Title of Invention	"A SYNERGISTIC COMPOSITION OF POLYMERIC BLEND USEFUL FOR PREPARATION FOR PREPARATION OF BIODEGRADABLE POLYMER DEVICE"
Abstract	A synergistic composition of polymeric blend useful for preparation of biodegradable polymer device: The invention provides to a synergistic composition of polymeric blend useful for preparation of biodegradable polymer device. The device may be in the form of micro particles, micro spheres, implants, pellets, discs, beads, rings film, sheets, capsules and useful for the controlled release or immobilization or supporting of active ingredients, such as drugs, dyes, proteins peptides, vaccines, hormones, steroids, enzymes, microorganisms, catalysts, flavors, nutrients, tracers, inhibitors, promoters. The composition comprises 1.76 to 5.28% by weight of one or more soft, fast degrading polymers and 1.76 to 5.28% by weight of one or more rigid, slow-degrading polymers , balance volatile organic solvent and optionally 3-20% by wt. an active ingredient.

Title of Invention

"A SYNERGISTIC COMPOSITION OF POLYMERIC BLEND USEFUL FOR PREPARATION FOR PREPARATION OF BIODEGRADABLE POLYMER DEVICE"

Abstract

A synergistic composition of polymeric blend useful for preparation of biodegradable polymer device: The invention provides to a synergistic composition of polymeric blend useful for preparation of biodegradable polymer device. The device may be in the form of micro particles, micro spheres, implants, pellets, discs, beads, rings film, sheets, capsules and useful for the controlled release or immobilization or supporting of active ingredients, such as drugs, dyes, proteins peptides, vaccines, hormones, steroids, enzymes, microorganisms, catalysts, flavors, nutrients, tracers, inhibitors, promoters. The composition comprises 1.76 to 5.28% by weight of one or more soft, fast degrading polymers and 1.76 to 5.28% by weight of one or more rigid, slow-degrading polymers , balance volatile organic solvent and optionally 3-20% by wt. an active ingredient.

