passes through the stage 2 filter element 208 . Coalesced water drops sink to the lower most portion of the module where it can be drained through a suitable drain.
[0056] Air inside the housing 14 is shown by the diagrammatic bubbles in FIG. 1 . Air between the outer side of the filtration element and the inside of the filter housing and air at the upper end of the filter housing can vent through the air vent passageway 46 to the interior of the center tube 76 . Any air that enters through the standpipe and becomes trapped on the dirty side of the filtration media within the central cavity 44 can vent to the upper end of filter housing through the media air vent 48 and then vent through the air vent 46 into the interior of the center tube. Once in the center tube, the air flows down to the base of the filter element and through the vent opening(s) 74 and from there through the drain hole 24 back to the fuel tank.
[0057] With reference to FIGS. 9-12 , the stage 2 fuel filter assembly 200 will now be described. The fuel filter assembly 200 is somewhat similar in construction to the fuel filter assembly 10 , with one of the biggest differences being that the fuel filter element of the filter assembly 200 does not include a media air vent and has a different flow direction.
[0058] With reference to FIG. 9 , the fuel filter assembly 200 includes a receptacle 202 having a fixed housing 204 and a removable receptacle cover 206 that is removably attached to the fixed housing, for example using threads. In use, the cover 206 is attached to the fixed housing 204 so that the two define an interior volume sufficient to receive the fuel filter element 208 . The interior of the receptacle 202 is in fluid communication with the receptacle of the stage 1 filter so that fuel that has been filtered by the stage 1 filter flows into the receptacle 202 for filtration by the fuel filter element 208 . The cover 206 is sealed with the fixed housing 204 to prevent fuel leaks from the interior thereof. The cover 206 can be removed from the fixed housing to access the interior volume for removal of the filter element.
[0059] As shown in FIGS. 9 and 12 , the fixed housing 204 includes a base end and a standpipe 210 extends upwardly from the base end into the interior of the fixed housing. In this embodiment, the standpipe 210 forms an outlet for fuel that has been filtered by the fuel filter element 208 . The base also includes a drain hole(s) 212 that is in fluid communication with the fuel tank or other fuel storage location through which air and/or fuel mixed with air is returned to the fuel tank after being vented from the fuel filter. Fuel can also drain through the drain hole(s) 212 back to the fuel tank when the filter element 208 is lifted upward so that the fuel filter assembly 200 can auto-drain during filter element changes.
[0060] Similar to the filter assembly 10 , the cover 206 also includes attachment structure defined on the interior thereof that detachably engages with corresponding structure formed at the upper end of the filter element 208 so that when the cover 206 is removed, the filter element 208 is removed with the cover. The filter element can then be removed from the cover for replacement. Attachment structures between a removable cover and a filter element for removing the filter element when the cover is removed are known in the art.
[0061] Turning now to the filter element 208 , the filter element is designed to filter the fuel already filtered by the stage 1 filter element prior to the fuel exiting the fuel module through the standpipe 210 . Thus, in the illustrated embodiment, the filter element 208 is designed for outside-in flow with the fuel flowing generally radially inwardly through the filter element which filters the fuel, enters the standpipe 210 through suitable openings, and then flowing out through the standpipe 210 .
[0062] With reference to FIGS. 9-11 , the filter element 208 includes a ring of filtration media 214 , a first or upper end cap 216 , a second or lower end cap 218 , and a center tube 220 . The filtration media 214 has a first or upper end 222 and a second or lower end 224 and circumscribes a central cavity 226 . In the illustrated embodiment, the filtration media 214 is pleated and is generally cylindrical in construction, although other forms and shapes of filtration media can be used.
[0063] The first end cap 216 is sealingly attached to the first end 222 of the filtration media using any suitable attachment method, for example using an adhesive or embedding the end 222 into the end cap 216 which can be made of plastic or metal. The first end cap 216 is a closed end cap in that fuel is not intended to flow through the end cap. However, as described further below, the end cap 216 includes an air vent passageway 226 , similar to the air vent passageway 46 of the filter element 12 , which permits venting of air through the end cap.
[0064] As best seen in FIGS. 10 and 11 , the end cap 216 includes a plate section 230 that is attached to the first end 222 of the filtration media 214 . The plate section 230 surrounds a skirt portion 232 that extends downwardly into the central cavity 226 . A plate 234 extends across the skirt portion 232 from the inner end of the plate section 230 to close the skirt portion. As with the filter element 12 , a plurality of resilient fingers extend upwardly from the end cap 216 for engagement with the attachment structure on the cover 206 to connect the filter element to the cover.
[0065] As shown in FIG. 10 , the air vent passageway 226 is formed in and extends through the plate 234 . This provides fluid communication between the upper end of the interior of the fuel filter assembly 200 and the central cavity 226 so that air from the upper end of the fuel filter can vent into the central cavity 226 .
[0066] The second end cap 218 is sealingly attached to the second end 224 of the filtration media using any suitable attachment method, for example using an adhesive or embedding the end 224 into the end cap 218 which can be made of plastic or metal.
[0067] With reference to FIGS. 10-12 , the second end cap 218 includes a plate section 240 that is attached to the second end 224 of the filtration media 214 . The plate section 240 surrounds a skirt portion 242 extending downwardly. A circumferential wall 244 interconnects the plate section 240 and the skirt portion 242 , and a skirt portion 246 extends upwardly from the inner edge of the circumferential wall 244 . The skirt portion 246 has a sufficient radial thickness in which a plurality of axially extending vent openings 248 are formed that extend through the skirt portion to place the upper side of the skirt portion 246 in fluid communication with the opposite side of the end cap 218 .
[0068] Returning to FIGS. 10 and 11 , the center tube 220 is disposed within the central cavity 226 . The center tube 220 has a first end 250 sealingly connected to the first end cap 216 and a second end 252 sealingly connected to the second end cap 218 . In particular, the first end 250 is attached to the skirt portion 232 of the end cap 216 and the second end 252 is attached to the skirt portion 246 (see FIG. 10 ). The attachment between the end 250 and the skirt portion 232 , and between the end 252 and the skirt portion 246 , can be accomplished in any suitable manner so long as fluid leakage between the surfaces is prevented, for example a friction fit, using adhesive, welding or combinations thereof.
[0069] The center tube 220 further includes a fuel outlet passageway 254 and one or more air vent passageways 256 . The passageways 254 , 256 are defined by a wall 258 within the center tube 220 that defines an opening 260 that extends from one side of the center tube to the other for fuel that has been filtered to enter into the standpipe 210 . At the base of the wall 258 a cylindrical tube 262 is formed through which the standpipe 210 can extend as shown in FIGS. 9 and 12 .
[0070] As best seen in FIG. 10 , a first cylindrical gasket 264 is disposed between the tube 262 and the skirt portion 246 to seal between the tube and the skirt portion. The gasket 264 also includes a cylindrical portion 266 that projects radially inward beyond the tube 262 for sealing with the outer surface of the standpipe 210 .
[0071] A second cylindrical gasket 268 is attached to the inner surface of the skirt portion 242 for sealing between the second end cap 218 and the base end of the fixed housing 204 when the filter element is installed.
[0072] The first and second gaskets 264 , 268 can be secured in any suitable manner, for example using snap features, using an adhesive, or being overmolded onto the respective skirt portions.
[0073] Returning to FIGS. 10 and 11 , the filter element 208 can also include a hydrophobic screen 270 surrounding the filtration media 214 . The screen 270 is designed to remove water from the fuel. The screen 270 has a first end connected to the plate section 230 of the first end cap 216 and a second end connected to the plate section 240 of the second end cap 218 . However, use of the hydrophobic screen 270 is optional.
[0074] Operation of the fuel filter 200 will now be described with reference to FIGS. 9 and 12 . During operation, fuel from the stage 1 filter enters into the receptacle 202 , flows radially inwardly through the filtration media which filters the fuel. After being filtered, the fuel flows into the opening 260 in the center tube 220 and into a suitable opening(s) in the standpipe 210 , and then out through the standpipe.
[0075] Air inside the receptacle 202 is shown by the diagrammatic bubbles in FIG. 9 . Air between the outer side of the filtration element and the inside of the receptacle and air at the upper end of the filter housing can vent through the air vent passageway 226 to the interior of the center tube 220 . Once in the center tube, the air flows down to the base of the filter element and through the vent opening(s) 248 and from there through the drain hole(s) 212 back to the fuel tank.
[0076] In addition, as illustrated in FIG. 12 , upon removal of the cover 206 , the filter element 208 also gets lifted up. When the filter element is lifted up, the filter element is unseated from base of the fixed housing 204 , thereby exposing the drain hole(s) 212 . Any fuel remaining in the housing 204 can drain through the drain hole(s) 212 and back to the fuel tank.
[0077] With reference to FIGS. 13-18 , another embodiment of a stage 1 fuel filter element 300 is illustrated that is configured for inside-out fuel flow. The fuel filter element 300 includes a center tube 302 that is generally cage-like in construction, but which includes an air vent passageway 304 that extends from a first solid end section 306 to a second solid end section 308 . The end section 306 seals with a skirt portion 310 formed on an upper end cap 312 , while the end section 308 seals with a skirt portion 314 formed on a lower end cap 316 . The upper end cap 312 is formed with an air vent passageway 318 which allows vent air to enter into the space 320 defined by the skirt portion 310 , the solid end section 306 , the end cap 312 , and a plate 322 that closes off the upper end of the center tube 302 . The air can then flow into the passageway 304 and down towards the base of the filter element 300 .
[0078] In addition, the solid end section 306 and the skirt portion 310 are configured to allow air to vent from the dirty side of the filtration media and through the solid end section 306 and the skirt portion 310 into the space 320 as shown by the arrows in FIGS. 13 and 17 . With reference to FIGS. 15 and 16 , the solid end section 306 of the center tube 302 includes a pair of opposing slots 324 formed therethrough. The skirt portion 310 includes a pair of opposing small grooves 326 (only one groove is visible in FIG. 16 ) that extend through the skirt portion and that when properly assembled are positioned adjacent to the slots 324 . The skirt portion 310 also includes a pair of keys 328 that fit into the slots 324 for properly orienting the center tube 302 .
[0079] As shown in FIG. 17 , air that is introduced into the fuel filter module via fuel entering the standpipe 330 collects on the dirty side of the filtration media. The air is able to vent through the slots 324 and then through the grooves 326 into the space 320 where the air can then enter the air vent passageway 304 for venting from the filter module.
[0080] With reference to FIGS. 13-14 and 18 , the base of the filter element 300 will now be described. A gasket 332 is installed on an inside of the center tube 302 . A first plurality of tabs 334 project radially inwardly from the upper end of the skirt portion 314 , while a second plurality of tabs 336 project radially inwardly from a lower end of the skirt portion. The lower end of the gasket 332 can be supported by or spaced from the tabs 334 . A second gasket 338 is disposed between the tabs 334 and the tabs 336 for sealing with the base of the fuel filter module.
[0081] As shown in FIGS. 13 and 18 , fuel to be filtered enters via the standpipe 330 . The fuel then flows radially outwardly through the filtration media which filters the fuel. After being filtered, the fuel then flows to the stage 2 filter. Optionally, a coalescing element 340 can be provided around the filtration media for coalescing water in the fuel.
[0082] Air within the filter housing can vent from the module via the air vent passageway 318 into the space 320 and through the passageway 304 . Likewise, air on the dirty side of the filtration media can vent through the slots 324 , through the channels 326 , into the space 320 and through the passageway 304 . The air in the passageway 304 flows to the base of the filter element where it exits the passageway 304 , flows through gaps between the tabs 334 and into a drain 342 (see FIG. 13 ) in the base of the module which can be fluidly connected to the fuel tank.
[0083] FIG. 19 illustrates an embodiment that is similar to FIG. 18 , but instead of the first set of tabs 334 , a continuous flange 350 is provided with a plurality of holes 352 formed in the flange 350 to allow air to vent through the flange 350 and into the drain 342 .
[0084] With reference to FIGS. 20-21 , another embodiment of a stage 2 fuel filter element 400 is illustrated that is configured for outside-in fuel flow. The fuel filter element 400 is similar in construction to the fuel filter element 300 including the center tube 302 , vent air passageway 304 , the air vent passageway 318 in the upper end cap, and the like. Since the fuel filter element 400 is similar in construction to the fuel filter element 300 , the fuel filter element 400 need not be described in detail. However, the fuel filter element 400 does not include the slots and grooves to allow air to vent from the dirty side of the filtration media and through the solid end section 306 and the skirt portion 310 into the space 320 .
[0085] As shown in FIG. 20 , fuel to be filtered enters through an inlet. The fuel then flows radially inwardly through the filtration media which filters the fuel. After being filtered, the fuel then flows into one or more openings in a standpipe 402 and out of the module.
[0086] Air within the module can vent from the module via the air vent passageway 318 into the space 320 and through the passageway 304 . The air in the passageway 304 flows to the base of the filter element where it exits the passageway 304 , flow through gaps between the tabs 334 and into a drain 342 in the base of the housing which can be fluidly connected to the fuel tank.
[0087] Although the upper end cap has been described as having a single air vent passageway, such as the passageway 46 , more than one air vent passageway can be provided in any of the described embodiments. Likewise, although a single media air vent has been described, more than one media air vent can be provided in any of the described embodiments.
[0088] The invention may be embodied in other forms without departing from the spirit or novel characteristics thereof. The embodiments disclosed in this application are to be considered in all respects as illustrative and not limitative. The scope of the invention is indicated by the appended claims rather than by the foregoing description; and all changes which come within the meaning and range of equivalency of the claims are intended to be embraced therein.
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A filter element that is provided with automatic air bleeding features to efficiently bleed air from a fuel filter module containing the filter element. The filter element has an upper end cap with one or two air vents. One of the vents provides a bypass for air through wet filter media through which air from the fuel supply may not be able to pass through easily. The inner air vent is located on the inside of a circle formed by attachment clips that attach the respective filter element to a removable cover. The inner air vent allows for air inside the filter module to be easily purged out via a drain hole on the fuel filter module, while providing resistance to fuel. The drain hole is provided on the filter module which is internally connected to the fuel outlet and therefore to the fuel tank.
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This application is a continuation in part of Ser. No. 08/158,157, filed Nov. 24, 1993, now abandoned which is a continuation of application Ser. No. 07/791,962 filed Nov. 12, 1991 now abandoned.
(C) 1994 S. M. Lobodzinski Ph.D. 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 whatsoever.
FIELD OF THE INVENTION
This invention relates to a Motion Video Transformation System (MVTS) and methods used in medical fields such as cardiology, radiology, dentistry, neurophysiology, etc., and more specifically, to a transformation system and method for combining the acquisition, display, processing and storage of digital motion image sequences in real-time with physiological data indexing through the use of a mass storage device and real time digital video data compression and decompression
BACKGROUND OF THE INVENTION
Diagnostic advances in the field of medical imaging coupled with technological progress in digital storage media, digital processing of video, as well as audio data and Very Large Scale Integration (VLSI) device manufacturing, are converging to make the display, archiving, and transmission of digital video economical in a wide variety of medical applications.
Buffering, storage, and transmission of digitized video is a desired and critical feature for most medical applications. Because uncompressed digital video requires large amounts of bandwidth, memory, and storage space, video image compression is vital in the design of economically feasible display and archiving systems.
Recent studies of compressed cardiac ultrasonic and X-ray still images suggest that compression techniques have the potential to offer a compromise between traditional image recording techniques and economics of real-time diagnostic video compression. The advances in lossless and lossy video compression algorithms will further improve the quality of compressed video in the future.
Unlike in ordinary video signals, medical applications require a precise correlation of every video frame in a video sequence to physiological events occurring in the imaged anatomies or processes, and further require an adaptive adjustment of the frame rate to suit these display requirements. It is therefore diagnostically advantageous to think of a diagnostic video as a sequence of digital video events, each corresponding to a physiological phenomenon such as a heart contraction or relaxation.
For example, the practice of ultrasonography requires video recording of patient data for diagnostic and record keeping purposes. A typical ultrasonographic study comprise a small number of still images and few minutes of full motion video recording. Also, in special applications, the simultaneous display of multiple cardiac cycles, such that side-by-side comparisons of previously recorded video sequences can be made with live video sequences, is required during an examination for diagnostic purposes.
Often times, access to patient records in the form of digital motion video is required so that physicians of various specialties located in different areas can participate in the diagnostic or review process concurrently.
Although most diagnostic imaging systems provide some sort of cine' loop review, they typically do not provide digital motion video recording, serial comparison, and display functions. Typically, the video recording is accomplished by professional grade video tape recorders using Super-VHS (S-VHS) format tapes attached to the diagnostic imaging system (DIS).
Diagnostic video is recorded at a constant frame rate (FR) (typically 30 frames per second or fps) onto the video tape, and bears no relevance to the physiological function of the imaged anatomy or process, such as cardiac cycles. A tedious manual process is required to search through the video tape to identify the appropriate video frames corresponding to the systole or diastole. The video taped echocardiographic examination data, such as patient name, identification number, machine settings, etc., are available only in a visual format. In other words, this information cannot be used for databasing applications.
On the whole, the diagnostic video review process is very time consuming and difficult due to the operational limitations of the video cassette recorder. Copies of originally recorded diagnostic video result in image resolution degradation which renders them more difficult to interpret accurately. Also, video tapes require a lot of storage space, and degrade further with time. Thus, video tapes are not an ideal media for medical record keeping.
In another example, angiographic coronary arteriography and ventriculography studies are performed either to diagnose the presence of heart disease or to aid in a procedure called Percutaneous Transluminal Coronary Angioplasty (PTCA).
Although digital motion video capture and visualization systems for X-ray angiography do exist, they are significantly different from the system to be described herein. The present day digital angiography systems do not utilize real-time video data compression, nor do they store routinely data from the completed studies to a removable mass storage media. Rather, the images are stored to a large random access memory (RAM) based image buffer for instant replay and visualization. Only selected still images of arteriograms and venriculograms are archived to an optical disk. The size of the buffer varies, but rarely exceeds 120 seconds worth of full motion video. The images are also simultaneously recorded on 35 mm cine' film for archiving. The digital angiography motion image review systems usually allow for repetitive visualization of single contrast injections, but do not allow for visual serial comparisons of selected cardiac cycles from different contrast injections.
More recent X-ray imaging equipment currently utilizes charge coupled devices (CCD) in place of traditional fluoroscopy, with full digital image archiving of uncompressed digital motion video to a high bandwidth video tape recorder. However, the high cost of such recorders limit their application to playback on dedicated workstations only, and does not allow for digital video image transmission, serial comparisons, and display in a multiple window fashion. The availability of multiple cardiac cycle display would be particularly useful during a PTCA procedure so that the progress of plaque removal from the arteries (called revascularization) can be monitored.
Furthermore, in the standard practice of coronary angiography, a 35 mm cine' film recording is always made, regardless of any digital image storage capability, due to the need for inexpensive means of image review and overreading by a referring physician. Thus, since the patient examination data is typically available only in the cine' film and the digital media format, it is impossible or very difficult to integrate all of the pertinent data into digital transmission networks.
Real-Time Video Compression
Motion video compression techniques are based on one of two basic compression methods. The first method is the intra-frame compression method, and the second method is the inter-frame compression method.
In the intra-frame method, all of the compression is accomplished within a single video frame, whereas in the inter-frame process, all of the compression is accomplished between successive video frames since many areas in video frames often do not change from one frame to the next.
Several international standards for the compression of digital video signals have emerged over the past decade, with more currently under development. Several of these standards involve algorithms based on a common core of compression techniques, such as the Consultative Committee on International Telegraphy and Telephony (CCITT) Recommendation H.120, the CCITT Recommendation H.261, the ISO/IEC Joint Picture Expert Group (JPEG) standard, and the Moving Picture Experts Group (MPEG) standard. The MPEG algorithm was developed as part of a joint technical committee of the International Standards Organization (ISO) and the International Electrotechnical Commission (IEC).
Need For Compression
A typical color video frame (640×480×24 resolution) produced by a DIS consists of 307,200 pixels, wherein each pixel is defined by 24 bits (one of 16.7 million colors), thereby requiring 921,600 bytes of memory. To archive one minute of National Television Standards Committee (NTSC) motion video, for example, one needs 27,648,000 bytes of memory. Clearly, these requirements are outside the realm of realistic storage capabilities in diagnostic medicine.
Furthermore, the rate at which the data needs to be stored and retrieved in order to display motion vastly exceeds the effective transfer rate of existing storage devices. Retrieving full motion color video at a rate described above (30 megabytes/sec) from present day hard disk drives, assuming an effective hard disk transfer rate of about 1 megabyte per second, is 30 times too slow.
From a CD-ROM, assuming an effective transfer rate of 150 kilobytes per second, the rate is about 200 times too slow. Technological progress in the area of image compression techniques resulted in methods of video compression aimed at reducing the size of the data sets while retaining high levels of image quality.
From the point of view of video bandwidth considerations, video compression methods can be grouped into two categories. The first category results in data loss and is called the lossy method. The second category does not lose data and is called the lossless compression method. The lossy compression method does not preserve all of the information in the original data, but it can reduce the amount of data by a significant factor without affecting the image quality in a manner detectable by the human eye. The lossless image compression method allows for the mathematically exact restoration of the image data. However, in order to achieve high compression ratios and still maintain a high image quality, computationally intensive algorithms must be relied upon. A real time (compression of each frame performed in less than ×milliseconds) video compression may be implemented using a number of techniques known in the art. Due to the attractiveness of standardized compression methods, several implementation solutions are currently available.
Balkanski, et. al., U.S. Pat. No. 5,253,078, discloses the implementation of a data compression/decompression system using a discrete cosine transform (DCT) and its inverse transform (IDCT), which are provided to generate a frequency domain representation of the spatial domain waveforms representing the video image. This technique is known as a motion JPEG compression.
Gonzales, et. al, U.S. Pat. No. 5,231,484, discloses another implementation method for MPEG standard which relies on predictive/interpolative motion-compensated hybrid DCT/DPCM coding and quantization of the digital cosine transform (DCT)coefficients.
Another efficient motion image compression technique is disclosed by Israelsen, U.S Pat. No. 5,247,357, wherein vector quantization allows for compression ratios ranging anywhere from 20:1 to 100:1. Vector quantification efficiency stems from its role as a pattern-matching algorithm, in which an image is decomposed into two or more vectors, each representing particular features of the image that are matched to a code book of vectors and coded to indicate the best fit.
As the technology develops, other image compression techniques will emerge in the future which may find application in the methods and system described herein, and such use is contemplated.
Digital archiving of uncompressed digital video data directly from a display buffer of diagnostic imaging systems (DIS) is also possible on certain models. An example of such system is an ultrasound imaging system such as the Hewlett-Packard Sonos 1500. The digital video data is available in a digital format at the output of the Sonos 1500 in an uncompressed format for external storage to a disk media. Digital video is written directly to a magneto-optical disk drive for storage.
The image acquisition is gated by the R wave of ECG and recorded at 30 frames per second to the disk. A typical cine' loop of 30 frames requires 40 megabytes of disk space. The system of the present invention differs significantly from the Sonos 1500 since the functions of system of the present invention relate to video processing and visualization through the use of video transformation techniques. In particular the system of the present invention provides real-time video and audio compression/decompression, temporal domain processing, continuous video indexing with physiological signals, and synchronized real-time serial comparisons of previously recorded video with archived studies, as well as live videos. Furthermore, as a benefit of real-time video compression, the system of the present invention can store significantly more studies to the storage media than Sonos 1500. For example, if MPEG-1 compression algorithm is used for video compression, the amount of storage required for a full frame one cardiac cycle consisting of 30 frames is approximately 200 kilobytes as compared to 40 megabytes required by Sonos 1500.
In another specific ultrasonography application called stress echocardiography known in the art, short digital video clips corresponding to single cardiac cycles are field-frame grabbed synchronously with ECG to the solid state memory of the computer. Due to the large amounts of solid state memory required for uncompressed digital video, only portions (areas of interest) of the displayed even or odd fields can be acquired, beginning with 50 millisecond delay after the detection of a gating signal (ECG pulse output). Manual "grab" initiates the acquisition process. If the operator misses the optimal acquisition time, the critical information may be lost resulting in a non-diagnostic test. The number of cine' loops in the solid state memory is usually less than 60 for a total number of frames of 480. The visualization or display of the digitized cine' loop is possible only after post processing and the number of loops displayed in a side-by-side fashion is limited to four. The cine' loops cover approximately 450 milliseconds of the cardiac cycle, which for a slow beating heart, is usually limited to a systole. A typical protocol allows for 8 fields per cycle with an inter-frame delay of 50 ms. Selected systolic cycles comprising of 8 field each and corresponding to echocardiographic views acquired at different stages of the exercise protocol are then displayed in the form of a "quad screen", i.e., four cycles at a time.
Complete stress echocardiography studies consisting of 2 or more sets (e.g. pre-exercise and post-exercise) of data for areas of interest of four echocardiographic views comprising eight fields each could be fitted in a 1.44 megabytes floppy disk, or an optical disk drive after run length encoding. The "video" storage to disk and retrieval are not real-time.
An example of a stress echocardiography system described above is the Dextra DX, by Dextra Medical Inc.
The methods of the present inventions are distinctively different from the described methods of stress echocardiography. The system of the present invention utilizes real-time image compression to store digitized video to a disk media in a continuous real-time fashion thus making it possible to store the entire study with no possibility of losing data. The amount of to video stored on a disk media could be as much as 60 minutes, thus resulting in hundreds of thousands of frames. Also the system of the present invention acquires physiological signals, such as ECG or blood pressure, continuously and simultaneously with video, thus making it possible to perform real-time video temporal domain processing and display while preserving full information in recorded video. The side-by-side display of diagnostic video in scalable windows in the system of the present invention can accommodate more than four independent bit streams played back directly from the storage media, unlike the stress echo systems which can display only the content of the solid state memory. Thus, in discussing the background of the invention above, one can appreciate the need for a device which will address the problems with the current practice of medical digital motion video image recording and display. There is a need for providing an apparatus and method for combining the acquisition, display, and processing of diagnostic digital video in real-time with physiological data indexing through the use of a mass storage device and real-time digital motion video data compression and decompression.
SUMMARY OF THE INVENTION
The Motion Video Transformation System (MVTS) and method of the present invention attempts to provide a system and method for combining diagnostic digital motion video acquisition, display, and processing with physiological data indexing through utilization of techniques of digital motion video compression through domain transformation.
The MVTS and method of the present invention utilizes video compression/decompression (video transformation) as an algorithm implemented on a video processor using one or more of the various compression methods known and available in the art.
Without limiting the scope of the present invention and its numerous applications in the field of medicine, an example of the present invention is described wherein the diagnostic imaging system is an Ultrasound System (US), otherwise known as an ultrasonograph, and is used in the context of cardiac imaging.
The MVTS and method of the present invention can be viewed as a medical video processing, visualization, archiving, and telecommunication system suitable for use with medical imaging devices delivering motion video pictures of anatomy, or graphical representations of physiological processes. The MVTS comprises components or subsystems that operate to: (1) reduce the data content of motion video sequences using digital motion video compression methods known in the art; (2) assign physiological timing events to the video frames in a sequence; (3) create physiologically meaningful digital motion image loops based upon these physiological timing event indexes; (4) enhance the display of video data through spatial and temporal domain processing; (5) store compressed diagnostic video to a commonly available mass storage device in real-time; (6) retrieve the compressed diagnostic video from the common mass storage device in real-time; (7) provide means for incorporation of compressed digital motion video into a computerized patient record; and (8) provide means for tele-consultations, diagnosis, and video data interchange with Digital Image Communications in Medicine (DIACOM)-compatible devices, or other similar means, over common data links.
More specifically, one component implements real-time video frame indexing with one or more physiological timing event markers or physiological signals. The video indexing operations are applied independently of digital motion video compression which reduces the image data bandwidth while retaining optimal visual quality of the image.
Another component comprises a subsystem for performing digital motion video compression necessary to meet the target bit-rate for a particular application. Examples of such algorithms include, but are not limited to, motion JPEG, Wavelet, Vector Quantization, MPEG or other video compression standard.
Yet another component comprises the circuits necessary to input physiological signals and event markers, or timing indexes, to the processing system. Examples of such signals may include, but are not limited to, ECG, blood pressure, EEG, etc.
Yet another component comprises a computer with software implementing algorithms for temporal and spatial domain image processing, image attribute extraction from the video signal, optical character recognition from video signal, image formatting, video sequence and loop calculations, video archiving and video transmission.
Another component comprises a subsystem for implementing bi-directional signals for control and status sensing of imaging devices. The control signals allow the imaging devices and the system described in this invention to function together to timely display either playback or on-line data as responses to control keyboard commands.
Another component comprises a video display processor which allows for display of multiple digital motion video streams in respective scalable windows. This method applies to serial comparisons of digital motion video sequences, stress echocardiography and other modalities, requiring more than one video stream to be displayed simultaneously on the screen.
Another component comprises a set of peripherals such as video monitor, mass storage devices, data import/export circuits and pointing or remote control device connected to the computer. These peripherals provide means for compressed video image storage and transmission.
All cooperating components or subsystems operate compatibly with each other and each may be individually modified to accomplish the same task, without necessarily requiring the modification of any of the other subsystems.
The image indexing subsystem may be used by itself and each of the subsystems may also be used with other digital motion video image implementations such as uncompressed digital video.
Another significant difference is the ability of the system of the present invention to provide frame accurate rapid random access to archived digital video streams and real-time playback.
Accordingly, it is an object of the present invention to provide a new and improved system and method for real-time high resolution digital recording of full motion compressed color diagnostic imaging motion video indexed with physiological markers, such as EGG or blood pressure, to a common mass storage device.
It is a further object of the present invention to provide a system and method for faster video review and diagnostic process through random access to specific frames, cardiac cycles or selected digital motion video sequences, as well as instant playback of previously compressed still and full motion digital video.
An additional object of the present invention is to provide automatic extraction of video attributes from on-screen data such as patient name, identification number, calibration information, display mode, etc., for automatic digital motion video sequence indexing and archiving into a database.
Another object of the present invention is to provide a system and method for creating a complete digital motion video history archived onto an inexpensive high capacity digital removable media as an alternative to video tape and cine' film.
Yet another object of the present invention is to provide improved visualization of angiographic digital motion video with synchronous display of cardiac cycles from different injections.
Still another object of the present invention is to provide for an integrated cardiac ultrasound and angiography digital motion video database for archival and retrieval.
Another object of the present invention is to provide medical digital motion video such as ultrasonic and angiographic data in physiologically determined sequences, displayed simultaneously in multiple scalable windows for improved display and serial comparisons.
A further object of the present invention is to provide for transmission of digital full motion medical studies through remote data links or Local Area Networks utilizing HL-7, DIACOM, or other similar standards.
Further objects and advantages of the present invention will become apparent from a consideration of the drawings and ensuing description.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a block diagram of the MVTS of the present invention.
FIG. 2 is a block diagram of a portion of the MVTS of the present invention wherein the diagnostic imaging system is an Ultrasound System (US).
FIG. 3 is a block diagram illustrating the components of the Video Processor (VP) circuit of FIG. 1.
FIG. 4 is an illustration of a monitor display showing the software generated control buttons and their control functions.
FIG. 5 is an illustration of a display screen format showing a visual catalog and a display area.
FIG. 6 is an illustration of multiple display window video streams scalable within the display area.
FIG. 7 is an illustration showing the synchronization of a slow and fast video cycle.
FIG. 8 is an illustration of a simultaneous multi-stream video display, including a live real-time video stream for comparison purposes.
FIG. 9 is an illustration of a video display showing display attribute data which can be processed for databasing purposes.
DESCRIPTION OF THE PREFERRED EMBODIMENT
A preferred embodiment of a Motion Video Transformation System (MVTS) 100 of the present invention is shown in FIG. 1, and the operation of the MVTS 100 is as follows. A Diagnostic Imaging System (DIS) 17 generates a video signal 14. The DIS 17 can be a standard original equipment manufacturer's apparatus such as an Ultrasound System (US) 200, otherwise known as an ultrasonograph. Other DIS 17 may be an X-ray angiography system, a cardiac Magnetic Resonance Imaging (MRI) apparatus, or other medical or non-medical diagnostic imaging apparatus. The video signal 14 can be generated in either analog or digital format.
A Video Processor (VP) 1 is in communication with the DIS 17 for receiving the video signal 14 from the DIS 17. The main function of the VP 1 is to reduce the bandwidth of the video signal 14 being generated by the DIS 17. Other functions which may be performed by the VP 1 include conversion and encoding of the video signal 14 from the DIS 17 to a format readable by a computer 6, as well as data formatting, scan conversion, and optical character recognition.
If Doppler flow imaging is used, an audio Doppler signal 18 becomes an essential part of the diagnostic data. The Doppler sound complements the diagnostic information in the video signal 14 of the DIS 17. An audio processor (AP) 2 is used to quantize and then compress the audio Doppler signal 18.
Audio compression/decompression can be carried out by a Digital Signal Processor (DSP) (not shown) such as the Motorola 5600, the Texas Instruments 3200 family, or an equivalent DSP. In a preferred embodiment of the MVTS 100, the ISO MPEG (2-11172) method with two channels and variable compression rates from 32 to 384 kilobytes per second, to achieve frame synchronized audio compression, is implemented in the DSP.
A control input interface 3 circuit senses control signals 15 which are generated by the DIS 17. These control signals 15 may include ON/OFF signals intended for an external Video Cassette Recorder (VCR) (not shown) such as record, pause, playback, rewind, fast forward, etc.
Referring to FIG. 2, as well as FIG. 1, upon sensing these control signals 15, the MVTS 100 of the present invention is able to perform control functions such as playback, rewind, stop, pause, or record, which are already implemented in the control structure of the DIS 17 and are intended for the external VCR. By capturing these control signals 15, the MVTS 100 can respond to the commands requested by an operator of the DIS 17 from its keyboard 26. A data port 12 is intended for supplying display attribute data 101 (as shown in FIG. 9) over a data link 19.
A control output interface 4 circuit is provided for controlling certain functions of the DIS 17 from an external device such as MVTS 100 which can be attached to the DIS 17.
For example, DIS 17 will display an MVTS 100 analog video output signal 16 from a D/A video encoder II 8 on an internal display monitor 25 (FIG. 2) if the status of MVTS 100 as signaled by control output interface 4 is "playback". The MVTS analog video output signal 16 is used as an input to DIS 17, which in FIG. 2 is an Ultrasound System (US) 200. The D/A video encoder II 8 converts digital display video signals into an analog format, such as composite NTSC, S-Video or RGB.
A Physiological Signal Acquisition (PSA) 5 circuit amplifies and converts the patient's 300 physiological signals such as but not limited to ECG, blood pressure and blood flow to a form suitable for processing by the computer 6. These signals carry information such as timing, function and state of the processes and phenomena taking place in imaged anatomies.
An example of physiological signal utilization by the MVTS 100 is an electrocardiogram which accurately times the heart contraction (systole) through detection of the QRS complex in the ECG signal. In case of arrhythmias, a blood pressure signal may be used as a marker, or physiological index, of cardiac events.
Timing the correlation of a video frame rate (FR) with physiological signals used for indexing is critical in applications such as stress echocardiography, stress radionuclide angiography, or contrast echocardiography studies.
The computer 6, in a preferred embodiment, is a standard original equipment manufacturer's computer with the following: (1) at least 8 megabytes of random access memory (RAM); (2) the capability for handling data transfer rates on a video display bus of at least 33 megabytes per second; (3) a dedicated I/O port; and (4) a mass storage controller (hard disk, optical disk, video tape) capable of handling at least 10 megabits per second sustained transfer rate between the computer memory and the storage media.
Examples of such a computer include, but are not limited to, an IBM compatible x86 processor system, an Apple Quadra 620 or higher, an IBM Power PC, and a Sparcstation 10 from Sun Microsystems. The function of the computer 6 is to provide system control, communication, display, and video storage functions for the MVTS 100.
A mass storage device 7 may be one or more of the various standard original equipment manufacturer's disk storage devices, such as magneto-optical recordable optical disks, digital audio tape, and Winchester disk drives. The mass storage device 7 must be able to provide a minimum sustained data transfer rate of 150 kilobytes/sec.
As shown in FIG. 1, the output of the VP 1 is passed to a Video Display Processor (VDP) 10. The VDP 10 computes the correct timing for displaying a video at a desired resolution on an external display monitor 13.
A Network Interface (NI) 11 is provided for facilitating the exchange of compressed video and audio data over either Local or Wide Area Networks (LAN/WAN). In a preferred embodiment, various network protocols such as TCP/IP, NetWare, and other similar protocols are supported by the MVTS 100. A data bus 53 provides for the interconnection of the computer 6, the mass storage device 7 and the NI 11 components.
Turning back to FIG. 2, a portion of the MVTS 200 is shown wherein the DIS 17 of FIG. 1 is the Ultrasound System (US) 200, such as the Sonos 1500 sonograph manufactured by Hewlett Packard.
FIG. 2 illustrates the components of a typical ultrasonograph, as embodied by the US 200. The US 200 system comprises a transducer 20 which receives echoes reflected by the patient's 300 body organs. The echo signals are processed by a signal formatter 21 which converts them into an analog Radio Frequency (RF) signal 35. The analog RF signal 35, in an analog form, contains the information about imaged anatomical structures. The analog RF signal 35 is then digitized in a digitizer 22 which converts it into a form suitable by a scan converter 23. After additional processing and scan conversion in the scan converter 23, the resulting diagnostic video signal is passed to a display buffer 24 and can be displayed on the US 200 internal display monitor 25. An A/D converter 33 is used to convert the MVTS 100 analog video output signal 16 from an external device into a form suitable for display on the display internal monitor 25. The data port 12 is used to output the display attribute 101 data. A video data port 38 is intended for accepting an external video signal 9 in digital format for display on the internal display monitor 25.
Processors 29 of the US 200 control all operations of the US 200. An internal physiological signal acquisition 27 circuit is provided for displaying ECG and blood pressure data in graphical format together with diagnostic video information on the internal display monitor 25. The keyboard 26 is used for issuing control and operational commands to the US 200. A peripheral control circuit 28 is used for interfacing external devices (not shown) such as printers, and VCRs. The US 200 is also capable of archiving uncompressed digital video to an archival storage unit 30. An audio output 39 circuit provides Doppler sound audio and a "beep" which is an audio burst corresponding to the ECG R wave.
The MVTS 100 may acquire the analog RF signal 35 directly from the signal formatter 21 prior to the scan conversion which takes place in the scan converter 23. The VP 1 digitizes the analog RF signal 35, performs video compression, and then stores the data to the mass storage device 7, which can be of removable kind. A digitized RF signal 32 may also be used as an input to VP 1.
The ability to process the digitized RF signal 32, and the analog RF signal 35 is important in "contrast echocardiography studies" where raw echo signals are analyzed. Contrast imaging modality requires careful preservation of all RF signal components, and longer recording periods are needed.
Another application of the MVTS 100 to the field of ultrasonography can be achieved by utilizing an output digital video signal 34 from the US 200 display buffer 24. The scan-converted output digital video signal 34 may be available directly from the display buffer 24. The output digital video signal 34 is then supplied directly to the VP 1 for compression.
Yet another application is the usage of the MVTS 100 in lieu of an external VCR to US 200. In one application, the US 200 has the capability of digitizing the MVTS analog video output signal 16 in A/D converter 33 shown in FIG. 2 for subsequent display on the internal display monitor 25. In another application, the US 200 has the capability of accepting the external digital video signal 9 via the video data port 38 shown in FIG. 2 for a subsequent display on the internal display monitor 25.
The scan-converted output digital video signal 34 is converted into an analog video signal by a D/A video encoder I 31 and a resulting US 200 video output analog signal 36 may be used as an input to the MVTS 100. The video output analog signal 36 may be in the form of NTSC composite, S-Video (Y/C), or RGB video signal in the form of a 525 line raster.
The VP 1 can accommodate a plurality of inputs from US 200. The manner in which the VP 1 processes the inputs will be described more fully hereinafter with particular reference to FIG. 3.
As shown in FIG. 3, which is a block diagram illustrating the components of the VP 1 circuit of FIG. 1, the VP 1 system may be functionally represented as comprising analog video buffers such as an analog video NTSC/PAL input 41, an S-Video input 42, and a RGB input 43. A video conversion and encoding circuit 45 performs the conversion and encoding of analog video signals to a form suitable for processing by a Video Transformation(VT) 47 processor. A digital input 40 which, in a preferred embodiment, may be a CCIR 601 serial component digital, a parallel interface such as SCSI-2, or other digital format is provided to supply digitized video data via a buffer 44 and a source selector 46 to the VT 47. The source selector 46 is used to switch between valid sources of video data.
The US 200 may encode additional information such as calibration and image format data into its video output analog signal 36 such as display format and image attributes. The VP 1 is capable of extracting this information from the video output analog signal 36 (FIG. 2) after video conversion via the video conversion and encoding 45 circuit as shown in FIG. 3, and prior to video compression in the VT 47.
The VP 1 can be embodied in a Very Large Scale Integration (VLSI) circuit as a programmable single-chip device, or in discrete components such as but not limited to the IIT VCP (IIT Inc.) or CL-550 (C-Cube, Inc). The VT 47 processor has separate digital video buses, an input video bus 50 and an output video bus 51. The VT 47 processor uses a DRAM frame buffer 48 to store the uncompressed and reference images in the process of compression. The VT 47 uses a program memory 49 which provides code for video compression algorithms, post processing and control functions. The VT code is loaded by the computer 6 (FIG. 2) to suit a particular processing requirement.
In addition to video compression/decompression, a program residing in the program memory 49 supervises the VT 47 which also performs error correction on the compressed data, multiplexes the compressed audio and video data and parses the bit stream protocol. Depending upon the program, the VT 47 can act as a full H.261 codec, JPEG, MPEG 1, or MPEG 2 encoder/decoder. In addition to video compression/decompression functions, the VT 47 provides programmable video pre- and post-processing functions including video scaling, temporal filtering and processing, output interpolation, color conversion and multistream video display.
Due to the high computational power of the VP 1, a number of real-time image processing functions can also be implemented as needed. The examples of such functions may include colorization of selected frames, cycles or portions of thereof, as well as image filtering and image quantization.
According to the present invention, a video signal in any of the analog input formats 41, 42, or 43, or the digital input format 40, generated by the US 200 is passed via the buffer 44, the source selector 46, and the input video bus 50 to the VT 47 for compression. Additionally, the audio Doppler signal 18 produced by the US 200 and digitized by the AP 2 (FIG. 2) may be supplied to the VT 47 for multiplexing with compressed video. The video signal 14 and audio Doppler signal 18 compressed in VT 47 are outputted to the output video bus 51. In a playback video mode, the compressed video and audio from the mass storage device 7 (FIG. 1) is passed via the input video bus 50 to the VT 47 for decompression. Certain types of processors which may be utilized by the computer 6 may be capable of real time video and audio decompression if asymmetrical compression techniques such as MPEG have been used by the VT 47 to compress the audio Doppler signal 18 and video (41, 42, 43, 40) signals. The decompressed digital output is then forwarded to the VDP 10 (FIG. 1).
Turning now to FIG. 4, software generated control buttons are displayed on either internal display monitor screen 25 or external display monitor 13. The display can be on the internal display monitor 25 of the US 200 if in an on-line mode, or on the external display monitor 13 of the MVTS 100 if in an off-line mode. A diagnostic video display 72 is shown as would be displayed on either the internal display monitor 25 (FIG. 2) or the external display monitor 13 (FIG. 1).
Referring to both FIG. 2 and FIG. 4, the selection of a record button 64 will begin the archiving of the digital video with underlying audio, physiological signals, and timing ECG marks to the mass storage device 7. The recording will continue until the selection of a stop button 68 or a stop issued by the control output interface 4 (FIG. 1). Fast rewind 61, single frame back 62, pause 63, fast forward 66, single frame forward 73 and loop 67 functions are also provided for video access and management in the customary manner.
Another function available in the MVTS of the present invention is the playback of recorded digital video and audio. The playback of compressed digital video and audio from the storage media 7 starts with the selection of a play button 65 and continues until the stop button 68 is selected or a stop control signal issued by control output interface 4 (FIG. 1).
As shown in FIG. 1, the computer 6 initiates playback process by retrieving compressed video data from the mass storage device 7 and passing it to the VP 1 for decompression. Decompressed video is then passed to the VDP 10. The playback modes include slow motion (inter frame interval longer than at the time of recording) and fast motion (inter frame interval shorter than at the time of recording). The access to playback functions which include a plurality of image display formats, such as slow motion, fast motion, display window size and frame rate is through a view button 69.
Video editing functions are activated after selecting an edit button 70, and include still frame selection, manual start and end of a video sequence. Manual editing functions are important in studies which have been collected from patients with cardiac rhythm disturbances.
Access to archived studies is through a file button 71. The MVTS 100 may have a built-in database for archiving of compressed diagnostic video sequences 93 with embedded audio and physiological signals, single video frame images 94, display attribute data 101 and video attribute data 95 referenced in FIG. 5 and FIG. 9. Upon selection of this button, a visual representation of archived studies is displayed as shown in FIG. 5. A visual catalog 99 which can comprise a single video frame representation of an archived video sequence 93 and a single video frame image 94 is displayed in a "postage stamp" format shown in FIG. 5. The video sequences may represent different echocardiographic windows such as apical four chamber views, parasternal short axis views etc. A composition of a desired display format is accomplished by placing a selection from the visual catalog 99 in a display area 98. The process of selection is known as "drag and drop". If only one study has been placed in the display area 98, it will be displayed in a full screen format as shown in FIG. 4. If more than one selection has been made, the MVTS 100 will automatically adjust the display area to accommodate the selected video streams representing the diagnostic studies. A multiple video stream display is shown in FIG. 6.
For example, compressed diagnostic video sequences 90, 91 and 92 have been selected from the visual catalog 99 and placed in the display area 98. The compressed diagnostic video sequence 90 of FIG. 5 comprises a diagnostic video display 97, physiological signal display 96 and video attribute data 95. The MVTS 100 will dynamically assign the display space to these studies which will be displayed with the video attribute data 95. The video attribute data 95 includes patient demographics, image annotations and other data associated with the video sequence.
In applications where the display of a cardiac function is required, a plurality of digital video streams can be displayed simultaneously on the internal display monitor 25 (FIG. 2) or the external display monitor 13 (FIG. 1) as shown in FIG. 6. The display window of each video stream 82, 83, and 84 is fully scalable. The VDP 10 (FIG. 1) has the ability to change the size of the display window video stream within the display area of the monitor 25 and 13. The video stream display window 83 has a different size than the display windows of video streams 82 or 84. Each display window video stream may also be displayed at a different frame rate (FR). A frame rate FR1 for the display window video stream 84 may be different than a frame rate FR2 for the video stream 82 or a frame rate FR3 for the video stream 83.
Referring now to FIG. 7, in order to visually synchronize periodic digital motion video segments such as cardiac cycles, they have to be displayed at the same speed, i.e., the temporal placement of the frames in the cycle must be the same and the inter-frame intervals must be preserved. Cycle synchronization is very important in stress echocardiography and X-ray angiography, where the patient management decisions are made from visual assessment of the cardiac wall motion and where the digital cycles of digital video sequences representing different projections are displayed simultaneously for comparison purposes.
The QRS timing from ECG or first derivative of the blood pressure may serve as a timing marker, or physiological index, in video signal annotation. The system first measures an average cardiac period for a given video sequence prior to data acquisition. A number of frames in each cycle will then be calculated as number of frames equals heart period divided by 33. Typically a sequence of video fields is grabbed from an interlaced video output analog signal 36 (as shown in FIG. 2). Each frame with its associated odd and even fields (11,12,21,22 etc.) will be numbered, starting with the first acquired frame, which is the end-diastolic for stress echocardiography applications, and its temporal position within a cardiac cycle will be stored together with compressed video data to the mass storage device 7 (FIG. 1).
The synchronization process of more than two video streams utilizes the same method as described by FIG. 7. The video streams comprise fields 11, 12, 21, 22, 31, 32, 41, 42, . . . 51, and are spaced evenly by 17 millisecond (ms) intervals in a slow cycle with a period of T=1000 ms. The odd fields are s11, s21, s31 and even fields are s12, s22, s32. In order to synchronize a faster cycle video stream with a period of T=500 ms with the slow cycle, only every other field of the slow cycle will be displayed simultaneously with the fast cycle in the following manner: s11 and f11; s31 and f21; s51 and f31 (wherein "s" designates the slow cycle and "f" designates the faster cycle), due to the smaller number of frames in the faster cycle.
The exact temporal locations of displayed frames in a slower cycle will be determined by the number of frames per cycle in the faster cycle. Since the display synchronization is a dynamic process, different frame configurations will be displayed differently depending upon the speed of the fastest cycle. It should be noted, that diagnostic video may be slower than 30 frames per second as exemplified by wide angle color Doppler displays. This method may be used for on-line serial comparisons of diagnostic video studies of archived (compressed) and live video. A method for display of full motion digital video data in a multiple window display format in a synchronized fashion is shown in FIG. 8.
Three digital video streams 85, 86 and 87, which have been previously selected from the visual catalog 99 as shown in FIG. 5, and a live video stream 88, are shown as displayed simultaneously on either the internal display monitor 25 or the external display monitor 13 in a synchronized fashion. An indexing arrow 80 shows the temporal location of the currently displayed video frame within the cardiac cycle, wherein B designates the begin of a cardiac cycle, and E designates the end of a cardiac cycle, corresponding to timing of the cardiac contraction.
Video streams may be recorded at different frame rates depending upon the DIS 17, wherein FR=k, p, q, and r. The number of frames in each cycle of the video stream is adjusted to fit the fastest rate within the multiple window display in a manner as explained with reference to FIG. 7.
Often times, a need arises to compare previously recorded video data with live video in a serial comparison. This is particularly important during a PTCA process or serial echocardiography studies. The synchronization of the video cycles from the storage with live video is accomplished by selecting a live video display format from view button 69 shown in FIG. 4. The selected display format as illustrated in FIG. 5 is complemented by a live video which is forwarded from DIS 17, via VP 1 to VDP 10 for display on an external monitor 13 as illustrated in FIG. 1. The methods of cycle synchronization, as explained in conjunction with FIG. 7, are applicable to live video synchronization in a serial comparison mode.
Tele-consultations and remote diagnosis are also important in practice of cardiac imaging, since the diagnostician may not be present at the imaging site. Examples of such applications include operating room imaging and mobile echocardiography. Because the bandwidth of diagnostic video after compression is significantly reduced (1.5 to 10 megabits per second (Mbps) depending on the compression method used by the VP 1), a network transmission of digital diagnostic video is possible over either local or wide area networks. The performance of digital video transmission over the network depends on the network operating system and the bandwidth of the link. A bandwidth of 15 Mbps (e.g. Ethernet protocol) is sufficient for real-time compressed video transmission. All functions of the disclosed MVTS 100 are available either in a multicast or point-to-point configurations over the described data links above.
Turning now to FIG. 9, to facilitate the transfer of pertinent information from the video recordings to a database, a video annotation method is used. A layout of a typical display contains display attribute data 101, diagnostic video display 72, and an ECG signal 103. In the US 200 system equipped with the data port 12, such as an RS-232 data port, the display attribute data 101 comprises the patient 300 data, along with the US 200 display parameter data, calibration settings and measurement data. This display attribute 101 is outputted via the data link 19 simultaneously with the diagnostic video. The computer 6 combines this information with compressed video data prior to storage to the mass storage device 7 (FIG. 1).
In US 200 systems which do not provide the data port 12, an Optical Character Recognition (OCR) algorithm is used to extract display attribute data 101 from the video display of the internal display monitor 25. The video signal 14 from the DIS 17 is forwarded to the VP 1 for processing and then to the computer 6. The display attribute data 101 is extracted from the video using OCR techniques and then combined in real-time with the digital video by the computer 6 prior to storage to the mass storage device 7 (FIG. 1).
The diagnostic video display 72, together with other patient 300 diagnostic information generated by MVTS 100 can be converted to a standard format such as American College of Radiology (ACR) and National Electrical Manufacturers Association (NEMA) (ACR-NEMA) Digital Imaging and Communications in Medicine (DIACOM) suitable for display on other DIACOM compliant medical diagnostic imaging devices.
While the above description contains many specificities, these should not be construed as limitations on the scope of the invention, but rather as an exemplification of preferred embodiments thereof. Many other variations are possible.
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A motion video system and method for use with diagnostic imaging systems for combining the acquisition, display, and processing of digital video in real-time with physiological data indexing through the use of a mass storage device and digital motion video data compression/decompression, and for delivering video sequences of anatomy or graphical representations of physiological processes. The system comprises components or subsystems that operate to reduce the data content of the diagnostic video data using compression methods, assign physiological timing events, or physiological indexes, to pictures in sequence, create physiologically meaningful digital video loops, enhance visualization of the video data through spatial and temporal domain processing, as well as side-by-side real-time video displays, and archive compressed diagnostic video on a mass storage device.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. patent application Ser. No. 10/029,595, filed Dec. 21, 2001, which is a continuation-in-part of U.S. patent application Ser. No. 09/265,715, filed Mar. 11, 1999. This application is also related to two other U.S. patent applications, filed on even date, entitled “Guidance of Invasive Medical Procedures Using Implantable Tags,” and “Position Sensing System with Integral Location Pad and Position Display.” All these related applications are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates generally to systems for determining the position of an object inside a human body, and specifically to the use of such systems in guiding tools and other devices used in medical procedures.
BACKGROUND OF THE INVENTION
[0003] The use of implanted markers or clips for surgical guidance is known in the art. For example, upon identifying a suspicious lesion in the breast, a radiologist may mark the location by inserting a simple radio-opaque wire at the location of the lesion while viewing an image of the breast under mammography. When a biopsy is subsequently performed, the surgeon follows the wire to find the exact location of the lesion, so as to be certain of removing tissue from the correct area of the breast. Radiologists currently use this sort of location marking for approximately 40% of all breast biopsies. This careful approach significantly reduces the occurrence of false negative biopsy findings and increases the overall diagnostic accuracy of the procedure.
[0004] Despite the proven usefulness of such simple biopsy markers, it would be preferable for the surgeon to be able to choose a pathway to the biopsy site independently, rather than having to follow the wire inserted by the radiologist. Furthermore, wire-based markers are not appropriate to other invasive procedures, such as lung biopsies, or to applications in which a marker must be left in the body for extended periods. It has therefore been suggested to use a wireless emitter, or “tag,” to mark target locations in the body for surgery and therapy. Such a tag contains no internal power source, but is rather actuated by an external energy field, typically applied from outside the body. The tag then emits ultrasonic or electromagnetic energy, which is detected by antennas or other sensors outside the body. The detected signals may be used to determine position coordinates of the tag. Passive ultrasonic reflectors are one simple example of such tags. Other passive tags receive and re-emit electromagnetic radiation, typically with a frequency and/or phase shift. Hybrid tags, combining ultrasonic and electromagnetic interactions, are also known in the art.
[0005] For example, U.S. Pat. No. 6,026,818, to Blair et al., whose disclosure is incorporated herein by reference, describes a method and device for the detection of unwanted objects in surgical sites, based on a medically inert detection tag which is affixed to objects such as medical sponges or other items used in body cavities during surgery. The detection tag contains a single signal emitter, such as a miniature ferrite rod and coil and capacitor element embedded therein. Alternatively, the tag includes a flexible thread composed of a single loop wire and capacitor element. A detection device is utilized to locate the tag by pulsed emission of a wide-band transmission signal. The tag resonates with a radiated signal, in response to the wide-band transmission, at its own single non-predetermined frequency, within the wide-band range. The return signals build up in intensity at a single (though not predefined) detectable frequency over ambient noise, so as to provide recognizable detection signals.
[0006] U.S. Pat. No. 5,325,873, to Hirschi et al., whose disclosure is incorporated herein by reference, describes a system to verify the location of a tube or other object inserted into the body. It incorporates a resonant electrical circuit attached to the object which resonates upon stimulation by a hand-held RF transmitter/receiver external to the body. The electromagnetic field generated due to resonance of the circuit is detected by the hand-held device, which subsequently turns on a series of LEDs to indicate to the user the direction to the target. An additional visual display indicates when the transmitter/receiver is directly above the object.
[0007] U.S. Pat. No. 6,239,724, to Doron et al., whose disclosure is incorporated herein by reference, describes a telemetry system for providing spatial positioning information from within a patient's body. The system includes an implantable telemetry unit having (a) a first transducer, for converting a power signal received from outside the body into electrical power for powering the telemetry unit; (b) a second transducer, for receiving a positioning field signal that is received from outside the body; and (c) a third transducer, for transmitting a locating signal to a site outside the body, in response to the positioning field signal.
[0008] U.S. Pat. No. 6,332,089, to Acker et al., whose disclosure is incorporated herein by reference, describes a medical probe such as a catheter, which is guided within the body of a patient by determining the relative positions of the probe relative to another probe, for example by transmitting nonionizing radiation to or from field transducers mounted on both probes. In one embodiment, a site probe is secured to a lesion within the body, and an instrument probe for treating the lesion may be guided to the lesion by monitoring relative positions of the probes. Two or more probes may be coordinated with one another to perform a medical procedure.
[0009] Passive sensors and transponders, fixed to implanted devices, can also be used for conveying other diagnostic information to receivers outside the body. For example, U.S. Pat. No. 6,053,873, to Govari et al., whose disclosure is incorporated herein by reference, describes a stent adapted for measuring a fluid flow in the body of a subject. The stent contains a coil, which receives energy from an electromagnetic field irradiating the body so as to power a transmitter for transmitting a pressure-dependent signal to a receiver outside the body. In one embodiment, the transmitter is based on a tunnel diode oscillator circuit, suitably biased so as to operate in a negative resistance regime, as is known in the art.
[0010] As another example, U.S. Pat. No. 6,206,835 to Spillman et al., whose disclosure is incorporated herein by reference, describes an implant device that includes an integral, electrically-passive sensing circuit, communicating with an external interrogation circuit. The sensing circuit includes an inductive element and has a has a frequency-dependent variable impedance loading effect on the interrogation circuit, varying in relation to the sensed parameter.
SUMMARY OF THE INVENTION
[0011] It is an object of some aspects of the present invention to provide methods and systems for guidance of medical procedures.
[0012] In preferred embodiments of the present invention, a wireless tag is implanted in a patient's body to mark the location of a planned diagnostic or therapeutic procedure. During the procedure, the region of the body under treatment is irradiated with electromagnetic radiation (typically radio frequency—RF—radiation) or ultrasonic radiation, causing the tag to return energy indicative of its location. The energy returned from the tag is detected by a receiver in order to determine the location and orientation of a therapeutic or diagnostic device, such as a surgical probe, relative to the tag. The radiation source and the receiver for detecting the returned energy may be integrated into the therapeutic or diagnostic device, or they may alternatively be contained in one or more separate units. In the latter case, when the receiver is separate from the therapeutic or diagnostic device, the receiver is preferably also capable of determining the position and orientation of the device.
[0013] The location and orientation of the therapeutic or diagnostic device relative to the tag within the body are shown on a display, for use by the treating physician in guiding the device to the appropriate location. In some preferred embodiments of the present invention, the display is integrated in a single unit with the therapeutic or diagnostic device that must be guided, for example, on a handle of the device. The operator is thus able to guide the device while looking only at the tool and the region under treatment, without having to look away toward a separate display as in systems known in the art.
[0014] Various different types of wireless tags may be used for the purposes of the present invention. Preferably, the tag is passive, in the sense that it contains no internal energy source, but rather derives all the energy that it needs to operate from the applied electromagnetic or ultrasonic radiation. Exemplary passive tags are described in the above-mentioned U.S. patent application Ser. No. 10/029,595 and in U.S. patent application Ser. No. 10/029,473, filed Dec. 21, 2001, which is assigned to the assignee of the present patent application and whose disclosure is likewise incorporated herein by reference. Other types of tags, as are known in the art, may also be used.
[0015] Systems and methods in accordance with embodiments of the present invention present invention are particularly useful in guiding biopsies and other invasive procedures performed on soft tissues, such as the breasts, lungs and gastrointestinal tract. Implantation of a passive tag can be used both to provide initial guidance to the location of a suspected lesion and to provide further guidance to return to the same location in subsequent treatment and follow-up. Such guidance systems may also be used in non-invasive therapies, such as focused radiotherapy and ultrasound, to focus high-intensity radiation from a source outside the body onto the precise location of a lesion. Other applications will be apparent to those skilled in the art.
[0016] There is therefore provided, in accordance with a preferred embodiment of the present invention, apparatus for performing a medical procedure on a tissue within a body of a subject, including:
[0017] a wireless tag configured to be fixed to the tissue and adapted to emit radiation, thereby causing first signals to be generated indicative of a location of the tag in the body;
[0018] an invasive medical tool, including:
[0019] a probe, which is adapted to penetrate into the body so as to reach the tissue;
[0020] a handle, fixed proximally to the probe, and adapted to be manipulated by an operator of the tool; and
[0021] a display, mounted on the handle, and adapted to present a visual indication to the operator of an orientation of the probe relative to the tag; and
[0022] a processing unit, coupled to process the first signals so as to determine coordinates of the tag relative to the probe, and to drive the display responsive to the coordinates.
[0023] Preferably, the invasive medical tool further includes a receiver, which is adapted to receive the radiation emitted by the wireless tag, and to generate the first signals responsive thereto for processing by the processing unit.
[0024] Further preferably, the invasive medical tool includes a tool position sensor, which is adapted to generate second signals indicative of the coordinates of the probe, and the processing unit is coupled to process the second signals together with the first signals so as to determine the coordinates of the tag relative to the probe. In a preferred embodiment, the apparatus includes one or more field generators, which are fixed in the external frame of reference and which are adapted to generate electromagnetic fields in a vicinity of the tissue, and the wireless tag and the tool position sensor include field sensors, in which electrical currents flow responsive to the electromagnetic fields, and wherein the first and second signals are indicative of the electrical currents flowing in the field sensors.
[0025] Preferably, the radiation emitted by the tag includes radio-frequency (RF) electromagnetic radiation. In a preferred embodiment, the apparatus includes one or more acoustic transmitters, which are adapted to transmit acoustic energy into the body in a vicinity of the tissue, and wherein the tag is adapted to receive and use the acoustic energy in generating the electromagnetic radiation.
[0026] Alternatively, the radiation emitted by the tag includes acoustic radiation.
[0027] Preferably, the display is adapted to present a further visual indication of a distance from the probe to the tag.
[0028] In a preferred embodiment, the invasive medical tool is adapted to perform a surgical procedure on the tissue. Additionally or alternatively, the invasive tool includes an endoscope.
[0029] There is also provided, in accordance with a preferred embodiment of the present invention, a method for performing a medical procedure on a tissue within a body of a subject, including:
[0030] fixing a wireless tag to the tissue;
[0031] actuating the tag to emit radiation, thereby causing first signals to be generated indicative of a location of the tag in the body;
[0032] introducing an invasive medical tool into the body by manipulating a handle of the tool;
[0033] processing the first signals so as to determine coordinates of the tag relative to the tool;
[0034] responsive to the coordinates, displaying a visual indication on the handle of the tool of an orientation of the tool relative to the tag; and
[0035] advancing the tool into the body to the tissue by manipulating the handle while observing the visual indication so that the tool reaches the tissue.
[0036] The present invention will be more fully understood from the following detailed description of the preferred embodiments thereof, taken together with the drawings in which:
BRIEF DESCRIPTION OF THE DRAWINGS
[0037] [0037]FIG. 1 is a schematic, pictorial illustration showing a partly-cutaway view of an implantable passive tag, in accordance with a preferred embodiment of the present invention;
[0038] [0038]FIG. 2 is a schematic, pictorial illustration showing a surgical probe that is guided to the location of a passive tag in the breast of a subject using a display on the probe, in accordance with a preferred embodiment of the present invention;
[0039] [0039]FIG. 3 is a flow chart that schematically illustrates a method for carrying out an invasive medical procedure on body tissue using a tag implanted in the tissue, in accordance with a preferred embodiment of the present invention;
[0040] [0040]FIG. 4 is a schematic, pictorial illustration showing a partly-cutaway view of an implantable passive tag, in accordance with another preferred embodiment of the present invention;
[0041] [0041]FIG. 5 is a schematic electrical diagram of a passive tag, in accordance with a preferred embodiment of the present invention;
[0042] [0042]FIG. 6 is a schematic, pictorial illustration of a system for guiding a surgical probe to the location of a passive tag in the breast of a subject, in accordance with a preferred embodiment of the present invention;
[0043] [0043]FIG. 7 is a schematic, pictorial illustration of a system for guiding a surgical probe to the location of a passive tag in the breast of a subject, in accordance with another preferred embodiment of the present invention;
[0044] [0044]FIG. 8 is a flow chart that schematically illustrates a method for carrying out an invasive medical procedure on body tissue using a tag implanted in the tissue, in accordance with a preferred embodiment of the present invention;
[0045] [0045]FIG. 9 is a schematic, pictorial illustration showing a cutaway view of an ultrasonic reflecting tag, in accordance with a preferred embodiment of the present invention;
[0046] [0046]FIG. 10 is a schematic, pictorial illustration of a system for guiding a surgical probe to the location of a passive tag in the breast of a subject, in accordance with still another preferred embodiment of the present invention;
[0047] [0047]FIG. 11 is a flow chart that schematically illustrates a method for carrying out an invasive medical procedure on body tissue using a tag implanted in the tissue, in accordance with a preferred embodiment of the present invention;
[0048] [0048]FIG. 12 is a schematic, pictorial illustration showing an endoscope that is guided to the location of a passive tag in the lung of a subject using a display on the endoscope, in accordance with a preferred embodiment of the present invention; and
[0049] [0049]FIG. 13 is a schematic, pictorial illustration of a system for guiding an endoscope to the location of a passive tag in the colon of a subject, in accordance with still another preferred embodiment of the present invention.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0050] [0050]FIG. 1 is a schematic, pictorial illustration that shows a partly-cutaway view of an implantable passive tag 20 , in accordance with a preferred embodiment of the present invention. Tag 20 of the type shown and described here is also referred to herein as a “beacon.” The tag comprises a RF antenna 22 , typically having the form of a coil, which is coupled to a capacitor 24 and additional circuitry 26 to define a resonant circuit. The coil, capacitor and circuitry are contained in a sealed, biocompatible package 28 , typically made of a plastic or other non-conducting material. In the embodiment pictured in FIG. 1, package 28 includes a base that can be grasped by a radiologist using a suitable inserter tool (not shown in the figures) to position tag 20 at a desired location in soft tissue of a patient.
[0051] Preferably, circuitry 26 comprises a tunnel diode (not shown), such as a 1 n 3712 diode, which is configured together with antenna 22 and capacitor 24 to form a tunnel diode oscillator circuit, as is known in the art. For example, the antenna may be formed by a small loop of 0.5 mm wire, and coupled to a 40 pF capacitor. Further details of the design of a tunnel diode oscillator circuit and its use in a wireless transponder are described in the above-mentioned U.S. Pat. No. 6,053,873. In brief, the oscillator circuit is excited by an externally-generated electromagnetic field at a first frequency (f 1 ), which causes the oscillator circuit to radiate a response field at another frequency (f 2 ). Tunnel diodes are particularly well suited for this purpose, because the characteristic I-V curve of a tunnel diode includes a portion in which the diode demonstrates “negative” resistance, i.e., as the voltage applied across the diode decreases, the current through the diode increases, causing oscillations to occur in the circuit. The oscillation frequency (f 2 ) differs from the normal resonant frequency of the circuit because of the effective capacitance of the tunnel diode. Typically, frequency f 2 differs from the excitation frequency f 1 by about 10%-40%. For example, an excitation frequency f 1 of 88 MHz may yield a response field having a frequency f 2 of 120 MHz. The intensity and direction of the response field can be used to “home in” on the location of tag 20 , as described below. Alternatively, other types of re-radiating oscillators may be used for this purpose, as well.
[0052] [0052]FIG. 2 is a schematic, pictorial illustration showing implantation of tag 20 in a breast 30 of a patient, and its use in guiding a surgical tool 32 , in accordance with a preferred embodiment of the present invention. Typically, tool 32 comprises a probe 34 , which is used, for example, to cut and extract a biopsy sample from breast 30 at the location marked by tag 20 . Tool 32 comprises an antenna assembly 36 , which is coupled to excitation and detection circuitry, contained either within tool 32 or in a separate processing unit (not shown in this figure). Antenna assembly 36 is driven to radiate RF energy at or near the excitation frequency f 1 of the circuitry in tag 20 . This excitation energy causes the tag to radiate a response field at frequency f 2 , which is detected by the antenna assembly. Typically, antenna assembly 36 comprises two or more antennas (not shown), spaced around the longitudinal axis of probe 34 . The difference between the respective field strengths sensed by the antennas at frequency f 2 is indicative of the direction and magnitude of the misalignment of the probe axis relative to the location of tag 20 . Based on the detected response fields, a display 38 on the handle of tool 32 guides the surgeon in directing probe 34 precisely to the location of tag 20 . When the signals from the antennas are equal, the probe axis is aligned with the tag.
[0053] [0053]FIG. 3 is a flow chart that schematically illustrates a method for performing a surgical procedure using tag 20 and tool 32 , in accordance with a preferred embodiment of the present invention. The tag is initially implanted in breast 30 by a radiologist, at an implant step 40 . This step is typically carried out while imaging the breast to determine the location of a suspicious lesion, so as to place tag 20 within or adjacent to the lesion. A surgeon then brings probe 34 into proximity with breast. Antenna assembly 36 transmits a RF field in the direction of probe 34 , toward breast 30 , at a power transmission step 42 . As noted above, the transmitted field is at or near the excitation frequency of the oscillator circuit in tag 20 . The oscillation thus engendered in the circuit causes it to radiate a response field, or beacon signal, at a beacon transmission step 44 .
[0054] Antenna assembly 36 receives the beacon signal, at a beacon reception step 46 , and the signal is processed to measure its strength and, optionally, its directional characteristics. These characteristics are used in driving display 38 to give the surgeon a visual indication of how probe 34 should be directed through the breast tissue in order to reach tag 20 . In one embodiment, display 38 simply gives a signal strength indication, and the surgeon directs the probe so as to maximize the signal strength. In another embodiment, the response signal is processed to generate a directional signal, typically using multiple antennas in assembly 36 , as described above. The antenna outputs are processed, using analog and/or digital differential processing circuitry, to drive a pointer or cursor on display 38 , indicating the direction from probe 34 to tag 20 . Optionally, tool 32 also provides an audible indication, such as a tone or sequence of tones, to cue the surgeon as to whether or not the probe is correctly directed to the target in breast 30 .
[0055] The surgeon uses the information provided by display 38 to guide probe 34 toward tag 20 , at a guidance step 48 . Steps 42 through 48 are repeated continually until the distal tip of probe 34 reaches the location of tag 20 , at a success step 50 . Successful penetration by the probe tip to the tag location can be determined in a number of different ways. For example, an antenna or other sensor may be incorporated in the probe near its distal tip in order to signal when the probe contacts the tag. Alternatively, each of the multiple antennas in assembly 36 can be used to find a respective directional vector, pointing from the antenna to the tag location. The crossing point of these vectors indicates the location of the tag. It is thus determined that the probe tip has reached the tag location when the distance from antenna assembly 36 to the vector crossing point is equal to the known length of probe 34 . At this point, display 38 preferably gives an indication of success, such as a change in color or audible signal. The surgeon can then complete the biopsy or other procedure that is warranted. Tag 20 may either be surgically removed as part of this procedure, or it may be left in place for future access.
[0056] [0056]FIG. 4 is a schematic, pictorial illustration that shows a partly-cutaway view of an implantable passive tag 54 , in accordance with another preferred embodiment of the present invention. Tag 54 comprises, in addition to antenna 22 , one or more position-sensing coils 56 . Application of electromagnetic fields to coils 56 by external field generators causes currents to flow in these coils. The amplitudes of the currents can be used to determine the position and orientation coordinates of the coils relative to the field generators (as shown below in FIG. 6). Exemplary methods for determining position and orientation of an invasive device using coils such as these are described in U.S. Pat. No. 5,391,199, to Ben-Haim, and in U.S. patent application Ser. No. 08/793,371 filed May 14, 1997 (PCT Patent Publication WO 96/05768, to Ben-Haim et al.), whose disclosures are incorporated herein by reference. Three position-sensing coils 56 can be used to provide six-dimensional location and orientation coordinates of tag 54 . For applications that do not require full, six-dimensional information, a single position-sensing coil is adequate.
[0057] Coils 56 are coupled to control circuitry 58 , which senses the currents flowing in the coils for use in determining the coordinates of tag 54 . Preferably, circuitry 58 generates signals in which the current magnitudes are encoded and causes these signals to be transmitted by antenna 22 . The signals are decoded and processed by an external processing unit to determine the coordinates of the tag. Optionally, tag 54 may also comprise one or more additional sensors 60 , which measure physiological parameters at the site of the tag in the body. Examples of such sensors include temperature sensors, pressure sensors, pH sensors, and other sensors for measuring physical and chemical properties of tissues with which tag 54 is in contact. Circuitry 58 encodes and transmits these sensor measurements, as well.
[0058] [0058]FIG. 5 is an electrical schematic diagram showing circuit elements of tag 54 , in accordance with a preferred embodiment of the present invention. Antenna 22 is preferably optimized to receive and transmit high-frequency signals, in the range above 1 MHz. Coil 56 , on the other hand, is preferably designed for operation in the range of 1-3 kHz, at which the external field generators generate their electromagnetic fields. Alternatively, other frequency ranges may be used, as dictated by application requirements. According to this embodiment, tag 54 can typically be made about 2-5 mm in length and 2-3 mm in outer diameter. Further aspects of this type of tag are described in the above-mentioned U.S. patent application Ser. No. 10/029,473.
[0059] To determine the position of tag 54 , electric fields are applied to the area of the patient's body containing the tag by a number of field generators in different, known positions and/or orientations. Preferably, each of the field generators has its own, distinct operating frequency. Control circuitry 58 measures the currents flowing in sensor coil 56 at the different field frequencies and encodes the measurements in a high-frequency signal transmitted via antenna 22 . Alternatively or additionally, the different field generators are time-multiplexed, each operating during its own preassigned time slots.
[0060] In the embodiment pictured in FIG. 5, circuitry 58 comprises a voltage-to-frequency (V/F) converter 62 , which generates a RF signal whose frequency is proportional to the voltage produced by the sensor coil current flowing across a load. Preferably, the RF signal produced by circuitry 58 has a carrier frequency in the 50-150 MHz range. The RF signal produced in this manner is modulated with a number of different frequency modulation (FM) components that vary over time at the respective frequencies of the fields generated by the field generators. The magnitude of the modulation is proportional to the current components at the different frequencies. A receiver outside the patient's body demodulates the RF signal to determine the magnitudes of the current components and thereby to calculate the coordinates of tag 54 .
[0061] Alternatively, circuitry 58 may comprise a sampling circuit and analog/digital (A/D) converter (not shown in the figures), which digitizes the amplitude of the current flowing in sensor coil 56 . In this case, circuitry 58 generates a digitally-modulated signal, and RF-modulates the signal for transmission by antenna 22 . Any suitable method of digital encoding and modulation may be used for this purpose. Other methods of signal processing and modulation will be apparent to those skilled in the art.
[0062] [0062]FIG. 6 is a schematic, pictorial illustration of a system 66 for guiding a surgical tool 76 to the location of tag 54 in breast 30 , in accordance with a preferred embodiment of the present invention. A power coil 68 generates a high-frequency RF field, preferably in the 2-10 MHz range. This field causes a current to flow in antenna 22 , which is rectified by circuitry 58 and used to power its internal circuits. Meanwhile, field generator coils 70 produce electromagnetic fields, preferably in the 1-3 kHz range, which cause currents to flow in sensor coil (or coils) 56 . These currents have frequency components at the same frequencies as the driving currents flowing through the generator coils. The current components are proportional to the strengths of the components of the respective magnetic fields produced by the generator coils in a direction parallel to the sensor coil axis. Thus, the amplitudes of the currents indicate the position and orientation of coil 56 relative to fixed generator coils 70 .
[0063] Circuitry 58 encodes the current amplitudes from coil 56 into a high-frequency signal, which is transmitted by antenna 22 . Alternatively, tag 54 may comprise separate antennas for receiving RF power and for transmitting signals, as described, for example, in the above-mentioned U.S. Pat. No. 6,239,724. The encoded signal is received by coil 68 or by another receiving antenna, and is conveyed to a processing unit 72 . Typically, processing unit 72 comprises a general-purpose computer, with suitable input circuits and software for processing the position signals received over the air from tag 54 . The processing unit computes position and, optionally, orientation coordinates of tag 54 , and then shows the tag coordinates on a display 74 .
[0064] Surgical tool 76 also comprises a position sensor 78 , comprising one or more coils similar in form and function to coils 56 in tag 54 . The fields produced by field generator coils 70 also cause currents to flow in sensor 78 , in response to the position and orientation of tool 76 relative to coils 70 . The current signals thus produced are also conveyed to processing unit 72 , either over the air, as in the case of tag 54 , or via wire. If sensor 78 transmits the signals over the air, it preferably uses a different carrier frequency from that of tag 54 so that the signals can be easily distinguished one from another.
[0065] Based on the signals from tag 54 and from sensor 78 , processing unit 72 computes the position and orientation of tool 76 relative to the location of the tag in breast 30 . A pointer and/or cursor is shown on display 74 to indicate to the surgeon whether the tool is aimed properly towards its target. Various methods of coordinate display may be used for this purpose, such as a three-dimensional grid mesh, a two-dimensional grid, a two- or-three dimensional polar representation, numerical coordinate readout, or other methods known in the art. Optionally, the positions of the tag and tool are registered, using their measured positions and orientations, with an image of breast 30 , such as an X-ray, CT or ultrasound image. The image of the breast is shown on display 74 , and icons corresponding to the positions of the tag and the tool are superimposed on the image. Further methods of display that are useful in image-guided surgery are described in the above-mentioned U.S. Pat. No. 6,332,098.
[0066] [0066]FIG. 7 is a schematic, pictorial illustration of a system 80 for guiding surgical tool 76 to the location of a tag 81 in breast 30 , in accordance with another preferred embodiment of the present invention. In this embodiment, a tag 81 receives its operating power not from an electromagnetic field (such as that of coil 68 ), but from acoustic energy generated by an ultrasound transmitter 82 . A tag of this sort is shown, for example, in the above-mentioned U.S. patent application Ser. No. 10/029,595. The acoustic energy generated by transmitter 82 excites a miniature transducer, such as a piezoelectric crystal, in tag 81 , to generate electrical energy. The electrical energy causes a current to flow in one or more coils in tag 81 , such as coil 56 described above. The currents in the coils in tag 81 generate electromagnetic fields outside breast 30 , which are in this case received by coils 70 (now acting as field receivers, rather than field generators). The amplitudes of the currents flowing in coils 70 at the frequency of the applied acoustic energy are measured to determine the position of tag 81 .
[0067] Alternatively, tag 81 may be similar in operation to tag 54 , in that sensor coil or coils 56 in the tag receive a field generated by coils 70 , and then circuitry in the tag transmits a signal indicating the amplitudes of the current components in coils 56 . In the embodiment of FIG. 7, however, the circuitry in the tag receives power not from coil 68 , but rather by rectifying the electrical energy generated by the piezoelectric crystal (or other transducer) in tag 81 in response to the acoustic energy applied by transmitter 82 . The tag may transmit its signal in pulses, rather than continuously, and a capacitor may be used to store energy in tag 81 in the intervals between the pulses, so that the transmitted signal is powerful enough to be received outside the body with good signal/noise ratio.
[0068] As in the preceding embodiment, sensor 78 is used to determine the position and orientation of tool 76 . Sensor 78 may either receive the fields generated by coils 70 , as described above, or it may be driven to generate fields, which are received by coils 70 .
[0069] The position signals generated by tag 81 and sensor 78 are received and processed by a combined location pad and display unit 84 . This unit takes the place of the separate processing unit 72 , coils 70 and display 74 used in the preceding embodiment. Unit 84 is preferably held by a stable, movable mount (not shown), enabling the surgeon to place the unit in proximity to breast 30 and in a position in which a display 86 on the unit can be viewed conveniently. Field generator coils 70 are built into unit 84 , so that the positions of tag 81 and tool 76 are determined relative to the unit. (Coils 70 are seen in the figure in cutaway view, but ordinarily would be contained inside the case of the unit, protected by a non-conductive cover.) Since it is not the absolute positions of tag 81 and tool 76 that are of concern, but rather their relative positions and orientations, the surgeon may move unit 84 during the surgery as required, in order to ensure that the signals from tag 81 and sensor 78 are sufficiently strong, that display 86 is easily visible, and that the unit itself does not interfere with the surgeon's work.
[0070] Display 86 preferably comprises a distance guide 88 and an orientation target 92 . A mark 90 on distance guide 88 indicates how far the tip of tool 76 is from the location of tag 81 . A cursor 94 on target 92 indicates the orientation of tool 76 relative to the axis required to reach the location of tag 81 . When the cursor is centered on the target, it means that tool 76 is pointing directly toward tag 81 . Display 38 (FIG. 2) preferably works on a similar principle.
[0071] [0071]FIG. 8 is a flow chart that schematically illustrates a method for performing a surgical procedure using system 80 , including tag 81 and combined location pad and display unit 84 , in accordance with a preferred embodiment of the present invention. A similar procedure may be carried out, mutatis mutandis, using the elements of system 66 , shown in FIG. 6. As described above with reference to FIG. 3, the procedure begins with implantation of the appropriate tag at the target location in breast 30 , at an implant step 100 . The tag is then energized by applying transmitter 82 to the breast, and driving the transmitter to generate acoustic energy, at an energizing step 102 . Alternatively, if tag 54 is used, coil 68 is used to energize the tag with RF power.
[0072] Energizing the tag causes it to transmit a location signal to unit 84 , at a tag transmission step 104 . At the same time, or in alternation with the tag transmission, sensor 78 conveys a location signal to unit 84 , as well, at a tool transmission step 106 . Unit 84 (or processing unit 72 , in the embodiment of FIG. 6) receives the location signals and determines the relative coordinates of tool 76 and tag 81 , at a coordinate determination step 108 . Based on this determination, the location and orientation of the tool relative to the tag are shown on display 86 in the manner described above.
[0073] The surgeon uses the information presented by display 86 to guide the distal end of tool 76 to the location of tag 81 , at a probe guidance step 110 . In typical operation, the surgeon holds the tool at a selected starting position and aims it toward tag 81 , using target 92 . The surgeon then advances the tool into breast 30 , keeping cursor 94 centered on target 92 . Steps 102 through 110 are repeated continually until mark 90 indicates that the tool has reached the location of tag 81 , at a success step 112 . The biopsy or other desired procedure can then be performed.
[0074] [0074]FIG. 9 is a schematic, pictorial, partly-cutaway illustration of an ultrasonic reflecting tag 120 , in accordance with another preferred embodiment of the present invention. Various tags of this sort, which are applicable to the purposes of the present invention, are shown and described in the above-mentioned U.S. patent application Ser. No. 10/029,595. Tag 120 in the present embodiment has the form of a spherical bubble, comprising a shell 122 that is struck by ultrasound waves generated by acoustic transducers outside the patient's body. The incident ultrasound waves induce the tag to resonate and to emit a detectable ultrasound echo. If shell 122 is spherical (as shown), then the emitted echo is generally isotropic, and triangulation of the echo can yield the location of the target in the body.
[0075] Preferably, shell 122 contains a medium 124 , and the shell and medium are configured so that tag 120 has a nonlinear vibrational response to incident ultrasonic radiation. Ultrasound waves having a frequency f 1 , emitted by the acoustic generators outside the patient's body, strike the shell, imparting energy to the shell and/or the contained medium. The shell then emits ultrasound waves at its resonant frequency f 2 , which is different from f 1 . The resonant frequency is determined by parameters such as the shell radius, Young modulus and thickness, as is known in the art. Preferably, to generate strong echoes, the design parameters of tag 120 and the excitation frequency f 1 are chosen so that f 2 is a multiple of f 1 .
[0076] [0076]FIG. 10 is a schematic, pictorial illustration showing a system 125 for guiding surgical tool 76 to the location of tag 120 in breast 30 , in accordance with a preferred embodiment of the present invention. This embodiment also uses the combined location pad and display unit 84 described above. Multiple ultrasonic transducers 126 are applied to breast 30 . Each transducer in turn is driven to generate a pulse of ultrasonic energy at frequency f 1 , and then to detect the echo signal returned by tag 120 at frequency f 2 . Alternatively or additionally, all the transducers may detect the echo returned due to the ultrasonic pulses generated by a single one of the transducers. The time delay between generation of the ultrasonic pulse and receipt of the echo indicates the distance from each of transducers 126 to tag 120 . Alternatively or additionally, the power of the echo signal received by each of transducers 126 may be used to determine the distances.
[0077] To determine the actual location of tag 120 in breast 30 , however, it is necessary to know the locations of transducers 126 . For this purpose, a sensor coil 128 is attached to each of the transducers. Energizing field generator coils 70 in unit 84 causes currents to flow in sensor coils 128 . The amplitudes of these currents, as noted above, depend on the locations and orientations of the sensor coils relative to the field generator coils. Unit 84 analyzes the currents flowing in sensor coils 128 in order to determine the position coordinates of transducers 126 . Based on these coordinates, along with the distances measured by ultrasound reflection from each of transducers 126 to tag 120 , unit 84 is able to determine the exact location of the tag in a fixed, external frame of reference.
[0078] The location and orientation coordinates of tool 76 relative to unit 84 are determined using sensor 78 , as described above, so that the distance and direction from the tool to tag 120 can also be calculated and displayed.
[0079] It will be observed that system 125 uses two sets of position measurements to find the location of tag 120 : location of transducers 126 relative to unit 84 , and location of tag 120 relative to the transducers. This added level of complication is not present in the embodiments described earlier. On the other hand, by comparison with tags 20 , 54 and 81 , tag 120 is extremely simply and inexpensive to fabricate and can be made very small if desired. Typically, tag 120 has a diameter less than 2 mm.
[0080] [0080]FIG. 11 is a flow chart that schematically illustrates a method for performing a surgical procedure using system 125 , including tag 120 , in accordance with a preferred embodiment of the present invention. In this embodiment, too, the procedure starts with implantation of tag 120 by a radiologist at the site of a suspected lesion in breast 30 , at an implant step 130 . Preferably, for this purpose, the material of shell 122 is selected so as to be clearly visible using standard imaging techniques. Then, in preparation for surgery, transducers 126 are fixed to the skin of breast 30 around the location of tag 120 , at a transducer fixation step 132 .
[0081] In order to find the relative positions and orientations of tool 76 and transducers 126 , field generator coils 70 are actuated, and the currents flowing in sensor 78 and sensor coils 128 are measured, at a RF location step 134 . Alternatively, other position sensing techniques may be used for this purpose. For example, optical sensing techniques may be used to find the coordinates of tool 76 and of transducers 126 at step 134 , since both tool 76 and transducers 126 are outside the patient's body. Ultrasonic position sensing techniques may likewise be used.
[0082] Transducers 126 are actuated, and the echoes received by the transducers from tag 120 are measured, at an echo measurement step 136 . The echoes are used to determine the distance from each of transducers 126 to tag 120 , as described above. (The order of steps 134 and 136 may alternatively be reversed.) Unit 84 then performs the necessary geometrical calculations and transformations to find the position and orientation of tool 76 relative to tag 120 , at a triangulation step 138 . The distance of the tool from the tag and the orientation of the tool relative to the direct approach axis to the tag are shown on display 86 , at a display step 140 , as described above.
[0083] The surgeon uses the information presented by display 86 to guide the distal end of tool 76 to the location of tag 120 , at a probe guidance step 142 . The surgeon advances the tool into breast 30 , keeping cursor 94 centered on target 92 , as described above. Steps 134 through 142 are repeated continually until mark 90 indicates that the tool has reached the location of tag 81 , at a success step 144 . The biopsy or other desired procedure can then be performed.
[0084] Although the preferred embodiments described above all relate to breast surgery, and particularly to breast biopsy, the devices and methods used in these embodiments may also be adapted to other procedures and to treatment of other body organs. For example, tags such as those described above may be implanted in body tissues to be treated by high-intensity focused radiation. Such techniques are typically used for ablation of tumors and other lesions inside the body. In therapeutic applications of this sort, the radiologist would implant the tag at the location to be treated, and the radiation sources to be used for the treatment would then be aimed at the tag location. Referring again to FIG. 10, for instance, if transducers 126 were of a type suitable to be used in high-intensity focused ultrasound (HIFU) treatment, they could be oriented and aimed toward the location of tag 120 using the position signals and display generated by unit 84 .
[0085] [0085]FIG. 12 is a schematic, pictorial illustration showing the use of tag 20 in a bronchoscopy procedure, in accordance with a preferred embodiment of the present invention. Tag 20 is fixed to a suspicious nodule 154 , which was discovered during an imaging procedure performed in a lung 150 of a patient 152 . A bronchoscope 156 is used to inspect and, possibly, to biopsy nodule 154 . It is also desirable to be able to return easily to the same nodule location for follow-up in subsequent bronchoscopic examinations. A physician 157 operates bronchoscope 156 by grasping and manipulating a handle 158 . Bronchoscope comprises elements similar to tool 32 shown in FIG. 2: antenna assembly 36 (suitably adapted and miniaturized) at the distal end of the bronchoscope, and display 38 on handle 158 . While viewing the display, physician 157 turns a steering knob 160 and advances the bronchoscope into lung 150 until it reaches the location of nodule 154 .
[0086] Although this embodiment is based on tag 20 , as shown in FIG. 1, the other RF-based tags described above (such as tag 54 shown in FIG. 4) may also be used for this purpose. Tags based on the use of ultrasound, on the other hand, are typically less satisfactory for pulmonary applications.
[0087] [0087]FIG. 13 is a schematic, pictorial illustration showing the use of tag 120 in a colonoscopy procedure, in accordance with a preferred embodiment of the present invention. In this example, tag 120 is fixed to a polyp 164 that was discovered in a colon 162 of a patient. Ultrasound transducers 126 (as shown in FIG. 10, but not in this figure) are fixed to the patient's abdomen, to enable the location of tag 120 to be determined, in the manner described above. A colonoscope 160 is advanced through colon 162 , and its position is tracked by means of sensor 78 . As the distal end of the colonoscope approaches the location of tag 120 , unit 84 displays the distance and direction from the colonoscope to the tag. Optionally, an icon indicating the position of tag 120 is superimposed on a video image of the interior of colon 162 that is formed by an image sensor in the colonoscope and displayed on a suitable video display.
[0088] Although the preferred embodiments described above are directed to certain specific medical and surgical procedures in particular body organs, other areas of application of the tags, ancillary equipment and methods of the present invention will be apparent to those skilled in the art. The principles of the present invention may similarly be applied to other types of surgery, including particularly minimally-invasive surgery, as well as endoscopic and non-invasive treatment and diagnostic modalities.
[0089] It will thus be appreciated that the preferred embodiments described above are cited by way of example, and that the present invention is not limited to what has been particularly shown and described hereinabove. Rather, the scope of the present invention includes both combinations and subcombinations of the various features described hereinabove, as well as variations and modifications thereof which would occur to persons skilled in the art upon reading the foregoing description and which are not disclosed in the prior art.
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Apparatus for performing a medical procedure on a tissue within a body of a subject includes a wireless tag configured to be fixed to the tissue and adapted to emit radiation, thereby causing first signals to be generated indicative of a location of the tag in the body. An invasive medical tool includes a probe, which is adapted to penetrate into the body so as to reach the tissue. A handle is fixed proximally to the probe, for manipulation by an operator of the tool. A display, mounted on the handle, presents a visual indication to the operator of an orientation of the probe relative to the tag. A processing unit processes the first signals so as to determine coordinates of the tag relative to the probe, and drives the display responsive to the coordinates.
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TECHNICAL FIELD
The present invention relates to a steering column attachment assembly and a method of use, and more specifically, a steering column attachment assembly for securing and adjustably locating a steering column to a dashboard assembly of an automotive vehicle.
BACKGROUND
Restoration and customizing of antique automobiles has become a growing hobby, and as result, created an entire automotive component industry focused on making original equipment (“OE”) replacement parts and improved aftermarket parts. An increased interest in hot rodding relatively newer cars by replacing original equipment manufacturer (“OEM”) parts with higher performance alternatives has also contributed to this burgeoning automotive component industry.
Replacement parts, whether styled after the OEM parts or improved versions are made for all major areas of the automobile, including for example, engine components, chassis components, interior cabin parts, steering assemblies, suspension kits, drive-train assemblies, frame and body parts. Reasons for replacement of various automotive components are not just to improve performance or to return the car to original condition by replacing worn or broken parts, but replacement also occurs for aesthetic reasons, including the appearance of replacement parts. Replacement parts can offer a new shape or be made from or covered in a new type of material such as stainless steel or chrome that might be preferred by the car owner over the OEM equipment.
The steering assemblies include steering components such as a steering column, steering gear box, rack and pinion, power steering pump and linkage parts such as tie rods and universal joints, all of which are often of interest for replacement by restorers and hot rodders of automobiles. The steering assemblies on many older vehicles may have relatively poor performance compared to modern designs. Owners of such older vehicles or hot rodders seeking to improve steering performance may replace OEM or aftermarket equipment with better performing or more reliable assemblies. Alternatively, the appearance of new steering assembly components can justify replacement by some enthusiasts.
SUMMARY
One example embodiment of the present disclosure includes a steering column attachment assembly for adjustably locating and securing after market steering columns to an automotive vehicle. The attachment assembly comprises a penannular flexible insert having inner and outer portions. The inner portion is contoured to the geometry of a steering column and includes an opening for receiving the steering column and the outer portion of the flexible insert comprising a plurality of sides. The attachment assembly further comprises a strap clamp having inner and outer regions and an opening provided to the inner region for receiving the penannular flexible insert. The inner region and outer region are formed from a plurality of sides corresponding to the plurality of sides of the outer portion of the flexible insert such that the plurality of sides of the flexible insert and corresponding plurality of sides of the inner region of the strap clamp are in contact during assembly. The strap clamp yet further comprises first and second upper region sides in the inner and outer region and a plurality of adjustable compression members adjustably located in the first and second upper sides to engage with the flexible insert. Spaced first and second radius ends extend along the flexible insert opening that compress and lock the steering column attachment assembly to the column when the compression members engage the flexible insert.
Another example embodiment of the present disclosure includes a steering column attachment assembly for adjustably locating and securing steering columns to an automotive vehicle. The attachment assembly comprises a penannular flexible insert having inner and outer portions. The inner portion is contoured to the geometry of a steering column, having an opening for receiving the steering column and the outer portion of the flexible insert comprising a plurality of sides. The attachment assembly further comprises a strap clamp having inner and outer regions and an opening provided to the inner region for receiving the penannular flexible insert. The inner region and outer region are formed from a plurality of sides corresponding to the plurality of sides of the outer portion of the flexible insert such that the plurality of sides of the flexible insert and corresponding plurality of sides in the inner region of the strap clamp are in contact during assembly. The strap clamp yet further comprises first and second upper region sides in the inner and outer region and a plurality of adjustable compression members for adjustably locating in the first and second upper region sides to engage with the flexible insert. Spaced first and second radius ends extend along the flexible insert opening that compress and lock the steering column attachment assembly to the column when the compression members engage the flexible insert. The attachment assembly further comprises a securing bracket that is positioned over the strap clamp for securing the strap clamp to the automotive vehicle. The securing bracket comprises first and second lower faces with attachment apertures for connecting corresponding fasteners to corresponding threaded connections located in first and second lower region sides located in the outer region plurality of sides of the strap clamp.
A further example embodiment of the present disclosure includes an attachment assembly for adjustably locating and securing a steering column to an underside of an automotive vehicle dashboard. The attachment assembly comprises a penannular flexible insert for protecting the column to be attached from scratching and adjustably locating and securing the column to the automotive vehicle having inner and outer portions. The inner portion is contoured to the outer geometry of a steering column and includes an opening for receiving the steering column. The outer portion of the flexible insert comprises first and second upper portion sides connected to respective first and second lower portion sides, and a bottom portion side connecting the first lower portion to the second lower portion. The attachment assembly further comprises a strap clamp featuring inner and outer regions and an opening provided to the inner region for receiving the penannular flexible insert. The inner region and outer region are formed from first and second upper region sides connected to respective first and second lower region sides, and a bottom region side connecting the first lower region side to the second lower region side. The first and second lower inner region and bottom inner region sides of the strap clamp are in contact during assembly with the first and second lower portion and bottom portion sides of the outer portion of the flexible insert, respectively. The strap clamp further comprises through the first and second upper region sides a plurality of tapped apertures for receiving adjustable compression members to engage with the first and second upper portion sides of flexible insert. Spaced first and second radius ends extending along the flexible insert opening compress and lock the steering column attachment assembly to the column when the compression members engage the flexible insert. The attachment assembly yet further comprises a securing bracket that is positioned over the strap clamp for securing the strap clamp to the automotive vehicle. The securing bracket features first and second lower faces with attachment apertures for connecting corresponding fasteners to corresponding threaded connections located in the first and second lower region sides in the outer region of the strap clamp.
BRIEF DESCRIPTION OF THE DRAWINGS
The foregoing and other features and advantages of the present invention will become apparent to one skilled in the art to which the present invention relates upon consideration of the following description of the invention with reference to the accompanying drawings, wherein like reference numerals refer to like parts throughout the drawings unless otherwise noted and in which:
FIG. 1 is a perspective exploded view of a typical steering column of the prior art illustrating welded lugs located along the shaft of the steering column;
FIG. 1A is a magnified view of a portion of the perspective view of FIG. 1 ;
FIG. 1B is a magnified assembled view of FIG. 1A ;
FIG. 2 is an exploded isometric view of a steering column attachment assembly constructed in accordance with one example embodiment of the present disclosure;
FIG. 3 is a magnified view of a portion of FIG. 2 ;
FIG. 4 is an exploded isometric view of a steering column attachment assembly secured to a steering column assembly;
FIG. 5 is a sectioned perspective view of a steering column attachment assembly secured to a steering column assembly;
FIG. 6 is an exploded perspective view of a steering column attachment assembly constructed in accordance to another embodiment of the present disclosure;
FIG. 7 is an elevated view of a securing bracket constructed in accordance with one embodiment of the present disclosure; and
FIG. 8 is an end view of FIG. 5 .
DETAILED DESCRIPTION
The present invention relates to a steering column attachment assembly and a method of use, and more specifically, a steering column attachment assembly for securing and adjustably locating a steering column to a dashboard assembly of an automotive vehicle.
The steering column attachment assembly of the present invention provides inter alia, versatility during installation of aftermarket or generic steering columns as well adjustability features that allow the location of the steering columns to be uniquely located to a desired position suitable to the owner or driver of the automotive vehicle.
Conventional OEM steering columns are secured to a vehicle dashboard using a number of lugs welded along the shaft of the column and attached by a mounting bracket, as illustrated by the steering assembly 10 in FIG. 1 . The steering assembly 10 of the prior art includes a steering wheel 12 attached to a column 14 at a first end 14 a and a second end 14 b that passes through the vehicle fire wall to a steering gear assembly (not shown). The steering column 14 typically includes four (4) pre-welded threaded lugs 16 that are received by corresponding apertures 18 in mounting bracket 20 , as best seen in FIG. 1A .
The mounting bracket 20 typically includes a main arcuate body 22 that surrounds the column 14 and a pair of supporting flanges 24 at the ends of the body for attaching the mounting bracket and steering column to a dashboard 26 of the vehicle. During assembly, the mounting bracket 20 is positioned such that the lugs 16 align with the apertures 18 for receiving an attachment bolt 36 , as best seen in FIG. 1B . A slot 28 is located in each respective support flange 24 for securing the mounting bracket and column 14 to the dashboard 26 via a respected mounting bolt 30 and threaded receiving hole 32 on the underside 34 of the dashboard 26 . The slots 28 allow for flexibility in positioning the bracket 20 based on the fixed location of the column controlled by the location of the lugs 16 and receiving holes 32 . Respective holding bolts 36 are fastened to each respective lug 16 , passing partially through and securing the mounting bracket 20 into the assembled position of FIG. 1B .
The typical OEM steering assembly 10 and illustrated method of attachment provides numerous shortcomings, including misaligned locations between lugs 16 illustrated for example by dimensions A and B in FIG. 1A or variance in location from a datum illustrated by dimension C in FIG. 1 . The misalignment or variance in location is typically a result of relaxed tolerances during manufacturing or poor quality. As a result, when steering columns 14 are removed and replaced with new or different columns, the lugs on the new or replacement column may not align with the bracket 20 or allow the bracket to align with receiving holes 32 . Such shortcomings are resolved by the novel construct and design of the steering column attachment assembly of the present disclosure.
Referring now FIG. 2 is an exploded isometric view of a steering column assembly 80 secured by a steering column attachment assembly 100 constructed in accordance with one example embodiment of the present disclosure. The steering column assembly 80 includes a steering wheel 102 attached to a column 104 comprising a cylindrical shaft 106 having a first end 106 a attached to the steering wheel and a second end 106 b that passes through the vehicle fire wall or floor panel 108 to a steering gear assembly (not shown). The steering column 104 in the illustrated embodiment is secured by the steering column attachment assembly 100 to an underside 110 of a dashboard 112 . The steering column 104 is typically a cylindrical shaft 106 having approximately a two-inch diameter.
The steering column attachment assembly 100 of the present disclosure attaches about the cylindrical shaft 106 of the column 104 as illustrated in FIGS. 2 and 3 , but could equally secure any geometrical shape or diameter column without departing from the spirit and scope of the claimed invention. In addition, the illustrated embodiment of FIGS. 2-3 depict the column 104 being attached to the under side 110 of the dashboard 112 , but could equally secure the column to any number of securing fixtures provided by the OEM other than dashboards used in automotive vehicles.
The steering column attachment assembly 100 comprises a penannular flexible insert 118 , a strap clamp 120 , and securing bracket 122 , as best seen in FIGS. 6-8 . The flexible insert 118 can be made from an elastomeric or polymeric material, and in the illustrated embodiment, the flexible material is ethylene propylene diene monomer (“EPDM”). The penannular flexible insert 118 includes an opening 124 , an inner portion 126 , and outer portion 128 . The inner portion comprises a dimension (“R”), slightly larger than the outer dimension of the column 104 , and in the illustrated embodiment FIGS. 2-3 , the inner portion is slightly larger than the diameter of the cylindrical shaft 106 of the column.
The outer portion 128 and strap clamp 120 comprise a five-sided pentagon. The outer portion 128 includes upper sides 130 , 132 , lower sides 134 , 136 and bottom 138 that are received in inner opening 140 of the strap clamp 120 in corresponding upper sides 142 , 144 , lower sides 146 , 148 , and bottom 150 , respectively. The outer portion 128 of the flexible insert 118 and corresponding sides and bottom are slightly smaller to allow for a slip-fit insertion of the flexible insert into an inner region 152 of the strap clamp as best illustrated in FIG. 3 . The upper sides 130 , 132 comprise radius ends 153 of increased thickness (“t 1 ”) that extend the length of the opening 124 for gripping the column 104 .
The strap clamp 120 in the illustrated example embodiment of FIG. 2 is made from steel and includes an outer region 154 . Located along the upper sides 142 , 144 are four (4) threaded or tapped holes 156 for receiving fasteners 158 . In the illustrated embodiment of FIG. 6 , fasteners 158 are ¼-28×⅜ inch long socket head (cup-point) set screws and the strap clamp is made from approximately 3/16 of an inch thick steel (“t 2 ”). Attached to the lower sides 146 , 148 of the strap clamp 120 are four (4) lugs 160 substantially symmetrically located about each lower side and with respect to each lower sides. In the illustrated embodiment of FIG. 6 , the lugs 160 are threaded to receive a 5/16-18 threaded fastener. Additionally, the flexible insert 118 , strap clamp 120 , and bracket 122 are all of approximately same length (“L”), and in the illustrated embodiment of FIG. 6 the length L is approximately four (4) inches. Each side and bottom in the illustrated embodiment is approximately two (2) inches in width (“w”).
The securing bracket 122 is similarly constructed as the OEM mounting bracket 20 . In fact, the flexible insert 118 and strap clamp 120 are designed to be received by most OEM mounting brackets. In an alternative embodiment, the steering column attachment assembly 100 comprises only the flexible insert 118 and strap clamp 120 , using an OEM mounting bracket to attach the steering column attachment assembly to the dashboard 112 or equivalent fixture. The securing bracket 122 of the illustrated embodiment comprises tangs 161 for securing dashboard 112 material or foam for aesthetic purposes.
In the illustrated embodiment of FIG. 3 , the securing bracket 122 is shown, attaching the strap clamp 120 and insert 118 to the underside 110 of the dashboard 112 , but could equally be attached by an OEM bracket without departing from the spirit and scope of the claimed invention. FIG. 7 is a side elevation view of the securing bracket 122 constructed in accordance with one embodiment of the present disclosure. FIG. 8 is a cross sectional end view of FIG. 5 , illustrating the interconnecting relationship between the flexible insert 118 , strap clamp 120 , and securing bracket 122 once assembled.
