Patent Application: US-201515305595-A

Abstract:
modified poly are suitable as carriers for bioactive substances , especially as injectable implants , without further additives . the polymers can be directly injected without using an organic solvent . furthermore , modified poly can be mixed with suitable biocompatible organic solvents and injected or realized as implants . the carriers are suitable for controlled active ingredient release in human and veterinary medicine .

Description:
fatty acid - modified poly ( glycerol adipates ) can be synthesized using the following or similar methods / 10 - 16 /. the structural element ( a ) ( dicarboxylic acid ) used is adipic acid , and glycerol , which comprises three hydroxyl groups , serves as the polyol ( structural element ( b )) ( fig1 ). polyglycerol adipate , which is the polymer backbone , is realized , for example , by way of an enzymatic reaction of divinyl adipate or dimethyl adipate with glycerol in tetrahydrofuran or another suitable solvent / 10 /. lauric acid , stearic acid , behenic acid or oleic acid are fatty acids used by way of example . the degree of substitution of the fatty acids ranges between 1 % and 100 % ( based on the hydroxyl groups in the poly ( glycerol adipate )) ( fig2 ). the oleic acid - and lauric acid - modified polymers have a liquid consistency at a temperature of 20 ° c . ( room temperature ). the stearic acid - and behenic acid - modified polymers have a solid consistency at 20 ° c . they melt in the range of 30 ° c . to 45 ° c . ( stearyl - modified poly ( glyercol adipate )) and between 50 ° c . and 65 ° c . ( behenyl - modified poly ( glycerol adipate )), respectively . in the case of the behenyl - and stearyl - modified polymers , an implantable shaped body can be obtained very easily by way of melt or extrusion processes . lauric acid - modified poly ( glycerol adipate ) ( degree of esterification 25 % based on free hydroxyl groups of the polyglycerol adipate ) is injected through a 25 - gauge needle in phosphate - buffered saline solution ( pbs , diluted 1 : 10 ). a spherical depot forms ( fig3 ). ( thus , if a bioactive substance is included , a depot dosage is provided , a depot dosage being defined in medicine as a form of medication that can be stored in the patient &# 39 ; s body for prolonged release .) lauryl acid - modified poly ( glycerol adipate ) ( degree of esterification 95 % based on free hydroxyl groups of the polyglycerol adipate ) is injected through a 25 - gauge needle in phosphate - buffered saline solution ( pbs , diluted 1 : 10 ). a spherical depot forms . oleic acid - modified poly ( glycerol adipate ) ( degree of esterification 15 % based on free hydroxyl groups of the polyglycerol adipate ) is injected through a 25 - gauge needle in phosphate - buffered saline solution ( pbs , diluted 1 : 10 ). a spherical depot forms . oleic acid - modified poly ( glycerol adipate ) ( degree of esterification 92 % based on free hydroxyl groups of the polyglycerol adipate ) is injected through a 25 - gauge needle in phosphate - buffered saline solution ( pbs , diluted 1 : 10 ). a spherical depot forms . fatty acid - modified poly ( glycerol sebacate ) polymers are produced analogously to the synthesis pathways published in / 10 /. the structural element ( a ) ( dicarboxylic acid ) used is sebacic acid , and glycerol , which comprises three hydroxyl groups , serves as the polyol ( structural element ( b )) ( fig1 ). poly ( glycerol sebacate ), which is the polymer backbone , is realized , for example , by way of an enzymatic reaction of divinyl sebacate with glycerol in tetrahydrofuran or another suitable solvent / 10 /. lauric acid , stearic acid , behenic acid or oleic acid are fatty acids used by way of example . the degree of substitution of the fatty acids ranges between 1 % and 100 % ( based on the hydroxyl groups of the poly ( glycerol sebacate ). the polymer backbone is produced from sorbitol , serving as the polyol , and adipic acid , serving as the dicarboxylic acid , analogously to the guidelines published for poly ( glycerol adipate ) and is modified with stearic acid . at a degree of esterification of 30 % ( 30 % degree of esterification based on free hydroxyl groups of the poly ( sorbitol adipate )), a polymer that is solid at room temperature and melts at 43 ° c . is created . an implantable shaped body can be obtained very easily