Full Text	The invention relates to a synergistic composition of polymeric blend useful for preparation of biodegradable polymer device. The device may be in the form of micro particles, micro spheres, implants, pellets, discs, beads, rings film, sheets, capsules, etc. and useful for the controlled release or immobilization or supporting of active ingredients, such as drugs, dyes, proteins peptides, vaccines, hormones, steroids, enzymes, microorganisms, catalysts, flavors, nutrients, tracers, inhibitors, promoters, etc. More particularly, this invention relates to a composition of polymeric blend which contains two polymers of which one is soft and the other is rigid at ambient temperature. Still more particularly, this invention relates to the preparation of polymeric blends of two polymers wherein both the polymers are biocompatible, biodegradable and mutually miscible, the biodegradation rate of the rigid polymer being significantly lower than that of the soft polymer such that, when the devices prepared out of these blends are exposed to a degrading medium, the soft, fast-degrading polymer in them degrades preferentially which results in rigid micro porous devices whose porosity is directly proportional to the content of the soft polymer, and which consists almost entirely of the rigid polymer. This invention also relates to the preparation of the above mentioned type of polymeric devices from the said type of blends into which active ingredients such as those mentioned above are incorporated. Devices prepared from the polymeric blends claimed in the present invention have potential applications in the field of controlled delivery of active substance such as drug, agriculture, pesticides, cosmetics, foodstuffs, enzyme immobilization, catalysis, biochemical and microbial reactions, imaging, separation technology. In prior art, many references are there on the use of blends of two or more polymers to improve processability or product quality . Prior art relating to the preparation of devices from biodegradable polymer blends is also known. Examples are (1) A. J. Domb, M. Maniar and A. T. S. Haffer, PCT Int. Apple. WO 92 13, 567, 20 Aug 1992. In this patent a blend of two or more biodegradable polymers is prepared by a oil/oil emulsion method wherein the two polymers used are Poly (lactic-co-glycolic acid) and Poly(lactic acid). The microspheres are prepared by oil/oil/water emulsion-solvent evaporation method. (2) T. Suzuki, Y. Nishioka, Y. Matsukawa, A. Matsumoto and M. Kobayashi, Eur. Pat. Appl. EP 595, 030, . 04 May 1994; consisting of blends of polyesters and/or polyanhydrides used as pharmaceutical carriers; e.g. Poly(lactic acid) and Poly(sebaccic acid). (3) A. J. Domb, J. Polym. Sci., Part A, Polym. Chem., 31, 1973 (1993). This paper describes the screening of miscible polymers from degradable polymer blends. Aliphatic, aromatic and copolymers of polyanhydrides are miscible in each other and form less crystalline compositions with a single melting point. The polyesters; Poly(lactide-glycolide), Poly(caprolactone), and Poly(hydroxybutyric acid) presented some miscibility with each other. However, the polyanhydrides were immiscible with the polyesters resulting in a complete phase separation. (4) S. J. Huang, O. Kitchen and L. J. DiBenedetto, Polym. Mater. Sci. Eng., 62, 804 (1990). But no prior art is known in which the blend of a soft, fast-degrading, fully synthetic, biodegradable and biocompatible polymer and a rigid, slow-degrading, fully synthetic, biodegradable and biocompatible polymer is used for the preparation of polymeric devices where the objectives are to reduce the porosity created during preparation of the devices, if prepared by solvent removal methods, and to obtain devices which develop, in a degrading environment, porosity which is proportional to the content of the soft polymer, thereby providing variability and control on porosity. Therefore, the blends prepared by the process of this invention are novel and of considerable practical significance. Accordingly, the present invention provides, a synergistic composition of polymeric blend useful for preparation of biodegradable polymer device which comprises 1.76 to 5.28% by weight of one or more soft, fast degrading polymers such as herein described and 1.76 to 5.28% by weight of one or more rigid, slow-degrading polymers as defined herein, balance volatile organic solvent and optionally 3-20% by wt. an active ingredient. It is to be noted that this technique of microsphere preparation does not involve any chemical reaction between the polymers and the solvents and the soft and rigid polymers. Yet the morphological and release characteristics of the composition so produced are entirely different from those of the components of the mixture taken individually due to synergism in the ingredients used. In one of the embodiments of the present invention, the process comprises of preparing a clear homogeneous solution mixture by dissolving a soft, fast - degrading polymer and a rigid, slow - degrading polymer in a volatile organic solvent and preparing microspheres from the said solution mixture by conventional microsphere preparation methods namely oil - in - water, oil - in -oil and water - in - oil - in - water emulsion. The oil-in-water system consists of an oil soluble active ingredient dissolved in volatile organic solvent along with the polymer forming the oil phase which is then injected into a 0.5% aqueous solution of Poly(vinyl alcohol), which is the water phase, forming an oil-in-water emulsion. The oil-in-oil system consists of an oil soluble active ingredient dissolved in a volatile organic solvent along with the polymer forming the oil i phase which is then injected into liquid paraffin or silicone oil containing 8% sorbitan monooleate. which is the oil 2 phase, forming an oil-in-oil emulsion. The water-in-oil-in-water system consists of a water soluble active ingredient dissolved in distilled water forming the water 1 phase, which is then emulsified in the volatile organic solvent containing the polymer to form the water-in-oil emulsion, which is further injected into' 0.5% aqueous solution of Poly(vinyl alcohol) which is the water 2 phase, forming a water-in-oil-in-water emulsion. In yet another embodiment of the invention, the composition comprises of mixing the melt of a soft, fast-degrading polymer and that of a rigid, slow-degrading polymer to obtain a homogeneous melt mixture, and preparing microspheres by conventional melt-dispersion methods. In still another embodiment of the present invention, the composition comprises of preparing a homogeneous melt mixture of one or more soft, fast-degrading polymers and one or more rigid, slow-degrading polymers and forming the said melt mixture, by the use of conventional processing techniques such as injection molding, extrusion. casting, coating, melt-pressing, melt-dispersion, etc. into devices such as implants, pellets, discs, rings, beads, films, sheets, etc. In yet another embodiment, the blends containing active ingredients were prepared by the process of the present invention which comprises of dissolving or dispersing, as solution or solid, the desired active ingredient in the said polymer solution mixture or melt, and processing the resultant mixture as described in any of the embodiments mentioned above. Some examples for the said soft polymers used for the preparation of the above mentioned devices are is Poly ( carboxyphenoxyualeric acid ) , Poly ( carboxyphenoxyoctanoic acid ) or a Poly (carboxyphenoxyvaleric -co - carboxyphenoxyoctanoic acid) copolymer and the said rigid polymer is Poly ( carboxyphenoxyhexane), Poly ( carboxyphenoxy-propane) or Poly ( carboxyphenoxypropane-co-sebasic acid) (85 : 15) copolymer. The active ingredient used is selected from drugs, dyes, proteins, peptides, vaccines, hormones, steroids, enzymes, microorganisms, catalysts, flavors, nutrients, tracers, inhibitors, promoters, etc. The composition is a synergistic mixture which has the morphological and release characteristic properties which are entirely different from either of the components of the ingredients. The ratio of the soft polymer to the rigid polymer in the blend that can be employed in the preparation of the said polymeric blends is dependent on several factors. The highest content of the soft polymer in the blend is limited to a level where the resultant micro spheres possess sufficient mechanical strength and are able to retain their individuality. In most cases a minimum of 10 percent of the rigid polymer would be required. Another criterion to be satisfied is the miscibility of the polymers to ensure the homogeneity of the microspheres. The present invention is described herein below by examples which are illustrative only and should not be construed to restrict the scope of the present invention in any matter. Example-1 100 mg of Poly(carboxyphenoxyvaleric acid) and 100 mg of Poly(carboxyphenoxy hexane) were dissolved in 2 ml of dichloromethane to get a clear, homogeneous solution. The solution was then injected through a hypodermic needle into 80 ml of 0.5 per cent aqueous solution of Poly(vinyl alcohol) which was stirred at 400 rpm in a round-bottom flask. 