The securing bracket 122 comprises an opening 162 , an inner area 164 , outer area 166 , securing flanges 168 , 170 , outer ends 172 , 174 , upper sides 176 , 178 , lower sides 180 , 182 , and bottom 184 . The securing bracket 122 in the illustrated example embodiment is made from is made from approximately 0.13 inches thick or 10 gauge steel and lower sides 180 , 182 and bottom 184 are slightly larger than corresponding lower sides 146 , 148 and bottom 150 of the strap clamp 120 to allow for a slip-fit insertion into the securing bracket as best illustrated in FIG. 8 . Located in lower sides 180 , 182 are fastening apertures 186 that are drill-through openings for receiving the body of corresponding fasteners 187 that pass through and thread into the strap clamp 120 , attaching the securing bracket 122 to the strap clamp. In the illustrated embodiment of FIG. 3 , the fasteners 187 are ⅜ inch bolts. The securing flange 168 and 170 include slots 188 for attaching the securing bracket 122 to the dashboard 112 by fasteners 190 in dash threaded fastener openings 192 .
The steering column attachment assembly 100 allows any generic column to be secured to a dashboard 112 of an automotive vehicle without worry of tolerances or lack thereof in pre-welded lugs. The strap clamp 120 further advantageously allows the column to be axially adjusted (see arrows A in FIG. 2 ) such that the location of the steering wheel 102 is at a desired location for the owner of the automotive vehicle. This is because the strap clamp 120 (unlike welded lugs on the steering column) can move up and down the column without restraint until the column is positioned in its desired location.
During installation, the flexible insert 118 is inserted into the inner opening 140 of the strap clamp 120 such that the respective lower sides and bottom are in contact with each other forming a moveable assembly 200 . The opening 124 of the flexible insert 118 and coupled strap clamp 120 of the moveable assembly 200 are inserted over the steering column 104 , as illustrated in FIG. 4 , wherein the flexible insert and strap clamp encapsulate more than half the steering column represented by dimension (“h”) illustrated in FIG. 8 . At this point of the installation, the moveable assembly 200 can move up and down (see arrows A in FIG. 4 ) the steering column 104 until the column is in the desired location of the automobile vehicle owner. When the steering column 104 is in its desired location, the moveable assembly 200 is positioned in a final location 210 such that the fastening apertures 186 of the securing bracket 122 align with the lugs 160 , allowing the fasteners 187 to connect with the lugs and the securing slots 188 to align with dash fastener openings 192 for the connecting of fasteners 190 .
When the final location 210 shown in FIG. 3 is determined, the fasteners 158 are inserted and tightened, drawing the flexible insert 118 and its radius ends 153 to lock the moveable assembly 200 into the final location along the column 104 . The radius ends 153 advantageously engulf and compress against the column 104 when the fasteners 158 are tightened, forming a locking distance (“d”<) smaller than the overall diameter (“D”) (see FIG. 8 ) of the column. The final location 210 is further secured to the column 104 by the pentagonal shape of both the flexible insert 118 and strap clamp 120 by upper sides 130 , 132 and 142 , 144 , respectively and fasteners 158 as illustrated in FIG. 8 .
Once the moveable assembly 200 is secured into the final location 210 , the securing bracket 122 or OEM mounting bracket is inserted over the moveable assembly such that the fastening apertures 186 align with respective lugs 160 . The securing bracket 122 or OEM mounting bracket is then attached to the dash 112 by inserting fasteners 190 through the respective securing slots 188 into dash threaded fastener openings 190 , thereby holding the steering column assembly 80 into a fixed location. Fasteners 187 are then used to further secure the moveable assembly 200 to the OEM mounting bracket or securing bracket 122 as shown in FIG. 8 .
What have been described above are examples of the present invention. It is, of course, not possible to describe every conceivable combination of components or methodologies for purposes of describing the present invention, but one of ordinary skill in the art will recognize that many further combinations and permutations of the present invention are possible. Accordingly, the present invention is intended to embrace all such alterations, modifications, and variations that fall within the spirit and scope of the appended claims.
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A steering column attachment assembly is disclosed for adjustably locating and securing after market steering columns to an automotive vehicle. The attachment assembly comprises a penannular flexible insert having inner and outer portions. The outer portion of the flexible insert comprises a plurality of sides. The attachment assembly also comprises a strap clamp having inner and outer regions and an opening provided to the inner region for receiving the flexible insert. The inner region and outer region are formed from a plurality of sides corresponding to the plurality of sides of the outer portion of the flexible insert such that the plurality of sides of the flexible insert and corresponding plurality of sides of the inner region of the strap clamp are in contact during assembly. The strap clamp features a plurality of adjustable compression members that engage the flexible insert.
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BACKGROUND
A chloralkali process is a process that produces chlorine or a related oxidizer and an alkaline salt such as sodium hydroxide (“NaOH,” also known as lye and caustic). Chlorine and NaOH are among the most produced chemicals in the world and are used in the manufacturing of a wide range of materials and products.
An exemplary chloralkali process is illustrated in FIG. 1 . The figure illustrates a typical brine electrolysis process 100 known to those skilled in the art using an electrolyzer. The electrolyzer of the illustrated typical brine electrolysis process 100 is a membrane cell 101 . The membrane cell 101 includes an anode compartment 102 , which contains an anode 103 and a cathode compartment 104 , which contains a cathode 105 . The anode and cathode compartments 102 , 104 are separated from each other by a membrane 106 . By way of example, the membrane 106 separating the anode and cathode compartments may be an ion exchange membrane. The membrane 106 separating the anode and cathode compartments may be operable to allow sodium ions and water to pass therethrough while preventing unreacted sodium chloride (NaCl) from entering the cathode compartment 104 . A direct current 107 may be passed through the anode 103 and cathode 105 . A stream 111 of saturated brine may be fed into the anode compartment 102 where chlorine from the NaCl is liberated at the positively charged anode 103 . A portion of the chlorine, in the form of a gas, may be collected 112 from the anode compartment 102 . Positively charged sodium ions from the NaCl migrate through the membrane 106 separating the anode and cathode compartments into the cathode compartment 105 .
In the cathode compartment 104 , hydrogen gas evolves from water molecules at the negatively charged cathode 105 . The hydrogen gas may be collected 108 from the cathode compartment 104 . The evolution of hydrogen from water also produces hydroxyl ions that react with the sodium ions to form NaOH. A portion of the NaOH is withdrawn 110 from the cathode compartment 104 . Water may be added 109 to, and the NaOH may be withdrawn 110 from, the cathode compartment 104 to maintain desirable levels of NaOH in the cathode compartment 104 . Accordingly, the overall reaction for the described chloralkali process is:
2NaCl+2H 2 O→Cl 2 +H 2 +2NaOH
A depleted brine (e.g., brine no longer saturated with NaCl) stream 113 may be removed from the anode compartment 102 . The depleted brine may be processed through brine processing 114 that prepares a saturated brine stream 111 to be fed into the anode compartment. Accordingly, a brine loop 115 comprises brine processing 114 to produce a saturated brine stream 111 , feeding the saturated brine stream 111 into the anode compartment 102 , the anode compartment 102 , and removing depleted brine from the anode compartment 102 via a depleted brine stream 113 which is then fed back into the brine processing 114 .
FIG. 2 illustrates a typical prior art brine loop 115 used in brine electrolysis. Hydrochloric acid (HCl) is added 201 to the depleted brine stream 113 removed from the anode compartment 102 to adjust the pH levels (e.g., increase acidity) of the depleted brine stream 113 . This reduces the solubility of chlorine gas within the stream. The depleted brine stream 113 may then be subjected to vacuum dechlorination 202 where chlorine gas is drawn 203 from the depleted brine stream 113 . A vacuum dechlorinated depleted brine stream 204 may be fed from vacuum dechlorination 202 and into chemical dechlorination 206 . NaOH may be added 205 to the vacuum dechlorinated depleted brine stream 204 to adjust the pH upward (e.g., to make the depleted brine stream neutral or slightly alkaline). The NaOH may also help to stop gaseous chlorine from evolving from the dechlorinated depleted brine stream 204 . The chemical dechlorination 206 may be achieved in a variety of ways known to those skilled in the art (e.g., by adding reducing agents such as sodium bisulfite (NaHSO 3 ) and/or sodium sulfite (Na 2 SO 3 )).
After chemical dechlorination 206 , the dechlorinated stream may be fed into a saturation step 207 where NaCl 208 may be added to create a saturated brine stream and water 209 may be added to replenish the volume of the stream and adjust the concentration of NaCl. Typically the NaCl 208 may include varying amounts of impurities that must be removed in order to run the membrane cell 101 at a high current efficiency. Major impurities typically include calcium, magnesium and sulfates. To remove these major impurities, the saturated brine stream may be passed through a precipitation process 210 . This is typically a reactor or reactors where sodium carbonate (Na 2 CO 3 ) and NaOH are added 211 to precipitate calcium carbonate (CaCO 3 ) and magnesium hydroxide (Mg(OH) 2 ). Depending on the particular impurities present, other reactions may be promoted.
The outflow of the precipitation process 210 may contain suspended solids from the precipitation process 210 and therefore is typically passed through a separation process 213 . The separation process 213 may include the use of one or more gravity settlers, and/or one or more media filters including pre-coat and non pre-coat filters. The separation process may, for example, remove 212 precipitated CaCO 3 and Mg(OH) 2 . The saturated brine stream may next be exposed to an optional activated carbon bed 214 to further remove any residual oxidizing materials. The saturated brine stream exiting the activated carbon bed 214 , or the brine stream exiting the separation process 213 if an activated carbon bed 214 is not present, may still contain unacceptable levels of impurities. To further remove these impurities (e.g., calcium, magnesium, iron), the saturated brine stream may next be passed through an ion exchange process 215 that may include passing the saturated brine stream through a column containing an ion exchange resin. After the ion exchange process 215 , the saturated brine stream 111 may be fed into the anode compartment 102 to complete the brine loop 115 .
Known variations exist with respect to the above-described exemplary processes. For example, by altering process chemistry and temperature, the membrane cell 101 can be used to produce chlorate. It is also known by those skilled in the art that various steps as shown in the brine loop 115 may be added, altered or removed based on, inter alia, the quality of materials used in the process or manufacturing considerations. For example, in a particular brine loop, the activated carbon bed 214 may not be present, particularly if the levels of oxidizing materials in the brine stream after separation 213 are below a certain level. Furthermore, chloralkali processing may be achieved using, for example, mercury cells or diaphragm cells in place of the described membrane cells.
SUMMARY
The present inventors have recognized that the above brine processing may benefit from the replacement or enhancement of known separation processing with filtration. Filtration, as compared to known separation processing, may reduce system complexity, reduce system operating costs, and/or increase the quality of the saturated brine being delivered to the electrolyzer. The present inventors have also recognized that the above processes may contain contaminants, particularly organics introduced with the NaCl and/or process water. These organics may often include biological organics that may be characteristic of the NaCl source. Such biological contaminants may, for example, include humic acid and/or residue from algae in seawater. The organics may build up on and/or reduce the efficiency of filters used in a chloralkali process. Maintenance of filters, such as replacing the filters when they lose efficiency or cleaning the filters using known cleaning methods, such as the use of dedicated cleaning solutions, may be costly and time consuming and counterbalance the aforementioned benefits of the use of filtration.
In view of the foregoing, an object of embodiments described herein is to provide improved methods and apparatuses to clean filters used in chloralkali processes, thereby, for example, reducing the maintenance and operating costs associated with filtration while maintaining the benefits associated with filtration. In certain chloralkali processing plants, filtration may have previously been considered not to be economically feasible due to contamination levels and the associated costs of filtration (e.g., replacement costs and/or cleaning costs) due to those contamination levels. However, the reduced equipment, maintenance and operating costs associated with embodiments of filter washing methods and systems described herein may facilitate the use of filtration where contamination levels previously discouraged such use.
Another objective of embodiments described herein may be to provide a cleaning solution for cleaning filters used in chloralkali processes, thereby eliminating and/or reducing the need for separate chemicals and/or materials to clean the filters. Embodiments described herein may provide methods of washing filters in situ with cleaning solution from the chloralkali process and returning the cleaning solution to the chloralkali process after the filters are washed. Such embodiments provide filter washing systems that have low equipment and material requirements. Embodiments described herein may provide filter washing systems for chloralkali processes yielding reduced chemical and operating costs, improved in-process brine stream quality, and reduced equipment down time.
In an aspect, a method of brine electrolysis is provided. The method may include providing a brine feed and treating the brine feed to form a treated brine solution. The treating may include mixing the brine feed with reactants to precipitate solids. The method may further include filtering the treated brine solution with a filter material to form a brine filtrate and purifying the brine filtrate to form a purified brine. The purifying may include removing cations from the brine filtrate through an ion exchange process. The filter material may be a non-precoated filter material. The filter material may be a membrane filter and may comprise expanded polytetrafluoroethylene (ePTFE). The method may further include providing an electrolytic cell. The electrolytic cell may include a cathode disposed in a cathode compartment and an anode disposed in an anode compartment. A membrane (e.g., an ion exchange membrane) may separate the anode and cathode compartments from each other. The method may further include feeding the purified brine into the anode compartment. Within the anode compartment, chlorine may be liberated from the purified brine at the anode, and sodium ion and water may migrate from the anode compartment through the membrane separating the anode and cathode compartments to the cathode compartment. This egress of sodium ion and chlorine from the anode compartment may result in the formation of depleted brine within the anode compartment. The method may further include removing the depleted brine from the anode compartment, adding an acid (e.g., HCl) to the depleted brine removed from the anode compartment, and separating, after the adding an acid step, the depleted brine into a feed solution and a remaining portion. The feed solution may then be subjected to vacuum dechlorination and chemical dechlorination. The method may further include adding NaCl to the feed solution and adjusting the concentration of NaCl by adding water to form the brine feed. The method may further include contacting the filter material with the remaining portion. The contacting of the filter material with the remaining portion may remove material from the filter material. The removed material may include organic material and/or mineral scaling.
In another aspect, an improved method of brine electrolysis is provided. The method comprises a brine solution saturation step, a treatment step, a filtration step, an ion exchange step, an electrolysis step, and at least one dechlorination step. A first output of the at least one dechlorination step may be an input to the brine solution saturation step. The improvement of the method may comprise providing a second output from the at least one dechlorination step and contacting a filter of the filtration step with at least a portion of the second output. The contacting of the filter with the at least a portion of the second output may remove materials (e.g., organic materials and/or mineral scale) from the filter. The filter may be a membrane filter.
In an embodiment, the at least one dechlorination step may comprise a first vacuum dechlorination step and a second chemical dechlorination step. The second output may be disposed after the first vacuum dechlorination and before the second chemical dechlorination step. The second output may contain between about 0.01 parts per million (ppm) and about 200 ppm of active chlorine.
In an arrangement, the contacting step may include soaking the filter with the at least a portion of the second output. The contacting step may include circulating the at least a portion of the second output through the filter under pressure. The contacting step may include a combination of soaking and circulating.
In still another aspect, a method of electrolysis of filtered brine is provided. The method may comprise providing a brine feed solution, filtering the brine feed solution with a filter material to form a brine filtrate, and providing an electrolytic cell. The electrolytic cell may have a cathode disposed in a cathode compartment and an anode disposed in an anode compartment. A membrane may separate the cathode compartment from the anode compartment. The method may further comprise feeding the brine filtrate into the anode compartment. The brine filtrate may undergo electrolysis in the electrolytic cell, forming depleted brine in the anode compartment. The method may further comprise removing the depleted brine from the anode compartment and contacting the filter material with the depleted brine solution after the removing step. The contacting of the filter material with the depleted brine solution may remove at least some material (e.g., organic material and/or mineral scale) from the filter material. The filter material may include one or more filter membranes.
In yet another aspect, a method of washing a filter used in a chloralkali process is provided. The method may comprise isolating the filter from the chloralkali process, removing a portion of a flow of brine from within the chloralkali process, contacting the portion of flow to the isolated filter, and returning the filter to the chloralkali process after the contacting step. The removal of the portion of the flow of brine may be from a point in the chloralkali process between an output of a membrane cell and an input of a chemical dechlorination apparatus. The contacting of the portion of flow to the isolated filter may wash the filter.
The washing of the filter may result in the removal of organic materials and/or mineral scaling from the isolated filter. Regarding organic materials, the contacting step may comprise changing the organic material from a first state to a second state, wherein the organic material in the second state has a reduced affinity toward the filter relative to the organic material in the first state. By way of example, organic material in the second state may be less likely to be collected at the filter relative to organic material in the first state. Regarding mineral scaling, the portion of the flow may be acidic and the contacting step may comprise removing mineral scaling from the filter.
In an embodiment, the method may further comprise returning the portion of the flow to the chloralkali process after the contacting step. The portion of the flow may be returned to the chloralkali process between the output of the membrane cell and the input of the chemical dechlorination apparatus.
In an arrangement, the isolating step and the returning the filter step may comprise actuating one or more valves. In this regard, the filter may remain in situ during the performance of the method obviating the need to move the filter for cleaning.
The removed portion of the flow may comprise between about 0.01 ppm and about 250 ppm of active chlorine. In an embodiment, the portion of the flow may be removed from between the output of the membrane cell and an input of a vacuum dechlorination apparatus. In another embodiment, the portion of the flow may be removed from between an output of the vacuum dechlorination apparatus and an input of a chemical dechlorination apparatus. The portion of the flow may be returned to a point in the chloralkali process between an output of a vacuum dechlorination apparatus and an input of a chemical dechlorination apparatus.
The chloralkali process may include a plurality of filters. The current method may comprise performing the isolating, removing, contacting, returning the filter, and returning the portion of the flow steps for each of the plurality of filters. The method may be performed for each of the plurality of filters in succession. While the method is being performed on a particular one of the plurality of filters, the other filters of the plurality of filters may continue to filter the portion of the flow of brine that remained within the chloralkali process.
In still another aspect, an apparatus for washing a filter used in a brine loop of a chloralkali process is provided. The apparatus may comprise a wash tank, a first fluid interconnection, a second fluid interconnection, and a third fluid interconnection. The wash tank may be operable to hold a predeterminable volume of liquid. The first fluid interconnection may fluidly connect the wash tank and a portion of the brine loop between an output of a membrane cell and an input of a chemical dechlorination apparatus. The second fluid interconnection may be between the wash tank and an upstream side of the filter. The third fluid interconnection may interconnect the wash tank and a downstream side of the filter. The apparatus may be operable to cause fluid to flow from the wash tank, then through the filter, and then back to the wash tank.
In an embodiment, the filter may be a non-precoated filter and/or a membrane filter. The filter may comprise a fluoropolymer membrane. The fluoropolymer may, for example, comprise polytetrafluoroethylene (PTFE), ePTFE, and/or polyvinylidene difluoride (PVDF).
In an arrangement, the apparatus may further comprise a fourth fluid interconnection between the wash tank and a portion of the brine loop between an output of a vacuum dechlorination apparatus and an input of a chemical dechlorination apparatus. Furthermore, the first fluid interconnection may fluidly interconnect the wash tank and a portion of the brine loop between an output of the membrane cell and an input of a vacuum dechlorination apparatus. In the present arrangement, fluid may be operable to flow through the first fluid interconnection into the wash tank and through the fourth fluid interconnection from the wash tank. In this regard, in the current arrangement the apparatus may be operable to draw fluid into the wash tank, via the first fluid interconnection, from a point in the chloralkali process between the output of the membrane cell and the input of a vacuum dechlorination apparatus. Further in this regard, the apparatus may be operable to return fluid, via the fourth fluid interconnection, from the wash tank to a point in the chloralkali process between the output of the vacuum dechlorination apparatus and the input of the chemical dechlorination apparatus.
In an embodiment, the first fluid interconnection may be between the wash tank and a portion of the brine loop between an output of a vacuum dechlorination apparatus and an input of a chemical dechlorination apparatus. In such an embodiment, the apparatus for washing a filter may further comprise a fourth fluid interconnection between the wash tank and the portion of the brine loop between the output of the vacuum dechlorination apparatus and the input of the chemical dechlorination apparatus. In the instant embodiment, fluid may be operable to flow through the first fluid interconnection into the wash tank and through the fourth fluid interconnection from the wash tank. In this regard, the apparatus may be operable to draw fluid into the wash tank, via the first fluid interconnection, from a point in the chloralkali process between the output of the vacuum dechlorination apparatus and the input of the chemical dechlorination apparatus. Further in this regard, the apparatus may be operable to return fluid, via the fourth fluid interconnection, from the wash tank to a point in the chloralkali process between the output of the vacuum dechlorination apparatus and the input of the chemical dechlorination apparatus.
The apparatus may comprise a pump operable to selectively pump fluid from the wash tank through the second fluid interconnection, through the fourth fluid interconnection, or through a combination of the second and fourth fluid interconnections. In this regard, fluid pumped through the second fluid interconnection may contact the upstream side of the filter.
In an embodiment where the first fluid interconnection is between the wash tank and a portion of the brine loop between an output of a vacuum dechlorination apparatus and an input of a chemical dechlorination apparatus, the apparatus may be operable to selectively flow fluid through the first fluid interconnection into the wash tank or through the first fluid interconnection from the wash tank. In this regard, the first fluid interconnection may be used to selectively fill or empty the wash tank.
In an arrangement, the apparatus may further comprise at least one fluid pump operable to pump fluid from the wash tank through the second fluid interconnection and through the filter. In an arrangement, the filter may be disposed downstream from a precipitation apparatus and upstream from an ion exchange apparatus.
In an embodiment, the apparatus for washing a filter may be operable to cause fluid to flow from the wash tank, then through the second fluid interconnection, then through the filter, then through the third fluid interconnection, and then back to the wash tank. Valving may be included that is operable to fluidly isolate the filter from the brine loop of the chloralkali process. Valving may also be included that is operable to fluidly isolate the apparatus for washing a filter from the brine loop.
In a configuration the brine loop may comprise a plurality of filters. The plurality of filters may be divided into a plurality of sub-groups. In such a configuration, the apparatus for washing a filter may further comprise valving operable to fluidly isolate, in succession, each of the sub-groups from the brine loop of the chloralkali process. Each of the sub-groups may comprise one and only one of the plurality of filters. Alternatively, some of the sub-groups may include a single filter and some of the sub-groups may contain multiple filters. Alternatively, each of the sub-groups may include more than one of the plurality of filters.
The various methods discussed above may be performed manually, automatically, or through a combination thereof. Moreover, the initiation of the performance of any of the methods may be achieved in an automated fashion, manually, or through a combination of automated and manual actions. Similarly, the apparatuses discussed above may be operable to function automatically and/or manually.
The various features, arrangements and embodiments discussed above in relation to each aforementioned aspect may be utilized by any of the aforementioned aspects. Additional aspects and corresponding advantages will be apparent to those skilled in the art upon consideration of the further description that follows.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is block diagram of a prior art chloralkali process flow.
FIG. 2 is block diagram of a brine loop of the prior art chloralkali process flow of FIG. 1 .
FIG. 3 is a block diagram of an embodiment of an improved brine loop of a chloralkali process flow.
FIG. 4 is a block diagram of an apparatus for washing a filter used in a brine loop of a chloralkali process.
DETAILED DESCRIPTION
FIGS. 1 and 2 represent exemplary membrane cells 101 and brine loops 115 known to those skilled in the art of brine electrolysis and/or chloralkali processing. Variation to these processes and apparatuses are also known to those skilled in the art. Turning to the separation step 213 of the brine loop 115 of FIG. 2 , known separation systems typically incorporate gravity settlers and media filters operable to remove a portion of the suspended solids that remain in the brine after the preceding precipitation 210 step.
FIG. 3 is a block diagram of an embodiment of an improved brine loop 300 of a chloralkali process flow. In the improved brine loop 300 , the separation step 213 , has been replaced with a filtration step 308 . Alternatively, the separation step 213 (or portions thereof) may be retained and the filtration step 308 may be positioned downstream of the separation step 213 (or retained portion thereof). The filtration step 308 may incorporate one or more filters. The filters may be operable to filter out suspended solids, for instance CaCO 3 and Mg(OH) 2 , that remain in the brine stream after the precipitation process 210 . The filtration step 308 may incorporate known back-pulse filtration techniques to occasionally remove 312 accumulated particles (e.g., accumulated CaCO 3 and Mg(OH) 2 particles) from the filters. The filters may also be operable to filter organic contaminants from the brine stream. In this regard, organic contaminants may accumulate on the filters and at least a portion of the accumulated organics may not be removed by typical back-pulse filtration methods. Some mineral scaling may also accumulate on the filters. The mineral scaling may also be resistant to removal using typical back-pulse filtration methods. The organic contaminants may, for example, be introduced with the NaCl 208 and process water 209 introduced during the saturation step 207 . These organic contaminants may negatively affect the performance of the anode compartment 102 and/or other processing equipment in the brine loop 300 . Accordingly, it may be beneficial to filter out these organics at the filtration step 308 .
As organics are filtered from the brine stream by the filters, the performance of the filters may degrade as materials (e.g., filtered organics, mineral scaling) build up on the filters. In this regard, the filters may need to be replaced or the materials that have built up on the filters may need to be removed at regular intervals. Typically, filter replacement is expensive. Filter washing may be a less expensive alternative to replacement, but typically would require special filter washing equipment along with dedicated filter washing chemicals.
The brine loop 300 of FIG. 3 illustrates an efficient alternative to filter replacement and/or special filter washing equipment using dedicated filter washing chemicals. In the brine loop 300 , fluid is taken from the brine stream via connection 301 from a point in the brine loop 300 after vacuum dechlorination 202 and prior to the addition of NaOH 205 . Such fluid taken from the brine stream will subsequently be referred to as cleaning solution.
The cleaning solution typically has a low pH value (e.g., is acidic) and may contain 20 - 30 parts per million (ppm) of active chlorine. This cleaning solution may be diverted to a wash tank 302 . Water or other substances may be added to the cleaning solution to enhance the washing process. From the wash tank 302 , the cleaning solution may be pumped by a pump 303 and run through one or more of the filters. The cleaning solution may be allowed to remain in contact with the one or more filters such that the one or more filters soak in the cleaning solution for a certain amount of time or the cleaning solution may be continuously pumped through the one or more filters for a certain amount of time. A combination of soak time and pumping may also be utilized. After running through the one or more filters, the cleaning solution may return to the wash tank 302 via fluid interconnection 305 . It may then be recirculated through the one or more filters an appropriate number of times. The composition of the cleaning solution may be operable to change the organic contaminants that may have built up on the one or more filters from a first state to a second state, where the organic contaminants in the second state have a reduced affinity toward the one or more filters. Accordingly, the organic contaminants in the second state may pass through the one or more filters. One exemplary mechanism by which this may occur is where the cleaning solution breaks down (e.g., oxidizes) long chain molecules of the organic contaminants that may have built up on the one or more filters into smaller constituent parts that are no longer attracted to the one or more filters and therefore may pass through the one or more filters. Additionally, the cleaning solution, which as noted may have a low pH value, may also be operable to clean non-organic contamination (e.g., mineral scaling) from the one or more filters. In this manner, the one or more filters may be cleaned by exposure to the cleaning solution. Generally, the organic contaminants in the second state (e.g., reduced affinity toward the one or more filters) will not be harmful to the equipment used in the brine loop 300 . The cleaning time may depend on several variables including contamination levels of the NaCl and introduced water, time between cleaning, and desired filter efficiency and may range, for example, from several minutes to an hour or more.
After washing of the one or more filters as described above, the cleaning solution may be returned to the wash tank 302 . The pump 303 may then pump the cleaning solution back into the brine loop 300 , returning the cleaning solution via a cleaning solution return interconnection 306 to a point in the process between vacuum dechlorination 202 and chemical dechlorination 202 . It will be appreciated that by using already existing, in-process chemicals and returning those chemicals to the process, such a cleaning process requires no separate washing chemicals and can be performed with the one or more filters in situ.
In another configuration, the cleaning solution for the cleaning process may be obtained from the brine stream via fluid connection 307 at a point in the brine loop 300 after the addition of HCl 201 and prior to vacuum dechlorination 202 . The brine stream at this point typically has a low pH and may contain about 200 ppm of active chlorine. Such obtaining of the cleaning solution for the cleaning process may include separating at least a portion of the brine stream into a feed solution, which may continue into the vacuum dechlorination step, and the cleaning solution, which may proceed to the wash tank 302 .
In yet another configuration, a single fluid interconnection may exist between the wash tank 302 and pump 303 , and the point in the chloralkali process between vacuum dechlorination 202 and chemical dechlorination 206 . In such a configuration, the same fluid connection that is used to draw process fluid from the chloralkali process to the wash tank 302 may be used to return fluid from the wash tank 302 to the chloralkali process.
FIG. 4 illustrates an exemplary configuration of a filter washing system 400 integrated with a chloralkali process. The wash tank 302 is interconnected to the chloralkali process at a valve 403 disposed between a vacuum dechlorination apparatus 401 and a chemical dechlorination apparatus 402 . Valve 403 may selectively divert a portion of the flow of the chloralkali process (e.g., from the flow between vacuum dechlorination apparatus 401 and chemical dechlorination apparatus 402 ) to the wash tank 302 . Once a sufficient amount of flow, which will subsequently be referred to as cleaning solution, has been collected in the wash tank 302 , the valve 403 may be set so that the normal chloralkali process flow from vacuum dechlorination apparatus 401 to chemical dechlorination apparatus 402 may continue.
A filtration apparatus 404 may be used to complete the filtration step 308 . The filtration apparatus 404 may contain any appropriate number of filters, such as filter 405 a or 405 b . The input 406 to the filtration apparatus 404 may come from the preceding precipitation step 210 and the output 407 of the filtration apparatus 404 may continue to a subsequent processing step (e.g., activated carbon bed 214 or ion exchange 215 ). The filters may be non-precoated filters. Non-precoated filters may include any filter that separates solids from a fluid directly without the use of precoats or body aids. The filters may be in the form of membrane filters, tubes and/or filter bags. The filters may, for example, include one or more layers of PTFE, ePTFE, PVDF and/or other fluoropolymer membranes. ePTFE, in particular, generally is chemically inert and is operable to withstand exposure to a wide range of harsh chemical environments without significant damage. The filters may be comprised of laminates that include one or more of above-mentioned materials laminated to felts or woven fabrics. The filters may, for example, comprise nonwoven and/or spunbond fabrics of PVDF, polypropylene, and/or polyethylene.
To wash a filter, the filter must first be isolated from the chloralkali process flow. For example, to wash filter 405 a , valve 408 a may be changed form its normal operating position (connecting input 406 to filter 405 a ) to a position where only cleaning solution from a wash tank source line 409 may enter into the filter 405 a . Furthermore, valve 410 a may be changed form its normal operating position (connecting filter 405 a to output 407 ) to a position where flow from the filter 405 a is diverted back to the wash tank 302 via a wash tank return line 411 . In this regard, the filter 405 a may be isolated from the chloralkali process flow and interconnected to the membrane filter washing system 400 . Meanwhile, other filters of the filtration apparatus 404 , such as filter 405 b may remain interconnected to the chloralkali process flow and may continue to operate in a normal fashion. The sizes and quantities of the various filters of the filtration apparatus 404 may be selected so that the chloralkali process flow may not be interrupted when one or more of the filters is removed form the chloralkali process flow for washing.
Once the filter 405 a is isolated from the chloralkali process flow and interconnected to the filter washing system 400 , the pump 303 may be activated and cleaning solution from the wash tank 302 may be circulated through the wash tank source line 409 , through valve 408 a , through filter 405 a , through valve 410 a , through wash tank return line 411 , and back into wash tank 302 . The fluid may be circulated in such a manner to wash the filter 405 a until the filter 405 a is satisfactorily cleaned. During the process, the pump 303 may be turned off or slowed down and the filter 405 a may be allowed to soak in the cleaning fluid. A combination of washing and soaking may be utilized to clean the filter 405 a.
Once the cleaning of the filter 405 a is completed, the cleaning solution may be returned to the wash tank 302 . The filter 405 a may then be rinsed, for example with water, to remove residual oxidizer that may present. The filter 405 a may then be returned to the chloralkali process flow by changing valve 408 a back to its normal operating position (connecting input 406 to filter 405 a ) and changing valve 410 a back to its normal operating position (connecting filter 405 a to output 407 ). A valve 412 may be then set to connect the wash tank 302 to the chloralkali process flow at a point 413 between the vacuum dechlorination apparatus 401 and the chemical dechlorination apparatus 402 . The pump 303 may then be activated and the cleaning solution may be pumped from the wash tank 302 back to the chloralkali process flow at point 413 .
Other filters of the filtration apparatus 404 may be washed in a similar manner. For example, filter 405 b may be washed by using valves 408 b and 410 b to isolate filter 405 b from the chloralkali process and interconnect the filter 405 b to the filter washing system 400 .
The washing of the filters described above may be achieved in an automated fashion, manually, or through any combination thereof. For example, once a washing cycle is initiated, the wash tank 302 may be automatically filed, the filter to be cleaned may be automatically isolated from the chloralkali process, the washing cycle may be automatically conducted, and then the cleaning solution may be automatically returned to the chloralkali process.
The initiation of the washing cycle may also be automated or it may be operator-initiated. For example, sensors (e.g., flow sensors, pressure sensors) may monitor the performance of the filters within the filtration apparatus 404 and a washing cycle may be automatically initiated when the monitored performance of a particular filter meets predetermined criteria (e.g., once a predetermined pressure drop across a filter is sensed). Alternatively, a technician may monitor the performance of the filtration apparatus 404 and initiate a washing cycle when certain conditions are met. In another exemplary method of initiation of a washing cycle, washing cycles may be manually or automatically initiated at predetermined intervals (e.g., based on time or flow). The length of the predetermined intervals may be dependent on many factors, such as contamination levels, contamination composition, and desired filter efficiency.
The foregoing description of embodiments has been presented for purposes of illustration and description. Furthermore, the description is not intended to limit the present invention to the forms disclosed herein. Consequently, variations and modifications commensurate with the above teachings, and skill and knowledge of the relevant art, are within the scope of the present invention as defined by the claims that follow.
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Filter wash methods and apparatuses for chloralkali processes are provided. The filter wash uses in-process fluids from the chloralkali process to wash filters. The in-process fluids may be drawn from a point in the chloralkali process where the in-process fluids contain active chlorine values such as bleach. A filter may then be isolated from the chloralkali process and contacted with the in-process fluids containing active chlorine values to wash the filter. The in-process fluids containing active chlorine values may be operable to oxidize organic material clinging to the filter, thereby cleaning the filter. After washing, the in-process fluids containing active chlorine values may be returned to the chloralkali process to a point at or near where they were drawn from. The filters may be membrane filters. The filters may comprise expanded polytetrafluoroethylene.
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DISCUSSION OF RELATED ART
Since the beginning of basketball, the slam dunk has been a popular athletic aspiration. Unfortunately, many people are unable to reach the rim. Although basketball is athletically demanding, some skills can be enhanced through a variety of devices.
Basketball assistance devices have been invented to make basketball easier and more fun. U.S. Pat. No. 5,833,557 to inventor Edward W. Cole discloses a two player trampoline basketball game structure with trampoline surfaces for basketballs to bounce within its framework. The structure provides trampolines for the basketballs assisting shots made by players. U.S. Pat. No. 5,967,911 to Oliver D. McAvoy shows a basket ball return used on a regular basketball court and placed under the basketball pole and net. This wedge shaped ramp returns a basketball to the player after the ball goes through the net.
Trampolines have also assisted basketball players in reaching the rim. Unfortunately, trampoline injuries are very common and risk of injury increases when the game is played on a trampoline. A variety of devices have been invented to make trampolines and jumping safer. U.S. Pat. No. 4,875,548 to Peter Lorsbach shows jump rescue apparatus having a rebound surface made of tensioned fabric held in an inflatable tube framework. U.S. Pat. Nos. 6,053,845, 6,261,207 to Publicover shows an enclosure net and frame for a trampoline having eight steel poles. Unfortunately, a user may be injured when accidentally jumping into a pole. A variety of other similar net and webbing structures have been used to make trampolines safer.
OBJECT OF THE INVENTION
An inflatable basketball structure on a trampoline allows height challenged users the opportunity to slam-dunk and otherwise fulfill athletic basketball fantasies in a safe environment.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a top view of the basketball structure.
FIG. 2 is a perspective view of the basketball structure.
FIG. 3 is a rear view of the basketball structure.
FIG. 4 is a side view of the basketball structure showing inflation chambers.
FIG. 5 is a side view of the basketball structure showing crumple zones.
FIG. 6 a is a perspective view of the basketball structure attached to a trampoline enclosure.
FIG. 6 b is a perspective view of the basketball structure attached to a trampoline enclosure.
FIG. 7 is a perspective view of the basketball structure attached to a circular inflatable enclosure.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The inflatable basketball structure resembles an ordinary basketball apparatus and includes an inflatable basketball backboard 150 , an inflatable basketball rim 160 , a basketball net 162 , an inflatable supporting pole 170 , and an inflatable safety enclosure 180 . FIG. 2 . The members are made of one or more inflatable cells. Several members can be made of a single cell. Each individual inflatable cell has an airtight inflatable chamber having an inflation valve 230 . The inflation valve 230 permits air to be introduced and removed from the chamber. Alternately, the airtight inflatable chamber can be outfitted with more than one valve 230 , an inflation valve and a separate deflation valve where the inflation valve only inflates the chamber and the deflation valve only deflates the chamber. FIG. 1 .
Members may be formed of an outside jacket layer providing additional structural support as an exoskeleton for an inside inflatable member inflated against the outside jacket layer to prevent buckling of the outside jacket layer. 840D Nyon with PU coating or a 1100D PVC Tarpaulin with Polyester Substrate are typical semi rigid fabric materials. The inside inflatable member can be made of 0.35 mm PVC with plasticizer and can be regulated by a supplied air pressure regulating device and air pump. FIG. 3 The inflatable basketball backboard 150 , inflatable basketball rim 160 , basketball net 162 , inflatable supporting pole 170 , and inflatable safety enclosure 180 are formed of an outside jacket layer providing additional structural support as an exoskeleton for an inside inflatable member inflated against the outside jacket layer to prevent buckling of the outside jacket layer.
Basketball Basket
The basketball rim 160 is made of a hoop of inflatable or padded material. A standard basketball net 162 can be used on the inflatable basketball hoop 160 by attaching the net 162 to the hoop 160 by means of detachable hook and loop tape. The hoop 160 holds the net via the hook and loop tape where a hook side is disposed on either the net or hoop and the loop side is disposed on the other side. The net detaches if a user's fingers are caught in the net.
The rim is attached to the backboard. The junction between the hoop and the backboard is reinforced by elastic cord that restores the hoop 160 to neutral position after a user dunks on the hoop. Elastic cord 161 connects the backboard to the hoop. The rim is flexible in relationship to the backboard and can flex when a user slam dunks. The backboard is in turn attached to the backboard pole. The backboard 150 can be made of a single planar rectangular inflatable member.
The backboard 150 has an outside jacket layer restraining an inflated inside inflatable member. The outside jacket layer is a tough and more rigid fabric providing additional structural support as an exoskeleton. The inside inflatable backboard member is inflated against the outside jacket layer to prevent buckling of the outside jacket layer. The outside jacket layer restrains the inside inflatable member from expansion beyond the size of the outside jacket layer. Alternatively, the backboard can also be made of a planar rectangular rigid core enveloped on the rear side by an inflatable member.
Supporting Pole
The inflatable basketball pole 170 is hollow and inflatable. Optionally, the pole has an outside jacket layer restraining an inflated inside inflatable member. The outside jacket layer is a tough and more rigid fabric providing additional structural support as an exoskeleton. Again, 840D Nyon with PU coating or a 1100D PVC Tarpaulin with Polyester Substrate are typical semi rigid fabric materials. The inside inflatable member is inflated against the outside jacket layer to prevent buckling of the outside jacket layer. The inside inflatable member can be made of 0.35 mm PVC with plasticizer and can be regulated to 2 psi tolerance by a supplied air pressure regulating device and air pump. The outside jacket layer restrains the inside inflatable member from expansion beyond the size of the outside jacket layer. The inside inflatable member is an inflatable airtight member having an inflation valve. The member has a single inflation valve 230 .
The height adjustable pole can height adjust by either forming intermediate inflation chambers FIG. 4 , 174 and FIG. 3 , 174 or a crumple zone FIG. 5 , 176 . In the first inflation chamber embodiment FIG. 4 , 174 , a number of intermediate independent chambers 174 have individual air inflation valves and form preferably a pair of independent inflation chambers. In the inflation chamber embodiment, the base portion of the inflatable basketball pole supports a number of independent chambers. The independent chambers in turn support the upper portion of the inflatable basketball pole. A user may inflate or deflate one or more of the chambers to raise or lower the height of the basketball hoop, rim, and backboard. Upon deflation of the independent chambers, the upper portion of the basketball pole decreases to a lower height, without affecting the air pressure of the base portion of the inflatable basketball pole or the upper portion of the inflatable basketball pole.
A user then secures the upper, lower and intermediate portions by pairs of upper and lower straps 178 of hook and loop tape. The upper and lower strap 178 maintains the relative position of the members in the inflation chamber 174 embodiment. The upper straps begin at a location above the upper intermediate inflation chamber 174 and secures to a corresponding lower strap 178 below the lowest intermediate inflation chamber 174 . Buttons or other hardware attachment means may connect the straps 178 to each other. The preferred means for securing the opposing pair of straps 178 is hook and loop tape. Similarly, a user can increase the height of the basket by detaching the straps and inflating the intermediate chambers 174 .
In the second basketball pole embodiment, FIG. 5 a crumble zone 176 is a user height adjustable section 176 of the basketball pole that allows a user to adjust the height of the basket. Unlike the inflation chamber embodiment, the crumble zone embodiment 176 has a single cell representing the basketball pole. The crumble zone 176 is a location on the basketball pole that can be deflated and restricted in height by a plurality of straps 178 , or other restriction means, so that the zone does not inflate to full height when restricted by a height restriction means.
The crumble zone 176 is defined by height restriction means such as upper straps 178 that connect to lower straps 178 . Upper straps connecting to lower straps allow partial inflation of the crumble zone 176 . When the air pressure is at full inflation air pressure, the crumble zone 176 is also at full pressure. The crumble zone 176 deflates upon deflation of the entire enclosure.
Instead of straps 178 , the sleeve representing the outside shell of the basketball pole can be modified to have height adjustable means. Common size adjustment means commonly used in shells of luggage applications include zippers closing a cascade of flaps to allow a user to zip up and contract selected portions of sleeves thus setting the full inflation height of the crumble zone. Here, a similar flap system can be used.
A user determines the desired height of the basket rim and can adjust straps and set the straps to the proper height. The proper height is marked on the straps. Once the straps are in place, the user inflates the device. The crumple zone straps 178 limit the total height of the basket rim while maintaining rigid inflation. The crumple zone 176 can be scored or prefolded to create a standard folding pattern that allows the zone 176 a specific repetitively formed shape instead of a random crumpled shape.
The net has hook and loop tape connecting the net 162 to the rim 160 . The loop side is attached to the net 162 while the hook side is attached to the rim 160 . If a user has a finger caught in the net, the net detaches to prevent injury to the user. The present embodiment further includes and an elastic cord 172 attaching the back of the backboard to the spine of the basketball pole. The spine is the rearward portion facing away from the face of the backboard. The elastic cord 172 restores the position of the backboard after a user dunks. The elastic cord 172 can be threaded through loops or a continuous sleeve stitched into the spine of the basketball pole. A plurality of elastic cords 172 may be used depending upon the restoring force desired. An elastic cord 172 connects the upper and lower portion in a similar manner and reinforces the hook and loop tape. The basketball pole has an outside covering that can be enveloped around the pole.
Enclosure
The crumple zone shares air pressure with the basketball pole and main wall members 182 , 184 , 186 . An air pump 122 can assist in maintaining air pressure by providing air to the enclosure and the basketball pole. The air pump 122 is preferably attached to the base of the enclosure, constantly providing air input. The inflatable structure enclosure 180 retains a basketball inside the enclosure by mesh netting 190 . Retaining the basketball enhances users safety and fun.
The three main wall members forming the enclosure includes the left wall 182 , the right wall 184 and the rear wall 186 . The standard wall consists of a top tubular member attached to a pair of side tubular members attached to a bottom tubular member. The four tubular members form a frame defining an aperture that is enclosed by netting stretched to span across the aperture. The inflatable basketball structure can be mounted on a trampoline with the left wall, right wall, and rear wall resting on the periphery of the rectangular trampoline. A rope or strap retains the enclosure to the trampoline frame and can attach the left wall 182 , right wall 184 and rear wall 186 to the frame.
The preferred embodiment has a rectangular enclosure with three main walls. Alternate embodiments may use circular or semicircular wall configurations. A wall includes a structure of inflatable frame members with netting spanning between inflatable frame members.
In an alternate freestanding embodiment, the basketball pole 170 , basket and rim 160 are separately inflated from the enclosure 180 . The assembly of the basketball pole, basket and rim forms a freestanding unit resting on the basketball pole base having no air communication with the protective enclosure 180 . The freestanding inflatable pole 170 is attached to the protective enclosure 180 by mounting straps 188 or mounting cord 188 and can be reconfigured to attach to other structures by mounting straps 188 or a mounting cord 188 .
The freestanding embodiment maximizes user configuration options and allows the basketball pole member 170 to be separated from the protective enclosure and attached to other non-inflated or inflated protective trampoline enclosures. Non-inflated protective trampoline enclosures having solid steel frames and retaining mesh netting are widely used. Some are described in U.S. Pat. Nos. 6,053,845, and 6,261,207 to Publicover. The freestanding inflatable pole can be attached to a wide variety of non-inflated structures by means of straps or cord.
The inflatable basketball structure may comprise an inflatable safety enclosure having three walls defining a semicircular instead of rectangular enclosure, and here the trampoline provided is a circular trampoline. The rear wall can be made of a frame formed by tube members or left without a mesh netting for an open appearance.
Call Out List of Elements
122 Air Pump
150 Basketball Backboard
160 Basketball Rim
161 Elastic Cord For Hoop
162 Basketball Net
170 Supporting Pole
172 Supporting Pole Shock Cord
174 Supporting Pole Height Adjustment Chamber
176 Supporting Pole Height Adjustment Zone
178 Supporting Pole Height Adjustment Straps
180 Safety Enclosure
182 Safety Enclosure Left Wall
184 Safety Enclosure Right Wall
186 Safety Enclosure Rear Wall
188 Safety Enclosure Tie Down Strap
190 Mesh Netting
200 Trampoline
220 Mounting Straps
230 Air Valve
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The inflatable basketball structure includes an inflatable basketball backboard, an inflatable basketball rim, a basketball net, an inflatable supporting pole, and an inflatable safety enclosure. The inflatable basketball structure on a trampoline allows height challenged users the opportunity to slam-dunk and otherwise fulfill athletic basketball fantasies in a safe environment.
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COPYRIGHT NOTICE
[0001] A portion of the disclosure of this patent document contains or may contain copyright protected material. The copyright owner has no objection to the photocopy reproduction by anyone of the patent document or the patent disclosure in exactly the form it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever.
TECHNICAL FIELD
[0002] This invention relates to a process to enhance the removal of water from wet gluten in a gluten dewatering operation. The invention allows for the improved dewaterability of the gluten solids by the addition of an anionic polymer such as sodium polyacrylate to a wet gluten stream prior to the dewatering step. The present invention is also effective with the use of a vacuum filtration and pressure filtration units.
BACKGROUND
[0003] In the wet milling of corn, the dry corn kernels processed in a series of unit operations in order to separate the four primary components of the corn kernel starch, germ, gluten and fiber. The first step in the process is inspection and cleaning of the corn where damaged or cracked kernels as well as foreign material that may have come in during shipping or harvest are removed. The next step is stepping where the kernels are soaked in water with 0.1% SO2 for 30 to 50 hours in order to hydrate and soften the kernels. During the steeping process the starch-gluten bonds are broken down in order to prepare the kernels for further processing. The steeped kernels are then sent to a grinding mill where they are essentially cracked open to expose the germ. The germ is removed, washed and dried by mechanical means in a number of different unit operations and then sent to a corn oil refining operation for further processing. The process stream containing the starch, fiber and gluten is then sent to a secondary grinding process where a much finer grind is performed. The fiber fraction is separated from the stream by filtration, washed and dried in a number of mechanical unit operations. The fiber fraction, which also contains the hull is sent to the feed house for incorporation in one of the animal feed co-products referred to as corn gluten feed. The remaining process stream containing the starch, gluten and water is sent to a series of bowl type or disk nozzle centrifuges. In these centrifuges the starch and gluten are separated from one another based upon the density difference of the two materials. The process stream containing the starch fraction is referred to as mill starch is then sent to a series of mechanical operations where the starch will be washed, concentrated and then dried. The starch can then be transferred to another part of the processing plant a raw material for a use in a number of different processes or products like conversion to fructose or dextrose.
[0004] The remaining stream containing the gluten, which at this point is called light gluten is processed in centrifuges where the solids are concentrated to about double that of the incoming stream and are referred to as heavy gluten. The heavy gluten containing 12% to 16% by weight solids is then dewatered using rotary drum vacuum filters to produce a gluten cake typically containing 35 to 40% solids. The gluten is transferred to the feed house operation by screw conveyor where the material will be dried to 88% solids and will be used as the primary component of a high value feed co-product referred to as corn gluten meal.
[0005] The steep water is typically concentrated by evaporation in order to recover the soluble protein extracted in the steeping process. Once concentrated it will be combined with fiber and hull extracted earlier in the wet milling process and dried to 88% solids to produce corn gluten feed.
[0006] In the corn wet milling process the fractionation of the corn kernel is an energy intensive process. There are a lot of mechanical unit operations involved in the various cleaning, separation and drying steps that must occur in order to prepare each of the primary components for the downstream processing operations. The gluten dewatering and drying process accounts for the second largest energy usage or about 28% of the total energy used in the corn wet milling operation. The gluten dewatering and drying process begins at the centrifuges just after the starch fraction is removed and the light gluten is transferred to a holding tank. The light gluten stream contains the bulk of the insoluble protein recovered in the wet milling process. The light gluten from the holding tank is pumped to the gluten concentration centrifuges, which are bowl type centrifuges used to concentrate the gluten solids from 7% to about 14% by weight solids. The heavy gluten is sent to a holding tank for further processing. The heavy gluten is then pumped to rotary drum vacuum filters, which are typically connected in parallel and are used to dewater the heavy gluten. The filters typically produce a gluten cake with a solids content in the range of 35% to 40% by weight solids. Depending upon size and throughput a typical wet mill may have as many as 5 or 10 large rotary drum vacuum filters in operation. Some plants may utilize horizontal vacuum belt filters such as a Larox Pannevis filter while others may utilize a pressure filtration devices like a Pneumapress pressure filter or Larox pressure filters. The operational parameters for the filters have optimized by the filter manufacturers and the operation personnel in the plants to achieve a balance between solids throughput and gluten cake moisture content. As the industry has have gradually improved the throughput and efficiency of some of the up front end processing techniques in the wet milling process for some plants the gluten dewatering process has become a production bottleneck. The production bottleneck in some plants may limit or reduce some of the production efficiencies gained in the front end of the plant.
[0007] The use of surfactants type chemistries in the corn wet milling process for gluten dewatering is known and is discussed in the flowing patents.
[0008] U.S. Pat. No. 5,283,322 discloses the use of selected nonionic surfactants for enhancing gluten dewatering. The nonionic surfactants claimed are those of the family of oxyalkylated sorbitan fatty esters, which are applied to the gluten stream and then processed, in the dewatering device.
[0009] U.S. Pat. No. 5,840,850 discloses the use of selected anionic surfactants for enhancing gluten dewatering. The anionic surfactants claimed are those particularly the sulfates and sulfonates, which are applied to the gluten stream and then processed, in the dewatering device.
[0010] U.S. Pat. No. 3,362,829 discloses a process for coating vital wheat gluten/powdered) with nonionic hydrophilic lipid selected from the class consisting of monoglycerides, salts of lactylic esters of fatty acids, polyoxyethylene stearate, and stearyl monoglyceridyl citrate whereby the gluten particles are characterized by stability against particle cohesion in neutral aqueous dispersions. The use of polyoxyethylene sorbitan monostearate in combination with hydrophilic lipids is also disclosed. It also discusses the use of a surface active agent to aid in initial dispersion of the vital wheat gluten.
[0011] The use of other pressure filtration equipment in the corn wet milling process for gluten dewatering is known and is discussed in the flowing patents.
[0012] U.S. Pat. No. 4,774,009 discloses a process for dewatering slurry streams produced from a corn wet milling process, and more particularly, a method for dewatering slurry product streams containing gluten, starch and bran using an automatic pressure filter.
SUMMARY
[0013] The current invention describes the following key aspects:
1. It is an advantage of the invention to assist in the dewatering of gluten. 2. It is an advantage of the invention to provide a method of production whereby a more stable form of the product is achieved. 3. It is an advantage of the invention allows a process logic that enabling a continuous or semi-continuous production of the gluten. 4. Provides a method for uninterrupted production. 5. Provides a method for improved production and throughput
DETAILED DESCRIPTION
[0019] The present inventors discovered that the addition of an anionic polymer of sodium polyacrylate to a wet gluten stream prior to the dewatering step enhanced the dewaterability of the gluten on the vacuum filtration and pressure filtration equipment. The typical gluten production process is a multiple step process in which the gluten dewatering process is a rate limiting step in both solids throughput and recovery. The conventional practice for gluten dewatering is concentration by centrifuge to 12-14% suspended solids, dewatering on a vacuum drum filter to 40% solids and then drying the gluten to greater than 88% solids (or less than 12% moisture) for storage and handling.
[0020] In particular it has been discovered that the addition of anionic polymer of sodium polyacrylate prior to dewatering in a filtration device at concentrations of 10 ppm to 2000 ppm significantly improve the dewatering ability of the filtration equipment. The dosages referenced are based upon product actives and the composition or dry solids content of the gluten stream being treated. The composition of the active polymer can be a homopolymer of Sodium acrylate or a copolymer with any of the following monomers: Sodium (Meth)acrylate, acrylamido-propylsulfonic acid sodium salt, acrylamide, methacrylamide, N-methylacrylamide, N,N-dimethyl acrylamide, vinylpyrolidone, N-vinylformamide, hydroxyethylacrylate.
[0021] Both laboratory tests and pilot testing have shown that the dewaterability of gluten can be improved by 5% to 30% in both vacuum filtration and pressure filtration equipment. The degree of improvement may be dependent upon the dosage of the processing aid and the composition and characteristics of the particular gluten stream.
EXAMPLES
[0022] All testing was conducted using process samples provided by major U.S. corn wet milling facilities. Samples used for the testing were obtained from several different sampling points in the gluten concentration and dewatering process. Samples of light gluten were collected from sampling points between the starch/gluten separation centrifuge and the gluten dewatering centrifuge. Samples of heavy gluten were collected from sampling points between the starch/gluten separation centrifuge and the rotary drum vacuum filters.
[0023] A modified buchner funnel technique was used as the laboratory testing apparatus. The testing apparatus was equipped with a vacuum sensing apparatus connected to a monitor with data logging capabilities. Suitable paper filters were used as the filtration media for the lab testing instead of standard filter cloth in order to eliminate the potential impact of residual material from sequential testing runs. The use of replaceable filter paper also reduced the effect of fouling of the filter fabric due to accumulation of the protienacious material on the surface and in the pores of the filter. The use of a filter paper also allowed solids determination of the entire gluten cake sample generated in the testing.
[0024] The laboratory experiments consisted of obtaining a suitable size sample of the desired gluten slurry for testing. The samples were continuously mixed to maintain sample homogeneity. A recirculated water bath was used to maintain the gluten at the desired temperature for testing. The gluten slurry was analyzed for total solids, total dissolved solids and total suspended solids in order to determine the desired sample size for testing. The desired test sample was then weighed out on a balance and conditioned with an appropriate dosage of the processing aid. The samples were placed on a programmable gang stirrer so that each sample received uniform mixing. The rapid mix and slow mix as well as standing time and mix speed rpm could be optimized for the particular sample or processing aid treatment. The samples would then be transferred to the buchner funnel apparatus into which had been placed a pre-weighed filter paper. The data acquisition system was used to collect the data from the vacuum dewatering profile of the sample. The vacuum source was maintained at 20 inches of mercury throughout the testing period. At the completion of the testing, the sample would be removed from the vacuum apparatus and a wet weight of the gluten cake was determined. The gluten cake sample was then dried to constant weight at in an oven in order to allow determination of the gluten cake moisture content. The raw data from the vacuum profiles then be plotted and analyzed in order to draw comparisons between the different treatment programs, scenarios and testing parameters. In most cases multiple runs of each sample were conducted in order to establish a baseline and eliminate some of the inherent variability in the testing method and sample consistancy. Data analysis ands comparisons were conducted on individual runs as well on data averages from multiple runs.
[0025] In each of the following examples a different gluten sample was tested. Tables 1 thru 11 provide summary tables for the results from each series of tests. Table 12 describes the processing aids that were evaluated in the testing.
EXAMPLE 1
[0026] This example illustrates the improved dewater ability of the heavy gluten as a result of treatment with selected processing aids. Multiple tests were conducted in order to eliminate some of the variability in the testing. In this testing gluten samples of 200 g were evaluated. Data from the testing showed that on average an 18.6% improvement in the rate of dewaterability was observed on the samples treated with Nalco TX-13368 prior to dewatering. The data also showed that the effective dosages were in the range of 200 to 400 ppm of product as treated. Testing also showed that TX-12621 was not effective in improving the rate of dewaterability.
[0000]
TABLE 1
Time to Vacuum
% Improvement
Sample
Break (min)
(avg Untreated)
Untreated
7.33
−3.79
Untreated
6.75
4.42
Untreated
7.25
−2.65
Untreated
6.92
2.02
Average
7.06
0.00
100 ppm TX-13368
6.50
7.96
200 ppm N-TX13368
5.33
24.53
200 ppm N-TX13368
6.17
12.64
Average
5.75
18.58
400 ppm TX-13368
5.83
17.45
600 ppm TX-13368
5.42
23.26
800 ppm TX-13368
5.17
26.80
100 ppm TX-12621
7.33
−3.79
300 ppm TX-12621
7.00
0.88
600 ppm TX-12621
6.92
2.02
750 ppm TX-12621
8.33
−17.95
EXAMPLE 2
[0027] This example illustrates the improved dewater ability of the heavy gluten as a result of treatment with selected processing aids. Multiple tests were conducted in order to eliminate some of the variability in the testing. In this testing gluten samples of 200 g were evaluated. Data from the testing showed that on average a 22.7% improvement in the rate of dewater ability was observed on the samples treated with Nalco TX-13368 prior to dewatering. The data also showed that the effective dosages were in the range of 400 to 500 ppm of product as treated.
[0000]
TABLE 2
Time to Vacuum
% Improvement
Sample
Break (min)
(avg Untreated)
Untreated
6.08
−1.00
Untreated
5.58
7.31
Untreated
6.25
−3.82
Untreated
6.17
−2.49
Average
6.02
0.00
400 ppm N-TX13368
4.83
19.77
400 ppm N-TX13368
4.50
25.25
400 ppm N-TX13368
5.00
16.94
400 ppm N-TX13368
4.25
29.40
400 ppm N-TX13368
4.67
22.43
Average
4.65
22.76
500 ppm N-TX13368
5.17
14.12
500 ppm N-TX13368
4.58
23.92
500 ppm N-TX13368
4.92
18.27
500 ppm N-TX13368
4.50
25.25
Average
4.79
20.39
EXAMPLE 3
[0028] This example illustrates the improved dewater ability of the heavy gluten as a result of treatment with selected processing aids. Multiple tests were conducted in order to eliminate some of the variability in the testing. In this testing gluten samples of 200 g were evaluated. Data from the testing showed that on average a 4.8% to 23.5% improvement in the rate of dewater ability was observed on the samples treated with Nalco TX-13368 prior to dewatering. The data also showed that the effective dosages were in the range of 200 to 500 ppm of product as treated.
[0000]
TABLE 3
Time to Vacuum
% Improvement
Sample
Break (min)
(avg Untreated)
Untreated
4.75
3.06
Untreated
4.83
1.43
Untreated
4.92
−0.41
Untreated
4.75
3.06
Untreated
5.25
−7.14
Average
4.90
0.00
200 ppm N-TX13368
4.42
9.80
200 ppm N-TX13368
4.33
11.63
200 ppm N-TX13368
5.08
−3.67
200 ppm N-TX13368
4.83
1.43
Average
4.67
4.80
300 ppm N-TX13368
4.17
14.90
300 ppm N-TX13368
4.33
11.63
300 ppm N-TX13368
4.42
9.80
300 ppm N-TX13368
4.75
3.06
Average
4.42
9.85
400 ppm N-TX13368
4.33
11.63
400 ppm N-TX13368
4.08
16.73
400 ppm N-TX13368
4.33
11.63
400 ppm N-TX13368
4.17
14.90
Average
4.23
13.72
500 ppm N-TX13368
3.92
20.00
500 ppm N-TX13368
3.58
26.94
Average
3.75
23.47
EXAMPLE 4
[0029] This example illustrates the improved dewater ability of the heavy gluten as a result of treatment with selected processing aids. Multiple tests were conducted in order to eliminate some of the variability in the testing. In this testing gluten samples of 200 g were evaluated. Data from the testing showed that on average a 14.5% improvement in the rate of dewater ability was observed on the samples treated with Nalco TX-13368 prior to dewatering. The data also showed that the effective dosages were in the range of 400 ppm of product as treated. Data also shows that Tween 80N was not effective in dewatering the heavy gluten. The data also shows that Nalco 8681 was not effective in improving the dewater ability of the heavy gluten.
[0000]
TABLE 4
Time to Vacuum
% Improvement
Sample
Break (min)
(avg Untreated)
Untreated
6.33
5.94
Untreated
6.67
0.89
Untreated
7
−4.01
Untreated
6.92
−2.82
Average
6.73
0.00
400 ppm N-TX13368
5.75
14.56
400 ppm N-TX13368
6.17
8.32
400 ppm N-TX13368
5.08
24.52
400 ppm N-TX13368
6.00
10.85
Average
5.75
14.56
250 ppm Tween 80
7.00
−4.01
500 ppm Tween 80
7.17
−6.54
1000 ppm Tween 80
7.67
−13.97
1000 ppm Tween 80
7.50
−11.44
250 ppm N-8681
11.67
−73.40
500 ppm N-8681
20.67
−207.13
Average
16.17
−140.27
EXAMPLE 5
[0030] This example illustrates the improved dewater ability of the heavy gluten as a result of treatment with selected processing aids. Multiple tests were conducted in order to eliminate some of the variability in the testing. In this testing gluten samples of 200 g were evaluated. Data from the testing showed that on average a 35.8% improvement in the rate of dewater ability was observed on the samples treated with Nalco TX-13368 prior to dewatering. The data also showed that the effective dosages were in the range of 400 ppm of product as treated.
[0000]
TABLE 5
Time to Vacuum
% Improvement
Sample
Break (min)
(avg Untreated)
Untreated
1
14.38
Untreated
1.17
−0.17
Untreated
1.17
−0.17
Untreated
1.08
7.53
Untreated
1.42
−21.58
Average
1.17
0.00
400 ppm N-TX13368
0.92
21.23
400 ppm N-TX13368
0.83
28.94
400 ppm N-TX13368
0.75
35.79
400 ppm N-TX13368
0.67
42.64
400 ppm N-TX13368
0.58
50.34
Average
0.75
35.79
EXAMPLE 6
[0031] This example illustrates the improved dewater ability of the heavy gluten as a result of treatment with selected processing aids. Multiple tests were conducted in order to eliminate some of the variability in the testing. In this testing gluten samples of 100 g and 200 grams were evaluated. Data from the testing with 100 gram samples showed that on average a 12.4% improvement in the rate of dewater ability was observed on the samples treated with Nalco TX-13368 prior to dewatering. Data from the testing with 200 gram samples showed that on average a 7.5% improvement in the rate of dewater ability was observed on the samples treated with Nalco TX-13368 prior to dewatering The data also showed that the effective dosages were in the range of 400 ppm of product as treated.
[0000]
TABLE 6
Time to Vacuum
% Improvement
Sample
Break (min)
(avg Untreated)
Untreated
1.08
−3.05
Untreated
1.17
−11.64
Untreated
1.08
−3.05
Untreated
1.08
−3.05
Untreated
0.83
20.80
Average
1.05
0.00
400 ppm N-TX13368
0.92
12.21
400 ppm N-TX13368
0.92
12.21
400 ppm N-TX13368
0.83
20.80
400 ppm N-TX13368
0.92
12.21
400 ppm N-TX13368
1.00
4.58
Average
0.92
12.40
200 g Samples
Untreated
3.08
7.60
Untreated
3.25
2.50
Untreated
3.67
−10.10
Average
3.33
0.00
400 ppm N-TX13368
2.83
15.10
400 ppm N-TX13368
3.00
10.00
400 ppm N-TX13368
3.42
−2.60
Average
3.08
7.50
Example 7
[0032] This example illustrates the improved dewater ability of the heavy gluten as a result of treatment with selected processing aids. Multiple tests were conducted in order to eliminate some of the variability in the testing. In this testing gluten samples of 100 g were evaluated. Data from the testing showed that on average a 19.4 to 27.7% improvement in the rate of dewater ability was observed on the samples treated with Nalco TX-13368 prior to dewatering. The data also showed that the effective dosages were in the range of 200 ppm to 400 ppm of product as treated.
[0000]
TABLE 7
Time to Vacuum
% Improvement
Sample
Break (min)
(avg Untreated)
Untreated
1.92
4.10
Untreated
2.08
−3.90
Untreated
2.17
−8.39
Untreated
1.92
4.10
Untreated
1.92
4.10
Average
2.00
0.00
400 ppm N-TX13368
1.42
29.07
400 ppm N-TX13368
1.50
25.07
400 ppm N-TX13368
1.42
29.07
Average
1.45
27.74
300 ppm N-TX13368
1.67
16.58
300 ppm N-TX13368
1.75
12.59
300 ppm N-TX13368
1.42
29.07
Average
1.61
19.41
200 ppm N-TX13368
1.67
16.58
200 ppm N-TX13368
1.42
29.07
200 ppm N-TX13368
1.67
16.58
Average
1.59
20.75
Example 8
[0033] This example illustrates the improved dewater ability of the heavy gluten as a result of treatment with selected processing aids. Multiple tests were conducted in order to eliminate some of the variability in the testing. In this testing gluten samples of 100 g were evaluated. Data from the testing showed that on average a 35.6% improvement in the rate of dewater ability was observed on the samples treated with Nalco TX-13368 prior to dewatering. The data also showed that the effective dosages were in the range of 200 to 400 ppm of product as treated.
[0000]
TABLE 8
Time to Vacuum
% Improvement
Sample
Break (min)
(avg Untreated)
Untreated
1.5
−3.69
Untreated
1.42
1.84
Untreated
1.42
1.84
Average
1.45
0.00
400 ppm N-TX13368
1.00
30.88
400 ppm N-TX13368
0.67
53.69
400 ppm N-TX13368
1.17
19.12
Average
0.95
34.56
Example 9
[0034] This example illustrates the improved dewater ability of the heavy gluten as a result of treatment with selected processing aids. Multiple tests were conducted in order to eliminate some of the variability in the testing. In this testing gluten samples of 100 g were evaluated. Data from the testing showed that on average a 7.1 to 26.5% improvement in the rate of dewater ability was observed on the samples treated with Nalco TX-13368 prior to dewatering. The data also showed that the effective dosages were in the range of 200 to 500 ppm of product as treated.
[0000]
TABLE 9
Time to Vacuum
% Improvement
Sample
Break (min)
(avg Untreated)
Untreated
1.17
8.88
Untreated
1.25
2.65
Untreated
1.33
−3.58
Untreated
1.25
2.65
Untreated
1.42
−10.59
Average
1.28
0.00
200 ppm N-TX13368
1.25
2.65
200 ppm N-TX13368
1.25
2.65
200 ppm N-TX13368
1.08
15.89
Average
1.19
7.06
300 ppm N-TX13368
1.00
22.12
300 ppm N-TX13368
1.17
8.88
300 ppm N-TX13368
1.25
2.65
Average
1.14
11.21
400 ppm N-TX13368
1.17
8.88
400 ppm N-TX13368
1.00
22.12
400 ppm N-TX13368
1.00
22.12
Average
1.06
17.71
500 ppm N-TX13368
0.92
28.35
500 ppm N-TX13368
1.08
15.89
500 ppm N-TX13368
0.83
35.36
Average
0.94
26.53
Example 10
[0035] This example illustrates the improved dewater ability of the heavy gluten as a result of treatment with selected processing aids. Multiple tests were conducted in order to eliminate some of the variability in the testing. In this testing gluten samples of 100 g were evaluated. Data from the testing showed that on average a 13.4 to 17.4% improvement in the rate of dewater ability was observed on the samples treated with Nalco TX-13711 prior to dewatering. The data also showed that the effective dosages were in the range of 200 to 500 ppm of product as treated.
[0000]
TABLE 10
Time to Vacuum
% Improvement
Sample
Break (min)
(avg Untreated)
Untreated
5.33
2.20
Untreated
5.17
5.14
Untreated
5.5
−0.92
Untreated
5.33
2.20
Untreated
5.92
−8.62
Average
5.45
0.00
400 ppm N-TX13711
4.42
18.90
400 ppm N-TX13711
4.58
15.96
400 ppm N-TX13711
4.50
17.43
Average
4.50
17.43
300 ppm N-TX13711
4.50
17.43
300 ppm N-TX13711
4.42
18.90
300 ppm N-TX13711
5.17
5.14
Average
4.70
13.82
200 ppm N-TX13711
5.08
6.79
200 ppm N-TX13711
4.83
11.38
200 ppm N-TX13711
4.25
22.02
Average
4.72
13.39
Example 11
[0036] This example illustrates the improved dewater ability of the heavy gluten as a result of treatment with selected processing aids. Multiple tests were conducted in order to eliminate some of the variability in the testing. In this testing gluten samples of 200 g were evaluated. Data from the testing showed that on average an 18.8% improvement in the rate of dewater ability was observed on the samples treated with Nalco TX-13368 prior to dewatering. The data also showed that the effective dosages were in the range of 200 to 500 ppm of product as treated.
[0000]
TABLE 11
Time to Vacuum
% Improvement
Sample
Break (min)
(avg Untreated)
Untreated
5.75
6.26
Untreated
6.17
−0.59
Untreated
6.25
−1.89
Untreated
6.17
−0.59
Untreated
6.33
−3.20
Average
6.13
0.00
400 ppm N-TX13368
5.17
15.72
400 ppm N-TX13368
5.42
11.64
400 ppm N-TX13368
4.67
23.87
400 ppm N-TX13368
4.67
23.87
400 ppm N-TX13368
5.17
15.72
Average
5.02
18.16
250 ppm N-8975
6.33
−3.20
500 ppm N-8975
5.33
13.11
750 ppm N-8975
6.42
−4.66
1000 ppm N-8975
5.83
4.96
Average
5.98
2.55
250 ppm N-8978
5.50
10.34
500 ppm N-8978
6.00
2.18
750 ppm N-8978
6.25
−1.89
1000 ppm N-8978
6.00
2.18
Average
5.94
3.20
Sodium Lauryl Sulfate
250 ppm Shepard WAC
6.25
−1.89
500 ppm Shepard WAC
6.00
2.18
750 ppm Shepard WAC
5.83
4.96
1000 ppm Shepard WAC
5.58
9.03
Average
5.92
3.57
Sodium Lauryl Sulfate
250 ppm SulfoChem SLS
5.67
7.56
500 ppm SulfoChem SLS
5.75
6.26
750 ppm SulfoChem SLS
5.75
6.26
1000 ppm SulfoChem SLS
5.83
4.96
Average
5.75
6.26
Example 12
[0037]
[0000]
Sample
Generic Description
Nalco TX-13368
Sodium Poly Acrylate/ACAM
Nalco TX-13711
Sodium Poly Acrylate
Nalco TX-12621
Anionic Flocculant
N-8975
Proprietary
N-8978
Proprietary
N-8681
High molecular weight nonionic copolymer
Tween 80
Polyoxylethylene sorbitan monooleate
Shepard WAC
Sodium Lauryl Sulfate
SulfoChem SLS
Sodium Lauryl Sulfate
[0038] The foregoing may be better understood by reference to the following examples, which are intended to illustrate methods for carrying out the invention and are not intended to limit the scope of the invention.
[0039] It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the invention and without diminishing its intended advantages. It is therefore intended that such changes and modifications be covered by the appended claims.
|
The invention relates to a method of dewatering corn gluten stream wherein coagulant is add to the corn gluten stream of the corn wet milling process. The method of dewatering corn gluten uses an effective amount of a coagulant of one or more anionic polymers, the anionic polymers comprising one or more anionic monomers. The method further includes a process for separating the water from the gluten using a solids/liquids filtration device.
| 0 |
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel cyanoguanidine derivatives and more particularly to novel cyanoguanidine derivatives which are advantageously usable in various applications such as, for example, an epoxy resin curing agent. This invention also relates to bis-cyanoguanidine type and cyanoguanidine type epoxy resin curing agents advantageously usable for hardening epoxy resins and to a thermosetting resin composition or a photocurable and thermosetting resin composition using the curing agent.
2. Description of the Prior Art
At the soldering step for mounting electronic parts as on the surface of a printed circuit board, the solder mask is used for the purpose of preventing the solder from adhering to impertinent portions and protecting the circuits from the external environment.
In consequence of the increased density of printed circuits in the board and in association with the problem of environmental pollution, the practice of using an alkali development type photocurable and thermosetting resin composition as the material for the solder mask has been popularized. As for the photocurable and thermosetting resin composition developable with an alkali aqueous solution, Kamayachi et al. U.S. Pat. No. 5,009,982 issued on Apr. 23, 1991 discloses a photocurable and thermosetting resin composition containing a photosensitive resin which is obtained by the reaction of a saturated or unsaturated polybasic acid anhydride with a reaction product of a novolak type epoxy compound and an unsaturated monocarboxylic acid and published Japanese Patent Application, KOKAI (Early Publication) No. (hereinafter referred to briefly as "JP-A") 3-289656 discloses a liquid photoimageable solder resist developable with an alkali aqueous solution, which uses a photosensitive resin obtained by the reaction of acrylic acid with a copolymer of an alkyl (meth)acrylate and a glycidyl (meth)acrylate and the subsequent reaction of a polybasic acid anhydride with the resultant reaction product. The alkali development type photocurable and thermosetting resin composition, however, is generally at a disadvantage in lacking storage stability because it is liable to gain in viscosity and form gel with the elapse of time. It is, therefore, marketed generally in the form of a two-component package which consists of a main agent formed mainly of a photosensitive resin and a hardener formed mainly of a thermosetting component. The consumer is expected to mix the main agent with the hardener at the time he makes use of the composition.
Incidentally, in the solder resist, a coating film formed of the photocurable and thermosetting resin composition is exposed to light and developed to produce a prescribed resist pattern and the resist pattern is thermally set by postcuring.
The alkali development type photocurable and thermosetting resin composition mentioned above is so adapted as to produce a solder resist film excelling in adhesiveness, hardness, resistance to heat, electrical insulation properties, or the like by using an epoxy resin, in general, as the thermosetting component and, during the course of the postcuring mentioned above, causing a copolymerization reaction between the carboxyl group in the side chain of the photosensitive resin and the epoxy group in the epoxy resin, in addition to the curing reaction of the thermosetting components. For the purpose of accelerating the reactions mentioned above during the course of the postcuring, an epoxy resin curing agent is generally used in combination with the epoxy resin.
Various compounds have been known as effective curing agents for epoxy resins. Cyanoguanidine (otherwise called "dicyandiamide") is well known as one of the curing agents. If cyanoguanidine is used in combination with an epoxy resin in the alkali development type photocurable and thermosetting resin composition, the mixture of the main agent with the hardener will be at a disadvantage in lacking storage stability and suffering from a short shelf life as a single liquid composition.
It is disclosed in International Publication WO 92/01726 that a substituted cyanoguanidine is useful as a curing agent for an epoxy resin. The invention disclosed in WO 92/01726 proposes to incorporate a specific substituent into cyanoguanidine for the purpose of improving the solubility thereof. Thus, it aims to provide a substituted cyanoguanidine compound which is soluble in various organic solvents.
Generally, a substituted cyanoguanidine compound which exhibits solubility in various organic solvents, however, readily reacts with an epoxy resin at normal room temperature because it also exhibits solubility in a liquid epoxy resin or in an epoxy resin solution. As a result, the photocurable and thermosetting resin composition which contains this substituted cyanoguanidine compound in combination with an epoxy resin has a short shelf life and is deficient in the potential curing property.
Redmon et al. U.S. Pat. No. 2,455,807 issued on Dec. 7, 1948 discloses substituted 3-cyanoguanidines which have aliphatic, aromatic, and heterocyclic substituents. They are claimed to be useful for the preparation of medicines, dyes, insecticides, antioxidants, vulcanization accelerators, plasticizers, resin modifiers, ion-exchange resins, and leather, paper, and textile processing agents. Their use as an epoxy resin curing agent is mentioned nowhere therein.
Compounds which resemble the cyanoguanidine derivatives of the present invention are disclosed in Journal of the Chemical Society, 1956, pp. 4422-4425 and JP-A-64-71,846. Particularly, JP-A-64-71,846 discloses 1,6-di(N 3 -cyano-N 1 -guanidino)hexane which is an intermediate useful for the production of bisbiguanidine and polybiguanidine to be used as disinfectants and biocides and chlorohexidine to be used as anti-fungus agents and antiseptics. The novel cyanoguanidine derivatives which the present invention aims to propose are mentioned nowhere in these publications. Neither is the use of the cyanoguanidine derivatives as an epoxy resin curing agent mentioned anywhere therein.
SUMMARY OF THE INVENTION
An object of the present invention, therefore, is to provide novel cyanoguanidine derivatives which are useful as an epoxy resin curing agent and also usable as an intermediate for other useful compounds.
Another object of the present invention is to provide an epoxy resin curing agent which is only sparingly soluble in various organic solvents and which possesses the so-called potential thermal reactivity, i.e. the ability to avoid reacting with an epoxy compound at low temperatures in the neighborhood of normal room temperature and react quickly therewith by the application of heat.
Still another object of the present invention is to provide a thermosetting resin composition which not only enjoys a long pot life but also excels in the so-called potential curing property, i.e. the ability to remain stable at low temperatures in the neighborhood of normal room temperature and cure quickly at high temperatures.
Yet another object of the present invention is to provide an alkali development type photocurable and thermosetting resin composition which excels in the photocuring property, the developability with an alkali aqueous solution, and the potential curing property and, at the same time, enjoys a long shelf life.
More specifically, the present invention has for its object the provision of an alkali development type photocuring and thermosetting resin composition which contains an epoxy resin curing agent possessing such potential thermal reactivity as mentioned above and, therefore, excels in storage stability, enjoys a long shelf life as a single liquid composition, and permits production of a cured coating film excelling in various properties such as adhesiveness, resistance to heat, resistance to chemicals, hardness, and electrical insulating properties which a solder resist is normally required to manifest.
To accomplish-the objects described above, in accordance with one aspect of the present invention, there is provided a novel cyanoguanidine derivative represented by the following general formula (1): ##STR3## wherein R 1 represents a substituent selected from the group consisting of the following substituents (a) through (k). ##STR4##
In accordance with another aspect of the present invention, there is provided an epoxy resin curing agent represented by the following general formula (1a): ##STR5## wherein R 2 represents a substituent selected from the group consisting of the following substituents (1) through (35). ##STR6##
In accordance with still another aspect of the present invention, there is provided a thermosetting resin composition which comprises an epoxy resin and an epoxy resin curing agent represented by the general formula (1a) mentioned above.
In accordance with yet another aspect of the present invention, there is provided a photocuring and thermosetting resin composition which comprises (A) a resin curable by an active energy radiation, which has at least two ethylenically unsaturated bonds in combination with a carboxyl group in the molecular unit thereof, (B) a photopolymerization initiator, (C) a diluent, (D) an epoxy resin, and (E) an epoxy resin curing agent, the epoxy resin curing agent (E) being a cyanoguanidine derivative represented by the following general formula (1b). ##STR7## wherein R 3 represents a substituent selected from the group consisting of the following substituents (1) through (34). ##STR8##
BRIEF DESCRIPTION OF THE DRAWINGS
Other objects, features, and advantages of the invention will become apparent from the following description taken together with the drawings, in which:
FIG. 1 shows an IR (infrared absorption) spectrum of 1,1-bis(3-cyanoguanidine) obtained in Synthesis Example 1;
FIG. 2 shows a 1 H-NMR (nuclear magnetic resonance) spectrum of 1,1-bis(3-cyanoguanidine) obtained in Synthesis Example 1;
FIG. 3 shows an IR spectrum of 3,9-bis(3-cyanoguanidinopropyl)-2,4,8,10-tetraoxaspiro[5.5]undecane obtained in Synthesis Example 2;
FIG. 4 shows a 1 H-NMR spectrum of 3,9-bis(3-cyanoguanidinopropyl)-2,4,8,10-tetraoxaspiro[5.5]undecane obtained in Synthesis Example 2;
FIG. 5 shows an IR spectrum of 2-cyanoguanidyl-4,6-diamino-S-triazine obtained in Synthesis Example 3;
FIG. 6 shows a 1 H-NMR spectrum of 2-cyanoguanidyl-4,6-diamino-S-triazine obtained in Synthesis Example 3;
FIG. 7 is a schematic diagram showing the basic concept of the determination of logarithmic damping factor in Example 3;
FIG. 8 is a fragmentary sectional view showing the state of determination of the logarithmic damping factor of a cured product by the use of an apparatus shown in FIG. 7; and
FIG. 9 is a schematic diagram showing the change in oscillation of a pendulum during the determination of the logarithmic damping factor in Example 3.
DETAILED DESCRIPTION OF THE INVENTION
The invention published in WO 92/01726, as remarked above, proposes the incorporation of a specific substituent in cyanoguanidine for the purpose of improving the solubility of the compound.
The present invention, utterly unlike the conventional approach of this kind, contemplates incorporating a specific substituent into cyanoguanidine thereby rendering the resultant cyanoguanidine derivative sparingly soluble in organic solvents, imparting improved potential thermal reactivity thereto, and enabling the specific substituent (functional group) contained therein to manifest the characteristic properties thereof.
The cyanoguanidine derivative of the present invention can be advantageously manufactured by the method of F. L. Rose and G. Swain (reported in J. Chem. Soc., 1956, pp. 4422-4425 mentioned above) and the method disclosed in JP-A-64-71,846.
Specifically, when an alkali dicyanamide such as, for example, sodium dicyanamide and a salt of an amine compound having a substituent R, preferably a hydrochloride thereof, are heated in a suitable solvent under reflux, they react in accordance with the following formula (2) to produce the cyanoguanidine derivative as aimed at. ##STR9##
In the cyanoguanidine derivatives according to the present invention which are represented by the general formula (1a) mentioned above, the bis-cyanoguanidine type derivatives having substituents R 2 of the formulas (1) through (21) are synthesized desirably in accordance with the following reaction formula (3). Specifically, when an alkali dicyanamide such as, for example, sodium dicyanamide and a salt of a diamine compound having a substituent R 4 , preferably a dihydrochloride thereof, are heated in a suitable solvent under reflux, they react in accordance with the following formula (3) to produce the bis-cyanoguanidine type derivative as aimed at. ##STR10##
In the reaction formula (3), the substituent R 4 means the residue which arises from the removal of a cyanoguanidyl group from the substituent R 2 .
In either of the reactions described above, the relevant reactants may be incorporated in practically stoichiometric proportions in the solvent. As the reaction solvent, water and alcohols having 1 to 6 carbon atoms, preferably 3 to 5 carbon atoms such as butanol, propanol, and ethanol, particularly desirably n-butanol, and mixtures of such alcohols with water may be used. It is also permissible to use such neutral solvents as dimethyl formamide and sulforan.
When water is used as the solvent, the reaction can be accelerated by the presence of a catalytic amount of a base. As the base, aliphatic or alicyclic amines and N-heterocyclic bases such as triethyl amine, N-methyl morpholine, and pyridine may be used. The pH of the reaction mixture at the start of the reaction is desired to be adjusted on an alkali side, preferably in the range of 8 to 10, from the viewpoint of yield. This pH adjustment can be effected by the amount of the base to be added to the reaction mixture.
The reaction is carried out by refluxing the reaction mixture at a temperature in the approximate range of from 75° C. to 170° C., preferably from 90° C. to 160° C. , generally in a stirred state for a period in the range of from 3 to 16 hours, preferably from 6 to 10 hours, depending on the temperature of heating. After the reaction is completed, the reaction solution is distilled, when necessary, to expel the solvent and then washed with water, a mixture of water and alcohol, or a mixture of water and acetone to clean the alkali salt (NaCl) and, at the same time, induce crystallization of the reaction product. The reaction product is separated by filtration from the salt-containing liquid phase. The separated solid is dried to obtain a finished product. The drying is desired to be effected by heating in a vacuum.
In accordance with one aspect of the present invention, there are provided novel cyanoguanidine derivatives represented by the general formula (1) mentioned above. A few of these novel cyanoguanidine derivatives will be cited below by way of example and the processes used for their synthesis will be specifically described below.
SYNTHESIS EXAMPLE 1
Synthesis of 1,1-bis(3-cyanoguanidine)
The reaction of sodium dicyanamide with hydrazine dihydrochloride proceeds as shown by the following formula (4) to produce 1,1-bis(3-cyanoguanidine) as aimed at. ##STR11##
This synthesis was specifically carried out in accordance with the following procedure.
In an eggplant type flask having an inner volume of 100 ml and equipped with a Dimroth condenser, 8.90 g (0.10 mol) of sodium dicyanamide (produced by Aldrich Corp.), 5.25 g (0.05 mol) of hydrazine dihydrochloride, 50 ml of water, and 0.02 g of triethylamine were charged. Then, the flask containing the reactants was placed in an oil bath and the reactants were stirred with a magnetic stirrer under a refluxed condition and thus left reacting for 5 hours at about 100° C.
After the reaction was completed, the reaction solution was distilled under a reduced pressure in an evaporator to expel the reaction solvent. The residue of the distillation and a mixture of water/methanol (mixing ratio of 2.5/1.5) added thereto were mixed thoroughly. The resultant mixture was passed through a glass filter. The solid consequently separated was dried in a vacuum drier at 80° C. for 8 hours, to obtain 3.9 g of light red 1,1-bis(3-cyanoguanidine) (yield 47.7%).
The resultant product, 1,1-bis(3-cyanoguanidine) (hereinafter referred to briefly as "2CG"), was analyzed by the use of a Fourier-transform spectrophotometer, FT-IR, to obtain an IR spectrum which is shown in FIG. 1. It is clearly noted from this spectrum that the peak due to the C-N stretching vibration of the cyanoguanidyl group of 2CG appears at a wave number of 1250 cm -1 , that due to the C═N stretching vibration at a wave number of 1651 cm -1 , and that due to the C≡N stretching vibration at a wave number of 2190 cm -1 .
The 1 H-NMR spectrum [solvent DMSO (dimethyl sulfoxide) and the internal standard TMS (tetramethyl silane)] of 2CG is shown in FIG. 2. The curve showing the proton integral ratio of each peak is additionally shown in FIG. 2.
SYNTHESIS EXAMPLE 2
Synthesis of 3,9-bis(3-cyanoguanidinopropyl)-2,4,8,10-tetraoxaspiro[5.5]undecane
The reaction of sodium dicyanamide with 3,9-bis(3-aminopropyl)-2,4,8,10-tetraoxaspiro[5.5]undecane dihydrochloride proceeds as shown by the following formula (5) to produce 3,9-bis(3-cyanoguanidinopropyl)-2,4,8,10-tetraoxaspiro[5.5]undecane aimed at. ##STR12##
This synthesis was carried out in accordance with the following procedure.
In an eggplant type flask having an inner volume of 50 ml and equipped with a Dimroth condenser, 0.89 g (0.01 mol) of sodium dicyanamide, 1.74 g (0.005 mol) of 3,9-bis(3-aminopropyl)-2,4,8,10-tetraoxaspiro[5.5]undecane dihydrochloride, and 10 ml of n-butanol were charged. Then, the flask containing the reactants was placed in an oil bath and the reactants were stirred with a magnetic stirrer under a refluxed condition and thus left reacting for 8 hours at about 118° C.
The reaction solution was after-treated by following the procedure of Synthesis Example 1, to obtain 1.99 g of 3,9-bis(3-cyanoguanidinopropyl)-2,4,8,10-tetraoxaspiro[5.5]undecane (yield 97.5%).
The resultant product, 3,9-bis(3-cyanoguanidinopropyl)-2,4,8,10-tetraoxaspiro[5.5]undecane (hereinafter referred to briefly as "ATU2CG") was analyzed by the use of a Fourier-transform spectrophotometer, FT-IR, to obtain an IR spectrum which is shown in FIG. 3. It is clearly noted from this spectrum that the peak due to the C═N stretching vibration of the cyanoguanidyl group of ATU2CG appears at a wave number of 1656 cm -1 and that due to the C≡N stretching vibration at a wave number of 2176 cm -1 .
The 1 H-NMR spectrum (solvent DMSO and the internal standard TMS) of ATU2CG is shown in FIG. 4. The curve showing the proton integral ratio of each peak is additionally shown in FIG. 4. In the diagram, the symbols (1) through (8) denote the symbols of the hydrogen atoms linked to the carbon atoms of the ATU2CG.
SYNTHESIS EXAMPLE 3
Synthesis of 2-cyanoguanidyl-4,6-diamino-S-triazine
The reaction of sodium dicyanamide with 2,4,6-triamino-S-triazine hydrochloride proceeds as shown by the following formula (6) to produce 2-cyanoguanidyl-4,6-diamino-S-triazine as aimed at. ##STR13##
This synthesis was carried out in accordance with the following procedure.
In an eggplant type flask having an inner volume of 100 ml and equipped with a Dimroth condenser, 8.9 g (0.10 mol) of sodium dicyanamide, 1.63 g (0.10 mol) of 2,4,6-triamino-S-triazine hydrochloride, and 20 ml of n-butanol were charged. Then, the flask containing the reactants was placed in an oil bath and the reactants were stirred with a magnetic stirrer under a refluxed condition and thus left reacting for 5 hours at about 118° C.
After the reaction was completed, the reaction solution was distilled under a reduced pressure in an evaporator to expel the reaction solvent. The residue of the distillation and a mixture of water/acetone (mixing ratio of 1.0/1.0) added thereto were mixed thoroughly. The resultant mixture was passed through a glass filter. The solid consequently separated was dried in a vacuum drier at 80° C. for 8 hours, to obtain 0.55 g of white 2-cyanoguanidyl-4,6-diamino-S-triazine (yield 28.5%).
The resultant product, 2-cyanoguanidyl-4,6-diamino-S-triazine (hereinafter referred to briefly as "MD"), was analyzed by the use of a Fourier-transform spectrophotometer, FT-IR, to obtain an IR spectrum which is shown in FIG. 5. It is clearly noted from this Spectrum that the peak due to the C≡N stretching vibration of the cyanoguanidyl group of MD appears at a wave number of 2195 cm -1 .
The 1 H-NMR spectrum (solvent DMSO and the internal standard TMS) of MD is shown in FIG. 6. The curve showing the proton integral ratio of the peaks is additionally shown in FIG. 6.
Synthesis examples of some other cyanoguanidine derivatives which may be advantageously used in the thermosetting resin composition and the photocurable and thermosetting resin composition will be specifically described below.
SYNTHESIS EXAMPLE 4
Synthesis of 1,1'-p-phenylene-bis-3,3'-cyanoguanidine
The reaction of sodium dicyanamide with p-phenylenediamine dihydrochloride proceeds as shown by the following formula (7) to produce 1,1'-p-phenylene-bis-3,3'-cyanoguanidine as aimed at. ##STR14##
This synthesis was carried out in accordance with the following procedure.
In an eggplant type flask having an inner volume of 50 ml and equipped with a Dimroth Condenser, 0.89 g (0.01 mol) of sodium dicyanamide, 0.91 g (0.005 mol ) of p-phenylenediamine dihydrochloride, 10 ml of n-butanol were charged. Then, the flask containing the reactants was placed in an oil bath and the reactants were stirred with a magnetic stirrer under a refluxed condition and thus left reacting for 8 hours at about 118° C.
After the reaction was completed, the reaction solution was distilled under a reduced pressure in an evaporator to expel the reaction solvent. The residue of the distillation and a mixture of water/methanol (mixing ratio of 2.5/1.5) added thereto were mixed thoroughly. The resultant mixture was passed through a glass filter. The solid consequently separated was dried in a vacuum drier at 80° C. for 8 hours, to obtain 0.98 g (yield 81.3%) of light gray 1,1'-p-phenylene-bis-3,3'-cyanoguanidine (hereinafter referred to briefly as "Ph2CG").
SYNTHESIS EXAMPLE 5
Synthesis of methylene-bis(1,1'-p-phenylene-3,3'-cyanoguanidine)
The reaction of sodium dicyanamide with 4,4'-diaminodiphenylmethane dihydrochloride proceeds as shown by the following formula (8) to produce methylene-bis(1,1'-p-phenylene-3,3'-cyanoguanidine) as aimed at. ##STR15##
This synthesis was carried out in accordance with the following procedure.
In an eggplant type flask having an inner volume of 50 ml and equipped with a Dimroth condenser, 0.89 g (0.01 mol) of sodium dicyanamide, 1.37 g (0.005 mol) of 4,4'-diaminodiphenylmethane dihydrochloride, 10 ml of n-butanol were charged. Then, the flask containing the reactants was placed in an oil bath and the reactants were stirred with a magnetic stirrer under a refluxed condition and thus left reacting for 8 hours at about 118° C.
After the reaction was completed, the reaction solution was distilled under a reduced pressure in an evaporator to expel the reaction solvent. The residue of the distillation and a mixture of water/methanol (mixing ratio of 2.5/1.5) added thereto were mixed thoroughly. The resultant mixture was passed through a glass filter. The solid consequently separated was dried in a vacuum drier at 80° C. for 8 hours, to obtain 1.33 g (yield 80.1%) of yellow methylene-bis(1,1'-p-phenylene-3,3'-cyanoguanidine) (hereinafter referred to briefly as "DDM-2CG").
In the cyanoguanidine derivatives according to the present invention which are represented by the general formula (1a) mentioned above, the compounds having substituents R 2 of the formulas (1) through (21) are bis-cyanoguanidine type derivatives which have two cyanoguanidyl groups at the opposite terminals and, therefore, possess six active hydrogen atoms linked to the nitrogen atoms of the cyanoguanidyl groups. Theoretically, therefore, they can react with six epoxy groups. The compounds having substituents R 2 of the formulas (22) through (35) are cyanoguanidine derivatives having amine type substituents incorporated therein. They exhibit notably high basicity and abound in reactivity with epoxy compounds. Nevertheless, these cyanoguanidine derivatives are generally sparingly soluble in various organic solvents, liquid epoxy compounds, or epoxy compound solutions. They avoid reacting with an epoxy group at normal room temperature but react with an epoxy group by application of heat. Thus, they can be used particularly advantageously as a potentially themoreactive curing agent for epoxy resin.
By combining a cyanoguanidine derivative of the present invention possessing these characteristics with an epoxy compound, there is obtained a thermosetting resin composition which excels in the so-called latent or potential curing property, i.e. the property of remaining stably at low temperatures in the neighborhood of normal room temperature and quickly curing at high temperatures, and enjoys a long pot life as well. Further, the thermosetting resin composition permits production of a cured epoxy resin whose hardness may be varied from a relatively low hardness to high hardness depending on the substituent incorporated in the cyanoguanidine derivative.
In accordance with another aspect of the present invention, therefore, there is provided a thermosetting resin composition which comprises an epoxy resin and an epoxy resin curing agent represented by the general formula (1a) mentioned above.
As the epoxy resin to be contained in combination with the cyanoguanidine derivative mentioned above in the thermosetting resin composition of the present invention, any of the well-known epoxy resins (including epoxy oligomers) which has at least one epoxy group, preferably two or more epoxy groups in the molecular unit thereof may be used. As typical examples, the glycidyl ether type epoxy resins such as the bis-phenol A type epoxy resin obtained by the reaction of bis-phenol A with epichlorohydrin in the presence of an alkali, the epoxide of a resin resulting from the condensation of bis-phenol A with formalin, and the equivalent using bromated bis-phenol A in the place of bis-phenol A may be cited. Novolak type epoxy resins such as the phenol novolak type, orthocresol novolak type, and p-t-butyl phenol novolak type epoxy resins which are obtained by glycidyl-etherifying the corresponding novolak resins with epichlorohydrin may be also cited. Then, the bis-phenol F type and the bis-phenol S type epoxy resins obtained by the reaction of epichlorohydrin on bis-phenol F and bis-phenol S are other concrete examples. Further, alicyclic epoxy resins possessing a cyclohexene oxide group, a tricyclodecene oxide group, or a cyclopentene oxide group; glycidyl ester resins such as phthalic diglycidyl ester, tetrahydrophthalic diglycidyl ester, hexahydrophthalic diglycidyl ester, diglycidyl-p-oxybenzoic acid, and dimeric acid glycidyl ester; glycidyl amine type resins such as tetraglycidyl diamino-diphenyl methane, triglycidyl-p-aminophenol, diglycidyl aniline, diglycidyl toluidine, tetraglycidyl methaxylylene diamine, diglycidyl tribromoaniline, and tetraglycidyl bis-aminomethyl cyclohexane; hydantoin type epoxy resins having glycidyl groups linked to their hydantoin rings; triglycidyl (or tris(2,3-epoxypropyl)) isocyanurate possessing a triazine ring; bixylenol type epoxy resins; and biphenol type epoxy resins are other examples. The epoxy resins mentioned above may be used either singly or in the form of a combination of two or more members.
The mixing ratio of the cyanoguanidine derivative mentioned above to the epoxy resin can be suitably set. From the standpoint of the characteristic properties of the cured coating film, however, the mixing ratio is desired to be such that the proportion of hydrogen of the amino group in the cyanoguanidine derivative falls in the range of from 0.05 to 1.0 mol per one mol of the epoxy group of the epoxy resin.
The thermosetting resin composition of the present invention, when necessary, may incorporate therein any of well-known organic solvents. Examples of the organic solvents include, but are not limited to: ketones such as methylethyl ketone and cyclohexanone; aromatic hydrocarbons such as toluene, xylene, and Ipsol #150 (trademark for tetramethyl benzene-based petroleum solvent of Idemitsu Petrochemical Co., Ltd.); glycol ethers such as cellosolve, butyl cellosolve, carbitol, butyl carbitol, propylene glycol monomethyl ether, dipropylene glycol monomethyl ether; and acetates such as ethyl acetate, butyl acetate, cellosolve acetate, butyl cellosolve acetate, carbitol acetate, butyl carbitol acetate, propylene glycol monomethyl ether acetate, and dipropylene glycol monomethyl ether acetate. These organic solvents may be used either singly or in the form of a combination of two or more members.
The thermosetting resin composition according to the present invention begins to undergo a curing reaction at a temperature in the approximate range of from 100° C. to 250° C. The epoxy compound thereof in a liquid state or in the form of a molten liquid is consequently converted into an insoluble or infusible solid three-dimensionally cross-linked product and eventually obtained as a cured article resembling a film or a sheet like an adhesive agent layer in structure. When a molding treatment is simultaneously carried out with this curing treatment, the cured article is obtained in the form of a shaped article such as, for example, a cast article, a pressed article or a laminated article. Optionally the curing treatment may be implemented by a two-stage process in which the curing reaction is temporarily suspended halfway along the entire course of reaction. In this case, a curable precondensate (so-called B-stage) which is still in a fusible and soluble state is obtained. The precondensate of this quality can be stably stored for a long time and can be used for the production of prepregs and for the production of a compression molding composition and a sintering powder, for example.
The thermosetting resin composition according to the present invention can be advantageously used in various technical fields such as those involving surface protection techniques, lamination techniques, or the like and in various industrial fields as electrical industry and building industry. It may be used, for example, as adhesive agents, protective coating materials for printed circuit boards, insulating resin varnishes, paints, lacquers, compression molding resin compositions, casting resin compositions, injection molding compounds, impregnating resin compositions, laminating resin compositions, sealing and filling resin compositions, and floor finishing resin compositions.
The present inventor has further ascertained by their study that when an alkali development type photocurable and thermosetting resin composition is produced by incorporating therein a cyanoguanidine derivative represented by the general formula (1b) mentioned above as an epoxy resin curing agent, this resin composition exhibits excellent storage stability, enjoys a long shelf life as a single liquid composition, and permits production of a cured coating film which excels in such properties as adhesiveness, resistance to heat, resistance to chemicals, hardness, and electrical insulating properties which a solder resist is required to possess.
Thus, in yet another aspect of the present invention, there is provided a photocurable and thermosetting resin composition which comprises (A) a resin curable by an active energy radiation (hereinafter referred to briefly as "radiation-curable resin") which has at least two ethylenically unsaturated bonds in combination with a carboxyl group in the molecular unit thereof, (B) a photopolymerization initiator or photosensitizer, (C) a diluent, (D) an epoxy resin, and (E) an epoxy resin curing agent, the epoxy resin curing agent (E) being a cyanoguanidine derivative represented by the general formula (1b) mentioned above.
Since the photocurable and thermosetting resin composition of the present invention contains the specific cyanoguanidine derivative mentioned above as the epoxy resin curing agent, it excels in storage stability, enjoys a long shelf life as a single liquid composition, and therefore augments the adaptability of the work for the manufacture of a solder resist film.
As the radiation-curable resin (A) mentioned above which has in combination at least two ethylenically unsaturated bonds and a carboxyl group in the molecular unit thereof, (1) the product obtained by the esterification of the epoxy group of a polyfunctional novolak type epoxy resin with the carboxyl group of an unsaturated monocarboxylic acid and the subsequent reaction of a saturated or unsaturated polybasic acid anhydride with the resultant hydroxyl group, (2) the product obtained by the reaction of (meth)acrylic acid with a copolymer composed of an alkyl (meth)acrylate and a glycidyl (meth)acrylate and the subsequent reaction of a saturated or unsaturated polybasic acid anhydride with the resultant reaction product, (3) the product obtained by the reaction of (meth)acrylic acid with a copolymer composed of a hydroxyalkyl (meth)acrylate, an alkyl (meth)acrylate, and a glycidyl (meth)acrylate and the subsequent reaction of a saturated or unsaturated polybasic acid anhydride with the resultant product, and (4) the product obtained by the partial reaction of a glycidyl (meth)acrylate with a copolymer composed of an alkyl (meth)acrylate and (meth)acrylic acid can be used, for example.
Since the radiation-curable resin mentioned above has numerous free carboxyl groups added to the side chain of a backbone polymer, the composition containing this resin is developable with a dilute aqueous alkali solution. When the applied coating film of the composition is developed after exposure to light and then postcured, the epoxy group of the epoxy resin separately added to the composition as a thermosetting component copolymerizes with the free carboxyl groups in the side chain of the radiation-curable resin mentioned above and converts the coating film into a solder resist film excellent in such properties as heat resistance, solvent resistance, acid resistance, adhesiveness, electrical properties, and hardness.
The acid value of the radiation-curable resin mentioned above should be in the range of from 40 to 160 mg KOH/g. Preferably, this acid value is from 50 to 140 mg KOH/g in the resin (1), from 50 to 150 mg KOH/g in the resins (2) and (4), and from 40 to 120 mg KOH/g in the resin (3) mentioned above. Any deviation of the acid value from the aforementioned range is undesirable because the resin will manifest insufficient solubility in an aqueous alkali solution if the acid value is less than 40 mg KOH/g. Conversely, the acid value exceeding 160 mg KOH/g will give cause to deteriorate the various properties of the cured film such as resistance to alkalis and electrical properties expected of a resist.
The resin (1) mentioned above is obtained by causing the product of the reaction of such a novolak type epoxy resin as will be specifically described hereinafter with an unsaturated monocarboxylic acid to react with such a dibasic acid anhydride as phthalic anhydride or such an aromatic polycarboxylic anhydride as trimellitic anhydride or pyromellitic anhydride. In this case, the resin obtained by the reaction of at least 0.15 mol of a polybacic acid anhydride with each of the hydroxyl groups possessed by the reaction product of the novolak type epoxy resin with an unsaturated monocarboxylic acid proves to be suitable. When the number of ethylenically unsaturated bonds present in the molecular unit of the resin is small, the produced composition has a low speed of photocuring. It is therefore desired to use a novolak type epoxy resin as the raw material. A bisphenol A type epoxy resin may be used in combination therewith for the purpose of lowering the viscosity of the ink.
Typical examples of the novolak type epoxy resins include phenol novolak type epoxy resins, cresol novolak type epoxy resins and novolak type epoxy resins of bisphenol A. The resins which are obtained by causing epichlorohydrin to react with the corresponding novolak resins by the conventional method may be effectively used.
Examples of the unsaturated monocarboxylic acids mentioned above include, but are not limited to: acrylic acid, methacrylic acid, cinnamic acid, and the reaction product of a saturated or unsaturated dibasic acid anhydride with a (meth)acrylate having one hydroxyl group per molecule. These unsaturated monocarboxylic acids may be used either singly or in the form of a combination of two or more members. Among other monocarboxylic acids cited above, acrylic acid and methacrylic acid, particularly acrylic acid, prove to be particularly desirable from the viewpoint of the photocuring property.