by way of melt or extrusion processes . in - vitro release of the fluorescent dye 1 , 1 ′- dioctadecyl - 3 , 3 , 3 ′, 3 ′- tetramethylindocarbocyanine perchlorate ( dii ): lauryl - substituted poly ( glycerol adipate ) polymers were loaded with the dii fluorescent dye ( 1 % m / m ), and 60 microliters were incubated at 37 ° c . in vitro in pbs . the following curves in fig4 show a controlled release of the model substance in vitro . the number behind the l symbolizes the degree of substitution of lauric acid based on free hydroxyl groups of the poly ( glycerol adipate ). in - vivo release of the fluorescent dye dii from lauryl - substituted poly ( glycerol adipate ) the polymers were loaded with the fluorescent dye 1 , 1 ′- dioctadecyl - 3 , 3 , 3 ′, 3 ′- tetramethylindocarbocyanine perchlorate ( dii ) ( 0 . 5 to 1 % m / m ), and 50 microliters were subcutaneously injected into skh1 mice . in - vivo fluorescence images of the dii - loaded lauryl - modified poly ( glycerol adipate ) polymers following the subcutaneous injection ( 50 microliters ) in shk1 hairless mice proved the in - vivo release through visible signals . the degree of substitution of the lauric acid was 95 % and 25 %, respectively . the results show a controlled in - vivo release over several weeks to months . surprisingly , it was found that the more lipophilic implant ( degree of substitution 95 % based on free hydroxyl groups ) is released more rapidly than the implant having a low substitution degree ( 25 % based on free hydroxyl groups ). the results demonstrate that the release of substances in vivo can be controlled by way of the degree of substitution with the fatty acid . production of liquid dexamethasone - containing implants . dexamethasone is incorporated into fatty acid - modified poly ( glycerol adipate ) at a concentration of 10 % m / m . the incorporation can take place at room temperature for the liquid polymers ( lauryl - and oleyl - modified poly ( glycerol adipate )). the dexamethasone - loaded ( lauryl - and oleyl - modified poly ( glycerol adipate ) polymers can be injected , given the liquid consistency thereof . production of solid dexamethasone - containing implants . dexamethasone is incorporated into fatty acid - modified poly ( glycerol adipate ) at a concentration of 20 % m / m . the polymers that are solid at room temperature ( such as stearyl - modified and behenyl - modified poly ( glycerol adipate )) are melted , and the active ingredient is homogeneously incorporated . in the case of the solid polymers , a suitably shaped body ( such as platelets or small rods ), which can be implanted , can be obtained by way of melting and solidification , compression or extrusion . nifedipine is incorporated into stearyl - modified poly ( sorbitol adipate ) at a concentration of 10 % m / m . for this purpose , the polymer is melted at 50 ° c ., and the active ingredient is homogeneously distributed under protection against light . the melted active ingredient - containing polymer is brought into the desired size and shape by solidification in a suitable mold . active ingredient - containing in - situ implant . stearyl - modified poly ( glycerol adipate ) is mixed with n - methylpyrrolidone ( nmp ) in a ratio of 1 : 1 ( m / m ). leuprorelin acetate is homogeneously incorporated at a concentration of 5 % ( m / m ). the preparation can be administered through a 25 - gauge cannula , and forms an implant in situ after contact with water or in the interior of the body . implant comprising covalently bonded betulinic acid . the polymer backbone made of poly ( glycerol adipate ) is synthesized according to the guidelines described in the literature / 10 /. instead of the fatty acids described in the literature / 10 /, the bioactive substance betulinic acid is covalently attached to the polymer backbone in an analogous reaction . the resultant betulinic acid poly ( glycerol adipate ) can either be converted into a desired implant form by melting or be applied as an in - situ implant with the aid of a biocompatible organic solvent ( such as nmp ). / 2 / k mader , g bacic , a domb , o elmalak , r langer and hm swartz . j pharm sci 86 : 126 , ( 1997 ). / 4 / a lucke , j kiermaier and a göpferich . pharm res 19 : 175 , ( 2002 ). / 5 / a lucke and a göpferich . eur j pharm biopharm 55 : 27 , ( 2003 ). / 6 / beck - 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