5 min after the addition of the solution, vacuum was applied to the system for one and a half hours. The hardened microspheres were isolated by filtering after diluting the Poly(vinyl alcohol) solution with distilled water and washing the microspheres. The microspheres were dried at room temperature for 4 hours over fused calcium chloride under vacuum. Example-2 100 mg of Poly(carboxyphenoxyvaleric acid) and 100 mg of Poly(carboxyphenoxy hexane) were dissolved separately in 1 ml of dichloromethane and these solution were mixed together to get a clear, homogeneous solution. 20 mg of lysozyme dissolved in 100 microlitres of distilled water was dispersed into the mixed polymer solution by soniccation. The resultant dispersion was then injected through a hypodermic needle into 80 ml of 0.5 per cent aqueous solution of Poly(vinyl alcohol) which is kept stirred at 400 rpm in a round-bottom flask. 5 min after the addition of the solution mixture vacuum was applied to the system for one and a half hours. The hardened microspheres were isolated by filtering after diluting the Polyvinyl alcohol) solution with distilled water and washing the microspheres. The microspheres were dried at room temperature for 4 hours over fused calcium chloride under vacuum. Example-3 100 mg of Poly(carboxyphenoxyvaleric-co-carboxyphenoxyoctanoic acid) 1:1 copolymer and 100 mg of Poly(carboxyphenoxyhexane) were dissolved in 2 ml of dichloromethane to get a clear, homogeneous solution. The solution was then injected through a hypodermic needle into 80 ml of 0.5 per cent aqueous solution of Polyvinyl alcohol) which was stirred at 400 rpm in a round-bottom flask. 5 min after the addition of the solution mixture, vacuum was applied to the system for one and a half hours. The hardened microspheres were isolated by filtering after diluting the Poly(vinyl alcohol) solution with distilled water and washing the microspheres. The microspheres were dried at room temperature for 4 hours over fused calcium chloride under vacuum. Example-4 100 mg of Poly(carboxyphenoxyvaleric-co-carboxyphenoxyoctanoic acid) 1:1 copolymer and 100 mg of Poly(carboxyphenoxyhexane) were dissolved in 2 ml of dichloromethane to get a clear, homogeneous solution. 20 mg of lysozyme dissolved in 100 microlitres of distilled water was dispersed into the mixed polymer solution by soniccation. The resultant dispersion is then injected through a hypodermic needle into 80 ml of 0.7 per cent aqueous solution of Polyvinyl alcohol) which is kept stirred at 400 rpm in a round-bottom flask. 5 min after the addition of the solution mixture vacuum was applied to the system for one and a half hours. The hardened microspheres were isolated by filtering after diluting the Poly(vinyl alcohol) solution with distilled water and washing the microspheres. The microspheres were dried at room temperature for 4 hours over fused calcium chloride under vacuum. Example-5 100 ml of Poly(carboxyphenoxyvaleric-co-carboxyphenoxyoctanoic acid) 3:1 copolymer and 100 mg of Poly(carboxyphenoxyhexane) were dissolved in 2 ml of dichloromethane to get a clear, homogeneous solution. 20 mg of lysozyme dissolved in 100 microlitres of distilled water was dispersed into the mixed polymer solution by soniccation. The resultant dispersion is then injected through a hypodermic needle into 80 ml of 0.5 per cent aqueous solution of Poly(vinyl alcohol) which is kept stirred at 750 rpm in a round-bottom flask. 5 min after the addition of the solution mixture vacuum was applied to the system for one and a half hours. The hardened microspheres were isolated by filtering after diluting the Poly(vinylalcohol) solution with distilled water and washing the microspheres. The microspheres were dried at room temperature for 4 hours over fused calcium chloride under vacuum. Example-6 50 mg of Poly(carboxyphenoxyvaleric-co-carboxyphenoxyoctanoic acid) 1:3 copolymer and 150 mg of Poly(carboxyphenoxyhexane) were dissolved in 2 ml of dichloromethane to get a clear, homogeneous solution. 20 mg of lysozyme dissolved in 100 microlitres of distilled water was dispersed into the mixed polymer solution by soniccation. The resultant dispersion is then injected through a hypodermic needle into 80 ml of 0.5 per cent aqueous solution of Poly(vinyl alcohol) which is kept stirred at 400 rpm in a round-bottom flask. 5 min after the addition of the solution mixture vacuum was applied to the system for one and a half hours. The hardened microspheres were isolated by filtering after diluting the Poly(vinyl alcohol) solution with distilled water and washing the microspheres. The microspheres were dried at room temperature for 4 hours under vacuum. Example-7 150mg of Poly(carboxyphenoxyvaleric acid) and 50 mg of Poly(carboxyphenoxy-hexane) were dissolved separately in 1 ml of dichloromethane and these solutions were mixed together to get a clear, homogeneous solution. 20 mg of bovine serum . albumin dissolved in 100 microlitres of distilled water was dispersed into the mixed f polymer solution by soniccation. The resultant dispersion is then injected through a hypodermic needle into 80 ml of 0.5 per cent aqueous solution of Poly(vinyl alcohol) which is kept stirred at 600 rpm in a round-bottom flask. 5 min after the addition of the solution mixture vacuum was applied to the system for one and a half hours. The hardened microspheres were isolated by filtering after diluting the Poly(vinyl alcohol) solution with distilled water and washing the microspheres. The microspheres were dried at room temperature for 4 hours over fused calcium chloride under vacuum. Example-8 100 mg of Poly(carboxyphenoxyvaleric acid) and 100 mg of PoIy(carboxyphenoxy- hexane) were dissolved in 2 ml of dichloromethane to get a clear, homogeneous solution. 10 mg of p-nitrophenol was dissolved in this solution. This solution was injected through a hypodermic needle into 80 ml of 0.5 per cent aqueous solution of Poly(vinyl alcohol) which is kept stirred at 400 rpm in a round-bottom flask. 2 min after the addition of the solution, vacuum was applied to the system for on and a half hours. The hardened microspheres were isolated by filtering after diluting the Poly(vinyl alcohol) solution with distilled water and washing the microspheres. The microspheres were dried at room temperature for 4 hours over fused calcium chloride under vacuum. Example-9 100 mg of Poly(carboxyphenoxyvaleric-co-carboxyphenoxyoctanoic acid) 3:1 copolymer and 100 mg of Poly(carboxyphenoxyhexane) were dissolved 2 ml of dichloromethane to get a clear, homogeneous solution. 10 mg of p-nitrophenol was dissolved in this solution. The solution is then injected through a hypodermic needle into 80 ml of 0.5 per cent aqueous solution of Poly(vinyl alcohol) which is kept stirred at 400 rpm in a round-bottom flask. 2 min after the addition of the solution mixture vacuum was applied to the system for one and a half hours. The hardened microspheres were isolated by filtering after diluting the Poly(viny alcohol) solution with distilled water and washing the microspheres. The microspheres were dried at room temperature for 4 hours over fused calcium chloride under vacuum. Example-10 100 mg of Poly(carboxyphenoxyvaleric acid) and 100 mg of Poly(carboxyphenoxy-hexane) were dissolved in 2 ml of dichloromethane to get a clear, homogeneous solution. 