Typical examples of the aforementioned acid anhydrides are dibasic acid anhydrides such as maleic anhydride, succinic anhydride, itaconic anhydride, phthalic anhydride, tetrahydrophtalic anhydride, hexahydrophthalic anhydride, methylhexahydrophthalic anhydride, endomethylene-tetrahydrophthalic anhydride, methylendomethylene-tetrahydrophthalic anhydride, chlorendic anhydride, and methyltetrahydrophthalic anhydride; aromatic polycarboxylic anhydrides such as trimellitic anhydride, pyromellitic anhydride, and benzophenone-tetracarboxylic dianhydride; and polycarboxylic anhydride derivatives such as 5-(2,5-dioxotetrahydrofuryl)-3-methyl-3-cyclohexene-1, 2-dicarboxylic anhydride.
The copolymers which are base polymers of the resins (2) and (3) mentioned above are obtained by using as monomers such alkyl (meth)acrylates and glycidyl (meth)acrylates or further hydroxyalkyl (meth)acrylates and copolymerizing these monomers by any of the well-known methods such as, for example, the method of solution polymerization.
The alkyl (meth)acrylates mentioned above are alkyl esters of acrylic acid or methacrylic acid. The alkyl group of the alkyl esters is an aliphatic hydrocarbon radical having from 1 to 6 carbon atoms. Examples of alkyl (meth)acrylates include, but are not limited to: esters of acrylic acid or methacrylic acid with methyl, ethyl, propyl, isopropyl, butyl, or hexyl.
The hydroxyalkyl (meth)acrylates mentioned above are hydroxyalkyl esters of acrylic acid or methacrylic acid. The hydroxyalkyl group of these hydroxyalkyl esters is desired to be an aliphatic hydrocarbon radical having from 1 to 6 carbon atoms and containing a primary hydroxyl group. The reason for this desirability is that it is desirable to select and use a hydroxyalkyl (meth)acrylate having a primary hydroxyl group as one of the component monomers of the aforementioned copolymer from the viewpoint of the ease with which the product of the reaction of the copolymer with (meth)acrylic acid is caused to react further with a polybasic acid anhydride. As typical examples of the hydroxyalkyl (meth)acrylates having a primary hydroxyl group, 2-hydoxyethyl acrylate, 2-hydroxyethyl methacrylate, etc. may be cited. It should be noted, however, that these are not exclusive examples.
In the copolymer as the basis of the resin (2) mentioned above, the molar ratio of an alkyl (meth)acrylate to glycidyl (meth)acrylate is desired to be in the range of from 40:60 to 80:20. In the copolymer as the basis of the resin (3) mentioned above, the molar ratio of hydroxyalkyl (meth)acrylate to an alkyl (meth)acrylate to glycidyl (meth)acrylate is desired to be in the range of 10-50:10-70:20-60, preferably in the range of 15-30:30-50:30-50. If the proportion of glycidyl (meth)acrylate to the copolymer is unduly low from the lower limits of the ranges mentioned above, the copolymer will be at a disadvantage in acquiring an unduly low photocuring property. Conversely, if this proportion exceeds the upper limits of the ranges mentioned above, the copolymer will be at a disadvantage in failing to allow the reaction of synthesis of a photosensitive resin to proceed smoothly.
The degree of polymerization of the copolymer obtained by copolymerizing the component monomers, as expressed by weight-average molecular weight, is desired to be in the range of from 10,000 to 70,000, preferably from 20,000 to 60,000. If the weight-average molecular weight is less than 10,000, the composition containing the resin will be at a disadvantage in acquiring unduly low dryness to the touch of finger. Conversely, if it exceeds 70,000, the composition will be at a disadvantage in acquiring an unduly low .developing property.
In the photocurable and thermosetting coating composition of the present invention, such vinyl compounds as styrene and methylstyrene may be used in a proportion not so large as to adversely affect the characteristic properties of the composition in addition to the component monomers mentioned above.
Typical examples of the photopolymerization initiators (B) mentioned above include benzoin and alkyl ethers thereof such as benzoin, benzoin methyl ether, benzoin ethyl ether, and benzoin isopropyl ether; acetophenones such as acetophenone, 2,2-dimethoxy-2-phenyl acetophenone, 2,2-diethoxy-2-phenyl acetophenone, 1,1-dichloroacetophenone, 1-hydroxycyclohexyl phenyl ketone, 2-methyl-1-[4-(methylthio)phenyl]-2-morpholinopropane-1-on, 2-benzyl-2-dimethylamino-1-(4-morpholinophenyl)-1-butanone; anthraquinones such as 2-methylanthraquinone, 2-ethylanthraquinone, 2-t-butyl anthraquinone, 1-chloroanthraquinone, and 2-amylanthraquinone; thioxanthones such as 2,4-dimethylthioxanthone, 2,4-diethylthioxanthone, 2-chlorothioxanthone, and 2,4-diisopropylthioxanthone; ketals such as acetophenone dimethyl ketal and benzyl dimethyl ketal; benzophenones such as benzophenone; and xanthones. These photopolymerization initiators may be used either singly or in the form of a combination of two or more members. Optionally such a photopolymerization initiator (B) may be used in combination with one or more well-known conventional photopolymerization accelerators such as of the benzoic acid type and the tertiary amine type.
The amount of the photopolymerization initiator (B) to be used suitably falls in the range of from 0.2 to 30 parts by weight, preferably from 2 to 20 parts by weight, based on 100 parts by weight of the radiation-curable resin (A) mentioned above. If the amount of the photopolymerization initiator to be used is less than 0.2 part by weight, the composition will suffer from inferior photocuring property. Conversely, if the amount exceeds 30 parts by weight, the composition will entail the disadvantage of exhibiting inferior quality for cured film and poor stability during storage.
As the diluent (C) mentioned above, a photopolymerizable monomer and/or an organic solvent may be used.
Typical examples of photopolymerizable monomers include 2-hydroxypropyl acrylate, 2-hydroxyethyl acrylate, N-vinylpyrrolidone, acryloyl morpholine, methoxytetraethylene qlycol acrylate, methoxypolyethylene glycol acrylate, polyethylene glycol diacrylate, N,N-dimethyl acrylamide, N-methylol acrylamide, N,N-dimethylaminopropyl acrylamide, N,N-dimethylaminoethyl acrylate, N,N-dimethylaminopropyl acrylate, melamine acrylate, diethylene glycol diacrylate, triethylene glycol diacrylate, propylene glycol diacrylate, dipropylene glycol diacrylate, tripropylene glycol diacrylate, polypropylene glycol diacrylate, phenoxyethyl acrylate, tetrahydrofurfuryl acrylate, cyclohexyl acrylate, trimethylol propane diacrylate, trimethylol propane triacrylate, glycerin diglycidyl ether diacrylate, glycerin triglycidyl ether triacrylate, pentaerythritol triacrylate, pentaerythritol tetraacrylate, dipentaerythritol pentaacrylate, dipentaerythritol hexaacrylate, isoborneolyl acrylate, cyclopentadiene mono- or di-acrylate, methacrylates corresponding to the acrylates enumerated abvoe, and mono-, di-, tri-, and higher polyesters of polybasic acids with hydroxyalkyl (meth)acrylates.
As for the organic solvent, ketones, aromatic hydrocarbons, cellosolves, carbitols, glycol ethers, and acetates as mentioned above may be used.
The diluents (C) enumerated above can be used either singly or in the form of a mixture of two or more members. The amount of the diluent to be used is desired to fall in the range of 30 to 300 parts by weight, preferably 50 to 200 parts by weight, based on 100 parts by weight of the radiation-curable resin (A) mentioned above.
Here, the aforementioned photopolymerizable monomer is used for the purpose of diluting the aforementioned radiation-curable resin thereby rendering the produced composition easily applicable, and imparting photopolymerizability upon the comosition. The amount of the monomer to be used is desired to fall in the range of 3 to 50 parts by weight, based on 100 parts by weight of the radiation-curable resin (A) mentioned above. If the amount of the monomer is less than 3 parts by weight, the composition will be at a disadvantage in failing to enhance the photocuring property. Conversely, if the amount exceeds 50 parts by weight, the composition will be at a disadvantage in failing to heighten dryness to the tack-free touch of finger.
The organic solvent is used for the purpose of dissolving and diluting the radiation-curable resin (A) mentioned above, allowing the resin to be applied in the from of a liquid, enabling the applied layer of the liquid to form a film by the drying, and allowing the film to be exposed to light by the so-called "contact type exposure".
As concrete examples of the epoxy resin (D) to be used in the photocurable and thermosetting resin composition, the epoxy resins enumerated as concrete examples of the epoxy resin for use in the thermosetting resin composition may be cited. Among other epoxy resins enumerated above, it is desirable to use as a main component a finely powdered epoxy resin which exhibits sparing solubility in an organic solvent, such as bis-phenol S type epoxy resins represented by the product of Nippon Kayaku Co., Ltd. marketed under trademark designation of "EBPS"-200, that of Asahi Denka Kogyo K.K. under trademark designation of "EPX"-30, and that of Dai-Nippon Ink & Chemicals, Inc. under trademark designation of "EPICLON" EXA-1514; diglycidyl terephthalate resin represented by the product of Nippon Oil and Fats Co., Ltd. under trademark designation of "BLEMMER"-DGT; triglycidyl isocyanurate represented by the products of Nissan Chemical Industries, Ltd. under trademark designation of "TEPIC" and "TEPIC-H" and that of Ciba-Geigy Ltd. under trademark designation of "ARALDITE" PT810; and bixylenol type or biphenol type epoxy resins represented by the products of Yuka-Shell K.K. under trademark designation of "EPIKOTE" YX-4000 and YL-6121. The epoxy resins may be used either singly or in the form of a combination of two or more members.
The amount of the epoxy resins to be incorporated in the composition as a thermosetting component is desired to be in the range of 5 to 100 parts by weight, preferably 15 to 60 parts by weight, based on 100 parts by weight of the radiation-curable resin (A) mentioned above.
The amount of the cyanoguanidine derivative to be incorporated in the photocurable and thermosetting resin composition of the present invention is desired to be in the range of from 0.5 to 5 parts by weight, based on 100 parts by weight of the radiation-curable resin (A) mentioned above. If the amount is less than 0.5 part by weight, the incorporated cyanoguanidine derivative will fail to manifest the thermosetting property as expected. Conversely, if the amount exceeds 5.0 parts by weight, the excess will entrain the drawback that the photocurable and thermosetting resin composition prepared in a single liquid formulation suffers from a decrease of shelf life and the formed solder resist film incurs deterioration of electrical properties (insulation resistance).
The thermosetting resin composition and the photocurable and thermosetting resin composition of the present invention, when necessary, may incorporate therein any of well-known epoxy resin curing accelerators or promotors for the purpose of promoting the curing reaction of the epoxy resin with the cyanoguanidine derivative. Examples of the epoxy resin curing promotors include, but are not limited to: imidazole and imidazole derivatives such as 2-methylimidazole, 2-ethylimidazole, 2-ethyl-4-methylimidazole, 2-phenylimidazole, 4-phenylimidazole, 1-cyanoethyl-2-phenylimidazole, 1-(2-cyanoethyl)-2-ethyl-4-methylimidazole; guanamines such as acetoguanamine and benzoguanamine; and amines such as benzyldimethyl amine, 4-(dimethylamino)-N,N-dimethylbenzyl amine, 4-methoxy-N,N-dimethylbenzyl amine, and 4-methyl-N,N-dimethylbenzyl amine. The promotors which are commercially available include products of Shikoku Chemicals Co., Ltd. marketed under trademark designation of "CUREZOL" 2MZ-A, 2MZ-OK, 2PHZ, 2P4BHZ, and 2P4MHZ (invariably imidazole type compounds) and products of Sun-Apro K.K. marketed under product codes of U-CAT3503X, U-CAT3502X (invariably isocyanate compounds blocked with dimethyl amine), for example.
When only the cyanoguanidine derivative mentioned above is added to the composition as an epoxy resin curing agent, the reaction in the post-curing treatment begins at such a high temperature as about 200° C. It is, therefore, desired to lower the reaction starting temperature by having an epoxy resin curing accelerator incorporated in the composition. If this accelerator is incorporated in an unduly large amount, the excess of the accelerator will entrain the drawback of shortening the shelf life of the photocurable and thermosetting resin composition prepared in a single liquid formulation. The amount of the epoxy resin curing accelerator to be incorporated in the composition, therefore, is desired to be in the range of from 0.1 to 2.0 parts by weight, based on 100 parts by weight of the radiation-curable resin (A) mentioned above.
Further, the thermosetting or the photocurable and thermosetting coating composition of the present invention may incorporate therein, depending on the desired properties thereof, a well known and widely used filler such as barium sulfate, silicon oxide, talc, clay, calcium carbonate, silica, kaolin, glass fiber, carbon fiber, mica, asbestos, and metal powder; a color pigment such as phthalocyanine blue, phthalocyanine green, titanium oxide, and carbon black; a thickening agent such as bentonite, organo-bentonite and finely powdered silica; an anti-foaming agent; an adhesiveness-imparting agent; a leveling agent; and a well known and widely used thermal polymerization inhibitor such as hydroquinone, hydroquinone monomethyl ether, pyrogallol, t-butyl catechol, and phenothiazine.
The photocurable and thermosetting coating composition which is prepared in accordance with the present invention is adjusted, when necessary, to a level of viscosity suitable for the coating method, applied by the technique of screen printing, curtain coating, spray coating, roll coating, or the like to a printed circuit board having a circuit already formed thereon, for example, and then dried at a temperature in the range of from 60° to 100° C., for example, thereby to evaporate the organic solvent from the coated composition and give rise to a tack-free coating film. Then, the composition coated on the printed circuit board is selectively exposed to an actinic ray through a photomask having a prescribed pattern and the composition in the unexposed areas of the coating film is developed with a dilute aqueous alkali solution to obtain a resist pattern. Thereafter, the photocured coating film is further thermally cured by subjecting to the heat treatment at a temperature in the range of from 140° to 200° C., for example. By this thermal treatment, in addition to the curing reaction of the aforementiond thermosetting components, the polymerization of the photocurable resin components is promoted and the copolymerization of this component with the thermosetting component are also facilitated so that the consequently produced resist film acquires improvements in various properties such as resistance to heat, resistance to solvents, resistance to acids, adhesiveness, electrical properties, and hardness. The composition proves particularly useful for the formation of a solder resist.
As an aqueous alkali solution to be used in the process of development mentioned above, aqueous alkali solutions of potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, sodium silicate, ammonia, amines, etc. can be used.
Examples of light sources which are advantageously used for the purpose of photocuring the composition include low-pressure mercury lamp, medium-pressure mercury lamp, high-pressure mercury lamp, ultra-high-pressure mercury lamp, xenon lamp, and metal halide lamp, for example. Also, a laser beam may be used as the actinic ray for exposure of the film.
Now, the present invention will be more specifically described below with reference to working examples. Wherever "parts" and "%" are mentioned hereinbelow, they invariably refer to those based on weight unless otherwise specified.
The abbreviations of cyanoguanidine derivatives used in the following working examples designate the following compounds.
ATU2CG: 3,9-bis(3-cyanoguanidinopropyl)-2,4,8,10-tetraoxaspiro[5.5]undecane having a substituent R 2 of (16) in the general formula (1a) mentioned hereinbefore.
2CG: 1,1-bis(3-cyanoguanidine) having a substituent R 2 of (2) in the general formula (1a).
Ph2CG: 1,4-bis(3-cyanoguanidino)benzene having a substituent R 2 of (6) in the general formula (1a).
DDM2CG: 4,4'-bis(3-cyanoguanidyl)diphenyl methane having a substituent R 2 of (7) in the general formula (1a).
HM2CG: 1,6-di(N 3 -cyano-N 1 -guanidino)hexane having a substituent R 2 of (1) (n=6) in the general formula (1a).
MD: 2-cyanoguanidyl-4,6-diamino-S-triazine having a substituent R 2 of (35) in the general formula (1a).
EXAMPLE 1
The reactivity of a given cyanoguanidine derivative with in epoxy resin was determined by the use of a differential scanning calorimeter (DSC). As the epoxy resin, a product (epoxy equivalent weight 190) of Yuka-Shell K.K. marketed under trademark designation of Epikote 828 was used. The cyanoguanidine derivative as a curing catalyst and the epoxy resin were formulated in amounts such that the hydrogen atoms in the amino groups of the cyanoguanidine derivative accounted for 0.40 mol (1.0 mol in the case of MD) per mol of the epoxy group of the epoxy resin. They were mixed in a mortar. About 10 mg of the resultant mixture was charged in an aluminum container for the DSC, weighed accurately, and used as a sample of known weight. The analyzer was a differential scanning calorimetric analyzer produced by Seiko Denshi Kogyo K.K. and marketed under product code of "SSC5200". The analysis was carried out in the air atmosphere at a temperature increasing rate of 5° C./minute.
The results are shown in Table 1. In all the cyanoguanidine derivatives analyzed, the appearance of a conspicuous heat peak due to a curing reaction was recognized. From the cell after the heating, a brown cured mass was invariably obtained.
TABLE 1______________________________________ Reaction Temperature of starting exothermic ExothermCompound temperature (°C.) peak (°C.) (J/g)______________________________________ATU2CG 138.4 184.8 371.72CG 147.8 187.1 284.9Ph2CG 208.2 249.3 251.8DDM2CG 112.8 249.3 251.8HM2CG 180.0 205.0 232.0MD 155.9 216.1 469.1______________________________________
EXAMPLE 2
The solubility of a given cyanoguanidine derivative in various organic solvents was determined. In an Erlenmeyer flask having an inner volume of 50 ml and fitted with a groundin stopper, 10 ml of a given organic solvent and a prescribed amount of the cyanoguanidine derivative were stirred at 25° C. for 30 minutes. The resultant mixture was filtered. The dissolved sample in the filtrate was isolated by vaporizing the solvent, dried and weighed. The solubility of the sample was calculated from the weight. The results are shown in Table 2.
TABLE 2______________________________________Compound Ethanol MEK Cyclohexane Water______________________________________ATU2CG Trace Trace Trace Trace2CG Trace Trace Trace TracePh2CG Trace Trace Trace TraceDDM2CG Trace Trace Trace TraceMD Trace Trace Trace Trace______________________________________
It is clearly noted from Table 2 that the cyanoguanidine derivatives according to the present invention are sparingly soluble in the various organic solvents.
EXAMPLE 3
A sample was prepared by mixing 0.18 g of ATU2CG with 0.50 g of epoxy resin, Epikote 828 in a mortar and applying the resultant mixture in a thickness of 100 μm to a copper plate 8 mm in thickness (14×60 mm). The sample was heated in a furnace at 210° C. for 66 minutes to cure the applied coat. The cured coat in the sample thus obtained was tested for properties by the use of a knife edge type pendulum in a rigid-body pendulum type viscoelasticity tester (produced by Orientic Corp. and marketed under trademark designation of "Rheovibron DDV-OPA III"), with the temperature of the sample elevated from room temperature to 250° C. at a temperature increasing rate of 30° C./minute.
Samples of cured coats were obtained by following the procedure mentioned above while using 0.07 g of 2CG, 0.11 g of Ph2CG, 0.15 g of DDM2CG, and 0.07 g of MD respectively in place of 0.18 g of ATU2CG. They were tested for properties in the same manner as described above. The physical properties of the resultant cured coats are shown in Table 3.
TABLE 3______________________________________Physical properties of cured coat Logarithmic dampingCompound Glass transition point (°C.) factor (ln)______________________________________ATU2CG 145 0.212CG 175 0.08Ph2CG 167 0.07DDM2CG 171 0.08MD 169 0.134______________________________________
The logarithmic damping factor (Δ) indicated in Table 3 above denotes the magnitude which is obtained by mounting a rigid-body pendulum 1 on a substrate 3 covered with a coating 2 as shown in FIG. 7 and FIG. 8, heating a heat block 4 supporting the substrate 3 and meanwhile measuring the variation in the oscillation of the pendulum 1, and computing the following formula (9) using the data of variation of oscillation of the pendulum obtained as shown in FIG. 9. The pointed end la of the pendulum 1 penetrated the coating 2 and reached the surface of the substrate and functioned as a fulcrum of the oscillation. ##EQU1##
The logarithmic damping factor is such that the softness of the cured coat increases in proportion as the magnitude of this factor increases. In all the samples used in the present example, that using ATU2CG produced the softest cured coat. This fact may be logically explained by a supposition that the effect of the flexibility of the substituent manifested itself in the cured coat. The samples using Ph2CG and DDM2CG clearly manifested the effects of their rigid aromatic rings. Incidentally, in the case of the cured coat using cyanoguanidine (abbreviation: CG), the glass transition point Tg is 166° C. and the logarithmic damping factor is 0.13. In the case of 2CG, the cured coat was fairly hard as compared with the cured coat using CG. This fact may be logically explained by a supposition that the number of cross-linking points increased.
EXAMPLE 4
Various cyanoguanidine derivatives were severally mixed with an epoxy resin (Epikote 828) so as to satisfy the ratio of 1 mol of active hydrogen equivalent weight per mol of the epoxy group of the epoxy resin. The compositions thus obtained were tested for variation of viscosity with time. The results are shown in Table 4 below.
TABLE 4______________________________________ Variation of viscosity with time Ratio of increase of Ratio of increase of viscosity by 7 days' viscosity by 1 standing at 50° C. month's standing atCompound (times) 25° C. (times)______________________________________CG (control) 1.35 2.13HM2CG 1.27 1.002CG 4.90 3.27Ph2CG 1.27 1.00______________________________________
It is clearly noted from Table 4 that HM2CG and Ph2CG in particular were stable to resist the effect of aging.
EXAMPLE 5
The product of the reaction of (i) 1 equivalent weight of a cresol-novolak type epoxy resin having an epoxy equivalent weight of 220 and possessing an average of 7 phenol ring residues and epoxy groups per molecule thereof with (ii) 1.05 equivalent weight of acrylic acid, was caused to react with 0.67 equivalent weight of tetrahydrophthalic anhydride in carbitol acetate as a solvent under normal pressure. The product of this reaction was a viscous liquid containing 52 parts by weight of carbitol acetate, based on 100 parts by weight of solid resin. As a mixture, it showed an acid value of 63.4 mg KOH/g. Hereinafter, this product will be referred to for convenience as "resin A".
______________________________________Composition (a)______________________________________Resin A 152.0 parts2-Methyl-1-[4-(methylthio)phenyl]-2- 17.0 partsmorpholino-propane-1-onModaflow (trademark of Monsanto Co., U.S.A. 3.0 partsfor a leveling agent)Silicone type anti-foaming agent (product of 4.0 partsShinetsu Chemical Industry Co., Ltd.marketed under product code of KS-66)Fastogen Green S (trademark of Dainippon Ink 1.5 partsand Chemicals Industries, Ltd.for a color pigment)Aerosil #200 (trademark of Nippon 2.0 partsAerosil Co., Ltd for silica)Barium sulfate 65.0 parts2PHZ 0.5 partProduct obtained in Synthesis Example 2 3.2 partsDipropylene glycol monomethyl ether 2.0 partsIPSOL #150 (trademark of Idemitsu 2.0 partsPetrochemical Co., Ltd. for a solvent)Total 252.2 parts______________________________________
The above components were kneaded with a three-roll mill to prepare a main agent. As a cross-linking agent for this main agent, the following epoxy resin composition was similarly kneaded with a three-roll mill to prepare a hardener.
______________________________________Composition (b)______________________________________N695 (product code of Dainippon Ink and 32.0 partsChemicals Industries, Ltd. for cresolnovolak type epoxy resin)Triglycidyl isocyanurate 10.0 partsDPHA (product code of Nippon Kayaku K.K. 20.0 partsfor a photopolymerizable monomer)Dipropylene glycol monomethyl ether 5.0 partsIPSOL #150 5.0 partsBarium sulfate 35.0 partsTotal 107.0 parts______________________________________
The main agent and the hardener prepared as described above were mixed in the following ratio to obtain a solder resist ink. The same mixing ratio of the hardener to the main agent was employed in the following Examples 6 to 8 and Comparative Example 1:
Main agent: hardener=70:30
EXAMPLE 6
A main agent was prepared by following the procedure of Example 5, except that 1.9 parts of the product obtained in Synthesis Example 4 was used in place of 3.2 parts of the product obtained in Synthesis Example 2. The hardener was same as that used in Example 5.
EXAMPLE 7
A main agent was prepared by following the procedure of Example 5, except that 2.6 parts of the product obtained in Synthesis Example 5 was used in place of 3.2 parts of the product obtained in Synthesis Example 2. The hardener was same as that used in Example 5.
EXAMPLE 8
A main agent was prepared by following the procedure of Example 5, except that 2.0 parts of hexamethylene-bis-cyanoguanidine was used in place of 3.2 parts of the product obtained in Synthesis Example 2. The hardener was same as that used in Example 5.
COMPARATIVE EXAMPLE 1
A main agent was prepared by following the procedure of Example 5, except that 1.0 part of cyanoguanidine was used in place of 3.2 parts of the product obtained in Synthesis Example 2. The hardener was same as that used in Example 5.
Evaluation of quality:
Each of the ink compositions obtained in Examples 5 to 8 and Comparative Example 1 was applied by the screen printing method onto the entire surface of a copper-clad substrate having a prescribed pattern formed in advance thereon and then dried at 80° C. for 20 minutes to give a tack-free coating film. Each coating film on the substrate was exposed to an actinic radiation according to a solder resist pattern through a negative film tightly superposed thereon to a dose of 800 mJ/cm 2 and then developed with an aqueous 1 wt % sodium carbonate solution for one minute to form a resist pattern thereon. The coating film on the substrate was thermally cured at 150° C. for 50 minutes to prepare a test substrate, which was tested for resistance to soldering temperature, acid resistance, alkali resistance, pencil hardness, and electrical property. The developing property and the storage stability of each ink composition mentioned above were determined by the methods to be described hereinafter.
(1) Test for drying time (developing property)
Each of the compositions obtained in the examples and the comparative example cited above was applied by the screen printing method onto the entire surface of a copper-clad substrate having a prescribed pattern formed in advance thereon and then predried at 80° C. for periods graduated at an interval of 10 minutes. The coating films consequently formed on the substrates were exposed to an actinic radiation according to a solder resist pattern through a negative film tightly superposed thereon. They were then developed with an aqueous 1 wt % sodium carbonate solution for one minute to test for life (the longest drying period allowing effective development).
(2) Resistance to soldering temperature
A given test substrate was coated with a rosin type flux, immersed for 30 seconds in a soldering bath set in advance at 260° C., washed with propylene glycol monomethylether acetate and ethanol for removal of the flux, and visually examined as to swelling and discoloration of the resist layer. The test substrates was further subjected to a peel test using a cellophane adhesive tape as to the peeling of the resist layer. The rating was made on the following three-point scale.
◯: Perfect absence of any discernible change
Δ: Only slight change of the resist layer
x: Presence of discernible swelling, peeling or discoloration of the resist layer
(3) Acid resistance
A given test substrate was immersed for 30 minutes in an aqueous 10 wt % sulfuric acid solution at normal room temperature, washed with water, and then subjected to a peel test using a cellophane adhesive tape to find the extents of peeling and discoloration consequently produced in the resist layer. They were rated on the following three-point scale.
◯: Perfect absence of any discernible change
Δ: Slight change of the resist layer
x: Presence of discernible swelling, peeling or discoloration of the resist layer
(4) Alkali resistance
A given test substrate was immersed for 30 minutes in an aqueous 10 wt % sodium hydroxide solution at normal room temperature, washed with water, and then subjected to a peel test using a cellophane adhesive tape to find the extents of peeling and discoloration consequently produced in the resist layer. They were rated on the following three-point scale.
◯: Perfect absence of any discernible change
Δ: Slight change of the resist layer
x: Presence of discernible swelling, peeling or discoloration of the resist layer
(5) Pencil hardness
In accordance with the testing method of JIS K-5400 6.14 using a pencil hardness tester, a given test substrate was placed under a load of 1 kg. This property was reported by the highest hardness which inflicted no dent on the coating. The pencils used for this test were "Mitsubishi® Hi-Uni" made by Mitsubishi Pencil Co., Ltd. (registered trademark).
(6) Electrical property
This property was determined by preparing a test substrate under the conditions mentioned above using a comb type electrode B coupon of IPC SM-840B B-25, applying a bias voltage of DC 500 V to the comb type electrode, and measuring the initial insulation resistance. This test substrate was left standing for 12 hours under the conditions of 121° C., 100% R.H., and two atmospheric pressure so as to be humidified. After humidification, the insulation resistance of the test substrate was determined in the same manner as described above. This insulation resistance is denoted in Table 5 as "after PCT". Another test substrate prepared in the same manner as described above was also subjected to humidification and measurement of the insulation resistance in the same manner as described above, except that a bias voltage of DC 100 V was applied thereto. This insulation resistance is denoted in Table 5 as "after PCBT".
(7) Storage stability
After the main agent was mixed with the hardener, the resultant ink composition was left standing in a thermostatic chamber kept at 40° C. for one week and then examined to find the extents of change in viscosity and evaluate stability during storage. The storage stability was rated on the following three-point scale.
◯: Change of viscosity less than 1.5 times the initial value
Δ: Change of viscosity not less than 1.5 times and less than 3 times the initial value
x: Change of viscosity not less than 3 times the initial value
The results of these evaluations are shown in Table 5.
TABLE 5______________________________________ ComparativeCharacteristic Example Exampleproperties 5 6 7 8 1______________________________________(1) Drying time (min.) 120 120 120 120 100(Developing property)(2) Resisrance to ◯ ◯ ◯ ◯ ◯soldering temp.(3) Acid resistance ◯ ◯ ◯ ◯ ◯(4) Alkali resistance ◯ ◯ ◯ ◯ ◯(5) Pencil hardness 6H 6H 6H 6H 6H(6) Electrical property,insulation resistance (Ω)Initial value 10.sup.12 10.sup.12 10.sup.12 10.sup.12After PCT 10.sup.12 10.sup.12 10.sup.12 10.sup.12After PCBT 10.sup.12 10.sup.12 10.sup.12 10.sup.12(7)Storage stability ◯ ◯ ◯ ◯ ×______________________________________
EXAMPLE 9
______________________________________Composition (a)______________________________________Resin A 150.0 partsSilicone type anti-foaming agent (KS-66) 2.0 parts2-Methyl-1-[4-(methylthio)phenyl]-2- 16.0 partsmorpholino-propane-1-onFastogen Green S 5.0 partsDipropylene glycol monomethyl ether 4.0 partsIPSOL #150 3.0 partsBarium sulfate 30.0 partsFinely powdered silica 30.0 partsProduct obtained in Synthesis Example 3 8.0 partsTotal 248.0 parts______________________________________
The above components were kneaded with a three-roll mill to prepare a main agent. As a cross-linking agent for this main agent, the following epoxy resin composition was similarly kneaded with a three-roll mill to prepare a hardener.
______________________________________Composition (b)______________________________________Dipropylene glycol monomethyl ether 12.0 partsIPSOL #150 12.0 partsDPHA 24.0 partsTriglycidyl isocyanurate 26.0 partsYX-4000 26.0 partsBarium sulfate 50.0 partsTotal 150.0 parts______________________________________
The main agent and the hardener prepared as described above were mixed in the ratio of 70:30 to obtain a solder resist ink.
COMPARATIVE EXAMPLE 2
A main agent was prepared by following the procedure of Example 9, except that 6.0 parts of melamine was used in place of 8.0 parts of the product obtained in Synthesis Example 3. The hardener was same as that used in Example 9.
Each of the ink compositions obtained in Example 9 and Comparative Example 2 was tested for electroless gold plating resistance as described below.
Electroless gold plating resistance:
The copper plane of a copper plated-throughhole printed circuit board having a prescribed pattern formed in advance thereon was surface-treated by (a) jet-scrub polishing with the use of an abrasive No. 270 (manufactured by Ishii Hyoki K.K.), washing with water and drying or (b) polishing with the use of a roll buff No. 1200 (manufactured by Ishii Hyoki K.K.), washing with water and drying. The resultant board was subjected to coating, drying, exposure, development and heating in the same manner as described above to thereby give a test piece. By using this test piece, electroless gold plating was effected by the method as specified below. Then the test piece was subjected to a peel test with the use of an adhesive cellophane tape and peeling conditions of the resist layer were evaluated on the following three-point scale.
◯: Neither any change in appearance nor peeling of the resist layer was observed.
Δ: No change in appearance was observed, though slight peeling of the resist layer was observed.
x: The resist layer suffered from lifting and plating penetration, and significant peeling of the resist layer was observed in the peeling test.
Method for electroless gold plating:
The test piece was degreased by dipping in an acidic degreasing solution (a 20% by vol. solution of Metex L-5B manufactured by Fuji Chemical Industries Co., Ltd.) at 30° C. for 3 minutes and then washed with water by dipping in running water for 3 minutes. Next, the test piece was subjected to soft etching by dipping in an aqueous 14.3 wt % ammonium persulfate solution at room temperature for 3 minutes and then washed with water by dipping in running water for 3 minutes. After dipping in an aqueous 10% by vol. sulfuric acid solution for one minute at room temperature, the test piece was washed with water by dipping in running water for 30 seconds to one minute. Then it was dipped in a catalyst solution (a 10% by vol. aqueous solution of Metal plate Activator 350 manufactured by Meltex Inc.) at 30° C. for 7 minutes to thereby add the catalyst thereto and then washed with water by dipping in running water for 3 minutes. This test piece having the catalyst added thereto was subjected to electroless nickel plating by dipping in a nickel plating solution (a 20% by vol. aqueous solution of Melplate Ni-865M, manufactured by Meltex Inc., pH 4.6) at 85° C. for 20 minutes. After dipping in an aqueous 10% by vol. sulfuric acid solution at room temperature for one minute, the test piece was washed with water by dipping in running water for 30 seconds to one minute. Next, the test piece was subjected to electroless gold plating by dipping in a gold plating solution (an aqueous solution of 15% by vol. of Aurolectroless UP manufactured by Meltex Inc. and 3% by vol. of gold potassium cyanide, pH 6) at 95° C. for 10 minutes. Then it was washed with water by dipping in running water for 3 minutes and with hot water by dipping in hot water at 60° C. for 3 minutes. After sufficient washing with water, thorough draining, and drying, an electroless gold plated test piece was obtained. The results are shown in Table 6.
TABLE 6______________________________________ ComparativeCharacteristic Example 9 Example 2______________________________________Electroless gold ◯ Δplating resistance______________________________________
While certain specific working examples have been disclosed herein, the invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The described examples are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by foregoing description and all changes which come within the meaning and range of equivalency of the claims are, therefore, intended to be embraced therein.
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Disclosed are novel cyanoguanidine derivatives which are usable as an epoxy resin curing agent and are represented by the following general formula (1). A thermosetting resin composition and a photocurable and thermosetting resin composition containing the following cyanoguanidine derivatives and other derivatives as the epoxy resin curing agent are also disclosed. ##STR1## wherein R 1 represents a substituent selected from the group consisting of the following substituents (a) through (k). ##STR2##
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This application is a continuation-in-part application of U.S. patent application Ser. No. 09/130,131, filed Aug. 6, 1998, now U.S. Pat. No. 5,997,499, which was a continuation-in-part application of U.S. patent application Ser. No. 09/090,433, filed Jun. 4, 1998.
BACKGROUND OF THE INVENTION
This invention relates generally to the field of cataract surgery and more particularly to a handpiece for practicing the liquefracture technique of cataract removal.
The human eye in its simplest terms functions to provide vision by transmitting light through a clear outer portion called the cornea, and focusing the image by way of the lens onto the retina. The quality of the focused image depends on many factors including the size and shape of the eye, and the transparency of the cornea and lens.
When age or disease causes the lens to become less transparent, vision deteriorates because of the diminished light which can be transmitted to the retina. This deficiency in the lens of the eye is medically known as a cataract. An accepted treatment for this condition is surgical removal of the lens and replacement of the lens function by an artificial intraocular lens (IOL).
In the United States, the majority of cataractous lenses are removed by a surgical technique called phacoemulsification. During this procedure, a thin phacoemulsification cutting tip is inserted into the diseased lens and vibrated ultrasonically. The vibrating cutting tip liquifies or emulsifies the lens so that the lens may be aspirated out of the eye. The diseased lens, once removed, is replaced by an artificial lens.
A typical ultrasonic surgical device suitable for ophthalmic procedures consists of an ultrasonically driven handpiece, an attached cutting tip, and irrigating sleeve and an electronic control console. The handpiece assembly is attached to the control console by an electric cable and flexible tubings. Through the electric cable, the console varies the power level transmitted by the handpiece to the attached cutting tip and the flexible tubings supply irrigation fluid to and draw aspiration fluid from the eye through the handpiece assembly.
The operative part of the handpiece is a centrally located, hollow resonating bar or horn directly attached to a set of piezoelectric crystals. The crystals supply the required ultrasonic vibration needed to drive both the horn and the attached cutting tip during phacoemulsification and are controlled by the console. The crystal/horn assembly is suspended within the hollow body or shell of the handpiece by flexible mountings. The handpiece body terminates in a reduced diameter portion or nosecone at the body's distal end. The nosecone is externally threaded to accept the irrigation sleeve. Likewise, the horn bore is internally threaded at its distal end to receive the external threads of the cutting tip. The irrigation sleeve also has an internally threaded bore that is screwed onto the external threads of the nosecone. The cutting tip is adjusted so that the tip projects only a predetermined amount past the open end of the irrigating sleeve. Ultrasonic handpieces and cutting tips are more fully described in U.S. Pat. Nos. 3,589,363; 4,223,676; 4,246,902; 4,493,694; 4,515,583; 4,589,415; 4,609,368; 4,869,715; 4,922,902; 4,989,583; 5,154,694 and 5,359,996, the entire contents of which are incorporated herein by reference.
In use, the ends of the cutting tip and irrigating sleeve are inserted into a small incision of predetermined width in the cornea, sclera, or other location. The cutting tip is ultrasonically vibrated along its longitudinal axis within the irrigating sleeve by the crystal-driven ultrasonic horn, thereby emulsifying the selected tissue in situ. The hollow bore of the cutting tip communicates with the bore in the horn that in turn communicates with the aspiration line from the handpiece to the console. A reduced pressure or vacuum source in the console draws or aspirates the emulsified tissue from the eye through the open end of the cutting tip, the cutting tip and horn bores and the aspiration line and into a collection device. The aspiration of emulsified tissue is aided by a saline flushing solution or irrigant that is injected into the surgical site through the small annular gap between the inside surface of the irrigating sleeve and the cutting tip.
Recently, a new cataract removal technique has been developed that involves the injection of hot (approximately 45° C. to 105° C.) water or saline to liquefy or gellate the hard lens nucleus, thereby making it possible to aspirate the liquefied lens from the eye. Aspiration is conducted with the injection of the heated solution and the introduction of a relatively cool irrigating solution, thereby quickly cooling and removing the heated solution. This technique is more fully described in U.S. Pat. No. 5,616,120 (Andrew, et al.), the entire contents of which is incorporated herein by reference. The apparatus disclosed in the publication, however, heats the solution separately from the surgical handpiece. Temperature control of the heated solution can be difficult because the fluid tubings feeding the handpiece typically are up to two meters long, and the heated solution can cool considerably as it travels down the length of the tubing.
Therefore, a need continues to exist for a surgical handpiece that can heat internally the solution used to perform the liquefracture technique.
BRIEF SUMMARY OF THE INVENTION
The present invention improves upon the prior art by providing a tip for a liquefracture surgical handpiece. The tip uses at least two channels or tubes. One tube is used for aspiration and at least one other tube is used to inject heated surgical fluid for liquefying a cataractous lens. The distal portion of the injection tube terminates just inside of the aspiration tube and directs the heated fluid through an orifice in the wall of the aspiration tube opposite the injection tube. The handpiece may also contain other tubes, for example, for injecting relatively cool surgical fluid.
Accordingly, one objective of the present invention is to provide a surgical handpiece having at least two tubes.
Another objective of the present invention is to provide a safer tip for a surgical handpiece having a pumping chamber.
Another objective of the present invention is to provide a surgical handpiece having a device for delivering the surgical fluid through the handpiece in pulses that do not directly enter the eye.
These and other advantages and objectives of the present invention will become apparent from the detailed description and claims that follow.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a front, upper left perspective view of the handpiece of the present invention.
FIG. 2 is a rear, upper right perspective view of the handpiece of the present invention.
FIG. 3 is a cross-sectional view of the handpiece of the present invention taken along a plane passing through the irrigation channel.
FIG. 4 is a cross-sectional view of the handpiece of the present invention taken along a plane passing through the aspiration channel.
FIG. 5 is an enlarged partial cross-sectional view of the handpiece of the present invention taken at circle 5 in FIG. 4 .
FIG. 6 is an enlarged partial cross-sectional view of the handpiece of the present invention taken at circle 6 in FIG. 3 .
FIG. 7 is an enlarged cross-sectional view of the handpiece of the present invention taken at circle 7 in FIGS. 3 and 4, and showing a resistive boiler pump.
FIG. 8 is a schematic cross-sectional view of a heating element boiler pump that may be used with the present invention.
FIG. 9 is an exploded, partial cross-section view of one embodiment of the handpiece of the present invention.
FIG. 10 is an enlarged cross-sectional view of one alternative tip design for use with the present invention.
FIG. 11 is an enlarged perspective of an alternative tip design for use with the present invention.
FIG. 12 is an enlarged cross-sectional view of the second tip design for use with the present invention illustrated in FIG. 11 .
FIGS. 13A-13C are enlarged perspective views of alternative orifice designs for use with the present invention.
DETAILED DESCRIPTION OF THE INVENTION
Handpiece 10 of the present invention generally includes handpiece body 12 and operative tip 16 . Body 12 generally includes external irrigation tube 18 and aspiration fitting 20 . Body 12 is similar in construction to well-known in the art phacoemulsification handpieces and may be made from plastic, titanium or stainless steel. As best seen in FIG. 6, operative tip 16 includes tip/cap sleeve 26 , tube 28 and tube 30 . Sleeve 26 may be any suitable commercially available phacoemulsification tip/cap sleeve or sleeve 26 may be incorporated into other tubes as a multi-lumen tube. Tube 28 may be any commercially available hollow phacoemulsification cutting tip, such as the TURBOSONICS tip available from Alcon Laboratories, Inc., Fort Worth, Tex. Tube 30 may be any suitably sized tubing to fit within tube 28 , for example 29 gauge hypodermic needle tubing. Alternatively, as best seen in FIG. 10, tube 30 ′ may be external to tube 28 ′ with a distal tip 27 that terminates within bore 29 of tube 28 ′ near distal tip 31 of tube 28 ′. Preferably, tube 30 ′ is angled at between 25° and 50° and terminates approximately 0.1 mm to 3.0 mm from distal tip 31 . Such an arrangement causes fluid exiting tube 28 ′ to reflect off of internal wall 33 of tube 28 ′ prior to exiting out of distal tip 31 , thereby reducing the intensity of the pressure pulse prior to contact with eye tissue. The intensity of the pressure pulse decays with distance from tip 31 ; consequently, efficiency is best for tissue that is held at or within tip 31 .
As best seen in FIG. 5, tube 30 is free on the distal end and connected to pumping chamber 42 on the proximal end. Tube 30 and pumping chamber 42 may be sealed fluid tight by any suitable means having a relatively high melting point, such as silver solder. Fitting 44 holds tube 30 within bore 48 of aspiration horn 46 . Bore 48 communicates with fitting 20 , which is journaled into horn 46 and sealed with O-ring seal 50 to form an aspiration pathway through horn 46 and out fitting 20 . Horn 46 is held within body 12 by O-ring seal 56 to form irrigation tube 52 which communicates with irrigation tube 18 at port 54 .
As best seen in FIG. 7, in a first embodiment of the present invention, pumping chamber 42 contains a relatively large pumping reservoir 43 that is sealed on both ends by electrodes 45 and 47 . Electrical power is supplied to electrodes 45 and 47 by insulated wires 49 and 51 , respectively. In use, surgical fluid (e.g. saline irrigating solution) enters reservoir 43 through port 55 , tube 34 and check valve 53 , check valve 53 being well-known in the art. Electrical current (preferably Radio Frequency Alternating Current or RFAC) is delivered to and across electrodes 45 and 47 because of the conductive nature of the surgical fluid. As the current flows through the surgical fluid, the surgical fluid boils. As the surgical fluid boils, it expands rapidly out of pumping chamber 42 through port 57 and into tube 30 (check valve 53 prevents the expanding fluid from entering tube 34 ). The expanding gas bubble pushes the surgical fluid in tube 30 downstream of pumping chamber 42 forward. Subsequent pulses of electrical current form sequential gas bubbles that move surgical fluid down tube 30 . The size and pressure of the fluid pulse obtained by pumping chamber 42 can be varied by varying the length, timing and/or power of the electrical pulse sent to electrodes 45 and 47 and by varying the dimensions of reservoir 43 . In addition, the surgical fluid may be preheated prior to entering pumping chamber 42 . Preheating the surgical fluid will decrease the power required by pumping chamber 42 and/or increase the speed at which pressure pulses can be generated.
While several embodiments of the handpiece of the present invention are disclosed, any handpiece producing adequate pressure pulse force, rise time and frequency may also be used. For example, any suitable handpiece producing a pressure pulse force of between 0.03 grams and 20.0 grams, with a rise time of between 1 gram/second and 20,000 grams/second and a frequency of between 1 Hz and 200 Hz may be used, with between 20 Hz and 100 Hz being most preferred. The pressure pulse force and frequency will vary with the hardness of the material being removed. For example, the inventors have found that a lower frequency with a higher pulse force is most efficient at debulking and removing the relatively hard nuclear material, with a higher frequency and lower pulse force being useful in removing softer epinuclear and cortical material. Infusion pressure, aspiration flow rate and vacuum limit are similar to current phacoemulsification techniques.
As best seen in FIG. 8, the fluid in reservoir 143 in pumping chamber 142 may also be heated by the use of heating element 145 that is internal to reservoir 143 . Heating element 145 may be, for example, a coil of 0.003 inch diameter stainless steel wire which is energized by power source 147 . The size and pressure of the fluid pulse obtained by pumping chamber 142 can be varied by varying the length and timing of the electrical pulse sent to element 145 by power source 147 and by varying the dimensions of reservoir 143 . The numbers in FIG. 8 are identical to the numbers in FIG. 7 except for the addition of “ 100 ” in FIG. 8 .
As best seen in FIGS. 3, 4 and 7 , surgical fluid may be supplied to pumping chamber 43 through tube 34 or, as seen in FIG. 9, surgical fluid may be supplied to pumping chamber 243 through irrigation fluid tube 234 which branches off main irrigation tube 235 supplying cool surgical fluid to the operative site. As seen in FIG. 9, aspiration tube 237 may be contained internally to handpiece 10 . The numbers in FIG. 9 are identical to the numbers in FIG. 7 except for the addition of “ 200 ” in FIG. 9 .
As best seen in FIGS. 11 and 12, in an alternative embodiment of the present invention, tube 330 is internal to tube 328 and distal tip 327 of tube 330 terminates within bore 329 of tube 328 . Internal wall 33 ′ of tube 328 may contain orifice 5 arranged so that the pressure pulse exiting tip 327 may be directed through orifice 5 . Such an arrangement aids in aspiration and followability of the targeted tissue.
As best seen in FIGS. 13A-13C, orifice 5 , 5 ′ and 5 ″ may have a variety of shapes, such as a grating (FIG. 13 A), round (FIG. 13B) or notched (FIG. 13C) to provide the desired interaction between the pressure pulse and the targeted tissue.
Any of a number of methods can be employed to limit the amount of heat introduced into the eye. For example, the pulse train duty cycle of the heated solution can be varied so that the total amount of heated solution introduced into the eye does not vary with the pulse frequency. Alternatively, the aspiration flow rate can be varied as a function of pulse frequency so that as pulse frequency increases aspiration flow rate increases proportionally.
This description is given for purposes of illustration and explanation. It will be apparent to those skilled in the relevant art that changes and modifications may be made to the invention described above without departing from its scope or spirit. For example, it will be recognized by those skilled in the art that the present invention may be combined with ultrasonic and/or rotating cutting tips to enhance performance.
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A tip for a liquefracture surgical handpiece. The tip uses at least two channels or tubes. One tube is used for aspiration and at least one other tube is used to inject heated surgical fluid for liquefying a cataractous lens. The distal portion of the injection tube terminates just inside of the aspiration tube and directs the heated fluid through an orifice in the wall of the aspiration tube opposite the injection tube. The handpiece may also contain other tubes, for example, for injecting relatively cool surgical fluid.
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BACKGROUND OF THE INVENTION
[0001] The most important barrier for efficient expression of foreign or native genes in any organism many times resides at the level of mRNA translation. As stability of mRNA is a major determinant of gene expression. According to the canonical model, the main signal for the ribosome to land on mRNA and start protein synthesis is the Shine-Dalgarno sequence, a purine-rich region located upstream of the start codon and complementary to the 3′-terminal sequence AUCACCUCCUUA (SEQ ID NO 1) (antiSD) of the 16S rRNA is thought that the SD-antiSD interaction directs the initiation codon to the P site of the 30S subunit at the first step of translation initiation, and that the efficiency of initiation and, eventually, of overall translation depends on the degree of complementarity of the two sequences: the tighter the SD duplex is, the more stable is the initiation complex and the higher the level of translation.
[0002] The 5′ untranslated region (5′ UTR) (also known as a Leader Sequence or Leader RNA) is the region of an mRNA that is directly upstream from the initiation codon. This region is important for the regulation of translation of a transcript by differing mechanisms in viruses, prokaryotes and eukaryotes. While called untranslated, the 5′ UTR or a portion of it is sometimes translated into a protein product. This product can then regulate the translation of the main coding sequence of the mRNA.
[0003] In many other organisms, however, the 5′ UTR is completely untranslated, instead forming complex secondary structure to regulate translation. The 5′ UTR has been found to interact with proteins relating to metabolism and proteins translate sequences within the 5′ UTR. In addition, this region has been involved in transcription regulation, such as the sex-lethal gene in Drosophila. The 5′ UTR begins at the transcription start site and ends one nucleotide (nt) before the initiation codon (usually AUG) of the coding region. In prokaryotes, the length of the 5′ UTR tends to be 3-10 nucleotides long while in eukaryotes it tends to be anywhere from 100 to several thousands nucleotides long. For example, the ste11 transcript in Schizosaccharomyces pombe has a 2273 nucleotide 5′ UTR while the lac operon in Escherichia coli only has 7 nucleotides in its 5′ UTR The differing sizes are likely due to the complexity of the eukaryotic regulation which the 5′ UTR holds, as well as the larger preinitiation complex which must form to begin translation.
[0004] The prokaryotic 5′ UTR contains a ribosome binding site (RBS), also known as the Shine Dalgarno sequence (AGGAGGU) which is usually 3-10 base pairs upstream from the initiation codon. As the 5′ UTR has a high GC content, secondary structures often occur within it. Hairpin loops are one such secondary structure that can be located within the 5′ UTR. These secondary structures also impact the regulation of translation. In prokaryotes, the initiation of translation occurs when IF-3 along with the 30S ribosomal subunit bind to the Shine-Dalgarno sequence of the 5′ UTR. This then recruits many other proteins that such as the 50S ribosomal subunit that allows for translation to begin.
[0005] Each of these steps regulates the initiation of translation. Translation machineries of Bacillus species are quite specific and require homologous ribosome binding sites RBS. The RBS usually contains a sequence GGAGG. It has an average free energy for binding is about −17 kcal/mol at 3′end of the 16S ribosomal RNA. Supplying an efficient Bacillus RBS sequence to the gene of interest is one solution, but it does not always work because the secondary structure around the translation initiation site also plays a pivotal role in determining translation efficiency. The sequence GGAGG in the RBS is usually highly conserved; and the spacer region between the GGAGG sequence and initiation codon is approximately eight bases long and rich in A and U nucleotides.
[0006] The absence of G and C residues around the RBS is thought to be optimal for ribosome binding. The crystals produced by Bacillus thuringiensis (Bt) mainly consist of Cry proteins, most of which are toxic for specific insects and consequently B. thuringiensis has been widely and successfully used as a biopesticides for more than 50 years. The crystal inclusion can account for up to 25% of the dry weight of B. thuringiensis cells. The mechanism for the massive expression of Cry proteins in B. thuringiensis has been investigated and involves numerous factors: transcriptional regulation, cry gene copy number, the stability of cry gene mRNA, and the accumulation and crystallization of Cry proteins.
[0007] Structure-based protein engineering of Cry toxins may direct the search for variants with broader susceptible species spectra, optimal potency, and stability properties. Cry2Aa is among an unusual subset of Cry proteins possessing broad insect species specificity by exhibiting high specific activity against two insect orders, Lepidoptera and Diptera. It is lethal to more lepidopteran species than the Cry1 toxins deployed against agriculturally important Lepidoptera and exhibits a low level of cross resistance in Cry1A-resistant insects. Also, the mode of action of Cry2Aa may be distinct from that of other Cry toxins. Thus, it could serve as a platform for the design of Cry toxins with broader susceptible species spectra and minimal Cry1A-derived cross resistance in the field.
[0008] Cry2A protein is of smaller mass having no C-terminal crystallization domain like that in the 130-140 kDa Cry proteins (e.g Cry1). The massive accumulation or crystallization of these Cry proteins generally requires the presence of additional proteins encoded by genes in the same operon. Additional protein of small size (29 kDa), have no insect toxicity and are not the main components of the crystals; rather, it enhances the accumulation or crystallization of their accompanying Cry protein. Consequently, it is described as an accessory proteins or helper protein. Helper protein is encoded by the orf1 and orf2 genes in the cry2A operon. Orf2 is necessary for the crystallization of Cry2A. It contains 11 tandem repeats of a 15/16 amino acid motif that is acidic in nature. Orf2 and Cry2A can be co-precipitated, evidence of interaction between the two proteins Indeed, Orf2 serves as a crystallization factor by interacting with the Cry2A protein, possibly acting as a template or scaffold.
[0009] To further investigate the role of Orf1 and Orf2 in Cry2A synthesis for potential applied use, we studied the effects of expressing cry2A alone or together with orf1 and orf2 by using the bioinformatics approach and experimental assessment. In this study, cyt1A promoter combined with the STAB-SD sequence (cyt1A-p/STAB-SD) was used as chimeric cyt1A-p/STAB-SD expression system has been shown to significantly improve synthesis of several Cry proteins and Bin toxins. Furthermore, the length and composition of the spacer region (RBS-ATG) was varied to scrutinize its effect on efficient production of Cry2Ac.
BRIEF SUMMARY OF THE INVENTION
[0010] A novel process for efficient expression of foreign gene in Bacillus host was developed by varying the length and nucleotide sequence in the spacer region between ribosomal binding sequence (RBS) and initiation codon (ATG) of the gene. Bacillus thuringiensis cry2Ac gene was selected as a model gene since it requires an upstream open reading frame designated as orf2 for its efficient expression and crystallization in Bacillus host. The ORF2 acts as chaperone and provides a nucleation centre for growing crystals of Cry2Ac. The role of ribosomal binding sequence (RBS) and spacer region (RBS-ATG) was analyzed in Cry2A expression without helper protein in Bacillus expression host.
[0011] Mutation in the RBS and spacer region were introduced by changing length and composition of naturally existing sequence. Bacillus thuringiensis cry2Ac gene was selected as a model gene that was expressed in acrystalliferous strain 4Q7 of the same species. Insecticidal crystal (Cry) toxins from Bacillus thuringiensis (Bt) are widely employed for biological control of pest insects through Bt formulations as well as transgenic plants. Cry2Ac has dual toxicity against lepidopteran as well as dipteran insects. cry2Ac gene appears as a third gene in an operon that consists of three open reading frames (orfs). In order to enhance activity of Cry2Ac toxin from HD29 strain of Bacillus thuringiensis subsp. galleriae ( Bacillus Genetic Stock Center ID 4G5; Serotype 5a5b), gene was over-expressed in acrystalliferous Bt strain 4Q7. The number as well as sequence of nucleotides between ribosomal binding site (RBS) and initiation codon (ATG) were altered in various constructs and were cloned in pSTAB shuttle expression vector containing the cyt1A promoter from B. thuringiensis subsp. israelensis combined with the STAB-SD sequence from B. thuringiensis subsp. morrisoni strain tenebrionis. The resulting plasmid was introduced in 4Q7, an acrystalliferous mutant strain of B. thuringiensis subsp. israelensis . Expression of cry2Ac varied greatly in all transformants, and was significantly enhanced in mutants having additional ATG in the spacer region. A maximum vigor of about 10 times was observed in pPFS-2Ac11 construct which also produced parasporal inclusions unlike wildtype Cry2Ac.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 depicts a protein synthesis in a prokaryotic system.
[0013] FIG. 2 depicts SDS-PAGE analysis of Cry2Ac mutants in the absence of both Orf1 and Orf2 under cyt1A promoter system (pSTAB).
DETAILED DESCRIPTION OF THE INVENTION
[0014] The entire 4.2-kb cry2Ac11 operon from HD29 was amplified by PCR and cloned in pSTAB shuttle expression vector containing the cyt1A promoters from B. thuringiensis subsp. israelensis combined with the STAB-SD sequence from B. thuringiensis subsp. morrisoni strain tenebrionis. The resulting plasmid was introduced in 4Q7, an acrystalliferous mutant strain of B. thuringiensis subsp. israelensis. Furthermore, Cry2Ac was produced in 4Q7 in the absence of both orf1 and orf2. Cultures, grown on nutrient agar overnight, were observed under phase-contrast microscope.
[0015] For analysis of protein contents of each construct, 500 μl of overnight cultures, grown in Pre-culture medium, were inoculated in 50 ml of NBG medium supplemented with 25 μg/ml erythromycin and grown at 30° C. for five days with vigorous shaking. Equal volume of each sample was run on 10% SDS-PAGE.
[0016] Further some mutations were introduced between RBS and ATG of the gene. The nucleotide sequence as well as number was altered in the spacer region as shown in Table 1. This was achieved by amplifying promoter and gene independently with primers having extra bases and then co-ligated them in pSTAB and transferred in 4Q7 strain of B. thuringiensis . The expressed protein was analyzed using SDS-PAGE while parasporal crystals were analyzed under phase contrast microscope.
[0000]
TABLE 1
N-terminal sequence of cry2Ac11 cloned in pHT3101 shuttle vector and
expressed in 4Q7 strain of B. thuringiensis
Sr.
Mutated
Expression in 4Q7
No.
construct
Sequence between RBS and ATG (5′→3′)
Inclusions
SDS-PAGE
1.
pPFS-2Ac11
Yes
+++
2.
pPFS-ATG1
No
−
3.
pPFS-ATG3
No
+++
4.
pPFS-ATG4
No
++
5.
pPFS-ATG5
No
−
6.
pPFS-ATG7
No
+++
7.
pPFS-Orf3
No
[0017] RNA was extracted from 14 hrs old cultures using Trizol reagent and used in Quantitative PCR to determine mRNA level of cry2Ac gene using real time PCR.
RESULTS
[0018] We investigated the quantitative relationship between stability of the secondary structure in 5′ translated region and protein expression levels in Bt. we systematically introduced random mutation in RNA hairpins along the translation initiation region starting from the RBS of mRNA up to the beginning of the coding region (RBS-ATG).
[0019] Previous results suggested that mRNA stability is dependent on the level of its translation. The smaller and more negative ΔG which is the free energy difference between folded and unfolded states, the more stable is the hairpin structure. Although the stability of the secondary structure around the SD sequence has been shown to be inversely related to expression level. High instability of this region provides only the accessibility of the ribosome was thought to play a key role in translation in bioinformatics tools. Although these two approaches differ to some extent, the predictive value of both models is similar, since the same key factors (the secondary structure around the start codon and the ribosome binding affinity) are taken as determining translation efficiency.
[0020] Despite the considerable values of these models, expression of wild ORF3 is low as this may be due to other steps of translation which act as limiting factor. Another reason behind this is that we express wild ORF3 without ORF2 under natural condition as it was studied by the literature that ORF2 duplication unit for Cry2Aa may provide attachment (matrix) or scaffold (scaffold) to the formation of crystals and can also help misfolded protein crystals refold into the right structure to immunize it to the risk of degradation, so as to enhance the protein crystal structure and stability. That's why wild ORF3 unit for Cry2Aa showed the lowest expression level.
[0021] The 29-kDa protein encoded as the Orf2 of the Cry2Ac11 operon acts like a chaperone, assisting Cry2Ac crystallization in acrystalliferous B. thuringiensis host. The same function of Orf2 from Cry2Aa operon has been reported. Cyt-P has been reported to enhance net synthesis of Cry4A and Cry11A in E. coli and B. thuringiensis , as well as Cyt1A production and crystal formation in B. thuringiensis . All of the above studies demonstrated that the effect of the 20-kDa on the Cry or Cyt protein synthesis is significant.
[0022] Operon and Orf2+Orf3 constructs produced adequate level of toxin. Cry2Ac Operon expressed Cry2Ac11 in the form of big crystals. Constructs lacking Orf2 did not produce any crystals when introduced in 4Q7 strain of B. thuringiensis.
[0023] ATG3, ATG4, ATG7 and 2Ac11 constructs produced higher level of toxin as compared to the wild type. None of them could produce parasporal inclusions in absence of Orf2 except for 2Ac11 construct that could produce parasporal inclusions visible under phase contrast microscope.
[0024] Although ATG3, ATG4, ATG5 and ATG7 showed almost equal messenger levels, but ATG5 failed to make higher concentration of Cry2Ac, whereas only 2Ac11 could produce parasporal inclusion bodies that showed the highest messenger level.
[0025] In the present invention, we tried to express Cry2Ac11 operon under Cyt-P promoter in absence of Orf1 as well as Orf2. Our principal findings are the following:
a. When Cry2Ac11 was expressed in the absence of Orf1 and Orf2, though under strong promoter system (pSTAB), overall yield of the protein was about five times less as compared to when co-expressed with Orf2 or entire operon. b. Expression level of cry2Ac has been enhanced up to 10 times by alteration in number and sequence of nucleotides between RBS and ATG. c. Sequence of nucleotides between RBS and ATG is critical for expression enhancement. d. qPCR revealed similar mRNA level in ATG3, ATG4, ATG5 and ATG7 constructs while the highest was exhibited by 2Ac11 construct. e. Addition of an ATG in the spacer region (RBS-ATG) augmented the protein expression many folds. in ATG3, ATG4, ATG7 and 2Ac11 constructs. f. Only pPFS-2Ac11 produced parasporal inclusions indicating its highest stability.
Bioinformatics Approaches
[0032] Salis et al. (2009) developed a mathematical model, called the RBS calculator, to compute the RBS strength. This model considers the energies involved in rRNA-mRNA interaction, mRNA folding, tRNA binding, and the energetic cost of sub-optimal spacing between the RBS and the start codon. This computational tool was proved effective in designing RBS sequences to control relative protein levels.
[0000]
TABLE 2
Translational efficiency of the mutant constructs as calculated using various softwares
RBS calculator
RBS
mFOLD
Start codon
designer:
Sr.
Mutated
ΔG
Translation
and
Translational
No.
construct
(kcal/mol)
initiation rate
position
Accuracy
Efficiency
1.
pPFS-2Ac11/4Q7
−0.17
58437.4
ATG (13)
NEQ
0.28
2.
pPFS-ATG1/4Q7
−0.50
55104.2
TTG (14)
not OK
0.052
3.
pPFS-ATG3/4Q7
2.50
73184.1
ATG (13)
Ok
0.29
4.
pPFS-ATG4/4Q7
2.20
35619.97
ATG (13)
Ok
0.031
5.
pPFS-ATG5/4Q7
2.20
35619.97
ATG (13)
Ok
0.14
6.
pPFS-ATG7/4Q7
1.70
143745.7
ATG (13)
Ok
0.291
7.
pPFS-ORF3/4Q7
3.10
14374
ATG (13)
Ok
0.291
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A process for efficient expression of a foreign gene in a Bacillus host was developed by varying the length and nucleotide sequence in the spacer region between ribosomal binding sequence (RBS) and initiation codon (ATG) of the gene. Bacillus thuringiensis cry2Ac gene was selected as a model gene because it requires an upstream open reading frame designated as orf2 for its efficient expression and crystallization in a Bacillus host.
| 2 |
BACKGROUND OF THE INVENTION
[0001] The present invention relates to foam buffing or polishing pads for rotary power buffing tools. More specifically, the present invention relates to an improved pad, a pad that is designed with a frustro-conical cut out in the central portion of the pad so that the polishing compound or dressing does not load up in the central portion as in prior pads, and a rounded outer edge to reduce scarring or marring of the finishing surface.
[0002] Buffing pads are known for use on finished surfaces, for example that of a vehicle, for smoothing, waxing and otherwise producing a finish or shine to the vehicle. Typically, when buffing out a vehicle, a buffing compound or polish is used. This compound generally includes a polishing grit, liquid base or paste solution.
[0003] In the typical art today, the buffing pad is attached to the buffing wheel as a single pad. These buffing pads tend to have a single planar surface from the radial inner most portions to the outer edges. Typically, in these operations, while the buffing material tends to be thrown out from the side edges, where centrifugal force acts most greatly on the material, it tends to build up or saturate the central area of the pad, where it does not get thrown out to the outside edge. For example, FIG. 5 shows buffing compound B, built up and saturated at the center of a prior art type buffing pad P. During buffing with these pads, the operator must often clean the compound from the center with a brush, called conditioning the pad. This build-up and saturation at the center creates problems during buffing of the vehicle surface and produces uneven results and excessive buffing time. Additionally, reconditioning the buffing pad takes time and is cumbersome, particularly at the center of the pad where the compound is hard to remove as the brush tends to rotate around the pad. Therefore, it is desirable in the art to solve the central loading up and re-dressing issues such that buffing may be more consistently accomplished.
[0004] Known foam buffs deal with the splashing, splattering or throwing outward of the buffing compound, or the issue of vibration, but none of them address the issue of the compound loading up in the center of the pad, or the compound reconditioning issues resulting from a planar pad. A pad patented by Rubino (U.S. Pat. No. 5,527,215) is a foam pad that introduces grooves or pathways in the foam in various configurations specifically to capture escaping finishing compound. Another pad patented by Hornby (U.S. Pat. No. 6,044,512) provides a concave working face that reduces vibration and compound splatter.
SUMMARY OF THE INVENTION
[0005] Therefore, in accordance with the present invention, there is provided a foam buffing pad for a rotary power buffing tool. The foam buffing pad has a thickness that allows for buffing of the surface without gouging or other problems. The density, weight and other characteristics of the pad will be dictated by the specific application. The working face of the present invention includes an outer periphery and a center portion. A chamfered edge is located on the buffing side outer periphery. A frustro-conical shape is cut out in the center portion, with the wider end toward the top buffing surface of the pad and the narrower end toward the back of the pad. The dimensions of the frustro-conical cut out will also be dictated by the specific application. The rear of the buffing pad of the present invention includes Velcro®, or other hook and loop, or mushroom-type fasteners for fastening the buffing pad to a rotary buffing device.
[0006] A further understanding of the present invention will be had in view of the description of the drawings and detailed description of the invention, when viewed in conjunction with the subjoined claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] The present invention will become more fully understood from the detailed description and the accompanying drawings, wherein:
[0008] [0008]FIG. 1 is a perspective view of the buffing pad of the present invention;
[0009] [0009]FIG. 2 is a front view of the buffing pad;
[0010] [0010]FIG. 3 is a side view of the buffing pad;
[0011] [0011]FIG. 4 is a sectional view along line 4 - 4 of FIG. 2, showing the chamfered edge and the frustro-conical cut out in the center of the buffing pad;
[0012] [0012]FIG. 5 is a side view of an existing prior art buffing pad showing buffing compound build up and saturation of the central portion; and
[0013] [0013]FIG. 6 is a side view of the pad of the present invention, illustrating dispersal of the buffing compound onto the working portion of the pad.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0014] The following description of the preferred embodiment(s) is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses.
[0015] Thus, in accordance with the present invention, there is provided a foam buffing pad that does not saturate or build up buffing compound in the center of the pad. Buffing pad 10 includes an outer periphery 12 and a center portion 14 . Buffing pad 10 is, preferably made from soft, non-marring foam material 18 , but it may also be of another like material as will be appreciated by those skilled in the art. In the present invention, the center portion 14 includes a hollowed out in a frustro-conical shape in order to prevent loading up of compound in the center of the pad. The outer periphery 12 includes a chamfered edge 16 . This allows for the foam to not burn or cut into the surface being polished and for buffing compound to not build up at the edge also. The central portion 14 includes a frustro-conical surface 20 thereon. The frustro-conical surface 20 allows any compound material that is at the center to move by centrifugal force outward to the edge of the pad, where it will be effectively dispersed for buffing of the finish. Thus, the pad has a wider portion 22 of the frustro-conical portion toward the working face 24 of the pad, and a narrower portion 26 of the frustro-conical portion at the back portion 28 of the pad. The chamfered edge 16 is at an angle “b” of about 35 degrees.
[0016] The frustro-conical cut out portion may generally have an angle “a” of from about 35 to about 75 degrees, and preferably from about 55 to about 65 degrees. In a preferred embodiment, the angle is at about 55 degrees. While the central center portion 14 is shown as a well defined frustro-conical portion 20 , with defined edges, the edges could also be rounded.
[0017] While the frustro-conical cut out portion of the present invention is shown in a particular pad environment, it will be readily appreciated by those skilled in the art that this type of cut out will be useful in other designs of buffing pads.
[0018] Thus, in accordance with the present invention, the buffing compound may be provided at the center of the pad or at the pad edges, and it works itself outwardly, by way of centrifugal force, onto the frictional area of the pad, as shown in FIG. 6. As shown herein, the frictional area is a substantially planar work area of the pad which performs the polishing function. The pad of the present invention does not saturate or build up buffing compound material in the center of the pad and, therefore, reduces reconditioning of the pad by the operator and is more effective and efficient for use by those in the art. Therefore, the present invention provides a useful improvement over the buffing pads used in the prior art.
[0019] Those skilled in the art can now appreciate from the foregoing description that the broad teachings of the present invention can be implemented in a variety of forms. Therefore, while this invention has been described in connection with particular examples thereof, the true scope of the invention should not be so limited, since other changes and modifications will become apparent to the skilled practitioner upon a study of the drawings, specification and following claims.
|
A buffing/polishing pad that is designed so that the buffing or polishing compound or dressing does not saturate or load up in the central portion of the pad. A frustro-conical cut out at the center of the pad biases buffing material towards movement from the center of the pad toward an outer peripheral edge.
| 1 |
FIELD OF THE INVENTION
The invention relates to a method for manufacturing an optical micro-mirror and a micro-mirror or array of micro-mirrors obtained by the method of the invention. These micro-mirrors are capable of being electrically controlled.
Micro-mirrors are used generally in systems implementing deflections of light beams and in particular in optical routing systems or in image projection systems.
BACKGROUND OF THE INVENTION
Electrically controlled micro-mirrors (most often using electrostatic, electromagnetic, piezoelectric, or thermoelastic forces) capable of generating digital or analog angular positions are known in the literature. They generally use hinge configurations making it possible, according to the complexity of the technological steps employed, to oscillate around an axis (simple hinge) or around two axes (double hinge) of rotation oriented most frequently orthogonally.
FIG. 1 a represents a view of such an electrostatically controlled micro-mirror enabling rotation on 2 perpendicular axes, utilized in optical routing systems. The fixed frame 2 of the micro-mirror and the movable parts 3 and 4 articulated, respectively, around hinges 5 and 6 that enable the desired rotations about the two orthogonal axes are made on the substrate 1 . Each axis of rotation passes through a distinct hinge. The moveable part 4 is covered with a high-reflectivity layer.
FIG. 1 b represents a highly diagrammatic cross-sectional view of the different elements forming this type of micro-mirror (section along the axis of the hinge 5 ). In addition, in this Figure the different control electrodes 7 , 8 , 9 and 10 of the micro-mirror are represented. The opposing electrodes 7 and 8 make it possible to turn the moveable part 3 about the axis 5 , which the opposing electrodes 9 and 10 make it possible to turn the moveable part about the axis 6 .
The manufacturing steps comprise, starting with a mechanical substrate, a sequence of deposits and etchings of suitable material enabling the realization of the different elements of the micro-mirror or micro-mirrors (control electrodes, moveable parts, hinges, etc.) and comprise the use of one or a plurality of sacrificial layers, removal of which makes it possible to liberate the moveable part(s).
There are many technological alternatives for obtaining such devices. In this respect, the references cited at the end of the description can be consulted.
Although in the detail of the structures and the sequences of technological steps implemented use a wide diversity of approaches, the devices developed today have the following points in common:
the materials used for producing the moveable part or parts of the micro-mirrors are, in the majority of cases, amorphous or polycrystalline (polycrystalline silicon, aluminum, various metals, etc.) deposited using very classical techniques (vacuum evaporation, cathodic sputtering, vapor phase deposition, CVD, etc.) the materials used for producing the sacrificial layers can be of different types (silica, various organic materials, etc.) but are always obtained by deposition techniques (CVD, rotary deposition, cathodic sputtering, etc.) that generally do not afford very precise control of the thicknesses utilized (typically several tens of nanometers for micron thicknesses) but that have the advantage of being very flexible to use.
The drawbacks of the prior art approaches are at several levels:
First of all, unsatisfactory precision in angular excursion (typically between 10 −1 and 10 −2 ) as the result of the use of sacrificial layers produced by deposition techniques that do not have very high degrees of thickness control. For certain system architectures, in particular those used for optical routing purposes, all of these points are prejudicial and none of the manufacturing methods proposed in the prior art makes it possible to overcomes them correctly. Moreover, poor mechanical properties of the amorphous or polycrystalline layers of the thin layers constituting the moveable part(s) that translates inter alia into a greater fragility and deformation after clearing, which perturbs the planeity of the surface.
This point is particularly important in the case of high surface micro-mirrors (of the order of a square millimeter or a fraction of a square millimeter) which must carry out an image function demanding excellent quality of optical wave surface.
SUMMARY OF THE INVENTION
The object of the present invention is to provide a method for forming an optical micro-mirror as well as the optical micro-mirror or an array of micro-mirrors obtained according to the method of the invention and not having the drawbacks of the prior art.
In particular, the micro-mirror obtained according to the method of the invention has excellent angular excursion precision, while having satisfactory angular excursion. In addition, the moveable part of the micro-mirror obtained according to the method of the invention has mechanical properties that result in obtaining excellent planeity. The micro-mirror of the invention can also be a hinged micro-mirror (single or double) as well as a pivoting micro-mirror; this latter type of micro-mirror is original and can just be obtained in virtue of the method of the invention.
More precisely, the object of the invention is a method for manufacturing an optical micro-mirror comprising a fixed part, a moveable part connected to the fixed part by articulation means, the moveable part comprising in addition reflection means. This method comprises the following steps:
a) realization of a stack formed of a mechanical substrate, an sacrificial layer of a specific thickness of thermal oxidation material called the first layer and an assembly for forming the moveable part and comprising at least one layer of material called the second layer;
b) realization of the articulation means;
c) realization of the moveable part by etching of at least the second layer of material so as to obtain at least one pattern;
d) removal at least in part of the sacrificial layer so as to clear said moveable part that is then connected to the rest of the micro-mirror corresponding to the fixed part by means of the articulation means.
The steps of the method of the invention can be carried out in the aforesaid order or in a different order; moreover, in certain embodiments, certain steps can be included in other steps. According to the invention, the substrate or the layers are not strictly formed from a single material; thus, the substrate can comprise a plurality of layers and the layers can comprise a plurality of sub-layers.
According to the invention, the use of a layer of thermal oxidation material makes it possible to have a layer whose thickness is extremely well-controlled that serves as sacrificial layer. The value of the angular excursion of the moveable part can thus be very precise and reproducible; it can also of a significant level.
Advantageously, the sacrificial layer of thermal oxidation material has a thickness of greater than or equal to 1 micron.
In the case of a silicon substrate, for example, the method of the invention makes it possible to obtain layers of thermal silica with a precision of the order of several nanometers on total thicknesses of several microns or several tens of microns, approximately 10 times better than those obtained in the prior art regarding thicknesses of the sacrificial layers; the gain in angular precision resulting therefrom is also of the order of a factor of 10.
The thermal oxidation layer can be partially removed; it must be etched at least in order to make it possible to clear the moveable part.
Preferably, the reflector means are realized on the second layer by deposition of a monolayer or multiple layers of reflector material such as metals like gold, silver, aluminum, for example, or dielectrics of SiO 2 /TiO 2 or SiO 2 /HFO 2 , for example; these materials are deposited, for example, by cathodic sputtering or vapor evaporation on the second layer, generally after step b).
If the second layer has sufficient reflectivity for the intended application, the reflector means are then realized on the second layer after epitaxy.
Advantageously, the method comprises in addition a step of epitaxy of the second layer, the reflector means being then realized using the second layer itself.
Epitaxy of the second layer makes possible an increase in the thickness of this layer with the best mechanical continuity possible and obtaining of a minimally deformable layer with high mechanical quality (namely mechanical strength) that conserves excellent planeity even after the step d) clearing step.
According to a preferred embodiment of the invention, the second layer is a layer of monocrystalline material. The use of monocrystalline material for the moveable part makes it possible to obtain high surface planeity on which the reflectivity layer is deposited.
According to a first embodiment of the invention, step a) comprises the realization of the thermal oxidation layer on the substrate, then the deposition of the second layer on the thermal oxidation layer.
Deposition is defined according to the invention as any type of deposition including the transfer of a layer.
For step a) either the different steps can be carried out or a wafer of semiconductor on insulator such as SOI commonly known as “Silicon on Insulator”, which is commercially available, can be used. In the latter instance, by way of example, the SOI substrates can be used to advantage using a wafer of thermal silica (for example, the wafers sold under the trade name “Unibon” by the SOITEC company).
According to a second embodiment of the invention, step a) comprises the transfer onto the mechanical substrate of the second layer, the substrate and/or the second layer comprising on their surfaces to be coated a thermal oxidation layer that will form after the application of the first layer.
Advantageously, the transfer comprises a sealing step (of the substrate or of the oxide on the one hand and of the second layer or the oxide layer on the other hand) by molecular adhesion. A sealing element could also be used for this sealing such as an adhesive, for example.
The second layer can be combined with an intermediate substrate by a liaison zone capable of enabling the removal of the intermediate substrate after application or, in certain instances, prior to application.
According to a first use of this application, said liaison zone is an embrittlement zone obtained by ion implantation (see especially U.S. Pat. No. 5,374,564-U.S. Pat. No. 6,020,252) and/or by the creation of porosity in the second layer, removal of the intermediate substrate is done along this embrittlement zone by an appropriate treatment such as the application of mechanical force and/or the utilization of a thermal treatment.
According to a second use of this transfer, this liaison zone is a sacrificial layer that is subjected to chemical attack in order to enable removal of the intermediate substrate.
The transfer technique used in this second embodiment makes possible the use of at least two wafers advantageously assembled using molecular adhesion techniques and also makes it possible to overcome the limitations of angular excursion without sacrificing precision relative to the thickness of the sacrificial layer(s) (which sets the conditions largely for the precision regarding angular excursion).
It also makes it possible to have a greater freedom for the realization of complex structures without sacrificing the fundamental advantages offered by the invention (mechanical quality of the moveable parts and precision of the angular excursions).
The thermal oxide layer is carried out preferably by high-temperature oxidation under dry atmosphere (between 800° C. and 1,100° C. under oxygen) or under humid atmosphere (between 800° C. and 1,100° C. under water vapor) and at atmospheric pressure or under high pressure.
According to one advantageous method for realizing the articulation means of the invention, before step d), local etching of the layer(s) disposed on top of the substrate is done so as to form at least one via and epitaxy is across each via, the epitaxial material in each via forming all or part of an articulation element of the articulation means.
The articulation elements can be produced respectively in several parts, especially in the case of the second embodiment using the transfer of the second layer. Thus, the articulation means of the invention are realized by:
local etching prior to application in such a fashion as to form at least one first via in the layer or layers disposed on top of the substrate and in such a fashion as to form at least one second via in the layer or layers disposed on the second layer, opposite to the substrate; epitaxy through the first via forming one part of an articulation element and epitaxy in the second via forming another part of the articulation element, these two parts being brought into opposition during the transfer and forming an articulation element after the transfer.
According to a first embodiment of the articulation means of a micro-mirror, a single articulation element is realized and disposed under the moveable part in such a fashion as to form a pivot for said part, said pivot connecting the moveable part to the fixed part. The pivot may or may not be centered under the moveable part, depending on the applications.
According to a second embodiment of the articulation means of a micro-mirror, two articulation elements are realized and disposed on either side of the moveable part in such a fashion as to form a hinge connecting it to the fixed part.
Preferably, according to this second method, the articulation means are realized by etching the second layer; this etching may be done at the same time as that of creation of the moveable part. Naturally, hinge-type articulation means can also be realized as hereinbefore described, by epitaxy across the vias.
According to a preferred embodiment of the invention the substrate is comprised of silicon, the first layer is a thermal oxide of silicon, the second layer is monocrystalline silicon and the articulation means are comprised of monocrystalline silicon.
Advantageously, the method of the invention uses an attenuation of the second layer for reducing the inertia of the moveable parts and allows functioning of the micro-mirror at higher frequencies.
This attenuation of the second layer can be realized either by the creation of an embrittlement zone at a depth in the second layer so that the remaining thickness, after removal of the surplus (the surplus can be an intermediate substrate), corresponds to the thickness desired for the second layer, either by using a chemical etching or reactive ion step or mechanochemical polishing until obtaining the desired thickness or even a combination of all of these techniques. If the attenuation step results in excessively thin thicknesses of the second layer, this thickness can be restored in an epitaxy step.
According to an advantageous embodiment of the invention making it possible to have high angular excursion of the moveable part, at least one cavity is made in the mechanical support opposite at least one zone of one of the extremities of the moveable part by etching of the substrate according to a form and geometric dimensions that make it possible to depart from the dimensional parameters of the micro-mirror and total angular excursion Δθ along the axis or different axes of rotation.
The cavity or cavities of the substrate are advantageously realized by anisotropic etching, for example by wet etching or by dry processes such as ion etching or reactive ionic etching. Generally, the substrate comprises in the case of a pivoting micro-mirror a peripheral cavity opposite to a peripheral zone of the extremity of the moveable part.
According to one embodiment, the micro-mirror being electrically controlled, the method of the invention comprises a step for realization of control means by the formation of opposing electrodes on the mechanical substrate and on the moveable part.
Advantageously, if the substrate and the moveable part are at least in the facing semiconductor parts, the electrodes are formed by ionic implantation of dopants whether or not followed by suitable thermal diffusion of the dopants.
The connection lines from the electrodes to a control electronics can be realized in different ways and especially also by ionic implantation of dopants whether or not followed by suitable thermal diffusion of the dopants. These lines are realized advantageously on the face of the substrate opposite the moveable part, the electrodes of the moveable part being connected to certain of these lines advantageously by means of articulation means. In addition, connections can be provided at the ends of these lines with a view of their connection to the control electronics.
According to another embodiment, the connection lines of the different electrodes are realized by plated-through holes through the substrate; the electrodes of the moveable part being connected to certain of said plated-through holes advantageously by means of the articulation means; connectors can in addition be provided at the ends of these lines with a view of their connection to the control electronics.
The invention can also make use of electrical control means utilizing forces other than electro-static forces and, for example, electromagnetic forces or piezoelectrical forces or even thermoelastic forces. By way of example, control of the moveable parts by magnetic forces (Laplace forces) requires the realization of adapted coils and magnets for generating the necessary magnetic fields.
According to one particular embodiment of the invention, the moveable part comprises at least two parts: a first part comprising the reflection means and at least one second part surrounding the first part, the articulation means connecting said second part to the fixed part and intermediate articulation means connecting the first part of the moveable part to the second part.
The articulation means of a micro-mirror can comprise at least one hinge or a pivot. The intermediate articulation means comprise at least one hinge.
Said hinge is realized advantageously by etching of the second layer according to a suitable pattern.
According to the invention, the use of a pivot makes it possible for the moveable part to move in all directions around an axis of symmetry passing through the pivot and perpendicular to the plane of the substrate.
When the articulation means and the intermediate articulation means are formed by hinges, in general one hinge composed of 2 elements is necessary for articulating each part of the moveable part, the elements of the hinge being disposed on either part of said moveable part. Each hinge allows a displacement of the part with which it is associated around an axis passing through the elements of the hinge called the hinge axis and which is parallel to the plane of the substrate. In order to increase the degrees of freedom of the moveable part, each hinge is disposed in such a fashion that its axis describes a specific angle, generally 90° to the axis of the other hinge, in a plane parallel to the substrate.
The method of the invention is applicable as well to the realization of an individual micro-mirror and to a array of micro-mirrors; these micro-mirrors being capable of being controlled independently of each other.
The invention relates also to the micro-mirror obtained according to the hereinbefore described method as well as to an array of such micro-mirrors.
According to the invention, the term array includes the strip, which is a special case of an array, in which the elements are arranged along a single axis.
BRIEF DESCRIPTION OF THE DRAWINGS
The characteristics and advantages of the invention will be more apparent in light of the following description. This description refers to exemplary embodiments, provided by way of illustration but non-limiting. It refers in addition to the attached figures, wherein:
FIG. 1 a–b already described, represents a hinged micro-mirror of the prior art that utilizes amorphous or polycrystalline materials for realizing the moveable part and the sacrificial layer;
FIGS. 2 a to 2 i diagrammatically represent in cross-section the different steps of a first method for manufacturing a micro-mirror according to the invention;
FIGS. 3 a to 3 g diagrammatically represent in cross-section the different steps of a second method for manufacturing the fixed part of a micro-mirror according to the invention;
FIGS. 4 a to 4 g diagrammatically represent in cross-section the different steps of a second method for manufacturing the moveable part of a micro-mirror according to the invention;
FIGS. 5 a to 5 e diagrammatically represent in cross-section the different steps making possible, after transfer of the structures obtained in FIGS. 3 g and 4 g , realization of a micro-mirror according to this second mode;
FIGS. 6 a to 6 g diagrammatically represent in cross-section the different steps of a third manufacturing method of the fixed part of a micro-mirror according to the invention;
FIGS. 7 a to 7 c diagrammatically represent in cross-section different positions of a moveable part connected to the fixed part by means of a pivot;
FIGS. 8 a and 8 b , respectively, provide an overall perspective of an example of pivot micro-mirror and an example of a simple hinged micro-mirror according to the invention;
FIGS. 9 a to 9 c represent top views of different micro-mirrors of the invention showing in particular different geometries of electrodes making possible rotations about one ( FIG. 9 a ), two ( FIG. 9 b ) or four ( FIG. 9 c ) axes of rotation.
DETAILED DESCRIPTION OF THE EMBODIMENTS
There are, of course, numerous alternatives making possible realization of the micro-mirrors of the invention.
We shall describe only two methods for manufacturing a micro-mirror knowing on the one hand that these methods make possible a collective formation of micro-mirrors and on the other hand that these methods are non-limiting. In addition, for the sake of simplification of the description, the case of utilization of articulation means employing a pivot has been chosen that has the advantage of enabling, using a single moveable part, rotations about a plurality of axes perpendicular to the axis of the pivot by simple modification of the geometry of the control electrodes and, by way of example, silicon has been chosen for the substrate, the second layer and the articulation means. These examples are, of course, non-limiting.
The first method is realized on a wafer while the second method is realized on two separate wafers A and B then transferred.
The first embodiment of the micro-mirror of the invention that is implemented on a wafer is illustrated in the different FIG. 2 .
For this (see FIG. 2 a in cross-section) a SOI (silicon on insulator) wafer is created or a wafer of this type available commercially is used.
In order to create this type of wafer, a non-doped silicon substrate 21 is used, onto which a dielectric layer 22 of thermal silica is grown. A surface monocrystalline silicon layer 20 is then deposited using any of the known deposition methods and in particular those for transferring a thin layer.
FIG. 2 b represents the realization of the electrodes of the electrical control by the formation of different doped zones 24 , 24 ′, and 23 in the superior part of the non-doped silicon substrate 21 and in the monocrystalline silicon surface layer 20 . These zones are obtained by ionic implantation of dopant atoms (generally boron or phosphorus) at different energies according to the desired depth of localization, whether or not followed by thermal annealing. According to the desired localization depths and the thickness of the dielectric layer 22 , the implantation energies will be typically between 20 and 300 keV and the implanted doses between 10 14 and 10 16 cm −2 . By way of example, in the layer 20 having a thickness W′ of typically between 0.1 micron and 0.6 micron, the implantation energies for forming the zones 23 will be low (15 to 100 keV); whilst in the substrate 21 the implanted ions must pass through the silica layer 22 having a thickness W and in part the silicon layer 21 , the implantation energies for forming the zones 24 and 24 ′ will be higher (generally greater than 100 keV). For a single-pattern moveable part a single doped zone 23 can suffice.
FIG. 2 c represents the formation of the site 25 of the future pivot by local etching of the layers 20 and 22 in order to form a via preferably above an implanted zone 24 ′.
FIG. 2 d represents an epitaxy step. This step makes possible at once realization of the doped monocrystalline silicon pivot and increasing the thickness of the surface silicon 20 in order to enhance the mechanical rigidity of that which will form the moveable part of the micro-mirror.
Realization of the articulation means is advantageously done using monocrystalline silicon in order to make it possible to obtain mechanically solid articulation means.
During the epitaxy step, doping of the epitaxial material can be modified and, for example, chosen to be higher at the start of the process (corresponding to the formation of the pivot 27 that is advantageously electrically connected to an implanted zone of the substrate) than at the end of the process where it is only a matter of increasing the thickness of the layer 20 for forming the monocrystalline silicon layer 26 , whose thickness can attain several microns depending on the desired specifications. The depression 28 which can appear in this epitaxial layer results from the presence of the local etching 25 .
FIG. 2 e represents a section of the device after the epitaxy step and attenuation, for example, by mechanochemical polishing necessary for clearing the depression 28 and obtaining a monocrystalline silicon layer 26 of perfect planeity. Other attenuation techniques can, of course, be used and in particular those described in the U.S. Pat. No. 5,374,564 or U.S. Pat. No. 6,020,252.
FIG. 2 f represents the realization of the reflection means by the formation on the layer 26 of a high reflectivity mirror layer 29 for micro-mirror usable wavelengths, for example, by metallic or multilayer dielectric deposition.
FIG. 2 g represents the etching step of the future moveable part of the micro-mirror. This etching, whose geometry and dimensions depend on the expected optical specifications and thus the intended applications (for example, square sides or circle diameters of the order of several tens of microns to several millimeters), uses layers 29 and 26 and eventually the thermal silica layer 22 .
This etching is done, for example, by any type of etching adapted to the materials used (ionic etching, reactive etching and/or chemical etching).
By way of example, for layers 29 of aluminum, 26 of silicon, this etching is done through a mask (not shown) by a first reactive ionic attack, for example using chlorinated gases for attacking the aluminum, then by a second reactive ionic attack, for example using an SF 6 gas for attacking the silicon.
FIG. 2 h represents a cross-section of the component after removal of the sacrificial silica layer 22 at least under the moveable part of the micro-mirror and hence the clearing of this moveable part. Removal of the layer 22 is done, for example, for a silicon oxide layer by chemical attack using fluorhydric acid or by reactive ionic attack using fluorinated gases.
In the structure represented in FIG. 2 h , the amplitude Δθ of the total angular excursion is determined by the height H of the pivot and the width L of the moveable part in its plane of rotation (sine Δθ=H/2L); the ends of the moveable part of the micro-mirror can then be situated abutting the substrate plane. This configuration thus has the drawback, for a given pivot height H, of entirely linking the total angular excursion Δθ and the dimension L of the moveable part in the plane of rotation considered.
FIG. 2 i provides a means for averting this drawback by creating cavities 19 in the support 21 whether crossing or not, whose inside borders are situated at a distance L′ from the axis of pivot less than L/2 and the outside borders at a distance L″ greater than L/2.
The angular excursion Δθ defined by the relation tangent Δθ=H/L′ does not depend then on L′ and not on L.
This cavity can be easily realized using the posterior surface of the wafer, for example by chemical etching preferably as illustrated in FIG. 2 i and consequently must cross the thickness of the silicon substrate.
The second embodiment of the invention that carries out the steps of the method on two wafers A and B then which transfers these wafers is represented in FIGS. 3 , 4 , 5 .
Preparation of the A Wafer
Using a mechanical support, for example an undoped silicon wafer 31 ( FIG. 3 a ), the different electrodes 33 , 33 ′ of the fixed part is realized by ion implantation of dopants whether or not followed by thermal annealing ( FIG. 3 b ). FIG. 3 c represents a thermal oxidation step of the substrate for forming a thermal oxide layer 32 of a perfectly controlled thickness and generally between 1 and 3 microns; in the course of this step done generally at high temperature, there is a diffusion of the dopants from the implanted zones and an increase of the volume occupied by these zones.
The steps represented in FIG. 3 b and FIG. 3 c can be reversed at the cost of augmentation of the implantation energies for realizing the doped zones 33 and 33 ′ (the ions implanted prior then cross the thermal silica layer).
FIG. 3 d represents the following step corresponding to the local etching 34 of the thermal silica layer 32 on top of the doped zone 33 ′ for forming a via. Then, FIG. 3 e represents an epitaxy step of the substrate that makes it possible to grow doped monocrystalline silicon in the via 34 . The part of the articulation element 35 thus formed is of a thickness generally very slightly greater than the thick ness of the silica layer 32 ; this part of the element will constitute one part of the future pivot. FIG. 3 f represents a mechanochemical polishing step intended to smooth the surface of the wafer A and “erase” any excess thickness from the articulation element 35 .
FIG. 3 g represents a cavity 36 etching step that makes it possible to depart form the dimensions of the moveable part and the maximal angular excursion Δθ of said part. The dimensions (position relative to the axis of the future pivot, width and depth) of the openings 36 are determined using the dimensions of the moveable part and of the desired angular excursion Δθ along the different axes of rotation.
Contrary to the case, wherein the method of the invention is realized using one wafer and wherein the cavities 19 must cross the substrate, in this second embodiment, wherein the method is realized using two wafers that are then transferred, the cavities 36 can have a thickness much less that the thickness of the substrate 31 . These cavities can be of any shape.
Preparation of the B Wafer
FIG. 4 represent the different steps for manufacturing the B wafer. First of all, a substrate 41 ( FIG. 4 a ), for example made of monocrystalline silicon, is used in which an electrode 43 is formed, for example by ionic implantation of dopants ( FIG. 4 b ), whether followed or not by thermal annealing. Then, a thermal oxide layer 42 ( FIG. 4 c ) is formed in the same fashion as for the layer 32 . This layer 42 is then etched to form a via 44 ( FIG. 4 d ) that extends up to the electrode 43 ; this opening has dimensions very close to those of the opening 34 ( FIG. 3 d ); an epitaxy step ( FIG. 4 e ) using monocrystalline silicon then makes it possible to form in the opening 44 another part of the articulation element that is made of doped monocrystalline silicon 45 . A mechanochemical polishing step ( FIG. 4 f ) allows, if necessary, obtaining a perfect smoothness of the surface of the B wafer.
The step illustrated in FIG. 4 g consists of creating a liaison zone 46 in the wafer 41 such as an embrittlement zone created, for example, by ion implantation. This zone delimits in the wafer a layer (hereinbefore called the second layer) of a thickness of typically between 0.1 and 2 microns between the silica layer 42 and the rest of the wafer (which can be an intermediate substrate). This embrittlement zone makes it possible to separate the second layer from the rest of the wafer, either before transfer but more generally after transfer (see in particular the U.S. Pat. No. 5,374,564 and U.S. Pat. No. 6,020,252).
Assembly of the A and B Wafers
The first step represented in FIG. 5 a consists of assembling the two wafers A and B, oxidized face against oxidized face. During this assembly, the positioning of the two wafers is realized so as to align the two articulation elements 35 and 45 and form a single element 47 which will be the future pivot.
Sealing can advantageously be done by the known molecular adhesion techniques.
The two wafers A and B being assembled, the superior part of the layer 41 of the B wafer is separated from the A and B assembly at the level of the embrittlement zone 46 . This separation can advantageously be done using a thermal and/or mechanical treatment. After this separation, there remains only (see FIG. 5 b ) a thin layer of monocrystalline silicon 41 ′ eventually comprising zones of different dopings.
If the layer 41 ′ is too thin, the method can in addition comprise (see FIG. 5 c ) an epitaxy step for increasing the thickness of the monocrystalline film 41 ′ in order to increase the mechanical rigidity of same which will form the moveable part of the mirrors; this step may be followed by a mechanochemical polishing step for planarizing the surface. The final thickness of this layer 41 ′ is, for example, 5 to 60 μm.
A layer 48 of high reflectivity of the working optical wavelengths either metallic or dielectric multilayer is then deposited on the layer 41 ′.
FIG. 5 d represents the following etching step of the layers 41 ′ and 48 according to the desired pattern for the mobile part of the future micro-mirror. This etching is done over a mask (not shown).
FIG. 5 e represents the step of clearing the moveable part around the pivot 47 by suppression of the sacrificial layers of thermal silica by chemical attack as described for FIG. 2 h , for example.
The different manufacturing steps presenting in the various FIGS. 2 to 5 can comprise numerous alternatives. In particular, the order of the different steps can, in certain cases, be reversed and certain of the steps can be modified.
Thus, for example, a single thermal oxidation layer could be realized on the A wafer and thus form the pivot using a single element in this layer; the monocrystalline silicon layer would be transferred directly onto this oxide layer.
Likewise, in lieu of creating a pivot, two articulation elements (in one part or in two parts, respectively) could be created in the thermal oxide in such a fashion as to form a hinge; in this instance, the articulation elements are preferably disposed on either side of the moveable part and between it and the fixed part.
The moveable part could also have been realized in two parts as in the prior art and an intermediate hinge formed by etching using appropriate patterns of the monocrystalline silicon layer.
In order to simplify the description, the connection lines of the electrodes and the contacts to the control electronics are not represented in the previous figures.
These connection lines can be realized in different ways and in particular by ionic implantation of dopants, whether or not followed by thermal diffusion appropriate to the dopants. These lines are realized advantageously on the front face of the support opposite to the moveable part, the electrode or electrodes of the moveable part being connected to certain of these lines advantageously by means of the articulation elements. These connection lines can also be realized by plated-through holes across the substrate, the electrode or electrodes of the moveable part being connected to certain of these plated-through holes advantageously by means of the articulation elements.
By way of example, FIG. 3 g only represents in dotted lines the realization across the substrate of the plated-though holes 70 connecting the electrodes 33 and 33 ′ to contacts 71 .
When the micro-mirror must turn about at least two perpendicular axes of rotation while preserving the advantage of separating the value of angular excursion Δθ from the dimension L of the moveable part, cavities completely surrounding the pivot 47 are advantageously realized in the substrate. In the case, wherein the connection lines are realized on the front face of the substrate, in order not to be cut by the cavities, the electrical connection lines (represented by way of example in FIG. 9 and designated by 60 ) supplying the different electrodes, the substrate is etched in order form there a peripheral cavity prior to forming the doped zones 33 , 33 ′.
FIG. 6 represent this alternative of the method.
Using a wafer 31 (see FIG. 6 a ), a cavity 36 is formed by etching done by different methods such as reactive ionic etching (corresponding to the shape of the cavity of FIG. 3 g ), wherein the preferred chemical etching (corresponding to the shape of the cavity of FIG. 6 b ) of the cavity 36 is determined using the shape (which can be circular, square, rectangular, octagonal, etc.) and dimensions of the moveable part of the micro-mirror and the value of the total angular excursion Δθ desired along the different axes of rotation; the value of the total angular excursion Δθ being otherwise capable of assuming different values Δθ 1 , Δθ 2 , etc. along each of the axes of rotation.
The other manufacturing steps are represented in FIG. 6 c (realization of the doped zones), FIG. 6 d (realization of the thermal oxide), FIG. 6 e (realization of a via 34 in the oxide layer), FIG. 6 f (epitaxy for realizing the pivot part), and FIG. 6 g (planarization of the structure) can be identical to those previously described. In order to obtain the final structure, it is then transferred onto the wafer obtained in FIG. 6 g , for example the wafer obtained FIG. 4 g and, as described with reference to FIG. 5 , the rest of the steps of the method are carried out. The micro-mirror obtained is represented in FIG. 7 .
Three examples of positions of the moveable part of the pivot micro-mirror are represented respectively in FIGS. 7 a , 7 b , 7 c.
FIG. 7 a represents the moveable part disposed in a plane parallel to the plane of the substrate; FIG. 7 b represents the moveable part that has pivoted on an axis of rotation perpendicular to that of the pivot and perpendicular to the plane of the figure; one of the ends of the moveable part is situated in the cavity 36 ; FIG. 7 c represents the moveable part that has pivoted about the same axis of rotation but at 180°, the opposing end of the moveable part is situated in turn in the cavity 36 .
FIG. 8 a provides a diagrammatic view in perspective of a pivot micro-mirror 47 and FIG. 8 b diagrammatically represents a perspective view of a simple hinged micro-mirror 57 , in this example said hinge being realized by etching of the second layer.
As mentioned above, the advantage of the pivot micro-mirrors for certain applications is that of making possible, in virtue of a convenient configuration of electrodes but without modification of the principal manufacturing steps, swinging along several axes of rotation and in particular along two perpendicular axes.
FIG. 9 a represents a top view of a layout of electrodes in the fixed part. The electrodes 33 making it possible to swing the moveable part along 2 positions about one single axis of rotation R 1 are two in number and are disposed symmetrically relative to the axis of rotation R 1 that passes through the pivot 47 ; the central electrode 33 ′ enables, together with the pivot, the electrical connection of the electrode of the moveable part.
FIG. 9 b represents an electrode geometry 33 enabling obtaining 4 positions about 2 perpendicular axes of rotation R 1 and R 2 passing through the pivot; these electrodes 33 are 4 in number and are paired 2 by 2, each electrode couple being disposes symmetrically relative to one of the axes; likewise, the central electrode 33 ′ enables together with the pivot the electrical connection of the electrode of the moveable part. Thus, a large number of electrode couples 33 disposed on either side of an axis of symmetry can be envisaged. FIG. 9 c provides an example of 4 axes of rotation (R 1 , R 2 , R 3 , R 4 ) at 45° to each other and 4 electrode couples 33 disposed in sectors around the axis of the pivot.
FIGS. 9 a , 9 b , and 9 c represent in transparency the different key elements of the micro-mirror. The sets of bottom electrodes 33 (electrodes of the fixed part) and the top electrode 43 (electrode of the moveable part) are represented; the bottom electrode 33 ′ that is electrically connected to the top electrode by the pivot 47 is drawn in dark gray while in FIG. 9 b the two sets of electrodes enabling control of the rotation of the micro-mirror along each of the perpendicular axes of rotation are drawn using two shades of lighter but different grays. The reflecting surface 48 of the moveable part and the tracks 50 and 51 of the etched zones 36 make possible the separation of the variable dimensions of the micro-mirror and total angular excursion Δθ are also represented.
Also very diagrammatically represented are the connection lines 62 of the electrodes to the contacts 60 ; these contacts being capable of being connected to a control electronics (not shown).
The different aforementioned functionalities are can, of course, be realized in the case of utilization of a single wafer and several wafers. However, the method utilizing at least two wafers makes possible more possibilities. The utilization of more than two wafers can make possible in particular the realization of more complex structures and particularly the realization of several superimposed moveable parts, one over the others, by means of articulation means; at least, the last moveable part comprising reflector means. The superpositioning of these moveable parts in the planes parallel to the substrate makes it possible to have a micro-mirror with still greater degrees of freedom. The method of the invention is in fact applied to this type of structure, in considering that each moveable part is realized successively over a substrate tat can then be either a moveable part realized prior or the first substrate corresponding to the fixed part.
References
“Mirrors on a chip”, IEEE SPECTRUM, November 1993
L. J. Hornbeck, “Micro-machining and micro-fabrication” “95”, October 1995, Austin (US)
D. J. Bischop and V. A. Aksyk, “Optical MEMS answer high-speed networking requirements”, Electronic Design, 5 Apr. 1999.
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A method for manufacturing an optical micro-mirror including a fixed part and a moveable part, with a reflection device connected to the fixed part by an articulation mechanism. This method realizes a stack including a mechanical substrate, a first layer of thermal oxidation material, and at least one second layer of material for forming the moveable part, realizes the articulation mechanism, realizes the reflection device on the second layer, realizes the moveable part by etching of at least the second layer of material, and eliminates the thermal oxidation layer to liberate the moveable part. Such an optical micro-mirror may find possible applications to optical routing or image projection systems.
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SUMMARY OF THE INVENTION
The present invention is embodied in a truck, trailer or other vehicle having a chassis or frame on which a body is mounted but which does not include a floor or bed on the chassis. The chassis is provided with a pair of longitudinally disposed guideways which receive a plurality of mobile pallets and such pallets may be interlocked with each other or may be selectively separated from each other so that all or a portion of the cargo may be introduced into or removed from the body of the truck. In this structure the pallets constitute the floor of the truck and include structure which prevents moisture and debris from being splashed or thrown onto the cargo. Normally the truck or vehicle includes one or more rear doors which protect the rear of the cargo; however, when one or more pallets have been removed from the truck, an auxiliary partition is provided to protect the cargo.