40 mg of lysozyme dissolved in 150 microlitres of distilled water was dispersed into the mixed polymer solution by soniccation. The resultant dispersion is then injected through a hypodermic needle into 80 ml of liquid paraffin containing 10 per cent dichloromethane and 8 per cent sorbitan monooleate and kept stirred at 400 rpm in a round-bottom flask. After 5 min 100 ml of petroleum ether was added over 20 min. The hardened microspheres were isolated by filtering and were washed with petroleum ether. The microspheres were dried at room temperature for 2 hours under vacuum. Example-11 100 mg of Poly(carboxyphenoxyvaleric acid) and 100 mg of Poly(carboxyphenoxy-hexane) were dissolved in 2 ml of dichloromethane and 10 mg of p-nitrophenol was dissolved in this. This solution was then injected through a hypodermic needle into 80 ml of liquid paraffin containing 15 per cent dichloromethane and 8 per cent sorbitan monooleate and kept stirred at 500 rpm in a round-bottom flask. 5 min after the addition of the solution mixture, 100 ml of petroleum ether was added over 20 min. The hardened microspheres were isolated by filtering and were washed with petroleum ether. The microspheres were dried at room temperature for 2 hours under vacuum. Example-12 100 mg of Poly(carboxyphenoxyvaleric acid) and 100 mg of Poly(carboxyphenoxy-hexane) were dissolved in 2 ml of chloroform to get a clear, homogeneous solution. 20 mg of lysozyme dissolved in 100 microlitres of distilled water was dispersed into the mixed polymer solution by soniccation. The resultant dispersion is then injected through a hypodermic needle into 80 ml of 0.5 per cent aqueous solution of Poly(vinyl alcohol) which is kept stirred at 400 rpm in a round-bottom flask. After 5 min vacuum was applied to the system for two hours. The hardened microspheres were isolated by filtering after diluting the Poly(vinyl alcohol) solution with distilled water, and washed. The microspheres were dried at room temperature for 4 hours over fused calcium chloride under vacuum. Example-13 100 mg of Poly(carboxyphenoxyvaleric acid) and 100 mg of Poly(carboxyphenoxy-hexane) were dissolved separately in 1 ml of dichloromethane and these solutions were mixed together to get a clear, homogeneous solution. 20 mg of lysozyme dissolved in 100 microlitres of distilled water was dispersed into the mixed polymer solution by soniccation. The resultant dispersion is then injected through a hypodermic needle into 80 ml of silicone oil containing 10 per cent dichloromethane and 7 per cent sorbitan monooleate and kept stirred at 400 rpm in a round-bottom flask. After 5 min, 100 ml of petroleum ether was added over 20 min. The hardened microspheres were isolated by filtering and were washed with petroleum ether. The microspheres were dried at room temperature for 2 hours under vacuum. Example-14 125 mg of Poly(carboxyphenoxyvaleric acid) and 375 mg of Poly(carboxyphenoxy-hexane) were taken in a glass cup of 2 ml capacity. The cup was heated to 170°C. After the polymers melted, the contents were mixed well and dispersed into 30 ml of stirred silicone oil maintained at 170°C in a 100 ml beaker. After 3 min, heating was stopped and the dispersion was allowed to cool to room temperature under continuous stirring. The dispersing medium was diluted with petroleum ether and the microspheres were filtered, washed, and dried under vacuum. Example-15 125 mg of Poly(carboxyphenoxyvaleric acid), 375 mg of Poly(carboxyphenoxy hexane) were taken in a glass cup of 2 ml capacity. 25 mg of microfined 5-fluorouracil was mixed "in it. The cup was heated to 170°C. After the polymers melted, the contents were mixed well and dispersed into 30 ml of stirred silicone oil maintained at 170°C in a 100 ml beaker. After 3 min, heating was stopped and the dispersion was allowed to cool to room temperature under continuous stirring. The dispersing medium was diluted with petroleum ether and the microspheres were filtered, washed, and dried under vacuum. Example-16 125 mg of Poly(carboxyphenoxyvaleric acid) and 375 mg of Poly(carboxyphenoxy-hexane) were packed compactly into a flat-bottomed glass ampoule of 1 cm internal diameter and 4 ml capacity which was wetted previously with liquid paraffin. The ampoule was heated to 175 C. After the polymers melted, vacuum (0.05 mm of Hg) was applied to the ampoule till the melt was totally clarified of air bubbles. The ampoule was then allowed to cool to room temperature. The ampoule was broken and the solid polymer block was removed. The block was wiped clean with n hexane. cut, and polished to obtain a disc. Example-17 20 mg of a water-soluble dye, viz. Brilliant Blue BL, was intimately mixed with 125 mg of Poly(carboxyphenoxyvaleric acid) and 375 mg of Poly(carboxyphenoxy-hexane). This mixture was packed compactly into a flat-bottomed glass ampoule of 1 cm internal diameter and 4 ml capacity which was wetted previously with liquid paraffin. The ampoule was heated to 175°C. After the polymers melted, vacuum (0.05 mm of Hg) was applied to the ampoule till the melt was totally clarified of air bubbles. The ampoule was then allowed to cool to room temperature. The ampoule was broken and the solid polymer block was removed. The block was wiped clean with n-hexane, cut, and polished to obtain a disc. Example-18 20 mg of a water-soluble dye, viz. Brilliant Blue BL, was intimately mixed with 125 mg of Poly(carboxyphenoxyvaleric acid) and 375 mg of Poly(carboxyphenoxy hexane). This mixture was packed compactly into a wire-extruding die of 1 cm internal diameter and 0.6 mm orifice diameter. The inner surface of the die was wetted with liquid paraffin before packing the polymer-dye mixture. The die was heated to 160 C using band heaters. After the polymers melted, the melt was extruded into a cooling bath containing liquid paraffin. The solidified extrudate was washed with n hexane, dried in vacuum, and cut into pellets of 3 mm length. Example-19 125 mg of Poly(carboxyphenoxyvaleric-co-carboxyphenoxyoctanoic acid) 3:1 and 375 mg of Poly(carboxyphenoxyhexane) were mixed and packed compactly into a wire-extruding die of 1 cm internal diameter and 0.5 mm orifice diameter. The inner surface of the die was wetted with liquid paraffin before packing the polymer dye mixture. The die was heated to 160°C using band heaters. After the polymers melted, the melt was extruded into a cooling bath containing liquid paraffin. The solidified extrudate was washed with n-hexane, dried, and cut into pellets of 3 mm length. The polymeric composition prepared in the present invention has several advantages over the ones known in prior art. The incorporation of the soft, fast-degrading polymer due to their better chain flexibility helps to form denser microspheres during the preparation of the microspheres by solvent removal methods. This minimizes the unwanted diffusional release through pores other than those intended to be created by the degradation of the soft polymer. The preferential degradation of the soft, fast-degrading polymer from the microspheres allows the generation of porosity in the release environment affording the release of the active ingredient. The porosity of these microspheres is directly proportional to the amount of the soft polymer in the blend which allows the preparation of microspheres with any desired level of porosity. We Claim: 1. A synergistic composition of polymeric blend useful for preparation of biodegradable polymer device which comprises 1.76 to 5.28% by weight of one or more soft , fast degrading polymers such as herein described and 1.76 to 5.28% by weight of one or more rigid, slow-degrading polymers as defined herein, balance volatile organic solvent and optionally 3-20% by wt. an active ingredient. 2. A synergistic composition as claimed in claim 1 , wherein the said soft polymer is Poly ( carboxyphenoxyualeric acid ) , Poly ( carboxyphenoxyoctanoic acid ) or a Poly (carboxyphenoxyvaleric -co - carboxyphenoxyoctanoic acid) copolymer and the said rigid polymer is Poly ( carboxyphenoxyhexane), Poly ( carboxyphenoxy-propane) or Poly ( carboxyphenoxypropane -co - sebasic acid) ( 85 : 15 ) copolymer. 3. A synergistic composition as claimed in claims 1 and 2 wherein the volatile organic solvent used is dichloromethane, chloroform or dichloroethane. 4. A synergistic composition as claimed in claims 1 to 3 wherein the active ingredient used is selected from drugs, dyes, proteins, peptides, vaccines, hormones, steroids, enzymes, microorganisms, catalysts, flavors, nutrients, tracers, inhibitors, promoters. 5. A synergistic composition of polymeric blend useful for preparation of biodegradable polymer device substantially described herein with reference to examples.

Full Text

The invention relates to a synergistic composition of polymeric blend useful for preparation of biodegradable polymer device. The device may be in the form of micro particles, micro spheres, implants, pellets, discs, beads, rings film, sheets, capsules, etc. and useful for the controlled release or immobilization or supporting of active ingredients, such as drugs, dyes, proteins peptides, vaccines, hormones, steroids, enzymes, microorganisms, catalysts, flavors, nutrients, tracers, inhibitors, promoters, etc. More particularly, this invention relates to a composition of polymeric blend which contains two polymers of which one is soft and the other is rigid at ambient temperature. Still more particularly, this invention relates to the preparation of polymeric blends of two polymers wherein both the polymers are biocompatible, biodegradable and mutually miscible, the biodegradation rate of the rigid polymer being significantly lower than that of the soft polymer such that, when the devices prepared out of these blends are exposed to a degrading medium, the soft, fast-degrading polymer in them degrades preferentially which results in rigid micro porous devices whose porosity is directly proportional to the content of the soft polymer, and which consists almost entirely of the rigid polymer. This invention also relates to the preparation of the above mentioned type of polymeric devices from the said type of blends into which active ingredients such as those mentioned above are incorporated. Devices prepared from the polymeric blends claimed in the present invention have potential applications in the field of controlled delivery of active substance such as drug, agriculture, pesticides, cosmetics, foodstuffs, enzyme immobilization, catalysis, biochemical and microbial reactions, imaging, separation technology.
In prior art, many references are there on the use of blends of two or more polymers to improve processability or product quality . Prior art relating to the preparation of
devices from biodegradable polymer blends is also known. Examples are (1) A. J.
Domb, M. Maniar and A. T. S. Haffer, PCT Int. Apple. WO 92 13, 567, 20 Aug 1992. In this patent a blend of two or more biodegradable polymers is prepared by a oil/oil emulsion method wherein the two polymers used are Poly (lactic-co-glycolic acid) and Poly(lactic acid). The microspheres are prepared by oil/oil/water emulsion-solvent evaporation method. (2) T. Suzuki, Y. Nishioka, Y. Matsukawa, A. Matsumoto and M. Kobayashi, Eur. Pat. Appl. EP 595, 030, . 04 May 1994; consisting of blends of polyesters and/or polyanhydrides used as pharmaceutical carriers; e.g. Poly(lactic acid) and Poly(sebaccic acid). (3) A. J. Domb, J. Polym. Sci., Part A, Polym. Chem., 31, 1973 (1993). This paper describes the screening of miscible polymers from degradable polymer blends. Aliphatic, aromatic and copolymers of polyanhydrides are miscible in each other and form less crystalline compositions with a single melting point. The polyesters; Poly(lactide-glycolide), Poly(caprolactone), and Poly(hydroxybutyric acid) presented some miscibility with each other. However, the polyanhydrides were immiscible with the polyesters resulting in a complete phase separation. (4) S. J. Huang, O. Kitchen and L. J. DiBenedetto, Polym. Mater. Sci. Eng., 62, 804 (1990).
But no prior art is known in which the blend of a soft, fast-degrading, fully synthetic, biodegradable and biocompatible polymer and a rigid, slow-degrading, fully synthetic, biodegradable and biocompatible polymer is used for the preparation of polymeric devices where the objectives are to reduce the porosity created during preparation of the devices, if prepared by solvent removal methods, and to obtain devices which develop, in a degrading environment, porosity which is proportional to the content of the soft polymer, thereby providing variability and control on

porosity. Therefore, the blends prepared by the process of this invention are novel and of considerable practical significance.
Accordingly, the present invention provides, a synergistic composition of polymeric blend useful for preparation of biodegradable polymer device which comprises 1.76 to 5.28% by weight of one or more soft, fast degrading polymers such as herein described and 1.76 to 5.28% by weight of one or more rigid, slow-degrading polymers as defined herein, balance volatile organic solvent and optionally 3-20% by wt. an active ingredient.
It is to be noted that this technique of microsphere preparation does not involve any chemical reaction between the polymers and the solvents and the soft and rigid polymers. Yet the morphological and release characteristics of the composition so produced are entirely different from those of the components of the mixture taken individually due to synergism in the ingredients used.
In one of the embodiments of the present invention, the process comprises of preparing a clear homogeneous solution mixture by dissolving a soft, fast - degrading polymer and a rigid, slow - degrading polymer in a volatile organic solvent and preparing microspheres from the said solution mixture by conventional microsphere preparation methods namely oil - in - water, oil - in -oil and water - in - oil - in - water emulsion.

The oil-in-water system consists of an oil soluble active ingredient dissolved in
volatile organic solvent along with the polymer forming the oil phase which is then injected into a 0.5% aqueous solution of Poly(vinyl alcohol), which is the water phase, forming an oil-in-water emulsion.
The oil-in-oil system consists of an oil soluble active ingredient dissolved in a volatile organic solvent along with the polymer forming the oil i phase which is then injected into liquid paraffin or silicone oil containing 8% sorbitan monooleate. which is the oil 2 phase, forming an oil-in-oil emulsion.
The water-in-oil-in-water system consists of a water soluble active ingredient dissolved in distilled water forming the water 1 phase, which is then emulsified in the volatile organic solvent containing the polymer to form the water-in-oil emulsion, which is further injected into' 0.5% aqueous solution of Poly(vinyl alcohol) which is the water 2 phase, forming a water-in-oil-in-water emulsion.
In yet another embodiment of the invention, the composition comprises of mixing the melt of a soft, fast-degrading polymer and that of a rigid, slow-degrading polymer to obtain a homogeneous melt mixture, and preparing microspheres by conventional melt-dispersion methods.
In still another embodiment of the present invention, the composition comprises of preparing a homogeneous melt mixture of one or more soft, fast-degrading polymers and one or more rigid, slow-degrading polymers and forming the said melt mixture, by the use of conventional processing techniques such as injection molding, extrusion.