It is an object of the invention to provide an apparatus for loading and unloading cargo from a vehicle such as a truck or trailer and the like which includes a plurality of pallets each of which is provided with support wheels so that the pallets can be rolled onto and off of the chassis or frame of the truck and such pallets constitute the bed or floor of the truck when they are located within the body. Normally the pallets are interconnected with each other; however, such pallets may be selectively separated so that a portion of the cargo of the truck may be discharged at one location and the remainder of the cargo transported to another location.
Another object of the invention is to provide an apparatus for loading and unloading cargo from trucks in a minimum of down time for the truck and which includes a plurality of portable pallets mounted on wheels and arranged so that the pallets may be rolled into or from the body of a truck so that the pallets can be loaded with a predetermined quantity of cargo without the truck being present and filled pallets may be removed from the truck body so that they can be disassembled after the truck or other vehicle has left.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view illustrating one application of the invention.
FIG. 2 is an enlarged transverse section on the line 2--2 of FIG. 1.
FIG. 3 is a longitudinal section on the line 3--3 of FIG. 2.
FIG. 4 is an enlarged fragmentary section on the line 4--4 of FIG. 2.
FIG. 5 is an enlarged vertical section taken longitudinally of the vehicle and illustrating the means for connecting the pallets together.
FIG. 6 is an enlarged section taken longitudinally of a pallet and illustrating one of the casters thereof.
FIG. 7 is an enlarged fragmentary section illustrating the rear end of the vehicle frame.
FIG. 8 is an enlarged fragmentary section on the line 8--8 of FIG. 3.
FIG. 9 is a section similar to FIG. 8 illustrating another embodiment.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
With continued reference to the drawings, a vehicle 10 is provided including a cab or tractor 11 and a body or trailer 12. The body 12 includes a frame or chassis 13 having a plurality of spaced generally parallel cross-beams 14 extending from side to side. The body 12 includes a pair of generally parallel side walls 15, a front wall 16, and a top wall 17 with the side walls being supported by upright studs or posts 18 and the top wall being supported by braces 19. In this structure the body of the vehicle does not include a conventional floor which normally is strong enough to support the weight of the cargo being transported as well as the weight of any pallets or the like on which the cargo is stacked.
A pair of guide forming support members 20 having a generally U-shaped cross-sectional configuration are mounted on the cross-beams 14. Such members extend longitudinally of the body in spaced generally parallel relationship with each other and are secured in position with the open side uppermost. With particular reference to FIG. 7, each of the channel members 20 is provided with a flared entrance 21 for a purpose which will be described later.
A plurality of pallets 24 are provided which may be selectively moved into or removed from the body 12 of the vehicle and each of such pallets is supported by a plurality of casters or other ground-engaging wheels 25 of conventional construction. Each pallet is of generally box construction and includes a relatively strong top wall 26 connected to a bottom wall 27 by side walls 28, front wall 29, rear wall 30 and a plurality of longitudinally and laterally extending braces 31. If desired, portions of the bottom wall 27 may be omitted to accommodate the wheels 25 or such wheels may be mounted on the bottom wall 27.
The pallets 24 preferably are selectively connected together in end-to-end relationship and in order to do this the forward portion of each of the pellets is provided with a shaft 32 on which a hub 33 of a latch hook 34 is rotatably mounted. The hooks 34 extends through an opening 35 in the front wall 29 of the pallet and is adapted to be received within an opening 36 in the rear wall 30 of the next adjacent pallet, or the latch hook of the leading pallet is adapted to be received in an opening 37 in the front wall 16 of the body 12.
As illustrated best in FIG. 5, the hub 33 includes a rearwardly extending projection or boss 38 which is connected to one end of a spring 39 the opposite end of which is attached to the pallet in a manner to impart a downward movement to the latch hook 34. In order to release the latch hook from a remote position, the hub 33 also includes an upwardly extending projection or boss 40 in which one end of a rod 41 is rotatably mounted and such rod extends rearwardly through the pallet. The opposite end of the rod 41 is pivotally connected to one end of a lever 42 which is pivotally mounted intermediate its ends on a pivot pin 43 carried by the pallet. The opposite end of the lever 42 extends through an opening 44 in the bottom wall 27 and functions as a handle so that movement of the lever 42 in one direction causes the hub 33 to rotate about the shaft 32 and release the latch hook. It is noted that the lever 42 may be releasably attached to the pallet in a conventional manner to prevent the latch hook 34 from being released accidentally.
Since the body of the vehicle does not include a floor, the top walls 26 of the pallets 24 support the cargo C while the bottom walls 27 prevent water or foreign debris from contacting such cargo. In order to prevent the passage of moisture between the pallets, each of the pallets is provided with a flexible resilient tubular bumper 45 mounted on the front wall 29 and adapted to engage either the front wall 16 of the body or the rear wall 30 of the next adjacent pallet.
With particular reference to FIGS. 2, 3 and 4, each of the pallets is provided with a plurality of guide rollers 48 mounted on shafts 49 carried by the pallet and each of such rollers extends outwardly through openings 50 in the side walls 28. The lower portion of the body 12 has a track or strip of metal 51 extending longitudinally thereof and located at a height to be engaged by the rollers 48 so that such rollers are in engagement with or contiguous to the track to eliminate or substantially reduce lateral shifting of the pallets when the vehicle is moving. Preferably the track 51 includes a lead-in portion 52 adjacent to the rear of the body to cause the pallets to be aligned generally centrally of the vehicle.
The cargo C which is stacked on the pallets normally does not extend beyond a vertical plane defined by the boundaries of the top wall 26 of the pallet and in order to prevent lateral shifting of the cargo an interior wall 53 extends substantially the full length of the body 12 and in spaced relationship to each of the side walls 15. Such interior walls 53 are positioned generally along the vertical plane defined by the side walls 28 of the pallet. As illustrated best in FIG. 2, the lower edge of the interior wall 53 is located at a higher elevation than the top wall 26 of the pallets.
In order to prevent water and other foreign materials from being splashed upwardly along the sides of the pallets, the body 12 is provided with a pair of inwardly extending plates or baffles 54 extending longitudinally of the body and located below the level of the bottom wall 27 of the pallets. Each of the pallets has a downwardly and outwardly extending L-shaped skirt 55 with the outwardly extending portion being spaced in generally parallel relationship with the bottom wall 27 and underlying the inner portion of the baffles 54. The baffles normally do not engage the skirt 55 but define a serpentine path which permits air to flow but which substantially prevents water from spashing onto the cargo.
With particular reference to FIGS. 3, 8 and 9, it is possible to remove one or more of the pallets from the body so that part of the cargo carried by the vehicle may be discharged at one loading dock after which the vehicle may be driven to another location. Since the pallets constitute the floor of the body, the absence of one or more pallets leaves a large opening in the bottom of the body which is exposed to the elements. In order to protect the cargo from the elements, as well as to prevent theft when the vehicle is not moving, one or more partitions 56 are provided which are adapted to be removed into position adjacent to the cargo carried by the rearmost pallet.
As shown best in FIG. 8, each partition 56 has at least one bearing or sleeve 57 fixed to the top thereof and such bearing or sleeve is rotatably mounted on a rod 58 which is secured to the studs 18 of the body adjacent to the upper braces 19. Normally the partition is swung upwardly and secured in a conventional manner (not shown) to the top wall 17 of the body so that the pallets may be moved freely into and out of the vehicle. When one or more of the pallets have been removed from the vehicle, the partition which is mounted on the rod 58 located adjacent to the trailing end of the rearmost pallet is swung downwardly so that the lower end of such partition abuts the rear wall 30 of such pallet. Preferably the partition is connected to the trailing pallet in any desired manner, as by a spring clip 59 which passes through the opening 36 in the rear wall 30. Additionally the lower end of the partition may be locked to such pallet by any conventional locking mechanism (not shown).
In the structure illustrated in FIG. 3, a separate partition 56 is provided for each pallet so that a selected partition may be used. With particular reference to FIG. 9, it is contemplated that a movable partition may be used by providing a longitudinally extending track 60 along each side of the body adjacent to the upper braces 19 and mounting a roller 61 on each end of the rod 58 so that such rollers are located within the tracks 60. It is noted that instead of a single roller at each end of the rod 58, a dolly or truck having a housing with a pair of spaced rollers rotatably mounted therein could be provided with the ends of the rod 58 being welded or otherwise attached to the housing of such dolly or truck. In this structure the partition may be moved along the track 60 to a desired location and swung downwardly to abut the rearmost pallet regardless of the number of pallets which have been removed from the body 12.
It is noted that the pallets may be moved into and out of the body 12 in any conventional manner, as by an endless cable mounted on the body and driven by a power plant, or such pallets may be moved by an external force such as an industrial truck or by one or more workmen physically moving the pallet. Also it is contemplated that additional conventional locking mechanisms (not shown) may be provided for releasably securing the pallets to the chassis of the vehicle to prevent movement of the pallets when the vehicle is in motion.
In the operation of the device, one or more pallets 24 may be loaded with cargo at a shipping point and if two or more pallets are going to the same destination, the loaded pallets may be connected together by aligning the pallets and pushing the rearmost pallet toward the leading pallet so that the latch hook 34 of the trailing pallet enters the opening 36 in the rear wall 30 of the leading pallet. When the vehicle 10 arrives at the loading dock, a loading ramp ordinarily is positioned to bridge the gap between the chassis 13 of the vehicle and the loading dock after which the loaded pallets are moved across the dock and the ramp into the body 12 of the vehicle. As the leading pallet approaches the body, the casters 25 on the pallets pass through the flared entrance 21 and onto the channel members 20 of the body. Any misalignment of the pallet is corrected by the guide rollers 48 along the sides of the pallet engaging the tracks 51 and aligning the pallets within the body. As the pallets move into the body, the skirts 55 of each of the pallets underlie the baffles 54 to prevent water and other foreign material from splashing onto the cargo during transit. If less than a full complement of pallets is moved into the body 12 of the vehicle, a selected partition 56 is swung downwardly from a raised inoperative position to a position in which the lower end of the partition abuts the rearmost pallet and is connected thereto. Since the pallets have been preloaded, the cargo may be transferred to the vehicle in a minimum of time. If the vehicle already has cargo which is to be discharged at the loading station, the pallets within the body of the vehicle are first removed therefrom after which the pallets bearing the cargo to be shipped are moved into the vehicle. The cargo being received may be unloaded at a later time after the vehicle has departed.
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An apparatus including a plurality of interconnected portable pallets on which cargo is placed and which may be selectively moved into or removed from a truck body. The pallets constitute the bed or floor of the truck and may be independently or simultaneously moved into the body of the truck or removed therefrom so that portions of the contents may be loaded or discharged from different loading docks or the entire contents of the truck may be loaded or discharged from the same dock. The cargo may be loaded on the pallet or pallets prior to insertion into the body of the truck and such cargo may be unloaded from the pallets after the truck has departed so as to reduce delay in the operation of the truck.
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The present invention relates to the trihydrate of pradofloxacin, to a process for its preparation and to antibacterial compositions comprising it.
The 8-cyano-1-cyclopropyl-7-(1S,6S)-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of the formula (I) will be referred to hereinbelow by its INN (International Non-proprietary Name) as pradofloxacin.
Pradofloxacin is known from WO 97/31001. According to this, it is prepared by reacting 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid with (1S,6S)-2,8-diazabicyclo [4.3.0]nonane in a mixture of dimethylformamide and acetonitrile in the presence of an auxiliary base. After admixing with water, pradofloxacin is extracted with dichloromethane from water and isolated by removing the extractant. This gives a powder which does not have any distinct crystal modification. However, it is a prerequisite for the preparation of medicaments that it is possible for an active ingredient which can be present in different crystal modifications to specify unambiguously in which crystal modification it is used to prepare the composition.
The sometimes amorphous powder which is obtained by the above-outlined preparation process is additionally hygroscopic. However, amorphous solids, and especially hygroscopic solids, are difficult to handle in pharmaceutical processing, since they have, for example, low bulk densities and unsatisfactory flow properties. In addition, special working techniques and equipment is required to handle hygroscopic solids in order to obtain reproducible results, for example with regard to the active ingredient content or the stability in the solid formulations produced.
Defined crystal forms of pradofloxacin are already known: modification A (WO 00/31075), modification B (WO 00/31076), modification C (WO 00/52009) and modification D (WO 00/52010), and also the semihydrochloride (WO 00/31077).
Active ingredients for medicaments should be present in forms which are stable even under unfavourable storage conditions, such as elevated temperature and atmospheric moisture. Changes, for example in the crystal structure are undesired, since these often also change important properties, for example the water solubility. In principle, thermodynamically stable crystalline forms of an active ingredient are therefore being sought.
It is an object of the invention to prepare a thermodynamically stable, defined crystal form of pradofloxacin which is suitable for pharmaceutical formulations owing to its properties.
BRIEF DESCRIPTION. OF THE DRAWINGS
FIG. 1 is the powder X-ray diffractogram of pradofloxacin trihydrate.
FIG. 2 is the structure of pradofloxacin trihydrate in crystal lattice.
DETAILED DESCRIPTION OF THE INVENTION
Surprisingly, the thermodynamically very stable, hitherto unknown pradofloxacin trihydrate has now been found.
The invention therefore provides pradofloxacin trihydrate; it can be illustrated by the following formula (II):
Pradofloxacin trihydrate has an X-ray powder diffractogram having the reflections (2 theta), reported in the following Table 1, of high and average intensity (>30% relative intensity).
TABLE 1
Reflections of average and high intensity (I Rel > 30%)
of pradofloxacin trihydrate:
2 θ (2 theta)
10.6230
14.1386
18.4032
20.9422
22.5604
22.8420
24.5165
25.8426
26.4972
26.8759
27.1231
The powder X-ray diffractogram of pradofloxacin trihydrate is reproduced in FIG. 1 .
In addition, it was possible to characterize pradofloxacin trihydrate by X-ray structural analysis of a single crystal. Characteristic data are:
Crystal system
monoclinic
Space group
P2 1
Dimensions of the
a = 12.4790(18) Å α = 90°.
unit cell
b = 12.1275(18) Å β = 111.009(6)°.
c = 15.010(2) Å γ = 90°.
Volume
2120.6(5) Å 3
The structure in the crystal lattice is shown in FIG. 2 .
Pradofloxacin trihydrate can be prepared by the following processes:
A solution of pradofloxacin in a polar aprotic solvent is heated to a temperature of 50° C. or more and then admixed with water which contains seed crystals of pradofloxacin trihydrate.
The solution in the polar aprotic solvent is added preferably at least to the same volume of water, more preferably to 2 to 4 times the volume. It may be advantageous to further heat the resulting mixture to a temperature in the range of 50° C. to the boiling point.
The polar aprotic solvent used should be miscible with water to a sufficient degree; preferred examples are dimethylformamide (DMF), acetonitrile, propionitrile and in particular N-methylpyrrolidone (NMP). It is also possible to use mixtures of these solvents.
Alternatively, pradofloxacin can be heated in water together with a small amount of pradofloxacin trihydrate, preferably to a temperature in the 50 to 100° C. range.
In addition, pradofloxacin trihydrate may also be obtained by reprecipitation via the salts, in which case pradofloxacin trihydrate seed crystals are appropriately added in the course of neutralization.
In the course of reprecipitation, preference is given to dissolving the pradofloxacin in a suitable acid in the presence of water. The solution is then neutralized to pH 7 with a base and the seed crystals are added.
In all processes, the pradofloxacin trihydrate precipitates out as a solid, if necessary after cooling (for example to room temperature).
If required, seed crystals can be prepared by storing a sample of pradofloxacin of the modification B for a prolonged period at an atmospheric moisture content of at least 97%, typically at room temperature.
Pradofloxacin trihydrate is surprisingly stable and is not converted to other crystal forms even in the course of prolonged storage. In addition, pradofloxacin trihydrate does not show any tendency to take up further water from the air. Finally, it can be purified in a simple manner by crystallization. For these reasons, it is outstandingly suitable for preparing medicament formulations, especially those in which the active ingredient is present as a solid. By virtue of its stability, it imparts to these formulations the desired long-lasting storage stability. It is thus possible with pradofloxacin trihydrate to prepare stable formulations of pradofloxacin in a defined and controlled manner.
Pradofloxacin trihydrate is outstandingly effective against pathogenic bacteria in the field of human or veterinary medicine. The action of pradofloxacin trihydrate and thus also its broad field of use corresponds to those of pradofloxacin.
The X-ray powder diffractogram for the characterization of pradofloxacin trihydrate was obtained with a STADI-P transmission diffractometer (CuK α radiation) with location-sensitive detector (PSD2) from Stoe.
The X-ray structural analysis of the single crystal was obtained with a Siemens P4 diffractometer, equipped with a SMART-CCD-1000 two-dimensional detector, a rotating anode (MACScience Co.) with MoK radiation, a graphite monochromator and a Siemens LT2 low temperature apparatus (T=−120° C.).
The examples which follow illustrate the invention without restricting it. The conditions used in the examples which follow are particularly preferred.
EXAMPLES
Example A
Recrystallization from NMP/Water
A.1 120 g of pradofloxacin are heated to 75° C. in 960 ml of peroxide-free N-methylpyrrolidone (NMP). This solution is poured through a fluted filter into 2880 ml of water which have been seeded with pradofloxacin trihydrate. The mixture is allowed to come to room temperature without stirring and left to stand at room temperature for one day. The solid is filtered off with suction, washed twice with 100 ml each time of water and dried under air.
Yield: 115.73 g, 84.9% of theory.
A.2 20 g of pradofloxacin are heated to 75° C. in 90 ml of peroxide-free NMP. Afterwards, 270 ml of water are added and the mixture is heated further to 100° C. The resulting solution is kept at this temperature for another 15 minutes, then cooled somewhat and seeded with pradofloxacin trihydrate. For crystallization, the mixture is left to stand overnight. The solid is filtered off with suction, washed twice with a little water and dried under air.
Yield: 20.44 g, 89.9% of theory.
In all cases, according to the X-ray powder images, pradofloxacin trihydrate was obtained.
Example B
Heating in Pure Water
5 g of pradofloxacin and 100 mg of pradofloxacin trihydrate are added to the amount of water specified and heated to the temperature specified for 3 hours.
TABLE 2
Modification conversion by heating in water
Experiment
Yield
Amount of water
Conditions
B.1
91%
25 ml
85° C.
B.2
93%
50 ml
85° C.
B.3
92%
100 ml
85° C.
In all cases, according to X-ray powder images, pradofloxacin trihydrate was obtained.
Example C
Reprecipitation Via Salt
TABLE 3
Reprecipitation of pradofloxacin
Amount
Yield
Experiment
Acid
(mmol)
%
Comment
C.1
Sulphuric acid
6
93.5
Precipitate at acidic pH
C.2
Acetic acid
6
92
C.3
Formic acid
6
81.7
C.4
Sulphuric acid
3
94.2
Precipitate at acidic pH
C.5
Acetic acid
6
89.8
Precipitated at 60° C.
and heat-treated
for 2 hours.
In each case, the specified amount of acid is dissolved in 12 ml of water, 2.4 g (6 mmol) of pradofloxacin are added, and the mixture is stirred for 15 minutes and subsequently neutralized to pH 7.0 with conc. ammonia solution. As soon as the solution becomes cloudy, seed crystals of pradofloxacin trihydrate are added. The mixture is stirred at room temperature overnight, then the solid is filtered off with suction and dried under air.
In all cases, according to X-ray powder images, pradofloxacin trihydrate was obtained.
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The present invention relates to the trihydrate of pradofloxacin, to a process for its preparation and to antibacterial compositions comprising them.
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This application is a continuation of application Ser. No. 07/957,867, filed Oct. 8, 1992, now abandoned.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a multi-stage storage case for cassettes for specimens for histopathological examination, or for sorting, storing or transporting cassette blocks made by setting the aforementioned specimen in the cassette using paraffin before or after cutting into slices for microscopic examination.
2. Description of the Prior Art
Hitherto, this kind of multi-stage storage case was made of a synthetic resin such as ABS resin and, as seen from FIGS. 9 and 10, its construction was such that the case housing 1 was made of a plurality (usually 6) of shelf units 2 and each shelf unit 2 has housed therein freely slidably a drawer 3, in which cassettes (or cassette blocks) 4 were stored. A pair of (left and right) indented stoppers 6 were formed under the front edge portion of a top unit 5 and shelf units 2, the rear wall 7 of each drawer 3 has formed thereon a pair of (left and right) projections 8 engageably with and disengageably from the indented stoppers 6 so as to ensure against sliding out of the drawer 3 (See FIG. 10.).
With a conventional multi-stage storage case as described above, there was an inconvenience of necessarily using one whole case even for transportation of a small number of cassettes 4 for which one or two drawers 3 suffices. Another problem was that when it suffices to pull out drawers 3 only partly to take in or take out the wanted number of cassettes 4, the drawer 3 partly pulled out inclined with the front end down, this resulting in spontaneous sliding of the drawer with its own weight and that of the cassettes 4 therein and possibly sliding completely out of the case to drop because of the disconnection of the projections 8 from the indented stoppers 6.
SUMMARY OF THE INVENTION
The object of the present invention is, therefore, to eliminate such defects through improvement of the conventional multi-stage storage case as mentioned above.
Other objects and advantages of the present invention will be apparent to those skilled in the art from the following detailed description.
In order to accomplish the aforementioned object, the multi-stage storage case of the present invention is characterized in that a plurality of U-sectioned shelf units are connected one upon another disconnectably between a base unit and a top unit one upon another, a drawer for cassettes or cassette blocks is slidably put in each shelf unit, a plurality of indented stoppers are formed longitudinally in the underside of said top unit and each shelf unit, an upward projection is provided on top of the rear wall of said drawer disengageably engaged with said indented stoppers and said drawers can be pulled out with said upward projections engaged with said indented stoppers.
It is preferred to provide recesses in the front edge portion of the topside of each shelf unit for locking the drawer and also provide indented stoppers on the front edge portion of the underside of the drawer, the aforementioned indented stoppers being engageable with and disengageable from the aforementioned recesses so as to enable locking of the drawer in the closed state.
It is also possible to provide a continuous indentation in the topside of the bottom plate of the drawer for preventing sliding of cassettes or cassette blocks.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a front view of a multi-stage storage case for cassettes or cassette blocks showing an embodiment of the present invention.
FIG. 2 is a left side view of the embodiment shown in FIG. 1
FIG. 3 is a sectional view taken along the line III--III of the embodiment shown in FIG. 1 with part thereof omitted.
FIG. 4 is a sectional view taken along the line IV--IV of the embodiment shown in FIG. 1 with part thereof omitted.
FIG. 5 is an arrow view taken along the line V--V of FIG. 3.
FIG. 6 is a sectional view taken along the line VI--VI of FIG. 3.
FIG. 7 is a sectional view taken along the line VII--VII of FIG. 3.
FIG. 8 is a sectional view taken along the line VIII--VIII of FIG. 5.
FIG. 9 is a front view of an example of conventional multi-stage storage case for cassettes or cassette blocks.
FIG. 10 is a sectional view taken along the line X--X of FIG. 9.
DETAILED DESCRIPTION OF THE INVENTION
An embodiment of the present invention will be described below in detail with reference to FIGS. 1-8.
The multi-stage case for storage of cassettes or cassette blocks (hereinafter called cassettes) are, as shown in FIGS. 1 and 2, in which a case housing 11 is made up of a plurality (6 in the illustrated case) of shelf units 14 connected one upon another, between a base unit 12 and a top unit 13, each shelf unit 14 including a drawer 15 and in each drawer 15 a plurality of cassettes 16 are arranged erect (See the lowermost drawer shown in FIG. 3). The base unit 12, the top unit 13, the shelf units 14 and the drawers 15 are all integrated molding of synthetic resins such as an ABS resin.
As shown in FIGS. 3 and 4, the base unit 12 is made up of a bottom plate 17 and legs 18 extending downward from each side of the bottom plate 17. On both (left and right) sides of the topside of the bottom plate 17, there are provided 3 pairs of stopping walls 20 having indented stoppers 19 at the front ends thereof and 4 pairs of guide walls 21, 22 are arranged erect alternately and longitudinally. The front edge of the bottom plate 17 is curved downward in an arc shape to facilitate applying fingers to the inside of a handle 44 of the drawer 15 at the lowermost in pulling out the drawer (See FIG. 1.).
As seen from FIGS. 3 and 4, the top unit 13 is made up of a top plate 24, a front wall 25, a rear wall 26 and side walls 27 extending downward from edges of the top plate and six longitudinal ribs 28 formed in parallel downward from the underside thereof. Of these ribs 28, as seen from FIG. 4, the two (left and right) longitudinal ribs 28 have guide grooves 29 formed between them and the side walls 27 and, as seen from FIGS. 3 and 4, and each has three square holes 30. The four inside longitudinal ribs 28, as seen from FIGS. 3 and 6, have a plurality (two in the illustrated case) of indented stoppers 31 at the lower front ends and between the front and rear ends.
As seen from FIGS. 3 and 4, the shelf unit 14 has U-shaped cross-section and is made up of a shelf board 32 having inverse L-sectioned (left and right) side walls 33 and a rear wall 34. The shelf board 32 is, as seen from FIGS. 3 and 4, connected with the side walls 33 via drawer guides 35, has access holes 36 about the center for disconnecting the shelf units, has four longitudinal, parallel ribs 37 formed on its underside, as shown in FIGS. 3 and 6, and on both (left and right) sides of the front end of the topside there are provided recesses 38 for locking the drawer 15, as shown in FIGS. 3 and 7.
The drawer guide 35, like the longitudinal ribs 28 on both (left and right) sides of the aforementioned top unit 13, forms guide grooves 29 between it and the side walls 33, there are provided square holes 30 at three longitudinal positions and the longitudinal ribs 37, like the central (inside) longitudinal ribs 28 extending downward from the aforementioned top unit 13, has indented stoppers 31 at the lower front edge and a plurality (two in the illustrate case) of points between the front and rear ends. On the topside of the side (left and right) walls 33, as shown in FIGS. 3-5, there are provided, as in the aforementioned base unit 12, three pairs of stopping walls 20 with indented stoppers 19 formed at the front end thereof and four pairs of guide walls 21, 22 arranged longitudinally and alternately. The base of the stopping walls 20 is formed by cutting off part of the side walls 33 in order to increase the elasticity of the stopping wall 20 (See FIG. 5.). The indented stoppers 19 of the stopping walls 20 formed erect on the base unit 12 and the shelf unit 14 are made freely engageable with and disengageable from the square holes 30 made in the shelf unit 14 or the top unit 12 placed immediately above by the elasticity of the stopping wall 20.
As seen from FIGS. 3-5, the drawer 15 is made up of a front wall 40, rear wall 41 and side (left and right) walls 42 extending erect from the bottom plate 39 and its interior is partitioned by partitions 43 into a plurality of spaces. A handle is formed before the front wall 40 and on the upper edge of the rear wall 41 there is formed a projection 45 as shown in FIG. 4. This projection 45 is formed freely engageable with and disengageable from the indented stopper 31 provided in the underside of shelf unit 14 or the top unit 13 placed immediately above. The bottom plate 39 has in its topside, as shown in FIGS. 5 and 8, a continuous longitudinal indentation 46 extending laterally to ensure against sliding of cassettes and also has in the front portion of the underside a plurality (4 in the illustrated case) of indented stoppers 47 as shown in FIGS. 3 and 7. These indented stoppers 47 are formed freely engageable with and disengageable from the drawer locking recesses 38 provided in the shelf unit 14 corresponding to the drawer 15.
The cassettes 16, when they are stored in the drawer 15 erect, as shown in FIG. 3, the necessary matters such as name and date can be written on the top side thereof.
In assembling the multi-stage storage case of the construction as described above, first, as shown in FIGS. 3, 4 and 6, the case housing 11 is assembled by first putting between the base unit 12 and the top unit 13 a plurality of shelf units 14 and then the stopping walls 20 and guide walls 21, 22 of the base unit 12 and each shelf unit 14 are inserted into the guide grooves 29formed in the underside of the shelf unit 14 or the top unit 13 immediately above and have each indented stopper 19 of each stopping wall 20 engaged in each square hole 30. Then, the drawer 15 is inserted into each shelf unit 14 with the handle 44 lifted up a little. The projection 45 of the rear wall 41 of the drawer 15 passes under indented stoppers 31 formed in the shelf unit 14 or the top unit 13 immediately above and, as shown in FIGS. 3 and 7, the indented stoppers 47 of the drawer 15 are engaged with the recesses 38 for locking of the shelf unit 14 and the drawer 15 is locked thereby.
In order to put the cassettes 16 into the drawer 15 of the multi-stage storage case thus assembled, first the handle 44 of the drawer 15 is lifted a little to disengage the recess 38 for locking the drawer 15 from the indented stopper 47 of the drawer 15, and then the drawer 15 is pulled out halfway (or entirely, if necessary). As shown in FIGS. 3 and 6, the drawer 15 inclines through its own weight the front end down, the projection 45 of the rear wall 41 engages the indented stoppers 31 of the shelf unit 14 immediately above or the top unit 13 to ensure against further sliding out of the shelf unit 14. The cassettes 16 are, as shown in FIG. 3, stored in the drawer arranged erect, with the side in which the referring index is written facing up, to make it easily visible and the drawer is then pushed in. The procedure is essentially the same when the cassettes are taken out of the drawer 15. The indentations 46 (See FIG. 8.) formed in the topside of the bottom plate 39 of the drawer 15 are for ensuring against sliding or falling of the cassettes 16 as the drawer 15 is pulled out or pushed in.
In disassembling the storage case into the base unit 12, the top unit 13 and and shelf units 14, all or part of the drawers 15 are pulled out, and then, with a hand inserted through the front opening of the shelf unit 14 and working with fingers through the access hole 36 to disengage the indented stoppers 19 of the stopping walls 20 of the base unit 12 or the shelf unit 14 from the square holes 30 in the shelf unit 14 or the top unit 13 for separation of the base unit 12, the top unit 13 or each shelf unit 14. It is thus possible to adjust the number of the shelf units 14 according to the number of cassettes 16 to be stored or disassemble a multi-stage storage case as a whole.
Although in this embodiment the depth of each drawer 15 was made uniform but in other embodiments drawers different in depth can be used in combination so as to enable an increase of the kinds of cassettes that can be stored in a single storage case.
Since, as described above, the present invention consists in putting a plurality of shelf units one upon another separably between the base unit and the top unit, the number of shelf units can be adjusted according to the number of cassettes or cassette blocks to be stored and, moreover, it is possible to use drawers different in depth in combination in a single storage case, this resulting in improved transporting and/or storing efficiency. Also, since the drawer can be pulled out stepwise with the projection formed on the upper edge of its rear wall engaged with a plurality of the indented stoppers provided in the top unit and each shelf unit immediately above, workability is improved with simultaneous increase of the drawer's holding capability to ensure against spontaneous sliding out of the drawer pulled out halfway.
It is also possible to prevent spontaneous sliding of drawers out of the case due to inclination of storage case since each drawer is locked in the closed state with the indented stopper provided in the drawer engaged with the locking recess provided in the shelf unit.
Further, by providing anti-sliding indentation in the topside of the bottom plate of the drawer it is possible to ensure against sliding or falling of cassettes or cassette blocks arranged erect in the drawer as it is pulled out or pushed in.
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A plurality of U-sectioned shelf units 14 are disconnectably mounted one upon another between a base unit 12 and a top unit 13, each drawer 15 for accommodating cassettes or cassette blocks 16 is inserted into each shelf unit 14, freely slidable and a projection 45 is formed on the upper edge of the rear wall 41 of the drawer 15 which disengageably engage with the indented stoppers 31 provided in the underside of the top unit 13 and each shelf unit 14 so that the drawer 15 can be pulled out stepwise because of the projection 45 being engaged with the indented stopper 31. It is convenient since the number of shelf units 14 disconnectably connected is adjustable as necessary. Also, the drawer 15 can be pulled out stepwise being stopped at any of the stoppers provided in the shelf unit, hence the drawer 15 pulled out halfway is ensured against further sliding out of the shelf unit.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a generally tubular, hydroformed cowl structure which is incorporated in an automotive body. The cowl extends laterally across the body either at the base of a windshield or at the base of the vehicle's rear window.
2. Disclosure Information
Automotive cowl structures are typically formed in two pieces, as shown in FIG. 6 . According to this prior art construction, the inner cowl, 100 , is stamped and then welded into place between the cowl sides of the vehicle. Then, the cowl top outer panel, 102 , is added to the cowl inner, usually by spot welding. This process necessitates a multi-step operation with attendant complexity and high cost, because separate welding machines must be employed to both weld the cowl top inner 100 to the body as a whole, and then to weld the cowl top outer 102 to the assembled body structure. The present inventive hydroformed cowl eliminates the need to weld and seal a separate top, while allowing reduced complexity in terms of parts needed to join the cowl with the cowl sides and the balance of the front end structure of a vehicle, while providing increased torsional rigidity and body integrity.
SUMMARY OF THE INVENTION
An automotive vehicle body includes a generally tubular, hydroformed cowl having at least one end with a plurality of integral mounting flanges. A cowlside member and a tubular, longitudinally extending engine compartment structural member are welded directly to the cowl flanges. Advantageously, the integral mounting flanges of the cowl are formed in a hydroforming die along with the balance of the cowl. The cowl's mounting flanges are vertically separated so as to allow the flanges to be welded to the top and bottom surfaces of a longitudinally extending engine compartment structure member.
According to another aspect of the present invention, the inventive cowl further has an integral double thickness flange which is employed for attaching the A-pillar of the body to the cowl. A long, double thickness flange extends laterally across the body and supports the vehicle's windshield. Optionally, an integral double-thickness flange extending laterally across the vehicle body at a lower portion of the cowl may be attached to a dash panel of the body.
According to yet another aspect of the present invention, a cowl may be hydroformed from a preform tube having two frustro-conical end sections either joined by a cylindrical midsection, or joined at the smallest diameter of each of the frustro-conical sections. Alternatively, the cowl may be hydroformed from a preform which includes a single frustro-conical preform tube. In any event, the preforms may be advantageously formed from metallic or non-metallic materials, including materials having different gauge thicknesses.
As formed, a hydroformed cowl structure for an automotive vehicle according to the present invention includes a hydroformed tubular member having a mid-section and a plurality of end sections which are generally larger than the mid-section. A plurality of lateral mounting flanges is also formed, preferably by the hydroforming die, integrally from each of the end sections so that the flanges are adapted to join the cowl structure to a plurality of structural members of an engine compartment. A cowl according to the present invention, as noted above, preferably includes A-pillar, windshield, and dash panel mounting flanges.
According to another aspect of the present invention, a method for assembling a body of an automotive vehicle includes the steps of hydroforming a cowl having integral, vertically separated mounting flanges, from a cylindrical preform having a non-constant diameter, and hydroforming at least one engine compartment structural member. Finally, the method includes welding the integral mounting flanges of the cowl directly to the structural member and to an A-pillar of the vehicle. Additional steps include welding of a dash panel to the cowl and mounting a windshield to the assembled A-pillar and cowl.
It is an advantage of the present cowl that a vehicle body may be produced with increased structural integrity, but at a lower cost due to the elimination of welding machines and stations and other ancillary operations such as sealing and installation of a cowl top.
It is a further advantage of the present invention that the body made with the current cowl is expected to exhibit increased resistance to unwanted noise vibration and harshness, particularly the phenomenon know as “cowl shake”.
Other advantages, as well as objects and features of the present invention, will become apparent to the reader of this specification.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a vehicle body having a hydroformed cowl according to the present invention.
FIG. 2 is a perspective view of a cowl according to the present invention.
FIG. 3 is a perspective view of a preform for hydroforming a cowl according to the present invention.
FIG. 4 is a perspective view of a second type of preform for hydroforming a cowl according to the present invention.
FIG. 5 is a perspective view of a third type of preform for hydroforming a cowl according to the present invention.
FIG. 6 is a perspective view of prior art stamped cowl and cowl top.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
As shown in FIG. 1 , vehicle body 10 has cowl 16 , which is attached to cowlside 22 and structural member 24 by means of weldments 20 which directly mount cowl 16 to the cowlside 22 and structural member 24 . This mounting is permitted by lateral mounting flanges 18 a and b . Flange 18 a is an upper flange, whereas flange 18 b is a lower flange. Together, flanges 18 a and 18 b allow direct welding of cowl 16 to cowlside 22 and structural member 24 , without the need for intermediate parts.
In addition to being welded to cowlside 22 and structural member 24 , cowl 16 is welded at A-pillar mounting flange 26 to A-pillar 28 . Mounting flanges 26 are double thickness flanges which are, as is the case with lateral mounting flanges 18 , formed within the hydroforming die itself. This obviates the need for additional steps or processes to create the lateral and A-pillar mounting flanges.
Cowl 16 has windshield support flange 34 , which is a double thickness flange, extending laterally across body 10 and supporting windshield 36 . Because windshield support flange 34 is integral with cowl 16 , there are no additional welding or sealing steps required to install windshield support flange 34 , as would be the case with many prior art windshield mounting systems.
Depending upon the needs of a particular automotive body into which the inventive hydroformed cowl is being installed, cowl 16 may include a dash panel mounting flange, 38 , ( FIG. 2 ) which is a double-thickness flange extending laterally across body 10 , and which may be attached to dash panel 40 by means of welding, bonding, mechanical fastening, or other types of fastening known to those skilled in the art and suggested by this disclosure.
FIG. 2 illustrates additional features of a cowl according to the present invention. In addition to flanges 18 a and b which are clearly seen in FIG. 2 , as well as windshield support flange 34 and dash panel flange 38 , it is seen that cowl 16 has a smaller dimensional mid-section 46 , with larger end sections 48 and 50 hydroformed integrally with mid-section 46 . The present inventors have determined that it is advantageous in certain applications to provide a preform for generating hydroformed part 16 as a laser welded blank having, as needed, different gauge thicknesses of metal or other materials joined together in an assembled preform which is placed in a hydroforming die and formed using conventional hydroforming practice.
FIG. 3 illustrates a first type of composite preform which two frustro-conical sections, 54 are joined by a single cylindrical section 56 . This type of construction could be used where the cowl's configuration includes a constant cross-sectional mid-section occupying a considerable portion of the cowl's total length, combined with much larger end sections for housing such items as a climate control system, a brake booster, and a driver control system such as pedals, a steering column, etc.
In certain cases, it may be desirable for a hydroformed cowl to have a generally varying cross section with the midpoint of the cowl being smaller than the ends, and in this case the preform construction of FIG. 4 which as before, contains laser welded blanks which may be of different metal thicknesses, may be optimal. For example, the metal gauge may be increased on the ends to accommodate more demanding loads imposed by structural strength considerations or mechanical equipment requirements.
FIG. 5 illustrates a third type of preform having a continuously varying diameter, which may be employed where the desired cowl structure is largely asymmetrical. This may arise, for example, in a vehicle in which a climate control air handling system is mounted almost entirely within the engine compartment of the vehicle, necessitating a larger cowl structure. The preform of FIG. 5 could further be useful if the cowl is “dry”, or in other words, not intended to permit an internal flow of rain water, as is the case with the cowl illustrated in FIGS. 1 and 2 .
Although the present invention has been described in connection with particular embodiments thereof, it is to be understood that various modifications, alterations, and adaptations may be made by those skilled in the art without departing from the spirit and scope of the invention set forth in the following claims.
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An automotive vehicle body includes a generally tubular, hydroformed cowl with integral mounting flanges which are welded to an engine compartment structural member and a cowlside member. The cowl may be hydroformed from several different preforms having both symmetrical and asymmetrical geometric characteristics.
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CROSS REFERENCE OF RELATED APPLICATION
This is a U.S. National Stage under 35 U.S.C 371 of the International Application PCT/CN2012/070042, filed Jan. 4, 2012, which claims priority under 35 U.S.C. 119(a-d) to CN 201110337121.1, filed Oct. 31, 2011.
BACKGROUND OF THE PRESENT INVENTION
1. Field of Invention
The present invention relates to an accessory of a balloon, particularly to a lighting/sounding device for a balloon that operates when the balloon is inflated.
2. Description of Related Arts
Balloons are decorations frequently used in daily life, and people most usually decorate the environment with inflated balloons.
However, the usage is too monotonous to meet diversified needs. So balloons with various special effects have been created, such as luminous balloons, lighting balloon and sounding balloons. Chinese patent application CN200610122541.7, for one, discloses a luminous balloon, which has a lighting effect and is characterized in that an LED lamp is taken as a light source and a light circuit device which supplies power to a silicon photocell is arranged in a plastic shell with an air hole. The luminous balloon has a simple frame, and is convenient to use and suitable not only for being held in hand after being sleeve jointed with a plastic pipe but also for being tied and dragged by a rope to float in the air or ornament the night scene. U.S. Pat. No. 7,344,267 discloses an illuminated toy balloon having an illuminating device and a cylindrical plug with an integrally-formed radially extending integral flange insertable within the balloon neck, wherein the illuminating device is provided within the balloon neck.
Since balloons are usually made of latex, aluminum film or plastic, how to install a lighting/sounding device becomes an important issue for a lighting/sounding balloon. As for the patent U.S. Pat. No. 7,344,267, a lighting device is installed at the neck of the balloon intake nozzle, which would affect inflation and use of the balloon and hence is not convenient enough. Then people think of a way to install a lighting/sounding device inside a balloon by fixing the device onto the balloon wall, such as the structure disclosed by the patent application GB20070004575 wherein a lighting device is fixed onto the inner wall of a balloon, but such a structure has a problem on how to control the lighting/sounding device inside the balloon.
Therefore, a seal sticker described in the patent application WO20110210 has become a key mechanism to control a lighting/sounding device inside a balloon. The disclosed seal sticker is used to disconnect the electric circuit of the lighting device, and the circuit is connected once the seal sticker is withdrawn, thereby controlling a lighting/sounding device to start. However, the seal sticker is not easy to process and install as the seal sticker needs to be inserted into the circuit of the lighting/sounding device, which increases difficulty and cost of processing, and withdrawal and then disposal of the seal sticker are especially a waste of resources and environmentally unfriendly.
SUMMARY OF THE PRESENT INVENTION
On the basis of the above problems, the present invention aims to provide a lighting/sounding device activated by inflation of a balloon, which facilitates control of the lighting/sounding device without affecting normal use and inflation of the balloon.
Another object of the present invention is to provide a lighting/sounding device activated by inflation of a balloon, which is easy to control, has a simple and practical structure, turns on and off the lighting/sounding device by taking full advantage of the principle of pressure, and conserves resources producing no environmentally unfriendly wastes.
To achieve the above objects, the present invention is carried out through the following technical solutions.
A lighting/sounding device activated by inflation of a balloon comprises a lighting lamp/sounder, a battery, and a housing at least covering the lighting lamp/sounder, wherein the housing comprises:
an inlet end to let air or other gases into the housing,
an outlet end to discharge the air or the other gases from the housing, and
an air channel to connect the inlet end and the outlet end so that a through passage for air flow is formed within the housing;
wherein the lighting lamp/sounder is provided in the air channel and has a sealing device for sealing off the air channel.
Before inflation of the balloon, a circuit of the lighting lamp/sounder is disconnected and the lighting lamp/sounder cannot be activated to operate; after the balloon is inflated, a gas pressure is generated within and forms a pressure difference between inside and outside the air channel, which pushes the lighting lamp/sounder towards the outer end of the air channel and seals the air channel; and, when the air channel is sealed up, the electric circuit of the lighting lamp/sounder is connected and the lighting lamp/sounder is activated to operate.
The sealing device is any one selected from the group consisting of an O-ring, a seal ring, and a seal coil (like a rubber ring), or a fitted mechanism formed between the lighting lamp/sounder and the housing. Such mechanisms as a tightly fitted or nested mechanism between the outside surface of the lighting lamp/sounder and the housing or a buckled mechanism between the lighting lamp/sounder and the housing are all able to seal off the air channel and thus can be referred to as a form of a sealing device.
The lighting lamp/sounder has a supporting and fixing holder that covers the lighting lamp/sounder at least from one cross section so that the lighting lamp/sounder has an outer wall at the cross section.
The outer wall is sleeved with a sealing device in a ring-shaped structure, and is located within the air channel.
In correspondence with the sealing device, at least a part of the air channel is cylindrical so as to seal off the air channel with the sealing device and connect the circuit of the lighting lamp/sounder.
In a preferred embodiment, the lighting lamp/sounder is provided at the outside with a seal coil or seal ring projecting from an exterior margin of the lighting lamp/sounder for close contact with the air channel to seal the air channel up.
The seal coil or seal ring projecting from the exterior margin of the lighting lamp/sounder has a same sealing function as the sealing device provided on an external surface.
The housing has a cross section in a shape of T, I, or trapezoid, so that the air channel forms a reduced neck portion around which a platform is provided; and a seal gasket is provided at one end of the lighting lamp/sounder, which projects from the end of the lighting lamp/sounder with a flat contact surface and has a diameter larger than a diameter of the reduced neck portion so that the contact surface is able to form a sealing contact with the platform, thereby sealing off the air channel.
The inner wall of the housing has a bell-like structure, the lighting lamp/sounder sleeved with the seal coil or seal ring is located inside the bell, and a clearance between the lighting lamp/sounder and the housing constitutes the air channel.
The lighting/sounding device is provided inside a balloon and is fixed onto an inner wall of the balloon by an external cover with an exhaust port connecting the outlet end of the lighting/sounding device to form the air channel.
Further, a piercing device is provided where the lighting/sounding device contacts the inner wall of the balloon inside the external cover, which has a pointed tip to pierce the inner wall of the balloon when the external cover is fixed onto the lighting/sounding device.
The inlet end has a top ring with a hollow middle part and a projecting top protrusion fixed onto the top ring via two side walls. The lighting lamp/sounder is held by the top ring to move so as to expose the air channel for discharging air.
The lighting lamp/sounder is elastically provided within the air channel and is supported by an elastic mechanism fixed inside the air channel and electrically conductive to close a control circuit of the lighting lamp/sounder. The elastic mechanism usually applies a metal spring or a metal spring plate.
The housing of the lighting/sounding device has an extending portion at the inlet end, which extends outwards for people to blow air into the balloon.
The lighting/sounding device is able to be installed at, tied to, or fixed onto a balloon nozzle; the lighting device is also able to be installed at any position other than the balloon nozzle and be fixed onto the balloon wall, either way is able to implement the present invention. The balloon and the lighting/sounding device is able to be bound together with an O-ring, a rope or a rubber ring; or the balloon is able to be pressed onto the lighting/sounding device by hydraulic pressure; or the balloon is able to be fixed onto the lighting/sounding device by adhesives.
A structure implementing the present invention uses an inner pressure of the balloon to start the lighting lamp/sounder, which makes the control of the lighting lamp/sounder easier and more liable.
Besides, the present invention allows provision of the lighting lamp/sounder either inside the balloon or at the balloon nozzle, which makes the lighting lamp/sounder easier to use; and since no additional control mechanism is needed, the present invention does not produce pollutive waste and is more environmental friendly and energy conservative.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an exploded diagram of the first embodiment of the presented invention.
FIG. 2 is a diagram of the first embodiment during inflation.
FIG. 3 is a diagram of the inflated first embodiment with an illuminated lighting lamp.
FIG. 4 is a diagram of the second embodiment of the presented invention.
FIG. 5 is a diagram of the second embodiment during inflation.
FIG. 6 is a diagram of the inflated second embodiment with an illuminated lighting lamp.
FIG. 7 is a diagram of the third embodiment of the presented invention.
FIG. 8 is a diagram of the third embodiment during inflation.
FIG. 9 is a diagram of the inflated third embodiment with an illuminated lighting lamp.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
To explain the objects, technical solutions and advantages of the present invention in a clearer way, here is a detailed description with reference to the drawings and the embodiment. It is to be understood that any embodiment described herein is intended to be illustrative, without any limitation to the present invention.
FIG. 1 shows the first embodiment of the present invention, which is a lighting device and mainly comprises, as shown, an LED lamp 1 , a holder 3 , button batteries 4 and a housing 5 .
In the embodiment, two contact pieces extend from a back end of the LED lamp 1 , wherein a first contact piece 11 is directly connected between the LED lamp 1 and the button batteries 4 ; and a second contact piece 12 bends outwards, extends along an outer wall of the holder 3 to a back of the button batteries 4 , and then bends inwards to form a bent portion 13 that is directed at the back of the button batteries 4 and is able to be connected to the button batteries 4 via a spring coil 72 so as to close an electric circuit and illuminate the LED lamp 1 .
The button batteries 4 normally number 1 to 4 (the drawings show two batteries in a way not limiting the number thereof in other implementations), which are provided along with the LED lamp 1 inside the holder 3 and are fixedly supported by the holder 3 . The holder 3 is sleeved with the hollow housing 5 with an inlet 51 at one end and an outlet 52 at the other end, and a clearance between the housing 5 and the holder 3 constitutes an air channel 6 . An inwardly inclined wall 53 is provided at an inner side of the inlet 51 while a ring-shaped seal coil 2 is fixed onto an outer wall of the holder 3 , and the seal coil 2 projects from the outer wall of the holder and is able to be clamped onto the inclined wall 53 more and more tightly to seal the air channel 6 .
To fix the lighting device onto a balloon wall, the housing 5 is fitted to an external cover 8 to get fixed. To be specific, the housing 5 has a projecting external thread 54 in an outer wall of a trailing end while the external cover 8 has an internal thread 82 in an inner wall, the external thread 54 engages with the internal thread 82 to fix the housing 5 with the external cover 8 , and furthermore, the balloon wall passes between the housing 5 and the external cover 8 so that the two are fixed thereto. (The internal thread 82 and the external thread 54 may have the same function in a way of indentation.)
In respect that the air channel 6 needs an exhaust passage, the balloon wall has to be pierced after the external cover 8 fixes the balloon wall and the housing 5 together, so an exhaust port 81 is provided at a center of the external cover 8 and a piercing cover 7 is further provided between the external cover 8 and the housing 5 , which is a ring-shaped cover (the piercing cover is not necessarily ring-shaped as long as the piercing cover is able to pierce the balloon wall) and has a projecting spike 71 directed at the exhaust port 81 at the center. When the external cover 8 fixes the balloon wall and the housing 5 together, a middle part of the external cover 8 will be concaved if the external cover 8 is pressed hard, and the spike 71 will protrude into the exhaust port 81 to pierce the balloon wall so as to form the exhaust passage.
The piercing cover 7 is further sleeved with a spring coil 72 made of metal to contact the bent portion 13 of the contact piece 12 and the button batteries 4 .
In other implementations without a piercing cover 7 , the spring coil 72 is directly fixed to the housing 5 instead, and the balloon wall is pierced from outside to form an air channel.
With reference to FIGS. 2 and 3 , the lighting device is installed inside the balloon 9 and fixed onto the balloon wall. During inflation of the balloon 9 through a balloon nozzle 91 , a pressure inside the balloon 9 is very low at beginning and a pressure difference between inside and outside the balloon is negligible, but when the inner pressure reaches a certain level, the pressure difference is large enough to discharge air through the air channel 6 in a direction of a arrow; then, the exhaust air pushes the holder 3 provided within the air channel 6 to slide outwards along the air channel 6 bringing the seal coil 2 on the holder 3 into contact with the inclined wall 53 ; and the air channel 6 will be sealed up to stop discharging air from the balloon 9 when the seal coil 2 comes into sealing contact with the inclined wall 53 .
As the spring coil 72 is settled in the housing 5 , the metal spring coil 72 gets held by the button batteries 4 when the holder 3 is sliding outwards, and the spring coil 72 gets compressed and comes into contact with both the button batteries 4 and the bent portion 13 formed by the contact piece 12 extending backwards, thereby connecting the circuit and illuminating the LED lamp 1 .
When the balloon 9 is deflated, the pressure difference between inside and outside the balloon 9 disappears and the spring coil 72 gets restored freely and releases the button batteries 4 and the holder 3 , and once the spring coil 72 is no longer in contact with the button batteries and the bent portion 13 formed by the contact piece 12 extending backwards, the circuit is disconnected and the LED lamp 1 is turned off.
In this way, the lighting device will be turned on under an effect of the internal pressure in the balloon and turned off once the internal pressure disappears. Such a structure achieves good results and is easy to use and control for requiring no other control mechanism.
FIGS. 4-6 show the second embodiment of the present invention, which, as shown in FIG. 4 , is a lighting device and mainly comprises an LED lamp 110 , a holder 130 , button batteries 140 and a housing 150 .
Likewise, two contact pieces extend from a back end of the LED lamp 110 , wherein a first contact piece 111 is directly connected between the LED lamp 110 and the button batteries 140 , and a second contact piece 112 bends outwards and extends along the outer wall of the holder 130 to the back of the button batteries 140 .
The button batteries 140 normally number 1 to 4 (the drawings show two batteries in a way not limiting the number thereof in other implementations), which are provided along with the LED lamp 110 inside the holder 130 and are fixedly supported by the holder 130 . The holder 130 is sleeved with the hollow housing 150 with an inlet at one end and an outlet at the other end, and a clearance between the housing 150 and the holder 130 constitutes an air channel 160 . An inwardly inclined wall 151 is provided at an inner side of the outlet while a ring-shaped seal coil 120 is fixed onto an outer wall of the holder 130 , and the seal coil 120 projects from the outer wall of the holder 130 and is able to be clamped onto the inclined wall 151 more and more tightly to seal the air channel 160 .
In this embodiment, the lighting device is usually provided at the balloon nozzle, so the housing 150 has two projections 152 and 154 at a middle part to form therebetween a ring-shaped groove 153 where an O-ring 191 for fixing the balloon and the lighting device is provided. Fixing the lighting device at the nozzle 192 of the balloon 190 makes it possible to put the lighting device of the present invention in the balloon nozzle, and thereby normal use of the balloon is not affected as the balloon is still able to be tied to a pipe or other accessories after inflation.
A metal spring coil 170 (or a metal spring plate, instead) within the air channel 160 functions as an elastic mechanism for connecting the contact piece 112 and the button batteries 140 to close the circuit. The metal spring coil 170 has a top ring 180 at the outer end, which is fixed on the inner wall of the housing 150 for positioning the metal spring coil 170 . The ring-shaped top ring 180 has a top protrusion 181 projecting from the center, which is fixed to the top ring 180 via a side wall 182 .
The top ring 180 is used to position the metal spring coil 170 , and the top protrusion 181 is mainly used to hold the metal spring coil 170 . Another function of the top protrusion 181 lies in that by pressing the top protrusion 181 , the button batteries 140 and the holder 130 are held and pushed into the balloon so as to deflate the balloon.
With reference to FIGS. 5 and 6 , air enters the balloon 190 in a direction of an arrow when the balloon 190 is inflated. At a beginning of inflation, the pressure inside the balloon 190 is very low and the pressure difference between inside and outside the balloon is negligible, but when the inner pressure reaches a certain level, the pressure difference is large enough to discharge air from the balloon through the air channel 160 so as to maintain pressure balance.
During discharge of the air, the exhaust air pushes the holder 130 provided within the air channel 160 to slide outwards along the air channel 160 bringing the seal coil 120 on the holder 130 into contact with the inclined wall 151 , and the air channel 160 will be sealed up to stop discharging air from the balloon 190 when the seal coil 120 comes into sealing contact with the inclined wall 151 .
At this time, the holder 130 is sliding outwards under the pressure and is displaced to such a position that the metal spring coil 170 gets held by the button batteries 140 , gets compressed and comes into contact with both the button batteries 140 and the contact piece 112 , thereby connecting the circuit and illuminating the LED lamp 110 .
The inflated balloon 190 is able to be deflated by pressing the top protrusion 181 inwards; when the pressure difference between inside and outside the balloon 190 is reduced to zero, the spring coil 170 gets restored freely and releases the button batteries 140 and the holder 130 ; and once the spring coil 170 is no longer in contact with the button batteries 140 and the contact piece 112 , the circuit is disconnected and the LED lamp 110 is turned off.
In this embodiment, the lighting device is placed inside the balloon nozzle 192 and is fixed by the O-ring 191 , whereas the outer end of the balloon nozzle 192 still has a structure of a flexible balloon wall. The balloon is able to be inflated in conventional ways, like by blowing with mouth, or using tools. After the balloon gets inflated, the nozzle 192 is able to be tied with a string or wound into a knot itself to achieve air tightness, and then the balloon is able to be hung up, stuck to a wall with an adhesive, or attached to a rod for use and entertainment.
FIGS. 7˜9 show the third embodiment of the present invention, which, as shown in FIG. 7 , is a lighting device and mainly comprises an LED lamp 210 , a holder 230 , button batteries 240 and a housing 250 .
Likewise, two contact pieces extend from a back end of the LED lamp 210 , wherein a first contact piece 211 is directly connected between the LED lamp 210 and the button batteries 240 , and a second contact piece 212 bends outwards and extends along the outer wall of the holder 230 to the back of the button batteries 240 .
The button batteries 240 normally number 1 to 4 (the drawings show two batteries in a way not limiting the number thereof in other implementations), which are provided along with the LED lamp 210 inside the holder 230 and are fixedly supported by the holder 230 . The holder 230 is sleeved with the hollow housing 250 with an inlet at one end and an outlet at the other end, and a clearance between the housing 250 and the holder 230 constitutes an air channel 260 . An inwardly inclined wall 251 is provided at an inner side of the outlet while a ring-shaped seal coil 220 is fixed onto an outer wall of the holder 230 , and the seal coil 220 projects from the outer wall of the holder 230 and is able to be clamped onto the inclined wall 251 more and more tightly to seal the air channel 260 .
This embodiment is similar to the embodiment shown in FIG. 4 in that the lighting device is usually provided at the balloon nozzle, so the housing 250 firstly has an extending portion 252 with two projections 254 at the back end and an outer end convenient for handhold. The extending portion 252 further has a projecting ring 253 to attach a string so that the balloon is able to be dragged or tied on other articles.
A metal spring coil 270 is provided within the air channel 260 for connecting the contact piece 212 and the button batteries 240 to close a circuit. The metal spring coil 270 has a top ring 280 at an outer end, which is fixed on an inner wall of the housing 250 . The ring-shaped top ring 280 has a top protrusion 281 projecting from a center, which is fixed to the top ring 280 via a side wall 282 .
The top protrusion 281 is mainly used to hold the metal spring coil 270 , but another function thereof lies in that by pressing the top protrusion 281 , the button batteries 240 and the holder 230 are held and pushed into the balloon so as to deflate the balloon.
With reference to FIGS. 8 and 9 , when the balloon 290 is integrated with the lighting device of the present invention, the two are able to be tightly fixed together by sleeving the projections 254 with the balloon nozzle 291 and providing a seal ring 292 between the two projections 254 .
As shown in FIG. 8 , air enters the balloon 290 in a direction of an arrow when the balloon 290 is inflated. At a beginning of inflation, the pressure inside the balloon 290 is very low and the pressure difference between inside and outside the balloon is negligible, but when the inner pressure reaches a certain level, the pressure difference is large enough to discharge air from the balloon through the air channel 260 so as to maintain pressure balance.
As shown in FIG. 9 , during discharge of the air, the exhaust air pushes the holder 230 provided within the air channel 260 to slide outwards along the air channel 260 bringing the seal coil 220 on the holder 230 into contact with the inclined wall 251 , and the air channel 260 will be sealed up to stop discharging air from the balloon 290 when the seal coil 220 comes into sealing contact with the inclined wall 251 .
At this time, the holder 230 is sliding outwards under the pressure and is displaced to such a position that the metal spring coil 270 gets held by the button batteries 240 , gets compressed and comes into contact with both the button batteries 240 and the contact piece 212 , thereby connecting the circuit and illuminating the LED lamp 210 .
The inflated balloon 290 is able to be deflated by pressing the top protrusion 281 inwards; when the pressure difference between inside and outside the balloon 290 is reduced to zero, the spring coil 270 gets restored freely and releases the button batteries 240 and the holder 230 ; and once the spring coil 270 is no longer in contact with the button batteries 240 and the contact piece 212 , the circuit is disconnected and the LED lamp 210 is turned off.
The foregoing is only a description of the present invention in combination with preferred embodiments, and the modes for implementation of the present invention are not limited thereby in any way. Any simple derivation or replacement that may be made by those of ordinary skill in the art without departing from the spirit of the invention is covered under the protection scope claimed therein.
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A lighting/sounding device activated by inflation of a balloon includes a lighting lamp/sounder, a battery, and a housing at least covering the lighting lamp/sounder. The housing includes an inlet end, an outlet end, and an air channel connecting the inlet end and the outlet end to form a through passage for air flow within the housing. The lighting lamp/sounder is provided within the air channel and has a sealing device for sealing off the air channel. When the balloon is not inflated, the lighting lamp/sounder cannot be activated; after the balloon is inflated, a pressure difference generated between inside and outside the balloon pushes the lighting lamp/sounder towards the outer end of the air channel and seals the air channel; and, when the air channel is sealed up, an electric circuit of the lighting lamp/sounder is closed and the lighting lamp/sounder is activated to operate.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to display units for displaying or merchandizing small articles such as rings and like jewelry and more specifically relates to pilfer proof display units for small articles.
2. Brief Description of the Prior Art
A merchandizer or collector of small articles inherently desires to display those articles for various purposes. Advantageously, merchandizing displays of small articles will permit a prospective customer to handle the merchandize. However, handling of small individual items poses a problem of possible theft by unscrupulous individuals. Heretofore, attempts have been made by the use of visual display cards of a relatively large size to permit a prospective purchaser to obtain a close look at the article. However, such displays restrict the prospective customer from complete handling of the article. For example, a ring may be so fastened to a display card that although the prospective purchaser may physically touch the ring, he or she is unable to place it upon a finger for viewing.
The pilfer proof display unit of this invention enables one to display small articles, such as rings, and like jewelry, in a manner enabling a prospective purchaser to handle, fit, try on, and generally use the article. However, the displayed article is firmly secured to the display unit in such a manner that its removal will actuate an alarm system to alert the displayer of the theft.
Representative of the published prior art are the disclosures found in U.S. Pat. Nos. 407,668 (1889); 777,823 (1904); 1,486,629; 1,816,598; 2,535,229; 3,002,795; 3,064,804; and 3,613,873.
SUMMARY OF THE INVENTION
The invention comprises a pilfer proof display case, which comprises;
A housing;
An open tray adapted to support an article for display, mounted on said housing, said tray having a display surface;
A portal communicating between the display surface and the interior of said housing, said portal being of a dimension insufficient to permit the passage of said article;
A line slidably mounted in said portal, said line having a first end extendable to said display surface and adapted to secure said article, said line having a second end;
A mass of a dimension which will not permit its passage through said portal, secured to said second end and suspended within the space defined by said housing;
An audible alarm, activatable upon removal of the line connection between said mass and said article.
The term "line" as used throughout the specification and claims is used to mean a flexible cord, rope, string, wire, monofilament, cable and the like.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a cross sectional side elevation of an embodiment unit of the invention.
FIG. 2 is a cross sectional side elevation of an alternate embodiment of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
A complete understanding of the invention may be readily obtained by referring to the accompanying drawings of FIGS. 1 and 2 in conjunction with the following description.
FIG. 1 is a cross sectional side elevation of an embodiment display unit 10 of the invention. Unit 10 comprises a housing 12 including as an upper surface a display tray 14. An access door 16 is secured by hinge 18 to one end of the display tray 14 to complete an enclosure of space 19 which is the interior of the housing. Mounted on post 20 within space 19 is a bell 22. Bell 22 is positioned directly beneath portals 24 which communicate between the display surface 25 and space 19. Passing through portals 24 are lines 26. Lines 26 may be any flexible cord, wire, rope, string, monofilament, or like flexible attaching line. Preferably, line 26 is a cable, most preferably of flexible steel. Line 26 is slidably mounted in portal 24 with a first end attached to a small article 30 for display on display surface 25. The first end of line 26 is adapted to be securely fastened to the article 30 so that detachment requires severing of the article 30 or line 26. The second end of line 26 is attached to a mass 28, preferably a heavy metal weight. The portals 24 should be of a dimension which permits the sliding of cable 26 therethrough, but denies passage of article 30 or mass 28. The length of line 26 should be sufficient to permit a prospective purchaser to move article 30 off display surface 25 (as shown in the drawing) for close examination. The length of line 26 should be such that mass 28 is suspended in space 19 above bell 22. In operation, the housing is enclosed or constructed so that one cannot simultaneously hold an article 30 and reach mass 28. With such a construction, a prospective thief, should he sever the connection between line 26 and article 30 will release mass 28 so that it falls upon bell 22 and provides an audible alarm to alert personnel to the fact that article 30 has been removed from display surface 25 in an unauthorized manner. When line 26 has not been detached from article 30, the structure of unit 10 is such that upon release by the prospective customer, article 30 will always be returned to its assigned position on display surface 25. This is because mass 28 will serve to snub article 30 against display surface 25 in its normal position.
Referring now to FIG. 2, an alternate embodiment unit 30 of the invention may be observed wherein the same numeric symbols have been assigned for structures analagous to those found in the embodiment 10 of FIG. 1. The embodiment 30 of FIG. 2 differs from embodiment 10 shown in FIG. 1 in that unit 30 is specifically designed for mounting on a counter. The unit 30 also provides a means for extending the drop distance between mass 28 and bell 22 upon unauthorized detachment of line 26 from an article 30. As shown, guide means 32 and 34, which are bars traversing space 19, guide the lines 26 into position over bell 22 which is in a lower extension of housing 12. The operation of unit 30 is essentially the same as that described above in relation to unit 10 of FIG. 1. A similar system, i.e.; employing guide means 32, 34 to direct mass 28 over a particular zone is particularly useful for a wall mounted unit wherein display surface 25 would be vertical.
Those skilled in the art will recognize that although the embodiments described above are relatively simple, many modifications may be made thereto without departing from the spirit of the invention. For example, the bell 22 may be replaced with a more sophisticated alarm system activated by the fall of mass 28. For example, line 26 may also be secured to an electrical switch which activates an electrical alarm system for continuous alarm sounding when mass 28 falls beyond its normal low position. For a further example, line 26 may be an integral part of an electrical system, severance of which activates a conventional alarm system. As further examples, the housing 12 may take on any desired shape, display tray 25 may be made more sophisticated and may be a separate but associated component, associated with housing 12.
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The disclosure is of a pilfer-proof display unit particularly useful for security of small articles such as rings and like jewelry while permitting a potential customer free access to the handling of the article.
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This application claims priority to U.S. Provisional Patent Application Ser. No. 60/844,517, entitled “High Concentration Pelletized Additive Concentrates for Polymer,” filed on Sep. 14, 2006, the entire content of which is hereby incorporated by reference.
BACKGROUND
The invention relates generally to the field of polymer additives and specifically to high concentration pelletized additive concentrates, or polymer stabilization agent or blends, used in various polymerization processes to enhance polymer stability.
Polymer additives and additive blends are typically used to protect polymers from thermo-oxidative degradation, to provide long term resistance to light or heat, to neutralize residual catalyst and to enhance performance properties of the finished product. Polymer additives typically come in powder, granule, or pellet form. These additives can be routinely added to the polymer during post reactor extrusion operations. Numerous techniques may be employed to introduce the additives to the polymer stream. In solution, suspension or slurry phase polymerization processes, additives and additive blends are frequently added to a liquid before being introduced to the post-reactor polymer-liquid slurry. Alternatively, the additives can be added to the final melt stream of polymer via a side arm extruder or other device which can melt the additive and introduce them to the polymer stream. In this case, there will typically be further mixing via an extruder or other mixing device and pumping of the polymer/additive mixture through a die for pelletizing the final polymer. In other polymerization processes such as a gas phase reactor, the polymer exits the reactor as a powdered “reactor granule.” In this case, additives can be added to the polymer in several different ways. The additives can be added to the solid “reactor granule” powder stream. This can be packaged off as a final saleable product or it can be further fed to an extruder or other melting device in order to mix and homogenize the polymer and disperse the additives into the molten polymer. When additives are added to the solid “reactor granule” powder stream, the additives can be introduced at this stage via their neat forms, typically powders, or via a concentrate or masterbatch form. This mixture is subsequently pumped through a die for pelletization. Alternatively, in this type of process, the additives can be introduced via a side arm extruder. The side arm extruder melts the additives and feeds them into a molten polymer stream where they are further mixed into the final polymers and pelletized. In all of these techniques, the addition of the additives in powder form can be difficult to handle and feed, and in the case of some additives, they pose a potential health, fire, and explosion risk. If the polymer system requires the addition of several components, the additives must be either pre-blended, or the use of more than one feeder is required. When a side-arm extruder is used, it is not common to feed the powdered additives directly for numerous reasons. In addition to the above mentioned issues with handling and feeding the additives in powder form to the side-arm extruder, the melting and viscosity behaviour of the additives and the additive mixtures are typically not suitable for direct addition via this method. As a result, the powdered additives can be made into a fairly low concentration masterbatch. This type of masterbatch typically is made by extruding a low concentration of additives with a polymer carrier resin that is similar and compatible with the main polymer being produced in the polymerization process. As a result, this masterbatch can be easily fed via a side-arm extruder.
Preparation of non-dusting pellet forms of additive blends solves many of these problems. U.S. Pat. No. 5,240,642 entitled “Process for Obtaining Granular Forms of Additives for Organic Polymers” describes a process for making low-dust granules of an additive blend including a phenol antioxidant and an acid neutralizer processed in the amorphous or molten state including using an extruder.
U.S. Pat. No. 5,844,042 entitled “Process for Obtaining Granular Forms of Additives for Organic Polymers” describes granular forms of additive blends prepared by forcing the blend through a die to form strands and then cutting said strands to form pellets.
U.S. Pat. No. 5,597,857, entitled “Low-Dust Granules of Plastic Additives” describes additive pellets comprising 10-100% calcium stearates.
U.S. Pat. No. 6,740,694B2 entitled “Preparation of Low-Dust Stabilizers” describes using a sub-cooled melt of an additive as a carrier liquid for other additives and as well as amorphous versions of stabilizers.
U.S. Pat. No. 6,515,052 entitled “Granular Polymer Additives and Their Preparation” describes using a solvent in a compaction process to improve the yield and quality of a compacted additive blend including a phosphite.
U.S. Pat. No. 6,800,228 entitled “Sterically Hindered Phenol Antioxidant Granules Having Balance Hardness” describes using a solvent for the preparation of compacted additive blends which including a phenol.
The inventions described above provide for low-dusting forms of additive blends that can be more conveniently and accurately fed to post reactor extrusion operations for addition to a polymer when added directly to a polymer stream that is in the solid phase and premixed or fed simultaneously with the polymer stream into an extruder or other melting device whereby the polymer is melted and the additives are then blended into molten polymer. When the additives require addition via a side-arm extruder and fed directly to a molten polymer stream, the above described additive blends are not used. In this case, masterbatches or concentrates of additives or additive blends in a compatible polymer carrier are used. Masterbatches have the benefit of low friability of the pellet, they can be air conveyed, fed, and extruded using conventional equipment and methods by a side arm extruder.
The preparation of masterbatches is well known in the art. Masterbatches simplify the addition of at least one component to the polymer blend. For economic reasons it is desirable to prepare masterbatches with high levels of additives, and minimize the use of the compatible polymer carrier. This minimizes the amount of masterbatch required to achieve a desired effect.
The preparation of high levels of mineral filled masterbatches is well known in the art. U.S. Pat. No. 6,713,545 B2 entitled “Universal Masterbatch” describes a masterbatch of up to 85% filler, plus a viscosity modifier in a universal SBS carrier. A difficulty in the preparation of masterbatches of high filler concentration is wetting out, mixing and dispersing the filler while maintaining an adequately low viscosity to be able to process the masterbatch. The addition of high levels of filler can greatly increase the viscosity of the masterbatch.
U.S. Pat. No. 6,255,395 B1 to Klosiewicz entitled “Masterbatches Having High Levels of Resin” describes incorporating high levels of hydrocarbon resins into a polymer carrier. The resin preferably has a softening point near or above the softening point of the carrier polymer and has a sufficient viscosity to allow an extruder to put work into the mixture. Preparation of the masterbatches is accomplished above the softening point of the resin.
Many polymer additives, when heated to typical masterbatch processing temperatures, pass through a crystalline melting point or an amorphous phase transition to form low viscosity fluids. Such low viscosity fluids can be difficult to incorporate into a polymer carrier at high levels. Poorly incorporated additive can migrate out of the finished masterbatch pellet. This can cause dusting, stickiness and or agglomeration of the masterbatch pellets. Furthermore the low viscosity additive can substantially decrease the viscosity of the carrier-additive blend, causing difficulties in the pelletization process. For these reasons, masterbatches of polymer additives, with melting points near or below typical masterbatch processing temperatures, are prepared at only low to medium additive levels. It would therefore be advantageous to prepare more economical highly-loaded additive masterbatches of these additives.
SUMMARY
A pelletized additive concentrate for a polymer comprising: at least one primary polymer additive present in a total amount of between about 20 wt. % and about 90 wt. % of the pelletized additive concentrate, the primary polymer additive having a primary polymer-additive melting temperature between about 100° C. and about 200° C.; and at least one primary carrier polymer present in a total amount of between about 10 wt. % and about 80 wt. % of the pelletized additive concentrate, the primary carrier polymer having a primary carrier-polymer melting temperature below the primary polymer-additive melting temperature.
A pelletized additive concentrate for a polymer comprising: a blend of two or more primary polymer additives present in a total amount of between about 20 wt. % and about 90 wt. % of the pelletized additive concentrate, each primary polymer additive having a primary polymer-additive melting temperature between about 100° C. and about 200° C.; and a blend of two or more primary carrier polymers present in a total amount of between about 10 wt. % and about 80 wt. % of the pelletized additive concentrate, each primary carrier polymer having a primary carrier-polymer melting temperature below the primary polymer-additive melting temperature; wherein the pelletized additive concentrate is processed at a temperature lower than the primary polymer-additive melting temperature but higher than, or equal to, the primary carrier-polymer melting temperature
The present invention also pertains to high concentration pelletized additive concentrates for polymer, or masterbatches, and methods of making masterbatches of polymer additives. The primary additives used in the present invention are crystalline additives having a peak melting temperature (or primary polymer-additive melting temperature), or amorphous additives having a glass transition temperature (or primary polymer-additive glass transition temperature) within the range of normal processing temperatures of polyolefin masterbatches. The invention illustrates a method of preparing high concentration masterbatches of the primary additive or pelletized additive concentrates, by processing below or near their peak melting or glass transition temperatures. These masterbatches are useful during polymer production, especially in the manufacture of polymers whereby after polymerization, the polymer is fed to an extruder or other device in which the polymer is molten in order to introduce additives to the molten polymer stream. This is especially true where a side-arm extruder is utilized to introduce the additives. Such additives are essential in improving properties, maintaining properties, and adding functionality or other features to said polymers. Using the techniques of the present invention, high concentrations of additives in a polymer resin carrier can be made which are dust free, and robust in that they are easily conveyed using pneumatic air conveying and are easily fed to an extruder or other device where they are melted and fed into a molten polymer stream. In this step, the additive blend is diluted to the final end-use level for stabilization or introduction of appropriate additive functionality to the polymer being produced. Such high concentration additive blends can also be useful when fed directly to the solid polymer and physically blended with the base polymer prior to the final melting, mixing, and pelletizing, or simultaneously fed to the final melting, mixing, and pelletizing of the base resin being produced. The high additive concentrations produced allow for significant cost savings as these blends are typically up to four times more concentrated than typical additive masterbatches that have been used for this purpose in the past.
DETAILED DESCRIPTION
The particulars of the invention shown herein are by way of example. They are meant to illustrate various embodiments of the invention and not meant to limit the principles or concepts of the invention.
Given below are the condensed and shortened (by no means exhaustive) customary definitions known in the art of certain terms which condensed definitions may aid in the description of the invention.
“Base Polymer”: The polymer which is to be colored, functionalized, or otherwise modified by the masterbatch or additives.
“Carrier polymer”: polymer used typically as the continuous phase that when combined with fillers, colorants or additives, it will encapsulate them to form a masterbatch. The carrier polymer should be compatible with the base polymer to be modified.
“Masterbatch:” a concentrate of fillers, colorants or additives properly dispersed into a carrier polymer, which is then blended into the base polymer to be colored or modified, rather than adding the filler, colorant or additive directly.
“LLDPE”: linear low density polyethylene.
“Melting Point”: the peak melting temperature of a crystalline or semi-crystalline polymer or polymer additive as measured by differential scanning calorimetry (DSC).
“Polymer Blend”: the final formulation resulting from the combination of the base polymer and a masterbatch, masterbatches, additive or additives.
“Softening Point”: the onset of melting temperature as measured by differential scanning calorimetry.
The pelletized additive concentrates, or masterbatch, of the present invention is composed of 2 or more components. One or more of these components is a primary carrier polymer or a blend of primary carrier polymers. The other one or more of the components is a primary polymer additive or blend of primary polymer additives present at a high concentration (>20 wt. % but below 90 wt. %, based on the total weight of the pelletized additive concentrate or masterbatch), characterized by a melting or softening point between 80°-210° C. (the primary polymer-additive melting point or softening point) and more preferably between 100°-200° C. The masterbatch is prepared at a temperature above the melting temperature of the primary polymer carrier (the primary polymer-carrier melting temperature), or blend of primary polymer carriers, and near or below the melting or softening point of at least one of the highly loaded primary additive. Optionally, there may be one or more additional common polymer additives present at a low concentration (<20%) chosen from any of the polymer additives and or fillers known to one skilled in the art. Optionally, there may also be one or more additional common carrier polymers present at low concentrations, preferably below 10 wt. % chosen from any of the carrier polymers known to one skilled in the art. The masterbatch is useful during polymer production, especially in manufacturing of polymers whereby after polymerization, the polymer is fed to an extruder or other device in which the polymer is molten in order to introduce additives to the molten polymer stream, especially via a side-arm extruder.
Unless otherwise specified, percent concentrations in this specification refer to weight percent (“wt. %”). Wt. % is calculated by dividing the weight of the polymer by the weight of all of the elements in the solution not including the solvent. For example, in a pelletized additive concentrate containing 20 grams of primary polymer additive and 80 grams of primary carrier polymer dissolved in a solvent, the wt. % of the primary polymer additive would be 20%.
Preferred carrier polymers of the present invention include polymers, such as polyethylene, polypropylene, ethylene-propylene copolymers, ethylene-alphaolefin copolymers, polystyrene, polypropylene, polybutene, ethylene vinyl acetate copolymers, ethylene vinyl alcohol copolymers, styrene-butadiene copolymers, copolymers, polyolefins, or blends thereof.
The primary polymer additive or additives present at high concentration in the masterbatch of the present invention include those additives known to those skilled in the art as antioxidants, light stabilizers and catalyst neutralizers. These additives include hindered phenols, phosphites, phosphonites, hindered amines, triazines, benzophenones, benzotriazoles, hydroxybenzoates, and metal stearates possessing a melting or softening point in the range of 80°-210° C. and more specifically in the range 100°-200° C.
Hindered phenols are known as antioxidants for plastics and contain one or more groups of the formula 1 given below:
where R 1 and R 2 are methyl, tert-butyl, unsubstituted alkyls, or substituted alkyls.
Hindered phenols useful as one or more of the highly loaded additives in the present invention should have a melting or softening point in the range of 80°-210° C., more preferably in the range of 100°-200° C. Hindered phenols particularly useful in the present invention include, but are not limited to:
{penterythritol tetrakis(3-(3,5-di-t-butyl-4-hydroxyphenol)propionate)};
{1,3,5-tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione};
{2,2′-ethlidenebis(4,6-di-tert-butylphenol)};
{4,4′-methylenebis(2,6-di-tertiary-butylphenol)}
{2,4,6-tri-tert-butylphenol};
Phosphites and phosphonites are also known as antioxidants for plastics. They are predominantly aromatic phosphites and phosphonites. Phosphites and phosphonites useful as one or more of the highly concentrated additives in the present invention have a melting or softening point in the range of 80°-210° C., more preferably in the range of 100°-200° C. Phosphites and phosphonites particularly useful in the present invention include, but are not limited to:
{tris-(2,4-di-t-butylphenyl)phosphite};
{bis(2,4-di-t-butylphenyl) pentaerythritol diphosphite};
{2,4,6 tri-t-butylphenyl 2 butyl 2 ethyl 1,3 propane diol phosphite};
{Tetrakis(2,4-di-tert-butylphenyl)[1,1-biphenyl]-4,4′-diylbisphosphonite};
Hindered amines useful in the present invention are principally known as hindered amine light stabilizers (“HALS”). They contain one or more groups of the Formula 2 below:
These compounds can be of low or high molecular weights and can be oligomeric or polymeric. HALS useful as the highly concentrated additive in the present invention should have a melting point in the range of 80°-210° C. More preferably, HALS useful in the present invention have a melting point in the range of 100°-200° C. HALS useful as the highly concentrated additive in the present invention include, but are not limited to:
where R=
{1,3,5-Triazine-2,4,6-triamine,N,N′″-[1,2-ethane-diyl-bis[[[4,6-bis-[butyl (1,2,2,6,6-pentamethyl-4-piperidinyl)amino]-1,3,5-triazine-2-yl]imino]-3,1-propanediyl]]bis[N′,N″-dibutyl-N′,N″-bis(1,2,2,6,6-pentamethyl-4-piperidinyl)-};
where n is 1 or greater,
{Poly[[6-[(1,1,3,3-tetramethylbutyl)amino]-1,3,5-triazine-2,4-diyl][(2,2,6,6-tetramethyl-4-piperidinyl)imino]-1,6-hexanediyl[(2,2,6,6-tetramethyl-4-piperidinyl)imino]]};
{1,6-Hexanediamine, N,N′-bis(2,2,6,6-tetramethyl-4-piperidinyl)-polymer with 2,4,6-trichloro-1,3,5-triazine, reaction products with N-butyl-1-butanamine an N-butyl-2,2,6,6-tetramethyl-4-piperidinamine};
where n is 1 or greater,
{Poly [(6-morpholino-s-triazine-2,4-diyl)[2,2,6,6-tetramethyl-4-piperidyl)imino]-hexamethylene[(2,2,6,6-tetramethyl-4-piperidyl) imino]]};
where n is 1 or greater
{1,6-hexanediamine, N,N′-bis(2,2,6,6-tetramethyl-4-piperidinyl)-, polymers with morpholine-2,4,6-trichloro-1,3,5-triazine};
{bis(1,22,6,6-pentamethyl-4-piperidinyl)-2-butyl-2-(4-hydroxy-3,5-di-tert-utylbenzyl) propanedioate};
{N,N′-bisformyl-N,N′-bis-(2,2,6,6-tetramethyl-4-piperidinyl)-hexamethylendiamine};
where n is 1 or greater
Oligomeric sterically hindered amine
Triazines useful in the present invention contain one or more groups of the Formula 3 given below:
Triazines useful as the highly concentrated additive in the present invention should have a melting point in the range of 80°-210° C. More preferably, triazines useful in the present invention have a melting point in the range of 100°-200° C. Triazines useful as the highly concentrated additive in the present invention include, but are not limited to:
{2-(4,6-bis-(2,4-dimethylphenyl)-1,3,5-triazin-2-yl)-5-(octyloxy)-phenol};
Benzophenones useful in the present invention are principally known as light absorbers. They contain one or more groups of the Formula 4 as given below:
Benzophenones useful as the highly concentrated additive in the present invention should have a melting point in the range of 80°-210° C. More preferably, benzophenones useful in the present invention have a melting point in the range of 100°-200° C.
Benzotriazoles useful in the present invention are principally known as light absorbers. They contain one or more groups of the Formula 5 given below:
Benzotriazoles useful as the highly concentrated additive in the present invention should have a melting point in the range of 80°-210° C. More preferably, benzotriazoles useful in the present invention have a melting point in the range of 100°-200° C. Benzotriazoles useful as the highly concentrated additive in the present invention include, but are not limited to:
{2-(2H-benzotriazol-2-yl)-4,6-bis(1-methyl-1-phenylethyl)phenol};
{2-(3′-tert-butyl-2′-hydroxy-5′-methylphenyl)-5-chlorobenzotriazole};
{2-(3′,5′-di-tert-butyl-2′-hydroxyphenyl)-5-chlorobenzotriazole};
{2-(2H-benzotriazol-2-yl)-4,6-ditertpentylphenol};
{2-(2H-benzotriazol-2-yl)-4-(1,1,3,3-tetramethylbutyl)phenol};
{2-(2H-benzotriazole-2-yl)-4-methylphenyl};
Hydroxybenzoates useful as the highly concentrated additive in the present invention should have a melting point in the range of 80°-210° C. More preferably, hydroxybenzoates useful in the present invention have a melting point in the range of 100°-200° C. Hydroxybenzoates useful as the highly concentrated additive in the present invention include, but are not limited to:
{2,4-di-tert-butylphenyl 3,5-di-t-butyl-4-hydroxybenzoate};
Metal stearates useful as the highly concentrated additive in the present invention should have a melting point in the range of 80°-210° C. More preferably, metal stearates useful in the present invention have a melting point in the range of 100°-200° C. Metal stearates useful as the highly concentrated additive in the present invention include, but are not limited to calcium stearate, zinc stearate, magnesium stearate, and lithium stearate.
The invention also comprises a method for processing a pelletized additive concentrate in a twin screw or multi screw extruder. In one embodiment of this method, the pelletized additive concentrate is maintained during a first stage or stages of the extruder at a temperature lower than the primary carrier-polymer melting temperature such that at least one primary polymer additive and one primary carrier polymer remain substantial as solid. The temperature is then increased at a later stage or stages such that melting, or partial melting, of at least one primary carrier polymer occurs.
In one embodiment of the invention, a primary polymer additive or primary additive blend is fed to an extruder together with a primary polymer carrier resin and forced through a die to produce pellets. During extrusion, the primary polymer carrier resin is melted, such that the melt temperature is maintained below or near the melting point of one or more of the primary additives that is present at a high concentration. The remaining un-melted particles are subjected to shear and or heat and are finely dispersed in molten polymer carrier resin.
The primary polymer additive or additives present at high concentration in the masterbatch of the present invention include the those additives known to those in the art as antioxidants, light stabilizers, and catalyst neutralizers. These additives, include hindered phenols, phosphites, phosphonites, hindered amines, triazines, benzophenones, benzotriazoles, and metal stearates where the peak melting temperature of the additive is in the range of temperatures typically used to process polyolefins, usually between about 200° C. and about 300° C. Additionally, the masterbatch may contain other additives and/or mineral fillers.
Typically, when preparing a masterbatch of, by way of example, an antioxidant blend in linear low density polyethylene carrier, the compounding step is carried out at a processing temperature in the range of 180°-210° C. and up to a temperature considerably higher, such as 300° C. These temperatures allow the melting and dissolution of certain antioxidant additives into the polymer, up to the solubility limits of the additive. Beyond the solubility limits the additive exists as a discrete dispersed phase in the LLDPE. The melted antioxidants typically have a viscosity significantly lower than the molten LLDPE. This can lead to an advantageous reduction in extruder torque and an increase in output at low antioxidant concentrations. However, at higher concentrations, the viscosity of the blend decreases to very low levels, which can cause difficulties in the pelletizing operations. The large difference in the viscosity of the molten antioxidant and carrier resin can make it difficult and even impossible to efficiently mix and disperse the additives. This poor mixing is evident in the finished masterbatch pellets, which can exhibit leaching of the poorly dispersed additive to the surface. This can lead to the formation of dust or stickiness or agglomeration of the masterbatch. During the pelletizing or cooling operations, leaching additive can also be evident in the pellet cooling water, which has associated unwanted processing and environmental effects. It has been discovered that by significantly lowering the processing temperature of these additives near or below the melting point of the highly concentrated antioxidant, a highly concentrated masterbatch can be efficiently made. The viscosity of the concentrate is not reduced to deleterious levels during processing by an additive in liquid form. It has surprisingly been found that the dispersion of the antioxidant blend can be maintained at a high level. Without wanting to be limited by theory, maintaining a high viscosity of the system allows an efficient grinding and or shearing action of the extruder on solid additives. As the carrier resin solidifies, any additive which is present as a discrete dispersed phase will be present as a relatively smaller particle whereby it is encapsulated within the continuous polymeric carrier resin phase and will not easily leach out of the high concentration masterbatch produced. In addition, some polymer additives which possess a high shear viscosity and melt strength near their melting or softening point, can be processed efficiently at temperatures up to just above their melting point.
In another embodiment of the invention, the dispersion and processing ease of the additives can be improved by an inline solid-state grinding step. During extrusion, the first zones of the extruder are maintained at a temperature below the melting point of the primary polymer carrier resin. This leads to an efficient grinding and mixing of the primary additives and polymer in the solid state in high shear regions within the extruder at interfaces such as between the extruder screw and die wall or in mixing sections containing kneading blocks or other mixing devices. In the following zones of the extruder, the temperature of the components is raised above the melting point of the carrier resin and near or below the melting point of at least one of the high concentration primary additive. Such an initial grinding step leads to a fine dispersion in the finished product. This can also eliminate the need for a pre-grinding and or premixing step. It also allows for a fine dispersion of additives while limiting the temperature downstream and the time that the polymer will spend in the molten state.
In yet another embodiment of the invention, a primary polymer additive or additive blend was fed to an extruder or other mixing device together with a primary polymer carrier resin and forced through a die and cut to produce pellets. During mixing, the primary polymer carrier resin was melted, such that the blend temperature was maintained above the melting temperature of the primary carrier polymer and below or near the melting point of one or more of the primary additives that was present at a high concentration. The remaining un-melted particles were subjected to shear and/or heat and were finely dispersed and encapsulated in the molten polymer carrier resin. Optionally one or more other additives or fillers may be present in the masterbatch. As the carrier resin solidified, any additive which was present as a discrete dispersed phase would be present as a relatively smaller particle whereby it was encapsulated within the continuous polymeric carrier resin phase and would not easily migrate out of the high concentration masterbatch produced.
In another embodiment of the invention, the mixing step is carried out in a twin-screw or planetary screw extruder, whereby the dispersion and processing ease of the additives is improved by an inline solid-state grinding step. During extrusion, the first zones of the extruder are maintained at a temperature below the melting point of the primary polymer carrier resin. This leads to an efficient grinding and mixing of the additives and polymer in the solid state in high shear regions within the extruder at interfaces such as between the extruder screw and die wall or in mixing sections containing kneading blocks or other mixing devices. In the following zones of the extruder, the temperature of the components is raised above the melting point of the primary carrier resin and near or below the melting point of at least one of the high concentration primary additive. Such an initial grinding step leads to a fine dispersion in the finished product. This can also eliminate the need for a pre-grinding and or premixing step. It also allows for a fine dispersion of additives while limiting the temperature downstream and the time that the polymer will spend in the molten state.
Example 1
A high concentration additive blend was prepared using the following steps. 6 lbs of GM-1224 (Nova chemicals) was tumble blended with 0.544 lbs of AO-10 (Irganox 1010, Ciba Specialty Chemicals), 0.692 lbs of AO-76 (Irganox 1076, Ciba Specialty Chemicals) and 2.764 lbs of AO-68 (Irgafos 168, Ciba Specialty Chemicals). This blend was then fed to a ZSK30 (Coperion) co-rotating twin screw extruder. The extruder was run with barrel temperatures set at 150 degrees Celsius at a screw speed of 300 RPM using a high-shear screw configuration. The temperature of the mixture at the exit of the extruder was 159 degrees Celsius—below the melting temperature of the Irgafos 168, which is approximately 185 degrees Celsius. The extrudate had a cloudy/milky white appearance indicating that the high concentration additive (Irgafos 168) was still in the solid state at the exit of the die. Good strands were formed under stable extrusion conditions and were cooled and cut into approximately ⅛-inch diameter by ⅛-inch pellets. 100 grams of pellets were placed into a convection oven and aged for 24 hrs at 60 degrees Celsius. The pellets were then removed from the oven and allowed to cool to room temperature for 24 hours. The resulting pellets were observed to be dust free having a smooth outer surface.
Example 2
A high concentration additive blend was prepared using the following steps. 5 lbs of GM-1224 (Nova Chemicals) was tumble blended with 0.68 lbs of Irganox 1010, 0.865 lbs of Irganox 1076 and 3.455 lbs of Irgafos 168. This blend was then fed to a ZSK30 (Coperion) co-rotating twin screw extruder. The extruder was run with barrel temperatures set at 150 degrees Celsius at a screw speed of 300 RPM using a high-shear screw configuration. The temperature of the mixture at the exit of the extruder was 157 degrees Celsius. The extrudate had a cloudy/milky white appearance, formed into good stable strands and were cut into approximately ⅛-inch by ⅛-inch pellets. 100 grams of pellets were placed into a convection oven and aged for 24 hrs at 60 degrees Celsius. The pellets were then removed from the oven and allowed to cool to room temperature for 24 hours. The resulting pellets were observed to be dust free having a smooth outer surface.
Example 3
A high concentration additive blend was prepared using the following steps. 4 lbs of GM-1224 (Nova chemicals) was tumble blended with 0.816 lbs of Irganox 1010, 1.038 lbs of Irganox 1076 and 4.146 lbs of Irgafos 168. This blend was then fed to a ZSK30 (Coperion) co-rotating twin screw extruder. The extruder was run with barrel temperatures set at 150 degrees Celsius at a screw speed of 300 RPM using a high-shear screw configuration. The temperature of the mixture at the exit of the extruder was 157 degrees Celsius. The extrudate had a cloudy/milky white appearance, formed into good stable strands, and were cut into approximately ⅛ inch by ⅛ inch pellets. 100 grams of pellets were placed into a convection oven and aged for 24 hrs at 60 degrees Celsius. The pellets were then removed from the oven and allowed to cool to room temperature for 24 hours. The resulting pellets were observed to be dust free having a smooth outer surface.
Example 4
A high concentration additive blend was prepared using the following steps. 3 lbs of GM-1224 (Nova chemicals) was tumble blended with 0.952 lbs of Irganox 1010, 1.211 lbs of Irganox 1076 and 4.837 lbs of Irgafos 168. This blend was then fed to a ZSK30 (Coperion) co-rotating twin screw extruder. The extruder was run with barrel temperatures set at 150 degrees Celsius at a screw speed of 300 RPM using a high-shear screw configuration. The temperature of the mixture at the exit of the extruder was 157 degrees Celsius. The extrudate had a cloudy/milky white appearance, formed into fairly stable strands, and were cut into approximately ⅛ inch by ⅛ inch pellets. The pellets appeared to be slightly more fragile than what was observed in examples 1, 2 and 3 above. 100 grams of pellets were placed into a convection oven and aged for 24 hrs at 60 degrees Celsius. The pellets were then removed from the oven and allowed to cool to room temperature for 24 hours. The resulting pellets were observed to be dust free having a smooth outer surface.
Example 5
A high concentration additive blend was prepared using the following steps. Dowlex 2047 (Dow Chemical) was ground using an attrition mill to approximately −20 US mesh. 4 lbs of the ground Dowlex 2047 (Dow Chemical) was tumble blended with 0.816 lbs of Irganox 1010, 1.038 lbs of Irganox 1076 and 4.146 lbs of Irgafos 168. This blend was then fed to a ZSK30 (Coperion) co-rotating twin screw extruder. The extruder was run with barrel temperatures set at 150 degrees Celsius at a screw speed of 300 RPM using a high-shear screw configuration. The temperature of the mixture at the exit of the extruder was 158 degrees Celsius. The extrudate had a cloudy/milky white appearance, formed into good stable strands and were cut into approximately ⅛ inch by ⅛ inch pellets. 100 grams of pellets were placed into a convection oven and aged for 24 hrs at 60 degrees Celsius. The pellets were then removed from the oven and allowed to cool to room temperature for 24 hours. The resulting pellets were observed to be dust free having a smooth outer surface.
Example 6
A high concentration additive blend was prepared using the following steps. Sclair 2114 (Nova Chemicals) was ground using an attrition mill to approximately −20 US mesh. 4 lbs of the ground Sclair 2114 was tumble blended with 0.816 lbs of Irganox 1010, 1.038 lbs of Irganox 1076 and 4.146 lbs of Irgafos 168. This blend was then fed to a ZSK30 (Coperion) co-rotating twin screw extruder. The extruder was run with barrel temperatures set at 150 degrees Celsius at a screw speed of 300 RPM using a high-shear screw configuration. The temperature of the mixture at the exit of the extruder was 154 degrees Celsius. The extrudate had a cloudy/milky white appearance, formed into good stable strands, and were cut into approximately ⅛ inch by ⅛ inch pellets. 100 grams of pellets were placed into a convection oven and aged for 24 hrs at 60 degrees Celsius. The pellets were then removed from the oven and allowed to cool to room temperature for 24 hours. The resulting pellets were observed to be dust free having a smooth outer surface.
Example 7
A high concentration additive blend was prepared using the following steps. 4 lbs of GM-1224 (Nova chemicals) was tumble blended with 0.816 lbs of Irganox 1010, 1.038 lbs of Irganox 1076 and 4.146 lbs of Irgafos 168. This blend was then fed to a ZSK30 (Coperion) co-rotating twin screw extruder. The extruder was run with barrel temperatures set at 210 degrees Celsius at a screw speed of 300 RPM using a high-shear screw configuration. The temperature of the mixture at the exit of the extruder was 214 degrees Celsius. The extrudate had a clear and transparent appearance. The strands had poor melt strength but some were cooled and cut into approximately ⅛ inch by ⅛ inch pellets. The pellets were translucent when first pelletized and then slowly became milky white in appearance. 100 grams of pellets were placed into a convection oven and aged for 24 hrs at 60 degrees Celsius. The pellets were then removed from the oven and allowed to cool to room temperature for 24 hours. The resulting pellets appeared to have some powder “dust” on the surface of the pellets.
Example 8
A high concentration additive blend was prepared using the following steps. 4 lbs of GM-1224 (Nova chemicals) was tumble blended with 0.816 lbs of Irganox 1010, 1.038 lbs of Irganox 1076 and 4.146 lbs of Irgafos 168. This blend was then fed to a ZSK30 (Coperion) co-rotating twin screw extruder. The extruder was run with barrel temperatures set at 50 degrees Celsius for the first 3 zones and 150 degrees Celsius for the last 3 zones and at a screw speed of 300 RPM using a high-shear screw configuration. The temperature of the mixture at the exit of the extruder was 151 degrees Celsius. The extrudate had a cloudy/milky white appearance, formed into good stable strands, and were cut into approximately ⅛ inch by ⅛ inch pellets. 100 grams of pellets were placed into a convection oven and aged for 24 hrs at 60 degrees Celsius. The pellets were then removed from the oven and allowed to cool to room temperature for 24 hours. The resulting pellets were observed to be dust free having a smooth outer surface.
Example 9
A high concentration additive blend was prepared using the following steps. 4.4 lbs of GM-1224 (Nova chemicals) was tumble blended with 4.4 lbs of Calcium Stearate HPLG (Chemtura). This blend was then fed to a ZSK30 (Coperion) co-rotating twin screw extruder. The extruder was run with barrel temperatures set at 210 degrees Celsius and at a screw speed of 300 RPM using a high-shear screw configuration. The temperature of the mixture at the exit of the extruder was 203 degrees Celsius. The extrudate had poor melt strength and it was not possible to pull a strand through a water bath for pelletizing. The barrel temperatures were then lowered 145 degrees Celsius set points. The resulting extrudate had a temperature of 127 degrees Celsius. All other process conditions remained the same. The extrudate strand was solid and smooth. It was pulled through a water bath to be cooled and pelletized.
Example 10
A high concentration additive blend was prepared using the following steps. 4.4 lbs of GM-1224 (Nova chemicals) was tumble blended with 4.4 lbs of Tinuvin 326 (Ciba Specialty Chemicals). This blend was then fed to a ZSK30 (Coperion) co-rotating twin screw extruder. The extruder was run with barrel temperatures set at 210 degrees Celsius and at a screw speed of 300 RPM using a high-shear screw configuration. The temperature of the mixture at the exit of the extruder was 202 degrees Celsius. The extrudate had very poor melt strength and it was very yellowish in color. The barrel temperatures were then lowered 155 degrees Celsius set points. The resulting extrudate had a temperature of 130 degrees Celsius. All other process conditions remained the same. The extrudate strand was solid and smooth. It was pulled through a water bath to be cooled and pelletized. It was less yellow in appearance.
Example 11
A high concentration additive blend was prepared using the following steps. 4.4 lbs of LF-0718 (Nova chemicals) was tumble blended with 4.4 lbs of HALS-944 (Chimassorb 944, Ciba Specialty Chemicals). This blend was then fed to a ZSK30 (Coperion) co-rotating twin screw extruder. The extruder was run with barrel temperatures set at 210 degrees Celsius and at a screw speed of 300 RPM using a high-shear screw configuration. The temperature of the mixture at the exit of the extruder was 202 degrees Celsius. The extrudate had very poor melt strength, it was surging and unable to pelletize. The barrel temperatures were then lowered 125 degrees Celsius set points. The resulting extrudate had a temperature of 114 degrees Celsius. All other process conditions remained the same. The extrudate strand was solid and smooth. It was pulled through a water bath to be cooled and pelletized.
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High concentration pelletized additive concentration or polymer stabilization agent or blends, and their preparations, used in various polymerization processes to enhance stability.
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BACKGROUND OF THE INVENTION
Rotary sanders and grinders have been formed in a wide variety of configurations which are adapted to be rotated as by an electric motor to move an abrasive surface relative to a work piece. The abrasive may be mounted upon a flat rotary surface or upon an extension from an annular surface.
One type of rotary sander having flexible radial abrasive strips and termed a surfacing apparatus is shown in an early U.S. Pat. No. 2,174,385 and later improvements to and variations thereof are shown, for example, in U.S. Pat. Nos. 2,257,061, 2,871,632, 3,533,198, 3,685,217 and 3,800,481. These types of sanders, sometimes called floppy sanders are widely marked for a variety of purposes and are known to be marketed under names such as "Grind-O-Flex", flap wheels and finger strip sanders.
The type of sander noted above may be formed with replaceable abrasive strips or with fixed strips; however, the cost of the latter is substantial to the user and the effort of replacing the strips of the former is formidable.
The present invention provides an improved rotary sander with radially extending abrasive having a simple readily replaceable abrasive.
SUMMARY OF INVENTION
The rotary sander of the present invention employs an annularly grooved disc or drum with radial slots extending outward from the groove and an end plate or cap for retaining a particularly formed and configured abrasive strip. The abrasive hereof is provided upon paper, plastic or cloth in elongated strip form which is folded and joined together to form a circle with radial flaps or fingers thereabout having abrasive on both flat sides thereof. Joinder of portions of the strip to attain the noted configuration is preferably accomplished by an adhesive and the circle may be reinforced by a thin ring of cardboard or the like also adhered to the plane side of the adhesive strip. It is also possible to form the abrasive element of more than one strip provided in end-to-end relationship.
The grooved disc of the present invention is dimensioned to accommodate insertion of the abrasive element in the annular groove thereof with the flexible flats or fingers extending radially outward of the disc through the radial slots. The end plate or cap is removably affixed to the disc over the groove and slots as by a cap nut threaded onto an end of a central shaft of the disc adapted to be inserted in a rotary driven chuck of a stationary or portable tool. Commonly such tools only rotate in one direction and it will be appreciated that the abrasive element hereof may be reversed in the disc or drum to thereby double the wear available with each element.
DESCRIPTION OF DRAWINGS
The present invention is illustrated as to particular preferred embodiments in the accompanying drawings, wherein:
FIG. 1 is an exploded perspective view of a preferred embodiment of a rotary sander in accordance with the present invention;
FIG. 2 is an end elevational view of an abrasive element in accordance with the present invention;
FIG. 3 is a partial enlarged view of the abrasive element of FIG. 2;
FIG. 4 is an end elevational view of a grooved disc or drum in accordance with the present invention; and
FIG. 5 is a side elevational view of the disc of FIG. 4.
DESCRIPTION OF PREFERRED EMBODIMENT
A complete rotary sander in accordance with the present invention is comprised of four elements illustrated in FIG. 1 and referring thereto there will be seen to be provided a grooved disc 12 having a shaft 13 extending axially therethrough in fixed relation thereto. An abrasive element 14 is provided to removably fit within the grooves of the disc 12. A cover plate 16 fits upon the grooved end of the disc 12 and has a central apperture 17 therethrough for fitting over a short threaded end 18 on the shaft 13. A cap nut 19 is adapted to be threaded on the shaft end 18 to secure the cover plate 16 on the disc and thus retain the abrasive elements in the disc.
Considering now the abrasive element of the present invention and referring particularly to FIGS. 2 and 3 of the drawings, it will be seen that same generally is provided as a circular configuration with radial arms or the like extending therefrom. As illustrated, there is provided a reinforcing ring 21 and upon the outer surface thereof there is affixed an elongated flexible strip 22 which may be formed of paper, cloth or possibly some type of plastic substrate 23 having on the outer surface thereof an abrasive material 24. This strip 22 may be cut or otherwise divided from a sheet of conventional sandpaper, emery cloth or other similar material and the abrasive material on the external surface thereof may be adhered in any conventional manner. The strip 22 extends a short distance peripherally of the ring 21 on the exterior surface thereof between successive outward folded portions or flaps 26, particularly as illustrated in FIG. 3 of the drawings. The short peripheral sections 27 of the strip are affixed to the ring 21 as by an adhesive 28 and the contacting surfaces of the folded flap 26 are also preferrably adhered together by the same adhesive. Successive folded flaps 26 separated by peripheral portions 27 are formed entirely about the ring 21 to thus define an annular element having equally spaced radial arms or flaps extending therefrom about the entire circumference thereof. It will be appreciated that the flaps or arms are flexible and the overall abrasive element 14 may be formed without the reinforcing ring 21 which is provided primarily for the purpose of facilitating insertion of the abrasive element in the grooved disc 12 described below.
The disc or drum 12 of the present invention is formed as a short cylinder of rigid material such as a plastic or light metal and is provided upon the front face 31 thereof with an annular groove 32 centered on the axis of the shaft end 18 and having a diameter equal to the diameter of the ring 21 of the abrasive element 14. The annular groove 32 extends into the front face 31 of the disc a depth substantially equal to the width of the abrasive strip 22 and the ring 21. There are also provided in the front face 31 of the disc 12 a plurality of radial slots 33 extending from the annular groove 22 radially outward to the other periphery of the disc 12. The radial slots 33 are provided with the same depth as the annular groove 32 and are equally spaced about the disc in position to accommodate the radial arms or flaps 26 of the abrasive element 14. The width of the radial slots 33 are made substantially or slightly greater than the width of the radial arms or flaps 22 of the abrasive element and the width of the annular groove 32 is made euqal or slightly greater than the total radial width of the annular rim 21 and strip sections 27 thereon. Under the circumstances wherein the abrasive element is formed without the reinforcing ring 21 the width of the annular groove 32 may be reduced to substantially the thickness of the abrasive strip 22.
The rotary sander of the present invention may be readily assembled merely by inserting abrasive element 14 in the annular groove 32 and radial slots 33 of the disc 12. With or without the reinforcing ring 21 this abrasive element may be readily inserted in the disc and it will be appreciated that the solid back surface 34 of the disc prevents the abrasive element from sliding too far to or even through the disc. The cover plate 16 is then inserted on the threaded shaft end 18 to lie against the front face 31 of the disc and the cap nut 19 is threaded onto the shaft end to lock the cover plate in position holding the abrasive element in the disc. The flexible flaps or arms of the abrasive strip 22 extends radially outward of the disc 12 so as to be available for sanding, grinding, polishing, brushing or buffing of a work piece when the sander is rotated to engage the flaps or the like with the work piece. The flexible nature of the flaps or arms 26 provide advantageous sanding surface, for example, wherein even curved surfaces may be readily operated upon. It will, of course, be appreciated that the threads in the shaft end 18 are properly oriented so that rotation of the sander will not loosen the nut 19 on the shaft end 18.
It will be appreciated that the radial flaps or arms of the present invention have an abrasive material on both sides of same. Inasmuch as most rotary sanders, drills or the like upon which the present invention may be employed are adapted to rotate in only one direction or are at least primarily employed by rotating in only a single direction, it is only necessary with the present invention to reverse the orientation of the abrasive element in the disc hereof in order to present a fresh sanding or abrasive surface when the original surface becomes worn. This is readily accomplished by removing the nut 19 and cover plate 16, withdrawing the abrasive element from the disc 12 and turning the abrasive element around and reinserting it in the disc. Reattachment of the cover plate by the nut 19 will then lock the abrasive element in position to be employed with a fresh sanding or abrading surface.
The grooved and slotted disc 12 with integral shaft and the cover plate and locking nut are substantially permanent, reusable units while the abrasive element 14 is replaceable. The abrasive element is readily and inexpensively formed by looping a continuous strip of sandpaper, emery cloth or the like into the form illustrated and described and gluing facing surfaces of the substrate 23 together to form the flaps or arms of the abrasive element. Under the circumstances where the reinforcing ring or core 21 is employed, the abrasive strip may be formed thereabout and glued thereto, as described above. It is also possible to otherwise affix the abrasive strip to the ring or core 21 as by mechanical means and it is also possible, in the absence of the ring 21, the mechanically affix the two sides of the flap 26 together, at least at the base thereof to alternatively form the abrasive element. It has, however, been found that the use of any of a variety of commercial adhesives is preferrable in manufacture of the abrasive unit.
In summary, it is noted that there has been described above a single rotary sander of the type having flexible arms or flaps extending radially from the periphery of a rotary unit. Although the present invention has been described with respect to a particular preferred embodiment thereof, it will be appreciated by those skilled in the art that numerous modifications and variations are possible within the scope of the present invention and thus it is not intended to limit the invention to the precise details of illustration or terms of description.
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An improved abrasive structure and holder for sanding or the like has a continuous strip of sandpaper or emery cloth folded and secured together to form a circle with radial flaps or fingers extending therefrom and may have a circular stiffener all for cooperating with an annularly grooved disc with radial slots and a cover plate to form a rotary sanding wheel.
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CROSS REFERENCE TO COPENDING APPLICATION
This application is a continuation in-part of copending application Ser. No. 024,326 filed March 10, 1987, now abandoned.
OBJECT OF THE INVENTION
The present invention, as expressed in the title of the Specification, relates to a pitting piercer of the type used in fruit-pitting machines, such as, for example, olive pitting machines, which piercer has been improved in order to increase the operation and efficiency thereof, and to carry out cutting of the fruit in addition, and simultaneously to, the pitting thereof.
BACKGROUND OF THE INVENTION
Nowadays, automatic machines are used for pitting certain fruits, specifically olives, in which machines the olives are supplied singly and in a continuous manner to a drum wherein is established a perimetral alignment of clamps for holding the olives during the pitting operation, said clamps being provided with a bore to allow a pitting piercer to pass therethrough, and thus also through the olive, thereby tearing out and expelling the pit therefrom.
The said piercers are made up of a cylindrical shaft, the diameter whereof depends on the size of the pit, with a divided end in order to allow and facilitate cutting of the olive meat prior to reaching the pit.
Such piercers perfectly fulfil the pitting function for which they have been designed. In practice, however, the market demands that the olives be cut into pieces in addition to being pitted, so that they may be used as dressing or seasoning in certain dishes.
In order to cover this area of the market, there are currently known slicing machines to which are supplied olives which have previously been pitted, and which are then cut into slices.
This solution evidently requires two different and independent operative processes, with two very costly machines, thus resulting in a considerable increase in the cost of the end product.
DESCRIPTION OF THE INVENTION
The pitting piercer object of the invention has been designed and structured with a view to achieving that, in addition to the olive-pitting operation, it may also carry out cutting thereof, such that it simultaneously effects pitting and cutting of the olive with one single machine and in a single operative process, with no apparent increase in cost and with a productivity similar to that of a machine working exclusively as a pitter.
More specifically, and in order to achieve the above, from the conventional cylindrical shape with a divided operative end for pitting the olive or fruit in question, the basic characteristics of the piercer object of the invention are centered on the fact that it includes a plurality of radial fins immediately after said divided end, which fins are preferably triangular in shape and have a blade-like front edge such that on introducing the piercer into the olive and immediately after pitting thereof, the said olive is simultaneously cut into a number of slices or strips equal to the number of fins provided on the pitting piercer.
Thus, the number of fins of the piercer may vary in accordance with the number and size of the pieces to be obtained, said fins being nevertheless evenly distributed, i.e., equiangularly spaced around the piercer, in order that the slices obtained on cutting are all of identical size.
DESCRIPTION OF THE DRAWINGS
In order to complete the description being made, and to assist a better understanding of the characteristics of the invention, a single sheet of drawings is attached to the present specification, as an integral part thereof, wherein the following has been shown in an illustrative and non-limiting manner:
FIG. 1 is a side elevational view of a pitting piercer for fruit pitting machines in accordance with the object of the present invention.
FIG. 2 is a rear elevational view thereof.
FIG. 3 is a front elevational view.
FIG. 4 is, finally, a similar view to that of FIG. 1, showing the said piercer duly fitted in a fruit pitting machine, at its extreme working position, having finished the operation of cutting and pitting the olive (shown with a dotted line).
PREFERRED EMBODIMENT OF THE INVENTION
In the light of these figures, it can be seen how the pitting piercer object of the invention is comprised, in a conventional manner, by a cylindrical body 1 provided with the conventional divisions or faces at its operative end with which it carries out the likewise conventional pitting function, whereas its opposite end comprises a threaded section 3 for engaging bushing 4 which, with the aid of nut 5, allows definite axial fastening thereof to driving rod 6 which supplies to the piercer the alternative movement necessary for its operation.
From this basic, conventional structure, the characteristics of the piercer of the invention are centered on the fact that, immediately after its divided end, the piercer is provided with a plurality of fins 7, placed axially along their generatrixes, which fins are variable in number, are preferably triangular in shape, and have a blade-like front edge for attacking the olive meat. Each fin has a first rear section with a triangular shape, one side 20 extending along axis 34, a second side 22 extending forwardly and radially outward to an apex 36, and a third side 24 extending forwardly and radially inward from the apex 36 to a second forward section 26. The third side 24 has an exposed cutting blade 8. The second section has a forward edge 28 which extends inclinedly rearwardly and radially inwardly toward the axis.
More specifically, in the practical embodiment shown in the figures, there are provided four cutting fins 7, but this number may obviously vary at will, to either increase or decrease, depending on the number of pieces to be obtained from the olive, said fins 7 nevertheless adopting an even distribution around the periphery of body 1 of the piercer. Thus, obviously if there are two fins established diametrically on the cylindrical body 1, the olive or fruit in question will be cut into two equal pieces; if there are three fins, three pieces will be obtained, and so on, the pieces obtained being identical in each case.
In accordance with this structure, and as shown in FIG. 4, the olives reach the working area of piercer 1 resting on the clamp, seat or holder 9, which in turn is situated on a conventional support disc 10, the divided end 2 of the body attacks the olive 11 and, once having cut through the meat of the olive in the direction of its major axis, abuts the pit dislodging and withdrawing same towards the outside, the pit being expelled through the inner bore of seat 9. In its position of maximum axial forward displacement shown in FIG. 4, the pitting piercer will not only have ensured complete withdrawal of the pit, but the blade-like edges 8 of fins 7 will furthermore have reached the front of seat 9 and the olive will thus have been simultaneously cut into a certain number of pieces or slices in addition to having been pitted, the number of slices obtained being the same as the number of cutting fins 7 of the piercer.
In this way, and in accordance with the object of the invention, cutting of the olive is obtained simultaneously to pitting thereof with the use of a conventional pitting machine, it being simply necessary to substitute conventional piercers for the pitting pierce described in the invention.
Thus, in accordance with applicant's invention, apparatus for depitting and cutting olives into slices in an olive pitting machine is provided with an elongated driving rod which is actuated in reciprocating motion to be moved backwardly and forwardly along its axis between an extreme rear position and an extreme forward position, said rod having a free end designated as a driving end. An elongated generally cylindrical body has first and second opposite ends and has an axis coincident with the rod axis, the first end of the cylinder being connected to the driving end of the rod whereby the body is moved backwardly and forwardly along the axis by the corresponding movement of the rod. First means for depitting and cutting an olive into slices is constituted by a plurality of spaced thin elongated fins which are integral with the second end of the body and extend forwardly of the body in the axial direction. Each fin has a first rear section with a triangular shape, one triangular side of the first section extending along the axis, a second triangular side extending forwardly and radially outward to an apex, a third triangular side extending forwardly and radially inward form the apex to a second forward section. The second section extends forwardly and parallel to the axis. The third side has an exposed cutting blade. The second section has a forward edge which extends inclinedly rearwardly and radially inwardly toward the axis. Second means includes an olive holder provided with a bore axially aligned with the axis and lying in a plane perpendicular to the axis for supporting an olive having a major axis aligned with the axis. The olive has a rear end disposed in the bore and a front end, the front end of the olive being spaced from the front edges of the second sections when the rod is in its extreme rear position. The front edges of the second sections penetrate the olive to engage the pit and depit the olive as the rod moves into its extreme forward position. The cutting blades of the third sides of the first sections slice the depitted olive into a like plurality of separate slices disconnected from each other.
The first means for depitting and cutting an olive into slices is constituted by a plurality of spaced thin elongated fins (7) which are integral with the second end of the body (1) and extend forwardly of the body in the axial direction. Each fin has a first rear section with a triangular shape, one triangular side (20) of the first section extending along the axis (34), a second triangular side (22) extending forwardly and radially outward to an apex (36) and a third triangular side (24) extending forwardly and radially inward from the apex to a second forward section (26) which extends forwardly and parallel to the axis. The third side having an exposed cutting blade (8). The second section (26) has a forward edge (28) which extends inclinedly rearwardly and radially inwardly toward the axis.
The second means includes an olive holder (9) provided with a bore (30) axially aligned with the axis lying in a plane perpendicular to the axis for supporting an olive (11) having a major axis aligned with the axis. The olive has a rear end disposed in the bore and a front end. The front end of the olive is spaced from the front edges of the second sections when the rod is in its extreme rear position. The front edges (28) of the second sections penetrate the olive (11) to engage the pit (32) to depit the olive as the rod moves into its extreme forward position. The cutting blade (8) of the third sides of the first sections slice the depitted olive into a like plurality of separate slices disconnected for each other.
It is not considered necessary to extend this description for a person skilled in the art to understand the scope of the invention and the advantages derived therefrom.
The materials, shape, size and arrangement of the elements may vary, provided this does not imply a change in the essentiality of the invention. The number of fins 7 may vary depending on the number of pieces or slices to be obtained from the olive, as shown in FIG. 2 in dotted lines.
The terms used in the description of the present specification should be understood in a wide and nonlimiting meaning.
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Fins have edges which extend forward from a body which is reciprocated back and forth by a driving rod. The fins also have cutting blades. Olives are depitted by causing the forward edges to penetrate the olives and engage the pits. The cutting blades then slice the depitted olive into separate disconnected slices.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to methods for the treatment or prevention of disease states induced by activation of the A2B receptor and mast cell activation.
2. Description of the Related Art
A key early event in allergic responses is the activation of mast cells by allergens. For example, in asthma, exposure to an allergen such as ragweed, triggers the release of allergic mediators such as histamine, leukotrienes, etc. from mast cells. The action of allergens to trigger mast cell degranulation is enhanced by adenosine in asthmatics, but not in non-asthmatics (Bjorck T, Gustafsson L E, Dahlen S E: Isolated bronchi from asthmatics are hyper responsive to adenosine, which apparently acts indirectly by liberation of leukotrienes and histamine. Am.Rev.Respir.Dis. 1992;145:1087-1091). Theophylline is a xanthine that is known to block adenosine receptors and is effective therapeutically to treat asthma (Barnes P J, Pauwels R A: Theophylline in the management of asthma: time for reappraisal?. European.Respiratory.Journal. 1994;7:579-591). For this reason, theophylline is thought to ameliorate the symptoms of asthma, at least in part by blocking adenosine receptors. However, enprofylline, another xanthine that also is used to treat asthma in Europe, was found not to block adenosine receptors in the therapeutic concentration range of 20-50 uM (Chapman K R, Ljungholn K, Kallen A: Long-term xanthine therapy of asthma. Enprofylline and theophylline compared. International Enprofylline Study Group. Chest 1994; 106:1407-1413). Hence it was concluded that enprofylline does not work by blocking adenosine receptors. However, this conclusion was based on an examination of enprofylline binding only to two of the four known adenosine receptor subtypes, A1 and A2A receptors.
Applicant and others have recently discovered that the A3 adenosine receptor on mast cells are responsible for adenosine-stimulated release of allergic mediators in rodent species (Jin X, Shepherd R K, Duling B R, Linden J: Inosine binds to A3 adenosine receptors and stimulates mast cell degranulation. J.Clin.Invest. 1997;100:2849-2857; Ramkumar V, Stiles G L, Beaven M A, Ali H: The A 3 adenosine receptor is the unique adenosine receptor which facilitates release of allergic mediators in mast cells. J.Biol.Chem. 1993;268:16887-16890). These findings are misleading in that applicant has found that the A3 receptor is not involved in the release of allergic mediators from other species, including human and dog. Rather, applicant discovered that in canine and human mast cells the A2B and not the A3 adenosine receptor is responsible for adenosine-facilitated mast cell degranulation (Auchampach J A, Jin J, Wan T C, Caughey G H, Linden J: Canine mast cell adenosine receptors: cloning and expression of the A3 receptors and evidence that degranulation is mediated by the A2B receptor. Mol.Pharmacol. 1997;52:846-860). FIG. 1 of the instant application shows that NECA (a nonselective agonist that activates A2B and A3 receptors) causes intracellular Ca 2+ and cyclic AMP accumulation in the human mast cell line, HMC-1. IB-MECA, a potent and selective agonist of the A3 receptor is poorly effective. These data suggest that the A2B receptor mediates these responses in HMC-1 human mast cells. Another published report also suggests that activation of A2B receptors is responsible for triggering interleukin-8 release from human HMC-1 mast cells (Feoktistov I, Biaggioni I: Adenosine A 2B receptors evoke interleukin-8 secretion in human mast cells--An enprofylline-sensitive mechanism with implications for asthma. J. Clin. Invest. 1995;96: 1979-1986).
8-Phenylxanthines, methods of their synthesis and their use in human and veterinary therapy for conditions associated with the cell surface effects of adenosine have been described (EP 0 203 721, published Dec. 13, 1986). However, this publication is silent as to whether adenosine receptors mediate this response and if so, which adenosine receptor subtype. Also, the subtype specificity of disclosed compounds is not described. In WO 90/00056, a group of 1,3-unsymmetrical straight chain alkyl-substituted 8-phenylxanthines were described as being potent bronchodilators. This disclosure is likewise silent as to the role of adenosine and the subtype specificity of disclosed compounds.
Methods of treating conditions related to the physiological action of adenosine have, to date, proven inferior due to the presence of multiple subtypes present in the animal tissue utilized (R. F. Bruns et al., (1986) Mol. Pharm. 29:331-346) and the differences between species in the affinity for adenosine analogs and the physiological effects of adenosine (Ukera et al., (1986) FEBS Lett, 209:122-128).
SUMMARY OF THE INVENTION
The present invention concerns the use of compounds identified as specific modulators of adenosine's physiological actions. The pharmacology of these compounds is characterized through the use of cloned human adenosine receptors of the A1, A2A, A2B and A3 class and their subtypes. Applicant has found that compounds identified as antagonists of the A2B adenosine receptor subtype are useful in preventing mast cell degranulation and are therefore useful in the treatment or prevention of disease states induced by activation of the A2B receptor and mast cell activation. These disease states include but are not limited to asthma, myocardial reperfusion injury, allergic reactions including but not limited to rhinitis, poison ivy induced responses, urticaria, scleroderm arthritis, other autoimmune diseases and inflammatory bowel diseases. The present invention is based on the finding that antagonists of the A2B adenosine receptor subtype have anti-inflammatory action.
Through the use of homogenous, recombinant adenosine receptors, the identification and evaluation of compounds which have selectivity for a single receptor subtype have now been accomplished. Moreover, because of the variable effects of adenosine documented in other species, the utilization of human adenosine receptor subtypes is advantageous for the development of human therapeutic adenosine receptor agonists, antagonists or enhancers. In previous research conducted by the Applicant, compounds which unexpectedly exhibit selective binding affinity for the human A2B adenosine receptor were identified, along with methods for using such compounds to overcome the disadvantages of using compounds of uncharacterized specificity. The compounds specifically block activities mediated through the activation of the A2B receptor subtype without substantially blocking the activities of other adenosine receptor subtypes. In particular, Applicant found that the use of such compounds, identified through the use of recombinant human adenosine receptors A1, A2A, A2B and A3, and functional assays, can specifically modulate the physiologic role of adenosine activation of various receptors.
Applicant has developed for the first time a radioligand binding assay for the A2B adenosine receptor (Linden, J. et al. U.S. patent application Ser. No. 08/670,175, filed Jun. 20, 1996, the entire disclosure of which is herein incorporated by reference). Using this assays system, applicant has discovered that enprofylline, in the therapeutic concentration range of 20-50 μM used to treat asthma, blocks recombinant human A2B adenosine receptors, but is a much weaker antagonist of other adenosine receptor subtypes (FIG. 2 and Table 1).
The release of enzymes, bioactive amines and arachidonic acid metabolites following mast cell activation causes vasoconstriction, edema, leukocyte accumulation, and ultimately, tissue damage. Mast cell degranulation is a component of mycardian reperfusion injury, hypersensitivity reactions (asthma, allergic rhinitis, and urticaria), ischemic bowel disease, autoimmune inflammation, and atopic dermatitis. Highly specific A2B adenosine receptor antagonists can be used to treat or prevent these diseases and pathologic effects that result from mast cell degranulation.
Mast cell degranulation is clearly involved in the pathophysiology of allergies such as asthma. Autoimmune diseases are also characterized by immune reactions which attack targets, including self-proteins in the body such as collagen, mistaking them for invading antigens. The resulting damage, caused at least in part by mast cell degranulation, is amenable to treatment by the method of this invention which comprises administration of selective A2B adenosine receptor antagonists effective to inhibit mast cell degranulation. Among these types of diseases, all of the following, but not limited to these, are amenable to treatment by the administration of selective A2B adenosine receptor antagonists: Addison's disease (adrenal), autoimmune hemolytic anemia (red cells), Crohn's disease (gut), Goodpasture's syndrome (idney and lungs), Grave's disease (thyroid), Hashimoto's thyroiditis (thyroid), idiopathic thrombocytopinic purpura (platelets), Insulin-dependent diabetes militus (pancreatic beta cells), multiple sclerosis (brain and spinal cord), myasthenia gravis (nerve/muscle synapses), Pemphigus vulgaris (skin), pernicious anemia (gastric parietal cells), poststreptococcal glomerulonephritis (kidney), psoriasis (skin), rheumatoid arthritis (connective tissue), sclerodenna (heart, lung, gut, kidney), Sjogren's syndrome (liver, kidney, brain, thyroid, salivary gland), spontaneous, infertility (sperm), systemic lupus erythematosus (DNA, platelets, other tissues).
Disease states associated with A2B adenosine receptor activation and mast cell degranulation include, but are not limited to asthma, myocardial reperfusion injury, allergic reactions including but not limited to rhinitis, asthma, poison ivy induced responses, urticaria, scleroderma, arthritis, and inflammatory bowel diseases.
The present invention is directed to the discovery that antagonists of A2B receptors are anti-inflammatory in man. A3 adenosine receptors also have an anti-inflammatory action, but are most important in rodent species. It has been found that enprofylline, a compound already used to treat asthma, blocks A2B adenosine receptors and that human HMC-1 mast cells have A2B receptors and that 8-phenylxanthines that block human A2B adenosine receptors-are-useful in the treatment or prevention of disease states induced by activation of the A2B receptor and mast cell activation. Also, applicant has discovered that BW-A493 is a potent and selective antagonist of human A2B adenosine receptors (Table 1).
A further aspect of the invention is the treatment of prevention of asthma, bronchoconstriction, allergic potentiation, inflammation or reperfusion injury in a human by administering to the human an amount of an adenosine A2B receptor specific inhibitor comprising an 8-phenylxanthine or 8-phenylxanthine derivative effective to antagonize activation of the adenosine receptor of the A2B subtype by adenosine.
The invention also relates to a method for treating a human suffering from an autoimmune disease selected from the group consisting of Addison's disease (adrenal), autoimmune hemolytic anemia (red cells), Crohn's disease (gut), Goodpasture's syndrome (kidney and lungs), Grave's disease (thyroid), Hashimoto's thyroiditis (thyroid), idiopathic thrombocytopinic purpura (platelets), insulin-dependent diabetes militus (pancreatic beta cells), multiple sclerosis (brain and spinal cord), myasthenia gravis (nerve/muscle synapses), Pemphigus vulgaris (skin), pernicious anemia (gastric parietal cells), post-streptococcal glomerulonephritis (kidney), psoriasis (skin), rheumatoid arthritis'(connective tissue), scleroderma (heart, lung, gut, kidney), Sjogren's syndrome (liver, kidney, brain, thyroid, salivary gland), spontaneous infertility (sperm), and systemic lupus erythematosus (DNA, platelets, other tissues), which comprises administering to the human an effective amount of a selective A2B adenosine receptor antagonist comprising a xanthine or a xanthine derivative having a meta-substituted acidic aryl at the 8 position to inhibit mast cell degranulation.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1A and 1B illustrate that 5-N-ethylcarboxamidoadenosine (NECA) but not N 6 -(2-iodo)benzyl-5'-N-methylcarboxamidoadenosine (IB-MECA) stimulates human mast cells to mobilize calcium and to accumulate cyclic AMP.
FIG. 2A is an illustration of competitive binding studies of theophylline and enprofylline for the rhA2B adenosine receptor.
FIG. 2B is an illustration of competitive binding studies of theophylline and enprofylline for the rhA3 adenosine receptor.
FIGS. 3A and 3B illustrate the functional effects of theophylline and enprofylline in modulating cAMP in HEK 293 cells transfected with A2B adenosine receptor cells.
FIG. 4 is an illustration of the functional effects of theophylline and enprofylline in modulating cAMPin HEK 293 cells transfected with A3 adenosine receptor cells.
FIG. 5 is an illustration of the effects of theophylline and enprofylline on inositol-(1,4,5)-trisphosphate (IP 3 ) generation.
FIG. 6 is an illustration of the effects of theophylline and enprofylline on intracellular calcium mobilization.
FIG. 7 is an illustration of structures to further identify compounds described in this application.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a method for achieving a blockade of the mast cell degradation response induced through adenosine activation of the A2B adenosine receptor subtype. The method comprises contacting cells bearing the A2B receptor with an amount of an adenosine A2B receptor subtype specific inhibitor comprising an 8-phenyl or 8-cycloalkyl substituted xanthine or 8-substituted xanthine derivative effective to block activation of the receptor by adenosine.
Further, the invention relates to a method for treating or preventing myocardial ischemia, inflammation, brain arteriole diameter constriction, and/or the release of allergic mediators. The method comprises using a specific inhibitor of the A2B adenosine receptor subtype to inhibit effects induced by adenosine mediated mast cell degranulation by contacting A2B receptor bearing mast cells with an amount of a selective A2B inhibitor comprising an 8-phenyl or 8-cycloalkyl substituted xanthine or 8- substituted xanthine derivative effective to prevent mast cell degranulation.
Further the invention relates to a method for preventing or treating asthma, bronchoconstriction, allergic potentiation, inflammation or reperfilsion injury in a human. The method comprises administering to the human an effective amount of an adenosine A2B receptor specific inhibitor comprising an 8-phenyl or 8-cycloalkyl substituted xanthine or substituted xanthine derivative to antagonize activation of the adenosine receptor of the A2B subtype by adenosine.
Further, the invention relates to a method for preventing mast cell degranulation in a human. The method comprises administering to the human an amount of an adenosine A2B receptor specific inhibitor comprising an 8-substituted xanthine or 8- substituted xanthine derivative effective to antagonize activation of the adenosine receptor of the A2B subtype by adenosine.
Further, the invention relates to a method for treating an autoimmune disease selected from the group consisting of Addison's disease (adrenal), autoimmune hemolytic anemia (red cells), Crohn's disease (gut), Goodpasture's syndrome (kidney and lungs), Grave's disease (thyroid), Hashimoto's thyroiditis (thyroid), idiopathic thrombocytopinic purpura (platelets), Insulin-dependent diabetes militus (pancreatic beta cells), multiple sclerosis (brain and spinal cord), myasthenia gravis (nerve/muscle synapses), Pemphigus vulgaris (skin), pernicious anemia (gastric parietal cells), poststreptococcal glomerulonephritis (kidney), psoriasis (skin), rheumatoid arthritis'(connective tissue), scleroderma (heart, lung, gut, kidney), Sjogren's syndrome (liver, kidney, brain, thyroid, salivary gland), spontaneous infertility (sperm), and systemic lupus erythematosus (DNA, platelets, other tissues). The method comprises administration to a patient in need thereof of an effective amount of a selective A2B adenosine receptor antagonist comprising an 8- substituted xanthine or 8-substituted xanthine derivative to inhibit mast cell degranulation.
Further, the invention relates to a method for the treatment or prevention of disease states mediated through activation of the A2B subtype of the adenosine receptor on mast cells by prevention of mast cell degranulation through blockade of the A2B subtype of the adenosine receptor. The method comprises contacting mast cells with an inhibitory effective amount of an adenosine A2B receptor specific inhibitor comprising an 8- substituted xanthine or 8-substituted xanthine derivative specific for the A2B receptor subtype. The disease state includes asthma, myocardial reperfusion injury, allergic reactions including but not limited to rhinitis, poison ivy induced responses, urticaria, scleroderma, arthritis, and inflammatory bowel diseases.
A preferred 8-phenyl or 8-cycloalkyl substituted xantine or 8- substituted xanthine derivative has the formula: ##STR1## wherein R 1 is a hydrogen, an alkyl, a cycloalkyl, or an aryl; R 2 is a cycloalkyl or an aryl; and R 3 is a phenyl, substituted phenyl, cycloalkyl or substituted cycloalkyl. Specifically, when the 8-phenyl substituted xanthine or 8-phenyl substituted xanthine derivative is BW 493, ##STR2## and R 3 is ##STR3## When enprofylline is selected as the 8-phenyl substituted xanthine or 8-phenyl substituted xanthine derivative, R 1 =H, R 2 =C--C--C and R 3 =H.
Preferably the 8-phenyl or 8-cycloalkyl substituted xanthine or 8-substituted xanthine derivative has an affinity for the A2B subtype of the human adenosine receptor which is at least one order of magnitude greater than the affinity for either the A1 or A2 subtypes of the human adenosine receptor effective to antagonize activation of the adenosine receptor of the A2B subtype by adenosine when: ##STR4## More preferably, the 8-phenyl or 8-cycloalkyl substituted xanthine or 8-substituted xanthine derivative has a pKi for the A2B subtype of 7 or greater and a pKi for other adenosine receptor subtypes of 6 or less. Most preferably, the 8-phenyl or 8-cycloalkyl substituted xanthine or 8- substituted xanthine derivative is BW 493.
The following examples are provided to further define but not to limit the invention defined by the foregoing description and the claims which follow:
EXAMPLE 1
Functional Responses Of Human HMC-1 Mast Cells to NECA and IB-MECA
In tests as described in "Canine Mast Cell Adenosine Receptors: Cloning and Expression of the A3 Receptor and Evidence that Degranulation is Mediated by the A2B Receptor," Molecular Pharmacology, 52:1-15 (1997) to, Auchampapch et al., that reference being incorporated herein by reference, intact cells were treated with the A3-selective agonist IB-MECA and the nonselective agonist NECA.
FIGS. 1A and 1B show (A) Intracellular Ca 2+ accumulation measured in cells pretreated with the Ca 2+ -sensitive fluorescent reporter, FURA and (B) Cyclic AMP accumulation measured by radioimmunoassay. The results are typical of triplicate experiments. FIGS. 1A and 1B show that NECA, but not IB-MECA stimulates canine mast cells to mobilize calcium and to accumulate cyclic AMP. Agonists of A1 or A2A adenosine receptors do not have these effects. These data suggest that canine mast cells are activated by A2B rather than A3 adenosine receptors.
EXAMPLE 2
Binding of Enprophylline and Theophylline to Human Adenosine Receptors
The xanthines theophylline and enprofylline (See FIG. 7) are used clinically to treat asthma. However, enprofylline has been reported to bind weakly to adenosine receptors. Lunell et al., Effects of enprofylline, a xanthine lacking adenosine receptor antagonism, in patients with chronic obstructive lung disease, European Journal of Clinical Pharmacoloy 22:395-402 (1982).
Competition for specific radioligand binding of enprophylline and theophylline was measured on membranes prepared from cells expressing (A) recombinant human A2B adenosine receptors and (B) recombinant human A3 adenosine receptors as described in "Molecular Characterization of Recombinant Human Adenosine Receptors," Drug Development Research, 39:243-252 (1996) to Robeva et al., which is incorporated herein by reference.
As shown in FIGS. 2A and 2B, each point is the mean standard error of the mean (SEM) of triplicate determinations. The results are typical of three experiments. In the competition binding studies shown, theophylline and enprofylline compete for [ 3 H]1,3-diethyl-8-phenylxanthine ([ 3 H]DPX, 5 nM) binding to rhA2B adenosine receptors as shown in FIG. 2A. Both antagonist have higher affinities for human A2B adenosine receptors than for human A3 adenosine receptors (see FIG. 2B) with A2B K i values of 7.1 μM and 5.6 μM for theophylline and enprofylline, respectively.
EXAMPLE 3
Functional Antagonism by Enprofylline and Theophylline of Recombinant A2B Receptor-Mediated Cyclic AMP Accumulation
Agonists were used to modulate cAMP in HEK 293 cells stably transfected the rhA2B adenosine receptors or rhA3 adenosine receptors. This procedure is also described in the Auchampach et al. publication.
FIGS. 3A and 3B shows antagonists of NECA-stimulated cyclic AMP accumulation in transfected HEK-293 cells by (A) theophylline and (B) enprofylline. Line (C) is Schild analysis of the data shown in (A) and (B).
NECA or IB-MECA produced a dose-dependent functional response in cells expressing rhA2B adenosine receptors or rhA3 adenosine receptors respectively. The addition of theophylline or enprofylline produced a progressive shift to the right in the potency of NECA in these functional assays. Schild analyses of the data gave A2B K i values of 16.7 μM for theophylline and 17.1 μM for enprofylline.
For rhA3 adenosine receptors, the A3-selective agonist, IB-NECA was used to generate dose-response curves for inhibition of isoproferenol-stimulated cyclic accumulation in the absence or presence of different concentrations of theophylline or enprofylline. IB-MECA produced dose-dependent inhibition of cAMP accumulation stimulated by 1 μM isoproterenol; the maximum inhibition was 50-70%. The presence of increasing concentrations of either theophylline or enprofylline shifted the dose-response curve progressively to the right, with K i values of 27.6 μM for theophylline and 39.6 μM for enprofylline based on Schild analysis (see FIG. 4). For both A2B and A3 receptors, the K i values of theophylline and enprofylline obtained from cAMP functions assays are in good agreement with the K i values calculated from radioligand competition binding assays.
EXAMPLE 4
Effect of Theophylline and Enprofylline of IP 3 Generation
On agonist stimulation, A2B adenosine receptors activate phospholipase C leading to inositol-(1,4,5)-trisphosphate (IP 3 ) formation, Characteristically, A2B-mediated effects are insensitive to blockage by pertussis toxin.
In this example, untransfected HEK-293 (HEK 293) or cells transfected with recombinant human A2B adenosine receptors were treated with the indicated compounds. IP 3 was measured in cells pretreated with [ 3 H]inositol. This procedure is also described in the Auchampach et al. publication.
As shown in FIG. 5, NECA at 10 μM produced a 3.5 fold increase in IP 3 formation in rhA2B adenosine receptor transfected HEK 293 cells. At 250 μM, both theophylline and enprofylline were able to block the increase in IP 3 produced by 10 μM NECA in human A2B adenosine receptor transfected HEK 293 cells. Neither antagonist affected basal levels of inositol phosphates.
EXAMPLE 5
Effect of Theophylline and Enprofylline on the Ca 2+ Mobilization
The activation of the phospholipase C pathway leads to intracellular calcium mobilization. NECA produces a dose-dependent increase in intracellular Ca 2+ content in human A2B adenosine receptor transfected cells.
HEK-293 cells transfected with recombinant human A2B adenosine receptors were treated with the compounds indicated in FIG. 6. Calcium mobilization was measured in cells preloaded with FURA. Again, this procedure is also described in the Auchampach et al. publication.
As shown in FIG. 6, theophylline or enprofylline at 100 μM totally blocks the Ca 2+ response induced by 1 μM NECA.
EXAMPLE 6
Screening to Identify Selective Antagonists of Recombinant Human A2B Adenosine Receptors
A series of compounds was screened to identify potent A2B selective antagonists. This was done in competition binding assays using recombinant human A1, A2A, A2B or A3 adenosine receptors, similar to that illustrated in FIGS. 2A and 2B.
TABLE 1______________________________________The following K.sub.i values (nM) show that BW-A493 is a potent and selective A2B antagonist: BW-A493 Enprofylline______________________________________A1 4980 ± 553 156,000 ± 109,000 A2A 1518 ± 797 32,000 ± 7,800 A2B 198 ± 52 7,000 ± 1,850 A3 922 ± 399 65,000 ± 12,100______________________________________
One should note that the lowest K i value corresponds to the highest affinity; BW-A493 and enprofylline are A2B selective. As shown above, BW-A493 is approximately 35 times more potent than enprofylline as an antagonist of human A2B adenosine receptors.
Examples 1 to 5 indicate that known anti-inflammatory compounds are antagonists of A2B. The Examples establish that enprofylline, a compound used to treat asthma, but which previously had an unknown mechanism of action, blocks human A2B adenosine receptors and that human HMC-1 mast cells have A2B receptors indicating that antagonists of A2B as well as A3 adenosine receptors have anti-inflammatory action. Example 6 identifies BW-A493 as a selective antagonist of human A2B adenosine receptors.
Enprofylline can be used in moderately severe asthmatic patients. Typically, a bolus injection of 1.5 mg/kg enprofylline is given over 20 minutes and then a maintenance infusion of 0.4 mg/kg/h is given for up to 24 hours.
While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the variations, adaptations, modifications as come within the scope of the following claims and their equivalents.
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The invention concerns the use of 8-phenylxanthines, 8-cyloalkylxanthines or 8- substituted xanthine derivatives to specifically modulate the physiologic role of the A2B adenosine receptor.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority to provisional patent application 61/034,450 which was filed on Jul. 29, 2008, and is hereby expressly incorporated by reference.
BACKGROUND
[0002] Dr. Ignacio Ponseti is an internationally famous physician and surgeon specializing in the treatment and management of a childhood deformity commonly know as a club foot. Dr. Ponseti has for many decades promoted the use of a foot and ankle abduction device, or orthosis, that is used to correct and prevent relapses of the club foot deformity. These abduction devices typically consist of a rigid bar connected between shoes worn by the child which bar separates the feet of the child and holds the feet in an outward rotation or abduction. Typically, if the condition is diagnosed early enough, this device is worn full-time for a period of months, but during the period of treatment, the angle of outward rotation is periodically adjusted.
[0003] The Ponseti technique, as it has become known throughout the world, has been highly successful in treating club feet without the necessity of corrective surgery. Many devices have been designed and used for many, many years in applying the Ponseti technique. Currently used devices that apply the Ponseti technique are shown in U.S. Pat. No. 7,267,657. In this patent, there are disclosed improvements in such devices which provide for quick release of the shoes from the abduction bar and which also provide a method for varying the abduction angle and locking it in place at a selected angle. Devices of this type have been extremely successful and are widely used by those who treat patients using the Ponseti technique. However, the devices allow the user limited movement in the horizontal and vertical planes. Typically the user must pivot on his or her feet to move forward or backward. Additionally, the rigid current foot abduction apparatuses make any movement difficult for the user. There is; therefore, a need for an improved orthosis that allows greater mobility in the horizontal and vertical planes for use in treating club feet and other gait issues using the Ponseti technique.
SUMMARY OF THE INVENTION
[0004] The improved abduction apparatus system for correcting gait issues allows the user, typically a patient with a club foot, greater mobility while wearing the brace. The at least two pivot points allow a greater range of movement in at least one of the horizontal and vertical planes. Several embodiments of the invention are possible to obtain the preferred result.
[0005] A first embodiment consists of a metal or plastic bar with connection means on the far sides of the bar. One coupling device is attached to each side of the metal bar and the coupling devices are pivotable in a vertical plane. Each coupling device is then attached to either a left footplate or a right footplate. The footplates are attached to the coupling device such that the angle of outward rotation may be periodically adjusted. The selected angle of outward rotation may be maintained once the footplate is firmly secured to the coupling device. The user of the foot abduction apparatus can lift up each foot in the vertical plane via the pivot point while maintaining the corrective angle of outward rotation. The user may achieve horizontal movement by manipulating the device in a “waddling” motion. The same embodiment also allows a user to more easily crawl if the user is unable to walk.
[0006] A second embodiment of the invention allows a user to manipulate the device in a horizontal plane. This embodiment consists of two rigid bars connected to coupling devices on both ends of the bars. The coupling device maintains the rigid members in parallel. Also attached to the coupling device are footplates which can receive a shoe. The rigid bars are attached to the coupling devices such that they are selectively pivotable at the point of connection. A user of the second embodiment attaches the shoes to the footplates. The user then manipulates the device by pushing one foot forward. The force causes the rigid bars to pivot allowing horizontal movement of the user's feet.
[0007] A third embodiment of the invention is similar to the first two and contains at least a second pivot point and an additional metal or plastic bar. The two bars are substantially in parallel and contain a means for attachment at each end. A connecting device is attached to each side of the bars. The bars may pivot about the coupling device in a horizontal direction while maintaining the bars in parallel. Each coupling device contains a third pivot point which may be attached to either a left footplate or a right footplate. The third pivot point allows movement in the vertical plane. Again the footplate contains a means to adjust and maintain the angle of outward rotation. A left shoe may then be attached to the left footplate and a right shoe attached to the right footplate. The user of this embodiment of the invention may simultaneously manipulate the device in a vertical and horizontal direction without the “waddling” motion associated with the first embodiment.
[0008] The coupling devices of the embodiments are preferably a one-piece plastic made from rotomolding or injection molding techniques. The attachments means may be of any of several know techniques for attachment but preferably the means is a standard screw. Additionally, the preferred embodiment contains a metal or rigid plastic base with means for attachment to the left or right footplate. The base is contained within a soft substance on all sides. The soft substance is preferably silicone rubber which allows greater comfort and reduces the potential of an allergic reaction to the wearer of the invention as it cushions the foot.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 is a perspective view generally from the top-rear of the invention showing the single bar embodiment;
[0010] FIG. 2 is a perspective view of possible connecting devices for the invention;
[0011] FIG. 3 is a top view of the double bar design without vertical movement;
[0012] FIG. 4 is a side view of the double bar design without vertical movement;
[0013] FIG. 5 is a top view of the double bar design with vertical movement;
[0014] FIG. 6 is a rear view of the double bar design with vertical movement;
[0015] FIG. 7 is a right side view of the shoe;
[0016] FIG. 8 is a cross-sectional view of the shoe taken at line 8 ;
[0017] FIG. 9 is a bottom perspective of the boot in which the rigid sole is inserted on the top of the silicone rubber;
[0018] FIG. 10 is a right side view of the shoe;
[0019] FIG. 11 is a cross-sectional view of the shoe taken at line 11 ; and
[0020] FIG. 12 is a bottom perspective of the boot in which the rigid sole is placed within the silicone.
DETAILED DESCRIPTION
[0021] Now referring to the drawings, FIG. 1 shows a single bar foot abduction system 2 comprising a rigid member 4 , a first coupling device 6 , a left shoe receiving member 8 , a left plate 12 , a second coupling device 14 , a right shoe receiving member 16 and a right plate 18 . The system 2 allows the user of the device to lift and lower each foot independently through a first pivot point 20 and a second pivot point 22 .
[0022] The rigid member 4 may be comprised of a left rigid member 24 and a right rigid member 26 . The left rigid member 24 and the right rigid member 26 substantially overlap one another and are housed in the bar adjuster device (not shown). The bar adjuster device allows the length of the overlap of the left rigid member 24 and the right rigid member 26 to be varied; thus, controlling the overall length of the rigid member 4 . The greater the overlap of the left rigid member 24 and the right rigid member 26 , the shorter the overall length of the rigid member 4 .
[0023] The rigid member 4 further comprises a first end 28 and a second end 30 . The first end 28 may be selectively attachable to the first coupling device 6 by several known methods; however, the preferred mode of attachment is by a nut and bolt (not shown in order to demonstrate shape of coupling device 6 ). The first coupling device 6 may then be selectively attachable to the left plate 12 by the preferred means of a nut 9 and bolt 11 . The left plate 12 may then be attached to the left receiving shoe member 8 . The angle of the left shoe receiving member 8 in relation to the rigid member 4 may be adjusted by loosening the attachment mechanism securing the first coupling device 6 to the left plate 12 , manipulating the left plate 13 to the desired angle, and then retightening the attachment mechanism.
[0024] The second end 30 may be selectively attachable to the second coupling device 14 in the same manner as the first end 28 is attached to the first coupling device 6 . Similarly to the left plate 12 and its attachment to the first coupling device 6 and its attachment to the left shoe receiving member 8 , the right plate 18 is selectively attachable to the second coupling device 14 and the angle between the right shoe receiving member 16 in relation to the rigid member 4 may be adjusted. Referring additionally to FIG. 2 , the first coupling device 6 and the second coupling device 14 may be of a variety of configurations that allow movement in a vertical plane.
[0025] After the angle between the left shoe receiving member 8 and the rigid member 4 , and the angle between the right shoe receiving member 16 and the rigid member 4 are set; the user inserts his left shoe and right shoe (neither shown) into the appropriate shoe receiving member 8 or 16 . Once inserted, the shoes are held in place by any of several known attachment means including a snap-on means. As the user elevates or lowers his right foot, the rigid member 4 pivots about a first pivot point 20 located at the point where the rigid member 4 and the first coupling device 6 selectively attach. As the user elevates or lowers his left foot, the rigid member 4 pivots about a second pivot point 22 located at the point where the rigid member 4 and the second coupling device 14 selectively attach. The user may move in a horizontal direction by pivoting on the bottom of the left plate 12 or the right plate 18 in a shuffling type motion.
[0026] Now referring to FIG. 3 and FIG. 4 , a second embodiment of a foot abduction system 202 is detailed. The system 202 comprises a first rigid member 204 , a second rigid member 206 , a first coupling device 208 , a second coupling device 210 , a left plate 212 , a right plate 214 , a left shoe receiving member 216 , and a right shoe receiving member 218 . The first rigid member 204 and the second rigid member 206 lie within the same horizontal plane and are spaced such that they are substantially parallel with one another. Each rigid member 204 , 206 are preferably made of metal or a rigid plastic and further comprise a first end 220 , 222 respectively and a second end 224 , 226 respectively. The first ends 220 , 222 are selectively attachable to the first coupling device 208 , while the second ends 224 and 226 are selectively attachable to the second coupling device 210 .
[0027] The first coupling device 208 and the second coupling device 210 are preferably made of plastic and each further comprise three segments 230 , 231 , 232 . The coupling devices are preferably made by rotomolding or injection molding techniques. The segment 232 is preferably substantially perpendicular to segments 230 , 231 . The segment 230 of the first coupling device 208 is selectively attachable to the first end 220 of the first rigid member 204 ; and the segment 230 of the second coupling device 210 is selectively attachable to the second end 224 of the first rigid member 204 . The segment 231 of the first coupling device 208 is selectively attachable to the first end 222 of the second rigid member 206 ; and the segment 231 of the second coupling device 210 is selectively attachable to the second end 226 of the second rigid member 206 .
[0028] Again referring to FIG. 3 and FIG. 4 , the segment 232 of the first coupling device 208 is selectively attachable to the left plate 212 . The means for attachment is preferably two standard screws. The segment 232 of the second coupling device 210 is selectively attachable to the right plate 214 , again with a two screw attachment. Once each of the segments 230 , 231 , 232 of each coupling device 208 , 210 are selectively attached, the preferred embodiment has the rigid members 204 , 206 , the left plate 212 and the right plate 214 in a position such that they remain in a fixed angle position. The first coupling device 208 and the second coupling device 210 may be located on an underside 250 of the rigid members 204 , 206 or on an upper surface 252 of the rigid members 204 , 206 , although the preferred embodiment is on the underside 250 of the rigid member.
[0029] The left shoe receiving member 216 may be attached to the left plate 212 by a variety of known techniques including a screw. Similarly, the right shoe receiving member 218 is attached to the right plate 214 . The left shoe receiving member 216 and the left plate 212 define an angle which may be adjusted and selectively fixed. The right shoe receiving member 218 and the right plate 214 define an angle which may be adjusted and selectively fixed. A shoe (not shown) may be of any of those well known in the art which have the capability of attaching to the left shoe receiving member 216 or right shoe receiving member 218 . Additionally, the left plate 212 is preferably angled downward such that the bottom of the left shoe receiving member 218 is the same elevation as the bottom of the first coupling device 208 when the left plate 212 is attached to the left shoe receiving member 216 and the first coupling device 208 . Similarly, the right plate 214 is preferably angled such that the bottom of the right shoe receiving member 218 is the same elevation as the bottom of the second coupling device 210 when the right plate 214 is attached to the right shoe receiving member 218 and the second coupling device 210 .
[0030] The points at which the rigid members 204 , 206 attach to the first coupling device 208 and second coupling device 210 define pivot points 260 . The rigid members 204 , 206 are pivotable upon the first coupling device 208 and the second coupling device 210 . A user can then manipulate the device 202 in a first plane which would typically be the horizontal plane. As the user moves the right shoe receiving member 218 or the left shoe receiving member 216 in the horizontal plane, the rigid members 204 , 206 pivot allowing horizontal movement. As the rigid members 204 , 206 are substantially in parallel and there are at least four pivot points 260 , the rigid members 204 , 206 remain substantially in parallel with one another during operation. The horizontal movement is depicted by the first position of the device 202 evidenced by the dashed lines and the second position indicated by solid lines. Additionally, the fixed positions of the left plate 212 and the right plate 214 ensure the angle defined by the left plate 212 and the left shoe receiving member 216 remain constant as well as the angle defined by the right plate 214 and the right shoe receiving member 218 remain constant during operation of the system 202 .
[0031] Now referring to FIG. 5 and FIG. 6 , a third embodiment of a foot abduction system 302 is detailed. The system 302 comprises a first rigid member 304 , a second rigid member 306 , a first coupling device 308 , a second coupling device 310 , a left plate 312 , a right plate 314 , a left shoe receiving member 316 , and a right shoe receiving member 318 . The first rigid member 304 and the second rigid member 306 lie within the same horizontal plane and are spaced such that they are substantially parallel with one another. Each rigid member 304 , 306 are preferably made of metal or a rigid plastic and further comprise a first end 320 , 322 respectively and a second end 324 , 326 respectively. The first ends 320 , 322 are selectively attachable to the first coupling device 308 , while the second ends 324 and 326 are selectively attachable to the second coupling device 310 .
[0032] The first coupling device 308 and the second coupling device 310 are preferably made of plastic or metal alloy and each further comprise three segments 330 , 331 , 332 . The coupling devices are preferably made by machining or injection molding techniques. The segment 332 is preferably substantially perpendicular to segments 330 , 331 . The segment 330 of the first coupling device 308 is selectively attachable to the first end 320 of the first rigid member 304 ; and the segment 330 of the second coupling device 310 is selectively attachable to the second end 324 of the first rigid member 304 . The segment 331 of the first coupling device 308 is selectively attachable to the first end 322 of the second rigid member 306 ; and the segment 331 of the second coupling device 310 is selectively attachable to the second end 326 of the second rigid member 306 .
[0033] Again referring to FIG. 5 and FIG. 6 , the segment 332 of the first coupling device 308 is selectively attachable to the left plate 312 . The segment 332 further comprises a slot 340 . The slot 340 is of a size and shape which allows left plate 312 to slide within the confines of the slot 340 . The segment 332 of the second coupling device 310 is selectively attachable to the right plate 314 . The segment 332 further comprises a slot 342 which is a size and shape which allow right plate 314 to slide within the confines of the slot 342 . The attachment means for connecting left plate 312 to the first coupling device 308 or the right plate 314 to the second coupling device 310 is preferably a bolt 350 and a nut 352 or a screw pin (not shown). Once each of the segments 330 , 331 , 332 of each coupling device 308 , 310 are selectively attached the preferred embodiment has the rigid members 304 , 306 , the left plate 312 and the right plate 314 in a position such that they remain in a fixed position to one another. The first coupling device 308 and the second coupling device 310 may be located on an underside 370 of the rigid members 304 , 306 or on an upper surface 372 of the rigid members 304 , 306 , although the preferred embodiment has the coupling devices on the upper surface 372 of the rigid members 304 , 306 .
[0034] The left shoe receiving member 316 may be attached to the left plate 312 by a variety of known techniques including a screw. Similarly, the right shoe receiving member 318 is attached to the right plate 314 . The left shoe receiving member 316 and the left plate 312 define an angle which may be adjusted and selectively fixed. The right shoe receiving member 318 and the right plate 314 define an angle which may be adjusted and selectively fixed. A shoe (not shown) may be of any of those well known in the art which have the capability of attaching to the left shoe receiving member 316 or right shoe receiving member 318 . Additionally, the left plate 312 and the right plate 314 are preferably angled downward such that the bottom of the left shoe receiving member 316 and the right shoe receiving member 318 are the lowest elevation points of the device 302 .
[0035] The points at which the rigid members 304 , 306 attach to the first coupling device and second coupling device define pivot points 380 . The rigid members 304 , 306 are pivotable upon the first coupling device 308 and 310 . A user can then manipulate the device 302 in a first plane which would typically be the horizontal plane. As the user moves the right shoe receiving member 318 or the left shoe receiving member 316 in the horizontal plane, the rigid members 304 , 306 pivot allowing horizontal movement. As the rigid members 304 , 306 are substantially in parallel and there are at least four pivot points 360 , the rigid members 304 , 306 remain substantially in parallel with one another during operation. Additionally, the fixed positions of the left plate 312 and the right plate 314 ensure the angle defined by the left plate 312 and the left shoe receiving member 316 remain constant as well as the angle defined by the right plate 314 and the right shoe receiving member 318 remain constant. The dashed lines of FIG. 5 indicate a first horizontal position while the solid lines indicate a second position.
[0036] In addition to movement in a horizontal plane, unique pivot points 362 , 364 allow vertical movement as well. As a user lifts the left shoe receiving member 316 , the right plate 314 pivots about pivot point 362 allowing vertical movement. Similarly, when the user lifts the right shoe receiving member 318 , the left plate 312 pivots about pivot point 364 which allows vertical movement. The vertical movement is depicted in FIG. 6 in which a first position is shown by solid lines and a second position is shown by dashed lines. A user may manipulate the device in both the horizontal and vertical planes simultaneously.
[0037] Now referring to FIG. 7 , FIG. 8 and FIG. 9 , a boot 400 which may be attached to the foot abduction apparatuses 2 , 202 , 302 detailed above is shown. The boot 400 comprises a flexible portion 402 and a rigid sole 404 . Specifically referring to FIG. 8 , a cross-sectional portion of the boot 400 is shown. A cavity 406 is formed within the flexible portion 402 . The shape of the cavity 406 corresponds to the shape of the rigid sole 404 . The rigid sole 404 is inserted into the cavity 406 . Once in place, the flexible portion 402 surrounds a bottom surface 408 of the rigid sole 404 . The flexible portion 402 is preferably made of silicone which possesses a cushioning characteristic. The cushioning characteristic allows the user of the boot 400 more comfort and greater shock absorption.
[0038] Again referring to FIG. 7 , the rigid sole 404 is substantially planar. Once the rigid sole 404 is inserted into the cavity 406 , attachment means 410 may be used to connect the boot 400 to the shoe receiving members described in the embodiments described above. Preferably, the attachment means 410 are standard screws that may be counter sunk in the rigid sole 404 . Any number of attachment means 410 may be utilized, but the preferred embodiment has three attachment means 410 .
[0039] The flexible portion 402 comprises a heel extension 412 which is at a substantial perpendicular in relation to the rigid sole 404 . The heel extension 412 is shaped such that it conforms to a user's bank ankle, heel and lower back calf. The heel extension 412 also allows straps (not shown) to be connected to stabilize and support a user's foot and ankle. A heel hole 414 in the flexible portion 404 allows a doctor or parent to observe the placement of a user's ankle and heel to verify the correct positioning of the user's foot. Additionally, the flexible portion 402 comprises two flaps 414 which substantially cover the user's foot. The flaps 414 also allow straps to span the width of the shoe while protecting the user from the friction created by such straps.
[0040] Now referring to FIG. 10 , FIG. 11 and FIG. 12 another embodiment of a shoe 500 for a foot abduction apparatus is detailed. The boot 500 comprises a flexible portion 502 and a rigid sole 504 . Specifically referring to FIG. 8 , a cross-sectional portion of the boot 500 is shown. A cavity 506 is formed within the flexible portion 502 . The shape of the cavity 506 corresponds to the shape of the rigid sole 504 . The rigid sole 504 is inserted into the cavity 506 . The flexible portion 502 further comprises an edge 522 which is flexible. The cavity 506 and the edge 522 may be manipulated in such a way that the rigid sole 504 can be placed in the cavity 506 . The edge 522 maintains the rigid sole 504 in the flexible portion 502 . The flexible portion 502 is preferably made of silicone which possesses a cushioning characteristic. The cushioning characteristic allows the user of the boot 500 more comfort and greater shock absorption.
[0041] Again referring to FIG. 10 , the rigid sole 504 is substantially planar. Once the rigid sole 504 is inserted into the cavity 506 , attachment means 510 may be used to connect the boot 500 to the shoe receiving members described in the embodiments described above. Preferably, the attachment means 510 are standard screws that may be counter sunk in the rigid sole 504 . Any number of attachment means 510 may be utilized, but the preferred embodiment has three attachment means 510 .
[0042] The flexible portion 504 comprises a heel extension 512 which is at a substantial perpendicular in relation to the rigid sole 504 . The heel extension 512 is shaped such that it conforms to a user's bank ankle, heel and lower back calf. The heel extension 512 also allows straps (not shown) to be connected to stabilize and support a user's foot and ankle. A heel hole 514 in the flexible portion 504 allows a doctor or parent to observe the placement of a user's ankle and heel to verify the correct positioning of the user's foot. Additionally, the flexible portion 502 comprises two flaps 514 which substantially cover the user's foot. The flaps 514 also allow straps to span the width of the shoe while protecting the user from the friction created by such straps.
[0043] Having thus described the invention in connection with the preferred embodiments thereof, it will be evident to those skilled in the art that various revisions can be made to the preferred embodiments described herein with out departing from the spirit and scope, of the invention. It is my intention, however, that all such revisions and modifications that are evident to those skilled in the art will be included with in the scope of the following claims.
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An improved foot abduction apparatus allowing movement in a horizontal and vertical plane. The embodiments allow a user to more easily manipulate the apparatus in one or both planes through the use of strategically placed pivot points. The device utilizes at least one rigid member attached to coupling devices which contain at least one pivot point. The specialized coupling devices may be selectively attached to shoe receiving member or plates which are well known in the art. Additionally the shoe receiving members are able to receive an improved shoe containing a sole member contained with a silicone boot.
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FIELD OF THE INVENTION
The invention relates to a new group of intrinsically electrically conductive alternating copolymers.
The invention also relates to a method of preparing such polymers.
The invention further relates to the application of such copolymers.
BACKGROUND OF THE INVENTION
Organic polymers are generally electrical insulators and therefore they are used as insulating material in electrical and electronic components. It is known that the polymer obtains electrically conductive properties if it contains a poly-conjugated bond system of, for example, double bonds, triple bonds, aromatic or hetero-aromatic rings. Said conductivity is termed intrinsic conductivity. Examples of such polymers are polyacetylene, polythiophene and polypyrrole. In general, the conductivity of these polymers is low because these polymers are semiconductors having a relatively large band gap of 1.5-4 eV. The conductivity can be increased by (electro)chemically oxidizing or reducing the polymer. Said oxidation or reduction treatment is termed doping. By oxidation p-type conductors are formed; by reduction n-type conductors are formed. In the oxidation or reduction treatment, charge carriers are formed on the polymer chains, which charges are compensated for by oppositely charged counterions. The expression "alternating copolymer" is to be understood to mean a polymer which is composed of two different monomers which are alternately incorporated in the polymer chain. In general, polymers are cheap and can be readily processed, so that it is attractive to use conductive polymers in conductive and semiconductive structures in (integrated) electronic circuits, electrodes for batteries, antistatic coatings and electromagnetic protective layers.
A conductive alternating copolymer is known from an article by J. Kowalik et al., Synthetic Metals, 41-43 (1991) 435-438. In said article, a description is given of a semiconductive alternating copolymer on the basis of benzoquinone and pyrrole which are reacted to form poly(2-pyrrolyl-1,4-benzoquinone). The polymer obtained is p-type semiconductive and "disordered" and is produced by oxidative polymerization of pyrrole and benzoquinone. The band gap of the polymer formed is not mentioned in said article.
A disadvantage of the known method is the presence of an oxidizing agent, namely p-chloranil, during the polymerization reaction, which causes the polymer obtained to be doped and p-type conductive. It is impossible or very difficult to obtain the undoped, i.e. intrinsically conductive polymer, from said polymer. A further disadvantage is the "disordered" polymer structure which adversely affects the conductivity.
SUMMARY OF THE INVENTION
It is an object of the invention to provide, inter alia, a new group of electrically (semi)conductive alternating copolymers which have a band gap of maximally 1.5 eV and which can be obtained by means of a simple condensation polymerization (polycondensation) process which, in addition, initially yields an undoped copolymer.
A further object of the invention is to provide a method of preparing such copolymers without using an oxidizing agent.
According to the invention, this object is achieved by an alternating copolymer which is characterized in that the (semi)conductive copolymer can be obtained by reacting an acceptor monomer unit A having an unsaturated ring structure which is substituted with at least two double-bonded oxygen atoms and at least one hydroxy group, with a donor monomer unit D formed by a homo or heterocyclic aromatic compound comprising at least two active hydrogen atoms, a polycondensation reaction taking place in the presence of a solvent, thereby forming said alternating (semi)conductive copolymer. The term "acceptor" is to be understood to mean a unit which is capable of accepting a negative charge, and the term "donor" is to be understood to mean a unit which is capable of donating a negative charge. In this connection, the expression "active hydrogen atom" is to be understood to mean a hydrogen atom which can be readily separated from the monomer during the polycondensation reaction. Examples of donor monomer units D comprising at least two active hydrogen atoms are given below. By virtue of the polycondensation reaction a strictly alternating and ordered structure of acceptors and donors . . . ADADADA . . . is obtained, the choice of the monomer units A and D resulting in the formation of a poly-conjugated bond system. The polymers obtained have a small to very small band gap, which leads to a substantial increase of the intrinsic conductivity. Said intrinsic conductivity, i.e. conductivity obtained without doping, is obtained at room temperature.
Suitable acceptor monomer units A are squaric acid (3,4-dihydroxy-3-cyclobutene-1,2-dione; see formula I of FIG. 1), croconic acid (4,5-dihydroxy-4-cyclopentene-1,2,3-trione; see formula II of FIG. 1 ) and 5,6-dihydroxy-5-cyclohexene-1,2,3,4-tetraone (see formula III of FIG. 1).
Suitable donor monomer units D are compounds having (5-6-5) or (6-6-6) heterocyclic ring systems which are, for example, used in dye chemistry. A few examples thereof can be found in J. Fabian et al., "Light Absorption of Organic Colorants", Springer Verlag, Berlin, 1980, page 189. In said publication, these compounds are used to prepare biscyanine dyes. The general class of said suitable donor monomers D is shown in formulae IVA and IVB and VA, VB and VC in FIG. 2. In said Figure, X 1 represents an --NR-- group; X 2 represents an O--, S-- or Se atom or an --NR--, --CR═CH--, --CHR--CH 2 -- or --C(alkyl) 2 --group and X 3 represents a --CR═ or --N═group. In said FIG., X 1 may also represent an S- or O-atom, where X 2 represents an S-atom or a --CR═CH--group and X 3 has the above-mentioned meaning. R represents an H-atom or an alkyl or alkoxy substituent having 1-18 C-atoms. These compounds have an extensive, conjugated structure and two active hydrogen atoms which react, during the polycondensation reaction, with the OH groups of the acceptor monomer units, such as squaric acid. A few special examples are shown in formulae VI and VII of FIG. 3.
The substituents R 1 and R 2 of the benzodihydropyrrole in accordance with formula VI of FIG. 3 denote a C 1 -C 18 alkyl group such as a methyl, butyl, or octadecyl group. The substituents R 3 and R 4 of the benzodithiazole in accordance with formula VII of FIG. 3 also denote a C 1-C 18 alkyl group such as a methyl, n-heptyl, n-dodecyl or n-octadecyl group. By virtue of the choice of the substituents R, those skilled in the art can widely vary the properties of the final copolymer, such as solubility, processibility and conductivity. A special example of a compound in accordance with formula VC of FIG. 2 is neocuproine (formula VIII of FIG. 3).
Another suitable donor monomer D is azulene (an aromatic 5-7 ring) which may or may not be substituted with, for example, an alkyl group.
Other suitable donor monomers D are thiophene oligomers such as bithienyl and terthienyl (formula IX of FIG. 3). The thiophene ring may be substituted with a group R 5 which is a C 1 --C 18 alkyl group or a C 1 -C 18 alkoxy group.
Another class of suitable donor monomers D is that of the aromatic diamines. The general formula is shown in formula X of FIG. 4. In said formula, Ar denotes an aromatic core and R 6 and R 7 denote an H-atom or a C 1 -C 18 alkyl group. A few examples of the aromatic core Ar are shown in formulae XI, XII, and XIII of FIG. 4. In said formulae R 8 and R 9 represent an H-atom or a C 1 -C 18 alkyl group; X 1 represents a --N═ or --CR═group and X 2 and X 3 represent an --NH-- or an --N(alkyl)-group or an S--, Se-- or O-atom. The alkyl group contains 1-18 carbon atoms. R represents an H-atom or an alkyl or alkoxy substituent containing 1-18 carbon atoms. Representatives thereof are, for example, p-phenylene diamine, 3,6-diamino acridine (formula XIV of FIG. 4) and thionine (formula XV of FIG. 4). The polycondensation product of diamines and, for example, squaric acid surprisingly gives an electrically conductive polymer; after all, the polymer formed is a polyamide which, as a class, is known as an insulator.
An example of an alternating copolymer in accordance with the invention is the polycondensation product of squaric acid (formula I of FIG. 1) and the compound in accordance with formula VI of FIG. 3, where R 1 and R 2 represent an n-octadecyl group (n--C 18 H 37 ). The polymer formed has formula XVI of FIG. 5 as the repeating unit. The squaric acid unit is negatively charged and serves as the charge acceptor. The benzo(1,2,4,5)bis(N-octadecyl-2-methyl-3-bis-methyldihydropyrrole) unit is positively charged and serves as the charge donor. The alternating sequence of donor units and acceptor units in combination with an extensive conjugated system gives an intrinsically conductive "self-doped" polymer. The conductivity of the polymer in accordance with formula XVI of FIG. 5 is 3.10 -5 S/cm at room temperature and the band gap is 1.0 eV. The polymer can be readily dissolved in various solvents, such as chlorobenzene. Instead of octadecyl groups, other alkyl groups, such as the methyl, n-heptyl and n-dodecyl group, can be chosen for R 1 and R 2 . In general, the solubility of the polymer in solvents increases as the length of the alkyl groups increases.
Another example of an alternating copolymer in accordance with the invention is the polycondensation product of croconic acid (formula II of FIG. 1 ) and the compound in accordance with formula VII of FIG. 3, where R 3 and R 4 represent a methyl group. The polymer formed has formula XVII of FIG. 5 as the repetitive unit. The croconic acid unit is negatively charged and serves as the charge acceptor. The benzo(1,2,4,5)bis(N-methyl-2-methylthiazole) unit is positively charged and serves as the charge donor. This "self-doped" polymer in accordance with formula XVII of FIG. 5 has a conductivity of 10 -5 S/cm at room temperature and of 2.5·10 -3 S/cm at 250° C. The band gap of this polymer is 0.5 eV and, hence, this polymer has semiconductive properties. Instead of methyl groups, other alkyl groups such as the n-heptyl-, the n-dodecyl- and the n-octadecyl group can be chosen for R 3 and R 4 , .
In accordance with the invention, squaric acid, croconic acid and 5,6-dihydroxy-5-cyclohexene-1,2,3,4-tetraone (formula III of FIG. 1) can also be copolymerized using neocuproine (formula VIII of FIG. 3), terthienyl (formula IX of FIG. 3) and 3,6 diamino acridine (formula XIV of FIG. 4). Also in this case polycondensation leads to the formation of electrically conductive alternating copolymers, the compounds in accordance with formulae VIII, IX and XIV serving as the donor unit in the polymer chains.
The object of providing a method of preparing an alternating copolymer is achieved in accordance with the invention by a method which is characterized in that equimolar quantities of bifunctional acceptor monomer units A and bifunctional donor monomer units D are mixed in a solvent and polymerized by polycondensation, thereby forming the alternating copolymer comprising repeating unit AD. As the acceptor monomer unit A a compound having an unsaturated ring structure is used which is substituted with at least two double-bonded oxygen atoms and at least one hydroxy group. As the donor monomer unit D a homo or heterocyclic aromatic compound having at least two active hydrogen atoms is used. Examples of the monomer units A and D have been mentioned above. The polycondensation reaction is carried out in a suitable solvent such as propanol, butanol, toluene or dimethyl sulphoxide.
In general, the alternating copolymers manufactured in accordance with the above method exhibit great thermal stability. In most of said copolymers no change can be observed after heating to 300° C. in air. Consequently, the sensitivity to oxygen is very small.
The conductivity of the alternating copolymers in accordance with the invention can be increased by means of dopants which are known per se. Dopants which are suitable for obtaining p-type conduction are, for example, I 2 , AsF 5 , SbF 5 , HBF 4 , perchlorate, sulphonate, SO 3 and FeCl 3 . With certain copolymers p-doping causes the absorption band to pass to the infrared portion of the spectrum. As a result, said copolymers become colourless. As semiconductive polymers are available, circuits can be manufactured which can be used in electronic devices. Also conductor tracks can be manufactured from the alternating copolymer in accordance with the invention and form an alternative to metal conductor tracks.
The alternating copolymers in accordance with the invention can also be used in antistatic layers or electromagnetic protective layers by dissolving the copolymer in question in a suitable solvent and, subsequently, providing it on the desired substrate by means of, for example, spin coating.
It is noted that in German Patent Application DE-A-3246319, a description is given of the preparation of a copolymer of pyrrole and squaric acid by anodic oxidation of a solution of said compounds in the presence of a conducting salt. The polymer obtained is p-doped and also contains the anion of the conducting salt as the counterion. By anodic oxidation, squaric acid is incorporated in the polypyrrole formed. In this manner no strictly alternating copolymer is formed but a block copolymer which, in addition to a sequence of pyrrole units, comprises squaric acid units, or a homopolymer is formed which consists of pyrrole doped with squaric acid.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will be explained in greater detail by means of exemplary embodiments and drawings, in which
FIG. 1 represents formulae I, II and III of monomer units A which can be used as acceptor units in alternating copolymers in accordance with the invention,
FIG. 2 represents formulae IV and V of monomer units D which can be used as donor units in alternating copolymers in accordance with the invention,
FIG. 3 represents formulae VI, VII, VIII and IX of a few special examples of monomer units D which can be used as donor units in alternating copolymers in accordance with the invention,
FIG. 4 represents formulae X, XI, XII, XIII, XIV and XV of aromatic diamines which can be used as donor monomer units D in alternating copolymers in accordance with the invention, and
FIG. 5 represents formulae XVI and XVII of repetitive units of representatives of electrically conductive alternating copolymers in accordance with the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
A. Preparation of a compound in accordance with formula VI, where R 1 =R 2 =n--C 18 H 37
The compound in accordance with formula VI of FIG. 3 is prepared using a benzodipyrrole and stearyl-p-chlorobenzene sulphonate. Said dipyrrole is prepared according to the method described in Chemical Abstracts, Vol. 76, 1972, abstract No. 72434m, where it is indicated by formula III. The stearyl-p-chlorobenzene sulphonate is prepared from p-chlorobenzene sulphonchloride and stearyl alcohol. A mixture of 99 grams of stearyl-p-chlorobenzene sulphonate, 18 grams (75 mmol) of said dipyrrole and 100 ml of chlorobenzene are heated for three hours at a temperature of 120° C.-140° C. A quantity of 100 ml of chlorobenzene is added to the paste formed, thereby forming a suspension. Said suspension is heated at a temperature of 120° C.-130° C. for 16 hours and then cooled, after which 200 ml of toluene are added. The solid is filtrated by vacuum filtration after which said solid is stirred with 250 ml of toluene and then filtered again. The solid obtained is stirred with a mixture of 16 grams of NaOH, 500 ml of water and 500 ml of toluene for 5 hours after which all of the solid has dissolved. The liquid layers are separated and the organic layer is washed with 500 ml of water, after which said layer is dried over Na 2 SO 4 and evaporated. The residue is crystallized from 500 ml of 96% ethanol thereby forming 13.75 grams (18,48 mmol) of the desired product VI, i.e. benzodihydropyrrole, where R 1 =R 2 =n--C 18 H 37 .
B. Preparation of Alternating Copolymer in Accordance with Formula XVI
A mixture of the benzodihydropyrrole in accordance with formula VI (2.40 grams, 3.23 mmol) which is prepared according to the above method, squaric acid (370 mg, 3.25 mmol), 150 ml of n-butanol, 100 ml of toluene and 3 drops of quinoline is refluxed for 20 hours while removing water by means of azeotropic distillation. After the mixture has cooled, it is filtered off by suction, after which the solid is washed with toluene. After drying at 90° C. the alternating copolymer in accordance with formula XVI thus obtained weighs 1.76 grams.
The conductivity of said copolymer in accordance with formula XVII, measured on a film by means of a four-point measurement (also termed potential-probe measurement) is 3.10 -5 S/cm. The band gap is 1.0 eV and is determined by the threshold of the continuous optical absorption in the near infrared (see C. Kittel, Introduction to Solid State Physics, 5th ed., John Wiley and Sons, 1976, page 210). The absorption spectrum is measured on a thin layer of the polymer on a glass plate, said polymer being provided from a solution in chlorobenzene.
EXAMPLE 2
A. Preparation of the Salt of the Compound in Accordance with Formula VII, where R 3 =R 4 =CH 3 .
The salt of the compound in accordance with formula VII of FIG. 3 is prepared according to the method described in Chemical Abstracts, Vol. 71, 1969, abstract No. 81344f, where it is indicated by formula III (dithiazole salt of methyl sulphate). In this form the compound is used in the polycondensation reaction with croconic acid.
B. Preparation of Alternating Copolymer in Accordance with Formula XVII
A mixture of 324 mg (2.0 mmol) of croconic acid-monohydrate, 945 mg (2.0 mmol) of the above-mentioned dithiazole salt, 30 ml of n-propanol, 800 mg of pyridine and 30 ml of dimethyl sulphoxide are refluxed for 3 hours. After evaporation a residue is obtained which is further concentrated under a vacuum at 100° C. to remove dimethyl sulphoxide. The residue thus obtained is mixed with a mixture of 50 ml of water and 50 ml of toluene for half an hour. Filtration by suction gives 900 mg of the alternating copolymer in accordance with formula XVII of FIG. 5. The conductivity at room temperature is 10 -5 S/cm and 2.5·10 -3 S/cm at 250° C. The band gap is 0.5 eV.
EXAMPLE 3
Alternating copolymer of squaric acid and the compound in accordance with formula VI, where R 1 =R 2 =n--C 4 H 9 .
In a manner analogous to that described in Example 1, the compound is prepared in accordance with formula VI of FIG. 3, where R 1 =R 2 =n--C 4 H 9 (n-butyl). In a manner analogous to that of said exemplary embodiment, an alternating copolymer is obtained by using squaric acid. The conductivity of the copolymer formed is 5.10 -5 S/cm. After doping with iodine vapor at a temperature of 80° C. the conductivity is 10 -2 S/cm.
EXAMPLE 4 to 5
The Table below gives a summary of the results of alternating copolymers obtained from the indicated acceptor monomer units A and donor monomer units D. The conductivity is measured on the undoped copolymer at room temperature.
__________________________________________________________________________ conductivityExample No. monomer A monomer D copolymer (S/cm) band gap (eV)__________________________________________________________________________4 squaric acid VI where R.sub.1 = R.sub.2 = CH.sub.3 10.sup.-8 1.05 squaric acid VI where R.sub.1 = R.sub.2 = C.sub.4 H.sub.9 3.10.sup.-6 1.06 squaric acid VI where R.sub.1 = R.sub.2 = C.sub.18 H.sub.37 3.10.sup.-5 1.07 croconic acid VI where R.sub.1 = R.sub.2 = CH.sub.3 2.10.sup.-88 squaric acid VII where R.sub.3 = R.sub.4 = C.sub.4 H.sub.9 5.10.sup.-79 croconic acid VII where R.sub.3 = R.sub.4 = CH.sub.3 10.sup.-5 0.510 croconic acid VII where R.sub.3 = CH.sub.3 and 10.sup.-4 R.sub.4 = C.sub.12 H.sub.2511 squaric acid neocuproine (VIII) 2.10.sup.-712 squaric acid terthienyl (IX) with 2.10.sup.-6 R.sub.5 = H13 croconic acid p-phenylenediamine 10.sup.-814 squaric acid diamino acridine (XV) 10.sup.-415 squaric acid thionine (XVI) 2.10.sup.-6__________________________________________________________________________
Alternating copolymers in accordance with the invention are intrinsically electrically conductive and have a band gap of maximally 1.5 eV.
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Polycondensation of, for example, squaric acid with a benzodihydropyrrole, benzodithiazole, neocuproine, terthienyl or an aromatic diamine gives a semiconductive alternating copolymer having a small band gap. It is alternatively possible to use croconic acid or 5,6-dihydroxy-5-cyclohexene-1,2,3,4-tetraone instead of squaric acid. An alternating copolymer of croconic acid and a methyl-substituted benzodithiazole has the following repetititve unit: ##STR1##
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BACKGROUND OF THE INVENTION
(1) Field of the Invention
The present invention relates to a vehicle body reinforcement structure.
(2) Description of the Related Art
Conventionally, a vehicle body reinforcement structure disclosed in U.S. Pat. No. 5,127,704, for example, has been known.
This conventional vehicle body reinforcement structure includes a dash lower cross member provided at an engine room side of a dashboard lower panel and extends in the lateral direction of a vehicle. The dash lower cross member also has a tunnel reinforcement that extends from an intermediate portion thereof along an upper surface of a tunnel part of a floor panel in a longitudinal direction of the vehicle. A rear-most end of the tunnel reinforcement is connected to a cross member mounted on an upper surface of the floor panel and extends in the lateral direction of the vehicle. This structure is intended to increase the stiffness of the tunnel part of the floor panel and to absorb a load applied by a frontal impact against the vehicle.
In the above-described conventional structure, however, the stiffness of the vehicle body is enhanced only at a certain portion of the vehicle body, i.e. the floor panel.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide a vehicle body reinforcement structure that may increase the vehicle body stiffness.
To attain the above object, the present invention provides a vehicle body reinforcement structure comprising: a vehicle body front member provided in a front part of a vehicle; a vehicle body rear member provided in a rear part of the vehicle; and a reinforcing member that extends between the vehicle body front member and the vehicle body rear member in a longitudinal direction of the vehicle, at least a portion of the reinforcing member being totally spaced apart from a floor panel such that said reinforcing member does not make contact with the floor panel.
BRIEF DESCRIPTION OF DRAWINGS
The nature of this invention, as well as other subjects and advantages thereof, will be explained in the following with the reference to the accompanying drawings, in which like reference characters designate the same or similar parts throughout the figures and wherein:
FIG. 1 is a perspective view showing a front part of a vehicle compartment interior including a reinforcing member according to an embodiment of the present invention;
FIG. 2 is an enlarged view showing a front part of the reinforcing member;
FIG. 3 is an enlarged view showing a rear part of the reinforcing member;
FIG. 4 is a view taken along line IV-IV of FIG. 1;
FIG. 5 is a view showing an operation of a shift lever;
FIG. 6 is a view showing a state in which a rear video monitor is used; and
FIG. 7 is a view showing a state in which the rear video monitor is housed in the reinforcing member.
DETAILED DESCRIPTION OF THE INVENTION
An embodiment of the present invention will now be described in detail with reference to the drawings.
FIG. 1 shows a reinforcing member 1 interposed between a driver seat and a passenger seat, neither of which is illustrated, that extends in a longitudinal direction of a vehicle. A front end of the reinforcing member 1 is attached to vehicle body front members, i.e. an upper surface of a convex tunnel part 3 formed on a floor panel 2 , a lower surface of an instrument panel 4 , and a dashboard panel 5 that divides an engine room and a vehicle compartment.
The reinforcing member 1 also functions as an armrest for the driver seat or the passenger seat in order to give occupants some comfort. Accordingly, the reinforcing member 1 is disposed at a suitable height and spaced apart from the floor panel 2 so that the reinforcing member 1 can function as the armrest. More specifically, at least a portion of the reinforcing member 1 adjacent to the driver and passenger seats is totally spaced apart from the floor panel 2 such that the reinforcing member 1 does not make contact with the floor panel. Further, a cushioning member 6 is provided at a position where the reinforcing member 1 can be used as the armrest such that the cushioning member 6 covers the reinforcing member 1 as shown in FIG. 4 . The cushioning member 6 is also attached pivotally to the reinforcing member 1 such that the cushioning member 6 is capable of opening and closing a space mentioned later. A container box 20 , capable of storing small items a the like, is formed in the space.
Further, as shown in FIG. 4, the reinforcing member 1 has such a bifurcated structure that, along a longitudinal direction thereof, the reinforcing member 1 is bifurcated into right and left portions, which extend substantially parallel with each other. Accordingly, a shift lever 7 of an automatic transmission can be adapted to pass through the space formed by the bifurcated structure of the reinforcing member 1 .
As shown in FIG. 2, the shift lever 7 includes a shift knob 7 A, an arm part 7 B, and a shift switch 7 C. The shift knob 7 A is provided at one end of the arm art 7 B and positioned above the reinforcing member 1 . The other end of the arm part 7 B passes through the space formed by the bifurcated structure of the reinforcing member 1 and is attached to a support member 9 fixed at the front art of the reinforcing member 1 such that the arm part 7 B may pivot about the support member 9 in the longitudinal direct on of the vehicle. Further, one end of a push rod 10 , which is connected to a shift cable S extending from an automatic transmission, not shown, is attached to a substantially middle portion of the arm part 7 B. The other end of the push rod 10 is attached to a mounting part 11 provided between the reinforcing member 1 and the lower surface of the instrument panel 4 such that the push rod 10 may slide therethrough. The shift switch is pivotally attached to the arm part 7 B and below the shift knob 7 A. By moving the shift switch 7 C, a lock member, not shown, which locks the shift lever 7 in predetermined positions can be released.
The position of the shift lever 7 can be selected among a Parking position, a Reverse position, a Neutral position, and a Drive position, and so forth, by moving the shift switch 7 C upward toward the shift knob 7 A as shown in FIG. 5 .
As shown in FIG. 2, at the upper side of the reinforcing member 1 , a release lever 8 for releasing a foot-operated parking brake is provided pivotally behind the shift lever 7 such that the parking brake is released when the release lever 8 is turned upward. The release lever 8 passes through an internal space of the reinforcing member 1 and is joined to a brake cable connected to a brake lock mechanism, not shown. A concaved part 1 A, which is sized to allow a fingertip to be inserted, is formed at an upper surface of the reinforcing member 1 and adjacent the release lever 8 so that the release lever 8 can be easily operated. With this arrangement, the parking brake can be released by inserting a fingertip into the concaved part 1 A and turning the release lever 8 upward.
A description will now be given of a mounting structure of the reinforcing member 1 in the rear part of the vehicle. As shown in FIG. 3, the rear end of the reinforcing member 1 is bent downward and attached to the rear part of the floor panel 2 , as a vehicle body rear member, that rises upward. The rear end of the reinforcing member 1 is also attached to a cross member 13 , as a vehicle body rear member, via a fixing member 12 . The fixing member 12 has one end thereof attached to the reinforcing member 1 and the other end thereof attached to the cross member 13 . The cross member 13 extends in the lateral direction of vehicle and has both ends thereof joined to a rear side frame, not shown.
A rear monitor 14 is mounted on the rear portion of the reinforcing member 1 as shown in FIG. 6 . The rear monitor 14 is attached to the reinforcing member 1 such that the rear monitor 14 may be housed in the space formed by the bifurcated structure of the reinforcing member 1 as shown in FIG. 7 .
It is to be understood, however, that there is no intention to limit the invention to the above-described embodiment, but certain changes and modifications may be possible within the scope of the appended claims.
For example, although in the above-described embodiment, the front end of the reinforcing member 1 is attached to three vehicle body front members, i.e. the tunnel part 3 , instrument panel 4 , and dashboard panel 5 , the present invention is not limited to this. The front end of the reinforcing member 1 may be attached only to one or two of the above three members.
Further, although in the above-described embodiment, the rear end of the reinforcing member 1 is attached to the floor panel 2 and the cross member 13 as the vehicle body rear members, the present invention is not limited to this. The rear end of the reinforcing member 1 may be attached to only one of the floor panel 2 and the cross member 13 .
Further, although in the above-described embodiment, the floor panel 2 has the tunnel part 3 , the present invention is not limited to this. The floor panel 2 may not have the tunnel part 3 . In the case where the tunnel part 3 is not provided, a wide space can be ensured between the reinforcing member 1 and the floor panel 2 and the space can be used to place items therein, or the like.
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A vehicle body reinforcement structure has a reinforcing member positioned at a predetermined height from a floor panel such that the reinforcing member may function as an armrest. The reinforcing member extends substantially at the center of a vehicle compartment in the longitudinal direction of a vehicle. This structure allows the reinforcing member to be disposed in the space of the vehicle compartment without causing an occupant to sense discomfort, and improves stiffness of the vehicle body.
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Cross Reference to Related Application
This application is a continuation-in-part of our earlier copending application Ser. No. 547,788, filed Feb. 7, 1975 and now abandoned.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to derivatives of polyglycerols having at least three glycerol units which are ethers resulting from the reaction of polyglycerol with a proper proportion of a reactive oxirane-containing hydrophobe compound.
In particular, the reactive oxirane-containing hydrophobe material is a glycidyl ether resulting from the action of epichlorohydrin upon a hydrophobic alcohol. A straight-chain fatty alcohol containing 6 to 20 carbon atoms may be used, or a suitable material may be derived by oxyalkylating a lower alcohol, one that would not itself be hydrophobic, with a sufficient proportion of propylene oxide and/or butylene oxide being used to impart the necessary hydrophobicity.
2. Description of the Prior Art
The preparation of various polyglycerols, by condensing glycerol in the presence of an alkaline catalyst at temperatures such as 100°-300° Centigrade is disclosed in Babayan et al. U.S. Pat. No. 3,637,774. The patent goes on to teach the making of various partial esters or full esters of such polyglycerols for various purposes, such as gelling agents, lubricants, wetting and dispersing agents, etc. The reaction of partial esters with alkylene oxides to form adducts is suggested. Such esters are, however, subject to hydrolysis under alkaline conditions.
The reaction of organic hydroxyl compounds (including polyglycerol) with alkylene oxides is disclosed in Moore U.S. Pat. No. 2,253,723. The patent discloses the use of stannic chloride as catalyst for the reaction of an alkylene oxide with virtually any organic hydroxyl-containing compound. Stannic chloride is completely unsuitable as a catalyst for the making of products in accordance with the present invention. Moreover, the patent does not mention the fatty epoxides which are used as reactants to produce the products of the present invention.
Alkali-stable nonionic surfactant compositions are known which result from the reaction of a fatty alcohol with a lower glycoside, in a manner similar to that described in U.S. Pat. No. 3,547,828 or U.S. Pat. No. 3,772,269. In these patents, neither the hydrophilic group nor the hydrophobic group has any similarity to those used in our composition; furthermore, such compositions differ chemically from those of the present invention, in that the hydrophobe is joined to the hydrophile through an acetal or a hemiacetal linkage, which is not stable in acid media.
U.S. Pat. No. 3,932,532 discloses the making of nonionic surfactants by reacting 1,2-alkylene oxides containing C 8 to C 20 alkyl groups with a particularly purified polyglycerol containing 3 or more glycerol units. Its teachings can be distinguished from those of the present invention both on the ground that the particular purification process set forth in the patent is not necessary and on the ground that the patent does not make it obvious to those skilled in the art that with a glycidyl-ether approach, results substantially as good can be obtained with the use of starting materials which are more readily available and less expensive.
U. S. Pat. No. 3,719,636 teaches making nonionic surfactants by reacting, for example, C 12 to C 14 fatty alcohols with several moles of glycidol ##STR1## When glycidol condenses, it yields (in effect) glycerol units. Working with glycidol has the drawback that the glycidol is not easy or inexpensive to make and that it is difficult to prevent the glycidol from self-polymerizing.
SUMMARY OF THE INVENTION
A polyglycerol containing at least three glycerol units, and usually five to thirty glycerol units, is reacted in a proper proportion, sufficient to substitute four to twenty-five percent of the hydroxyl groups of the polyglycerol, with a reactive oxirane-containing hydrophobe compound, in particular, a glycidyl ether of a C 6 to C 20 alcohol or a mono-or poly-glycidyl ether derived from a polyoxyalkylene compound prepared from propylene oxide, butylene oxide, ethylene oxide and mixtures thereof. An essential characteristic of this hydrophobe element is that the total hydrophobe alkylene oxide component has an average oxygen/carbon atom ratio of not greater than 0.40. Surfactant compositions result which have solubility and stability in a variety of concentrated ionic solutions, especially in basic media, and are biodegradeable in many instances. The use of the glycidyl-ether approach makes it unnecessary to use fatty epoxides, which are sometimes expensive or not readily available.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The first step is the preparation of a polyglycerol containing a desired average number of glycerol units may be performed in any suitable manner, as is well known to those skilled in the art. One satisfactory procedure, involving dehydration of glycerol in the presence of an alkaline catalyst at 100 to 300 degrees Centigrade is adequately disclosed in Babayan et al. U.S. Pat. No. 3,636,774, the disclosure of which is hereby incorporated by reference.
The next step is the preparation of the glycidyl ether (or its precursor).
Epichlorohydrin reacts with an alcohol ROH according to the equation ##STR2## Such preparation is well known to those skilled in the art--see, for example, U.S. Pat. No. 2,314,039. In the foregoing, R may be, for example, an alkyl radical of 6 to 20 carbon atoms. This implies that the surfactants of the invention are made from the corresponding fatty alcohols, rather than from fatty 1,2-epoxides.
Those skilled in the art will also appreciate that it will not always be necessary or desirable to isolate the glycidyl ether ##STR3## the intermediate monohalohydrin ether
R--O--CH.sub.2 --CHOH-CH.sub.2 --Cl
will itself in many cases react under basic conditions with the material containing glycerol units to yield an equivalent product.
The glycidyl-ether approach is not limited to the use of fatty alcohols; it is also possible to start with lower alcohols like n-butanol and n-propanol plus propylene oxide, alone or with a suitable minor proportion of ethylene oxide, and make a suitably alkoxylated hydrophobic alcohol, which is then susceptible of being converted by reaction with epichlorohydrin to a corresponding glycidyl ether. In making such materials, a ratio of oxygen atoms to carbon atoms of about 0.4 or lower is observed.
A next step is the reaction of the glycidyl ether (or its precursor) with the polyglycerol. This is preferably done under basic conditions.
It is essential that the hydrophobe material be used in proper proportion in relation to the polyglycerol, such that about 4 to 25 percent of the hydroxyl groups of the polyglycerol are substituted by a reaction with the oxirane-containing hydrophobe. If less than about 4 percent of the hydroxyl groups of the polyglycerol are substituted, there is usually not obtained a sufficiently powerful surfactant effect because the composition remains too hydrophilic. On the other hand, the substitution of more than about 25 percent of the hydroxyl groups of the polyglycerol is generally to be avoided, because this makes the composition more hydrophobic than is ordinarily desirable and because this results in lower solubility of the product composition in water and in alkaline media.
Surfactant compositions of the invention as prepared in their anhydrous form range from viscous liquids to glassy, thermoplastic solids. For handling purposes, they are conveniently diluted with water to form solutions containing 50 to 80 weight percent of solids.
Appropriate conditions of temperature and pressure, as well as the use of proper catalysts, solvents, etc., for the reaction of polyglycerol with the oxirane-containing hydrophobe are critical to the success of this invention, as will be recognized by those skilled in the art. In general, the reaction may be practiced at temperatures ranging from about 100 to 200 degrees Centigrade and at atmospheric pressure.
These surfactant materials have several possible uses. They include use as a surfactant in alkaline bottle-washing compositions, baths for the kier boiling of cotton, alkaline paper-pulp deinking compositions, electrolytic baths for the cleaning of metal parts or for the electrodeposition of metal, foam-type or other industrial alkali cleaning media, and textile-treating formulations. They may be used as a component of shampoos, cosmetics, heavy-duty detergents and other cleaning products. They may be used, moreover, as intermediates for the production of other valuable chemical products; for example, they may be sulfonated to yield anionic surfactants, or polyoxyalkylated to yield other surfactants of a desired hydrophobic-hydrophilic balance and/or molecular weight. In many circumstances, nonionic surfactants according to the invention are incorporated, in amounts sufficient to impart substantial surface-active properties, in aqueous solutions containing 0.1 to 50 weight percent of an alkali-metal hydroxide, such as sodium hydroxide or potassium hydroxide.
In accordance with the invention, the proportions of polyglycerol and the hydrophobe-moiety precursor are such that an average molecule of product nonionic surfactant material of the invention is of the formula
Z--CH.sub.2 --CHZ--CH.sub.2 --[OCH.sub.2 --CHZ--CH.sub.2 ].sub.n --Z
where n is an integer from 2 to 29 and each Z is selected from the group consisting of OH and R and 4 to 25 percent of said Z's are R, where R is selected from the group consisting of
(1) --OCH 2 --CHOH--CH 2 --OR, where R is selected from the group consisting of
(a) a long-chain alkyl group containing 6 to 20 carbon atoms, and
(b) a polyoxyalkylene glycol ether radical (CH 2 --CHR 2 --O--) P -R 3 , where R 2 is selected from the group consisting of hydrogen, methyl and ethyl, p is an integer from 3 to 20, and R 3 is an alkyl radical containing 1 to 6 carbon atoms, the average oxygen/carbon atom ratio of the radical (CH 2 --CHR 2 --O) p being not greater than 0.4, and
(2) a divalent radical having the structure --O--(--CH 2 --CHR 2 --O--) q --CH 2 --CHOH--CH 2 --O-- in which q is an integer from 6 to 40 and R 2 is selected from the group consisting of hydrogen, methyl and ethyl, the average oxygen/carbon atom ratio of the radical (--CH 2 --CHR 2 --O) q being not greater than 0.4, each end of said divalent radical functioning as an R in a molecule of the formula Z--CH 2 --CHZ--CH 2 --[OCH 2 --CHZ--CH 2 ] n --Z.
The invention described above is illustrated by the following specific examples, in which the parts are by weight unless otherwise specified. The examples are to be interpreted as illustrative and not in a limiting sense.
EXAMPLE I
A mixture of 2-hydroxy-3-chloropropyl ethers of straight-chain C 10 -C 12 alcohols is prepared and reacted with polyglycerol having an average of five glycerol units in a weight ratio of three parts by weight of polyglycerol per part of the mixture of glycidyl ethers.
To a flask, there are charged 495 grams (3 mols) of a mixture of C 10 to C 12 straight-chain alcohols, 1.5 gram of boron trifluoride etherate as catalyst, and 335 grams (3.6 moles) of epichlorohydrin. The material in the flask is provided with a nitrogen blanket and heated over a period of about 2 hours at a temperature of about 56° to 60° C, with the alcohols and catalyst being present in the flask initially and with the epichlorohydrin being charged to the flask during the 2-hour period mentioned above. Materials in the flask are stirred during the two hours and thereafter for an additional two hours, while the material in the flask is permitted to cool to about 33° C. Sodium bicarbonate (3 grams) is charged to the flask, which is then subjected to an absolute pressure of 2 millimeters of mercury and heated over a period of one hour to approximately 103° C, and then permitted to cool. There is thus prepared a product comprising approximately 830 grams of a mixture of 2-hydroxy-3-chloro-propyl ethers of C 10 to C 12 alcohols.
The glycidyl-ether precursor product mentioned above is reacted with polyglycerol to obtain a surfactant. To a reaction flask, there are charged 300 grams of a polyglycerol having an average of 5.4 glycerol units, and 43.4 grams of an aqueous solution containing 50 weight percent of sodium hydroxide. Water is removed from the charge by heating it to between 100° and 150° C while subjecting it to a vacuum (200 to 3 millimeters of mercury absolute pressure) over a period of about 2 hours. The reaction flask is then repressurized with nitrogen to atmospheric pressure and, with constant stirring, there are added over a period of about 30 minutes 100 grams of the mixed chlorohydrin-ether product prepared above, while maintaining a temperature on the order of 130 to 165° C.
Tests on the product were conducted as in Example 1. A one weight percent aqueous solution has a pH of 11.10 and remains substantially clear at temperatures of up to 50° C. A Draves sink time of 246 seconds is observed for a 0.1 weight percent aqueous solution, and a surface tension of 28.9 dynes per centimeter.
The Draves sink test, originally described by C. Z. Draves and R. G. Clarkson in volume 20, American Dyestuff Reporter, pages 201-208 (1931), has been adopted as Standard Test Method 17-1952, reported in the Technical Manual of the American Association of Textile Chemists and Colorists (1964).
EXAMPLES 2-9
A polyglycerol is prepared by dehydrating glycerol in the presence of sodium hydroxide as catalyst, obtaining a polyglycerol having an average number of glycerol units per molecule as indicated below in Table No. I, and thereafter, the polyglycerol so produced is reacted, in the proportions indicated in Table No. I, with a material providing a suitable hydrophobic moiety, to produce a surfactant material having the indicated properties. For the sake of completeness, the results of Example 1 are also included in Table I.
TABLE I______________________________________Results of Tests of Various Poly-glycerol + Hydrophobe Surfactant Hydro-Ex. GU phobe Ratio ST DS CP S______________________________________1 5 B 3 28.9 246 50 Sol.2 10 A 3.2 28.8 65 >100 Sol.3 10 A 2.3 29.7 110 >57 Sol.4 20 B 3 28.5 126 94 Sol.5 17 B 2 28.1 78 63 >106 17 B 3 29.5 110 98 >107 17 B 3 28.8 189 100 >108 17 C 2 26.3 62 30 >109 17 D 2 27.3 75 51 >10______________________________________ GU = average number of glycerol units in polyglycerol A = glycidyl ether of C.sub.10 alkanol B = glycidyl ether of mixture of C.sub.10 -C.sub.12 alkanols C = glycidyl ether of straight-chain C.sub.8 alkanol D = glycidyl ether of mixture of straight-chain C.sub.8 -C.sub.10 alkanol Ratio = parts by weight of polyglycerol per part of hydrophobe ST = Surface tension, dynes per centimeter, 0.1% (wt.) solution DS = Draves sink time, seconds CP = cloud point, °C. S = solubility in 25 wt. percent solution of NaOH Sol. = soluble, percentage not measured.
The foregoing results demonstrate that various surfactant materials having substantial solubility in alkali may be made, starting with a polyglycerol having an average of 5 to 20 glycerol units per molecule and reacting said polyglycerol with different glycidyl ethers.
EXAMPLE 10
A polyglycerol having an average of 17 units of glycerol per molecule is prepared by dehydrating glycerol. A C 18 alkanol is reacted first with epichlorohydrin and then with a base, to obtain a glycidyl ether. Then three parts of said polyglycerol are reacted with one part of said glycidyl ether, to obtain a nonionic material having surfactant properties.
EXAMPLE 11
A polyglycerol having an average of 20 glycerol units per molecule is prepared by dehydrating glycerol. A C 16 alkanol is reacted with propylene oxide in a mole ratio of 1:3 to produce a propoxylated C 16 alkanol, and then the propoxylated alkanol is reacted, first with epichlorohydrin and then with a base, to obtain a glycidyl ether. Two parts of the polyglycerol are reacted with one part of the glycidyl ether, to obtain a nonionic material having surfactant properties.
EXAMPLE 12
Glycerol is dehydrated to obtain a polyglycerol having an average of 18 glycerol units per molecule. Decyl alcohol is reacted with ethylene oxide in a mole ratio of 1:5, to produce an ethoxylated decanol, and then the ethoxylated decanol is reacted, first with epichlorohydrin and then with a base, to obtain a corresponding glycidyl ether. Then three parts of the polyglycerol are reacted with one part of the glycidyl ether to obtain a nonionic material having surfactant properties.
EXAMPLE 13
Glycerol is dehydrated to obtain a polyglycerol having an average of ten glycerol units per molecule. A C 20 alkanol is reacted with propylene oxide in a mole ratio of 1:5, to obtain a propoxylated C 20 alkanol, and then the propoxylated C 20 alkanol is reacted first with epichlorohydrin and then with a base, to obtain a glycidyl ether. Two parts of the polyglycerol are reacted with one part of the glycidyl ether, to obtain a nonionic material having surfactant properties.
EXAMPLE 14
A surfactant is made by reacting a 17-unit polyglycerol with a monochlorohydrin ether of an oxypropylated n-butanol having a molecular weight of approximately 464 (n-butanol plus about 7 oxypropylene units). The product thus corresponds to the case, within the general formula indicated hereinabove, where Z = --OCH 2 --CHOH--CH 2 --O--R 3 , and R 3 is a polyoxyalkylene glycol ether radical
--O--(CH--CHR 5 --O) p R 6 , where R 5 is methyl, p = 7, and R 6 is n-butyl, and the percentage of the Z's that are R is 5.5 percent.
To a 500-milliliter flask there are charged 200 grams of 17-unit polyglycerol, and after warming to 90° C at atmospheric pressure under a blanket of nitrogen, there are added 30 grams of a 50 weight percent aqueous solution of sodium hydroxide. Then the materials in the flask are subjected to stripping conditions (temperature 110° to 155° C and absolute pressure of 400 to 10 millimeters of mercury) for 25 minutes to remove water. The reactor is repressurized with nitrogen to atmospheric pressure, and then there are added dropwise over a period of 1 hour and 25 minutes 100 grams of a glycerol α-monochlorohydrin ether of a 7-unit-oxypropylated n-butanol, the temperature being maintained during the addition at approximately 140° C. The reaction is permitted to continue for two hours, after which the reactor is permitted to cool, yielding 309.5 grams of a tan paste product.
The product gives, in an aqueous solution containing 0.1 weight percent, a Draves sink time (3-gram hook) of 102.6 seconds and a surface tension of 29.7 dynes per centimeter. A 1 weight percent aqueous solution is milky at temperatures greater than 25° C, and has a pH of 11.45. In dynamic foam height tests, no foaming is observed, either at 49° or at 25° C. The dynamic foam height test is disclosed in an article by H. E. Reich et al. in the Apr. 1961 issue of Soap and Chemical Specialties, volume 37, page 55.
EXAMPLE 15
Example 14 is repeated, except that there is used a different monochlorohydrin ether of somewhat greater molecular weight, namely one based upon n-butanol oxypropylated to an average molecular weight of 673 (approximately 10 oxypropyl units). There is obtained a tan paste product weighing 310 grams.
The product gives, in aqueous solution containing 0.1 weight percent, a Draves sink time (3-gram hook) of 197.1 seconds and a surface tension of 30.8 dynes per centimeter. A 1 weight percent aqueous solution is milky at temperatures greater than 25° C, and has a pH of 11.68.
EXAMPLE 16
Distilled n-octyl glycidyl ether is reacted with a 9.4-unit polyglycerol on a 1:1 weight ratio, yielding a nonionic surfactant.
To a four-necked flask of 500-ml. capacity there are charged 100 grams of a 9.4-unit polyglycerol and 1 gram of a 50 weight percent aqueous solution of sodium hydroxide, and the contents of the flask are then stripped for 10 minutes at 120°-130° C and 25-10 mm. of mercury absolute pressure. The vacuum is then released to atmospheric pressure by the admission of nitrogen, and then, with the material in the reaction flask at about 140° Centigrade, there are gradually added over 12 minutes 100 grams of a purified glycidyl ether of n-octanol. At the conclusion of the addition of the glycidyl ether, the cloudiness of the reaction mixture suddenly disappears, leaving a clear light-amber liquid, with an accompanying rise in pot temperature up to 170° C, owing to heat of reaction. The reaction is continued for one hour at 153° to 146° C under a blanket of atmospheric-pressure nitrogen, and thereafter 50 grams of distilled water are added to obtain a clear, medium-amber product in the form of an 80 weight percent solution. Further dilution yields a 0.1 weight percent solution having a Draves sink time (3-gram hook) of 38.2 seconds and a surface tension of 28.0 dynes per centimeter.
EXAMPLE 17
Example 16 is repeated, except that in place of distilled n-octyl glycidyl ether, there is used a glycidyl ether based upon a mixture of C 8 to C 10 alkanols. Again there is obtained a medium-amber solution containing 80 weight percent of solids. Further dilution yields a 0.1 weight percent solution having a Draves sink time (3-gram hook) of 56.4 seconds and a surface tension of 29.3 dynes per centimeter. A 1 weight percent aqueous solution is milky and has a pH of 10.0.
While we have shown and described herein certain embodiments of our invention, we intend to cover as well any change or modification therein which may be made without departing from its spirit and scope.
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Nonionic surfactant compositions are made by reacting a 3 to 30-unit polyglycerol as hydrophile with a hydrophobic glycidyl ether in sufficient quantity to substitute 4 to 25% of the hydroxy groups of the polyglycerol. By using glycidyl ethers (which can be made conveniently by reaction of hydrophobic alcohol with epichlorohydrin) it becomes possible to avoid the expense of working with long-chain 1,2-epoxides. The surfactant compositions obtained have solubility and stability in a variety of concentrated ionic solutions, and especially in basic media.
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FIELD OF INVENTION
[0001] The present invention relates generally to magnetic levitation system but more particularly to a magnetic levitation car that runs on a magnetized road.
BACKGROUND OF THE INVENTION
[0002] The concept of a magnetic levitation train has been around for than 60 years now. This was a brainchild of a German Scientist Hermann Kemper. On Aug. 14, 1934, he received a patent for the magnetic levitation of trains in Germany.
[0003] In the mid 1900s, Britain became the first country to introduce a magnetic levitation service. It was to link two terminals at Birmingham airport about 400 meters long and a top speed of about 10-mph. However it was recently replaced with a bus service due to difficulty of getting spare parts.
[0004] Since then, there has been a lot of research and experiments for Magnetic Levitation Trains. In Germany, the TRANSAPID project is one intended to connect Berlin and Hamburg using this principle. If it all works on time then it should be operational by 2005. The journey time will be no more than 60 minutes for the 292-km giving rise to an impressive 292 kph average speed.
[0005] In Japan, after fundamental tests in the laboratory to verify the feasibility of high-speed running at 500 kph, the construction work of a 7-km test track began in Japan's Miyazaki Prefecture in 1975. The manned two-car vehicle registered a speed of 400.8 kph in 1987. In 1997, the project in a three-car train set achieved world speed records, attaining a maximum speed of 531 kph in a manned vehicle run on December 12 and a maximum speed of 550 kph in an unmanned vehicle on December 24. On Apr. 14, 1999, a five-car train set surpassed the speed record, attaining a maximum speed of 552 kph in a manned vehicle run.
[0006] The principle of a magnetic train is that it floats on a magnetic field and is propelled by a linear induction motor. They follow guidance tracks with magnets. These trains are often referred to as Magnetically Levitated, which is abbreviated, to Maglev.
[0007] Maglev is a system in which the vehicle runs levitated from the guide way (corresponding to the rail tracks of conventional railways) by using electromagnetic forces between super conducting magnets on board the vehicle and coils on the ground. A maglev train floats about 10 mm above the guide way on a magnetic field. It is propelled by the guide way itself rather than an onboard engine by changing magnetic fields. Once the train is pulled into the next section the magnetism switches so that the train is pulled on again. The Electro-magnets run the length of the guide way.
[0008] The primary advantage of a magnetic levitated train is maintenance. Because the train floats along there is no contact with the ground and therefore no need for any moving parts. As a result there are no components that would wear out. This means that trains and track would need no maintenance at all. The second advantage is that because maglev trains float; there is no friction and noise. And finally, the speed as a result it is more viable for said maglev trains to travel extremely fast, i.e. about 500 kph.
[0009] However, there are several disadvantages with maglev trains. Maglev guide paths are bound to be more costly than conventional steel railways. The other main disadvantage is lack with existing infrastructure. For example, if a high-speed line between two cities is built, then high-speed maglev trains can only serve both cities but would not be able to serve other lines or normal railways branching out therefrom which require normal speed. This means that maglev trains are strictly limited only to high-speed lines and not flexible enough to serve other lines.
[0010] Although the Maglev technology has been around for quite some time now, however its application was concentrated on the use of trains.
[0011] After a careful and thorough research and conceptualization of the Principle of Magnetic Levitation, a break through technology has been adapted wherein such principle is applied to cars. This off the railroad application of Maglev Technology will certainly transform the way people move in the future.
[0012] Basically the concept and propulsion between the Maglev trains the Maglev car may seem similar, but they work differently from each other. Unlike the Maglev train, which run and work only on a Maglev rail track in a very limited route whereby its movement and direction is very limited, the Maglev car on the other hand works like an automobile, and can freely move anywhere it goes, and with distinct feature and characteristic wherein it can move in an Omni directional manner.
[0013] The primary object of this invention therefore is to provide a Magnetic Levitated car that solves the drawbacks inherent to the existing Maglev trains.
[0014] Another object of this invention is to provide a Magnetic Levitated car that runs on magnetic roads, uses magnets instead of tires and runs by means of batteries instead of gas,
[0015] Still an object of this invention is to provide a Magnetic Levitated car that is environment friendly since no air pollutants that comes off the car nor noise that is being produced thereof.
[0016] Yet, an object of this invention is to provide a Magnetic Levitated car having a polarity similar to the polarity of the magnetic roads that when engaged, the car floats or suspended in mid-air.
[0017] A further object of this invention is to provide a Magnetic Levitated car having electro-magnetic wheels that uses the opposite polarity with respect to the polarity of the magnetic road in an “off” and “on” manner. This will cause an attraction intermittently creating therefore movement from one point to another point in one direction or to a different direction as to turning, depending on the rotation of the electro-magnetic wheels.
[0018] These and other objects and advantages will come to view and be understood upon a reading of the detailed description when taken in conjunction with the accompanying drawings.
[0019] [0019]FIG. 1 is a perspective view of the present invention for a Magnetic Levitated car;
[0020] [0020]FIG. 2 is a plan view of the disposition of the magnetic suspension stabilizers and electromagnetic wheels at the bottom of the car;
[0021] [0021]FIG. 3 is a sectional view of the magnetic suspension stabilizer and the magnetic road showing the levitation thereof;
[0022] [0022]FIG. 4 is an illustrative view of the electro-magnetic wheel in relation with the magnetic road; and
[0023] [0023]FIG. 5 is sectional view of the electromagnetic wheel.
DETAILED DESCRIPTION
[0024] Referring now to the several views of the drawing, shown is magnetic levitated car generally designated as reference numeral 10 .
[0025] Said magnetic levitated car 10 comprises a car body 11 (shown in dotted lines) and a magnetic levitation system 12 disposed at the bottom portion 13 of said car body 11 .
[0026] Said magnetic levitation system 12 consists of a main magnetic suspension stabilizer 14 disposed centrally at the bottom portion 13 of said car body 11 , a pluralty of small magnetic suspension stabilizer 15 spacedly disposed around said main magnetic suspension stabilizer 14 preferably along the sides to provide stability preventing the car body 11 from tilting, a plurality of electro-magnetic wheels 16 spacedly disposed in a predetermined location around said magnetic suspension stabilizers as shown in FIG. 2, and a magnetic track 17 having a plurality of magnets spacedly spread out along a track having their polarity facing the same polarity with that of the magnetic suspension stabilizer thereby repelling each other to provide levitation therefore.
[0027] Said main and small magnetic suspension stabilizers 14 and 15 are preferably made of permanent magnets and the like such as Neodymium Iron Boron, Samarium Cobalt and the like, and each of said stabilizers is being defined by a suspension stabilizer housing 18 confining a magnetic crown 39 having a circular cavitation 19 at the bottom surface 20 that receives a frusto-conical shaped magnetic core 21 therein. As shown in the drawing the magnetic crown 39 has its bottom polarity, i.e. the circular cavitation 19 similar to the adjacent polarity of the magnetic core 21 , say the upper portion of the magnetic crown 39 has a south polarity while the opposing side or circular cavitation 19 has the north polarity. The upper portion of the magnetic core 21 has likewise the north polarity such that circular cavitation 19 would push or repel the upper portion of the magnetic core 21 . The bottom portion 22 of the magnetic core 21 therefore possesses the south polarity. To secure the magnetic core 21 suspended in mid-air, a bottom magnetic ring 23 is lockably secured at the bottom of the suspension stabilizer housing 18 . The bottom magnetic ring 23 likewise has its nearest polarity similar to the bottom portion 22 of the magnetic core 21 , in this case, the South Pole. With this set up, the magnetic core 21 is suspended in mid-air inside the suspension stabilizer housing 18 causing it therefore to freely move or rotate. Should there be any disturbance caused by outside forces which would cause the car body 11 to be outbalanced or tilt, the magnetic suspension stabilizer would actually absorb such. This would prevent said car body from tilting or being outbalanced.
[0028] As shown in FIGS. 1 and 2, the whole car 10 is floating above the magnetic track 16 being laid on with a plurality of equally spaced magnetic elements 24 having the same material as that of the stabilizers. The upper side of said magnetic elements 24 are laid on said track with the exposed sides having a similar polarity with that of the bottom portion 22 of said magnetic core 21 . In as much that the bottom portion 22 of said magnetic core 21 has the south polarity, the upper side of said magnetic elements 24 also have the same south pole thereby repelling the magnetic core 21 of said car 10 .
[0029] To provide propulsion, said car 10 has electro-magnetic wheels 16 driven by prime moving means such as electric motor 25 which is run by batteries, preferably solar batteries. Said electric motor 25 is co-axially disposed with a commutator assembly 26 secured on said car body 11 . Said commutator assembly 26 which is an arcuated member covering at least three quarters of a ring, consists of at least three (3) commutator housing 27 each covering one circumferential quadrant of a ring and being provided with a T-shaped commutator insulator 28 traversing the entire length of the bottom portion thereof, and a negative and a positive commutator 29 and 30 disposed at the opposing side of said T-shaped commutator insulator 28 . Said electric motor 25 is provided with a shaft 31 centrally projecting therefrom and being rotatably connected with an armature assembly 32 . Said armature assembly 32 in the form of a ring consists of at least three sectors of armature coils 33 electrically connected with respective electromagnetic foot 34 . Said electromagnetic foot 34 being disposed in between two adjacent armature coils 33 is a metal plate attached to respective armature coil 33 and when charged with electricity, would be converted to electromagnet. Cantileveredly mounted on top of said electromagnetic foot 34 is a pair of opposing brush holder 35 , respectively provided with brush 36 in a manner that the top portion of said brush 36 is engaged respectively with the negative and positive commutators 29 and 30 . To ensure that the brushes 36 are always in contact with said commutators, said brushes 36 are supported at the bottom with respective leaf springs 37 that are secured on said electro-magnetic foot 34 . In order to ensure that the brush and commutator are always in engagement position, the top portion of the electromagnetic foot 34 is provided with a guide way 38 whereby the lower end of the T-shaped commutator insulator travels 28 .
[0030] In operation, while the armature assembly is being rotated by the electric motor, the armature is charged with electricity converting the electromagnetic foot to electromagnet. The magnetic field created would attract the magnetic road or track 17 and would push the vehicle either forward or backward depending on the rotation of the motor. As would be seen in the drawing, once the commutator is passed with electricity, the brush would transfer the electricity and charge the armature coil thereof. Since the commutators cover only three quarters, the remaining quarter is open which creates an interruption in the supply of electricity to the armature coils. This switching “on” and “off” of electricity in the armature coils actually makes the electro-magnetic foot crawls the magnetic road or track.
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A magnetic levitated car comprising a car body that is made to float on a magnetic road laid on with a plurality of spaced apart magnets, at least one magnetic suspension stabilizer disposed spacedly at the bottom of said car body, and at least one electro-magnetic wheel provided at the bottom of said car body. The bottom portion of said magnetic suspension stabilizer has a polarity similar to that of the magnets laid on the road to provided repulsion therefore that will levitate said car body.
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BACKGROUND OF THE INVENTION
The invention concerns new hexanor-brassinolid-22-ethers, processes for the production of these compounds, as well as compositions containing the same and having growth-regulatory activity for plants.
A plant growth promoting steroid, the brassinolid, has been isolated from the pollen of rape, and the structure has been determined (M. D. Grove et al., Nature, Vol. 281.216 (1979)). However, the growth-regulatory activity of this compound is not satisfactory.
Syntheses for this steroid are also known (J. Org. Chem. 44, 5002 (1979); Steroids 39, 89 (1982)). In these publications it is claimed that sterine side chains (with 8 to 10 carbon atoms), cis hydroxyl groups at C 22 and C 23 , as well as alkyl groups at C 24 are essential for the brassino steroid activity.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide new brassinolid analogs which display outstanding plant growth-regulatory characteristics, however possess a simpler structure in comparison with the known analogous compounds, and are more easily prepared from a technical point of view.
This object is attained according to the present invention by a composition which is characterized by a content of a hexanor-brassinolid-22-ether of the Formula ##STR3## wherein
Z is the group ##STR4##
OR 2 and OR 3 are oriented cis 2α, 3α or 2β, 3β,
R 2 and R 3 are the same or different and are each hydrogen, formyl, C 2 -C 7 -alkyl-CO--, C 2 -C 7 -alkoxy-C 1 -C 3 -alkyl-CO-- or aryl-CO-- and
R 23 is straight-chain or branched C 1 -C 7 -alkyl or C 1 -C 7 -alkoxy-C 1 -C 3 -alkyl.
By providing these new compounds, one succeeds in synthesizing, in surprising manner, simple structures with which, compared to the known brassinolid-derivatives, the three asymmetry centers (C 22 , C 23 , C 24 ) in the side chain are avoided, and therewith also the expensive separation of the diastereomers occurring with the syntheses at C 22 and C 23 .
The compounds according to the present invention prove to be outstanding for the regulation of plant growth of various culture plants, and match the above mentioned products of the same activity direction in their activity spectra as well as in their compatibility.
The compounds according to the present invention make possible a promotion of the vegetative growth of culture plants, in certain concentration ranges, but also its restraint. In other respects it is possible to obtain certain multiple yields by means of influencing the generative phase.
In general, the substances work themselves into the membrane system of the culture plant, and alter its permeability for various substances.
Under certain conditions an anti-stress activity can be provided.
Since the compounds according to the present invention cause not only qualitative and quantitative alterations in the plants but also changes in metabolism, they are classified in the category of plant growth regulators, which distinguish through the following use possibilities:
Restraint of the vegetative growth of woody and weed plants, for example at road borders, railroad plants, and others, in order to prevent too voluptuous a growth. Growth restraint of grains, in order to eliminate depositing or breakage upon bending, with cotton for increasing the yield.
Influencing the branching of vegetative and generative organs of ornamental and culture plants, for increasing the onset of blooming, or with tobacco and tomato for restraining side shoots.
Improving the food quality, for example an increase in sugar content with sugar cane, sugar beets, or fruit, and a more uniform ripening of the harvested goods, which leads to higher yields.
Increasing the resistance against stress, thus for example against climatic influences, such as cold and dryness, but also against phytotoxic influence of chemicals.
Influencing the latex flow of rubber plants.
Formation of parthenocarpic fruit, pollen sterility and sexual influence are likewise use possibilities.
Control of the germination of seeds or the driving out of buds.
Defoliation or influencing the fruit fall in order to facilitate harvesting.
The compounds according to the present invention are suitable particularly for influencing the vegetative and generative growth of several legumes, such as for example soybeans and beta-beets.
The application amounts generally run between 0.001 and 1 kg active substance per hectare, indeed according to purpose of use, however if necessary also higher application amounts can be employed.
The time of use depends upon the purpose of use and the climatic conditions.
As substituents R 2 and R 3 according to the Formula I, mention may be made of acyl groups selected from formyl, the C 2 -C 7 -alkyl-CO-groups, the C 2 -C 7 -alkoxy-C 1 -C 3 -alkyl-CO-groups and the aryl-CO-groups, such as for example acetoxy, methoxyacetoxy, ethoxyacetoxy, propionyloxy, butyryloxy, valeryloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, dimethylacetoxy, diethylacetoxy, benzyloxy and phenylacetoxy.
As substituents R 23 mention may be made of methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, tert.-butyl, n-pentyl, n-hexyl and n-heptyl as C 1 -C 7 -alkyl groups, and of methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, among others, as C 1 -C 7 -alkoxy-C 1 -C 3 -alkyl groups.
The compounds according to the present invention can be used either alone, in mixture with one another, or with other active substances. If necessary, defoliation, plant protection or pest control agents can be added, indeed according to the desired purpose.
In so far as a broadening of the activity spectrum is desired, also other "biocides" can be added. For example, suitable as herbicidally effective mixing partners are those active substances that are set forth in Weed Abstracts, Vol. 31, 1981, under the title "Lists of common names and abbreviations employed for currently used herbicides and plant growth regulators in weed abstracts", which is hereby incorporated by reference. Moreover, also non-phytotoxic materials can be used, which can provide a synergistic increase in activity with herbicides and/or growth regulators, such as among others wetting agents, emulsifiers, solvents and oily additives.
Expediently the active substances according to the present invention or their mixtures can be applied in the form of preparations such as powders, spray agents, granulates, solutions, emulsions or suspensions, with the addition of liquid and/or solid carrier materials or diluting agents and, if necessary, wetting, adhering, emulsifying and/or dispersing aids.
Suitable liquid carrier substances include, for example, water, aliphatic and aromatic hydrocarbons such as benzene, toluene, xylene, cyclohexanone, isophorone, dimethylsulfoxide, dimethylformamide, and, moreover, mineral oil fractions.
Suitable solid carrier materials include, for example, mineral earths such as tonsil, silica gel, talc, kaolin, attaclay, limestone, silicic acid and plant products, such as meal.
As surface-active substances, mention may be made by way of example of calcium lignin sulfonate, polyoxyethylene-alkylphenolethers, naphthaline sulfonic acids and their salts, phenol sulfonic acids and their salts, formaldehyde condensate, fatty alcohol sulfate as well as substituted benzene sulfonic acids and their salts.
The portion of active substance or substances in the various preparations can range within broad limits. For example, the composition may contain about 10 to 80% by weight active substance, about 90 to 20% by weight liquid or solid carrier, as well as if necessary up to 20% by weight surface-active material.
The application of the composition can follow in customary manner, for example with water as carrier in spray brew amounts of about 100 to 1000 liter/ha. An employment of the composition in the so-called low-volume or ultra-low-volume techniques is likewise possible, as is their application in the form of so-called microgranulates.
For production of the preparations, the following components may be employed, by way of example:
A. SPRAY POWDER
(a)
80% by weight active substance
15% by weight kaolin
5% by weight surface-active substance based upon the sodium salt of N-methyl-N-oleyl-taurine and the calcium salt of lignin sulfonic acid
(b)
50% by weight active substance
40% by weight clay minerals
5% by weight cell pitch
5% by weight surface-active substance based upon a mixture of the calcium salt of lignin sulfonic acid with alkylphenolpolyglycolethers.
(c)
20% by weight active substance
70% by weight clay minerals
5% by weight cell pitch
5% by weight surface-active substance based upon a mixture of the calcium salt of lignin sulfonic acid with alkylphenolpolyglycolethers
(d)
5% by weight active substance
80% by weight tonsil
10% by weight cell pitch
5% by weight surface-active substance based upon a fatty acid condensation product
B. EMULSION CONCENTRATE
20% by weight active substance
40% by weight xylene
35% by weight dimethylsulfoxide
5% by weight mixture of nonylphenylpolyoxyethylene or calcium dodecylbenzene sulfonate
C. PASTE
45% by weight active substance
5% by weight sodium aluminum silicate
15% by weight cetylpolyglycolether with 8 Mol ethylene oxide
2% by weight spindle oil
10% by weight polyethyleneglycol
23 parts water.
The new compounds according to the present invention can be produced, for example, by reacting compounds of the Formula ##STR5## with chlorotrimethylsilane and zinc into compounds of the Formula ##STR6## reacting the compounds of Formula III by osmium-tetroxide-catalyzed hydroxylation with t-butyl-hydroperoxide or with N-methyl-morpholin-N-oxide, into compounds of the Formula ##STR7## or with silver acetate and iodine in aqueous acetic acid to form compounds of the Formula ##STR8## and then reacting the compounds of Formula IV or Formula V with peracids to form compounds of the Formula ##STR9## with or without then etherifying the 22-hydroxyl group by means of reacting of its 22-sulfonic acid-ester with an alkali alcoholate, wherein R 2 and R 23 have the above given meaning.
For representation of the compounds according to the present invention, one proceeds for example from 20-acetoxymethyl-5α-pregnane-3,6-dione of Formula II and reacts this in known manner with chlorotrimethylsilane and zinc into compounds of the Formula III.
The further reaction into 2α,3α-cis-glycols of Formula IV follows according to known methods, namely through the osmium tetroxide-catalyzed hydroxylation with 80% t-butylhydroperoxide or with N-methyl-morpholine-N-oxide.
One arrives at the 2β,3β-cis-glycols or their derivatives of Formula V by means of Prevost reaction with silver acetate and iodine in aqueous acetic acid.
The production of the B-ring lactone of Formula I follows through Baeyer-Villiger oxidation with peracids such as trifluoroperacetic acid, performic acid, permaleic acid of the 6-ketosteroids of Formulas IV and V.
The etherification of the 22-hydroxyl group follows in known manner through reaction of a 22-sulfonic acid ester with an alkali alcoholate. Beforehand in advantageous manner a protection of the 2,3-diol grouping, for example as acetonide, is necessary, a hydrolysis of the 22-acetate and reaction of the obtained 22-alcohol with a sulfonic acid chloride, such as methane sulfonic acid chloride, benzene sulfonic acid chloride or p-toluene sulfonic acid chloride being required.
In an alternative synthesis sequence, the etherification of compounds of Formula III can be performed, which is to be joined to the hydroxylation into the cisglycols and thereafter the oxidation into the B-ring lactones of Formula I, which likewise form a part of the subject of the present invention.
The 2,3-alcohols of Formula I can be partially or completely esterified.
The novel features which are considered 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.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
EXAMPLE 1
(a) 20 g of 20S-acetoxymethyl-5α-pregnane-3,6-dione are dissolved in 200 ml tetrahydrofuran. 40 g zinc dust and 37.5 ml trimethylchlorosilane are added thereto and the mixture is heated at reflux for 1.5 hours under argon gasification. After cooling down, the mixture is sucked off by a vacuum, washed with tetrahydrofuran and methanol, and the filtrate is then compressed in a vacuum. After water precipitation, drying of the crude product and filtration over silica gel, it is recrystallized from ethanol-water. In this manner 11.5 g of 20S-acetoxymethyl-5α-pregn-2-ene-6-one are obtained.
MP: 77°-78° C.
(b) 8.4 g of 20S-acetoxymethyl-5α-pregn-2-en-6-one are dissolved in 50 ml tetrahydrofuran, reacted with 5 g N-methylmorpholin-N-oxide, 15 ml water and 20 ml t-butanol, and under stirring, a solution of 100 mg osmiumtetroxide in 15 ml tetrahydrofuran is added. The reaction solution is stirred for 21 hours at room temperature and under exclusion of light. Subsequently it is precipitated in sulfuric acid ice water, which was reacted with 500 mg sodium sulfide, the product is sucked off by vacuum, washed with water, withdrawn in methylene chloride, and evaporated in a vacuum. The crude product (8.6 g) is dissolved in 36 ml pyridine, and after addition of 18 ml acetanhydride and 860 g dimethylaminopyridine, left standing for 2 hours at room temperature. After water precipitation, sucking off of the product in a vacuum, washing with water and then drying, it is recrystallized from acetone-hexane. In this manner 6.1 g of 20S-acetoxymethyl-2α,3α-diacetoxy-5α-pregnane-6 -one are obtained.
MP: 199°-200° C.
Through chromatography of the mother liquor, a further 2.2 g of the above compound are obtained, and 1.6 g 20S acetoxymethyl-2β,3β-diacetoxy-5α-pregnan-6-one.
MP: 142.5°-143.5° C.
(c) 7.5 ml of 30% hydrogen peroxide are suspended in 45 ml methylene chloride, cooled to -10° C., and slowly 46 ml trifluoroacetic acid anhydride are added dropwise, so that the interior temperature does not rise above +10° C. Subsequently, 7.8 g of 20S-acetoxymethyl-2α,3α-diacetoxy-5α-pregnan-6-one, dissolved in 40 ml methylene chloride, are added, followed by stirring for 75 minutes at room temperature. For further working up the product is diluted with methylene chloride and then washed with water and compressed in a vacuum. After chromatography on silica gel and recrystallization from acetone-hexane, one obtains 6.4 g 20S-acetoxymethyl-2α,3α-diacetoxy-B-homo-7-oxa-5α-pregnan-6-one, MP: 228.5°-230° C., and 650 mg of 20S-acetoxymethyl-2α,3α-diacetoxy-B-homo-6-oxa-5α-pregnane-7-one,
MP: 227.5°-229° C.
(d) 3.9 g of 20S-acetoxymethyl-2α,3α-diacetoxy-B-homo-7-oxa-5α-pregnane-6-one are dissolved in 40 ml methanol and 40 ml methylene chloride, and after addition of a solution of 2.5 g potassium hydroxide in 25 ml methanol, stirred for 40 minutes at 20° C. Thereafter the mixture is acidified with acetic acid, precipitated in ice water, after which the product is sucked off in a vacuum, washed with water and then dried. After recrystallization from methanol-methylene chloride, one obtains 2.7 g of 2α,3α-dihydroxy-20S-hydroxymethyl-B-homo-7-oxa-5α-pregnane-6-one.
MP: 242°-244° C.
(e) 1.4 g of 2α,3α-dihydroxy-20S-hydroxymethyl-B-homo-7-oxa-5α-pregnane-6-one are dissolved in 60 ml acetone, followed by an addition of 0.2 ml borotrifluoride-etherate, and then 90 minutes' stirring at 20° C. After an addition of 0.2 ml pyridine, the mixture is compressed in a vacuum, dissolved in ethyl acetate, washed with water and then evaporated. In this manner there are obtained 1.7 g amorphous 2α,3α-isopropylidenedioxy-20S-hydroxymethyl-B-homo-7-oxa-5.alpha.-pregnane-6-one.
1.4 g of the acetonide are dissolved in 6 ml pyridine, cooled to 0° C., reacted with 1 g p-toluene sulfonyl chloride, and then stirred for 3 hours at room temperature. After water precipitation, sucking off of the product in a vacuum, washing with water and then drying, it is recrystallized from ether. In this manner is obtained 2α,3α-isopropylidenedioxy-20S-toxyloxymethyl-B-homo-7-oxa-5.alpha.-pregnane-6-one.
MP: 146°-148° C.
(f) 500 mg 2α,3α-isopropylidenedioxy-20S-tosyloxymethyl-B-homo-7-oxa-5.alpha.-pregnane-6-one in 5 ml toluene are reacted with 1 g potassium propylate, dissolved in 2.5 ml dimethylsulfoxide, followed by stirring for 16 hours at room temperature. Thereafter the reaction mixture is cooled to 5° C., 3.5 ml of 36% perchloric acid are added, followed by stirring for 5 hours at 20° C. After working up and crystallization from ether, one obtains 385 mg 2α,3α-dihydroxy-20S-propoxymethyl-B-homo-7-oxa-5α-pregnane-6-one.
MP: 122°-124° C.
In analogous manner the following are produced:
2α,3α-dihydro-20S-ethoxymethyl-B-homo-7-oxa-5α-pregnane-6-one, MP: 125.5°-127.5° C.
2α,3α-dihydroxy-20S-(2'-methylpropyloxymethyl)-B-homo-7-oxa-5.alpha.-pregnane-6-one, MP: 135°-136° C.
2α,3α-dihydroxy-20S-(2',2'-dimethylpropyloxymethyl)-B-homo-7-oxa-5α-pregnane-6-one
2α,3α-dihydroxy-20S-(n-pentyloxymethyl)-B-homo-7-oxa-5α-pregnane-6-one.
EXAMPLE 2
(a) 1.3 g of 20S-acetoxy-2β,3β-diacetoxy-5α-pregnane-6-one are reacted with trifluoroperacetic acid, as described in Example 1(c). After working up, chromatography and recrystallization, one obtains 1.1 g 20S-acetoxy-methyl-2β,3β-diacetoxy-B-homo-7-oxa-5α-pregnane-6-one, MP: 212.5°-213.5° C., and 130 mg 20S-acetoxymethyl-2β,3β-diacetoxy-B-homo-6-oxa-5α-pregnane-7-one, MP: 190.5°-191.5° C.
(b) 1.1 g 20S-acetoxymethyl-2β,3β-diacetoxy-B-homo-7-oxa-5α-pregnane-6-one are reacted as described in Example 1(d)-(f). In this manner are obtained 280 mg 2β,3β-dihydroxy-20S-propyloxymethyl-B-homo-7-oxa-5α-pregnane-6-one, MP: 105°-108° C.
In analogous manner the following are produced:
2β,3β-dihydroxy-20S-methoxymethyl-B-homo-7-oxa-5α-pregnane-6-one, MP: 93°-95° C.
2β,3β-dihydroxy-20S-ethoxymethyl-B-homo-7-oxa-5α-pregnane-6-one
2β,3β-dihydroxy-20S-ethoxymethyl-B-homo-6-oxa-5α-pregnane-7-one.
EXAMPLE 3
(a) 22.6 g of 20S-acetoxymethyl-5α-pregn-2-en-6-one in 200 ml methylene chloride and 250 ml methanol are stirred with 2.5 g potassium hydroxide for 5 hours at room temperature and under argon atmosphere. The mixture is then neutralized with acetic acid, compressed and then precipitated in water. The product is sucked off in a vacuum, washed with water and then dried. Through recrystallization from methylene chloride/isopropylether there are obtained 18.3 g 20S-hydroxymethyl-5α-pregn-2-en-6-one, MP: 169.5°-170.5° C.
(b) 5 g 20S-hydroxymethyl-5α-pregn-2-en-6-one are reacted in 20 ml pyridine with 5 g p-toluene sulfonylchloride, and stirred for 3.5 hours at room temperature. Thereafter the mixture is precipitated in ice water, the product is sucked off in a vacuum, washed and then dried. Through recrystallization from ether-pentane, there are obtained 7 g 20S-tosyloxymethyl-5α-pregn-2-en-6-one.
MP: 156°-158° C.
(c) 5.4 g of the above tosylate are heated in 170 ml ethanol and 40 ml toluene with 4.5 g potassium ethylate, for 3 hours under reflux. After neutralization with acetic acid, the mixture is evaporated in a vacuum, withdrawn in acetic ester, washed with water and then evaporated. After recrystallization from methanol, one obtains 4.4 g 20S-ethoxymethyl-5α-pregn-2-en-6-one, MP: 64°-66° C.
(d) 4.4 g 20S-ethoxymethyl-5α-pregn-2-en-6-one are dissolved in 25 ml tetrahydrofuran, reacted with 2.5 g N-methylmorpholine-N-oxide, 7.5 ml water and 10 ml tert.-butanol, after which under stirring a solution of 50 mg osmium tetroxide in 15 ml tetrahydrofuran is added. The reaction solution is stirred 16 hours at room temperature. After working up and acetylation as in Example 1(b), one obtains after recrystallization from acetone/hexane 3.15 g 2α,3α-diacetoxy-20S-ethoxymethyl-5α-pregnan-6-one.
MP: 183°-184° C.
(e) 1.5 ml 30% hydrogen peroxide are suspended in 9 ml methylene chloride, cooled to -10° C., and 8.9 ml trifluoroacetic acid anhydride are slowly added dropwise, so that the interior temperature does not rise above +10° C. Subsequently there are added 1.5 g 2α,3α-diacetoxy-20S-ethoxymethyl-5α-pregnane-6-one, dissolved in 8 ml methylene chloride, followed by stirring for 1 hour at 22° C. After working up, chromatography and recrystallization from acetone/hexane, there are obtained 1.2 g 2α,3α-diacetoxy-20S-ethoxymethyl-B-homo-7-oxa-5α-pregnane-6-one, MP: 189.5°-191° C., and 150 mg 2α,3α-diacetoxy-20S-ethoxymethyl-B-homo-6-oxa-5α-pregnane-7-one, MP: 198°-200° C.
(f) 890 mg 2α,3α-diacetoxy-20S-ethoxymethyl-B-homo-7-oxa-5α-pregnane-6-one in 15 ml methanol are stirred for 20 minutes at 20° C. with 500 mg potassium hydroxide, and then further worked up. After recrystallization from ether/pentane, one obtains 695 mg 2α,3α-dihydroxy-20S-ethoxymethyl-B-homo-7-oxa-5α-pregnane-6-one, MP: 128°-130° C.
In analogous manner the following are produced:
2α,3α-dihydroxy-20S-methoxymethyl-B-homo-7-oxa-5α-pregnane-6-one, MP: 151°-152° C.
2α,3α-dihydroxy-20S-ethoxymethyl-B-homo-6-oxa-5α-pregnane-7-one, MP: 136°-137° C.
2α,3α-dihydroxy-20S-butoxymethyl-B-homo-7-oxa-5α-pregnane-6-one
2α,3α-dihydroxy-20S-2',2'-dimethylpropoxymethyl-B-homo-7-oxa-5.alpha.-pregnane-6-one
2α,3α-dihydroxy-20S-methoxyethoxymethyl-B-homo-7-oxa-5α-pregnane-6-one, MP: 46°-48° C.
2α,3α-dihydroxy-20S-propoxyethoxymethyl-B-homo-7-oxa-5α-pregnane-6-one
2α,3α-dihydroxy-20S-methoxyethoxymethyl-B-homo-6-oxa-5α-pregnane-7-one
2α,3α-dihydroxy-20S-butoxyethoxymethyl-B-homo-7-oxa-5α-pregnane-6-one.
EXAMPLE 4
2 g 2α,3α-dihydroxy-20S-methoxymethyl-B-homo-7-oxa-5α-pregnane-6-one are dissolved in 20 ml pyridine, cooled to 0° C. and then reacted with 2 ml acetic anhydride. The reaction mixture is then stirred for 5 hours at 0°-5° C., cast into ice water, sucked off in a vacuum, washed and then dried. After recrystallization from acetone/hexane there are obtained 1.6 g 2α-acetoxy-3α-hydroxy-20S-methoxymethyl-B-homo-7-oxa-5α-pregnane-6-one.
MP: 121°-122° C.
In analogous manner, the following are prepared:
2α-acetoxy-3α-hydroxy-20S-ethoxymethyl-B-homo-7-oxa-5α-pregnane-6-one, MP: 92°-93.5° C.
2α-acetoxy-3α-hydroxy-20S-methoxyethoxymethyl-B-homo-7-oxa-5.alpha.-pregnane-6-one, an amorphous substance
3β-acetoxy-2β-hydroxy-20S-ethoxymethyl-B-homo-7-oxa-5α-pregnane-6-one, MP: 97°-98° C.
2α-acetoxy-3α-hydroxy-20S-ethoxymethyl-B-homo-6-oxa-5α-pregnane-7-one, MP: 111°-112.5° C.
The compounds according to the present invention represent as a rule crystalline colorless and odorless substances which are difficultly soluble in water, conditionally soluble in aliphatic hydrocarbons such as petroleum ether, hexane, pentane and cyclohexane, well soluble in halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethylether, tetrahydrofuran and dioxane, carboxylic acid nitriles such as acetonitrile, ketones such as acetone, alcohols such as methanol and ethanol, carboxylic acid amides such as dimethylformamide, and sulfoxides such as dimethylsulfoxide.
The next Examples illustrate the use possibilities of the compounds according to the present invention, and follow in the form of the above-given preparations.
EXAMPLE 5
Soybeans are soaked with the compounds according to the present invention dissolved in a solvent, in an amount of 50 g active substance per 100 kg seed goods.
For germination, the seeds are placed in glass tumblers with 3 ml water. After 7 days cultivation at 25° C., the following symptoms are evaluated:
shortening and thickening of the hypocotyls, twisting of the hypocotyl necks, reduction of the root layout.
The evaluation follows by classification according to the scheme 0-4, whereby 0=no activity and 4=strongest activity.
______________________________________ Evaluation ofCompounds according to the Invention Symptoms______________________________________2α,3α-dihydroxy-20S--ethyoxymethyl-B--homo- 47-oxa-5α-pregnane-6-one2α,3α-dihydroxy-20S--(2'-methylpropyloxy- 4methyl)-B--homo-7-oxa-5-pregnane-6-one2α,3α-dihydroxy-20S--methoxymethyl-B--homo- 37-oxa-5α-pregnane-6-one2α,3α-dihydroxy-20S--methoxyethoxy-methyl- 2B--homo-7-oxa-5α-pregnane-6-oneControl 0______________________________________
EXAMPLE 6
Beta-beets are placed in a greenhouse and treated in a hydro-culture vessel with 5 and 10 ppm of the active substance, provided as a powdery preparation. After 10 days, the lengthening of the leaves and the beet diameters are determined in comparison to the control. The leaves following the cotyledons are considered.
______________________________________ ppm PercentCompounds active Lengthening PercentAccording to sub- of the Leaves Beetthe Invention stance 5 6 7 Diameter______________________________________2α,3α-dihydroxy- 5 162 141 383 14220S--ethoxymethyl- 10 121 100 383 145B--homo-7-oxa-5α-pregnane-6-one2α,3α-dihydroxy- 5 102 102 233 11520S--propoxymethyl- 10 114 105 317 115B--homo-7-oxa-5α-pregnane-6-one______________________________________
The findings show that the substances according to the present invention lead to an intense stimulation of the vegetative growth of the beets, which signifies an increase in yield.
EXAMPLE 7
The test substances are applied, dissolved in an acetone-containing lanolin oil, to Pinto beans. The application was done after the second internodes had obtained a length of 2 mm. Application amounts of 10, 50 and 100 μg active substance were employed. The evaluation was performed after three days.
In the following Table the percent lengthenings and the classification numbers for the internode growth are set forth. The classification numbers refer to the degree of bending and thickening of the internodes (from 0 to 5).
______________________________________Compounds According to theInvention 100 μg 50 μg 10 μg______________________________________2α,3α-dihydroxy-20S--ethoxy- 20 (4) 131 (4) 39 (1)methyl-B--homo-7-oxa-5-pregnane-6-one2α,3α-dihydroxy-20S--(2'- 39 (4) 25 (3) 0methylpropyloxymethyl)-B--homo-7-oxa-5-pregnane-6-one______________________________________
The findings prove that the compounds according to the present invention cause an intensive stimulation of the vegetative growth.
It will be understood that each of the elements described above, or two or more together, may also find a useful application in other types of growth-regulating compounds differing from the types described above.
While the invention has been illustrated and described as embodied in hexanor-brassinolid-22-ethers, processes for the production of these compounds, as well as compositions containing the same having growth regulatory activity for plants, it is not intended to be limited to the exemplary details, since various modifications may be made without departing in any way from the spirit of the present invention.
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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New hexanor-brassinolid-22-ethers are disclosed, of the formula ##STR1## wherein Z is the group ##STR2## OR 2 and OR 3 are oriented cis 2α, 3α or 2β, 3β, R 2 and R 3 are the same or different and are each hydrogen formyl, C 2 -C 7 -alkyl-CO--, C 2 -C 7 -alkoxy-C 1 -C 3 -alkyl-CO-- or aryl-CO--, and R 23 is straight-chain or branched C 1 -C 7 -alkyl or C 1 -C 7 -alkoxy-C 1 -C 3 -alkyl. Also disclosed are processes for the production of these compounds as well as compositions containing the same having growth-regulatory activity for plants.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a process for the fabrication of submicron copper interconnection on integrated circuit structure by depositing directly a metal layer on the resist layer via displacement deposition to replace the original copper seed layer, followed by copper electroplating to form a submicron copper interconnection.
2. Description of the Related Prior Art
In order to coordinate the increasingly smaller but higher efficient integrated circuit (IC), the fabrication of the interconnection must meet the requirement of deep submicron level. However, due to properties such as resistance, electromigration impedance and the like, aluminum used in traditional process becomes no more advantageous. On the contrary, copper exhibits several advantages such as low resistance, higher melting point, as well as better electromigration impedance. Further, problems associated with the prior art, such as the unavailability of reactive ion etching process and the diffusion into oxide layer, have now been overcome through the research and development of Dual Damascene process. Therefore, copper is now considered as the best material for the next generation IC interconnection.
So far, copper deposition process is a relatively important process for IC or printed circuit board industries, especially for the fine circuit with high aspect ratio. Techniques employing copper as the interconnection in the integrated circuit generally deposit copper through one of following processes: sputtering, physical vapor deposition, chemical vapor deposition, electrochemical deposition and the like.
As to the physical vapor deposition, problems with respect to the overhangs of contact opening have been now in a very difficult state. As to the chemical vapor deposition, a difficulty to be solved is that non-volatile CuCl 2 solid would be generated during the process. Therefore, substituting aluminum circuit with high conductive copper circuit must be conducted with other manners, such as copper deposition by electroplating, for example, that disclosed in U.S. Pat. No. 5,256,274. The depositing solution disclosed in that patent contained 12 ounce of copper sulfate pentahydrate per gallon water, 10% sulfuric acid, 50 ppm chloride ion and 0.4% additives. After researching and developing over 10 years, IBM Company claimed in the end of 1997 that a copper circuit of sub-0.25 micro on IC chip had been accomplished successfully by a electrochemical deposition method. Heretofore, the advantage of copper deposition has been recognized by the semiconductor industry.
Before deposition of copper layer by electroplating manner, a layer of diffusion barrier layer and a thin membrane of seed copper layer must be deposited on the silicon wafer by sputtering or chemical vapor deposition process. The diffusion barrier layer is, at the present time, composed predominantly of titanium nitride (TiN) or tantalum nitride (TaN) and is on a primary object of preventing the diffusion between the copper layer and the dielectric silicon dioxide (SiO 2 ). The copper seed layer is used for conducting electric current during electroplating.
For the academic research on displacement reaction, Yosi Shacham-Diamand et al. proposed in The Electrochemical Society 144 P. 898-908, 1997, a formula for wet activating titanium nitride surface by a solution and yielding a Cu layer as the seed layer for electroplating or electroless plating, thereby preparation of the seed layer by the expensive PVD or CVD process can be eliminated. On the other hand, for the industrial research, IBM Company proposed a process for activating the surface titanium nitride with a solution containing hydrofluoric acid or copper sulfate and subsequently displacement depositing a copper seed layer. This process was described in detailed in their ROC Patent Application No. 86119270.
Deposition of a metal layer on the surface of the barrier layer material by displacement deposition had been taught in several U.S. patents. For example, Baum et al. disclosed in U.S. Pat. No.4,574,095, a process for depositing palladium on a silicon substrate by catalyzing reaction under light irradiation, and subsequently depositing copper by electroless plating thereto.
Wong disclosed in U.S. Pat. No.5,358,907 that, using displacement plating, metal from IB, IIB, IIIA, IVB, VB, VIB, VIIB or VIIIB groups can be deposited on silicon substrate or silicon-containing compound, wherein the formulation of the displacement solution contained hydrofluoric acid (HF).
Valery M. Dubin et al. disclosed in U.S. No. 5,891,513 the use of the displacement process on the integrated circuit, wherein, a solution consisting of 0.001-2 mol/l of copper ion, 0.001-5 mol/l of fluoride ion, and 0.01-10g/l of surfactant could be used to deposit a copper seed layer on a titanium nitride substrate, and then carried out an electroless plating to increase the thickness of the copper layer.
There is still a need in the art a low cost process for fabricating a reliable copper interconnection structure useful for submicron wiring in the integrated circuit chip.
SUMMARY OF THE INVENTION
Accordingly, the invention relates to a low cost process for fabricating copper interconnection structure useful for submicron circuit wiring in the integrated circuit chip, the process comprising displacement depositing a thin metal layer on trench or via subjected to lithographic process, and then depositing a conductor therein by an electroplating or electroless plating process with a solution containing additives to form a metal wiring structure of interconnections or external circuit.
The invention provides also a process for fabricating a interconnection structure on an integrated circuit, the process comprising steps of depositing an insulating dielectric layer on a silicon wafer substrate; defining and forming lines or via through lithographic process and then depositing a layer of barrier material thereon; dipping said substrate in an activating solution and performing displacement deposition to deposit a thin metal layer on the surface of said barrier layer; electrochemical depositing a conductor therein with a solution containing surfactant to form interconnection circuit; and, finally, forming metal interconnection structure by a planarizing or chemical mechanical polishing process (CMP).
Accordingly, one object of the invention is to lower the producing cost of integrated circuit by activating a substrate with a solution and performing displacement deposition to deposit a metal layer thereon as a conducting layer required for subsequent electroplating process, whereby the copper seed layer as the conducting layer by physical or chemical vapor deposition can be avoided and hence the expensive cost on vacuum equipment can be saved.
Another object of the invention is to fill a substantially uniform copper layer on submicron wiring, wherein the aspect ratio of the via is greater than 1, while the width of the via or wiring can be as small as less than 0.2 micron.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention, as well as its many advantages, may be further understood by the following detailed description and drawings in which:
FIG. 1 shows schematically the structures of silicon wafer previously deposited an oxide layer and a dielectric layer thereon;
FIG. 2 shows schematically the structures of the silicon wafer of FIG. 1 after applying a photoresist layer;
FIG. 3 shows schematically the structures of the silicon wafer of FIG. 2 after being subjected to a lithographic process;
FIG. 4 shows schematically the structures of the silicon wafer of FIG. 3 after depositing a barrier material;
FIG. 5 shows schematically the structures of the silicon wafer of FIG. 4 after depositing a copper seed layer through PVD or CVD process;
FIG. 6 shows schematically the structures of the silicon wafer of FIG. 5 after fully filling vias on the surface of the wafer with copper through an electroplating process;
FIG. 7 shows schematically the structures of the silicon wafer of FIG. 6 after being subjected to a final planarizing and CMP treatment;
FIG. 8 shows schematically the structures of the silicon wafer of FIG. 5 after depositing a palladium layer instead of a copper seed layer as in FIG. 5;
FIG. 9 illustrates the deposition of a layer of palladium on a planar tantalum nitride substrate through displacement deposition catalyzed by ammonium hydrogen fluoride;
FIG. 10 illustrates the deposition of a layer of palladium on a planar titanium nitride substrate through displacement deposition catalyzed by potassium iodide;
FIG. 11 shows the silver metal deposited on the surface of titanium nitride through displacement plating;
FIG. 12 illustrates the deposition, after the displacement deposition process, of a copper layer on the surface of palladium/tantalum nitride/silicon substrate directly through an electroplating process; and
FIG. 13 shows the result of filling fine via through an electroplating process with a displacement depositing solution containing surfactant PEG5000.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Electroplating is one type of electrochemical deposition methods, and is based on the respective electrochemical half-reactions occurred at the cathode and the anode under an applied voltage, wherein an oxidation reaction occurs at the anode and a reduction reaction at the cathode, i.e., metal ions in the electrolytic solution is reduced into elemental state and deposited on the surface of the electrode plate. It is this principle that current method utilizes to fabricate copper interconnection that connects elements in various portions of the integrated circuit. Its process can be illustrated as in FIGS. 1 to 7 .
In FIG. 1, numerical reference 1 indicates the initial substrate, that is, the wafer itself. Numerical reference 2 and 4 is the nitride layer of the silicon substrate, i.e., silicon nitride (SiN), while 3 indicates the dielectric layer generated after a heat treatment, namely, the oxide of silicon, i.e., silicon dioxide (SiO 2 ).
The numerical reference 8 in FIG. 2 indicates a photoresist that coats the surface of the substrate and corresponds to a photomask as required by the wiring over the entire integrated circuit.
FIG. 3 shows schematically the result after micro-lithographic etching process, and it is found that part of the dielectric layer and of nitride layer had been removed. Thereafter, the photoresist is removed.
In FIG. 4, a layer of diffusion barrier material 5 is deposited over the dielectric layer, such as titanium nitride (TiN), tantalum nitride (TaN) or tantalum, which functions to prevent the diffusion of copper layer into the dielectric layer during the subsequent heat treatment that might affect the transmission in the interconnection.
FIG. 5 illustrates the deposition of a copper seed layer 6 through physical vapor deposition (PVD) or chemical vapor deposition (CVD), which is used as a conducting layer for electroplating thereafter.
FIG. 6 illustrates, by conducting via the copper seed layer deposited above, trenches or vias are fully filled in a manner of electroplating, where the area indicated at 7 is the copper layer plated via this manner.
FIG. 7 shows the substrate after polishing the protruding part on the surface through a final planarization and chemical mechanical polishing process. The steps as described in FIGS. 1 to 7 can be repeated to fabricate multi-layer copper interconnection structure.
Steps illustrated in FIG. 8 is the process provided according to the invention to replace the step of depositing seed layer with a vacuum equipment as illustrated in step 5 . According to the invention, a wet activating formula is provided to activate the barrier material 5 , that is, tantalum nitride or titanium nitride, deposited as described in FIG. 4, and also allows a contact displacement reaction to be occurred between them and the metal ions in the solution. The formula comprises 0.2-20 g/l of palladium ionic compound, 0.6-60 g/l of halogen ionic compound, 0.9-9 g/l of an inorganic acid, and 10-1000 ppm of a surfactant.
Thus, in one aspect of the invention, a process for displacement depositing a seed layer over a barrier layer on a substrate is provided, wherein said seed layer thus deposited can act as an electrically conducting layer required during filling fine vias through electroplating; said process comprising steps of:
(1)preparing displacement deposition solution, consisting of 0.2-20 g/l of palladium ionic compound, 0.6-60 g/l of halogen ionic compound, 0.09-9 g/l of inorganic acid and 10-1000 ppm of surfactant, and having a pH of about 1 to 7.0; and
(2) immersing said substrate having a barrier material deposited thereon in said depositing solution prepared as in step (1) at a temperature of 20 to 70° C. for 1-20 minutes.
Palladium compound useful in the process of the invention is for example, palladium halide (PdX 2 ), palladium nitrate [Pd(NO 3 ) 2 ], palladium sulfate (PdSO 4 ), palladium perchlorate [Pd(ClO 4 ) 2 ] or palladium acetate [Pd(OA c ) 2 ].
Suitable palladium halide is, for example, palladium chloride (PdCl 2 ), palladium bromide (PdBr 2 ), or palladium iodide (PdI 2 ). Halogen ionic compound useful in the process of the invention is for example, fluoride, chloride, bromide or iodide compound, derived from hydrogen halide or ionic compound form from hydrogen halide with metal from Group IA and IIA.
Inorganic acid useful in the process of the invention is for example, nitric acid (HNO 3 ), sulfuric acid (H 2 SO 4 ), hydrogen fluoride (HF), hydrogen chloride (HCl), hydrogen bromide (HBr) or hydrogen iodide (HI) and perchloric acid (HClO 4 ).
Suitable surfactant useful in the process of the invention is for example, polyethylene glycol, polypropylene glycol, or ethylene oxide (EO)/propylene oxide (PO) copolymer.
In the process of the invention, said barrier layer is tantalum nitride (TaN) or titanium nitride (TiN).
In one embodiment, a formula of depositing solution is consisted of 1.77 g/l of palladium chloride (PdCl 2 ), 5.7 g/l of ammonium hydrogen fluoride (NH 4 F.HF) and 0.63 g/l of nitric acid (HNO 3 ).
In the second step of the process according to the invention comprises dipping the substrate having a deposited resist material thereon into the displacement reaction solution for about 5minutes. The displacement reaction solution has a pH in a range of 1 to 7, preferably 4 to 5, a temperature of 20-70° C., preferably 40° C.
Palladium chloride in the formula functions as the source of palladium ions, while ammonium hydrogen fluoride plays a critical role for driving this reaction. In effect, ammonium hydrogen fluoride itself is a buffer solution of hydrogen fluoride. Moreover, since the solubility of palladium chloride in the aqueous solution is not high, nitric acid is used to increase the solubility of palladium chloride and adjusting the pH of the solution.
In the present invention, the displacement deposition can be carried out not only on the silicon substrate, various silicides, or titanium nitride substrate, but also on the tantalum nitride to substrate. With respective to the barrier material acting as copper conductor, tantalum nitride has better reliability and chemical stability than titanium nitride having cylindrical structure. This facilitates the industrial applicability of the invention. FIG. 9 illustrates the deposition of a dense layer of palladium on the planar tantalum nitride substrate through displacement depositing of palladous ion.
Further, in the present invention, within the composition of the displacement solution, not only copper ion can react with titanium nitride substrate, other metals such as palladium and silver, can also be deposited, through displacement plating, on the surface of titanium nitride substrate and acted as the conducting layer required for subsequent electroplating.
Thus, in another aspect of the invention, a process for displacement depositing a seed layer over a titanium nitride barrier layer on a substrate is provided, wherein said seed layer thus deposited can act as an electrically conducting layer required during filling fine vias through electroplating; said process comprising steps of:
(1) preparing displacement deposition solution, consisting of 0.2-20 g/l of silver ionic compound, 0.6-60 g/l of halogen ionic compound, 0.09-9 g/l of inorganic acid and 10-1000 ppm of surfactant, and having a pH of about 1 to 7.0; and
(2) immersing said substrate having a barrier material deposited thereon in said depositing solution prepared as in step (1) at a temperature of 20 to 70° C. for 1-20 minutes.
Suitable silver ionic compound useful in the process of the invention is silver nitrate (AgNO 3 ) or silver perchlorate (AgClO 4 ). Suitable halogen ionic compound useful herein is for example, fluoride, chloride, bromide or iodide compound, derived from hydrogen halide or ionic compound form from hydrogen halide with metal from Group IA and IIA.
Suitable inorganic acid useful herein is for example, nitric acid (HNO 3 ) or perchloric acid (HClO 4 ).
Suitable surfactant is for example, polyethylene glycol, polypropylene glycol, or ethylene oxide (EO)/propylene oxide (PO).
FIG. 11 shows the deposition of silver on surface of the titanium nitride substrate in displacement depositing manner in one embodiment of the invention, wherein the composition of the formulation used is: 0.2-20 g/l of ionic silver compound, 0.6-60 g/l of halogen ionic compound, 0.9-9 g/l of inorganic acid and 10-1000 ppm of surfactant.
In addition, in the present invention, the strong toxic hydrofluoric acid is not necessarily used in the composition of the displacement depositing solution. This acid can be replaced with ammonium hydrogen fluoride, i.e., the buffer solution of hydrofluoric acid. Furthermore, other halogen ions can be used to replace hydrofluoric acid to drive the contact displacement reaction between metal ions and the substrate. FIG. 10 illustrate the contact displacement reaction of palladium catalyzed by potassium iodide and the deposition thereof on the surface of the titanium nitride substrate.
The inventor believes that the reaction between the barrier material with metal ions in the solution occurs primarily due to the participation of halogen ions. The overall reaction can be generally divided into two half-reactions, wherein the oxidation reaction results in the formation of a complex between the barrier material such as tantalum nitride or titanium chloride, and halogen ion, accompanied with release of electron. The complex may be in a form of titanium hexahalide (TiX 6 2− ) or tantalum hexahalide (TaX 6 − ) complex ions. In addition, electrons released can be received by metal ions in the solution such that the metal ion is reduced into metal atom and deposited on the substrate. These metal ions include copper ion, silver ion and palladium ion, all of them being elements having a high reduction potential, which means that these metal ions are susceptible to oxidation and reduction reaction and hence readily reduced into atomic state. This is why tantalum nitride and titanium nitride both having relatively high chemical stability can be deposited with metal ion thereon through displacement plating.
After carrying out displacement deposition over the barrier material, a copper layer can be deposited and its thickness be increased through electrochemical approach such as electroplating or electroless plating. In one embodiment of the invention, electroplating process commonly used in the industry was used to fill vias. The fundamental formulation of the electroplating solution is: 75 g/l of anhydrous copper sulfate (CuSO 4 ), 92 g/l of sulfuric acid and 200 ppm of chloride ion. FIG. 12 illustrates the deposition of a copper layer over the surface of palladium/tantalum nitride/silicon substrate through electroplating process after the displacement plating.
However, since the diameter of vias to be filled is extremely small, less than about 1.0 micron, the wettability of the depositing solution is also very important. Therefore, a surfactant must be added in the displacement depositing solution or electroplating solution.
As to the additive, H. G. Greutz et al. disclosed in U.S. Pat. No. 4,110,176 that, by using polyalkanol quaternary ammonium salt formed from the reaction product, a bright, low stress and ductile copper layer could be deposited from the acidic copper depositing solution. Dahms et al. in U.S. Pat. No. 4,975,159 compiled and tabulated many types of additives, including lactam formed from alkyloxylation, sulfur-containing compound having aqueous solubilizing groups, and organic compounds. The present invention adopts polyethylene glycol as the additive in the displacement deposition and electroplating solutions, which is different from the prior art techniques. FIG. 13 shows the result of filling fine via through an electroplating process with a displacement depositing solution containing surfactant PEG5000.
As the electroplating system, the present invention adopts the apparatus of R. J. Contolinii as reference, which comprises a main deposition bath, a circulating filtering system, and a automatic controlling system. The main deposition bath is designed as in cylindrical shape, wherein the bath is divided into inner, middle and outer regions. The inner region is the region where electroplating is carried out. The deposition bath is a cylinder in a dimension of 10 cm diameter and 7.5 cm height, has a bottom but not lid, and a wall thickness of about 5 mm. The bottom of the deposition bath has a fixed glass tube which has an opening of 1 cm diameter and a height of 5 mm, and which is perpendicular to the bath bottom. That glass tube is communicated with external pipes, pumps and flowmeter and is functions as the inlet of external depositing solution into the inner bath region. In this configuration, a design of injection flow is set up such that the depositing solution can flush the cathode directly to enhance the mass transfer effect of the metal ion. The middle bath region functions mainly as an overflow region and a filtering channel. The bottom of the middle region is the part extended from the bottom of the inner region. The wall height of the middle region is 11 cm. The outer region of the main deposition bath is in a closed design with a capacity of 1.8 liter, which envelops the middle and inner bath regions. Two openings, low and high, are provided on the bath wall, both in a diameter of 8 mm, and are the inlet and outlet of water from a thermostat, respectively. By circulating water flow of constant temperature, the depositing solution can be kept at a constant temperature such that the electroplating process can be operated at a constant temperature.
In the design of the electroplating bath, in addition to provide the electroplating devices as the cathode and the anode, other sensors can be incorporated, such as reference electrode, thermometer, pH meter and the like, as well as controlling the temperature by means of a thermostat. Moreover, the injection flow type of agitation design that can control flow rate makes most of the operation be carried out in the electroplating bath without using additionally any sub-bath. The volume of the depositing solution in the bath is about 1 liter. The cylindrical design of the main bath forms an approximately symmetric configuration with the arrangement of the cathode and the anode taking upper and lower positions, respectively. The object of this design is to make the distribution of the electric field and fluid field within the deposition bath being more symmetric and the operation of the experiment simpler.
Prior to be drawn into the deposition bath, the depositing solution has to be subjected to active carbon treatment to remove organic impurities and then filtered through filters of 10μ, 5μ, and 1μ, respectively. The circulating filtering system in the electroplating process is consisted primarily of a pump and two filters that can filter off 1μ and 0.2μ, respectively, at a filtering rate of 1.5 L/min., to remove small particulates in the depositing solution. The automatic controlling system is consisted of a potentiostat and a computer processor containing a Autolab software. For example, a potentiostat Model 362 available from EG&G Company can provide deposition bath a constant current and the Autolab software can monitor the current and read data at any time.
EXAMPLE
Depositing solution formulation 1
Palladium chloride
10
g/l
Sodium chloride
30
g/l
Nitric acid
4.5
g/l
Polyethylene glycol
400
ppm
Depositing solution formulation 2
Silver nitrate
12
g/l
Sodium chloride
35
g/l
Nitric acid
5.0
g/l
Polyethylene glycol
500
ppm
Depositing solution formulation 3
Silver nitrate
15
g/l
Sodium chloride
40
g/l
Nitric acid
6.0
g/l
EO/PO copolymer
600
ppm
Many changes and modifications in the above described embodiment of the invention can, of course, be carried out without departing from the scope thereof. Accordingly, to promote the progress in science and the useful arts, the invention is disclosed and is intended to be limited only by the scope of the appended claims.
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A process for the fabrication of submicron copper interconnection useful on IC structures without deposition of copper seed is described. A dense metal layer can be deposited through contact displacement reaction between diffusion barrier layer and metal ions in solution under appropriate conditions. The metal layer formed by the displacement deposition can serve as the conducting material for subsequent copper electroplating. Moreover, the costly process for applying seed layer through CVD or PVD can be eliminated.
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RELATED APPLICATION
[0001] This application is a continuation-in-part of copending U.S. patent application Ser. No. 11/752,207, filed May 22, 2007.
FIELD OF THE INVENTION
[0002] This invention relates generally to bumper systems and methods and, more particularly, to a safety bumper system and method for a high profile vehicle, such as a pick-up truck or sport utility vehicle.
BACKGROUND OF THE INVENTION
[0003] In recent years, sport utility vehicles (“SUV's”) and pick-up trucks have become increasingly popular, particularly in the U.S. auto market. SUV's and trucks generally have a higher profile than conventional passenger vehicles. In a collision, for example where a truck or SUV rear-ends a conventional passenger vehicle, there is a potential that the bumper of the larger vehicle will contact the conventional passenger vehicle above the level of its bumper.
[0004] The consequences of such a bumper-on-vehicle collision can be devastating. The portion of the vehicle body above the bumper of a typical passenger vehicle is generally comprised of sheet metal, and is less structural in nature than the bumper or frame of the vehicle body. The bumper of the taller vehicle can more readily penetrate the sheet metal than it could a bumper or frame, potentially causing increased damage and creating a heightened risk of injury or death of persons traveling in the passenger vehicle. Similar risks can be created from impacts on the front or side portions of conventional passenger vehicles, as well.
[0005] The present invention is concerned with addressing the damage and injury risks associated with the height differential between a typical truck and/or SUV as compared to a conventional passenger vehicle.
SUMMARY OF THE INVENTION
[0006] In accordance with an embodiment of the present invention, a safety bumper system is disclosed. The system comprises, in combination: first and second vertical members adapted to be coupled to a frame of a high profile vehicle; impact pads coupled to a front surface of the first and second vertical members; wherein each impact pad comprises an upper region and a lower region, wherein an outer surface of the lower region slopes outwardly and includes a plurality of grooves; and means for attaching the first and second vertical members to a frame of a vehicle.
[0007] In accordance with another embodiment of the present invention, a safety bumper system is disclosed. The system comprises, in combination: a high profile vehicle having a frame and at least one bumper; first and second vertical members adapted to be coupled to the frame of the high profile vehicle proximate the bumper; wherein the vertical members are adapted to be coupled so that a bottom portion thereof is approximately nine inches above a surface of a road; impact pads coupled to a front surface of the first and second vertical members, wherein each impact pad comprises an upper region and a lower region, wherein an outer surface of the lower region slopes outwardly and includes a plurality of grooves; and means for attaching the first and second vertical members to the frame of the high profile vehicle.
[0008] In accordance with a further embodiment of the present invention, a method for providing enhanced safety for a high profile vehicle is disclosed. The method comprises the steps of: providing a high profile vehicle having a frame and at least one bumper; coupling first and second vertical members to the frame of the high profile vehicle proximate the bumper; wherein the vertical members are coupled so that a bottom portion thereof is approximately nine inches above a surface of a road; and providing impact pads coupled to a front surface of the first and second vertical members, wherein each impact pad comprises an upper region and a lower region, wherein an outer surface of the lower region slopes outwardly and includes a plurality of grooves.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 is a perspective view of a sport utility vehicle, having a safety bumper system consistent with an embodiment of the present invention.
[0010] FIG. 2 is a perspective view of a safety bumper system consistent with an embodiment of the present invention, with a sport utility vehicle to which the system is attached shown in phantom.
[0011] FIG. 3 is a side view of a pick-up truck, having a safety bumper system consistent with an embodiment of the present invention.
[0012] FIG. 4 is a top view of a safety bumper system, consistent with an embodiment of the present invention.
[0013] FIG. 5 is a front view of a safety bumper system, consistent with an embodiment of the present invention.
[0014] FIG. 6 is a side, partially exploded view of a safety bumper system, consistent with an embodiment of the present invention.
[0015] FIG. 7 is a perspective view of a sport utility vehicle, having a safety bumper system consistent with an embodiment of the present invention.
[0016] FIG. 8 is a perspective view of a safety bumper system consistent with an embodiment of the present invention, with a sport utility vehicle to which the system is attached shown in phantom.
[0017] FIG. 9 is a side view of a pick-up truck, having a safety bumper system consistent with an embodiment of the present invention.
[0018] FIG. 10 is a top view of a safety bumper system, consistent with an embodiment of the present invention.
[0019] FIG. 11 is a front view of a safety bumper system, consistent with an embodiment of the present invention, in which an impact pad is shown on a first half of the safety bumper system with a plate portion attached thereto shown in phantom, and a plate portion is shown on a second half of the safety bumper system with an impact pad attached thereto shown in phantom.
[0020] FIG. 12 is a side view of a safety bumper system, consistent with an embodiment of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0021] Referring first to FIGS. 1-3 , an embodiment of a safety bumper system 10 (hereinafter “system 10 ”) consistent with an embodiment of the present invention is shown. The system 10 generally comprises two vertical bumpers 12 , which are positioned in a perpendicular relationship to a bumper 14 of a vehicle 16 .
[0022] Referring specifically to FIGS. 4 and 6 , in one embodiment, the bumpers 12 of the system 10 comprise vertical members 20 and impact pads 22 positioned in front of the vertical members 20 . The vertical members 20 are preferably formed from a high strength material. In one embodiment, the vertical members 20 comprise channel iron, which has a U-shaped cross-section which more readily permits attachment to a vehicle frame 24 . A preferred embodiment consists of a vertical member 20 comprised of channel iron having a width of about 2.5 to 3.0 inches, a thickness of 0.1875 inches, and a depth of about 1.5 inches. In a preferred embodiment, the impact pads 22 may have a thickness of about 2.0 to 2.5 inches for enhanced impact absorption. Preferably, the impact pads 22 are composed of molded rubber or some other suitable material.
[0023] It is preferred to mount the vertical members 20 to the vehicle 16 by welding or otherwise coupling the vertical members 20 directly to the vehicle frame 24 . Such coupling limits the possibility that one or both of the bumpers 12 could become separated from the vehicle 16 in the event of a collision. Referring now to FIG. 5 , when in position, and in order to optimize effectiveness, it is preferred to couple the bumpers 12 to the frame 24 so that a bottom portion of the bumpers 12 is approximately nine inches above a surface of a road 30 on which the vehicle 16 is traveling—a distance defined by the line between points A and B. This positioning should permit the system 10 to extend sufficiently to contact a bumper surface for an overwhelming majority of conventional passenger vehicles that are currently on the market.
[0024] In one embodiment, as shown in FIG. 6 , the bumpers 12 may each further include a bumper cover 26 , which may be of a material commonly used as conventional bumper covers, to enable the system 10 to be visually conformed to the vehicle 16 , including the bumper 14 .
[0025] In one embodiment, the system 10 may be provided during manufacture of a vehicle 16 , so that a vehicle 16 may be sold as a new car with the system 10 in place. In another embodiment, the system 10 may be provided as an after-market attachment, and may be coupled to a vehicle 16 that is already in use.
[0026] Turning now to FIGS. 7-12 , another embodiment of a safety bumper system 40 (hereinafter “system 40 ”) consistent with an embodiment of the present invention is shown. Similar to the system 10 , the system 40 generally comprises two vertical bumpers 42 , which are positioned in a perpendicular relationship to a bumper 14 of a vehicle 16 .
[0027] Referring specifically to FIGS. 10 and 12 , in one embodiment, the bumpers 42 of the system 40 comprise vertical members 50 and impact pads 52 positioned in front of the vertical members 50 . The vertical members 50 are preferably formed from a high strength material. In one embodiment, the vertical members 50 comprise channel iron, which has a U-shaped cross-section which more readily permits attachment to a vehicle frame 24 . A preferred embodiment consists of a vertical member 50 comprised of channel iron having a width of about 2.5 to 3.0 inches, a thickness of 0.1875 inches, and a depth of about 1.5 inches.
[0028] Preferably, the impact pads 52 are composed of molded rubber or some other suitable material. Each impact pad 52 preferably has an overall width of approximately 4.0 inches and an overall length of approximately 12.0 inches. In a preferred embodiment, the impact pads 52 include an upper region 60 and a lower region 62 . The upper region 60 preferably has a thickness of about 2.0 to 2.5 inches for enhanced impact absorption, and preferably extends for a length of approximately 6.0 inches. Preferably, the lower region 62 has a length of approximately 6.0 inches. The lower region 62 preferably slopes outwardly, such that it angles away from the vehicle 16 when in position thereon, as seen in FIGS. 7-9 . In this regard, in a preferred embodiment, a portion of the lower region 62 that is adjacent to the upper region 60 may have a thickness of about 2.0 to 2.5 inches, while a bottom portion 64 (as seen in FIG. 12 ) of the lower region 62 may have a thickness of about 3.0 inches, preferably 3.131 inches. In the event of a collision, the outward sloping of the lower region 62 may assist in preventing an impacting vehicle from sliding upwardly or downwardly along the vertical bumpers 42 upon impact with a vehicle outfitted with the system 40 .
[0029] The lower region 62 further includes a plurality of grooves 54 . In a preferred embodiment, the lower region 62 includes six grooves 54 . However, the lower region 62 may include more or less than six grooves 54 . Preferably, the uppermost groove 54 on each impact pad 52 is positioned approximately 6.249 inches from the top of each impact pad 52 . Preferably, each groove 54 is substantially V-shaped, wherein each “V” forms an angle of approximately 45 degrees. In a preferred embodiment, each groove 54 has a depth of approximately 0.5 inches. Preferably, the distance between consecutive grooves 54 is approximately 1.0 inch. In the event of a collision, the grooves 54 would help an impacting vehicle to become jammed therein, thereby assisting in preventing an impacting vehicle from sliding upwardly or downwardly along the vertical bumpers 42 upon impact with a vehicle outfitted with the system 40 .
[0030] For purposes of attaching the impact pads 52 to the vertical members 50 , each vertical bumper 42 preferably further includes a plate 66 coupled to an inner surface of the impact pad 52 , as seen in FIG. 12 . The plate 66 , in turn, may be coupled to the vertical member 50 . Preferably, the plate 66 is composed of cold rolled steel or some other suitable material. In a preferred embodiment, each plate 66 has a length of approximately 12.0 inches, a width of approximately 4.0 inches, and a thickness of approximately 0.5 inches. Each plate 66 includes a plurality of openings 56 , through which fasteners may be inserted in order to couple the plate 66 to the impact pad 52 . In the embodiment shown in FIGS. 11 and 12 , three openings 56 are included in each plate 66 , but more or less openings 56 may be employed.
[0031] In order to couple each plate 66 to each impact pad 52 , washers 58 may be positioned over each opening 56 and fasteners may be inserted through each opening 56 and into the impact pad 52 . Each plate 66 may be secured to each vertical member 50 by welding or otherwise coupling each plate 66 to each vertical member 50 . Preferably, each washer 58 has a diameter of approximately 2.0 inches.
[0032] It is preferred to mount the vertical members 50 to the vehicle 16 by welding or otherwise coupling the vertical members 50 directly to the vehicle frame 24 . Such coupling limits the possibility that one or both of the bumpers 42 could become separated from the vehicle 16 in the event of a collision. Referring now to FIG. 11 , when in position, and in order to optimize effectiveness, it is preferred to couple the bumpers 42 to the frame 24 so that a bottom portion of the bumpers 42 is approximately nine inches above a surface of a road 30 on which the vehicle 16 is traveling—a distance defined by the line between points A and B. This positioning should permit the system 40 to extend sufficiently to contact a bumper surface for an overwhelming majority of conventional passenger vehicles that are currently on the market.
[0033] In one embodiment, the bumpers 42 may each further include a bumper cover (not shown), which may be of a material commonly used as conventional bumper covers, to enable the system 40 to be visually conformed to the vehicle 16 , including the bumper 14 .
[0034] In one embodiment, the system 40 may be provided during manufacture of a vehicle 16 , so that a vehicle 16 may be sold as a new car with the system 40 in place. In another embodiment, the system 40 may be provided as an after-market attachment, and may be coupled to a vehicle 16 that is already in use.
[0035] Although particular embodiments of the invention have been described in detail for purposes of illustration, various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the invention is not to be limited, except as by the appended claims.
[0036] For example, variation of the measurements disclosed herein would be possible without departing from the spirit or scope of the present invention. In addition, while the system 10 is shown in FIGS. 1-3 as being coupled to the front portion of the vehicle 16 , it should be noted that the system 10 could be coupled—additionally or in the alternative—to a rear bumper 18 of the vehicle 16 . Similarly, while the system 40 is shown in FIGS. 7-9 as being coupled to the front portion of a vehicle 16 , it should be noted that the system 40 could be coupled—additionally or in the alternative—to the rear bumper 18 of the vehicle 16 .
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A safety bumper system for a high profile vehicle, such as a pick-up truck or sport utility vehicle. The system comprises of a pair of vertical members which are coupled to the frame of a high profile vehicle, proximate one of the bumpers. The members are coupled so that they extend downward sufficiently to contact a bumper of a conventional passenger vehicle in the event of a collision between the high profile vehicle and the passenger vehicle. Impact pads are positioned over the vertical members, and bumper covers may be positioned over the pads. The impact pads may slope outwardly and include a plurality of grooves, in order to assist in preventing a conventional passenger vehicle from sliding upwardly or downwardly along the safety bumper system upon impact with the high profile vehicle.
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FIELD OF THE INVENTION
[0001] This invention relates to a ball drying implement for use by an official to dry such game balls as footballs or soccer balls and more particularly to a wearable pouch with an interior of water absorbing material.
BACKGROUND OF THE INVENTION
[0002] A football player or fan will be familiar with an official's use of a towel to dry the game ball when a game is being played in rain or snow.
[0003] The use of a pouch for the purpose of drying footballs has been suggested known in the art. One such pouch is shown in a Stephenson U.S. Pat. No. 5,615,769. That pouch has an outer waterproof covering and an interior, removable moisture-absorbent liner. The pouch has at its top an opening closable by a flap and held closed by hook and loop fasteners. In use the pouch's sides are tied closed by laces. Insertion and retrieval of the football is through the upper opening so that it appears one hand would be needed to pull back the closure flap and the remaining hand of the wearer would be needed to insert or retrieve the football. The pouch is supported by a strap hung from the official's neck and shoulders.
[0004] In another U.S. patent, U.S. Pat. No. 5,730,287 to Martin, a pair of stretchable bag-like ball carriers are attached by a long cord to be draped over the wearer's shoulders. The ball carriers stretch about the exterior of a pair of footballs to hold extra footballs for a game, and they protect those footballs from the weather. There is no, mention of drying the football once it has been in use. Other patents such as those to Hendren U.S. Pat. No. 5,813,080 and Lamonakis et al. U.S. Pat. No. 5,372,414 relate to towels that can be worn for the purpose of drying a ball and include multiple layers. In the Hendren patent, an outer layer of toweling is separated from an inner chamois layer by a water impervious layer. The Hendren arrangement is not a pouch for holding a ball, but rather a multilayer towel. The Lamonakis et al. patent shows a bell-shaped “skirt” of water repellent material that is placed over a towel to keep dry the towel. Lamonakis et al. contemplate inverting the entire arrangement to expose the towel so that a ball can be wiped. The arrangement is not a pouch that can carry a ball or enclose a ball as it is being dried.
[0005] There remains a need, therefore, for a ball drying pouch for use, e.g., with footballs or soccer balls in wet conditions wherein the ball can be inserted easily and one handedly and similarly easily retrieved once the ball has been rubbed dry by an interior water-absorbent liner.
BRIEF SUMMARY OF THE INVENTION
[0006] In accordance with the present invention a ball drying pouch has an exterior layer of substantially water impervious flexible sheet material and an inner lining layer of water absorbent material. The exterior and interior layers are formed, as by sewing or folding, into a pouch capable of containing a ball to be dried. The top and bottom of the pouch so fashioned is closed. One or both side edges of the pouch form openings into which the ball can be inserted. Because the bottom of the pouch is permanently closed, there is little likelihood that an official using the pouch will drop the ball, but only one hand is needed to insert the ball from the side into the pouch to be briefly rubbed, and then retracted, again by a single hand. A busy on-field official can thus readily accomplish drying the ball without diverting his or her attention from other activities on the field.
[0007] In a preferred exemplary embodiment the interior layer of the pouch is chamois. Also in the exemplary preferred embodiment the pouch has attachment provisions for securing the pouch to the official's person or clothing. Typically in the preferred embodiment the pouch is secured to the wearer's belt at two locations along the top of the pouch. One preferred attachment arrangement includes strap loops that receive a wearer's belt to hold the pouch in place. The strap loops can have fasteners that open and close to open and close the loops about the wearer's belt. The strap loops are in one exemplary embodiment sewn to the pouch body. Similarly in one exemplary embodiment the interior water absorbent layer is sewn to the exterior water repellent or impervious layer.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1 is a fragmentary front view of an official wearing a ball drying pouch in accordance with the present invention;
[0009] FIG. 2 is an enlarged front view of the pouch of FIG. 1 and shows its side openings and loop fasteners;
[0010] FIG. 3 is an enlarged fragmentary perspective view showing the manner of assembly of the pouch and the loop fasteners; and
[0011] FIG. 4 is a further fragmentary front view of the official inserting a football into the ball drying pouch of FIG. 1 .
DETAILED DESCRIPTION
[0012] As seen in FIG. 1 , a football official 10 wears a pouch 12 secured to his belt 14 by a pair of strap loops 16 and 18 .
[0013] As shown in FIG. 2 the pouch has a closed top edge 20 , a closed bottom edge 22 , and a pair of side edges 24 and 26 at which are formed openings 28 and 30 . Fixed to the pouch at or near the top edge 20 are a pair of strap loops 32 and 34 for securing the pouch to an official's belt. A pair of quick fasteners 36 and 38 of a known commercially available kind permit opening and closing of the loops 32 and 34 . Other fasteners than those shown can be used as desired. For example Velcro loop and hook fastening patches, snaps, ties or any other known, convenient fastener suitable to bring together the two strap pieces into a loop will suffice. Likewise fastening devices other than the strap loops can hold the pouch 12 in place. For example, hook and loop fastening patches secured to the pouch and the official's uniform could be used to secure the pouch. Clips positioned to clip onto the official's belt loops and attached at or near the top edge 20 of the pouch 12 is a further example alternative.
[0014] The construction of the pouch is better illustrated from FIG. 3 . In the illustrated exemplary embodiment shown, the pouch is formed by an exterior layer 40 of substantially waterproof or water repellent material such as vinyl or other plastic. An interior layer 42 is of chamois or other water absorbent material. In this exemplary embodiment the chamois layer 42 is sewn to the external water resistant material 40 as indicated at 44 , 46 and 48 . At the top edge of the pouch 12 , several strips of binding material 50 , 52 and 54 (seen in FIG. 2 ) are sewn along the edge. The strips straddle the top edge of the brought-together layers and have down-turned edges. Stitching 48 shown in FIG. 3 stitches together the edges of the strips 50 , 52 and 54 and the top four edges of the layers 40 and 42 . The straps that form the strap loops 32 and 34 have strap ends sewn into the interior of the pouch as indicated at 56 . In this particular exemplary embodiment the bottom of the pouch is formed by a seam 58 where the four layers of material are brought together, turned inward and sewn at 46 . It will also be appreciated that, alternatively, a single piece of the multilayer material could be folded at the bottom to form the bottom edge 22 .
[0015] As illustrated in FIG. 4 , because the pouch 12 is open at its sides it is easy for an official to insert a ball, dry the ball and extract the ball with little attention to those operations and without even looking at the pouch and ball. As previously stated this has the advantage of permitting the official to pay more attention to the activities on the field. While stitching has been shown to join the inner and outer layers of the exemplary pouch, it will be appreciated that other means such as hook and loop fastening patches, snaps, laces or other connection means may be used to secure the chamois or other water absorbent layer within the exterior. Also while the joiner of the two layers has been shown in the preferred embodiment as being permanent, the interior lining could be removable if, for example, hook and loop fastening or other easily separable fastening means are used. Also, while both sides of the pouch of the exemplary embodiment have been shown as open, it will be appreciated that just one side could be open without unduly increasing the difficulty of inserting the ball, drying the ball and retrieving the ball for play.
[0016] While a particular exemplary and preferred embodiment has been shown, it will be appreciated that many changes, modifications or revisions in the described ball drying pouch may be made as will be appreciated by those skilled in the art and without departure from the spirit and scope of the invention as set forth in the appended claims.
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A ball drying pouch for, e.g., a football or soccer ball has an absorbent interior liner and a water repellent exterior layer. Fasteners permit the pouch to be worn by an official. The top and bottom edges of the pouch are permanently closed. One or both side edges afford an opening for insertion of a ball for drying.
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This is a divisional of application No. 07/723,038 filed Jun. 28, 1991, now U.S. Pat. No. 5,280,095 Jan. 18, 1994.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a fine particulate crosslinked type N-vinylcarboxylic acid amide resin, a microgel of the crosslinked type N-vinylcarboxylic acid amide resin comprising said resin swelled (gelled) with water or an organic solvent, and a thickener, dispersion stabilizer or lubricant comprising said microgel as the main component. More specifically, the present invention relates to a fine particulate crosslinked type N-vinylcarboxylic acid amide resin having an excellent chemical stability and affinity for water and organic solvents such as alcohols, particularly exhibiting a high thickening ability, dispersion stability and lubricity by absorbing a liquid in which inorganic or organic ions coexist in the system to be gelled, a microgel having a wide usage in various fields due to the excellent characteristics and functions of said resin, and a hydrophilic (organic solvent-philic) thickener, dispersion stabilizer or lubricant comprising said microgel as the main component.
2. Description of the Related Art
In the prior art, fine particles of a crosslinked hydrophilic gel exist as a dispersion of swelled fine particles in water, and the dispersion thereof is a non-Newtonian flow even at a low concentration, and exhibiting a remarkably high viscosity different from that of a water-soluble linear polymer which exists as a solution in water, as is widely known in the art, and has been variously utilized as a thickener, dispersion stabilizer, lubricant for aqueous gel-like products and cosmetics.
As the crosslinked type fine particles known in the art, for example, synthetic polymers such as the crosslinked type polyacrylic acid (carboxyvinyl polymer) and the crosslinked type acrylic acid copolymer may be included.
These crosslinked type fine particles, however, are all crosslinked products of the polymeric electrolyte type, and therefore, exhibit an excellent thickening ability for water containing no electrolyte but exhibit only remarkably low thickening ability for an aqueous liquid containing a large amount of organic or inorganic ions, such as a natural extract, surfactant, perfume, colorant, reactive dye for printing, and cement slurry. This is considered to be a result of a reduced expansion of the chains because of a suppression of a dissociation of the polymeric electrolyte, which is the backbone chain of the crosslinked product in the presence of ions. Further, when polyvalent metal ions exist, an ion crosslinking occurs through the backbone carboxylic acid, whereby a crosslinked polymer with a substantially higher crosslinking density than required is formed, and this lowers the thickening ability.
To overcome the drawback mentioned above, Japanese Unexamined Patent Publication (Kokai) No. 59-232107 discloses crosslinked type fine particles comprising acrylic acid or methacrylic acid ester copolymerized therein as the crosslinked type acrylic acid copolymer fine particles. This method obtains ion resistant crosslinked type fine particles by introducing nonionic and lipophilic backbone chain constituting units into the polymeric electrolyte backbone chain, but the ratio of (meth)acrylic acid ester copolymerized is as small as 3.5% by weight or less, and the ion resistance is not always satisfactory. Further, if the amount of the hydrophilic monomer is increased, the affinity for water may be lowered, and thus a possibility exists that a transparent gel-like product can not be obtained.
In water absorptive resins known in the art, an aqueous dispersion thereof exhibits a viscosity, but because of greater particle size, the system as a whole becomes nonuniform and therefore, does not exhibit a thixotropic viscous behavior.
Further, among natural polymers, such as those which are not fine particles but exhibit a viscous behavior similar to the crosslinked type fine particles, there may be included natural gums such as gum tragacanth, locust bingham, sodium alginate, carrageenan, and guar gum. These natural polymers, although they contain the groups of electrolytes, exhibit a relatively good thickening ability also for an aqueous liquid containing a large amount of ions. Natural polymers, however, are not only cost-inefficient, but also are susceptible to attack by microorganisms, bringing the problem of corruption, and have a peculiar color and odor, and thus the scope of use thereof is limited.
Crosslinked type fine particles can be obtained according to the preparation processes, in addition to Japanese Unexamined Patent Publication (Kokai) No. 59-232107 described above, disclosed in Japanese Unexamined Patent Publication (Kokai) Nos. 59-80411 and 2-258813, by carrying out a precipitation polymerization in an organic solvent. The crosslinked type fine particles also can be prepared by polymerizing an acrylic acid monomer in an aqueous concentrated solution of a salt. In these publications, however, a preparation example using an N-vinylamide compound is not disclosed.
SUMMARY OF THE INVENTION
Accordingly, an object of the present invention is to eliminate the defects possessed by a thickener by using a water absorptive resin as represented by the sodium polyacrylate crosslinked product, particularly a low thickening ability in a liquid wherein inorganic or organic ions coexist (electrolyte solution) or a low chemical stability which is a drawback of natural polymeric compounds or chemically modified products thereof, and further, develop a substance having an affinity not only for aqueous systems but also for other organic solvents such as alcohols, and also exhibiting a thixotropic and free flowing thickening property instead of a sticky thickening ability (fiber forming property) with a tacky substance.
Other objects and advantages of the present invention will be apparent from the following description.
In accordance with the present invention, there is provided a fine particulate crosslinked type N-vinylcarboxylic acid amide resin having an average particle size of 10 μm or less, comprising the backbone chains of a homopolymer or copolymer comprising the repeating units (A) or (A) and (B) of the formulae: ##STR2## wherein R 1 , R 2 and R 3 each independently represents a hydrogen atom or a methyl group; X represents a group --COOY, wherein Y represents a hydrogen atom, an alkali metal, a C 1 -C 18 alkyl group or a lower alkyl group, preferably C 1 -C 4 alkyl group, substituted with hydroxyl group, a dialkylamino group or a quaternary ammonium group; a group --CONHZ, wherein Z represented a hydrogen atom or a lower alkyl group substituted with a dialkylamino group, a quaternary ammonium group, sulfonic acid or an alkali metal salt thereof, preferably a C 1 - C 4 alkyl group; a cyano group, a 2-ketopyrroridinyl group, a lower alkoxy group, preferably a C 1 -C 2 alkoxy group, a lower acyl group, preferably a C 1 -C 4 acyl group, a lower alkoxycarbonyl group, preferably a C 1 -C 4 alkoxycarbonyl group or a lower alkyl group, preferably C 1 -C 4 alkyl group substituted with sulfonic acid or an alkali metal salt thereof, M represents a hydrogen atom, an alkali metal (e.g. Na, K) or ammonium group, with a proviso that when R 3 is methyl group X is not a cyano group, 2-ketopyrrolidinyl group, a lower alkoxy group, a lower acyl group, a lower alkoxycarbonyl group and a lower alkyl group substituted with sulfonic acid or an alkali metal salt thereof, p represents 0 or 1, and the molar ratio of m:n represents 30-100:70-0 and a microgel of a crosslinked type N-vinylcarboxylic acid amide resin comprising said resin gelled with water or an organic solvent, and further a thickener, a dispersion stabilizer or lubricant comprising said microgel as the main component.
In accordance with the present invention, there is also provided a process for preparing a fine particulate crosslinked type N-vinylcarboxylic acid amide with an average particle size of 10 μm or less, which comprises precipitation (co)polymerizing 30 to 100 mole % of (A) a compound represented by the formula (I): CH 2 ═CHNR 1 COR 2 , wherein R 1 and R.sup. 2 each independently represent a hydrogen atom or a methyl group and 0 to 30 mole % of (B) at least one of fumaric acid, maleic acid or iraconic acid or salts thereof, N-vinyl-2-pyrrolidone or compounds of the formula (II): CH 2 ═CR 3 X, wherein R 3 represents hydrogen atom or a methyl group, X represents a group --COOY, wherein Y represents a hydrogen atom, a C 1 -C 18 alkyl group or a lower alkyl group substituted with a hydroxyl group or a dialkylamino group, a group --CONHZ, wherein Z represents a hydrogen atom or a lower alkyl group substituted with a dialkylamino group or sulfonic acid; a cyano group, a lower alkoxy group, a lower acyl group, a lower alkoxycarbonyl group or a lower alkyl group substituted with sulfonic acid, with a proviso that when R 3 is a methyl group, X is not a cyano group, a lower alkoxy group, a lower acyl group, a lower alkoxycarbonyl group and a lower alkyl group substituted with sulfonic acid, in a non-aqueous type solvent which dissolves uniformly the reaction components upon initiation of the reaction, and further, converting the carboxyl groups or sulfonic acid groups in the molecules with an alkali metal hydroxide, if necessary.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Representative specific examples of the respective monomer components of the crosslinked type N-vinylcarboxylic acid amide resin of the above formula are shown below.
Component A: N-vinylformamide, N-vinylacetamide, N-methyl-N-vinylformamide, N-methyl-N-vinylacetamide or the like, particularly preferably N-vinylacetamide.
Component B: acrylic acid, methacrylic acid (hereinafter, called comprehensively (meth)acrylic acid) or their alkali metals salts such as sodium salts and potassium salts; alkyl ester such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, stearyl, palmityl or the like;
hydroxy lower alkyl esters such as hydroxyethyl, hydroxypropyl, hydroxybutyl or the like; lower alkyl esters substituted with lower alkylamino groups such as dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, diethylaminomethyl, diethylaminoethyl, diethylaminopropyl, diethylaminobutyl or the like; lower alkyl esters substituted with quaternary amino groups such as trimethylammonioethyl ester halides, trimethylammoniopropyl ester halides, triethylammonioethyl ester halides, triethylammoniopropyl ester halides or the like;
amides; amides substituted with lower alkylamino groups such as dimethylaminomethylamide, dimethylaminoethylamide, dimethylaminopropylamide, dimethylaminobutylamide, diethylaminomethylamide, diethylaminoethylamide, diethylaminopropylamide, diethylaminobutylamide or the like; lower alkyl amides substituted with quaternary amino groups such as trimethylammonioethylamide halides, trimethylammoniopropylamide halides, triethylammoethylamide halides, triethylammoniopropylamide halides or the like;
lower alkyl amides substituted with sulfonic acid or alkali metal sulfonic acid such as sulfomethylamide, sulfoethylamide, sulfopropylamide, sulfobutylamide, sodium sulfomethylamide, sodium sulfoethylamide, sodium sulfopropylamide, sodium sulfobutylamide, potassium sulfomethylamide, potassium sulfoethylamide, potassium sulfopropylamide, potassium sulfobutylamide or the like;
acrylonitrile; N-vinyl-2-pyrrolidone; vinyl ethers such as methyl vinyl ether, ethyl vinyl ether, propyl vinyl ether, butyl vinyl ether or the like; vinyl ketones such as methyl vinyl ketone, ethyl vinylketone or the like; lower vinyl carboxylates such as vinyl acetate, vinyl propionate or the like;
allylsulfonic acids or alkali metal salts thereof such as allylsulfonic acid, sodium allylsulfonate, potassium allylsulfonate or the like; maleic acid, sodium maleate, potassium maleate, fumaric acid, sodium fumarate, iraconic acid, sodium itaconate, potassium itaconate or the like.
Among the above, particularly preferable are (meth)acrylic acid, sodium (meth)acrylate, methyl (meth)acrylate, ethyl (meth)acrylate, propyl (meth)acrylate, butyl (meth)acrylate, hydroxyethyl (meth)acrylate, dodecyl (meth)acrylate, and stearyl (meth)acrylate, hydroxypropyl (meth)acrylate, hydroxybutyl (meth)acrylate, dimethylaminoethyl (meth)acrylate, trimethylammonioethyl (meth)acrylate chloride, acrylamide, sulfopropylacrylamide, sulfobutylacrylamide, sodium sulfopropylacrylamide, sodium sulfobutylacrylamide, acrylonitrile, methyl vinyl ether, ethyl vinyl ether, methyl vinyl ketone, ethyl vinyl ketone, vinyl acetate, sodium allylsulfonate, N-vinyl-2-pyrrolidone, maleic acid, sodium maleate, itaconic acid, and sodium itaconate.
The copolymer, must contain at least 30 mole % of the component A, as at a ratio lower than that, the ion resistance and absorbability of the organic compounds and the light resistance, which are the specific features of the microgel of the present invention, cannot be fully exhibited. Particularly, when the ion resistance is important, it is preferable to contain 40 mole % or more of the component A, more preferably 50 mole % or more. By incorporating an alkyl ester of acrylic acid or methacrylic acid as the copolymer component, a hydrophobic moiety can formed in addition to the hydrophilic moiety based on the component A in the molecule, thereby obtaining a function like that of a surfactant and thus contributing to a further stabilization of the dispersed particles. However, when used as the hydrophilic thickening agent, the ratio of an alkyl ester of acrylic acid or methacrylic acid is limited to about 5 mole %, and it should be borne in mind that if it is too high, the hydrophobic property is increased, and thus it is possible that the inherent properties of the microgel of the present invention as the hydrophilic thickener may be impaired.
The thickening performance can be further effectively exhibited by adding 20 mole % to less than 50 mole % of anionic components such as acrylic acid, methacrylic acid of the component B, and further, neutralizing the pH to 6-10, if necessary. With less than 20 mole % of the component B or at a pH outside of the above range, the backbone chains of the copolymer will be expanded to a leser extent, whereby the effect of thickening ability will be insufficient although there may be a salt resistance.
For the crosslinking agent usuable in the present invention, a polymerizable compound having at least two unsaturated groups in one molecule is used, and representative specific examples thereof are shown below.
N,N'-lower alkylene bisacrylamides such as N,N'-methylenebisacrylamide, N,N'-1,2-ethylenebisacrylamide, or the like; alkylene glycol di(meth)acrylates such as ethylene glycol di(meth)acrylate, propylene glycol di(meth)acrylate, or the like;
polyalkylene glycol di(meth)acrylates such as diethylene glycol di(meth)acrylate, triethylene glycol di(meth)acrylate, polyethylene glycol di(meth)acrylate, dipropylene glycol di(meth)acrylate, polypropylene glycol di(meth)acrylate or the like;
polyol tri(meth)acrylates such as trimethylolpropane tri(meth)acrylate, pentaerythritol tri(meth)acrylate, or the like;
divinyl compounds such as divinyl benzene, divinyl ether, or the like.
trimethylolpropanediallyl ether, pentaerythritoltriallyl ether, triallyl phosphate, tetraallyloxyethane, sucrose allyl ester or the like.
N,N'-lower alkylenebis(N-vinylcarboxylic acid amide) such as N,N'-methylenebis(N-vinylacetamide), N,N'-1,3-propylenebis(N-vinylacetamide), N,N'-1,4-butylenebis(N-vinylacetamide), N,N'-1,5-pentylenebis(N-vinylacetamide), N,N'-1,6-hexylenebis(N-vinylacetamide), N,N'-1,7heptylene bis(N-vinylacetamide), N,N'-1,8-octylenebis(N-vinylacetamide), N,N'-1,9-nonlylenebis(N-vinylacetamide), N,N'-1,10-decylenebis(N-vinylacetamide), N,N'-diacetyl-N,N'-divinyl-1,3-butanediamine, N,N'-diacetyl-N,N'-divinyl- 2,5-hexanediamine, N,N'-diacetyl-N,N'-divinyl2,4-pentanediamine, N,N'-diacetyl-N,N'-divinyl-2,2-diethyl-1,3-propanediamine, N,N'-diacetyl-N,N'-divinyl-2,5-dimethyl-2,5-hexanediamine, N,N'-diacetyl-N,N'-divinyl-2,4-dimethyl-2,4-pentanediamine, N,N'-diacetyl-N,N'-divinyl-2,2-dimethyl-1,3-propanediamine, N,N'-diacetyl-N,N'-divinyl-2-ethyl-1,5-hexanediamine, N,N'-diacetyl-N,N'-divinyl-2-ethyl-2-methyl-1,3propanediamine, N,N'-diacetyl-N,N'-divinyl-2-methyl-1,3-butanediamine, N,N'-diacetyl-N,N'-divinyl-2-methyl-1,5-pentanediamine, N,N'-1,3-propylenebis(N-vinylformamide), N,N'-1,4-butylenebis(N-vinylformamide), N,N'-1,5-pentylenebis(N-vinylformamide), N,N'-1,6-hexylenebis(N-vinylformamide), N,N'-1,7-heptylenebis(N-vinylformamide), N,N'-1,8-octylenebis(N-vinylformamide), N,N'-1,9-nonylene-bis(N-vinylformamide), N,N'-1,10-decylenebis(N-vinylformamide), N,N'-diformyl-N,N'-divinyl-1,3-butanediamine, N,N'-diformyl-N,N'-divinyl-2,5-hexanediamine, N,N'-diformyl-N,N'-divinyl-2,4-pentanediamine, N,N'-diformyl-N,N'-divinyl-2,2-diethyl-1,3-propanediamine, N,N'-diformyl-N,N'-divinyl-2,5-dimethyl-2,5-hexanediamine, N,N'-diformyl-N,N-divinyl-2,4-dimethyl-2,4-pentanediamine, N,N'-diformyl-N,N'-divinyl-2,2-dimethyl-1,3-propanediamine, N,N'-diformyl-N,N'-divinyl-2-ethyl-1,3-hexanediamine, N,N'-diformyl-N,N'-divinyl-2-ethyl-2-methyl-1,3-propanediamine, N,N'-diformyl-N,N'-divinyl-2-methyl-1,3-butanediamine, N,N'-diformyl-N,N'-divinyl-2-methyl-1,5-pentanediamine, N,N'-diformyl-N,N'-divinyl-2-methyl-1,5-pentanediamine, N,N'-diacetyl-N,N' -divinyl-1,3-bis(aminomethyl)cyclohexane, N,N'-diacetyl-N,N'-divinyl-1,4-bis(aminomethyl)cyclohexane, N,N'-diformyl-N,N'-divinyl-1,3-bis(aminomethyl)cyclohexane, N,N'-diformyl-N,N'-divinyl-1,4-bis(aminomethyl)cyclohexane or the like;
N,N'-diacetyl-N,N'-divinyl-α,ω-diaminopolyesthers) such as N,N'-3-oxa-1,5-pentylenebis(N-vinylacetamide), N,N'-3,6-dioxa-1,8-octylenebis(N-vinylacetamide), N,N'- 3,6,9-trioxa-1,11-undecylenebis (N-vinylacetamide), N,N'-3,6,9,12-tetraoxa-1,14-tetradecylenebis (N-vinylacetamide), N,N'-3-oxa-1,5-pentylenebis (N-vinylformamide), N,N'-3,6-dioxa-1,8-octylenebis (N-vinylformamide), N,N'-3,6,9-trioxa-1,11-undecylenebis (N-vinylformamide), N,N'-3,6,9,12-tetraoxa-1,14-tetradecylenebis(N-vinylformamide), N,N'-(1,4-dimethyl)-3-oxa-1,5-pentylenebis(N-vinylacetamide), N,N'-(1,4,7-trimethyl)-3,6-dioxa-1,8-octylenebis(N-vinylacetamide), N,N'-(1,4,7,10-tetramethyl)-3,6,9-trioxa-1,11-undecylenebis(N-vinylacetamide), N,N'-(1,4,7,10,13-pentamethyl)-3,6,9,12-tetraoxa-1,14-tetradecylenebis(N-vinylacetamide), N,N'-(1,4-dimethyl)-3-oxa-1,5-pentylene bis(N-vinylformamide), N,N'-(1,4,7-trimethyl)-3,6-dioxa-1,8-octylenebis(N-vinylformamide), N,N'-(1,4,7,10-tetramethyl)-3,6,9-trioxa-1,11-undecylenebis(N-vinylformamide), N,N'-(1,4,7,10,13-pentamethyl)-3,6,9,12-tetraoxa-1,14-tetradecylenebis(N-vinylformamide) or the like;
N,N'-xylylenebis(N-vinylcarboxylic acid amide) such as p-xylylenebis(N-vinylformylamide), p-xylylenebis(N-vinylacetamide), m-xylylenebis(N-vinylformylamide), m-xylylenebis(N-vinylacetamide) or the like.
Among the above, particularly preferable are N,N'-methylene bisacrylamide, N,N'-1,4-butylenebis(N-vinylacetamide), N,N'-1,6-hexylenebis(N-vinylacetamide), N,N'-1,10-decylenebis(N-vinylacetamide), N,N'-3-oxa-1,5-pentylenebis(N-vinylacetamide), N,N'-3,6-dioxa-1,5-octylenebis(N-vinylacetamide), N,N'-p-xylylenebis(N-vinylacetamide), N,N'-diacetyl-N,N'-divinyl-1,4bis(aminomethyl)cyclohexane, trimethylolpropane tri(meth)acrylate, pentaerythritol tri(meth)acrylate, divinylbenzene, tetraallyl-oxyethane, triallyl phosphate, trimethylolpropane diallyl ether, pentaerythritol triallyl ether, sucrose allyl ether, or the like.
The amount of the crosslinking agent to be used in the present invention is not particularly limited, but is generally 0.01 to 10 mole %, preferably 0.1 to 6.0 mole %, more preferably 0.5 to 4.0 mole %, based on the monomer components. In this connection, if the amount of the crosslinking agent is more than 10 mole % based on the monomer components, the crosslinking density of the resin obtained becomes too high, whereby the swelling ratio will be remarkably lowered to sometimes exhibit no thickening effect. On the other hand, if it is less than 0.01 mole %, the ratio of the polymer chains not crosslinked will be increased, whereby the resin becomes readily soluble in water or an organic solvent to exhibit a fiber forming property, and thus does not have a thixotropic property as the thickener. The mixture of two or more compounds mentioned above can also be used.
The amount of the crosslinking agent is considerably larger than that of the crosslinked hydrophilic resins in general, and this is absolutely necessary for obtaining the desired crosslinking density. However, in the microgels of the present invention, since they are fine particles, no gelatin-like mass is formed and a good flow characteristic can be exhibited in spite of the high crosslinking density thereof.
As the polymerization process for the fine particulate crosslinked N-vinylamide resin according to the present invention, the precipitation polymerization process can be employed.
The process comprises dispersing or dissolving the monomer components and the crosslinking agent in a nonaqueous solvent, thoroughly removing the dissolved oxygen and elevating the temperature to a reaction initiation temperature. Then, an initiator is added to carry out the reaction, and the resin formed with the progress of the reaction is precipitated as fine particles in the solvent. By filtration, drying and maceration of the resin, a fine particulate resin is obtained. As the reaction solvent, there may be employed one which is not necessarily required to uniformly dissolve the reaction components at room temperature, but uniformly dissolves the reaction components (monomer components and crosslinking agent) upon initiation of the reaction, and further in which the resin formed is insoluble, but a stable non-aqueous solvent generally stable during a radical polymerization may be employed without particular limitation. Representative specific examples thereof are set forth below.
Aromatic or aliphatic hydrocarbons such as benzene, toluene, xylene, ethylbenzene, hexane, heptane, octane or the like, aliphatic ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone or the like, esters such as ethyl acetate, butyl acetate, isopropyl acetate or the like, alkyl amides such as dimethylformamide, dimethylacetamide or the like, sulfoxides such as dimethylsulfoxide or the like, and so on.
Among the above, it is particularly preferable to use benzene, toluene, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate.
As the polymerization initiator, peroxides, organic peracids, azobis type compounds which can be uniformly dissolved in the solvent may be employed, and their representative examples are as shown below.
t-butyl peroxide, t-amyl peroxide, cumyl peroxide, acetyl peroxide, propionyl peroxide, benzoyl peroxide, benzoyl isobutyryl peroxide, lauroyl peroxide, t-butyl hydroperoxide, cyclohexyl hydroperoxide, tetralin hydroperoxide, t-butyl peracetate, t-butyl perbenzoate, bis(2-ethylhexylperoxy dicarbonate), 2,2-azobis-1-butyronitrile, phenylazotriphenyl-methane.
Among the above, particularly the use of benzoyl peroxide, t-butyl hydroperoxide, 2,2-azobis-i-butyronitrile is preferred.
The amount of the polymerization initiator to be used in the present invention is not particularly limited, but may be, for example, 0.01 to 5 mole % based on the monomer components, preferably 0.05 to 3 mole %, particularly 0.1 to 2%. In this connection, if the amount of the polymerization initiator is more than 10 mole % based on the monomer components, the polymerization degree of the backbone chain cannot be made higher, but the ratio of the polymer chains not crosslinked will be increased, whereby the polymer tends to become readily soluble in water or an organic solvent and sometimes does not act as a thickener. On the other hand, if the amount of the polymerization initiator employed is less than 0.01 mole %, the conversion of the polymerization reaction cannot be made higher, and thus a drawback arises in that the residual amount of the monomer is increased. Other reaction conditions also are not particularly limited, but may be as generally described below.
Amount of solvent employed: equal to 20-fold of the monomers, preferably equal to 15-fold, particularly equal to 10-fold of the monomers;
Polymerization initiation temperature: 50° C. to the boiling point of the solvent;
Reaction time: about 3 to 8 hours.
The resin thus obtained has a molecular structure in which a linear polymer comprising a homopolymer of an N-vinylcarboxylic acid amide or a copolymer together with other copolymerization components forms the backbone chain, which is crosslinked with a crosslinking agent to give a three-dimensional structure, and primarily, the size of the molecule and the state of the crosslinked state, i.e., the molecular weight, the crosslinking density and the particle size of the backbone chain are most important for obtaining the functions as the thickener, dispersion stabilizer, and lubricant of the resin according to the present invention.
For example, theoretically the thickening performance can be improved by making the backbone chain as large as possible, but the number of molecules not participating in the crosslinking will be increased and the solubility will become higher, whereby the distance between the crosslinks will be increased to remarkably lower the thixotropic property of the gel formed by absorption of the liquid. Therefore, the average polymerization degree of the backbone chain is preferably 500,000 to 100, more preferably 400,000 to 1000, particularly 200,000 to 10,000, and the crosslinking density is 1/10,000 to 1/10, preferably 1/1000 to 3/50, more preferably 1/200 to 1/25.
When the backbone chain is a copolymer, there is slight difference in structure depending on the difference in reactivity of the copolymerized component. For example, when acrylamide, maleic acid, etc. are employed as the copolymerized component, alternate copolymerization will frequently occur, although this depends on the molar ratio charged in the reaction. On the other hand, when acrylic acid, etc. is employed, a block copolymerization will frequently occur, while a random copolymerization well occur in the case of vinyl acetate, etc. However, the difference in structure of the backbone chain copolymer depending to the reactivity of the copolymerized component may add respective characteristic functions in individual use examples, but it is not essential as a whole in the functions as the thickener, dispersion stabilizer, lubricant of the resin according to the present invention.
Further, the fine particulate resins according to the present invention can effect an excellent thickening effect to water, various organic solvents and mixtures thereof, although conventional crosslinked polyacrylic acids, which are typical thickening agents, dispersion stabilizers and bubricants can effect their functions only to water or a mixture of water and a lower alcohol. Typical examples of organic solvents, which can be thickened by the present fine particulate are those mentioned below, which are generally called solvents having a relatively high polarity:
Alcohols such as methanol, ethanol, 1-propanol, 2-buternol, isobutyl alcohol, isoamyl alcohol, cyclopentanol, allyl alcohol, 1,1,1,3,3,3-hexafluoro-2-propanol, 2-methoxyethanol, 2-ethoxyethanol, 2-butoxyethanol, 2-aminoethanol, ethylene glycol, trimethylene glycol, propylene glycol, 1,4-butane diol, 1,3-butane diol, α,3-butane diol, triethylene glycol, glycerol; phenols such as phenol, cresol; other solvents such as formaldehyde, acetic acid, 2-pyrrolidinone, dimethyl sulfoxide, pyridine. Furthermore, examples of solvent mixtures of organic solvents, each of which is not thickenable alone or is difficult to be thikened by the present thickner, but which are thickenable as a mixture, are water-organic solvent mixtures such as those of water with, for example, N,N-dimethylformamide, phenol, acetone, tetrahydrofuran, or dioxane; those of organic solvents such as ethanol-acetone, ethanol-chloroform, ethanol-benzene, ethanol-ethylacetate, methanol-methylene chloride, and ethyl acetate-acetic acid.
Although it is not clear why the present resins can thicken the above-mentioned wide variety of solvents, the polarity of the solvent system to be thickned is considered as a measure of the intensity of the interaction between the crosslinked type N-vinyl carboxylic acid amide resin, according to the present absorbent, and the solvent system. As measures for representing the intensity of the polarity of solvents, a dielectric constant (ε), a solubility parameter (δ), a solvent polarity parameter (E T or Z value) and the like are known in the art. As a result of various analyses, the above-mentioned absorbable organic solvents all have an E T value of 45 or more in the case of a single solvent and an E T value of 43 or more in the case of a mixed solvent. Further, it has been confirmed that solvents having an E T value of less than the above-mentioned values are not substantially thickned by the present adsorbents. Thus, it can be defined that organic solvents which are thicknable by the present resins are those having an E T value of 45 or more in the case of a single solvent and an E T value of 43 or more in the case of a mixed solvent. Especially, the good correlations between the E T value and the thickening effect exist in those having an E T value of 50 or more, more preferably 53 or more, as either a single solvent or a mixed solvent.
EXAMPLES
The present invention is described in more detail with reference to Examples, which in no way limit the scope of the present invention.
EXAMPLE 1
A solution of 99 g of N-vinylacetamide and 1.0 g of N,N'-methylenebis(acrylamide) as the crosslinkig agent dissolved in 900 g of benzene was boiled, 0.1 g of azobis(isobutyronitirile) was added as the initiator thereto and the boiling state was maintained. With the progress the polymerization, the polymer formed was precipitated into benzene, which was filtered and vacuum dried at 40° C. for 24 hours and macerated, to obtain a white fine powder with an average particle size of 2 μm.
The thickening ability of the fine powder was evaluated, in terms of a viscosity of 1% dispersion in pure water when neutral (pH 6-8), and the results are shown in Table 1. Further, the salt resistant when sodium chloride was added to the solution was evaluated in terms of the dispersion viscosity. The results are shown in Table 2.
EXAMPLE 2
The reaction was carried out by the same procedure as in Example 1, except that N-vinylformamide was used in place of N-vinylacetamide, to obtain a white fine powder with an average particle size of 4 μm.
EXAMPLE 3
The reaction was carried out by the same procedure as in Example 1, except that ethyl acetate was used as the polymerization solvent in place of benzene, to obtain a white fine powder with an average particle size of 2 μm.
EXAMPLE 4
A solution of 70 g of N-vinylacetamine, 30 g of acrylic acid, and 2.0 g of divinylbenzene as the crosslinking agent dissolved in 900 g of ethyl acetate was boiled, 0.4 g of azobisisobutyronitrile was added as the initiator, and the boiling state was maintained. With the progress of the polymerization, the polymer formed was precipitated into ethyl acetate. Then, the same procedure as in Example 1 was carried out to obtain a white fine powder with an average particle size of 2 μm. The tests of the thickening ability and salt resistance performance were conduct in the same manner as in Example 1, and the results are shown in Table 1 and able 2.
EXAMPLE 5
The reaction was carried out in the same way as in Example 4 except that 55 g of N-vinylacetamide and 45 g of acrylic acid was used in place of 70 g of N-vinylacetamide and 30 g of acrylic acid, to obtain a white powder with an average particle size of 2.5 μm. The tests of thickening ability and salt resistance were conducted in the same manner as in Example 4, and the results are shown in Table 1 and Table 2.
EXAMPLE 6
A solution of 90 g of N-vinylacetamide, 10 g of methacrylic acid and 1.5 g of tetraallytloxyethane as the crosslinking agent dissolved in 500 g of ethyl acetate was boiled, 0.3 g of benzoyl peroxide was added as the initiator, and the boiling state was maintained. With the progress of polymerization the formed polymer was precidpitated into ethyl acetate, and then the same procedure as in Example 1 was carried out to obtain a white fine powder with an average particle size of 2 μm.
EXAMPLE 7
A solution of 70 g of N-vinylacetamide, 29 g of acrylic acid, 2.0 g of tetraallyloxy-ethane as the crosslinking agent dissolved in 600 g of ethyl acetate was boiled, 0.3 g of benzoyl peroxide was added as the initiator, and the boiling state was maintained. With the progress of the polymerization, the formed polymer was precipitated into ethyl acetate, and then the same procedure as in Example 1 was carried out to obtain a white fine powder with an average particle size of 2 μm.
EXAMPLE 8
A solution of 90 g of N-vinylacetamide, 9 g of methacrylic acid, 1 g of stearyl methacrylate and 1.0 g of pentaerythritol triacrylate as the crosslinking agent dissolved in 900 g of acetone was boiled, 0.3 g of cumyl peroxide was added as the initiator, and the boiling state was maintained. With the progress of the polymerization, the formed polymer was precipitated into ethyl acetate, and then the same procedure as in Example 1 was carried out to obtain a white fine powder with an average particle size of 1.5 μm.
EXAMPLE 9
A solution of 80 g of N-vinylacetamide, 20 g of 2-acrylaide-2-methylpropanesulfonic acid and 0.8 g of N,N'-butylenebis(N-vinyl;acetamide) as the crosslinking agent dissolved in 900 g of acetone was boiled, 0.3 g of cumyl peroxide was added as the initiator, and the boiling state was maintained. With the progress of the polymerization, the polymer formed was precipitated into ethyl acetate, and then the same procedure as in Example 1 was carried out to obtain a white fine powder.
EXAMPLE 10
A solution of 90 g of N-vinylacetamide, 10 g of methyl vinyl ether and 3.0 g of divinyl ether as the crosslinking agent dissolved in 900 g of acetone was boiled, 1.0 g of t-butyl hydroperoxide was added as the initiator, and the boiling state was maintained. With the progress of the polymerization, the formed polymer was precipitated into ethyl acetate, and then the same procedure as in Example 1 was carried out to obtain a white fine powder with an average particle size of 3 μm.
EXAMPLE 11
A solution of 60 g of N-vinylacetamide, 40 g of acrylamide and 3.0 g of N,N'-methylenebisacrylamide as the crosslinking agent dissolved in 900 g of acetone was boiled, 0.4 g of azobisisobutyronitrile was added as the initiator, and the boiling state was maintained. With the progress of the polymerization, the formed polymer was precipitatyed into ethyl acetate, and then the same procedure as in Example 1 was carried out to obtain a white fine powder with an average particle size of 3 μm.
EXAMPLE 12
The reaction was carried out according to entirely the same procedure as in Example 11 except that ethyl vinyl ether was used in place of acrylamide to obtain a white fine powder with an average particle size of 3 μm.
EXAMPLE 13
A solution of 85 g of N-vinylacetamide, 15 g of vinyl acetate and 3.0 g of N,N'-butylenebis(N-vinylacetamide) as the crosslinking agent dissolved in 900 g of acetone was boiled, 0.3 g of azobisisobutyronitrile was added as the initiator, and the boiling state was maintained. With the progress of the polymerization, the formed polymer was precipitated into ethyl acetate, and then the same procedure as in Example 1 was carried out to obtain a white fine powder with an average particle size of 3 μm.
EXAMPLE 14
A solution of 70 g of N-vinylacetamide, 30 g of acrylic acid and 2.5 g of trimethylolpropane trimethacrylate as the crosslinking agent dissolved in 700 g of benzoyl peroxide was boiled, 0.3 g of azobisisobutyronitrile was added as the initiator, and the boiling state was maintained. With the progress of the polymerization, the formed polymer was precipitatyed into ethyl acetate, and then the same procedure as in Example 1 was carried out to obtain a white fine powder with an average particle size of 2 μm.
EXAMPLE 15
The reaction was carried out by the same procedure as in Example 4, except that 40 g of N-vinylacetamide, 30 g of 2-acrylamide-2-methylpropanesulfonic acid and 30 g of acrylic acid to obtain a white fine powder with an average article size of 4 μm.
EXAMPLE 16
The reaction was carried out by the same procedure as in Example 14 except that triallyl phosphate was used in place of trimethylolpropane trimethacrylate to obtain a white fine powder with an average particle size of 4 μm.
EXAMPLE 17
The reaction was carried out by the same procedure as in Example 4, except that trimethylolpropane diallyl ether was used in place of divinylbenzene to obtain a white fine powder with an average particle size of 2 μm.
EXAMPLE 18
The reaction was carried out by the same procedure as in Example 4, except that N,N'hexylenebis(N-vinylacetamide) was used in place of divinylbenzene to obtain a white fine powder with an average particle size of 2 μm.
EXAMPLE 19
The reaction was carried out by the same procedure as in Example 1 except N,N'-(diacetyl)-N,N'-(divinyl)-1,3-bis(aminomethyl)cyclohexane was used in place of N,N'-methylenebis acrylamide to obtain a white fine powder with an average article size of 1 μm.
EXAMPLE 20
The reaction was carried out by the same procedure as in Example 4, except that N,N'-butylenebis(N-vinylacetamide) was used in place of divinylbenzene to obtain a white fine powder with an average article size of 1 μm.
EXAMPLE 21
The reaction was carried out by the same procedure as in Example 4 except methyl ethyl ketone was used in place of ethyl acetate as the solvent to obtain a white fine powder with an average article size of 5 μm.
EXAMPLE 22
The reaction was carried out by the same procedure as in Example 4 except that toluene was used in place of ethyl acetate as the solvent to obtain a white fine powder with an average article size of 1 μm.
EXAMPLE 23
The reaction was carried out by the same procedure as in Example 1 except that isopropyl acetate was used in place of benzene as the solvent to obtain a white fine powder with an average article size of 1 μm.
EXAMPLE 24
Into a solution of 70 g of N-vinylacetamide, 30 g of acrylic acid, 1.5 g of N,N'-butylenebis(N-vinylacetamide) as the crosslinking agent dissolved in 900 g of ethyl acetate was bubbled nitrogen at 1 (liter/min.) for 30 minutes, and the solution then elevated to a temperature of 70° C. As the initiator, 0.3 g of azobisisobutyronitrile was added, and this state was maintained at 80° C. in a nitrogen atmosphere. With the progress of the polymerization, the formed polymer was precipitated into ethyl acetate, and then the same procedure as in Example 1 was carried out to obtain a white fine powder with an average particle size of 1 μm. The tests of the thickening ability and salt resistance were conducted in the same manner as in Example 1, and the results are shown in Table 1 and Table 2.
EXAMPLE 25
The reaction was carried out by the same procedure as in Example 24 except that 100 g of N-vinyl acetamide was used in place of ethyl acetate as the solvent, to obtain a white fine powder with an average article size of 1 μm.
EXAMPLE 26
The reaction was carried out by the same procedure as in Example 25 except that the polymerization temperature was changed from 70° C. to 90° C. to obtain a white fine powder with an average article size of 2.1 μm.
EXAMPLE 27
Into a solution of 70 g of N-vinylacetamide, 29 g of acrylic acid, 1 g of stearyl methacrylate, 2.0 g of pentaerythritol triacrylate as the crosslinking agent dissolved in 900 g of acetone was bubbled nitrogen at 1 (liter/min.)liter/min.) for 30 minutes, and the solution then elevated to a temperature of 50° C. As the initiator, 0.3 g of azobisisobutyronitrile was added, and this state was maintained at 50° C. in a nitrogen atmosphere. With the progress of the polymerization, the formed polymer was precipitated into ethyl acetate, and then the same procedure as in Example 1 was carried out to obtain a white fine powder with an average particle size of 1 μm. The tests of the thickening ability, salt resistance were conducted in the same manner as in Example 1 was carried out to obtain a white fine powder with an average particle size of 1.5 μm.
EXAMPLE 28
The reaction was carried out by the same procedure as in Example 27 except that 95 g of N-vinyl acetamide, 5 g of vinyl acetate, in place of 70 g of N-vinylacetamide, 29 g of acrylic acid, 1 g of stearyl methacrylate, and 2.0 g of trimethylolpropane diallyl ether were used in place of pentaerythritol triacrylate as the crosslinking agent to obtain a white fine powder with an average particle size of 0.2 μ.
EXAMPLE 29
The reaction was carried out by the same procedure as in Example 26 except that 90 g of N-vinylacetamide and 10 g of maleic anhydride was used in place of 70 g of N-vinylacetamide and 30 g of acrylic acid to obtain a white fine with an average article size of 2.0 μm.
EVALUATION TESTS
1) Thickening ability.
By measuring the 1% aqueous dispersion viscosity, when neutral (pH 6-8), of the fine powders obtained in Examples 1, 4, 5 and 24, the thickening abilities of these fine powders were evaluated. The results are shown in Table 1.
TABLE 1__________________________________________________________________________ Example Comparative Example 1 4 5 24 1 2 3 4 5 6 7 8__________________________________________________________________________Viscosity of 1% 5000 10500 12000 11000 65000 6000 500 4000 1000 7000 55000 7000dispersion in deionizedwater(CPS)pH of 1% dispersion in 6.2 6.3 6.2 6.5 6.4 6.5 6.3 6.4 6.3 6.5 6.5 8.0deionized water__________________________________________________________________________
Method of Measuring viscosity of Pure water Dispersion
Into a tall 200 ml beaker was charged 198 g of deionized water, and 2 g of the fine powder obtained in Example was dispersed therein so that no mass was formed. The viscosity of the 1% aqueous dispersion thus obtained was measured by using a BL type viscometer under the conditions of a No. 4 rotor, 30 rpm, and 320° C. In the Example wherein the monomers containing carboxylic acids such as acrylic acid, methacrylic acid, etc, and anhydride are copolymerized, the viscosity was measured after neutralizing with 10% aqueous NaOH to a pH of 6.0-8.0.
2) Salt resistance
The salt resistance when sodium chloride was added to the 1% dispersion used in the deionized water dispersion viscosity measurement as described above was evaluated in terms of the dispersion viscosity. The results are shown in Table 2.
SALT RESISTANCE TEST
In the 1% aqueous dispersion prepared according to the deionized water dispersion viscosity measuring method, NaCl wa added and dissolved to the solid concentrations in the liquid as shown in Table 2, and the viscosities were measured.
TABLE 2__________________________________________________________________________Amount ofNaCl added Example Comparative Example(%) 1 4 5 24 1 2 3 4 5 6 7 8__________________________________________________________________________0 5000 10500 12000 11000 65000 6000 500 4000 800 7000 55000 70000.1 3400 7200 7500 7400 1000 800 230 2800 400 3500 2000 45000.2 2200 5400 5900 5800 30 28 160 1800 130 2600 900 30000.5 520 1700 2600 2400 4 4 100 350 30 950 10 6501.0 150 550 1050 950 4 4 100 100 20 550 5 1902.0 50 240 650 500 4 4 100 80 20 150 5 90__________________________________________________________________________
3) Solubility in Ethyl alcohol
A 1% dispersion of the fine particles obtained in each Example was prepared with ethyl alcohol (purity 99%), and the solubilities in ethyl alcohol of the resins were compared. The results are shown in Table 3.
4) Dispersion stability of Talc
To observe the degree of the effect of the dispersibility of the fine particles obtained in the respective Examples, 1% aqueous dispersions of a pH of 6-8 were prepared, and 10 g of the dispersion and 10 g of talc were mixed, and the precipitation after 24 hours was observed. The results are shown in Table 3.
5) Lubricity
To observe the degree of the effect of lubricity, a 0.1% aqueous dispersion of a pH of 6-8 was prepared and the sample solution coated by an applicator to a thickness of 200 μm on a plate made of defatted metal, and the dynamic coefficient of friction was measured immediately by a plane pressurizing member (9 cm 2 ) using a surface characteristic tester (Heidon). The results are shown in Table 3.
TABLE 3__________________________________________________________________________ Example Comparative Example 1 4 7 8 1 2 4__________________________________________________________________________Solubility in Dissolved Swelled Swelled Swelled Insoluble Insoluble Swelledethyl alcoholDispersibility + + + + ± - -of talcLubricity + + + + + + -__________________________________________________________________________ Dispersibility of talc +: no precipitation observed, and stable dispersion state maintained ±: slight precipitation observed. -: mostly precipitated. Lubricity +: friction coefficient: less than 0.01 (high lubricity) ±: friction coefficient: 0.01 to 0.3 -: friction coefficient: more than 0.3 (low lubricity). 6) Dissolution in organic solvent
A 100 mg amount of the fine particulate resin obtained in Example 1 was added to 50 ml of organic solvents and it was visually observed how the resins are dissolved in the solvents, while occasionally stirring, at room temperature. The resins having a good solubility were dissolved for 30 minutes to several hours, to increase the viscosity of the solution. Those having no solubility were remained, even after one week, in the form of near white powder. The solubility was evaluated as follows:
++: Dissolved within one day
+: Dissolved at a slow rate
-: Not dissolved even after one week
These results are shown, together with the E T value of each solvent, in Tables 4 and 5 (single solvent) and Table 6 (mixed solvent). There were no solvents in which the resin was dissolved within one day to several days. The abbreviations in Tables 4 to 6 are as follows:
HFIP : 1,1,1,3,3,3-hexafluoro-2-propanol
THF : Tetrahydrofuran
DMSO: dimethylsulfoxide
NMP: N-methylpyrolidinone
DMF : N,N,-dimethylacetamide
DMA c : N,N-dimethylacetamide
TABLE 4______________________________________Solvent Solubility E.sub.T______________________________________HFIP ++ 65.3water ++ 63.1phenol ++ 61.4p-cresol ++ 60.8glycerol ++ 57formamide ++ 56.6glycol ++ 56.3methanol ++ 55.5trimethyleneglycol ++ 54.9propylene glycol ++ 54.11,4-butandiol ++ 53.5triethleneglycol ++ 53.51,3-butandiol ++ 52.82-methoxyethanol ++ 52.3allyl alcohol ++ 52.1N-methylacetamide + 52ethanol ++ 51.92-aminoethanol ++ 51.82,3-butandiol ++ 51.8acetic acid ++ 51.22-ethoxyethanol ++ 511-propanol ++ 50.71-butanol + 50.22-butoxyethanol ++ 50.2ethyl acetoacetate - 49.4amyl alcohol - 49.1______________________________________
TABLE 5______________________________________Solvent Solubility E.sub.T______________________________________isoamyl alcoho ++ 491-hexanol + 48.8isopropyl alcohol + 48.6isobuthyl alcohol ++ 48.62-pyrolidinone ++ 48.31-octanol - 48.32-butanol ++ 47.1cyclopentanol ++ 47acetonitrile + 46DMSO - 45NMP - 44.1DMF - 43.8DMAc - 43.7acetone - 42.2nitroenzene - 42metylene chloride - 41.1pyridine - 40.2chloroform - 39.1ethylacetate - 38.1THF - 37.4chlorobenzene - 36.81,4-dixane - 36.3diethylamine - 35.4benzene - 34.5triethylamine - 33.3cyclohexane - 32.1______________________________________
TABLE 6______________________________________ Composition ofSolvent mixture solvent Solubility E.sub.T______________________________________water-dioxane 0:100 - 36 10:90 - 46 30:70 ++ 51 50:50 ++ 54 100:0 ++ 63ethanol-acetone 0:100 - 42 10:90 - 47 50:50 ++ 51 100:0 ++ 52chloroform-ethanol 0:100 ++ 52 12:88 ++ 51 50:50 ++ 48 60:40 ++ 47 70:30 ++ 46 80:20 ++ 46 90:10 ++ 44 100:0 - 39methanol-methylene 0:100 - 41chloride 4:96 - 46 9:91 ++ 48 39:61 ++ 51 100:0 ++ 56water-acetone 0:100 - 42 20:80 - 48 40:60 - 51 50:50 - 52 60:40 ++ 53 100:0 ++ 63water-THF 0:100 - 37 40:60 - 48 80:20 ++ 51 100:0 ++ 63______________________________________
COMPARATIVE EXAMPLE 1
A 1% deionized water dispersion was prepared by using a crosslinked type polyacrylic acid (Carbopol 940: B. F. Goodrich) in place of the polymer in Example 1, and the thickening ability and the salt resistance were measured in the same manner as in Example 1. The results are shown in Table 1 and Table 2. Also, evaluations of the ethyl alcohol solubility, dispersion stability of talc, and lubricity were conducted in the same manner as in Example 1. The results are shown in Table 3.
COMPARATIVE EXAMPLE 2
By using a commercially available sodium polyacrylate type water absorbent resin, a 1% aqueous dispersion was prepared and thickening ability and salt resistance were measured in the same manner as in Example 1. The results are shown in Table 1 and Table 2. Also, evaluations of the ethyl alcohol solubility, dispersion stability of talc, and lubricity were evaluated in the same manner as in Example 1. The results are shown in Table 3.
COMPARATIVE EXAMPLE
A solution of 70 g of N-vinylacetamide, 30 g of acrylic acid, 20.0 g divinylbenzene as the crosslinking agent dissolved in in 900 g of ethyl acetate was boiled, 0.4 g of azobisisobutyronitrile was added as the initiator and the boiling state was maintained. With the progress of the polymerization, the formed polymer was precipitated into ethyl acetate, and then the same procedure as in Example 1, a white fine powder was obtained. The tests of the thickening ability and salt resistance were conducted in the same manner as in Example 1, and the results are shown in Table 1 and Table 2.
COMPARATIVE EXAMPLE 4
The reaction was carried out by the same procedure as in Comparative Example 3, to obtain a white fine powder. The 1% dispersion exhibited no thixotropic liquid property. The tests of the thickening ability and salt resistance were conducted in the same manner as in Comparative Example 3, and the results are shown in Table 1 and 2. Also, evaluations of the ethyl alcohol solubility, dispersion stability of talc, and lubricity, were made in the same manner as in Example 1. The results are shown in Table 3.
COMPARATIVE EXAMPLE 5
The reaction was carried out in the same manner as in Comparative Example 3, except that the 20.0 g of divinylbenzene of the crosslinking agent was changed to 2.0 g, and the amount of azobisisobutyronitrile of the initiator added was changed 0.4 g to 11.0 g, to obtain a white fine powder. The tests of thickening ability and salt resistance were conducted in the same manner as in Comparative Example 3, and the results are shown in Table 1 and Table 2.
COMPARATIVE EXAMPLE 6
The reaction was carried out in the same manner as in Comparative Example 3 except that the 20.0 g of divinylbenzene was changed to 2.0 g, and the amount of azobisisobutyronitrile of the initiator added was changed 0.4 g to 0.01 g to obtain a white fine powder. The 1% dispersion exhibited no thixotropic liquid property. The tests of the thickening ability and salt resistance were conducted in the same manner as in Comparative Example 3, and the results are shown in Table 1 and Table 2.
COMPARATIVE EXAMPLE 7
The reaction was carried out in the same manner as in Comparative Example 3, except that 20.0 g of the divinylbenzene of the crosslinking agent was changed to 2.0 g, and 30 g of acrylic acid was changed to 109 g of N-vinylacetamide and 90 g of acrylic acid to obtain a white fine powder. The tests of the thickening ability and salt resistance were conducted in the same manner as in Comparative example 3, and the results are shown in Table 1 and Table 2.
COMPARATIVE EXAMPLE 8
A solution of 70 g of N-vinylacetamide, 30 g of sodium acrylate and 0.3 g of N,N'-butylenebis(N-vinylacetamide) dissolved in 400 g of water was adjusted to a temperature of 40° C. As the initiator, 0.4 g of 2,2'-azobis(2-amizinopropane) dihydrochloride was added, and the state of 40° C. was maintained. With the progress of the polymerization, the viscosity of reaction mixture became increased, until it finally became a gelatin-like transparent solid mass. The mass was macerated, dehydrated to remove the water contained in acetone, vacuum dried at 40° C. for 24 hours, and then crushed to obtain a white powder. The 1% dispersion exhibited no thixotropic liquid property. The tests of the thickening ability and salt resistance were conducted in the same manner as in Comparative Example 1, and the results are shown in Table 1 and Table 2.
APPLICATION EXAMPLE 1: WARP GLUE
Using an aqueous glue solution having the following composition;
______________________________________partially saponified polyvinyl alcohol 7.0 wt. partsprocessed starch (corn starch) 3.0 wt. partsacrylic glue 0.5 wt. partspolymer of Example 4 0.3 wt. partsoil agent 0.6 wt. partswater 88.6 wt. parts______________________________________
the glueing, drying and wind-up were carried out for a warp beam comprising 5000 No. 40 cotton monofilament. The glued warp obtained had good physical properties and fabricability.
APPLICATION EXAMPLE 2: MOISTURIZING HAND LOTION
______________________________________A deionized water 85 wt. parts glycerine 5 wt. parts propylene glycol 1 wt. parts methyl p-hydroxybenzoate 0.2 wt. parts propyl p-hydroxybenzoate 0.1 wt. partsB mineral oil 5 wt. parts paraffin wax 1 wt. parts glycol stearate 1 wt. parts acetylated lanoline alcohol 0.6 wt. parts dimethicone 0.5 wt. parts polymer obtained in Example 7 0.2 wt. partsC triethanolamine 0.2 wt. parts PEG-15-cocamine 0.2 wt. partsD fragrance q.s.______________________________________
The components A were mixed with stirring at 70° C., the oil components, excluding the polymer of Example 7, were mixed, and then the polymer of Example 7 was added and mixed at 70° C. To the components A were added the components B, and the mixture was vigorously agitated for 30 minutes, followed by an addition of the components C to neutralize the mixture, and the fragrance was added with stirring and the mixture cooled. Thus, a hand lotion having a good dispersibility of the oil components and a stable product viscosity with a lapse of time was obtained.
APPLICATION EXAMPLE 3; FACIAL CLEANSING CREAM
______________________________________A deionized water 78 wt. parts polymer of Example 8 0.2 wt. parts glycerine 5 wt. parts PEG-8 0.5 wt. parts methyl p-hydroxybenzoate 0.1 wt. parts imidazolidinyl urea 0.3 wt. partsB paraffin wax 0.5 wt. parts capric acid triglyceride 2 wt. parts mineral oil 13 wt. partsC triethanolamine 0.2 wt. parts PEG-15-cocamine 0.2 wt. parts______________________________________
In deionized water was dispersed the polymer of Example 8, and the remainder of the component A was added, followed by stirring at 70° C. The oil components of B were mixed at 70° C., and the components B were added slowly to the components A, the mixture was vigorously agitated, and then the components C were added to neutralize the mixture, followed by cooling with stirring. Thus, a facial cleansing cream with a good dispersion of the oil components and a smooth feeling was obtained.
APPLICATION EXAMPLE 4: SUN SCREEN LOTION
______________________________________A deionized water 81.2 wt. parts polymer of Example 8 0.2 wt. parts methyl p-hydroxybenzoate 0.2 wt. parts propyl p-hydroxylbenzoate 0.2 wt. partsB coconut oil 5 wt. partsC triethanolamine 0.2 wt. partsD octyldimethyl PABA 5 wt. parts benzophenone 3 wt. parts octyl salicylate 5 wt. partsE fragrance q.s.______________________________________
In the purified water was dispersed the polymer of Example 8, and the remainder of the components A was added, followed by stirring well. To the components A were slowly added the components B and the mixture was stirred, then the components C were added to neutralize the mixture and the UV-ray absorbers of the components D were uniformly mixed. The resultant mixture was added to a neutralizing solution, stirred, and the perfume was added. Thus, a sun screen lotion with a good dispersion of the UV-ray absorber was obtained.
APPLICATION EXAMPLE 5: PRINTING GLUE
A polymer dispersion was obtained by adding 20 parts by weight of the polymer obtained in Example 11 to 70 parts by weight of mineral spirit (isoparaffin mixture having a boiling point of 207°-254° C.), followed by stirring for 20 minutes. Then, 10 parts by weight of sodium carbonate was mixed, while stirring, with the dispersion, followed by stirring for 20 minutes to prepare a 20% polymer mixture.
Using the following black and red dyes, two types of basic printing glue compositions were prepared.
______________________________________ Composition A Composition B______________________________________cold water 38.5 wt. parts 32.3 wt. partssilicone antifoamer 0.25 wt. parts 0.25 wt. partssurfactant*.sup.1 0.25 wt. parts 0.25 wt. partsreactive red 24*.sup.2 4.0 wt. parts --reactive black 8*.sup.2 -- 8.0 wt. partsurea 10 wt. parts 10 wt. partssodium m-nitrobenzene 0.5 wt. parts 0.5 wt. partssulfonatehot water 37.5 wt. parts 37.5 wt. parts20% polymer mixture 6.0 wt. parts 7.5 wt. partsKHCO.sub.3 3.0 wt. parts 2.5 wt. partsNa.sub.2 CO.sub.3 -- 1.2 wt. parts______________________________________ *.sup.1 hexaoxyethylene nonylphenyl ether *.sup.2 monochlorotriazine dye (Chiba Geigy)
The silicone antifoamer and surfactant were dissolved in cold water in a container provided with an agitator. To this solution, the dye was added, followed by adding the urea and sodium m-nitrobenzene sulfonate dissolved in hot water. Thereafter, the 20% polymer mixture was added and KHCO 3 and/or Na 2 CO 3 were further formulated to obtain the desired printing glue composition.
Using the printing glue composition prepared above cotton fabrics were screen printed. After printing, the printed fabrics were dried at 100° C. for 5 minutes and then steam heated using a saturated streams at 105° C. for 10 minutes, followed by rinsing with cold water. The fabrics were then stirred at 100° C. for 5 minutes in an aqueous solution of Igepal CO-630, followed by rinsing with cold water and drying at 100° C. for 10 minutes. The reflectance R was measured and the lightness (k/s) was calculated from the following equation.
Lightness(k/s)=(100-R)2/2R
Furthermore, the viscosity of the printing glue composition was determined using BH type viscometer at 20 rpm. The results are shown below.
______________________________________Composition Viscosity of composition (cps) k/s______________________________________A 12000 381B 7800 2842______________________________________
By using the polymer according to the present invention, it is observed that the compound exhibits a high glue viscosity and good salt resistance.
Furthermore, no substantial legginess is found and the desired screen print can be effected with a good dying ratio by a flowability suitable for the screen printing.
APPLICATION EXAMPLE 6: ZINC ALKALI BATTERY
A zinc alkali battery provided with an anode cell containing an arrode agent mainly composed of manganese dioxide, a separator and a zinc cathode was prepared according to a conventional manner.
To 196 g of a 40% aqueous potassium hydroxide solution saturated with zinc oxide, 2 g of the polymer obtained in Example 5 was added and uniformly dispersed therein. Further, 10 g of a powder of mercury-zinc alloy containing 0.02% indium, 0.05% lead and aluminum was dispersed to obtain the zinc cathode.
The zinc cathode using the polymer obtained in the present invention exhibited a good stability, because the viscosity thereof was not changed, and no separation due to dispersion and liquid leakage occurred even when the zinc cathode was stored for a long time. Furthermore, the battery obtained therefrom had electrical discharge characteristics such that a continuous discharge time (i.e., a time in which the battery voltage is lowered to 0.9 V) of 5 hours at 20° C.
APPLICATION EXAMPLE 7: LIQUID CLEANSER
Liquid cleansers having the following formulations were prepared.
______________________________________ Formulation A Formulation B______________________________________Silicon dioxide (size 2-100 μm) 7 wt. parts --Bentonite (size 2-150 μm) -- 10 wt. partsPolymer of Example 14 0.3 wt. parts 0.3 wt. partsHexaoxyethylene lauryl ether 3 wt. parts 3 wt. parts(HLB 12)Ethanol 3 wt. parts 3 wt. partsWater 86.7 wt. parts 83.7 wt. partsTriethanolamine q.s. (adjusting to pH 7)Viscosity of composition (cps) 1500 1800BL type viscosimeter 30 rpm______________________________________
The liquid cleanser using the polymer according to the present invention was maintained in a stable state, without separation, when stored for a long time. Especially, when the system was subjected to a freezing-remelting cycle for a long time, the remelting system exhibited a good stability. Furthermore, since the dispersibility was good, a wide surface area could be cleansed with a small amount of the cleanser and since the viscosity was low, the cleanser was easily shaken out and discharged from the container.
APPLICATION EXAMPLE 8: LIQUID SHAMPOO
Liquid shampoo compositions having the following formulations were prepared.
______________________________________ Composition A Composition B______________________________________Triethanolamine lauryl sulfate 20 wt. parts 18 wt. partsLauric diethanolamide 3 wt. parts --Lauric monoethanolamide -- 2 wt. partsPropylene glycol 10 wt. parts --Polymer of Example 10 0.5 wt. parts --Polymer of Example 10 -- 0.5 wt. partsTriethanolamine 2 wt. parts 7 wt. partsBismuth oxychloride 1 wt. parts --(iridescent pigment)Zinc pyrithione -- 1 wt. parts(water-insoluble bactericide)Flavour q.s. q.s.Coloring agent q.s q.s.Water 63.5 71.5Viscosity of composition 450 500BL type viscometer 30 rpm______________________________________
The liquid shampoo using the polymer obtained in the present invention exhibited a good stability, without causing the precipitation of bismuth oxychloride or zinc pyrithine even after storing at 50° C. or room temperature for 3 months. Especially, when the liquid shampoo was subjected to a freezing-remelting cycle for a long time, the remelted shampoo still exhibited a good stability. Furthermore, since the viscosity was low, the shampoo was easily shaken out and discharged from the container.
APPLICATION EXAMPLE 9: GELLED NAIL LACQUER REMOVER
A gelled Nail Lacquer remover having the following formulation was prepared.
______________________________________A Acetone 288 wt. parts Deionized water 38 wt. parts Propylene glycol 38 wt. parts Polymer of Example 9 8 wt. partsB PEG-15-cocamine 8 wt. partsC Glycerol 20 wt. parts______________________________________
The polymer of Example 9 was dispersed in the acetone, followed by adding the remaining component A and stirring at 70° C. The component B was then gradually added and neutralized and stirred, and finally, the component C was added to obtain a transparent gelled product. The removal effect thereof was good.
APPLICATION EXAMPLE 10: LIQUID DETERGENT (FOR SOIL ADHERED TO WALLS AND CEILINGS OF, FOR EXAMPLE, KITCHENS)
Liquid detergents having the following formulations were prepared.
______________________________________ Composition A Composition B______________________________________Sodium dodecylbenzene 3 wt. parts --sulfonateNonaoxyethylene lauryl ether -- 5 wt. partsSodium metasilicate 2 wt. parts --Sodium hydroxide -- 2 wt. partsPolymer of Example 5 2.5 wt. parts 3 wt. partsWater 92.5 wt. parts 90 wt. partsViscosity of composition (cps) 4000 3500BL type viscometer 30 rpm______________________________________
The liquid detergent using the polymer obtained in the present invention exhibited a good stability, without changes in the viscosity or a separation even when the detergent was stored for a long time (at 35° C. for 60 days). Furthermore, the retentionability of the liquid detergent on a vertically placed polypropylene plate was good since, when detergent was attached to the vertical surface of the polypropylene, the detergent did not flow down.
APPLICATION EXAMPLE 11: LIQUID DETERGENT (FOR FUNGUS SOIL ATTACHED TO TILE JOINT PORTIONS AND WALLS OF, FOR EXAMPLE, BATH ROOMS)
Liquid detergents having the following formulations were prepared.
______________________________________ Composition A Composition B______________________________________Sodium dodecylbenzene 1 wt. part --sulfonateSodium metasilicate 2 wt. part --Sodium hydroxide -- 1 wt. partSodium hypochlorite 2 wt. part 2 wt. partSilicon dioxide 30 wt. part --Polymer of Example 14 2 wt. part 3 wt. partWater 63 wt. part 94 wt. partViscosity of composition (cps) 3300 7300BL type viscometer, 30 rpm______________________________________
The liquid detergent using the polymer obtained in the present inventions exhibited a good stability, without changes in the viscosity or a separation even when the detergent was stored for a long time (35° C. for 60 days). Furthermore, the retentionability of the liquid detergent on a vertically placed polypropylene plate was good since, when the detergent was attached to the vertical surface of the polypropylene, the detergent did not flow down.
APPLICATION EXAMPLE 12: SUSTAINED RELEASE PREPARATION FOR ORAL CAVITY (PREPARATION COMPRISING AN ADHESIVE LAYER AND A MEDICINE LAYER APPLIED BY ATTACHING TO TUNICA MUCOSA ORIS)
Oral preparations having the following preparations were prepared.
______________________________________ Preparation Preparation A B______________________________________(A) Composition foradhesive layerPolymer of Example 4 5 wt. part 5 wt. partEthylcellulose 1 wt. part 0.2 wt. partGlycerol fatty acid ester 1 wt. part --Titanium dioxide 0.4 wt. part --Caster oil -- 0.5 wt. partEthanol 60 wt. part 60 wt. part(B) Composition formedicine layerVinyl acetate resin 10 wt. part 10 wt. partHydroxypropylmethyl 1 wt. part 1 wt. partcelluloseacetate succinateTriethyl citrate 0.5 wt. part 0.5 wt. partAcetone 10 wt. part 10 wt. partMethanol 2 wt. part 2 wt. partProstaglandin E.sub.2 0.1 --Prostaglandin E.sub.1 -- 0.1 wt. part______________________________________
The above composition for adhesive layer was spread over a release paper, followed by drying to obtain an adhesive sheet having a thickness of 100 μm. Then, the composition for the medicine layer was spread over the adhesive layer, followed by drying to form a medicine layer having a thickness of 100 μm.
The sustain-release preparations for an oral cavity according to the present invention can be applied as a sheet-like oral poultice, and a desired long time sustained adhesion and medicine release can be obtained.
APPLICATION EXAMPLE 13: POULTICE
A poultice having the following formulation was prepared.
______________________________________ Composition______________________________________Polymer of Example 4 4.5 wt. partSodium polyacrylate 2.5 wt. partGlycerol 20 wt. partKaolin 10 wt. partPurified water 52 wt. partl-Menthol q.s.Methyl salicylate______________________________________
The polymer of Example 4 and sodium polyacrylate were dispersed in glycerol, and then a suspension of the kaolin in the purified water was added thereto, followed by adding the methyl salicylate and others. After kneading, the composition was spread over a non-woven fabric to obtain the poultice.
APPLICATION EXAMPLE 14: GELLED OINTMENT (TRANSPARENT)
A 3 g amount of the polymer obtained in Example 5 was swollen in 25 g of distilled water. On the other hand, 3 g of ketoprofene and 2 g of hydroxypropyl cellulose (HPC-M available from Nippon Soda K.K.) were dissolved in a mixed solvent of 39 of ethanol and 10 g of isopropanol and the resultant solution was added to the above-prepared polymer, followed by thoroughly stirring. To the resultant mixture, 0.4 g of diisopropanol amine dissolved in 17.6 g of distilled water was added and stirring was effected until the mixture became totally uniform, to thus obtain the desired translucent gelled ointment composition.
APPLICATION EXAMPLE 15: GELLED OINTMENT (CREAMY)
A 2 g amount of the polymer obtained in Example 5 was swollen in 66 g of distilled water. On the other hand, 3 g of ketoprofen and 1 g of polyethleneglycol monostearate (MYB-40 available from Nikko Chemicals K. K.) were dissolved in a mixed solvent of 39 g of ethanol and 10 g isopropanol and the resultant solution was added to the above polymer, followed by thoroughly stirring. To this mixture, 0.4 g of diisopropanol amine dissolved in 17.6 g of distilled water was added, followed by thoroughly stirring until the mixture became totally uniform, to obtain the desired white creamy ointment composition.
The fine particulate crosslinked type N-vinylamide resin of the present invention has an excellent chemical stability, an affinity for water and polar solvents such as alcohols, is little influenced by the effect of metal ions, if any, in the system, exhibits a high thickening ability and dispersing stability by absorbing and gelling these liquids, and yet the thickening action does not produce a tacky substance having a fiber forming property, but extremely fine microgels, and thus provides numerous excellent effects not found in the thickener with water absorptive resins known in the art. More specifically, the fine particulate crosslinked type N-vinylamide resin of the present invention has the ability to exist as a dispersion of fine particles by gelling with various aqueous solutions containing electrolytes or certain kinds of organic solvents, and said gel dispersion has a thixotropic property, whereby functions and effects such as a thickening ability, dispersibility (dispersion stability), and lubricity can be exhibited. Also, where a high strength is not required, such as in aromatic agents for domestic use, a form imparting property can be exhibited by use at a relatively higher concentration, and further, it has an ability to slowly release water, alcohols, and pharmaceutical held therein by absorption. Therefore, the fine particulate crosslinked type N-vinylacetamide resin and the hydrophilic microgel of said resin has a wide diversity of applications that required such characteristic functions.
Specific representative examples of these uses, such as those as set forth below, may be mentioned. Of course, these are merely exemplary, and the use of the resin of the present invention is not limited thereto.
1) Commodity, toiletary, cosmetics, pharmaceutical fields:
Heat mediums (heat accumlant, exothermic, heat insulator), aromatic, deodorant, drying agent, liquid detergent, soft finishing agent, cleanser, toothpaste, shampoo, emulsion stabilizer such as lotion, humectant, lubricant, sustained release pharmaceutical (oral, parenteral, percutaneous agents), external agents (poultice, ointment, trauma coating agent), mucosa administration (protective) preparation, lubricants for the intrabody insertion type medical instruments, materials for dentrifice.
2) Agricultural, horticultural, civil engineering construction fields:
Coating of seed, fertilizer, agricultural medicine preparation improvement (binder, slow release), improvement of soil, medium, prevention of frost, dew formation.
3) Chemicals for industrial use:
Lubricants, glues, electrolytes supports (battery, sensor).
The specific use methods and the amount used of the crosslinked type N-vinylamide resin of the present invention depend on the respective uses, and cannot be generally defined, but as a rule, will be different from the standard embodiments in the respective uses. Nevertheless, a use example not found in the prior art can be expected due to the excellent functions and effects thereof, and the amount can be reduced to the extent of the effect required.
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A fine particulate crosslinked type N-vinylcarboxylic acid amide resin having an average particle size of 10 μm or less comprising backbone chains of a homopolymer or copolymer comprising repeating units (A) or (A) and (B) of the formulae: ##STR1## wherein R 1 , R 2 and R 3 each independently represent a hydrogen atom or methyl group; X represents a group --COOY, wherein Y represents a hydrogen atom, an alkali metal, a C 1 -C 18 alkyl group or a lower alkyl group substituted with hydroxyl group, a dialkylamino group or a quaternary ammonium group; a group --CONHZ, wherein Z represents a hydrogen atom or a lower alkyl group substituted with a dialkylamino group, a quaternary ammonium group, a sulfonic acid or an alkali metal salt thereof; a cyano group, a 2-ketopyrroridinyl group, a lower alkoxy group, a lower acyl group, a lower alkoxycarbonyl group or a lower alkyl group substituted with sulfonic acid or an alkali metal salt thereof; M represents a hydrogen atom, an alkali metal or an ammonium group, with proviso that when R 3 is a methyl group, X is not a cyano group, a 2 -ketopyrrolidinyl group, a lower alkoxy group, a lower acyl group, a lower alkoxycarbonyl group and a lower alkyl group substituted with sulfonic acid or an alkali metal salt thereof, p represents 0 or 1, and the molar ratio of m:n represents 30-100:70-0.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser. No. 12/051,152, filed Mar. 19, 2008, which is a divisional of U.S. patent application Ser. No. 10/310,720, filed Dec. 4, 2002, U.S. Pat. No. 7,811,312, which are incorporated herein by specific reference.
BACKGROUND OF THE INVENTION
[0002] 1. The Field of the Invention
[0003] The present invention relates to the design and method of use for an implant to help realign angular and rotational deformities in long bones in patients with active growth plates.
[0004] 2. Related Technology
[0005] As a result of congenital deformation, traumatic injury or other causes, long bones such as the femur, tibia and humerus may grow out of alignment, causing deformity of the limb and biomechanical abnormalities. While some deformities are asymptomatic or may resolve spontaneously, it is often necessary to intervene surgically to realign these limbs. For the patients requiring surgical intervention, both osteotomy with realignment of the bone and epiphyseal stapling are currently accepted methods of treatment.
[0006] One common method of surgical bone realignment is by means of an osteotomy, or cutting of the bone, followed by realignment of the bone. In some procedures the bone is cut laterally, transverse to the longitudinal axis of the bone. Then the bone is realigned. A bone graft is then placed in the resulting wedge space. The bone and the bone graft are stabilized by orthopedic fragment fixation implants such as screws and bone plates. In an alternative osteotomy procedure, a bone wedge is removed. The bone is realigned, and similar implants are used to secure the bone. A third method of deformity correction via osteotomy is to first cut the bone, then apply an external frame attached to pins drilled through the skin and into the bone. By adjusting the frame, either intraoperatively or postoperatively, the bone is straightened.
[0007] Because osteotomy methods require a relatively large incision to create bone cuts, they are relatively invasive; they disrupt the adjacent musculature and may pose a risk to the neurovascular structures. An additional disadvantage of these procedures is the potential risk of damage to the growth plate, resulting in the disruption of healthy limb growth. Consequently, this procedure may be reserved for bone alignment in skeletally mature patients in whom the growth plates are no longer active.
[0008] One less invasive method of bone alignment involves the placement of constraining implants such as staples around the growth plate of the bone to restrict bone growth at the implant site and allow the bone to grow on the opposite side. First conceived in 1945 by Dr. Walter Blount, this method is known as epiphyseal stapling. Typically epiphyseal stapling is more applicable in young pediatric patients and adolescents with active growth plates. A staple is placed on the convex side of an angular deformity. Since the bone is free to grow on the concave side of the deformity, the bone tends to grow on the unstapled side, causing the bone to realign over time. Once the bone is aligned, the constraining implants are typically removed.
[0009] As long as the growth plate is not disturbed, this type of intervention is generally successful. However, the procedure must be done during the time that the bone is still growing, and the physiodynamics of the physis (growth plate) must not be disturbed. With proper preoperative planning and placement of the implants, the surgeon can use the implants to slowly guide the bone back into alignment.
[0010] The implants currently used in epiphyseal stapling procedures are generally U-shaped, rigid staples. The general design has essentially remained the same as those devised by Blount in the 1940's. Since these implants are rigid, they act as three-dimensional constraints prohibiting expansion of the growth plate. They are not designed to allow flexibility or rotation of the staple legs with the bone sections as the bone is realigned. Due to the constraints of these staple implants, the planning associated with the placement of the implants is overly complicated. Consequently, the surgeon must not only determine where to position the implant across the physis, but also must account for the added variables of implant stiffness, implant strength and bone-implant interface rupture.
[0011] The force associated with bone growth causes bending of these implants proportionate to their stiffness. Depending on the strength of the implant, these loads could eventually cause the implants to fracture under the force of bone realignment. This can make them difficult or impossible to remove. These same forces can also cause the implants to deform, weakening the bone-to-implant interface. This weakening may result in migration of the implant out of the bone, risking damage to the adjacent soft tissues and failure of the procedure.
SUMMARY OF THE INVENTION
[0012] The invention relates to an orthopedic bone alignment implant system that includes a guide wire, a link and bone fasteners. The guide wire serves to locate the growth plate under fluoroscopic guidance. The bone fasteners and the link function together as a tether between bone segments on opposite sides of the physis. As the bone physis generates new physeal tissue, the bone alignment implant tethers between engagers on the bone segments. This tethering principle guides the alignment of the bone as it grows.
[0013] Although applicable in various orthopedic procedures involving fracture fixation, the bone alignment implant is also applicable to the correction of angular deformities in long bones in which the physis is still active.
[0014] The distal end of the guide wire is used to locate the physis. Once its tip is placed in the physis, it is driven partly into the physis to function as a temporary guide for the link. The delivery of the implant over the guide wire assures that the link is properly placed with the bone fasteners on opposite sides of the physis. This will minimize the chance of damaging the physis throughout bone realignment. The link is then placed over the guide wire and oriented such that openings through the link for the bone fasteners are on either side of the physis. For pure angular correction, these openings would be collinear with the long axis of the bone; for rotational correction, they would be oblique to its axis.
[0015] The bone fasteners are then placed through the openings in the link and into the bone, connecting the sections of bone on opposite sides of the physis with the implant. Alternatively, guide pins can be used to help align canullated fasteners.
[0016] The implant is designed such that it partially constrains the volume of the bone growth on the side of the physis that it is placed. The implant guides the growth of new bone at the physis such that the growth direction and resulting alignment is controlled. The implant limits the semi-longitudinal translation of the bone fasteners yet allows for the bone fasteners to freely rotate with the bone segments as the angular or torsional deformity is straightened.
[0017] In some embodiments of this invention, both the link and the fasteners are rigid, but the connection between them allows for relative movement of the fasteners. In other embodiments the link is flexible allowing the fasteners to move with the bone sections. In other embodiments, the fasteners have flexible shafts allowing only the bone engager of the fasteners to move with the bone sections. In still other embodiments, both the link and the shafts of the fasteners are flexible, allowing movement of the bone sections.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] Various embodiments of the present invention will now be discussed with reference to the appended drawings. It is appreciated that these drawings depict only typical embodiments of the invention and are therefore not to be considered limiting of its scope.
[0019] FIG. 1 is an anterior view of the knee showing a genu valgum deformity (knee knocking) in the femur and the insertion of a guide wire approximately parallel to the physis;
[0020] FIG. 2 is a sagittal view of that described in FIG. 1 showing the placement of the guide wire in the physis;
[0021] FIG. 3 is an anterior view of the knee showing the placement of a link and drill guide over the guide wire and the use of the guide to place two guide pins for fasteners on opposite sides of the physis;
[0022] FIG. 4 is a sagittal view of the placement of the link described in FIG. 3 showing the position of the two guide pins on opposite sides of the physis;
[0023] FIG. 5 is an alternative method of applying the link over the guide wire in which the link is placed first, then the fasteners are placed through the openings in the link;
[0024] FIG. 6 is a sagittal view of the link placement also shown in FIG. 5 ;
[0025] FIG. 6A is a top plan view of the link shown in FIG. 6 ;
[0026] FIG. 7 is an anterior view showing an alternative method of drilling of holes in the bone over the guide pins to prepare the bone for the fasteners;
[0027] FIG. 8 is an anterior view of the link showing the placement of the fasteners through the link and into the bone segments;
[0028] FIG. 9 is a sagittal view of the fasteners and link described in FIG. 8 ;
[0029] FIG. 10 is an anterior view as seen after the physeal tissue has grown and the bone alignment implant assembly has been reoriented as the bone is realigned;
[0030] FIG. 11 is a sagittal view of the bone alignment implant placed on a rotational deformity;
[0031] FIG. 12 is the same sagittal view described in FIG. 12 after the rotational deformity has been corrected;
[0032] FIG. 13 is a perspective view of a threaded fastener;
[0033] FIG. 14 is a perspective view of a barbed fastener;
[0034] FIG. 15 is a perspective view of an alternative embodiment of the bone alignment implant with rigid link and fasteners, with joints allowing restricted movement between them;
[0035] FIG. 16 is a perspective view of an alternative embodiment of the bone alignment implant showing a flexible midsection of the link with rigid material surrounding the openings;
[0036] FIG. 17 is a perspective view of an alternative embodiment of the bone alignment implant showing a flexible midsection of the link made from a separate flexible member with rigid material surrounding the openings;
[0037] FIG. 18 is a perspective view of an alternative embodiment of the bone alignment implant showing flexible woven material throughout the body of the link with reinforcement grommets surrounding the openings;
[0038] FIG. 19 is a perspective view of an alternative embodiment of the bone alignment implant showing the link made from a flexible band of material;
[0039] FIG. 20 is a perspective view of an alternative embodiment of the bone alignment implant showing the link made from a flexible ring of braided material that is joined in the midsection, forming two openings;
[0040] FIG. 21 is a side view of an alternative embodiment of the bone alignment implant showing bone fasteners that have flexible shaft sections;
[0041] FIG. 22 is a side view of an alternative embodiment of the bone alignment implant showing two barbed bone fasteners attached to a flexible link; and
[0042] FIG. 23 is a side view of an alternative embodiment of the bone alignment implant showing one barbed bone fastener and one threaded bone fastener connected to a flexible link.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0043] Referring to FIG. 1 , a schematic anterior view of the human knee joint is depicted in which a distal femur 10 is proximal to a proximal tibia 5 and a proximal fibula 6 . A distal femoral physis 1 , or growth plate, separates a distal epiphyseal section 3 from a proximal metaphyseal section 2 of the distal femur 10 . Likewise a proximal tibial physis 1 ′ separates a proximal epiphyseal section 3 ′ from a metaphyseal section 2 ′ of the proximal tibia 5 and a proximal fibula physis 1 ″ separates a proximal epiphyseal section 3 ″ of a proximal fibula 6 from a metaphyseal section 2 ″ of the proximal fibula 6 . Although the invention described herein is adaptable to nearly all of the long bones in the body, only the example of correcting one type of an angular deformity in the distal femur will be described in detail. The principles described herein can be adapted to other deformities and other bones such as the tibia, fibula, humerus, radius and ulna.
[0044] By example, an angular deformity 4 in the femur 10 known as genu valgum or knock-knee is shown in FIG. 1 . The angular deformity 4 is the angle between a pretreatment longitudinal axis 12 of the femur 10 and a post treatment projected longitudinal axis 13 of the femur 10 . A bone alignment implant will be placed on the medial side of the femur 10 . In this case, the medial side of the femur 10 is curved in a convex arc. Hence, this side of the deformity is called a convex side 16 because the angular deformity 4 bends the femur 10 in a curve that is angled away from or convex with respect to the medial side. A concave side 17 is on the opposite side of the femur 10 . Likewise, the angular deformity 4 is angled towards the concave side 17 .
[0045] A guide wire 8 , as shown in FIG. 1 , is used to locate the physis and guide the bone alignment implant to the surgical site. The guide wire 8 comprises a long axis 11 , a distal section 9 that is shaped to fit into the physeal tissue, and a periphery 14 that is typically a constant size and shape. In this case, the shape of the guide wire 8 along the long axis 11 is essentially cylindrical so the shape of the periphery 14 is round and does not change except for in the distal section 9 . However, the periphery 14 can be a variable cross-section that changes shape or size along the length of the long axis 11 .
[0046] In this example, the long axis 11 of the guide wire 8 is placed into and approximately parallel with the physis 1 and is aligned approximately in the same plane as the angular deformity 4 . As shown in FIG. 1 , the distal section 9 of the guide wire 8 is partly inserted into the physis 1 . Since the cartilaginous physis 1 is of less density than the surrounding bone, the surgeon can either poke the distal section of the guide wire 8 into the bone until the physis 1 is located, or the surgeon can use fluoroscopic x-ray (not shown) or other bone density detection means (not shown) to determine the location of the physis 1 relative to the distal section of the guide wire 8 to place the guide wire 8 in a direction that is approximately parallel with the physis 1 .
[0047] FIG. 2 is a sagittal view approximately perpendicular to the anterior view described in FIG. 1 . For reference, a patella 7 is shown on the anterior side of the femur 10 and tibia 5 . For clarity, in this example the guide wire 8 is straight and has a constant round outer periphery 14 . Consequently, only the outer periphery 14 of the guide wire 8 is shown and appears as a circle in FIG. 2 . FIG. 2 shows the placement of the guide wire 8 in the physis between the femoral metaphyseal section 2 and the distal femoral epiphyseal section 3 . This is the preferred placement of the guide wire 8 . The guidewire 8 is used to locate an area in the physis that will eventually be bridged by the bone alignment implant 9 that will tether between two sections of the bone. In FIG. 2 , the two sections of bone that will be tethered by the bone alignment implant 9 are the distal femoral proximal epiphyseal section 3 and the femoral metaphyseal section 2 .
[0048] FIG. 3 is an anterior view of the knee showing the placement of a link 30 and a guide 20 over the guide wire 8 . The guide 20 is used to place a first guide pin 40 and a second guide pin 50 on opposite sides of the physis 1 . The link 30 has an outer periphery 34 that defines the outer material bounds of the link 30 , a bone side 37 that is the side of the link that is placed against the bone, a first opening 31 and a second opening 32 .
[0049] First, the guide 20 and link 30 are placed over the guide wire 8 by guiding the guide wire 8 over a guide opening 33 in the link 30 and the guide hole 23 in the guide 20 . Then the first guide pin 40 is driven through a first hole 21 in the guide 20 and through the first opening 31 in the link 30 into the metaphyseal bone 2 , and the second guide pin 50 is driven through a second hole 22 in the guide 20 and the second opening 32 in the link 30 into the distal epiphyseal section 3 . Once the first guide pin 40 and the second guide pin 50 are placed, the guide 20 is removed.
[0050] FIG. 4 is a sagittal view of the placement of the link 30 described in FIG. 3 . The position of the first guide pin 40 is through the first opening 31 in the link 30 . The position of the second guide pin 50 is through the second opening 32 in the link 30 . The guide pin 40 and guide pin 50 are on opposite sides of physis 1 . Likewise, the first opening 31 and the second opening 32 are on opposite sides of the physis 1 .
[0051] FIG. 5 is an anterior view showing an alternative embodiment of the link 30 placed on the medial femur 10 . In this embodiment, a first set of spikes 35 and a second set of spikes 36 on the bone side 37 of the link 30 help to keep the link 30 in place prior to the placement of a first bone fastener 70 and a second bone fastener 80 . The first set of spikes 35 is positioned near the first opening 31 and the second set of spikes 36 is positioned near the second opening 32 in the link 30 . Hence, as the link 30 is placed across the physis 1 , the first set of spikes 35 contacts the metaphyseal section 2 and the second set of spikes 36 contacts the epiphyseal section 3 . In this embodiment, the first bone fastener 70 is placed through the first opening 31 in the link 30 then into the metaphyseal section 2 and the second bone fastener 80 is placed through the second opening 32 in the link 30 then into the epiphyseal section 3 .
[0052] FIG. 6 is a sagittal view of the link 30 on the femur 10 showing the location of the first set of spikes 35 near the first opening 31 on the metaphyseal section 2 side of the physis 1 and the location of the second set of spikes near the second opening 32 on the epiphyseal section 3 side of the physis 1 .
[0053] As shown in FIG. 6A , link 30 can further be defined as having a top surface 150 that is opposite the bottom surface 37 . Bottom surface 37 was also previously referenced as bone side 37 in FIG. 3 . Both bottom surface 37 and top surface 150 extend between a first side edge 152 and an opposing second side edge 154 . Likewise, both bottom surface 37 and top surface 150 longitudinally extend between a first end 156 and an opposing second end 158 . A first recess 162 is centrally formed on first side edge 152 while a second recess 164 is centrally formed on second side edge 154 .
[0054] In the embodiment depicted, guide opening 33 is centrally disposed between first opening 31 and second opening 32 with guide opening 33 being smaller than openings 31 and 32 . Each of openings 31 , 32 , and 33 are aligned along a central longitudinal axis 160 that extends between first end 156 and second end 158 . Recesses 162 and 164 can be positioned on opposing sides of guide opening 33 such that a linear line 166 extending between recesses 162 and 164 intersect guide opening 33 . The length of linear line 166 extending between recesses 162 and 164 is a first width of link 30 . Linear line 166 is shown in the present embodiment as extending orthogonal to longitudinal axis 160 .
[0055] Link 30 can also be formed so that a linear line 168 can extend between side edges 152 and 154 so as to intersect with first opening 31 . Line 168 is shown extending orthogonal to longitudinal axis 160 and measures a second width of link 30 . Because of recesses 162 and 164 , the first width is smaller than the second width. A linear line 170 can similarly extend between side edges 152 and 154 so as to intersect with second opening 32 . Line 170 is shown extending orthogonal to longitudinal axis 160 and measures a third width of link 30 . The first width of link 30 is smaller than the third width.
[0056] FIG. 7 is an anterior view of the placement of the link 30 , first guide pin 40 , and second guide pin 50 as previously described in the sagittal view shown in FIG. 4 . FIG. 7 also shows a bone preparation tool 60 that can be used to prepare a bore 28 in the bone prior to the first fastener 70 or second fastener 80 placements. The bone preparation tool 60 can be a drill, tap, rasp, reamer, awl or any tool used to prepare a bore in bone tissue for a fastener. The bone preparation tool 60 is used to prepare a bore 28 on the bone near the second opening in the epiphyseal section 3 for the second fastener 80 . A bone preparation tool 60 can also be used to prepare the bone in the metaphyseal section 2 for the first fastener 70 . In the case of the example shown in FIG. 7 , the bone preparation tool 60 is placed over the second guide pin 50 , through the second opening 32 , and into the epiphyseal section 3 . However, the bone preparation tool 60 can also be placed directly through the second opening 32 without the guidance of the second guide pin 50 . The bone preparation tool 60 is used if needed to prepare the bone to receive the first fastener 70 and second fastener 80 . Once the bone is prepared, the bone preparation tool 60 is removed from the surgical site.
[0057] The first fastener 70 is then placed over the first guide pin 40 , through the first opening 31 , and into the metaphyseal section 2 . The second fastener 80 is placed over the second guide pin 50 , through the second opening 32 and into the epiphyseal section 3 . If the first guide pin 40 and second guide pin 50 are not used, the first fastener 70 is simply driven through the first opening 31 and the second fastener 80 is simply driven through the second opening 32 without the aid of the guide pins 40 and 50 .
[0058] FIG. 8 is an anterior view showing the position of a bone alignment implant 15 on the convex side 16 of the angular deformity 4 . The bone alignment implant 15 comprises the link 30 , the first fastener 70 , and the second fastener 80 . The bone alignment implant 15 functions as a tether connecting the metaphyseal section 2 and the epiphyseal section 3 . The first fastener 70 and the second fastener 80 are placed on opposite sides of the physis 1 . As the physis 1 generates new physeal tissue 90 , the physeal tissue 90 will fill in between the metaphyseal section 2 and the epiphyseal section 3 in the space subjected to the least resistance. The bone alignment implant 15 restricts the longitudinal movement between the epiphyseal section 3 and the metaphyseal section 2 on the convex side 16 of the angular deformity 4 .
[0059] FIG. 9 shows the sagittal view of that described for FIG. 8 . The bone alignment implant 15 functioning as a tether restricting the longitudinal movement between the epiphyseal section 3 and the metaphyseal section 2 .
[0060] As shown in FIG. 10 , in a patient with an active physis, the newly generated physeal tissue 90 fills in more on the side of the bone that is not tethered by the bone alignment implant 15 . Hence, a net gain 95 of physeal tissue 90 forces the bone to align in the direction of an angular correction 97 .
[0061] Select embodiments of the bone alignment implant 15 comprise the first fastener 70 having a first engager 75 , the second fastener 80 having a second engager 85 and the link 30 . The link 30 , the first fastener 70 and the second fastener 80 function together as tethers between a first engager 75 on the first fastener 70 and a second engager 85 on the second fastener 80 , guiding movement between the epiphyseal section 3 and metaphyseal section 2 of bone.
[0062] FIG. 11 and FIG. 12 show an example of using the bone alignment implant to correct a torsional abnormality between the metaphyseal section 2 and the epiphyseal section 3 . The link 30 is placed across the physis 1 at an angle 18 that is related to the amount of torsional deformity between the bone sections 2 and 3 . As the physis 1 generates new physeal tissue 90 , the bone alignment implant 15 guides the direction of growth of the bone to allow a torsional correction 98 of the bone alignment.
[0063] Different fastening devices designs that are well known in the art can be functional as fasteners 70 and 80 . The basic common elements of the fasteners 70 and 80 are seen in the example of a threaded fastener 100 in shown in FIG. 13 and a barred fastener 120 shown in FIG. 14 .
[0064] The threaded fastener 100 , and the barbed fastener 120 both have a head 73 comprising a head diameter 74 , a drive feature 72 and a head underside 71 . The drive feature in the threaded fastener 100 is an internal female hex drive feature 102 . The drive feature in the barbed fastener 120 is an external male drive feature 122 . The shape of the underside 71 of the barbed fastener 120 is a chamfer cut 124 and the underside of the threaded fastener 100 is a rounded cut 104 . The underside 71 shape of both the threaded fastener 100 and the barbed fastener 120 examples are dimensioned to mate with shapes of the first opening 31 and the second opening 32 in the link 30 .
[0065] Directly adjacent to the head 72 on both threaded fastener 100 and the barbed fastener 120 is a fastener shaft 79 with a shaft diameter 76 . Protruding from the shaft 79 is the aforementioned engager 75 with a fixation outer diameter 77 . This fixation diameter varies depending on the bone that is being treated and the size of the patient. Typically this diameter is from 1 mm to 10 mm. The shaft diameter 76 can be an undercut shaft 125 , as shown in the barbed fastener 120 , with a diameter 76 smaller than the fixation outer diameter 77 . The shaft diameter can also be a run out shaft 105 as shown in the threaded fastener 100 with a diameter 76 larger than or equal to the fixation diameter 77 . In either case, the shaft diameter 76 is smaller than the head diameter 74 . This allows fasteners 70 and 80 to be captured and not pass completely through the openings 31 and 32 in the link 30 .
[0066] In the case of the threaded fastener 100 , the engager 75 comprises at least one helical thread form 103 . Although the example of a unitary continuous helical thread 103 is shown, it is understood that multiple lead helical threads, discontinuous helical threads, variable pitch helical threads, variable outside diameter helical threads, thread-forming self-tapping, thread-cutting self-tapping, and variable root diameter helical threads can be interchanged and combined to form an optimized engager 75 on the threaded fastener 100 . The engager 75 on the barbed fastener 120 is shown as a uniform pattern of connected truncated conical sections 123 . However, it is understood that different barbed fastener designs known in the art such as superelastic wire arcs, deformable barbs, radially expandable barbs, and barbs with non-circular cross-sections can be interchanged and combined to form an optimized engager 75 on the barbed fastener 120 .
[0067] Protruding from the engager 75 at the distal end of both the threaded fastener 100 and the barbed fastener 120 is a fastener tip 78 . The fastener tip 78 can either be a smooth conical tip 126 as shown in the barbed fastener 120 , or a cutting tip 106 as shown on the threaded fastener 100 . Although a cutting flute tip is shown as the cutting tip 106 on the threaded fastener, other cutting tips designs including gimble and spade tip can be used.
[0068] In the example of the barbed fastener 120 , a canulation bore 128 passes through the head 73 , the shaft 79 , the engager 75 , and the tip 78 . This canulation bore 128 allows placement of the fasters 70 and 80 over the guide pins 40 and 50 . Although not shown on the example of the threaded fastener 100 in FIG. 13 , it is understood that the fasteners 70 and 80 , regardless of their other features, can either be of the cannulatted design shown in the barbed fastener 120 example or a non-cannulatted design as shown in the threaded fastener 100 example.
[0069] Fasteners 70 and 80 can be made in a variety of different ways using a variety of one or more different materials. By way of example and not by limitation, fasteners 70 and 80 can be made from medical grade biodegradable or non-biodegradable materials. Examples of biodegradable materials include biodegradable ceramics, biological materials, such as bone or collagen, and homopolymers and copolymers of lactide, glycolide, trimethylene carbonate, caprolactone, and p-dioxanone and blends or other combinations thereof and equivalents thereof. Examples of non-biodegradable materials include metals such as stainless steel, titanium, Nitinol, cobalt, alloys thereof, and equivalents thereof and polymeric materials such as non-biodegradable polyesters, polyamides, polyolefins, polyurethanes, and polyacetals and equivalents thereof.
[0070] All the design elements of the threaded fastener 100 and barbed fastener 120 are interchangeable. Hence either of the fasteners 70 and 80 can comprise of any combination of the design elements described for the threaded fastener 100 and the barbed fastener 120 . By way of one example, the first fastener 70 can be made from a bioabsorbable copolymer of lactide and glycolide and structurally comprise an external male drive feature 122 , a run out shaft 105 , a multiple-lead, non-continuous helically threaded engager 75 , with a cutting flute tip 106 and a continuous canulation 128 . Likewise the second fastener 80 can be made from a different combination of the features used to describe the threaded fastener 100 and the barbed fastener 120 .
[0071] Although the examples of barbed connected truncated conical sections 123 and helical thread forms 103 are shown by example to represent the bone engager 75 , it is understood that other means of engaging bone can be used for the engager 75 . These means include nails, radially expanding anchors, pressfits, tapers, hooks, surfaces textured for biological ingrowth, adhesives, glues, cements, hydroxyapatite coated engagers, calcium phosphate coated engagers, and engagers with tissue engineered biological interfaces. Such means are known in the art and can be used as alternative bone engagement means for the first bone engager 75 on the first fastener 70 or the second bone engager 85 on the second fastener 80 .
[0072] Different embodiments of the bone alignment implant 15 invention allow for different means of relative movement between the two bone sections 2 and 3 . Nine embodiments of the bone alignment implant 15 are shown in FIG. 15 through FIG. 23 . These embodiments are labeled 15 A through 151 .
[0073] In a rigid-bodies embodiment 15 A shown in FIG. 15 , both the link 30 and the fasteners 70 and 80 are rigid, but a first connection 131 and a second connection 132 between each of them allows for relative movement between the link 30 and the fasteners 70 and 80 resulting in relative movement between the bone sections 2 and 3 . In embodiments 15 B, 15 C, and 15 D of this invention shown in FIG. 16 , FIG. 17 and FIG. 18 , the link 30 is deformable allowing the fasteners 70 and 80 to move with the bone sections 2 and 3 . In embodiments 15 E and 15 F shown in FIG. 19 and FIG. 20 , the connections between the link 30 and the fasteners 70 and 80 along with the deformable link 30 allow the fasteners 70 and 80 to move with the bone sections 2 and 3 . In an embodiment 15 G shown in FIG. 21 , the fasteners 70 and 80 are deformable allowing movement of the bone sections 2 and 3 . In embodiments 15 H and 15 I shown in FIG. 22 and FIG. 23 , the fasteners 70 and 80 are fixed to a flexible link 30 .
[0074] A rigid-bodies embodiment 15 A of the bone alignment implant 15 is shown in FIG. 15 . In the rigid-bodies embodiment 15 A, the link 30 is a rigid link 130 . In the rigid bodies embodiment 15 A, the first fastener 70 is free to rotate about its axis or tilt in a first tilt direction 60 or a second tilt direction 61 and is partially constrained to move in a longitudinal direction 62 by the confines of the size of the first opening 31 and the first shaft diameter 77 , and partially constrained to move in the axial direction by the confines of the size of the first opening and the diameter 74 of the head 73 of the first fastener 70 . The first opening 31 is larger in the longitudinal direction 62 than is the shaft diameter 77 of the first fastener 70 . This allows for relative movement at the first joint 131 in a combination of tilt in the first direction 60 , tilt in the second direction 61 , and translation in the axial direction 63 .
[0075] Similar tilt and translation is achieved between the second fastener 80 and the link 30 at the second joint 132 . The second fastener 80 is also free to rotate or tilt in a first tilt direction 60 ′ or a second tilt direction 61 ′ and is partially constrained to move in a longitudinal direction 62 ′ by the confines of the size of the second opening 32 and the shaft diameter of the second fastener 80 . The second opening 31 is larger in the longitudinal direction 62 ′ than is the shaft diameter of the second fastener 80 . This allows for relative movement at the second joint 132 in a combination of tilt in the first direction 60 ′ and tilt in the second direction 61 ′ and limited translation in the axial direction 63 ′.
[0076] The combination of relative movement between the first joint and the second joint allows for relative movement between the bone sections 2 and 3 when the rigid bodies embodiment 15 A of the bone alignment implant 15 is clinically applied across an active physis 1 .
[0077] A flexible link embodiment 15 B of the bone alignment implant 15 is shown in FIG. 16 . In the deformable link embodiment 15 B, the link 30 is represented by a deformable link 230 that allows deformation of the sections 2 and 4 as the physis 1 grows in a first bending direction 64 and a second bending direction 65 . However, the maximum length between the first opening 31 and the second opening 32 of the deformable link 230 limits the longitudinal displacement 62 between the head 73 of the first fastener 70 and the longitudinal displacement 62 ′ between the head 83 of the second fastener 80 . Since the heads 73 and 83 are coupled to the respective bone engagers 75 and 85 , and the bone engagers 75 and 85 are implanted into the respective bone segments 2 and 3 , the maximum longitudinal displacement of the bone segments 2 and 3 is limited by the deformed length between the first opening 31 and second opening 32 of the link 30 , and the flexibility and length of the fasteners 70 and 80 .
[0078] Also shown in FIG. 16 is a material differential area 38 on the link 30 . The material differential area 38 is an area on the link 30 where material is either added to the link 30 or removed from the link 30 in relationship to the desired mechanical properties of a central section 39 of the link 30 . The central section 39 is made stiffer by adding material to the material differential area 38 .
[0079] The central section 39 is made more flexible by removing material from the material differential area 38 . Similarly the central section 39 is made stiffer by holding all other variables constant and decreasing the size of the guide opening 33 . The central section 39 is made more flexible by increasing the size of the guide opening 33 . Hence the desired stiffness or flexibility of the link 30 is regulated by the relative size of the material removed or added at the material differential areas 37 and 38 and the relative size of the guide opening 33 with respect to the outer periphery 34 in the central section 39 of the link 30 .
[0080] It is also understood that the relative stiffness and strength of the link 30 and structural elements such as the central section 39 is dependent on the material from which it is made. The link 30 and structural elements such as the central section 39 therein can be made in a variety of different ways using one or more of a variety of different materials. By way of example and not by limitation, the central section 39 can be made from medical grade biodegradable or non-biodegradable materials. Examples of biodegradable materials include biodegradable ceramics, biological materials, such as bone or collagen, and homopolymers and copolymers of lactide, glycolide, trimethylene carbonate, caprolactone, and p-dioxanone and blends or other combinations thereof and equivalents thereof. Examples of non-biodegradable materials include metals such as titanium alloys, zirconium alloys, cobalt chromium alloys, stainless steel alloys, Nitinol alloys, or combinations thereof, and equivalents thereof and polymeric materials such as non-biodegradable polyesters, polyamides, polyolefins, polyurethanes, and polyacetals and equivalents thereof.
[0081] FIG. 17 shows a flexible cable embodiment 15 C of the bone alignment implant 15 . The flexible cable embodiment 15 C comprises a flexible cable link 330 joined to the first fastener 70 by a first eyelet 306 on the first side 310 and joined to the second fastener 80 by a second eyelet 307 on the second side 311 . The first eyelet 306 has a first opening 331 through which the first fastener 70 passes. The second eyelet 307 has a second opening 332 through which the second fastener 80 passes. A flexible member 339 connects the first eyelet 306 to the second eyelet 307 . The flexible member 339 allows relative movement between the first eyelet 306 and the second eyelet 307 , except the longitudinal displacement 62 and 62 ′ is limited by the length between the first opening 331 and the second opening 332 . This is proportional to the length of the flexible member 339 .
[0082] The flexible member 339 is connected to the first eyelet 306 and the second eyelet 307 by means of joined connections 318 and 319 . These joined connections 318 and 319 are shown as crimped connections in this example. However, the flexible member 339 can be joined to the link 30 by other means such as insert molding, welding, soldering, penning, pressfitting, cementing, threading, or gluing them together.
[0083] FIG. 18 shows a flexible fabric embodiment 15 D of the bone alignment implant 15 . The flexible fabric embodiment 15 D comprises a flexible fabric link 430 joined to the first fastener 70 and the second fastener 80 . The flexible fabric link 430 comprises a first grommet 406 on a first side 410 and joined to the second fastener 80 by a second grommet 407 on a second side 411 . The first grommet 406 has a first opening 431 through which the first fastener 70 passes. The second grommet 407 has a second opening 432 through which the second fastener 80 passes. A flexible fabric 439 connects the first grommet 406 to the second grommet 407 . The flexible fabric 439 allows relative movement between the first grommet 406 and the second grommet 407 , except the longitudinal displacement 62 is limited by the length between the first opening 431 and the second opening 432 . A guide hole grommet 433 may be employed to reinforce the guide pin opening 33 .
[0084] The grommets function as reinforcement structures that prevent the flexible fabric from being damaged by the fasteners 70 and 80 . The grommets can be made from medical grade biodegradable or non-biodegradable materials. Examples of materials from which the grommet can be made are similar to those bioabsorbable and non-biodegradable materials listed as possible materials for the fasteners 70 and 80 .
[0085] The flexible fabric 439 comprises woven or matted fibers of spun medical grade biodegradable or non-biodegradable materials. A wide variety of materials may be used to make the flexible fabric 439 . For example, wire, fibers, filaments and yarns made therefrom may be woven, knitted or matted into fabrics. In addition, even non-woven structures, such as felts or similar materials, may be employed. Thus, for instance, nonabsorbable fabric made from synthetic biocompatible nonabsorbable polymer yarns, made from polytetrafluorethylenes, polyesters, nylons, polyamides, polyolefins, polyurethanes, polyacetals and acrylic yarns, may be conveniently employed. Similarly absorbable fabric made from absorbable polymers such as homopolymers and copolymers of lactide, glycolide, trimethylene carbonate, caprolactone, and p-dioxanone and blends or other combinations thereof and equivalents thereof may be employed. Examples of non-biodegradable non-polymeric materials from which the flexible fabric can be made include metals such as stainless steel, titanium, Nitinol, cobalt, alloys thereof, and equivalents thereof.
[0086] A band embodiment 15 E is shown in FIG. 19 in which a band 530 that is a continuous loop or band of material that functions as the link 30 . The band embodiment 15 E allows both movement at the first joint 131 and second joint 132 and allows deformation within the link 30 . The shafts 79 of the first fastener 70 and second fastener 80 are both positioned in the inside 531 of the band 530 . The band can be either a fabric band made from the same materials described for the flexible fabric 439 of the flexible fabric embodiment 15 D, or the band 530 can be a unitary, continuous loop of a given biocompatible material such as a bioabsorbable polymer, non-biodegradable polymer, metal, ceramic, composite, glass, or biologic material.
[0087] In the band embodiment 15 E, the band 530 tethers between the head 73 of the first fastener 70 and the head 83 of the second fastener 80 as the physeal tissue 90 generates and the bone is aligned. One advantage of the band embodiment 15 E is that after the desired alignment is obtained, the band 530 can be cut and removed without removing the fasteners 70 and 80 . Furthermore, as with all of the embodiments of the bone alignment device 15 A, 15 B, 15 C, 15 D, 15 F, 15 G, 15 H and 15 I, the fasteners 70 and 80 can be made from a biodegradable material and left in place to degrade.
[0088] A crimped band embodiment 15 F of the bone alignment device 15 is shown in FIG. 20 . The crimped band embodiment 15 F is similar to the band embodiment 15 E in that it allows both movement at the first joint 131 and second joint 132 . The crimped band embodiment 15 F comprises a crimped band link 630 that comprises a band 632 that loops around the head 73 of the first fastener 70 and the head 83 of the second fastener 80 . However, the link 30 in the crimped band embodiment 15 F has an additional ferrule feature 631 comprising a loop of deformable material that brings a first side 634 and a second side 635 of the band together forming the first opening 32 and the second opening 31 . A bore 633 in the midsection of the ferrule 631 passes through the crimped band link 630 to form the aforementioned guide pin hole 33 .
[0089] As with the band embodiment 15 E, an advantage of the crimped band embodiment 15 F is that after the desired alignment is obtained, the band 632 can be severed across the boundaries of the first opening 31 and the boundaries of the second opening 32 . This provides a means for the crimped band link 630 to be removed without removing the fasteners 70 and 80 .
[0090] A deformable fastener embodiment 15 G is shown in FIG. 21 . The deformable fastener embodiment 15 G comprises a first deformable fastener 770 with a deformable shaft 776 , a link 30 and a second fastener 780 . The second fastener 780 may also have a deformable shaft 786 as shown in the deformable fastener embodiment 15 G. However, it may also have a nondeformable shaft. The second fastener 780 may also be in the design or material of any of the combinations of aforementioned threaded fasters 100 or barbed fasteners 120 . Likewise, the second fastener 780 can have a flexible shaft 786 , as shown in the example of the deformable fastener embodiment 15 G in FIG. 21 , and the first fastener 770 can be in the design or material of any of the combinations of aforementioned threaded fasters 100 or barbed fasteners 120 .
[0091] The flexibility of the flexible shafts 776 and 786 of the fasteners 770 and 780 can be simply a result of the material selection of the flexible shaft 776 and 786 , or can be the result of a design that allows for flexibility of the shaft. For example, the flexible shaft 776 and 786 can be manufactured from a material such as the aforementioned biocompatible polymeric materials or superelastic metallic materials such as Nitinol that would deform under the loads associated with bone alignment. The flexible shafts 776 and 786 could also be manufactured from biocompatible materials typically not considered to be highly elastic such as stainless steel, titanium, zirconium, cobalt chrome and associated alloys thereof, and shaped in the form of a flexible member such as cable, suture, mesh, fabric, braided multifilament strand, circumferentially grooved flexible shaft, filament, and yarn.
[0092] Connections 778 and 788 between the flexible shafts 776 and 786 and the associated engagers 775 and 785 of the fasteners 770 and 780 can be unitary and continuous, as is typically the case for fasteners 770 and 780 made entirely from the aforementioned biocompatible polymeric materials and superelastic metallic materials. The connections 778 and 788 can also be joined connections as is the case for flexible shafts 776 and 786 made from flexible members. Although the example of a pressfit connection is shown as the means of the connections 778 and 788 in the deformable fastener embodiment 15 G shown in FIG. 21 , these joined connections 778 and 788 can be crimped, welded, insert molded, soldered, penned, pressfit, cemented, threaded, or glued together.
[0093] Heads 773 and 783 are connected to the respective flexible shafts 776 and 786 by respective head connections 779 and 789 . These head connections 779 and 789 can also be unitary and continuous, as again is typically the case of fasteners 70 and 80 made entirely from the aforementioned biocompatible polymeric materials and superelastic metallic materials. The head connections 779 and 789 can also be joined connections, as is the case for flexible shafts 776 and 786 made from flexible members. Although the example of a pressfit connection is the means of the connections 779 and 789 in the deformable fastener embodiment 15 G shown in FIG. 21 , these joined connections 779 and 789 can also be crimped, insert molded, welded, soldered, penned, pressfit, cemented, threaded, or glued together.
[0094] Embodiments of the bone alignment implant 15 are shown in FIGS. 22 and 23 in which the first fastener 70 and second fastener 80 are fixedly joined to the link 30 that is flexible.
[0095] A paired fastener embodiment 15 H is shown in FIG. 22 in which similar designs of paired fasteners 870 and 880 are fixedly joined to a flexible link 830 by means of joined connections 831 and 832 . These joined connections 831 and 832 are shown as insert molded connections in this example in which the link is formed within the fastener by means of molding the molded fasteners 870 and 880 around the flexible link 830 . However, the paired fasteners 870 and 880 can be joined to the link 830 by other means such as crimping, welding, soldering, penning, pressfitting, cementing, threading, or gluing.
[0096] In the paired fastener embodiment 15 H, the first paired fastener 870 and the second paired fastener 880 are shown in FIG. 22 as barbed style fasteners similar to the aforementioned barbed fastener 120 . However, the paired fasteners 870 and 880 can also be similar to the aforementioned threaded fastener 100 or can comprise of any combination of the design elements described for the threaded fastener 100 and the barbed fastener 120 .
[0097] A non-paired fastener embodiment 151 is shown in FIG. 23 in which different designs of fasteners 970 and 980 are fixedly joined to a flexible link 930 by means of joined connections 931 and 932 . These joined connections 931 and 932 are shown as insert molded connections in this example in which the link is formed within the fastener by means of molding the molded fasteners 970 and 980 around the flexible link 930 . However, the fasteners 970 and 980 can be joined to the link by other means such as crimping, welding, soldering, penning, pressfitting, cementing, threading, or gluing.
[0098] While the present invention has been disclosed in its preferred form, the specific embodiments thereof as disclosed and illustrated herein are not to be considered in a limiting sense as numerous variations are possible. The invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. No single feature, function, element or property of the disclosed embodiments is essential. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. The following claims define certain combinations and subcombinations that are regarded as novel and non-obvious. Other combinations and subcombinations of features, functions, elements and/or properties may be claimed through amendment of the present claims or presentation of new claims in this or a related application. Such claims, whether they are broader, narrower or equal in scope to the original claims, are also regarded as included within the subject matter of applicant's invention. All changes that come within the meaning and range of equivalency of the claims are to be embraced within their scope.
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A method for correcting an angular deformity in a bone includes positioning a link across a physis of the bone, the link having a first portion with a first opening, a second portion with a second opening, and a central portion extending between the first portion and the second portion, the central portion being more flexible than the first portion or the second portion. A first bone engager and second bone engager are advanced through the first opening and the second opening, respectively, and into the bone on opposing sides of the physis. The physis is allowed to generate more physeal tissue on a side of the bone opposite the link so as to reduce the angular deformity.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a rotary crusher for crushing waste metal products such as, for example, compressors, air conditioners or refrigerators, particularly those containing combustibles. More particularly, the invention relates to the rotary crusher in which exhausted smoke can easily be treated and in which gas concentration can be precisely monitored to prevent an explosion.
2. Description of the Prior Art
In the conventional recycling of wasted metal products including iron and copper, the products are broken into adequate size and then the iron and copper materials are separated therefrom by, for example, a magnetic separation technique. In crushing the waste metal products, a rotary crusher is generally used to facilitate the subsequent separation process. The rotary crusher has a rotor with hammers mounted on its periphery so that the waste products can be crushed while being compressed by the hammers.
If the crusher breaks oil-containing metal wastes such as compressors, smoke arises in the crusher. The smoke travels having ridden on an airflow generated by rotation of the rotor and then emerges from an outlet of the crusher together with crushed pieces. Therefore, an exhaust processor having a ventilation fan is generally placed near the outlet of the crusher in order to collect the smoke.
When metal wastes containing a flammable material such as oil is rushed, explosion may occur. Accordingly, the crusher needs an explosion-proof system. Hitherto, the explosion-proof system is implemented by, for example, blowing inert gas or water vapor into the crusher according to the concentration of oxygen in the crusher that is detected by an oxygen sensor to maintain the oxygen concentration under the explosion limit. Such an explosion-proof system is disclosed in, for instance, Japanese laid-open patent publication H6-226137.
However, the conventional rotary crusher has following drawbacks:
(1) In order to vent the exhausted smoke from the crusher completely, the inlet capacity of the ventilation fan must be greater than the exhaust capacity of the crusher. Accordingly, increase of the exhaust capacity of the crusher by, for example, increasing the speed of rotation of the rotor results in necessity of use of the suctionventilation fan having a higher inlet capacity. This in turn increases the size of the exhaust processor. Also, the exhaust processor with such a high inlet capacity fan may draw in light-weight pieces such as, for example, insulating paper or copper together with the smoke. The pieces caught by the fan do not only bring about clogging of the fan, but also reduce the wastes recycling efficiency.
(2) The concentration of oxygen or flammable gas near a crushing point should be precisely monitored by, for example, an oxygen sensor to prevent explosion from taking place during crushing. When the oxygen sensor is placed in the crusher, the sensor should be disposed in a recess or protected with a cover to avoid its breakdown by collision with the crushed pieces. However, since the air stream is apt to stay in the recess or in the cover, the gas concentration tends to become uneven. Therefore, in the conventional crusher, an accurate measurement of the oxygen concentration has been difficult to achieve.
(3) When the explosion-proof means such as introduction of inert gas or water vapor is employed, pipes and nozzles must be installed in the crusher to introduce the gas. This complicates the construction of the crusher.
SUMMARY OF THE INVENTION
It is accordingly an object of the present invention to provide an apparatus for, and a method of operating such apparatus, for crushing products containing flammable material, in which an exhausted smoke can easily be processed and in which gas concentration can be precisely monitored to prevent an explosion. Another object of the present invention is to provide a recycling system that has a high recycling efficiency and that is safely operable.
In accordance with a first aspect of the present invention, a crushing apparatus comprises:
a rotor having a crushing means on a periphery thereof;
a casing for enclosing said rotor, the casing having an inlet and an outlet for materials to be crushed;
exhaust-circulating means for returning a part of exhaust gas from the outlet to the inlet of said casing; and
exhaust-processing means for ventilating and processing the exhaust gas exhausted from said casing.
The advantage of this invention is the ability to reduce the exhaust capacity of the crusher casing. This downsizes the exhaust-processing section of the apparatus and prevents the exhaust-processing section from sucking light-weight crushed pieces, thereby allowing a smooth operation of the crushing apparatus.
Preferably, the crushing apparatus comprises a gas sensor disposed in a gas pathway of said exhaust-circulating means. This arrangement makes it possible to measure accurately a gas concentration in the crusher casing.
Further, the crushing apparatus preferably comprises water-supply means for supplying water according to an output signal from said gas sensor in the gas pathway or near a terminal of the gas pathway of said exhaust-circulating means. By arranging the water supplier in such a manner, an explosion during crushing can be prevented with simple construction.
More preferably, the crushing apparatus comprises a crushed-piece sensor for detecting pieces sucked by said exhaust-processing means, an outlet smoke sensor for detecting leaked smoke without being sucked by said exhaust-processing means, and an inlet smoke sensor for detecting leaked smoke from the inlet of said casing of the apparatus. These sensors help a smooth operation of the crushing apparatus.
In accordance with another aspect of the present invention, a method of operating the crushing apparatus is characterized in that:
if the crushed-piece sensor detects the crushed pieces, an inlet capacity of said exhaust-processing means is reduced until said crushed-piece sensor does not detect the pieces, but;
if the outlet-smoke sensor detects the smoke, an circulating capacity of said exhaust-circulating means is increased within a range that said inlet-smoke sensor does not detect the smoke.
In this manner, the smoke leakage from the inlet and outlet of the crusher casing is minimized, so that suction of the crushed pieces by the exhaust-processing means is prevented.
Preferably, if the gas concentration measured by the gas sensor is higher than a predetermined value, the water-supply means operates. This infallibly prevents an explosion which would otherwise occur in the crusher.
More preferably, if the gas concentration measured by the gas sensor is still higher than the predetermined value after a predetermined period from the start of operation of the water-supply means, the crushing apparatus stops operating. This further lowers the possibility of occurrence of the explosion.
In accordance with still another aspect of the present invention, a waste-recycling system comprises:
a crushing apparatus of the present invention;
a transport means for transporting crushed pieces exhausted from said crushing apparatus; and
a magnetic separator disposed above said transport means to collect ferrous components from the crushed pieces. In the waste-recycling system, suction of the crushed pieces by the exhaust-processing means is prevented. Accordingly, the waste-recycling system is smoothly operative and has a high recycling efficiency. Also, since a precise forecast of an explosion is possible, the system can be operated safely.
BRIEF DESCRIPTION OF THE DRAWINGS
The above and other objects and features of the present invention will become more apparent from the following description of a preferred embodiment thereof with reference to the accompanying drawings, throughout which like parts are designated by like reference numerals, and wherein:
FIG. 1 is a schematic diagram of a waste-recycling system including a rotary crusher of the present invention;
FIG. 2 is a block diagram showing a control system for controlling a ventilating fan and an exhaust-circulating fan;
FIG. 3 is a flowchart showing a controlling procedure of the exhaust-ventilation fan and the exhaust-circulating fan;
FIG. 4 is a block diagram showing a control system for controlling a water-shower device; and
FIG. 5 is a flowchart showing a controlling procedure of the water-shower device.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The application is based on an application No. 11-281378 filed in Japan, the content of which is incorporated herein by reference.
Referring to FIG. 1, a waste-recycling system 1 includes a feeder 4 , a rotary crusher 10 , a transporter 34 which is, for example, a vibrating conveyer, magnetic separators 36 and 37 , and a receiving box 38 . The waste-recycling system 1 operates as follows: First, the feeder 4 supplies metal wastes 32 such as compressors to the rotary crusher 10 , in which the wastes 32 are crushed into pieces 40 . The transporter 34 transports the crushed pieces 40 discharged from the crusher 10 , and the magnetic separator 36 and 37 magnetically separate the pieces 40 into ferrous and non-ferrous elements. The box 38 receives the non-ferrous pieces that are not salvaged by the magnetic separator 36 and 37 .
The crusher 10 includes a rapidly rotating rotor 12 having breaking means 14 such as hammers or cutters on its periphery; a casing 16 enclosing the rotary crusher 10 ; an exhaust processor 18 ; and an exhaust circulator 25 . The metal wastes 32 supplied from an inlet 16 a travel through an injection chute 16 b towards the rotor 12 . The wastes 32 are compressed and shorn into pieces 40 between the rotating hammers 14 and fixed cutters (not shown) that are arranged on the casing 16 around the rotor 12 . The crushed pieces 40 pass through a gate 16 c and an ejection chute 16 d and then emerge from the outlet 16 e.
When the metal wastes 32 are oil-loaded products such as compressors, oil in the wastes 32 must be removed before they. are thrown into the crusher 10 . However, the oil sticking to and/or wetting inner wall surfaces of the metal wastes is difficult to remove completely, and therefore, a small quantity of oil usually remains in the compressor 32 when the latter is supplied to the crusher 10 .
If the wastes include oil even in a small quantity, smoke is generated by impact and friction that occur during crushing. In the rotary crusher 10 , a high-speed rotation of the rotor 12 carrying the hammers 14 produces an air stream flowing from inlet 16 a to outlet 16 e . By the air stream, the generated smoke is exhausted from outlet 16 e together with the crushed pieces 40 .
In order to vent and process the smoke, the exhaust-processor 18 is installed near the outlet 16 e . The exhaust processor 18 draws in the smoke via a duct 19 with an ventilation fan 20 to process the smoke in processing section 22 by, for example, adsorption. To absorb the smoke completely, an inlet capacity of the ventilation fan 20 must be greater than an exhaust capacity of the crusher 10 . However, excessive increase of the inlet capacity of the exhaust processor 18 results in inhaling of light-weight pieces such as insulated papers or cupric scraps by the processor 18 . If a large amount of light-weight pieces are drawn in, a filter 21 in the exhaust processor is quickly clogged and, as a result, requires frequent replacement or cleaning. This prevents smooth operating of the crusher 10 and lowers its recycling efficiency.
In order to substantially eliminate such an unfavorable influence, it is preferable to lower the exhaust capacity of the crusher 10 . However, the exhaust capacity of the crusher 10 depends on a rotating rate of the hammer 14 , which rate relates to a crushing ability of the crusher 10 . Therefore, the exhaust capacity cannot be simply decreased. According to the present invention, a part of the exhaust from the casing 16 is returned to the inlet side of the rotor in the casing 16 by an exhaust circulator (an exhaust-circulating means) 25 , so that the exhausting capacity of the crusher 10 is reduced while keeping its crushing ability. For example, a circulation duct 24 having circulation fan 26 is connected to the ejection shoot 16 d and the injection shoot 16 b . The circulation duct 24 returns a part of the exhaust from the ejection shoot 16 d to the injection shoot 16 b . This reduces the exhaust capacity of the crusher 10 .
The circulation duct 24 is preferably placed above the gate 16 c so that the crushed pieces do not irrupt into the duct 24 . If the circulation duct 24 and the inhalation duct 24 are disposed so as to cooperate with each other in inhaling the exhausted smoke, different arrangements from that in FIG. 1 may be employed. For example, the circulation duct 24 may be connected to the inhalation duct 24 before the ventilation fan 20 instead of being connected to the ejection shoot 16 d . Further, the inhalation duct 19 may be connected directly to the ejection shoot 16 d instead of being placed adjacent to the outlet 16 e.
In order to prevent an explosion that may occur while crushing wastes including flammable material such as oil, the crusher 10 of this embodiment has an oxygen sensor (a gas sensor) 28 in the gas pathway of the circulation duct 24 to monitor an oxygen concentration in the circulation duct 24 . Alternatively, a gas sensor sensing a concentration of flammable material may be used. The oxygen sensor 28 can measure an accurate concentration of the oxygen, because the airflow does not stay in the circulation duct 24 and the oxygen sensor does not have a protecting cover on it. Since the air passing through the circulation duct 24 is blown into the casing 16 , the oxygen concentration in the duct 24 reflects that in the casing 16 . Preferably, the circulation duct 24 is connected near the point where the hammer 14 initially contact with the fixed cutter so that the oxygen concentration in the circulation duct 24 truly reflects the oxygen concentration near the first impacting point of the hammer 14 . Since the explosion is apt to occur at that first impacting point, the explosion occurrence may be precisely predicted by monitoring the oxygen concentration at that point. When the oxygen concentration in the circulation duct 24 increases over a limit value that is predetermined in reference to the lowest possible concentration oxygen at which the flammable material may explode, a water-shower device (a water-supply means) 30 starts to spray water. The wind generated by the circulation fan 26 carry the sprayed water into the casing 16 to rise the water concentration. Increase of the water concentration in the casing 16 lowers the oxygen concentration therein. If the oxygen concentration is lowered under the limit value corresponding to the lowest possible concentration oxygen at which the flammable material may explode, the explosion will not occur. As long as the wind by the fan 26 can carry the water into the casing 16 , the water shower 30 may be disposed at different places. For example, the shower 30 may be placed near the terminal of the circulation duct 24 . By using the water shower 30 , the water concentration in the casing 16 can be controlled without installing pipes and nozzles for introducing the water vapor in the casing 16 .
Hereinafter, an example of operating method of the rotary crusher 10 according to the present invention will now be described. First, the controlling method of the ventilation fan 20 and the circulation fan 20 to minimize a smoke leak from the outlet 16 e is described. FIG. 2 is a block diagram showing a controlling system for controlling the ventilation fan 20 and the circulation fan 26 . A controller 46 is electrically connected to a crushed-piece sensor 23 for detecting pieces stuck on the filter 21 in the exhaust processor 18 ; an inlet-smoke sensor 42 for detecting leaked smoke from the inlet 16 a of the casing 16 ; and an outlet-smoke sensor 44 for detecting smoke leaked from the outlet 16 e of the casing 16 that has not inhaled by the exhaust processor 18 . For example, a photo sensor may be utilized as the crushed-piece sensor 23 , the inlet-smoke sensor 42 or the outlet-smoke sensor 44 .
FIG. 3 is a flowchart showing the controlling method of the ventilation fan 20 and the circulation fan 26 . At step S 1 , the crusher 10 starts operating, and the crushed-piece sensor 23 , the inlet-smoke sensor 42 and the outlet-smoke sensor 44 are activated. At step S 2 and step S 3 , the circulation fan 26 and the ventilation fan 20 start operating, respectively. At step 4 , the determination is made whether the smoke leaks or not from the outlet 16 e by signals from the outlet-smoke sensor 44 . If the smoke has not been detected, the procedure advances to step S 7 , and if the smoke has been detected, the procedure advances to step S 5 at which the rotation speed of the ventilation fan 20 is increased by a predetermined value. At subsequent step S 6 , if the smoke has still been detected, the procedure returns to step S 5 , while if the smoke has no longer been detected, the procedure advances to step S 7 .
At step S 7 , in order to prevent the exhaust processor 18 from inhaling light-weight crushed pieces such as insulation sheets and cupric scraps, the determination is made whether crushed pieces are stuck or not on the filter 21 in the exhaust processor 18 . If the crushed piece has not been detected, the procedure advances to step S 9 . In contrast, if the crushed piece has been detected, the procedure advances to step S 8 at which the rotation speed of the ventilation fan 20 is reduced by a predetermined value. The step S 7 and the step S 8 are repeated until new sticking of the crushed pieces are no longer detected.
At step S 9 , the determination is made again whether the smoke leaks or not from the outlet 16 e . If the smoke has not been detected, the procedure returns to step S 4 , while if the smoke has been detected, the procedure advances to steps S 10 ˜S 14 at which the smoke leakage from the outlet 16 e is suppressed by adjusting the rotation speed of the circulation fan 26 .
Steps S 10 ˜S 14 will be described in detail. First, at step S 10 , the rotation speed of the circulation fan 26 is increased by a predetermined value. At subsequent step S 11 , if the smoke leakage from the outlet 16 e has been still detected, the procedure returns to step S 10 , while if the smoke leakage has no longer been detected, the procedure advances to step S 12 . At step S 12 , the determination is made whether the smoke leaks or not from the inlet 16 a by the inlet-smoke sensor 42 . If the smoke has not been detected, the procedure returns to step S 4 , while the smoke has been detected, the procedure advances to step S 13 at which the rotation speed of the circulation fan 26 is reduced by a predetermined value. At subsequent step S 14 , if the smoke leakage has been still detected from the inlet 16 a , the procedure returns to step S 13 , while if the smoke leakage has not been detected the procedure returns to step S 4 . The reason why judges the presence of the smoke leakage from the inlet 16 a is that excess returning of the exhaust to the inlet side of the casing 16 may cause a backflow in the casing 16 a which results in smoke leakage from the inlet 16 a.
By operating the crusher 10 in this manner, the smoke leakage from the inlet 16 a and the outlet 16 e can be minimized while preventing the inhaling of the light-weight pieces by the exhaust processor 18 .
The controlling method of the water-shower device for preventing an explosion in the rotary crusher 10 will be described. FIG. 4 is a block diagram showing a control system for controlling the water-shower device and other devices. A controller 46 is electrically connected to the oxygen sensor 28 , the crusher 10 , an alarm 29 and the water-shower device 30 . A power supplier 45 supplies electric power to all of these devices.
FIG. 5 is a flowchart showing the controlling method of the water-shower device 30 and other devices. First, at step S 21 , the rotary crusher 10 starts operating and the oxygen sensor 28 is activated. At step S 22 , the oxygen concentration in the circulation duct is determined. If the oxygen concentration is less than 5%, monitoring of the oxygen concentration is continued. In contrast, the oxygen concentration is over 5%, the procedure advances to step S 23 at which the alarm 29 start alerting and subsequently advances to step S 24 at which the water-shower device 30 starts spraying. The spraying of the water increases the water concentration in the crusher 10 to reduce the oxygen concentration therein relatively.
When a predetermined time has passed from the operation start of the water-shower 30 , the procedure advances to step 25 . At step 25 , if the oxygen concentration in the circulation duct 24 has been reduced under 5%, the procedure advances to step S 26 at which the water-shower device stops spraying and further advances to step S 27 at which the alarm 29 stops. Then, the procedure returns to step S 22 at which the monitoring of the oxygen concentration is continued. In contrast, the oxygen concentration has not been reduced under 5% at step S 25 , the procedure advances to step S 28 at which the crusher 10 stops operating because a possibility of the explosion is quite high.
In this manner, the oxygen concentration in the circulation duct 10 is kept under 5%, so that the atmosphere in the crusher 10 is kept out of an explosion region of the flammable gas generated from oil. The explosion threshold of the oxygen concentration depends on the kind of the flammable gas. Accordingly, the limit value of the oxygen concentration (in this example, 5%) must be adjusted according to the kind of oil in the wastes 32 . When a flammable gas sensor is employed instead of the oxygen sensor 28 , similar control method can be applied. In such a case, the limit value of the flammable gas concentration is determined according to the explosion limit of the flammable gas.
EXAMPLE
In the rotary crusher shown in FIG. 1, an inverter-driven fan having a capacity of 130 M 3 /min and a head 630 mmAq was adopted as the ventilation fan 20 . Varying the specification of the circulation fan 26 , the change of gas capacity at the inlet 16 a and the outlet 16 e was measured. Also, the change of the driving frequency of the ventilation fan 20 required to inhale all of the smoke exhausted from the outlet 16 e was measured.
Comparative Example
When the circulation fan 26 was stopped and the circulation duct 24 was close, the gas capacity at the inlet 16 a and the outlet 16 e was 16 M 3 /min and 59 M 3 /min, respectively. The inverter frequency of the ventilation fan 20 required to inhale all the smoke was 50 Hz.
Example 1
When the capacity and head of the circulation fan was 70 M 3 /min and 50 mmAq, the gas capacity at the inlet 16 a and the outlet 16 e was reduced to 13.6 M 3 /min and 44 M 3 /min, respectively. The inverter frequency of the ventilation fan to inhale all the smoke was reduced to 45 Hz.
Example 2
When the capacity and head of the circulation fan was 125 M 3 /min and 35 mmAq, the gas capacity at the inlet 16 a and the outlet 16 e was reduced to 12 M 3 /min and 39 M 3 /min, respectively. The inverter frequency of the ventilation fan to inhale all the smoke was reduced to 35 Hz.
These results are summarized in Table 1. In Table 1, the parenthesized values indicate a percentage expression of the gas capacity and the inverter frequency when those in the comparative example are taken as 100%.
TABLE 1
Inverter
Freq. of
Specification of
Gas Capacity
Gas Capacity
Inhalation
Circulation Fan
at Inlet
at Outlet
Fan
Comparative
0
M 3 /min
16 M 3 /min
59 M 3 /min
50 Hz
Example
0
mmAq
(100%)
(100%)
(100%)
Example 1
70
M 3 /min
13.6 M 3 /min
44 M 3 /min
45 Hz
50
mmAq
(85%)
(75%)
(90%)
Example 2
125
M 3 /min
12 M 3 /min
39 M 3 /min
35 Hz
35
mmAq
(75%)
(60%)
(70%)
Although the present invention has been fully described by way of examples with reference to the accompanying drawings, it is to be noted here that various changes and modifications will be apparent to those skilled in the art. Therefore, unless such changes and modifications otherwise depart from the spirit and scope of the present invention, they should be constructed as being included therein.
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An apparatus for crushing waste metal products includes a rotor having crushing means on a periphery thereof and a casing enclosing the rotor. The casing has an inlet and an outlet for products to be crushed. An exhaust gas from the casing is partly returned to the inlet of the casing by a circulator. The rest of the exhaust gas is ventilated and processed by an exhaust processor. An oxygen concentration is monitored in a gas pathway of the circulator to control the gas concentration in the casing. If the oxygen concentration is high, a water shower sprays into the casing.
| 1 |
[0001] The present invention relates to a protective composition for skin which protects against bacterial, viral and fungal infection In particular, the invention relates to anti-infective (infection preventing) products, to be used to control infections caused by gram positive organisms such as Methicillin Resistant Staphylococcus aureus (MRSA), Pneumococci and Vancomycin Resistant Enterococci (VRE) as well as gram negative bacteria such as Escherichia coli and Pseudomonas aeruginosa The invention provides a durable handcream which is retained on the hands despite use of the hands More particularly the invention relates to a protective handcream of the type known as a “barrier” handcream The invention also provides body lotions, liquid soaps, shampoos, soap bars and creams generally, which are protective.
BACKGROUND OF THE INVENTION
[0002] Although medical science is continually advancing with new techniques and drugs being developed almost daily, cross-infection in hospitals is still a common occurrence with major implications Micro-organisms may be acquired and transmitted by one of the following routes. direct contact, airborne or via formites. Although these routes are well understood and procedures to control them are standard practice, pathogenic organisms still exist in the hospital environment.
[0003] The spread of infection by direct contact is considered to be the most important method of transmission both for gram positive and gram negative organisms, and it is agreed that the hands of hospital personnel play an important role in the transmission of infection
[0004] Many different organisms exist on the skin. Some belong to the normal flora of the skin and are harmless commensals, which may however, on occasion, become opportunist pathogens in patients who are unusually susceptible to infection such as those in intensive care units Organisms on the skin can be classified into three categories
[0005] Transient organisms—micro-organisms which are deposited on the skin but do not multiply there,
[0006] Temporary residents—contaminants which multiply on the skin and persist for short periods;
[0007] Resident organisms—permanent inhabitants of the skin which colonise the deeper crevices of the skin and hair follicles.
[0008] Removal or killing of the transient flora is generally considered sufficient to prevent the transfer of cross-infection in hospital, but removal of the resident flora is an to additional advantage which should be achieved if possible
[0009] Skin disturbances lead to difficulties in the process of skin cleansing Patients with eczema are often colonised by Staphylococcus aureus to a greater extent than even those suffering from the strongly scaling disease psoriasis. Patients with an atopic eczema are also more frequently colonised because their skin is not as smooth as those with completely healthy skin. Extensive and frequent use of antiseptic-detergent preparations, such as those used in hospitals, causes moderate to severe drying of the skin of the hands, and indeed small wounds on the fingertips in some cases. Low relative humidity during winter results in additional stress to the skin. More than half the nurses involved in one clinical study had increased numbers of bacteria on their hands after only one week's use of an antiseptic detergent preparation (Ojajarvi, J. 1978). The increase was thought to be due to the drying and skin damaging effects of frequent hand washing between every patient contact, but the age of the personnel and nature of duties undertaken were also contributory factors.
[0010] Currently a source of major concern is the appearance of resistant strains of bacteria which survive the cleansing processes, and which have become resistant to antiseptics, antibacterials and antibiotics which originally destroyed them. No amount of hand washing is capable of removing these micro-organisms. Of particular importance amongst the gram positives are resistant strains of Staphylococcus aureus (Methicillin Resistant Staph. aureus —MRSA), resistant Pneumococci and Enterococci (Vancomycin Resistant Enterococci—VRE)
[0011] There is an ever increasing awareness of the need to reduce cross infections in hospitals This awareness has increased with the appearance of these resistant Strains The spread of these infections now has enormous consequences for patient care with patients dying, hospital stay increasing, and hospital budgets soaring. Drugs used to fight MRSA are now responsible for up to 10% of the drug bill at some U.S. hospitals
[0012] Guidelines prepared by Health Departments around the world recommnend, in the absence of anything better, that hand washing is the most important factor currently available in preventing the spread of MRSA and other pathogenic bacteria. These guidelines recommend washing the hands with an antiseptic detergent (e.g. Chlorhexidine-containing hand washes), before and after each patient contact.
[0013] The research of Ojajarvi (1978) referred to above shows the limitations of these recommendations. Furthermore, the work of Aly and Maibach (1979) proved that chlorhexidine significantly reduced the normal flora of the hands. These synthetic antiseptic containing preparations suppress the protective gram positive population (My & Maibach, 1976), resulting in a potentially harmful shift towards gram negative colonisation Long-term and frequent use of detergents containing synthetic bacteriostatic agents may lead to detrimental overgrowth of a particular bacterial species which would otherwise have been unable to survive on normal healthy skin.
[0014] In addition, allergic contact dermatitis caused by Chlorhexidine gluconate and diacetate has been reported by Reynolds et al (1990) and Knudsen et al.(1991).
[0015] By far the most alarming problem was the incidence of a hospital outbreak of Chlorhexidine-resistant Proteus mirabilis resulting in an outbreak of urinary-tract infections affecting 90 patients in Southampton between July 1980 and May 1985 (Dance et al 1987)
[0016] These results show that handwashing alone can not prevent the spread of infections
[0017] Boddie et al 1992, J Dairy Sci 75 1725-1730 discusses the use of post-milking teat germicides containing Lauricidin (Registered Trade Mark for glycerol monolaurate), saturated fatty acids, lactic acids and lauric acid Various compositions were determined against new IMI (intra-mammary infection) caused by Staphylococcus aureus and Streptococcus agalactiae in three controlled infection trials
[0018] Each of the compositions contained Lauricidin (TM) and lactic acid. Two of the compositions further contained lauric acid
[0019] Kabara (1983) “Medium Chain Fatty Acids and Esters” discusses the history of various types of soaps, and further discusses the suitability of various fatty acids as food additives It is stated therein that it is well established that unsaturated fatty acids exhibit an antibacterial influence on gram-positive micro-organisms. The inhibitory effects of unsaturated fatty acids are stated to increase as the number of double bonds in the molecule increase
[0020] International Application PCT/US95/02588 (Publication No. WO95/26710) discusses a personal skin moisturising and cleansing bar composition which comprises both a skin cleansing agent and a lipid moisturising agent in the same bar, which deposits an effective amount of the lipid on the skin of the user in a bath or shower. The bar composition contained both Na lauric soap and lauric acid. The bar thus cleanses and leaves a moisturising lipid layer on the skin. It is not said to have any anti-microbial properties and does not take the form of a leave-on cream or lotion.
[0021] U.K Patent Application No 675,152 discloses oleaginous cosmetic cleansing creams which are used to loosen and dissolve dirt from the skin and which are easily removed from the skin using water alone. Use in these compositions of monoesters of substantially saturated fatty acids of about 12 to 18 carbon atoms with saturated aliphatic polyhydric alcohols of 2 to 3 carbon atoms is disclosed. The composition of Examples 2 to 7 discloses the use of a para hydroxy benzoic acid as a preservative. It is expressly stated that this preservative proved not to be needed in the formulations of these Examples The creams are distinct from those of the present invention in that they are designed to be removed from the skin and do not have anti-microbial properties
[0022] German Patent Application No DE 3 339 196 discloses laurylamido-ethyl- trimethylammonium chloride and its use as an antimicrobial preservative and disinfectant
[0023] U.S. Pat. No 2,900,306 relates to a deodorant stick, comprising a solid alcohol base and having dispersed therein a water soluble soap or salt of saturated higher fatty acids having essentially 12 to 14 carbon atoms This product is a deodorant not an anti-microbial cream.
OBJECT OF THE INVENTION
[0024] The object of the invention is to produce a product which overcomes all of the above mentioned problems, In particular the object of the present invention therefore is to produce a topical preparation which would be:
[0025] supplemental to handwashing—(or in place of where necessary);
[0026] antibacterial—(against gram positive, especially MRSA and VRE, and gram negative bacteria such as E. coli ),
[0027] antifungal and antiviral;
[0028] of natural origin as far as possible -(thereby reducing the chance of resistance occurring), hypoallergenic—(thereby reducing the possibility of contact dermatitis);
[0029] acting as a protective “chemical” glove—(thereby always maintaining sterility),
[0030] inexpensive—(so as to be affordable to all hospital budgets);
[0031] attractive to use—(so that hospital staff will not want to avoid hand sterilization as is currently often the case)
[0032] Further objects of the invention are
[0033] (a) To use a naturally occurring compound as active ingredient, which might reduce the incidence of resistance and allergies
[0034] (b) To provide a product that nourishes the skin and thereby prevents drying and skin damage due to frequent use of antibacterial detergents
[0035] (c) To replace natural components of the skin that are vital parts of the antibacterial defense system of the skin that are removed by washing
[0036] (d) To create an active “liquid glove” (protective mantle) on the skin that prevents infections by the above mentioned bacterial species
[0037] (e) To provide an attractive, reasonably inexpensive agent that is easy to use and does not require handwashing facilities
SUMMARY OF THE INVENTION
[0038] According to the present invention there is provided a protective composition for inhibiting bacterial growth on the skin comprising
[0039] (i) a physiologically acceptable carrier or base,
[0040] (ii) a preservative,
[0041] (iii) an active ingredient for protecting the skin; and
[0042] (iv) a skin protectant
[0043] characterised in that the active ingredient is selected from a C 8 to C 20 fatty acid, one or more parabens, or a combination thereof.
[0044] The fatty acid is preferably lauric acid or a lauric acid salt such as a sodium salt. The fatty acid is present in an amount of 0.05 to 5% w/v, preferably 0.2 to 1% w/v and more preferably 0 5% w/v.
[0045] A paraben or a combination of parabens may be present in the composition. Suitable parabens are methyl and propyl paraben or a combination of methyl and propyl paraben. The composition can suitably contain methyl and propyl parabens in about a 1-1 ratio (w/v) Methyl and propyl paraben are preferably present in an amount of 0.05 to 1% w/v, preferably 0.2 to 0.3% w/v and more preferably 0 25% w/v
[0046] A suitable skin protectant is Simethicone (also known as Dimethicone) Simethicone can be present in an amount of 3 to 10% w/v, preferably 4 to 6% w/v and more preferably 5% w/v
[0047] As an optional extra ingredient, the protective composition may contain an antioxidant, such as Vitamin E (alpha-tocopherol) in an amount of 0 2 to 1% w/v, preferably 0 4 to 0 6% w/v and more preferably 0 5% w/v
[0048] The invention also provides the use of a C 8 to C 20 fatty acid as defined above for use in the manufacture of a protective composition for inhibiting the growth of bacteria, particularly Methicillin Resistant Staphylococcus aureus (MRSA), Vancomycin Resistant Enterococci and gram negative organisms, particularly coliforms and pseudomonants. One or more parabens may also be used to prepare the protective composition
[0049] The invention also provides the use of C 8 to C 20 fatty acid in the inhibition of bacterial, fungal and viral growth and more particularly the use of such a fatty acid together with one or more parabens to inhibit bacterial, fungal or viral growth.
[0050] Suitably the paraben can act both as an active ingredient and as a preservative in the above defined composition The fatty acids are active against both gram positive and gram negative organisms while parabens are particularly active against gram negative organisms.
DETAILED DESCRIPTION
[0051] In order to achieve the objectives mentioned above it was decided to use products already found in the body and which have been shown to have natural antimicrobial activity. Being naturally occurring they should be hypoallergenic at active concentrations. Certain constituents of milk have been shown to have anti-viral and antibacterial activity (see discussion of Boddie et al, 1992, J. Dairy Sci. 75:1725-1730 above) The active factor appears to be a fatty acid C 18:2 Fatty acids and their antimicrobial activity have also been described. Both fatty acids and monoglycerides have these properties and are well documented in the literature. Lactic acid, another naturally occurring component is also known to be inhibitory to both Gram-positive and Gram-negative organisms
[0052] A cream in accordance with the invention comprises
[0053] (a) fatty acids (C 8 -C 20 ) and their salts preferably lauric acid (C 12 ) sodium salt in concentrations of 0 05-5 0%, preferably 0.2 to 1%, more preferably 0.5% w/v
[0054] It is believed that certain derivatives of lauric acid e g Lauricidin (glycerol monolaurate) exhibits anti-infective properties in the treatment Intra-Mammary Infections (IMI) as reported by Boddie et al. 1992. Moreover, monoesters of lauric acid are thought to prevent transmission of viruses such as AIDS, hepatitis B and herpes and are therefore used in a liquid antiseptic handwash (GB-B-2193892 of Colgate Palmolive Company) The antiviral activity of milk isolated in the fatty acid fraction has been reported (Kabara, J J 1980)
[0055] Esters of fatty acids were not incorporated into the product since it is well known that the Fatty Acid Modifying Enzyme (FAME) inactivates a series of bactericidal fatty acids (C 11 -C 24 ) by esterifying them with certain alcohols as reported by Kapral et al. 1992.
[0056] (b) A skin protectant Simethicone (also known as Dimethicone), a mixture of dimethyl polysiloxanes and silica gel, acts as a skin protectant and is used in many established “skin protecting” formulations to ensure the retention of the active ingredients on the skin. Here used in a concentration of 3-10%, preferably 4 to 6%, more preferably 5% w/v.
[0057] (c) A well-established cream base (oil in water) preserved by a potent antimicrobial preservative system such as Parabens or Nipa Esters™ (available from Nipa Laboratories Ltd., U.K.) (e.g methyl and propyl paraben sodium salts) with supporting anti-infective properties. The preferred concentration of a 1 1 mixture of parabens is 0.05-1% w/v, preferably 0.2 to 0 3% w/v, more preferably 0 25% w/v
[0058] Parabens are known to be effective in low concentrations against both bacteria and fungi Propylparaben is considered to be antifungal (Merck index)
[0059] The cream may also optionally contain
[0060] Vitamin E (alpha-tocopherol) acts as a antioxidant. It is used in concentrations of 0 2-1% preferably 0 4 to 0.6%, more preferably 0.5% w/v It prevents oxidation of essential cellular constituents and prevents the formation of toxic oxidation products formed from unsaturated fatty acids that have been detected in its absence.
[0061] Structures of
[0062] Lauric acid sodium salt (I)
[0063] methyl paraben sodium salt (II) and propyl paraben sodium salt (III)
[0064] After washing with an antiseptic detergent or antiseptic soap, if necessary, lie barrier cream of the invention is applied by rubbing a fixed, dispensed amount into the hands The application of further amounts of cream can be done at any stage The cream has the advantage over normal antiseptic soaps that the active ingredient, once applied, act continuously on the skin and is not washed off, after application, as is the case with the antiseptic soaps Dispensers for the cream can be placed wherever convenient, and a source of water for washing is not essential The application of this formulation is not limited to hospitals or consulting rooms but may be used by anyone dealing with the public at large and in danger of infection such as bank tellers, bus conductors, etc Other possible users are those involved in the production of pharmaceuticals and food products It is not the intention to replace hand washing altogether but rather to use the cream to maintain sterility after handwashing or in places where hand washing is not possible
[0065] It is also intended that the cream could be used as an antiseptic wound dressing for wounds which are or may become infected by bacteria
[0066] It is also intended that the barrier cream can be applied as a total body application for those patients who are too fragile to move or bath and who might be colonised by bacteria, viruses or fungi, resistant or otherwise.
[0067] In a series of tests the moisturising cream base has been found to be highly acceptable to both male and female users indicating that the product will probably be used more often than the use of hand washing with antiseptic soaps.
[0068] In a manner similar to that for creams described above, soaps, liquid soaps, body lotions, shampoos or the like, can be made in accordance with the invention
BRIEF DESCRIPTION OF THE DRAWINGS
[0069] [0069]FIG. 1 a+b: Viable counts of MRSA strain S13 in the presence of varying concentrations of Lauric acid Na salt The MRSA strain S13 was chosen in all assays since it is the most resistant isolate to the parabens.
[0070] [0070]FIG. 2 a+b The effects of 0 50% and 1 75% (w/v) solutions of lauric acid Na salt on MRSA isolate S13 at 37° C.
[0071] [0071]FIG. 3 Comparison of the clearing effect of individual methyl or propyl paraben Na salts on E. coli and Ps aeruginosa
[0072] [0072]FIG. 4. Comparison of the combined effects of methyl and propyl paraben Na salts (in solution) on E. coli and Ps. aeruginosa
[0073] [0073]FIG. 5 a+b Effects of 0.25% (w/v) methylpropyl paraben Na salt (1:1 ratio) and 0 50% (w/v) of lauric acid Na salt on selected bacterial stains
[0074] [0074]FIG. 6 a +B Effects of methyl/propyl paraben Na salt 0.25% (w/v) (1:1 ratio) and/or lauric acid Na salt 0.50% (w/v) on E. coli (lab isolate)+survival of E. coli in the presence of methyl/propyl paraben Na salt 0 25% (w/v) (1:1 ratio) and/or lauric acid Na salt 0 50% (w/v).
[0075] [0075]FIG. 7 a+b. Effects of methyl/propyl paraben Na salt 0.25% (w/v) (1:1 ratio) and/or lauric acid Na salt 0.50% (w/v) on MRSA isolate S13+survival of MRSA isolate S13 in the presence of methyl/propyl paraben Na salt 0.25% (w/v) (1:1 ratio) and/or lauric acid Na salt 0.50% (w/v)
[0076] [0076]FIG. 8 a+b: Effects of methyl/propyl paraben Na salt 0.25% (w/v)(1:1 ratio) and/or lauric acid Na salt 0.50% (w/v) on+ Ps. aeruginosa (lab isolate)+survival of Ps. aeruginosa (lab isolate) in the presence of methyl/propyl paraben Na salt 0.25% (w/v).
[0077] [0077]FIG. 9 a+b Effects of methyl/propyl paraben Na salt 0.25% (w/v) (1:1 ratio) and/or lauric acid Na salt 0.50% (w/v) on Vancomycin-resistant enterococci+survival of Vancomycin-resistant Enterococci in the present of methyl/propyl paraben Na salt 0.25% (w/v) (1 1 ratio) and/or lauric acid Na salt 0.50% (w/v)
METHODS
[0078] Well Diffusion Assay
[0079] An overnight culture of the bacterium in question was diluted 1 1,000 in sterile ¼X Ringers solution and 1 ml of this was used to inoculate 500 mls of sterile Tryptic Soy Agar (TSA) Note TSA is a complex medium which is capable of sustaining a wide variety of bacteria 20 ml aliquots of this seeded agar were then poured into sterile petri-dishes and allowed to solidify
[0080] After solidification the desired number of wells were sucked out of the agar using an inverted pasteur pipette which was attached to a vacuum manifold
[0081] One of these wells was designated the control well for all tests and to this 50 μl of the solvent used to dilute the test compounds was added.
[0082] When the test reagents were added all plates were incubated at the optimum temperature for the bacterium concerned, 30° C. for Pseudomonas aeruginosa and 37° C. for all other bacteria, the right way up
[0083] Determination of the Cell Counts
[0084] This was achieved by a number of different techniques depending on the circumstances involved The techniques used were:
[0085] 1 Standard spread plate technique.
[0086] This involves spreading a 100 μl aliquot of the desired dilution onto well dried agar plates using an alcohol flamed hockey stick.
[0087] 2 Pour plate technique:
[0088] In this method 1 ml samples of the diluted culture are placed into a sterile petri dish and then sterile cooled agar is added The plate is then gently swirled to facilitate a heterogeneous mixing of the sample and the agar and allowed to solidify before being incubated at the temperature of choice in an inverted manner
[0089] 3 Spot/drop plating method
[0090] This method involves the placing of a sample or the diluted sample onto a pre-dried agar plate but the sample is allowed to dry into the plate Usually an aliquot of 5-20 μl is chosen to be thus plated This method offers the advantages of being both economical in terms of agar plates (several drops can be readily accommodated on one agar plate) and also accurate
[0091] All plates were incubated for 16 hours before being counted
[0092] All dilutions were carried out in ¼X Ringers solution and all bacteria were grown up in Tryptic Soy Broth (TSB)
[0093] 4 Determination of the cell survival/percentage killing of a culture with respect to exposure to a given agent
[0094] In this method a sample of a fresh overnight culture was titred and a sample (usually 5 mls) was added to either broth (100 mls) containing the test reagents or sterile water (100 mls) and test agents.
[0095] Immediately a sample (T o ) was taken and plated using one of the techniques listed above At regular intervals thereafter other samples were also removed, diluted and plated
[0096] These results were then counted and graphed Error is 1 standard deviation of the mean.
[0097] Definitions Used
[0098] bactericidal the suffix cide (Latin cida, to kill), refers to any agent (chemical or physical) which is able to kill (at least) some types of (vegetative) bacteria, some agents can also irreversibly inactivate bacterial spores
[0099] bacteriostatic the suffix static (Greek: staticos causing to stand or stopping), refers to any agent which inhibits the growth and (particularly) the reproduction of (at least) some types of(vegetative) bacteria
[0100] killing the resultant inability of individual cells to grow when plated onto agar and incubated at their optimum temperature having been exposed to anti-infective agent
[0101] sources of citations Singleton, Sainsbury, Dictionary of Microbiology, Wiley & Sons
Reagents Used Reagents State Solvent Stock conc lauric acid powder distilled water 0.25-5% w/v lauric acid sodium salt desiccated distilled water 0.25-5% w/v methyl paraben sodium salt powder distilled water 0.1-5% w/v propyl paraben sodium salt powder distilled water 0.1-5% w/v
RESULTS
[0102] The Effect of Lauric Acid Sodium Salt on MRSA
[0103] The cell killing effects of lauric acid sodium salt on MRSA was studied and the results shown in FIGS. 1 a and b
[0104] As can be seen the effects of lauric acid Na salt are quite profound in respect to isolate S13, 0 50% lauric acid Na salt is capable of reducing a population of MRSA in water held at 37° C. by 99.8% over 2 hrs. However, this seems to be an anomaly in that the higher concentration of the lauric acid Na salt (1 75%) was not as efficient in its killing effect <99 0% killing over the same period of time This would seem to imply that the availability of water would play an essential role on the killing effect experienced by MRSA
[0105] This experiment was then repeated and the results shown in FIGS. 2 a and b From FIG. 1 b it can be seen that 1 75% (w/v) of lauric acid Na salt acts more rapidly than 0 50% but its effects would appear to level off rapidly as if there was only a subpopulation that was sensitive to this concentration, while its killing effect is closely followed by the 0.50% lauric acid Na salt which again is capable of killing a greater number of MRSA, 99 6% killing after 30 mins
[0106] The results shown in FIGS. 1 and 2 differ because of evaporation of the alcohol carrier necessary to keep the higher concentration of lauric acid in solution Once evaporated the activity would stop as no more lauric acid would be available having precipitated out
[0107] Role of Methyl and Propyl Paraben
[0108] The effects of both methyl and propyl paraben Na salts on gram-negatives were studied when added individually and the results given in FIG. 3 This was assayed using the well diffusion technique Note that there is a difference in the sensitivity of E. coli and Ps aeruginosa to the different paraben derivatives Notice also that their concentrations are 1-5% (w/v)
[0109] The effects of both methyl and propyl paraben Na salts combined in a 1 1 ratio on gram-negatives are shown in FIGS. 4 Notice that the concentration required to give a significant clearing zone has been reduced extraordinarily presumably due to synergistic effect obtained by the combination of the two parabens
[0110] From FIG. 5 a+b it was determined that the mode of action of the parabens was to primarily bactericidal in respect to the gram negatives and the MRSA S13 isolate.
[0111] The results shown in FIG. 6 a and b indicate that lauric acid Na salt in combination with the parabens acts as a bactericidal since the starting number of organisms 10 8 dropped 2 logs within 30 sec No survivors were detected after 35 mins This action is presumably due to a synergistic effect since none of the isolated components is capable of killing E. coli that efficiently.
[0112] As shown in FIGS. 7 a and b the parabens have little or no effect on the MRSA isolate This would have been expected as this strain was chosen for its resistance to the paraben mixture. Lauric acid does elicit killing effect, but again the combination of the parabens and the lauric acid Na salt seems to act synergistically and most efficiently
[0113] [0113]FIGS. 8 a and b show that lauric acid Na salt is not effective against gram-negative Ps. aeruginosa although some killing does occur. There is slight killing due to the parabens but the combination of lauric acid Na salt and the parabens proves once again to result in a synergistic effect.
[0114] Anti-Bacterial Efficacy of Lauric Acid Na Salt in Comparison to the Parabens
[0115] The results shown in FIGS. 9 a and b demonstrate that the parabens have no effect against enterococci in comparison to lauric acid Na salt and the combination of lauric acid Na salt and the parabens Lauric acid Na salt alone or in combination with the parabens is bactericidal and kills off Vancomycin-resistant Enterococci instantaneously since no survivors were found to be present when the samples were plated after 5 mins The control sample which was incubated at the same temperature was able to remain at the same levels as when initially inoculated 4 63×10 7 cfu/ml (cfu=colony forming units) was the T o count This indicates that a 100% kill rate was experienced
[0116] Use of 0 50% of Lauric Acid Na Salt
[0117] These results give strong evidence to endorse the use of 0.50% lauric acid Na salt as opposed to a higher concentration as an even higher rate of killing is achieved using the lower dose It may however take slightly longer to achieve using 0.50% of lauric acid Na salt but this killing time is relatively rapid and therefore the lower level could be used rather than >1% of lauric acid Na salt.
[0118] In Vivo Studies
[0119] A survey in December 1990 of potential users among medical staff showed the Staphylococcus aureus hand carriage rate to be 19 1% (MRSA 5.35%). This was at a time when a previously known handwash was used routinely as a hand disinfectant. A blind clinical trial was carried out on 21 volunteers using the cream of the invention after handwashing with ordinary, non-antiseptic soap and compared them with 26 who abstained from washing their hands with the previously known handwash but who used ordinary, non-antiseptic soap only for three days None of the individuals applying the barrier cream had evidence of S. aureus on their hands In contrast, five of the 26 (19 2%) volunteers using non-antiseptic soap only had S. aureus on their hands
[0120] A follow up survey showed the hand carriage rate of S.aureus among medical staff to be 3% (1% MRSA) We have found no S.aureus carriages on the hands of staff who routinely used the barrier cream All these in vivo studies were performed single-blind, i e the users were unaware of the composition or expected effects of the cream
[0121] The components of the cream are highly efficient in inhibiting gram-positive and gram-negative organisms such as
[0122] Methicillin-resistant Staphylococcus aureus (MRSA)
[0123] Pneumococci
[0124] Enterococci (especially Vancomyan-resistant Enterocci)
[0125] [0125] Escherichia coli
[0126] [0126] Pseudomonas aeruginosa
[0127] The barrier cream has great potential for reducing cross-infection by hand contact with the above mentioned organisms There is no evidence of any unwanted effects (e.g skin irritation) on hands after prolonged usage
[0128] Tests carried out indicate excellent staff compliance as the cream is popular due to its non-greasy natural feel and as the condition of skin on the hands is improved
[0129] Example of Barrier Cream—Formulation
Cream Composition % w/v of the total composition g Cream base emulsifying wax (Lanette Sx) 9.0 white petroleum jelly 15.0 liquid paraffin 6.0 active ingredient lauric acid sodium salt 0.5 preservative methyl paraben and propyl paraben 0.25 sodium salts (1 l) antioxidant alpha-tocopherol 0.5 barrier dimethicon 350 5.0 fragrance camalia 0.35 dem. water 63.40
[0130] Methyl paraben is sold under the Trade Mark NIPAGIN M. PROPYL paraben is sold under the Trade Mark NIPASOL (available from Nipa Laboratories Ltd., Glamorgan, U K)
[0131] Summary of Results of In Vitro Research
[0132] Percentage of cells killed after 5 minutes exposure to various active ingredients:
0.5% 0.25% lauric acid Parabens lauric acid Na salt + Bacterium Na salt Na salt Parabens Na salt E. coli >90 0 >99 Ps. aeruginosa >13 0 >99 MRSA (S13) >97 >65 >99 Vancomycin Resistant 100 33 100 Erterococcus
[0133] All bacteria tested were sensitive to the effects of lauric acid to a greater or lesser extent Vancomycin-resistant Enterococci were totally destroyed by lauric acid alone Pseudomonas aeruginosa showed only 13% destruction with lauric acid alone, no effect with the Parabens only but almost total destruction with the combination This demonstrates a synergistic effect between lauric acid and the Parabens against Pseudomonas The effect on MRSA (S13) was also increased by the inclusion of the Parabens, however lauric acid alone was responsible for more than 97% destruction after 5 minutes The effects of lauric acid Na salt on the Vancomycin-resistant Enterococcus (FPL050) were also tested This strain appears to be extremely sensitive to lauric acid as no survivors were found to be present when samples were plated after 5 mins.
[0134] References
[0135] Aly, R and Maibach, H I (1976), Effect of antimicrobial soap containing chlorhexidine on the microbial flora of skin, Appl Environ Microbiol. 31, 931-5
[0136] Aly, R and Maibach, H. I (1979), Comparative study on the antimicrobial effect of 0.5% chlorhexidine gluconate and 70% isopropyl alcohol on the normal flora on hands, Appl. Environ Microbiol 37 855-7
[0137] Boddie, R L and Nickerson, S C. (1992), Evaluation of post-milking teat germicides containing Lauricidin, saturated fatty acids, and lactic acid, J Dairy Sci 75, 1725-30
[0138] Dance, D A, Pearson, A D, Seal. D V and Lowes, J A (1987), A hospital outbreak caused by a chlorhexidine and antibiotic-resistant+ Proteus mirabilis, J Hosp Infect 10, 10-6
[0139] Kabara, J J (1980), Nutrition Reviews, 38, 235-7
[0140] Kabara, J J (1983) Medium Chain Fatty Acids and Esters, in Antimicrobials in Foods Edited by A. L Branen & P M Davidson, New York, Marcel Dekker, 109-139
[0141] Kapral, F A , Smith, S and Lal, D ( 1992), The esterification of fatty acids by Staphylococcus aureus fatty acid modifying enzyme (FAME) and its inhibition by glycerides, J Med Microbiol, 37, 235-7
[0142] Knudsen, B, B. and Avnstorp, C. (1991), Chlorhexidine gluconate and acetate in patch testing, Contact Dermatitis 24, 45-49
[0143] Ojajarvi, J. (1978), Aspects of infection control, Hands as Vectors of disease, Imperial Chemical Industries Limited, Pharmaceutical Division, Alderley Park Macclesfield, Cheshire, England
[0144] Reynolds, N. J. and Harman, R R (1990), Allergic contact dermatitis from chlorhexidine diacetate in a skin swab, Contact Dermatitis 22, 103-4.
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The present invention relates to a protective composition for skin which protects against bacterial, viral and fungal infections. The compositions comprises a C8-C20 fatty acid, one or more parabens or a combination of these. The composition of the invention is. particularly effective in controlling infection caused by MRSA as well as other organisms. The invention provides protective hand creams such as barrier hand creams as well as body lotions, liquid soaps, shampoos, soap bars and creams generally, all of which
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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a hose used for conveying a refrigerant containing an ester oil, or a similar electrically insulating oil, as a refrigerator oil (lubricant) to an electrically driven compressor. This invention is suitable for use with, among others, an electrically driven compressor in an automobile air conditioner.
2. Description of the Related Art
FIG. 1 shows by way of example a hose which has hitherto been used for transporting a refrigerant to an engine driven compressor in an automobile air conditioner. It comprises an inner tube 1 of rubber, such as IIR (butyl rubber), a reinforcing layer 2 formed by e.g. braided fiber and an outer tube 3 of rubber, such as EPDM (ethylene-propylene-diene rubber). This structure has been employed to give the hose resistance to vibration, and resistance and impermeability to a refrigerant composed of a refrigerator oil of the PAG (polyalkylene glycol) type and a flon (e.g. Freon) substitute, such as HFC (hydrofluorocarbon).
A hybrid car driven by both a gasoline engine and an electric motor, and an economical car having a gasoline engine adapted to stop instead of idling are being developed for practical use to avoid the global environmental problems caused by the massive consumption of gasoline. In either event, the air conditioner which can be employed is of the type in which an electrically driven compressor is employed instead of an engine driven one which does not work if the engine is stopped.
An electrically driven compressor is required to have a high degree of electric insulation, since a motor is installed in a refrigerator. Accordingly, it is necessary to change the refrigerator oil of the PAG type to an ester oil, such as POE (polyol ester), having a high degree of electrically insulating property. It is necessary to ensure a high degree of waterproofness against an external source in order to maintain the high electric insulation of the compressor and avoid the hydrolysis of the ester oil.
It has, however, been a drawback of the hose as shown in FIG. 1 that the IIR forming the inner tube 1 is likely to swell easily with an insulating oil, such as an ester oil, and cannot be expected to be satisfactorily resistant or impermeable to any refrigerant for an electrically driven compressor. It has been another drawback thereof that the hose as a whole is not so designed as to be highly waterproof, but fails to resist any invasion of water through its wall from an external source satisfactorily.
Although no such problem may arise from a metal pipe used for transporting a refrigerant to an electrically driven compressor in a cabinet refrigerator, etc., it is impossible to use a metal pipe for transporting a refrigerant to a compressor in an automobile air conditioner, since a metal pipe is too rigid to withstand vibration of the moving automobile, or its engine.
SUMMARY OF THE INVENTION
It is, therefore, an object of this invention to provide a hose for transporting a refrigerant to an electrically driven compressor which is highly permeation resistant to an electrically insulating oil, and highly waterproof, unlike the known hose as described above, and is vibration resistant so that it is particularly suitable for practical use in an automobile air conditioner.
This object is essentially attained by a hose for transporting a refrigerant containing an electrically insulating oil as a refrigerator oil to an electrically driven compressor, the hose having a wall comprising at least:
(1) a thin resin layer forming its innermost layer; and
(2) a laminated layer including a metallic foil, or a metallic layer formed by vapor deposition.
The above and other objects and advantages of the invention will become more apparent from the following description and the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a partly cutaway perspective view of a known hose for transporting a refrigerant to an engine driven compressor;
FIG. 2 is a partly cutaway perspective view of a hose according to a first preferred embodiment of this invention for transporting a refrigerant to an electrically driven compressor;
FIG. 3A is a perspective view of the hose shown in FIG. 2 partly cutaway to show each laminated layer in the wall;
FIG. 3B is a cross sectional view of a part of the same laminated layer;
FIG. 3C is a view similar to FIG. 3B, but showing a modified form of the laminated layer;
FIG. 4 is a partial longitudinal sectional view of the hose shown in FIG. 2; and
FIG. 5 is a partial transverse sectional view of the hose shown in FIG. 2 .
DETAILED DESCRIPTION OF THE INVENTION
According to a first aspect of this invention, there is provided a hose for transporting a refrigerant containing an electrically insulating oil as a refrigerator oil to an electrically driven compressor, the hose having a wall comprising:
(1) a thin resin layer forming its innermost layer; and
(2) a laminated layer including a metallic foil, or a metallic layer formed by vapor deposition.
The innermost thin resin layer is highly resistant and impermeable to an electrically insulating oil, such as an ester oil (and HFC), and makes the hose of this invention suitable as a hose for transporting a refrigerant containing an electrically insulating oil as a refrigerator oil to an electrically driven compressor. The laminated layer including a metallic foil, or a metallic layer formed by vapor deposition (preferably a metallic foil) makes the hose highly waterproof and prevents any invasion through its wall of water from an external source. Thus, the use of the hose according to this invention makes it possible to ensure the high electrically insulating property of an electrically driven compressor, and also to effectively avoid the hydrolysis of an ester-type oil, if used. Unlike a rigid metal pipe, the hose having a wall comprising a thin resin layer and a laminated layer as described above is satisfactorily flexible for use with an electrically driven compressor in an automobile air conditioner despite the vibration of the moving automobile and its engine.
According to a second aspect of this invention, there is provided a hose in which the thin resin layer in the wall of the hose according to the first aspect thereof is a product of extrusion molding. This is an advantageous method of forming the innermost resin layer. A thin resin layer having an appropriate thickness is easy to form by extrusion onto, for example, a rubber or resin mandrel, and an outer layer, such as of rubber, is also easy to form by extrusion molding simultaneously or sequentially.
According to a third aspect of this invention, there is provided a hose in which the resin layer according to the first or second aspect thereof has a thickness not exceeding 200 microns. The resin layer having a thickness not exceeding 200 microns ensures the high flexibility of the hose despite its wall being composed of the resin and laminated layers.
According to a fourth aspect of this invention, there is provided a hose in which the laminated layer according to any of the first to third aspects thereof comprises a helically wound, or longitudinally lapped tape of a laminated sheet prepared by laying a resin film on any of the following:
(a) a metallic foil;
(b) a metallic foil and a reinforcing material; and
(c) a metallic layer formed by vapor deposition. The resin film in the laminated layer protects the metallic foil, etc. effectively from being damaged or broken by fatigue, even if the hose may be bent or deformed, so that the hose may remain highly waterproof for a long time. The helically wound, or longitudinally lapped tape makes the laminated layer very easy to form on the hose which is a cylindrical body. The reinforcing material used with the foil as in (b) above has a sufficiently high stretch resistance for protecting the foil from being broken, even if a stretching or bending force which is stronger than what can be overcome by the resin film may act upon the wall of the hose. The metallic layer formed by vapor deposition as in (c) above is effective for preventing any sudden reduction in water proofness of the wall of the hose when the wall is stretched or bent by a very strong force unless the laminated sheet as a whole is broken, since the layer formed by vapor deposition is not broken by stretching.
According to a fifth aspect of this invention, there is provided a hose in which the helically wound, or longitudinally lapped tape according to the fourth aspect thereof has its edge portions overlapping each other and bonded to each other. The overlapping edge portions of the laminated layer bonded to each other give it a still higher level of water tightness.
According to a sixth aspect of this invention, there is provided a hose in which the laminated layer according to any of the first to fifth aspects thereof is surrounded by a reinforcing layer formed by braiding reinforcing fiber or wire, and an outer layer of an appropriate rubber. The reinforcing layer surrounding the laminated layer improves the strength of the hose as a whole against bursting, breaking or stretching, while giving a greater protection to the laminated layer. The outer layer is effective for protecting the radially inward reinforcing and laminated layers against deterioration by environmental factors, such as weather, heat, rainwater, chemicals and oils.
According to a seventh aspect of this invention, there is provided a hose including an intermediate layer of rubber formed between the thin resin layer and the laminated layer according to any of the first to fifth aspects of this invention, or between the laminated and reinforcing layers according to the sixth aspect thereof. The intermediate layer of rubber protects the laminated layer against any undesirable wrinkling or bending without lowering the flexibility of the hose (or its vibration resistance) to any undesirable extent, and improves the adherence of the thin resin, or reinforcing layer to the laminated layer and thereby the durability of the hose. The intermediate layer is effective for protecting the laminated layer, or its metallic foil, etc. from being damaged or broken, particularly when it is formed between the thin resin and laminated layers.
Description will now be made in further detail of this invention and the first to seventh aspects thereof.
Use of the Hose
The refrigerant hose of this invention can be used without any limitation for transporting a refrigerant containing an ester oil, or a similar electrically insulating oil as a refrigerator oil (or lubricant) to any electrically driven compressor. Typical examples of its use include its use with an electrically driven compressor in an automobile air conditioner, an ordinary cabinet refrigerator and a household air conditioner, but the most preferable use thereof is its use with an electrically driven compressor in an automobile air conditioner which requires an electrically insulating hose having a high resistance to an ester oil, or like oil, and a high flexibility (or vibration resistance).
Overall Construction of the Hose
The hose of this invention has a wall comprising (1) a thin resin layer forming its innermost layer and (2) a laminated layer including a metallic foil, or a metallic layer formed by vapor deposition. The hose may further include in its wall another component or layer surrounding its thin resin layer, or surrounded by or surrounding its laminated layer. Typical examples of such variations include a hose according to the sixth aspect of this invention having a reinforcing layer, or an outer layer of rubber, or both, and a hose according to the seventh aspect of this invention having an intermediate layer of rubber formed between the thin resin and laminated layers, or between the laminated and reinforcing layers.
Thin Resin Layer
The thin resin layer forms the innermost layer of the wall of the hose according to this invention. It can be formed by any appropriate method, but is preferably formed by extrusion molding, since it is an easy process, as stated before. The layer may be of any resin, since a resin layer is generally highly permeation resistant to an ester, or a similar electrically insulating oil, or an HFC refrigerant, as compared with rubber, etc., even if it may be of small thickness.
Thin Resin Layer Formed by Extrusion Molding
The resin layer formed by extrusion molding is, however, preferably of, for example, a polyamide resin such as nylon 6, nylon 66, nylon 12 or a copolymer thereof, a blended resin containing a polyamide resin, or an ethylene-vinyl alcohol copolymer resin, as every such resin is highly resistant and impermeable to an electrically insulating oil, or an HFC refrigerant.
A particularly preferable material for the layer is a blended polyamide and modified polyolefin resin which is highly flexible, while being highly resistant and impermeable to an electrically insulating oil, or an HFC refrigerant. More specific examples include a blended product obtained by blending appropriate proportions of a modified polyolefin, such as a graft polymer prepared by the graft polymerization of a polyolefin consisting basically of ethylene and/or propylene, with an unsaturated carboxylic acid or a derivative thereof, and a polyamide resin, such as nylon 6, nylon 66, nylon 12 or a copolymer thereof.
The resin and laminated layers may directly adjoin each other, or may be bonded to each other by a thin thermoplastic resin film heated therebetween, but it is usually advisable to form an intermediate layer of rubber therebetween, as stated below.
If the resin layer is of a blended polyamide and modified polyolefin resin, an intermediate layer of rubber surrounding it is preferably of rubber not having any polar functional group, e.g. IIR, a halogenated IIR such as Cl- or Br-IIR, ethylene-propylene rubber (EPM), or EPDM, while the blended resin preferably contains 1 to 10% by weight of ε-caprolactam having a good affinity for the rubber, and the resin and rubber layers are preferably bonded to each other by e.g. a chlorinated rubber adhesive or a phenolic adhesive, so that the two layers may maintain a greatly improved adherence to each other.
The resin layer may be of any thickness enabling the hose to be satisfactorily flexible, but preferably has a thickness not exceeding 200 microns, and more preferably not exceeding 100 microns. A resin layer having an extremely small thickness (for example, less than 50 microns) is often likely to lack uniformity in thickness, or even have a broken portion or portions.
Laminated Layer
The laminated layer may be of any construction if it includes a metallic foil, or a metallic layer formed by vapor deposition, but it is preferably composed of (a) a metallic foil, (b) a metallic foil and a reinforcing material, or (c) a metallic layer formed by vapor deposition, and a resin film laminated thereon.
The laminated layer is preferably formed by helically winding or longitudinally lapping a laminated sheet prepared in the form of a tape by laminating a resin film on any of the materials mentioned as (a) to (c) above. A helically wound layer is formed by winding a tape helically into a completely cylindrical shape with no gaps, and a longitudinally lapped layer is formed by using a tape having a width sufficiently large to encircle the inner layer, placing it in parallel to the longitudinal axis thereof and lapping it completely therearound to form a cylindrical shape.
The laminated sheet is usually prepared by fusing, or adhesively bonding a resin film onto both sides of any of the materials (a) to (c). A laminated sheet including (c), a metallic layer formed by vapor deposition, may be prepared either by forming a metallic layer on a resin film by vapor deposition, and fusing or bonding another resin film onto the metallic layer, or by forming a metallic layer on each of two resin films by vapor deposition, and fusing or bonding the metallic layers of the two films to each other.
The resin film may be of any resin, but is preferably of a thermoplastic resin, such as a polyamide (PA), polyethylene-terephthalate (PET), or ethylene-vinyl alcohol copolymer resin. There are no specific limits for rigidity or thickness, but preferably it has a flexural modulus of 1,000 to 100,000 kgf/cm 2 and a thickness of 5 to 100 microns.
The metallic foil and reinforcing material as in (b) above may or may not be bonded to each other, but are preferably bonded to each other, since the reinforcing material exhibits a greater reinforcing effect when bonded to the foil. The reinforcing material may be surround or be surrounded by the foil, but is more effective when surrounding the foil. The foil and reinforcing material may or may not be bonded to the resin film laid thereon.
Any material can be used as the reinforcing material if it exhibits a high stretch resistance, but it is preferable to use a material having a high flexibility, as well as a high stretch resistance. Examples of the preferred materials are a wire mesh, and a reinforcing fabric, such as canvas, or nonwoven fabric, preferably of aramid, carbon or glass fiber having a high stretch resistance, though a resin film of high strength can also be used.
The helically wound, or longitudinally lapped tape preferably has its edge portions overlap each other to ensure the water tightness of the laminated layer, and more preferably has its overlapping edge portions bonded to each other to ensure a still higher level of water tightness.
Other Components of the Hose
The refrigerant hose of this invention, which comprises the resin and laminated layers, may include an additional component layer or layers, as stated before. A few examples of additional layers will now be described.
A reinforcing layer may be formed to surround the laminated layer. The reinforcing layer is not specifically limited in construction, but may, for example, comprise a braided wire layer, a braided layer of reinforcing fibers, two spiral layers of reinforcing fibers wound spirally in opposite directions to each other, or two such spiral layers between which an intermediate layer of rubber is disposed. A braided layer of reinforcing fibers, such as aramid or polyester fibers, is preferred to ensure the flexibility of the hose.
An outer layer of rubber may be formed as the outermost layer of the wall of the hose. It may be of any rubber, but is preferably of e.g. chloroprene rubber (CR), butyl rubber (IIR), chlorosulfonated polyethylene rubber (CSM), or ethylene-propylene-diene rubber (EPDM), as every such rubber is of high weatherability.
An intermediate layer of rubber (a first intermediate layer of rubber) is preferably disposed between the resin and laminated layers. It is effective for, for example, improving the adhering contact between the resin and laminated layers and reducing the wrinkling or bending of the laminated layer to protect its foil, etc. from being damaged or broken. If a reinforcing layer is formed to surround the laminated layer, it is effective to form an intermediate layer of rubber (a second intermediate layer of rubber) therebetween. The second layer is also effective for e.g. protecting the laminated layer. The first and second intermediate layers may be of any rubber, but are preferably of, for example, IIR, nitrile rubber (NBR) or CSM, as every such rubber is high in refrigerant permeation resistance and flexibility.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention will now be described more specifically by a few preferred forms of its embodiment as shown in the drawings.
Preferred Embodiment 1
FIG. 2 shows a refrigerant hose 4 having a wall which comprises a thin resin layer 5 formed by extrusion molding and having a thickness of about 150 microns, a first intermediate layer 6 of butyl rubber, a laminated layer 7 which is shown in detail in FIGS. 3A and 3B, a second intermediate layer 15 of butyl rubber, a reinforcing layer 8 formed by braiding an appropriate kind of reinforcing fibers and an outer layer 9 consisting of CR, as viewed in the order of their appearance radially outwardly across the wall.
The laminated layer 7 is formed from a laminated sheet 14 prepared by sandwiching with an adhesive an aluminum foil 12 and a resin sheet used as a reinforcing material 13 between an inner resin layer 10 and an outer resin layer 11 each consisting of a thin film of thermoplastic PET, as shown in FIGS. 3A and 3B. The foil 12 is integrally bonded to the reinforcing material 13 by an adhesive not shown, and is held thereby so that no tension acting upon the laminated layer 7 may affect the foil 12 . Although FIGS. 3A and 3B show the foil 12 surrounded by the reinforcing material 13 , their positions can be reversed.
The laminated layer 7 is formed by the laminated sheet 14 in the form of a tape wound helically about the first intermediate layer 6 of rubber, as shown in FIG. 4 . The laminated sheet 14 has its edge portions overlap each other, and its overlapping portions are bonded to each other by an adhesive to ensure the permeation resistance of the wall of the hose against water, etc., coming from any external source.
A modified form of laminated layer 7 can be formed by applying a tape 14 longitudinally to the first intermediate layer 6 of rubber and lapping it thereabout, as shown in FIG. 5 . The tape 14 has its edge portions overlap each other, and its overlapping portions are preferably bonded to each other by an adhesive.
Modified Embodiment 1
The reinforcing material 13 may be excluded from the laminated sheet 14 forming the laminated layer 7 , and the laminated sheet 14 may be composed of an inner resin layer 10 , an outer resin layer 11 and a metallic foil 12 bonded therebetween, as shown in FIG. 3 C.
Modified Embodiment 2
The first intermediate layer 6 of rubber may be excluded from the hose 4 shown in FIG. 2 .
While the invention has been described by the preferred embodiments thereof, variations thereto will occur to those skilled in the art within the scope of the present inventive concepts which are delineated by the following claims.
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A hose for conveying a refrigerant to an electrically driven compressor in an automobile air conditioner has a wall formed by at least an innermost thin resin layer and a laminated layer including a metallic foil or a metallic layer formed by vapor deposition. It is excellent in electric insulation, refrigerant resistance, waterproofness and vibration resistance.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Patent Application Ser. No. 60/985,770 filed Nov. 6, 2007; the disclosures of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
1. Technical Field
The present invention generally relates to health care devices and, more particularly, to a portable wash basin cart that is used to hold a patient's personal wash basin in a mobile, sanitary manner.
2. Background Information
Health care providers in a variety of environments often require a portable wash basin that is individual to the patient. Health care providers currently use a portable wash basin that must be carried back and forth from a bathroom for filling, emptying, cleaning, and refilling. Lower back pain is a common complaint of the users. These portable wash basins are typically a simple rectangular bucket that holds the wash and waste water. The wash basins are typically placed on available table, couch, or bed space when they are being used with the patient. When full of water, the basins are fairly heavy and unwieldy. Current was basins often cause spills and contamination to the support surface as well as surrounding areas.
BRIEF SUMMARY OF THE INVENTION
The invention provides a wheeled cart configured to removably carry a patient's personal wash basin in a sanitary manner. The cart also allows the personal wash basin to be emptied and cleaned in a sanitary manner. The cart also allows the personal wash basin to be filled and moved without straining the back muscles of the user. The invention also provides a disposable personal wash basin for use with the cart.
The invention also provides a personal wash basin having a funnel-shaped outlet that protrudes from the lower surface of the personal wash basin. The funnel-shaped outlet may cooperate with a funnel-shaped outlet of the cart to minimize contact between the cart and contaminated waste water. The personal wash basin may be made from a thin, flexible material, such as a plastic, that may be disposable or recyclable.
In one configuration, the invention provides a portable wash basin cart for health care providers; the portable wash basin cart including: a frame; a personal wash basin defining an outlet; the personal wash basin being carried by the frame; a funnel carried by the frame; the outlet of the personal wash basin being aligned with the funnel; and a flexible drain pipe connected to the funnel.
Another configuration of the invention provides a portable personal wash basin cart that includes: a wheeled frame; a base basin carried by the wheeled frame; the base basin having a bottom wall defining an outlet; and a personal wash basin removably carried by the base basin; the personal wash basin having a bottom wall defining an outlet; the outlets being aligned when the personal wash basin carried by the base basin.
Each of the configurations described above may include flexible tube that allows water from a sink to be directed into the personal wash basin. Each of the configurations described above may include a frame that includes a handle with a lid for the personal wash basin connected to the handle.
A further configuration of the invention provides a portable personal wash basin cart that includes includes a base basin that is fixed to a cart frame and adapted to receive the patient's personal wash basin. The two basins may interlock at outlet funnels so that the personal wash basin is stable when held by the base basin. The outlet funnels allow the patient's personal wash basin to be drained without removing it from the base basin. The funnel-shaped opening prevents fluid from the personal basin from fouling the bottom of the base basin. A flexible drain pipe is removably connected to the outlet of the funnel-shaped opening. The drain pipe has an outlet adapted to fit onto a toilet bowl so the personal basin may be emptied directly into a toilet. To facilitate such draining, the outlet end of the drain pipe may be held by a C-shaped bracket that fits over the edge of a toilet bowl and holds the outlet end of the pipe in place. Caps are connected to both ends of the drain pipe and to the funnel-shaped opening to selectively close the openings. The cap for the funnel-shaped opening is used when the drain pipe is detached for cleaning. The cart includes a hook to hold the outlet end of the drain pipe so that the outlet is raised when not in use to limit dripping.
Another configuration of the invention provides a cart with a pair of basin holders. The dual configuration has the capacity to accommodate twice the amount of water/waste while providing the same sanitary benefits as the single unit.
The different features of the configurations described above may be combined in different combinations to form additional configurations. Each of the configurations described above may be provided with telescoping legs to allow the user to adjust the height of the device.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
FIG. 1 is a front perspective view of an exemplary configuration of a portable wash basin cart.
FIG. 2 is a top plan view of the cart of FIG. 1 with the lid in a different position.
FIG. 3 is a perspective view, partially in section, taken along line 3 - 3 of FIG. 2 .
FIG. 4 is a side elevation view of the portable wash basin cart of FIG. 1 .
FIG. 5 is a rear elevation view of the portable wash basin cart of FIG. 1 with the lid closed.
FIG. 6 is an exploded perspective view of the portable wash basin cart of FIG. 1 .
FIG. 7 is a perspective view of the portable wash basin cart of FIG. 1 attached to a sink faucet.
FIG. 8 is a perspective view of the portable wash basin cart of FIG. 1 emptying waste water into a toilet.
FIG. 9 is a perspective view of an exemplary double basin cart with the lids in their open positions.
FIG. 10 is an enlarged perspective view of the encircled portion of FIG. 3 .
FIG. 11 is a perspective view of the portable wash basin cart with the lid closed.
Similar numbers refer to similar parts throughout the specification.
DETAILED DESCRIPTION OF THE INVENTION
The portable wash basin cart of the invention is indicated generally by the numeral 2 in the accompanying drawings. Portable wash basin cart 2 allows a personal wash basin 3 filled with waste water to be safely moved from one location to another with little risk that the waste water will spill out of cart 2 to contaminate an area that must then be cleaned. Personal wash basin 3 may be in the form of a stand-alone wash basin that is relatively rigid and capable of standing up while full of water. In another configuration, personal wash basin 3 may be provided in the form of a thin, flexible polymeric liner. The thin liner version of personal wash basin 3 may be disposable or recyclable. Portable wash basin cart 2 includes a flexible drain pipe that allows the user to safely drain waste water from personal wash basin 3 without strain on the user's back and with little risk of spilling the waste water during the draining process.
Cart 2 includes a frame 4 that is supported by at least two wheels 6 . Frame 4 may include four vertical legs 5 connected together with upper and lower sets of arms 7 disposed perpendicular to legs 5 . Legs 5 may be in the form of telescoping members to allow the height of cart 2 to be readily adjusted. The telescoping members may be held with friction or a ratchet that allows the user to adjust all four legs simply by lifting up or pushing down on was basin 3 . A common release catch also may be used to permit the adjustments. Each wheel 6 may be selectively locked with a brake 8 . Brakes 8 may be a lever-type or friction-type that prevent the wheel from freely rotating. When only two wheels 6 are used on cart 2 , one end of cart 2 must be lifted to roll cart 2 along the ground. Three or four wheels 6 are typically used so that cart 2 may be readily rolled from place to place without lifting a portion of frame 4 . Frame 4 may be fabricated from any of a variety of materials such as metal, plastic, or wood. In one exemplary configuration, frame 4 is fabricated from plastic or PVC tubes that are relatively light-weight and easy to sanitize. When plastic or PVC tubes are used to form frame 4 , corner joints and adhesive may be used to connect arms 7 with legs 5 . Mechanical connectors, such as screws, bolts, or rivets, may be used to secure the joints.
Frame 4 may be configured to define a storage shelf 10 , a plurality of shelves 10 , or a basket 10 that is adapted to hold supplies. Shelf 10 may be disposed just below a set of arms 7 to define a recessed shelf 10 with arms 7 defining a lip disposed about the perimeter of shelf 10 .
Frame 4 also may define a handle 12 that allows the user to grip cart 2 and control the movement of cart 2 . A lid 14 configured to cover wash basin 3 may be carried by handle 12 in a manner that allows lid 14 to be moved between open and closed positions. A pair of legs 15 connect lid 14 to handle 12 . Each leg 15 may include a sleeve that is rotatably carried by handle 12 to allow lid 14 to rotate between different positions. Handle 12 has an elongated, substantially horizontal portion that extends across the width of basin 2 where legs 15 are connected. Handle 12 includes a pair of L-shaped ends that have vertical portions that drop down from the ends of the elongated, horizontal portion and horizontal offset portions that connect to frame 4 . The offset portions provide space for a tray or shelf 13 disposed intermediate basin 3 and handle 12 . Tray 13 may be removably carried on the horizontal offset portions of the L-shaped ends of handle 12 . When completely open, lid 14 may hang down from frame 4 so that it will not accidentally fall down over the top of the wash basin on the user's hands or arms. The closed position of lid 14 ( FIG. 11 ) is used to cover personal wash basin 3 to prevent accidental splashes when cart 2 is being moved from place to place.
A flexible tube 16 may be used to fill personal wash basin 3 from a sink. Flexible tube 16 includes a faucet adapter 18 that fits a variety of common kitchen or bathroom sink faucets so that person wash basin 3 may be filled with clean water from a variety of locations. Tube 16 also prevents the user from having to lift a full wash basin 3 from a sink to cart 2 . Tube 16 may have a spray attachment on the cart end of tube 16 . Tube 16 may pass through an opening in tray 13 that functions to hold the spray attachment when tube 16 is not in use.
Portable wash basin cart 2 is configured to hold personal wash basin 3 that is typically filled with water or a water/soap combination used to attend to a patient. Basin 3 is personal to the patient and thus must be removed from cart 2 if cart 2 is used with a different patient. As such, basin 3 is removably carried by frame 4 .
Basin 3 is typically plastic and may be any of a variety of shapes such as round, oval, square, rectangular, or the like. A typical rectangular wash basin 3 is depicted as an example in the drawings. Basin 3 may be provided with its own lid that is snapped over the upper lip of basin 3 so that basin 3 may be sealed closed when removed from cart 2 .
Basin 3 may be provided with a drain opening 24 defined by the bottom wall 26 of basin 3 . A plug 28 is used to seal opening 24 when basin 3 is in use. Plug 28 may be secured to the top edge of basin 3 with a pull chain 30 to allow the user to pull plug 28 without reaching into the waste water in basin 3 . In one configuration of the invention, drain opening 24 is defined by a wall 29 that protrudes downwardly from bottom wall 26 . The protruding wall 29 may be shaped in the form of a funnel as shown in FIGS. 3 and 10 .
In one configuration of the invention, frame 4 is configured to removably receive basin 3 directly. In the exemplary configuration of the invention depicted in the drawings, frame 4 includes a base basin 40 sized to removably receive personal wash basin 3 . In either example, a personal wash basin with or without funnel 29 may be removably held by frame 4 .
Wash basin 3 includes an upper flange 42 that rests on top of the upper lip of base basin 40 . Upper flange 42 of wash basin 3 defines a pair of handles 43 that allow basin 3 to be lifted from basin 40 . Flange 42 defines an opening adjacent each handle 43 so that the user may insert her hand between handle 43 and frame 4 when lifting basin 3 . Each handle 43 is C-shaped when viewed from above. Each handle 43 is integrally formed with flange 42 . Each handle 43 includes a rounded bottom wall that is spaced from the basin wall of basin 3 as shown in FIG. 3 so that the user's fingers may be slipped between handle 43 and the basin wall when basin 3 is being lifted. As shown in FIG. 3 , each handle 43 is disposed within base basin 40 when personal wash basin 3 is carried by frame 4 . This position ensures that any water splashing from basin 3 into the handle holes will be directed into base basin 40 and not onto the patient's floor.
Base basin 40 has a bottom wall 44 that includes a funnel 50 configured to receive funnel 29 so that personal wash basin 3 is supported from below by the contact between funnel 29 and funnel 50 . Funnel 50 defines the drain opening of basin 40 and allows basin 3 to be emptied without removing it from cart 2 . Funnel 50 is positioned directly below opening 24 so that little, if any, waste water draining from basin 3 will contact the inner surface of bottom wall 44 . Funnel 50 may be integrally formed with basin 40 or may be connected in an appropriate manner such as a press fit. Funnel 50 may have a larger diameter opening than opening 24 . An elbow joint may be connected to funnel 50 to direct waste water rearwardly. A removable cap may be provided to seal funnel 50 or the elbow joint when a drain pipe 60 is removed. As shown in FIG. 10 , funnel 50 is configured to position the outlet of funnel 29 substantially evenly with the outlet of funnel 50 to minimize contact between waste water being drained from basin 3 and base basin 40 . Funnels 29 and 50 may be configured to position bottom wall 26 spaced from bottom wall 44 so that basin 3 may be easily removed from base basin 40 .
Flexible drain pipe 60 is removably connectable to the outlet of funnel 50 . Drain pipe 60 has an outlet 62 adapted to fit onto the edge of a toilet bowl so personal basin 3 may be emptied directly into a toilet. To facilitate such draining, outlet 62 of drain pipe 60 may be held by a C-shaped bracket 64 that fits over the edge of a toilet bowl and holds outlet 62 of pipe 60 in place. As shown in FIG. 5 , the legs of the C-shaped bracket diverge so that the bracket may be used with a variety of different bowl rims. Caps may be removably connectable to both ends of drain pipe 60 to selectively close its openings. The caps are used when drain pipe 60 is detached from funnel 50 . Frame 4 includes a hook 68 to hold outlet 62 of drain pipe 60 so that outlet 62 is raised when not in use to limit dripping. A support 70 may hang from tray 13 to support pipe 60 .
Another configuration of the invention provides cart 2 that removably receives a pair of personal wash basins 3 . The dual configuration has the capacity to accommodate twice the amount of the water or waste water while providing the same sanitary benefits as the single unit 2 .
Cart 2 may be used by fitting basin 3 into frame 4 and fitting plug 28 into opening 24 . Cart 2 is then moved adjacent a water source wherein tube 16 is used to fill basin 3 with water. Lid 14 may then be closed and cart 2 is wheeled to a position adjacent the patient. The user opens lid 14 and performs the care needed by the patient. When cart 2 has a double basin, one basin may be used for clean water while the other is used for waste water. Once the user is ready is empty the waste water from basin 3 , the user may close lid 14 and move cart 2 into a bathroom. The user checks the connection between drain pipe 60 and funnel 50 , clips outlet end 62 to the edge of a toilet, and removes cap 66 . The user then pulls chain 30 to remove plug 28 and the water drains directly into the toilet. Cart 2 thus prevents the patient's sink from being fouled with waste water. The user may then clean personal basin 3 by connecting tube 16 to a sink and washing basin 3 while basin 3 remains in cart 2 . Cleaning basin 3 in this manner further prevents contamination of the patient's sink. Basin 3 may then be removed from cart 2 and left with the patient. Cart 2 is reused with the next patient by inserting the next patient's personal basin into frame 4 and repeating the process.
In the foregoing description, certain terms have been used for brevity, clearness, and understanding. No unnecessary limitations are to be implied therefrom beyond the requirement of the prior art because such terms are used for descriptive purposes and are intended to be broadly construed.
Moreover, the description and illustration of the invention is an example and the invention is not limited to the exact details shown or described.
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A wheeled cart is configured to removably carry a patient's personal wash basin. The cart includes a lid that covers the personal wash basin when the cart is moved from a bathroom to the patient so that liquid in the wash basin cannot splash out onto the floor if the cart strikes an obstruction. A flexible tube is provided for filling the basin from a sink. A drain pipe is provided to empty the wash basin without the need to lift the wash basin. A disposable thin personal wash basin having a funnel-shaped outlet may be used with the cart to minimize potential contamination.
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TECHNICAL FIELD
[0001] The present invention relates to methods of powder coating heat sensitive substrates, products that result from such methods, heat sensitive substrates powder coated in two layers and related methods, products, sub-assemblies and assemblies.
[0002] A range of heat sensitive substrates are encountered which require an effective surface coating.
[0003] Existing surface coating regimes that rely upon powder coating are those hereinafter shown in FIGS. 1 and 2 . Each involves either preheating (either with radiant infrared or with convection heat or combination of both) or the application of a liquid primer coating prior to the presentation of the powder coating thereto.
BACKGROUND
[0004] PCT/EP96/03264 of MIDASLR (published as W097/05965) discloses a method for coating surfaces in general, and decorating them with powders of various colours characterised by: applying to the surface to be decorated, previously treated for this application, a layer of powdered coating material of colour corresponding to the desired background for the decoration to be obtained, heating the surface treated in this manner to a temperature lower than the backing temperature of the powdered coating material, but sufficient to fix it to the surface to be decorated, applying to the surface prepared in this manner at least one powder of colour corresponding to the coloured motif to be reproduced, distributing it in accordance with the desired pattern of this motif, subjecting the surface treated in this manner to final baking for a time and at a temperature sufficient to securely fix said powder to said surface.
[0005] W 0 97/05965 whilst speaking in respect of a heating temperature for at least the preliminary powder coating of from 75 to 90° C. is silent as to how this can be achieved other than to refer to a traditional powder coating line having pairs of catalytic heating panels, heating lamps, ultraviolet lamps, etc between which the two surfaces to be decorated is passed.
[0006] The present invention recognises an advantage for heat sensitive substrates where a conveyor advance of a product can be passed plural infrared sources thereby, in each passage passed the plural sources, to elicit a desirable effect but with the temperatures being controllable by the relativity of the conveyor speed to the intensity and output of each infrared source and the spacing of them mutually apart. In addition, there is also seen an advantage, for the purpose of temperature control, of having one or more of the infrared sources controlled as to output-by, for example, its own pulsing of its maximum output.
[0007] Thereafter one prior art regime cures the thus applied powder coating with infrared radiation and/or with convention heat thereby to provide the coated component.
[0008] Another procedure relies upon thermal melting and flowing of the powder coat reliant on infrared radiation and/or convection heat and thereafter a UV curing step thereby to provide the coating component.
[0009] Such prior art procedures provide adequate coatings for many substrates but not for heat sensitive substrates which present gassing difficulties and/or are liable to damage owing to the heats that may be required by such processes. Difficulties can compound at edges and profiled regions.
[0010] As used herein “heat sensitive substrates” (“HSS”) include any substrate of a kind where such conventional processes tend to be less than optimal. One such substrate is that frequently referred to as “engineered wood substrates” (“EWS”) typified plywood by many resin bound lignocellulosic fibrous composites (e.g. MDF, particle board, OSB, LBL, etc.) or even some such compositions not requiring an added resin system (e.g. hardboard). Other heat sensitive fibres include carbon fibres. Such carbon fibre/resin systems can be degraded as far as strength is concerned is subjected to excessive heats. Other heat sensitive substrates (“HSS”) include any less tolerant to temperature than, say, EWS or as intolerant to temperature as EWS.
[0011] As used herein “powder coating” includes or refers to any procedure where electrostatic attachment of a coating material (“powder”) is involved irrespective of whether or not the coating material is in a solids and/or liquid form (a true powder) prior to any cure or drying thereof.
[0012] As used herein the term “and/or” means “and” or “or” or, where permitted by the context, both.
[0013] As used herein the term “(s)” following a noun means either or both the singular and plural forms of that noun.
[0014] Reference herein to a “powder” (subject to the foregoing comment in respect of powder coating) preferably includes any powder of a kind capable of at least a partial cure under the action of heat such as that derived from an IR (infrared) source and in the case of the second powder coating a powder both or either capable of being cured by a IR heating source and/or melted and/or melded with an IR heating source and being cured in that molten and/or the post molten state under the action of a UV source.
[0015] Reference herein to “preheating” is preferably (but not necessarily) to ensure sufficient conductivity for subsequent powder deposition reliant on electrostatic attachment. Likewise partial cure heating, etc.
[0016] As used herein “cure” (and related words such as “curing”) includes polymerisation, etc. or other chemical reformation, irrespective of whether or not to completion.
[0017] As used herein the terms “pulse” or “pulsed” mean, in respect of exposure to infrared radiation, subjection to oscillating heat and relaxation periods (“Oscillating Relaxation Periods” or “ORP”). During the relaxation period or periods (arising from movement relative to plaques, or vice versa, rather than heating control of the plaques) the energy absorbed by the coating (immediate surface of the product exposed) is allowed to uniformly disperse across the previously irradiated surface e.g as shown in FIG. 5 as opposed to FIG. 4 hereof. Nonetheless, prior art type pulsing plaques can be used (and preferably are used), in addition, to provide some semblance of heating control for the non relaxation periods (e.g as in FIG. 6 ).
[0018] “ORP” includes both the singular or plural.
[0019] The present invention recognises an advantage to be derived from a sequential coating procedure.
BRIEF DESCRIPTION OF THE INVENTION
[0020] In one aspect the invention is a method of coating a substrate to provide a product which comprises or includes the steps of
[0021] heating the substrate sufficiently to enable its powder coating,
[0022] applying a coating of a powder (“the first powder coating”) to the sufficiently heated substrate,
[0023] at least partially heat curing the first powder coating,
[0024] applying a subsequent powder coating (whether the same powder or different) (“the second powder coating”) to the at least partially cured and still sufficiently heated first powder coating, and
[0025] heat curing the second powder coating,
[0026] wherein the at least partial curing of first powder coating and/or the curing of the second powder coating involves movement of a surface of the substrate or coated substrate relative to plural infrared (“IR”) radiant heat sources thereby to provide a pulsing of exposure to the maximum heating effect of each heat source irrespective of whether or not one or more of such heat sources itself or themselves pulse its or their infrared output.
[0027] Preferably the curing of the second powder coating involves movement relative to plural infrared radiant heat sources.
[0028] Preferably the curing of the second powder coating completes the curing of the first powder coating.
[0029] Preferably at least one of the heat sources itself is a pulsing infrared radiant heat source.
[0030] Preferably the relative movement is continuous.
[0031] Alternatively, but less preferred, the relative movement is intermittent.
[0032] Most preferably the heating of the substrate is with an infrared radiant heat source or sources and there is movement of the substrate relative thereto.
[0033] Preferably the infrared radiant heat sources are stationary.
[0034] Preferably the substrate and developing product is carried by a conveyor.
[0035] Preferably a majority of said heating, at least partial heat curing and heat curing involves pulsing infrared heat sources passed which the substrate or developing product is carried.
[0036] In another aspect the invention is a method of coating a heat sensitive substrate which comprises or includes the steps of
[0037] pre-heating the heat sensitive substrate,
[0038] applying a first coating of a powder,
[0039] at least partially curing the powder coating,
[0040] applying a subsequent powder coating (whether the same powder or different) (“the second powder coating”) over the at least partially cured first powder coating, and either
[0041] (i) curing the second powder coating, or
[0042] (ii) causing the melting and flowing of the second powder coating and thereafter UV curing that coating.
[0043] wherein at least one of the pre-heating, at least partial curing and curing steps involves presentation to spaced infrared (“IR”) sources (e.g thereby to provide a pulsing of IR exposure).
[0044] Preferably the IR sources are intermittent or variable in output.
[0045] In still another aspect the invention is a method of coating a heat sensitive substrate which comprises or includes the steps of
[0046] pre-heating with infrared heating the surface of the heat sensitive substrate,
[0047] applying a first coating of a powder to the heated surface,
[0048] at least partially curing the first powder coating with infrared heating,
[0049] applying a subsequent powder coating (whether the same powder or different) (“the second powder coating”) over at least the partially, cured first powder coating, and either
[0050] (i) infrared curing the second powder coating, or
[0051] (ii) (a) causing with infrared heating the melting and flowing of the second powder coating, and
(b) thereafter UV curing that coating,
[0053] wherein at least one of the infrared heating steps involves movement relative to spaced infrared sources.
[0054] Preferably at least one or the infrared sources pulses or varies in output.
[0055] In another aspect the invention is a method of coating engineered wood substrate which comprises or includes the steps of
[0056] pre-heating the heat sensitive substrate,
[0057] applying a first coating of a powder,
[0058] at least partially infrared radiation curing the powder coating,
[0059] applying a subsequent powder coating (whether the same powder or different) (“the second powder coating”), and
[0060] infrared radiation curing the second powder coating,
[0061] wherein each of said infrared radiation steps involves spaced infrared radiation sources.
[0062] Preferably at least some of such sources pulse or vary in output.
[0063] The use of spaced IR heat sources spaced relative to a conveying direction to treat each of two powder applications to a heat activated substrate.
[0064] Preferably said spaced IR heat sources pulse in output.
[0065] Any product being a substrate coated by a method or as a result of a use.
[0066] As a product, any product that includes at least in part a heat sensitive substrate that has been coated by two layers, a first layer being of a powder coating, and the second layer being of a powder coating, the coating procedure has been characterised in that:
[0067] the substrate was preheated prior to the application of the first coating of powder and such preheating was with a IR heating source and/or otherwise with a heating source controlled to provide sufficient heating for the purpose (e.g. to enable powder retention) without any substantial damage to the substrate,
[0068] the first coating of powder is at least partially cured under the action of at least one controlled IR heating source thereby to reduce damage to the heat sensitive substrate, and
[0069] the second powder coating is either cured by at least one controlled infrared heating source or a combination of at least one controlled infrared heating source and a source of UV,
[0070] wherein the control has in at least one case required the use of spaced and/or pulsing IR sources.
[0071] In still another aspect the invention is a product of an engineered wood substrate or at least in part of an engineered wood substrate wherein the substrate, prior to any coating, has been subjected to surface heating to achieve at least some measure of heat induced degassing thereof and heat activation of the surface, and thereafter at least two powder coating layers have been applied with the innermost layer being at least partially cured reliant on infrared heating prior to application of any further layer(s) and the subsequent layer or subsequent layers being cured by infrared heating or a combination of infrared heating and UV radiation.
[0072] In still another aspect the invention is a coating on a heat sensitive substrate which is or was a green or partially cured powder coat having thereover a subsequently applied and cured powder coating, the cured powder coating having been powdered over the first coating subsequent to at least a partial curing thereof.
[0073] In still another aspect the invention is a coated substrate, said substrate optionally being heat sensitive,
[0074] wherein the coating has been of at least two powder applications,
[0075] and wherein the first powder application prior to the powder application of its contiguous layer was green cured,
[0076] and wherein the combined coatings have been subjected to the heat from intermittent or varying infrared sources thereby to provide at least melting and flowing of the outer layer, and, optionally, some further curing of the inner layer.
[0077] The invention is also a product of a method of the present invention.
[0078] In another aspect the present invention consists in a method of coating a heat sensitive substrate which comprises or includes the steps of
[0079] pre-heating the heat sensitive substrate,
[0080] applying a first coating of a powder,
[0081] at least partially curing the powder coating,
[0082] applying a subsequent powder coating (whether the same powder or different) (“the second powder coating”), and either
[0083] (i) curing the second powder coating, or
[0084] (ii) (a) causing the melting and flowing of the second powder coating, and
(b) UV curing that coating.
[0086] Preferably in one or more of the pre-heating, partial curing and curing steps infrared radiation is used serially or intermittently so as to provide temperature relaxation (preferably ORP).
[0087] In one option step (i) is used.
[0088] In another option step (ii) is used.
[0089] Preferably step (ii)(b) at least substantially follows step (ii)(a).
[0090] Optionally and preferably the preheating is with infrared heat (optionally with ORP)
[0091] Preferably the at least partial cure of the first coating is “green curing”.
[0092] As used herein “green curing” means melt, flow and partial curing.
[0093] Optionally such at least partial cure is with infrared radiant heat in, for example, an IR oven preferably with ORP.
[0094] The powder(s) used can be any of those used with acknowledged prior art procedures.
[0095] Preferably the second powder coating is of a similar powder to that of the first powder coating, but can be different and/or include different additives and/or modifiers.
[0096] In one option (option (i)) the second powder coating is heat cured reliant upon infrared radiant heat preferably with ORP.
[0097] Preferably said infrared radiant heat is intermittent (pulses) or variable from its plaques. Preferably the plaques are spaced so as to provide oscillating relaxation periods (“ORP”) even though we preferably use an IR oven with pulsing plaques.
[0098] In another variant, i.e. option (ii), infrared radiant heat [optionally intermittent or variable] (preferably with ORP, for example, in an infrared oven with a series of spaced pulsing plaques) is used to melt and flow the second powder coating prior to UV curing thereof.
[0099] In still another aspect the present invention consists in a method of coating a heat sensitive substrate which comprises or includes the steps of
[0100] pre-heating the heat sensitive substrate,
[0101] applying a first coating of a powder,
[0102] partially curing the powder coating,
[0103] applying a subsequent powder coating (whether the same powder or different) (“the second powder coating”) over the partially cured first powder coating, and either
[0104] (i) curing the second powder coating, or
[0105] (ii) causing the melting and flowing of the second powder coating and thereafter UV curing that coating.
[0106] Preferably at least one, two or more of the pre-heating, partial curing and final curing steps involved IR irradiation of a pulsed and/or having an ORP character.
[0107] Optionally and preferably the preheating is with infrared heat.
[0108] Optionally such partial cure is with infrared radiant heat in, for example, an IR oven (optionally with pulsing plaques) preferably with ORP.
[0109] Preferably the second powder coating is of a similar powder to that of the first powder coating.
[0110] In one option (option (i)) the second powder coating is heat cured reliant upon infrared radiant heat preferably with ORP.
[0111] Preferably said infrared radiant heat is intermittent or variable. Preferably has ORP (preferably using an IR pulse plaque oven).
[0112] In another variant, i.e. option (ii), infrared radiant heat [optionally intermittent or variable] (preferably with ORP, for example, in an infrared pulse plaque oven) is used to melt and flow the second powder coating prior to UV curing thereof.
[0113] In another aspect the present invention consists in a method of coating a heat sensitive substrate which comprises or includes the steps of
[0114] pre-heating with infrared heating the surface of the heat sensitive substrate (preferably with ORP),
[0115] applying a first coating of a powder to the heated surface,
[0116] at least partially curing the first powder coating with infrared heating (preferably with ORP),
[0117] applying a subsequent powder coating (whether the same powder or different) (“the second powder coating”) over at least the partially cured first powder coating, and either
[0118] (i) infrared curing the second powder coating (preferably with ORP), or
[0119] (ii) (a) causing with infrared heating (preferably with ORP) the melting and flowing of the second powder coating, and
(b) thereafter UV curing that coating.
[0121] Preferably the at least partial cure of the first coating is “green curing”.
[0122] Preferably the second powder coating is of a similar powder to that of the first powder coating.
[0123] In one option (option (i)) the second powder coating is heat cured reliant upon intermittent or varying infrared radiant heat plaques staged so also to provide ORP.
[0124] Preferably it is pulsed (preferably using an IR pulse oven).
[0125] In another variant, i.e. option (ii), infrared radiant heat [optionally intermittent or variable] (preferably pulsed, for example, in an infrared pulse oven) is used to melt and flow the second powder coating prior to UV curing thereof
[0126] In a further aspect the present invention consists in a method of coating engineered wood substrate which comprises or includes the steps of
[0127] pre-heating the heat sensitive substrate,
[0128] applying a first coating of a powder,
[0129] at least partially curing the powder coating,
[0130] applying a subsequent powder coating (whether the same powder or different) (“the second powder coating”), and either
[0131] (i) curing the second powder coating, or
[0132] (ii) (a) causing the melting and flowing of the second powder coating and
(b) thereafter UV curing that coating.
[0134] Preferably step (ii)(b) at least substantially follows step (ii)(a).
[0135] Optionally and preferably the preheating is with infrared heat preferably with ORP.
[0136] Preferably the at least partial cure of the first coating is “green curing”.
[0137] Optionally such at least partial cure is with infrared radiant heat in, for example, an IR oven preferably with ORP.
[0138] Preferably the second powder coating is of a similar powder to that of the first powder coating.
[0139] In one option (option (i)) the second powder coating is heat cured reliant upon infrared radiant heat.
[0140] Preferably said infrared radiant heat is intermittent or variable so as to provide ORP. Preferably it is pulsed (preferably using an IR pulse oven).
[0141] In another variant, i.e. option (ii), infrared radiant heat [optionally intermittent or variable preferably with ORP] (preferably ORO, for example, in an infrared pulse plaque oven) is used to melt and flow the second powder coating prior to UV curing thereof.
[0142] In yet a further aspect the present invention consists in a method of coating an engineered wood substrate which comprises or includes the steps of
[0143] (A) pre-heating the heat sensitive substrate,
[0144] (B) applying a first coating of a powder,
[0145] (C) at least partially curing the powder coating,
[0146] (D) applying a subsequent powder coating (whether the same powder or different) (“the second powder coating”), and
[0147] (E) either
(i) curing the second powder coating, or (ii) (a) causing the melting and flowing of the second powder coating and
(b) thereafter UV curing that coating,
[0151] wherein at least one or more of steps (A), (C), (E) [(i) or (ii)(a)] uses infrared heating which optionally [and preferably] is intermittent or varying so as to cause the desired outcome(s), i.e. without any substantial damage to the substrate. Preferably ORP heating regime(s) is (are) used.
[0152] Optionally and preferably the preheating is with infrared heat.
[0153] Preferably the at least partial cure of the first coating is “green curing”.
[0154] Optionally such at least partial cure is with infrared radiant heat in, for example, an IR oven.
[0155] Preferably the second powder coating is of a similar powder to that of the first powder coating.
[0156] In one option (option (i)) the second powder coating is heat cured reliant upon infrared radiant heat.
[0157] Preferably said infrared radiant heat is intermittent or variable. Preferably it is pulsed (preferably using an IR pulse oven).
[0158] In another variant, i.e. option (ii), infrared radiant heat [optionally intermittent or variable] (preferably ORP, for example, in an infrared pulse oven) is used to melt and flow the second powder coating prior to UV curing thereof.
[0159] In still another aspect the present invention consists in a method of coating a heat sensitive substrate which comprises or includes the steps of
[0160] (A) pre-heating the heat sensitive substrate,
[0161] (B) applying a first coating of a powder,
[0162] (C) at least partially curing the powder coating,
[0163] (D) applying a subsequent powder coating (whether the same powder or different) (“the second powder coating”), and
[0164] (E) either
(i) curing the second powder coating, or (ii)(a) causing the melting and flowing of the second powder coating, and
(b) thereafter IN curing that coating,
[0168] wherein at least one or more of steps (A), (C), (E) [(i) or (ii)(a)] uses infrared heating which optionally [and preferably] is intermittent or varying so as to cause the desired outcome(s), i.e. without any substantial damage to the substrate. Preferably ORP heating regime(s) is (are) used.
[0169] Optionally and preferably the preheating is with infrared heat.
[0170] Preferably the at least partial cure of the first coating is “green curing”.
[0171] Optionally such at least partial cure is with infrared radiant heat in, for example, an IR oven.
[0172] Preferably the second powder coating is of a similar powder to that of the first powder coating.
[0173] In one option (option (i)) the second powder coating is heat cured reliant upon infrared radiant heat.
[0174] Preferably said infrared radiant heat is intermittent or variable.
[0175] Preferably it is pulsed to provide ORP (preferably also using IR pulse oven plaques).
[0176] In another variant, i.e. option (ii), infrared radiant heat [optionally intermittent or variable] (preferably to provide, for example, in an infrared pulse plaque oven) is used to melt and flow the second powder coating prior to UV curing thereof.
[0177] In a further aspect the present invention consists in the use of pulsed (i.e to provide ORP) (or varying or intermittent) IR heat to treat each of two powder applications to a heat activated substrate (optionally with LW curing of the outer layer).
[0178] In a further aspect the present invention consists in any product being a substrate coated by a method or in a use in accordance with the present invention.
[0179] In yet a further aspect the present invention consists in, as a product, any product that includes at least in part a heat sensitive substrate that has been coated by two layers, a first layer being of a powder coating, and the second layer being of a powder coating, the coatings being characterised in one or more of the following:
[0180] (a) the substrate was preheated prior to the application of the first coating of powder and such preheating was with a IR heating source and/or otherwise with a heating source controlled to provide sufficient heating for the purpose (e.g. to enable powder retention) without any substantial damage to the substrate,
[0181] (b) the first coating of powder is at least partially cured and preferably green cured preferably under the action of a controlled preferably IR heating source thereby to reduce damage to the heat sensitive substrate,
[0182] (c) the second powder coating is either cured by a controlled infrared heating source or a combination (preferably first) of a controlled infrared heating source and a source of UV.
[0183] Preferably at least one IR heating is to provide an ORP regime.
[0184] In still a further aspect the present invention consists in a product of an engineered wood substrate or at least in part of an engineered wood substrate wherein the substrate, prior to any coating, has been subjected to surface heating to achieve at least some measure of heat induced degassing thereof and heat activation of the surface, and thereafter at least two powder coating layers have been applied with the innermost layer being at least partially cured reliant on infrared heating prior to application of any further layer(s) and the subsequent layer or subsequent layers being cured by infrared heating or a combination of infrared heating and UV radiation.
[0185] Preferably at least one IR heating is to provide an ORP regime.
[0186] In still a further aspect the present invention consists in a coating on a heat sensitive substrate which is or was a green or partially cured powder coat having thereover a subsequently applied and cured powder coating, the cured powder coating having been powdered over the first coating subsequent to at least a partial curing thereof.
[0187] Preferably the curing of the subsequently applied layer has the effect of further curing the initial layer.
[0188] Preferably at least one (and preferably more) of the preheating, at least partial curing and curing steps has involved at least in part infrared (optionally intermittent and/or varying infrared).
[0189] In another aspect the invention consists in a coated substrate, said substrate optionally being heat sensitive,
[0190] wherein the coating has been of at least two powder applications,
[0191] and wherein the first powder application prior to the powder application of its contiguous layer was green cured,
[0192] and wherein the combined coatings have been subjected to the heat from at least intermittent or varying infrared sources thereby to provide at least melting and flowing of the outer layer, and, optionally, some further curing of the inner layer.
[0193] Preferably the inner layer was dusted to a thickness of from 20 to 60 microns (preferably 30-40 microns) and the subsequent layer was dusted to about 40 to 80 microns thick over the residue of the inner layer [preferably to a total thickness of from 60 to 140 microns].
[0194] Optionally, the outer layer can be UV cured.
[0195] In another aspect the invention is a coating procedure which involves at least one of curing or partial curing with ORP in a sequenced powder coating regime.
BRIEF DESCRIPTION OF THE DRAWINGS
[0196] A preferred form of the present invention will now be described with reference to the accompanying drawings in which,
[0197] FIG. 1 shows a prior art powder coating procedure when being used less than optimally with a heat sensitive substrate,
[0198] FIG. 2 like FIG. 1 shows a conventional powder coating procedure being used less than optimally with a heat sensitive substrate,
[0199] FIG. 3 shows processes of the present invention,
[0200] FIG. 4 shows Temperature (T) build up in a conventional IR pulse plaque oven,
[0201] FIG. 5 shows (e.g with two relaxation periods by way of example) the lesser T build up using (preferably pulsed IR plaques) serially separated so as to provide relaxation periods, and
[0202] FIG. 6 is a flow diagram showing as the powder coated product passes through the IR the product is subjected to oscillating heat and relaxation periods. During the relaxation period the energy absorbed by the coating (immediate surface of the product) is allowed to uniformly disperse across the previously irradiated surface.
DETAILED DESCRIPTION OF THE INVENTION
[0203] The following for the type of powder coatings can be used for either or both coatings and are preferably of the resin/binder type. These include powder coatings based on the following resin chemistries (including variations thereof, and not limited to):
Polyester Epoxy Epoxy Polyester Polyester - hydroxyalkylamide Polyurethane Acrylic Epoxy-Acrylate Acrylo-Polyurethane Acrylo-Polyester.
[0213] Additionally they can include powder coatings that may contain flexibility modifying additives for example those based on core/shell acrylic rubber.
[0214] When processing HSS we have found it preferably to use a heating source that is controllable and directly able in which to localise and thus minimise heat transfer into the substrate but make it conductive enough to powder coat evenly.
[0215] To solve this problem we have evolved two techniques of advantage in the procedures of the present invention.
[0216] 1. Dual Coating (2 stage application—optionally single or double pass)
[0217] 2. Electromagnetic Radiation Pulsing (ERP), preferably IR with ORP or ORPs.
[0000] Process Overview:
[0218] The process involves the pre-conditioning of the substrate which in one embodiment is an engineered wood substrate (EWS). This is achieved by way of applying a minimum level of heat to increase conductivity of the EWS, whilst not unduly diminishing its physical integrity.
[0219] A first “dusting” layer of powder of a powder coating system is applied to the EWS (approximately 30-40 microns), this is then followed by a “green cure” (i.e. melt, flow & partial curing) of the dusting layer by way of an IR heating, which blocks off and seals the EWS.
[0220] A secondary coat of powder coating is then applied (approximately 50-60 microns) over the dusting coat.
[0221] The final thickness of the powder coating, then being approximately 80-100 microns, which is then cured to the specification required.
[0222] The final curing preferably ensures (e.g with ORP) that the EWS does not receive too high a level of IR heat input. This involves only allowing just enough heat be absorbed by the powder coating so as to polymerise it to the level specified. Too much heat will result in off-gassing, cracking and degradation of the EWS, which will lead to post cure cracking (PCC) and loss of the EWS mechanical properties such as “screw-ability”.
[0000] A Preferred Procedure:
[0223] The EWS is preferably loaded on to the coating conveyor's line at the loading zone. The EWS is prepared by removing any loose particles from its surface by way of air jets, de-nibbler, brush or the like. This process provides a smooth surface, free from objects that would disrupt the final coated film.
[0224] The EWS undergoes pre-treatment by passing it thru a booster oven. This booster oven is preferably IR heating (with or without ORP) but could also be convection heating or a combination IR/Convection. The booster oven raises the EWS temperature to a predetermined level prior to powder coating.
[0225] The EWS enters the “dusting” booth where a layer of powder is deposited on one or more of its surfaces. The dusting layer is ideally between 30 and 40 microns, but could be anywhere between 20 and 60 microns. The powder particles adhere to the grounded and warm EWS.
[0226] The dust coated EWS passes next through the “green cure” oven where the powder is heated to bring about melting, flow-out and allow partial polymerisation of the powder. This is preferably with IR radiation using ORP.
[0227] Following the green cure oven the EWS enters a second powder coating booth where a new layer of powder is deposited on the previously coated surfaces. The new layer is ideally between 50 and 60 microns but could be anywhere between 40 and 80 microns. The powder particles adhere to the grounded and still warm EWS.
[0228] The fully coated EWS enters the IR Pulse Plaque Oven configured to provide ORP where the heat is directed to the surface in such a way so as to largely only heat the combined powder layer.
[0229] By employing a “Dual Coating” technique (whether within a single or double pass operation), a significant reduction in coating defects is achieved. This reduction in the number of defects ultimately addresses appearance and performance needs. This lowers the overall reject rate of powder coated EWS. By dust coating the EWS first we are sealing the substrate and reducing dehydration of the EWS in order to provide us with an evenly conductive surface for the final coat.
[0230] By using this method we are able to achieve repeatedly, uniform and consistent film builds.
[0231] The ORP technique was developed to limit heat transfer into the substrate whilst allowing the powder increased dwell time in which to cure. By way of this process the two main issues of supplying a pre-finished totally cured HSS are addressed,
[0232] 1 . Limiting heat build-up in the HSS
[0233] 2 . Provide an environment in which the powder can go through its three states of Melt, Flow and Cure.
[0234] Use of the ORP technique coupled with the particular pulsing plaque layout ( FIG. 1 ) for the IR pulse oven, we lower the heat intensity on the substrate, leaving the integrity of the substrate intact as well as evening the energy out across all six edges of a usual panel type product, which allows us to achieve a uniform cure of the powder.
[0235] A process layout, which enables us to apply powder to a wide range of HSS including but not limited to plywood and MDF, is used which will not jeopardise the integrity of the products being processed.
[0000] Suitable powders for powder coatings include those available from each of:
[0000]
Orica Powder Coating Limited 31B Hillside Road Wairau Valley Auckland 1310
Ameron (New Zealand) Limited 5 Monahan Road Mt Wellington Auckland 1006
Dulux Powder Coatings 51 Winterton Road Clayton VIC 3168 Australia
Akzo Nobel Powder Coatings Akzo Nobel Pty Limited 51 McIntyre Road Sunshine, Melbourme Victoria 3020 Australia
DuPont Powder Coatings USA, Inc 9800 Genard Rd. Houston, Tex. 77041 USA
Tigerwerk Lack-u.Farbenfabrick Gmbh & Co. KG Negrellistr. 36 4600 Wels Austria
Suitable platens include those available from each of platen manufacturers:
Catalytic Industrial Systems 20 th and Sycamore Independence, Kans. 67301, USA
Vulcan Catalytic Systems Portsmouth Business Park 207 High Point Road, PO Box 555 Portsmouth, R.I. 02071-0855 USA
Heraeus Noblelight GmbH Heraeusstraβe 12-14 63450 Hanau Germany
Infratech-USA 939 North Vernon Avenue, Azusa Calif. 91702 USA
Suitable UV sources include those sources available from any of:
Fusion UV Systems, Inc 910 Clopper Road Gaithersburg, MD 20878-1357 USA
Nordson Corp., UV Curing Systems 555 Jackson St. Amherst OH 44001-2496 USA
Heraeus Noblelight GmbH Heraeusstraβe 12-14 63450 Hanau Germany
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A method of coating a substrate such as a heat sensitive engineered wood substrate which involves sequential powder coating where at least one and preferably both powder coating steps involves the use of fixed infrared heat sources (optionally pulsing themselves) passed which the developing product (the substrate and its coatings) moves thereby to provide a heat relaxation between maximum exposure to each (optionally pulsing) infrared source. Preferably the first coating is green cured only prior to the application of the second powder coating. Preferably similar pulsing heat sources are used for the initial heating of the substrate so as to enable powder coating.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation (and claims the benefit of priority under 35 USC 120) of U.S. application Ser. No. 09/860,622, filed May 18, 2001, which claims priority to Provisional Application Ser. No. 60/205,656, filed May 18, 2000. The disclosures of the prior applications are considered part of (and are incorporated by reference in) the disclosure of this application.
BACKGROUND OF THE INVENTION
[0002] The present invention provides a fire extinguishing and fire retardant delivery method and system to suppress and extinguish fires, in particular, wildfires. Wildfires, which include forest and range fires, are fully self-sustaining and are either of such a size or in such a location, which make them unmanageable by conventional means. Current technologies for wildfire suppression are fuel starvation and/or removal and aerial delivery of suppression agents, such as water and retardant slurries. The self-sustaining nature of wildfires means that they generate very large incoming airflows, vertical updrafts and turbulence, which provide fuel/air sourcing and mixing. These airflow patterns generated by these fires make it difficult to deliver slurry retardant and/or water to the core of the fire. Delivery of such materials to the core of the fire can cool, block infrared transmission, and deprive the fire of fuel. The system of the present invention provides a method and means for delivering to a fire target, a retardant or extinguishing material in a thermal and/or pressure-sensitive container.
[0003] Another direct application of the type of container embodied in this patent is the use as a non-lethal weapon. The rupture of the canister can have a stun effect coupled with the disbursement of material into a crowd.
SUMMARY OF THE INVENTION
[0004] A fire suppression or extinguishing method is provided comprising the step of confining a fire extinguishing or suppressing agent in slurry, liquid or gaseous form within a phase-change canister which comprises a shell of such an agent in solid form. The optimum system uses an agent in solid form which sublimates at atmospheric pressure at temperatures above about −150° C. The container is designed and delivered in close proximity to burning substances such that the container ruptures releasing the agent onto the burning substance.
[0005] The container is formed such that the shell comprises an agent in solid form and the inner core is filled with an agent in slurry, liquid or gaseous form.
[0006] The container may be made on an apparatus comprising a shaped molding cavity for receiving the liquid agent to form a shell; a feature for cooling the surface to solidify the liquid to form the shell, a feature for filling the shell with the liquid agent and sealing the shell to form the container, and a feature for releasing the container from the molding surface. Another apparatus for forming the container comprises a shaped molding cavity for receiving the liquid agent to form a shell; a feature to solidify the liquid to form the shell by a pressure-controlled phase change and a feature for releasing the container from the molding surface
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] [0007]FIG. 1 is a partial cut-away view of a container according to the invention for delivery to afire.
[0008] [0008]FIG. 2 is a cross-section of an apparatus for preparing the container shown in FIG. 1.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0009] The present invention includes a designed phase-change canister material delivery system as applied to a fire extinguishing method and system in which the delivery capsule is formed by confining a fire extinguishing agent within a designed phase-change container comprising the shell of a fire extinguishing agent in solid form. The container is delivered and allows delivery, in close proximity to burning substances such that release of the agent from the ruptured container and the container itself extinguishes or suppresses the fire.
[0010] The fire extinguishing or fire retardant agents typically used in the present invention are materials which can be totally absorbed and/or dispersed into the target environment, yet which are benign relative to the target environment. The preferred materials for the solid shell of the container are solid carbon dioxide, ice or other solid fire retardant or extinguishing agents. Carbon dioxide and ice are the preferred materials for use as the shell as a non-lethal weapon. As explained in more detail below, the container may be sealed under pressure or it may be unpressurized. The shell material is selected so that the shell material itself also serves as a fire extinguishing or retarding agent, thereby enhancing the material itself also serves as a fire extinguishing or retarding agent, thereby enhancing the effects of the material dispersed from the container. The shell composition and thickness are designed so that it will weaken or fail, releasing the enclosed material, either by the phase change of the shell material, i.e. melting or sublimation, and/or by bursting of the shell upon impact.
[0011] The shell thickness of the container may be readily determined by those of ordinary skill in the art based on the type of material to be dispersed, the desired radius of dispersement, the time-delay, if any, between the placement of the container and the moment of dispersement, and the target environment conditions for dispersement of the encased material. A property of the container wall is that in the target environment it will undergo a change in phase consistent with that which would readily disperse or be absorbed by the target environment. Typically, the shell will change its physical state in accordance with the system state variables at the target or environment. That is, the shell material will melt and/or sublime at the temperature or other environmental conditions at the target site.
[0012] The materials may be distributed at the target site by bursting of the container. For example, a shell of solid carbon dioxide may contain a core of a liquid dioxide, water, or other extinguishing agent or fire retarding agent. The shell may also, for example, be made of ice and contain a core of liquid carbon dioxide, water or other extinguishing agent or retarding agent. Furthermore, the shell may be made of a solid retardant and/or extinguishing agent and the core may contain liquid carbon dioxide, water, or other extinguishing agent and/or retarding agent. The contents may be pressurized or not, depending on the timing of the burst, desired radius of dissipation or desired dispersion method. Typically, the core material will be sublimable at a temperature above about −150° C. up to about 100° C. The bursting of the container due to changes in environmental conditions or impact at the target site is much more desirable than the use of explosives. Explosive bursting charges are environmentally unacceptable, can add undesirable debris to the environment and generate incendiary materials as a result of the explosion process.
[0013] Another method of release of the materials is by diffusion mixing. The material within the container, i.e. bacterial agents or chemical agents may be diffusion driven for dispersion and thus may require a release mechanism involving the erosion of the container wall.
[0014] Finally, release may be triggered by an environmental effect, such as thermal or pressure activation such that the thermodynamic and mechanical properties of the shell and the contents serve as rupture triggers within the container.
[0015] The containers may be delivered from aircraft or thrown or shot into the target area using catapults, air pressure guns and the like.
[0016] Referring to FIG. 1, there is shown a partial cutaway of one embodiment of a container according to the present invention. The container comprises a shell 10 and a hollow interior containing a slurry, liquid or gas of a fire extinguishing or fire retarding material 11 . The shell 10 is also made of a fire extinguishing or retarding material. Indentations 10 a serve to facilitate release of the container from the mold from which it is made. Preferably, the container is of a relatively large size, having an interior volume determined by the fire suppression application. It can carry charges of sufficient amounts of material such as carbon dioxide, which will at room temperature be converted into a large volume of gaseous carbon dioxide and some liquid carbon dioxide. The vapor pressure of liquid carbon dioxide rises with temperature, and can reach approximately 1,000 atmospheres at temperatures of about 160° C. Thus, the containers in the practice of the invention when using carbon dioxide as an interior component should be constructed to resist rupture when introduced into a fire until the maximum internal stress in the shell wall is exceeded by either or both the internal pressure built up or external forces. In practice, the charged container is introduced into the fire by being dropped, thrown or shot into the blaze. The heat of the fire primarily reduces the shell thickness, and thus its overall strength to a point where the internal pressures cause shell rupture and disburse the contained material. This is assuming that the shell was not designed to rupture on impact. The heat of the fire raises the temperature slightly within this container design. The container explodes spreading the contents into the surrounding area. The liquid and gaseous contents expand rapidly with the liquid material phase changing to gaseous, thus chilling the surrounding area as well as displacing hot gases and replacing them with CO 2 . The contents of the container, as well as the shattered container particles are rapidly vaporized to provide a blanket in the target area which serves to smother and extinguish the blaze.
[0017] The process of the invention may be employed with containers of varying size, from those which are very small, which may be manually thrown or dropped into the fire to those which must be either mechanically catapulted to the fire or dropped from an aircraft or balloon suspended above the fire.
[0018] Referring to FIG. 2, there is shown an apparatus for forming a container according to FIG. 1 by controlled temperature time phase transition. For convenience, only half of the apparatus is shown with the mirror image of the other half (not shown) required to make a complete container. There is a piston 12 having a surface 13 in the shape of desired shape of the container with ridges (not shown) that form indentations such as 10 a in the exterior surface of the shell which serve to promote release of the shell from the mold. This piston can be cooled with a cooling agent such as liquid nitrogen, which is introduced through conduit 14 . The piston 12 is compressed to form the shell from fluid (liquid, slurry or gaseous) initially introduced through line 15 . The shell is then filled through conduit 15 with the liquid, slurry or gas materials intended to comprise the core. The sealing piston 16 is utilized to seal the contents within the shell. The forming and sealing pistons 12 and 16 are then withdrawn, respectively, from each half of the formed container and the container is released from the surface 13 . Alternatively, a solid shell can be formed using a similar apparatus having walls sufficient to withstand the necessary pressure for a controlled pressure-time phase transition.
[0019] As shown, the liquid nitrogen coolant is supplied from pressurized tank 17 where it is collected in depressurized traps 18 . Excess nitrogen gas is vented through vent 19 .
[0020] Carbon dioxide is supplied from tank 20 from which it is filtered through filter 21 and depressurized in traps 22 . The carbon dioxide which will be frozen to form the shell of the canister is introduced via conduit 23 to surface 13 . The carbon dioxide which will form the liquid/gas/solid contents of the container is introduced via line to conduit 15 .
[0021] The hydraulic system for manipulating pistons 12 and 16 is provided by hydraulic fluid storage tank 24 and pump 25 . The flow of hydraulic fluid is controlled by valve controllers 26 to compress pistons 16 or 12 , respectively, by pressuring compartments 26 or 27 . The pistons 16 or 12 are withdrawn, respectively, by pressuring compartments 29 or 28 .
[0022] Materials other than carbon dioxide may be utilized in tank 20 , such as water or aqueous slurries or solutions of fire retardant agents.
[0023] It is understood that certain changes and modifications may be made to the above containers and apparatus without departing from the scope of the invention and it is intended that all matter contained in the above description shall be interpreted as illustrative and not limiting the invention in any way.
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A fire extinguishing and fire retarding method is provided comprising the step of confining a fire extinguishing and fire retarding agent in slurry, liquid or gaseous form within a shell wherein the shell comprises such an agent in solid form. An agent such as ice water, or liquid carbon dioxide is useful when employing the shell as “non-lethal” device. The solid shell is sublimable and will burst upon impact or upon exposure to the environmental conditions at the target site to release the contents of the shell as well as the fragments of the shell onto the target site.
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