casting, coating, melt-pressing, melt-dispersion, etc. into devices such as implants, pellets, discs, rings, beads, films, sheets, etc.
In yet another embodiment, the blends containing active ingredients were prepared by the process of the present invention which comprises of dissolving or dispersing, as solution or solid, the desired active ingredient in the said polymer solution mixture or melt, and processing the resultant mixture as described in any of the embodiments mentioned above.
Some examples for the said soft polymers used for the preparation of the above mentioned devices are is Poly ( carboxyphenoxyualeric acid ) , Poly ( carboxyphenoxyoctanoic acid ) or a Poly (carboxyphenoxyvaleric -co - carboxyphenoxyoctanoic acid) copolymer and the said rigid polymer is Poly ( carboxyphenoxyhexane), Poly ( carboxyphenoxy-propane) or Poly ( carboxyphenoxypropane-co-sebasic acid) (85 : 15) copolymer. The active ingredient used is selected from drugs, dyes, proteins, peptides, vaccines, hormones, steroids, enzymes, microorganisms, catalysts, flavors, nutrients, tracers, inhibitors, promoters, etc.
The composition is a synergistic mixture which has the morphological and release characteristic properties which are entirely different from either of the components of the ingredients. The ratio of the soft polymer to the rigid polymer in the blend that can be employed in the preparation of the said polymeric blends is dependent on several factors. The highest content of the soft polymer in the blend is limited to a level where the resultant micro spheres possess sufficient mechanical strength and are able to retain their individuality. In most cases a minimum of 10 percent of the rigid polymer would be required. Another criterion to be satisfied is the miscibility of the polymers to ensure the homogeneity of the microspheres.

The present invention is described herein below by examples which are illustrative
only and should not be construed to restrict the scope of the present invention in any matter.
Example-1 100 mg of Poly(carboxyphenoxyvaleric acid) and 100 mg of Poly(carboxyphenoxy hexane) were dissolved in 2 ml of dichloromethane to get a clear, homogeneous solution. The solution was then injected through a hypodermic needle into 80 ml of 0.5 per cent aqueous solution of Poly(vinyl alcohol) which was stirred at 400 rpm in a round-bottom flask. 5 min after the addition of the solution, vacuum was applied to the system for one and a half hours. The hardened microspheres were isolated by filtering after diluting the Poly(vinyl alcohol) solution with distilled water and washing the microspheres. The microspheres were dried at room temperature for 4 hours over fused calcium chloride under vacuum.
Example-2 100 mg of Poly(carboxyphenoxyvaleric acid) and 100 mg of Poly(carboxyphenoxy hexane) were dissolved separately in 1 ml of dichloromethane and these solution were mixed together to get a clear, homogeneous solution. 20 mg of lysozyme dissolved in 100 microlitres of distilled water was dispersed into the mixed polymer solution by soniccation. The resultant dispersion was then injected through a hypodermic needle into 80 ml of 0.5 per cent aqueous solution of Poly(vinyl alcohol) which is kept stirred at 400 rpm in a round-bottom flask. 5 min after the addition of the solution mixture vacuum was applied to the system for one and a half hours. The hardened microspheres were isolated by filtering after diluting the Polyvinyl alcohol) solution with distilled water and washing the microspheres. The
microspheres were dried at room temperature for 4 hours over fused calcium
chloride under vacuum.
Example-3
100 mg of Poly(carboxyphenoxyvaleric-co-carboxyphenoxyoctanoic acid) 1:1 copolymer and 100 mg of Poly(carboxyphenoxyhexane) were dissolved in 2 ml of dichloromethane to get a clear, homogeneous solution. The solution was then injected through a hypodermic needle into 80 ml of 0.5 per cent aqueous solution of Polyvinyl alcohol) which was stirred at 400 rpm in a round-bottom flask. 5 min after the addition of the solution mixture, vacuum was applied to the system for one and a half hours. The hardened microspheres were isolated by filtering after diluting the Poly(vinyl alcohol) solution with distilled water and washing the microspheres. The microspheres were dried at room temperature for 4 hours over fused calcium chloride under vacuum.
Example-4 100 mg of Poly(carboxyphenoxyvaleric-co-carboxyphenoxyoctanoic acid) 1:1 copolymer and 100 mg of Poly(carboxyphenoxyhexane) were dissolved in 2 ml of dichloromethane to get a clear, homogeneous solution. 20 mg of lysozyme dissolved in 100 microlitres of distilled water was dispersed into the mixed polymer solution by soniccation. The resultant dispersion is then injected through a hypodermic needle into 80 ml of 0.7 per cent aqueous solution of Polyvinyl alcohol) which is kept stirred at 400 rpm in a round-bottom flask. 5 min after the addition of the solution mixture vacuum was applied to the system for one and a half hours. The hardened microspheres were isolated by filtering after diluting the Poly(vinyl alcohol) solution with distilled water and washing the microspheres. The
microspheres were dried at room temperature for 4 hours over fused calcium
chloride under vacuum.
Example-5 100 ml of Poly(carboxyphenoxyvaleric-co-carboxyphenoxyoctanoic acid) 3:1 copolymer and 100 mg of Poly(carboxyphenoxyhexane) were dissolved in 2 ml of dichloromethane to get a clear, homogeneous solution. 20 mg of lysozyme dissolved in 100 microlitres of distilled water was dispersed into the mixed polymer solution by soniccation. The resultant dispersion is then injected through a hypodermic needle into 80 ml of 0.5 per cent aqueous solution of Poly(vinyl alcohol) which is kept stirred at 750 rpm in a round-bottom flask. 5 min after the addition of the solution mixture vacuum was applied to the system for one and a half hours. The hardened microspheres were isolated by filtering after diluting the Poly(vinylalcohol) solution with distilled water and washing the microspheres. The microspheres were dried at room temperature for 4 hours over fused calcium chloride under vacuum.
Example-6 50 mg of Poly(carboxyphenoxyvaleric-co-carboxyphenoxyoctanoic acid) 1:3 copolymer and 150 mg of Poly(carboxyphenoxyhexane) were dissolved in 2 ml of dichloromethane to get a clear, homogeneous solution. 20 mg of lysozyme dissolved in 100 microlitres of distilled water was dispersed into the mixed polymer solution by soniccation. The resultant dispersion is then injected through a hypodermic needle into 80 ml of 0.5 per cent aqueous solution of Poly(vinyl alcohol) which is kept stirred at 400 rpm in a round-bottom flask. 5 min after the addition of the solution mixture vacuum was applied to the system for one and a half hours. The hardened microspheres were isolated by filtering after diluting the Poly(vinyl alcohol)
solution with distilled water and washing the microspheres. The microspheres were
dried at room temperature for 4 hours under vacuum.
Example-7 150mg of Poly(carboxyphenoxyvaleric acid) and 50 mg of Poly(carboxyphenoxy-hexane) were dissolved separately in 1 ml of dichloromethane and these solutions were mixed together to get a clear, homogeneous solution. 20 mg of bovine serum
. albumin dissolved in 100 microlitres of distilled water was dispersed into the mixed
f polymer solution by soniccation. The resultant dispersion is then injected through a
hypodermic needle into 80 ml of 0.5 per cent aqueous solution of Poly(vinyl alcohol)
which is kept stirred at 600 rpm in a round-bottom flask. 5 min after the addition of
the solution mixture vacuum was applied to the system for one and a half hours. The
hardened microspheres were isolated by filtering after diluting the Poly(vinyl
alcohol) solution with distilled water and washing the microspheres. The
microspheres were dried at room temperature for 4 hours over fused calcium chloride
under vacuum.
Example-8
100 mg of Poly(carboxyphenoxyvaleric acid) and 100 mg of PoIy(carboxyphenoxy-
hexane) were dissolved in 2 ml of dichloromethane to get a clear, homogeneous
solution. 10 mg of p-nitrophenol was dissolved in this solution. This solution was
injected through a hypodermic needle into 80 ml of 0.5 per cent aqueous solution of
Poly(vinyl alcohol) which is kept stirred at 400 rpm in a round-bottom flask. 2 min
after the addition of the solution, vacuum was applied to the system for on and a
half hours. The hardened microspheres were isolated by filtering after diluting the
Poly(vinyl alcohol) solution with distilled water and washing the microspheres. The
microspheres were dried at room temperature for 4 hours over fused calcium chloride
under vacuum.
Example-9
100 mg of Poly(carboxyphenoxyvaleric-co-carboxyphenoxyoctanoic acid) 3:1 copolymer and 100 mg of Poly(carboxyphenoxyhexane) were dissolved 2 ml of dichloromethane to get a clear, homogeneous solution. 10 mg of p-nitrophenol was dissolved in this solution. The solution is then injected through a hypodermic needle into 80 ml of 0.5 per cent aqueous solution of Poly(vinyl alcohol) which is kept stirred at 400 rpm in a round-bottom flask. 2 min after the addition of the solution mixture vacuum was applied to the system for one and a half hours. The hardened microspheres were isolated by filtering after diluting the Poly(viny alcohol) solution with distilled water and washing the microspheres. The microspheres were dried at room temperature for 4 hours over fused calcium chloride under vacuum.
Example-10
100 mg of Poly(carboxyphenoxyvaleric acid) and 100 mg of Poly(carboxyphenoxy-hexane) were dissolved in 2 ml of dichloromethane to get a clear, homogeneous solution. 40 mg of lysozyme dissolved in 150 microlitres of distilled water was dispersed into the mixed polymer solution by soniccation. The resultant dispersion is then injected through a hypodermic needle into 80 ml of liquid paraffin containing 10 per cent dichloromethane and 8 per cent sorbitan monooleate and kept stirred at 400 rpm in a round-bottom flask. After 5 min 100 ml of petroleum ether was added over 20 min. The hardened microspheres were isolated by filtering and were washed with petroleum ether. The microspheres were dried at room temperature for 2 hours under vacuum.
Example-11
100 mg of Poly(carboxyphenoxyvaleric acid) and 100 mg of Poly(carboxyphenoxy-hexane) were dissolved in 2 ml of dichloromethane and 10 mg of p-nitrophenol was dissolved in this. This solution was then injected through a hypodermic needle into 80 ml of liquid paraffin containing 15 per cent dichloromethane and 8 per cent sorbitan monooleate and kept stirred at 500 rpm in a round-bottom flask. 5 min after the addition of the solution mixture, 100 ml of petroleum ether was added over 20 min. The hardened microspheres were isolated by filtering and were washed with petroleum ether. The microspheres were dried at room temperature for 2 hours under vacuum.
Example-12
100 mg of Poly(carboxyphenoxyvaleric acid) and 100 mg of Poly(carboxyphenoxy-hexane) were dissolved in 2 ml of chloroform to get a clear, homogeneous solution. 20 mg of lysozyme dissolved in 100 microlitres of distilled water was dispersed into the mixed polymer solution by soniccation. The resultant dispersion is then injected through a hypodermic needle into 80 ml of 0.5 per cent aqueous solution of Poly(vinyl alcohol) which is kept stirred at 400 rpm in a round-bottom flask. After 5 min vacuum was applied to the system for two hours. The hardened microspheres were isolated by filtering after diluting the Poly(vinyl alcohol) solution with distilled water, and washed. The microspheres were dried at room temperature for 4 hours over fused calcium chloride under vacuum.
Example-13
100 mg of Poly(carboxyphenoxyvaleric acid) and 100 mg of Poly(carboxyphenoxy-hexane) were dissolved separately in 1 ml of dichloromethane and these solutions were mixed together to get a clear, homogeneous solution. 20 mg of lysozyme

dissolved in 100 microlitres of distilled water was dispersed into the mixed polymer
solution by soniccation. The resultant dispersion is then injected through a hypodermic needle into 80 ml of silicone oil containing 10 per cent dichloromethane and 7 per cent sorbitan monooleate and kept stirred at 400 rpm in a round-bottom flask. After 5 min, 100 ml of petroleum ether was added over 20 min. The hardened microspheres were isolated by filtering and were washed with petroleum ether. The microspheres were dried at room temperature for 2 hours under vacuum.
Example-14
125 mg of Poly(carboxyphenoxyvaleric acid) and 375 mg of Poly(carboxyphenoxy-hexane) were taken in a glass cup of 2 ml capacity. The cup was heated to 170°C. After the polymers melted, the contents were mixed well and dispersed into 30 ml of stirred silicone oil maintained at 170°C in a 100 ml beaker. After 3 min, heating was stopped and the dispersion was allowed to cool to room temperature under continuous stirring. The dispersing medium was diluted with petroleum ether and the microspheres were filtered, washed, and dried under vacuum.
Example-15
125 mg of Poly(carboxyphenoxyvaleric acid), 375 mg of Poly(carboxyphenoxy hexane) were taken in a glass cup of 2 ml capacity. 25 mg of microfined 5-fluorouracil was mixed "in it. The cup was heated to 170°C. After the polymers melted, the contents were mixed well and dispersed into 30 ml of stirred silicone oil maintained at 170°C in a 100 ml beaker. After 3 min, heating was stopped and the dispersion was allowed to cool to room temperature under continuous stirring. The dispersing medium was diluted with petroleum ether and the microspheres were filtered, washed, and dried under vacuum.
Example-16
125 mg of Poly(carboxyphenoxyvaleric acid) and 375 mg of Poly(carboxyphenoxy-hexane) were packed compactly into a flat-bottomed glass ampoule of 1 cm internal diameter and 4 ml capacity which was wetted previously with liquid paraffin. The ampoule was heated to 175 C. After the polymers melted, vacuum (0.05 mm of Hg) was applied to the ampoule till the melt was totally clarified of air bubbles. The ampoule was then allowed to cool to room temperature. The ampoule was broken and the solid polymer block was removed. The block was wiped clean with n hexane. cut, and polished to obtain a disc.
Example-17
20 mg of a water-soluble dye, viz. Brilliant Blue BL, was intimately mixed with 125 mg of Poly(carboxyphenoxyvaleric acid) and 375 mg of Poly(carboxyphenoxy-hexane). This mixture was packed compactly into a flat-bottomed glass ampoule of 1 cm internal diameter and 4 ml capacity which was wetted previously with liquid paraffin. The ampoule was heated to 175°C. After the polymers melted, vacuum (0.05 mm of Hg) was applied to the ampoule till the melt was totally clarified of air bubbles. The ampoule was then allowed to cool to room temperature. The ampoule was broken and the solid polymer block was removed. The block was wiped clean with n-hexane, cut, and polished to obtain a disc.
Example-18
20 mg of a water-soluble dye, viz. Brilliant Blue BL, was intimately mixed with 125 mg of Poly(carboxyphenoxyvaleric acid) and 375 mg of Poly(carboxyphenoxy hexane). This mixture was packed compactly into a wire-extruding die of 1 cm internal diameter and 0.6 mm orifice diameter. The inner surface of the die was wetted with liquid paraffin before packing the polymer-dye mixture. The die was

heated to 160 C using band heaters. After the polymers melted, the melt was
extruded into a cooling bath containing liquid paraffin. The solidified extrudate was washed with n hexane, dried in vacuum, and cut into pellets of 3 mm length.
Example-19
125 mg of Poly(carboxyphenoxyvaleric-co-carboxyphenoxyoctanoic acid) 3:1 and 375 mg of Poly(carboxyphenoxyhexane) were mixed and packed compactly into a wire-extruding die of 1 cm internal diameter and 0.5 mm orifice diameter. The inner surface of the die was wetted with liquid paraffin before packing the polymer dye mixture. The die was heated to 160°C using band heaters. After the polymers
melted, the melt was extruded into a cooling bath containing liquid paraffin.
The solidified extrudate was washed with n-hexane, dried, and cut into pellets of 3 mm length.
The polymeric composition prepared in the present invention has several advantages over the ones known in prior art. The incorporation of the soft, fast-degrading polymer due to their better chain flexibility helps to form denser microspheres during the preparation of the microspheres by solvent removal methods. This minimizes the unwanted diffusional release through pores other than those intended to be created by the degradation of the soft polymer. The preferential degradation of the soft, fast-degrading polymer from the microspheres allows the generation of porosity in the release environment affording the release of the active ingredient. The porosity of these microspheres is directly proportional to the amount of the soft polymer in the blend which allows the preparation of microspheres with any desired level of porosity.

We Claim:
1. A synergistic composition of polymeric blend useful for preparation of biodegradable polymer device which comprises 1.76 to 5.28% by weight of one or more soft , fast degrading polymers such as herein described and 1.76 to 5.28% by weight of one or more rigid, slow-degrading polymers as defined herein, balance volatile organic solvent and optionally 3-20% by wt. an active ingredient.
2. A synergistic composition as claimed in claim 1 , wherein the said soft polymer is Poly ( carboxyphenoxyualeric acid ) , Poly ( carboxyphenoxyoctanoic acid ) or a Poly (carboxyphenoxyvaleric -co - carboxyphenoxyoctanoic acid) copolymer and the said rigid polymer is Poly ( carboxyphenoxyhexane), Poly ( carboxyphenoxy-propane) or Poly ( carboxyphenoxypropane -co - sebasic acid) ( 85 : 15 ) copolymer.

3. A synergistic composition as claimed in claims 1 and 2 wherein the volatile organic solvent used is dichloromethane, chloroform or dichloroethane.
4. A synergistic composition as claimed in claims 1 to 3 wherein the active ingredient used is selected from drugs, dyes, proteins, peptides, vaccines, hormones, steroids, enzymes, microorganisms, catalysts, flavors, nutrients, tracers, inhibitors, promoters.
5. A synergistic composition of polymeric blend useful for preparation of biodegradable polymer device substantially described herein with reference to examples.

Documents:

1772-del-1998-abstract.pdf

1772-del-1998-claims-(cancelled).pdf

1772-del-1998-claims.pdf

1772-del-1998-complete specification(granted).pdf

1772-del-1998-correspondence-others.pdf

1772-del-1998-correspondence-po.pdf

1772-del-1998-description (complete).pdf

1772-del-1998-form-1.pdf

1772-del-1998-form-2.pdf

1772-del-1998-form-3.pdf

1772-del-1998-form-4.pdf

1772-del-1998-form-9.pdf

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Patent Number

192831

Indian Patent Application Number

1772/DEL/1998

PG Journal Number

21/2004

Publication Date

22-May-2004

Grant Date

14-Nov-2005

Date of Filing

26-Jun-1998

Name of Patentee

COUNCIL OF SCEINTIFIC AND INDUSTRIAL RESEARCH

Applicant Address

RAFI MARG, NEW DELHI 110001, INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	PAYYAPPILLY ANTONY THOMAS	NATIONAL CHEMICAL LABORATORY, PUNE MAHARASHTRA, INDIA
2	TURUMELLA PADMAJA	NATIONAL CHEMICAL LABORATORY, PUNE MAHARASHTRA, INDIA
3	MOHAN GOPALKRISHNA KULKARNI	NATIONAL CHEMICAL LABORATORY, PUNE MAHARASHTRA, INDIA

PCT International Classification Number

C08L 67/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA