the matrix polymers according to the invention can be readily processed to depot forms . they exhibit good particle formation properties in the known processes , like solvent evaporation or spray drying , and are particularly suitable for production of microparticles . the object of the invention is a branched - chain ester from a polyol containing at least one substituent with electrolyte properties with acid groups , consisting of polyhydroxy - carboxylic acids having a molecular weight to 500 , 000 . substituents with electrolyte properties are understood to mean those present at least partially in the dissociated form in the hydrophilic medium . the object of the invention is also a reaction product from a polyol containing at least one substituent with electrolyte properties with acid groups consisting of polyhydroxy - carboxylic acids having a molecular weight to 500 , 000 . the substituents contained in the polyesters according to the invention with electrolyte properties can be formed from a strong or weak acid or a strong or weak base and can also be present in the form of their salts . they preferably consist of a strong acid or a weak base and are present in the form of their salts . the object of the invention is therefore also a product in which the substituent exhibiting electrolyte properties is formed from a sulfo group , a primary , secondary or tertiary amine or a carboxyl group . the polyol containing substituents with electrolyte properties can consist of the same or different alicyclic or aliphatic units linked to each other in chain - like fashion and exhibit a linear or cyclic structure . such polyols can be appropriately substituted poly - or oligomers of carbohydrates , for example , inulin , dextrans , xylans , cyclodextrins or consist of appropriately substituted polymers from the same or different alkene units , like substituted polyvinyl alcohol or copolymers from substituted or unsubstituted polyvinyl alcohol or acetylated polyvinyl alcohol partially acetylated with acrylic acid , α - or β - methacrylic acid , acrylamine , α - or β - methacrylamine , acrylonitrile or α - or β - methacrylonitrile . dextran sulfate , diethylaminoethyldextran , xylan sulfate , diethylaminoethylxylan , cyclodextrin sulfate , partially sulfonated polyvinyl alcohol , copolymers of partially sulfonated polyvinyl alcohol , polyvinyl alcohol or polyvinyl alcohol partially acetylated with acrylic acid , acrylamine , acrylonitrile , α - or β - methacrylic acid , α - or β - methacrylamine or α - or β - methacrylonitrile , as well as their salts , are preferred . the corresponding alkali salts , especially na salts , and their halogen salts , especially chlorides , are particularly preferred . sulfonated polyvinyl alcohol or its copolymers can be produced by sulfonating the corresponding polyvinyl acetate or its copolymers by alcoholysis in an appropriate alcohol ( for example ethanol ) containing h 2 so 4 / so 3 , followed by neutralization . if the reaction is run in , say , ethanol containing 5 % h 2 so 4 / so 3 , and neutralized , about 20 % of the hydroxyl groups will become sulfonated . copolymers containing polyvinyl alcohol or partially acetylated polyvinyl alcohol can be produced by acid or alkaline hydrolysis of the corresponding copolymer containing polyvinyl acetate . the polymeric hydroxycarboxylic acid groups can be constructed from one , two , three or more specific hydroxycarboxylic acids . examples of hydroxycarboxylic acids that can be used according to the invention are lactic acid , glycolic acid , β - hydroxypropionic acid , β - hydroxybutyric acid , δ - hydroxyvaleric acid or ε - hydroxycaproic acid . polyhydroxycarboxylic acids from lactic and / or glycolic acid are preferred . copolymers from lactic and glycolic acid whose acid groups consist of 25 to 50 mol % glycolic acid units are particularly preferred . the lactic acid units can be present in the optically pure form ( d - or l - lactic acid ) or as the mixtures of the isomers . the substituted polyol esters according to the invention can be produced by converting an appropriately substituted polyol with one or more hydroxycarboxylic acid ( s ) in the dimeric or lactone form in the presence of a catalyst suitable for ring - opening polymerization , for example , tin , zinc , tin chloride , zinc chloride , titanium tetrachloride , aluminum chloride , tin octoate or aluminum triisopropyl oxide . tin octoate or aluminum triisopropyl oxide are preferably used . for polymerization , the reaction components are mixed together and with the catalyst and reacted at elevated temperature . the compounds formed according to the invention can be isolated and purified in the known manner . they are particularly suitable as a depot matrix material for drugs . production of branched - chain plga with dextran sulfate - na ( dss ) as backbone material 28 g d , l - lactide ( la ), 22 g glycolide ( ga ) and 0 . 5 g dss ( sigma , mw 500 , 000 ) with one to two so 3 groups per monomer were introduced into a 100 ml nitrogen flask , scavenged with nitrogen and heated in an oil bath temperature controlled to 170 ° c . under a nitrogen atmosphere until the monomers melted . 200 mg tin octoate was then injected into the melt during continuous agitation and , after half an hour , the reaction temperature was reduced to 150 ° c ., where the reaction was continued for another 3 . 5 hours . after cooling to room temperature , the product was dissolved in 100 ml methylene chloride and washed three times with distilled water to eliminate dss residues . the polymer solution was then filtered through a glass suction filter (# 3 ), the product precipitated in ethanol and dried to constant weight for a few days in vacuum . 28 g d , l - lactide ( la ), 22 g glycolide ( ga ) and 0 . 5 g deaed ( sigma , mw 500 , 000 ) with one to two amino groups per monomer were introduced into a 100 ml nitrogen flask , scavenged with nitrogen and heated to 150 ° c . in an oil bath under a nitrogen atmosphere until the monomers melted . 200 mg tin octoate was then injected into the melt during continuous agitation and the reaction run for 4 hours at 150 ° c . after cooling to room temperature , the product was dissolved in 100 ml methylene chloride and washed three times with distilled water to eliminate deaed residues . the polymer solution was then filtered through a glass suction filter (# 3 ), the product precipitated in ethanol and dried to constant weight for a few days in vacuum . production of branched - chain plga with a copolymer from partially or fully hydrolyzed polyvinyl acetate and crotonic acid ( β - methacrylic acid ) as backbone polymer ( pvacca ) 2 g pvacca was dissolved in 100 ml methanol at 40 ° c . and mixed with 1 ml of aqueous naoh solution ( 40 %), whereupon poly ( vinyl alcohol - cocrotonic acid ) precipitated within 2 to 3 minutes . after half an hour , the product was filtered off , washed a few times with methanol , extracted for 5 hours in a soxhlet device with methanol and dried . a white product with a degree of saponification greater than 99 . 5 % was obtained . 2 . 6 g pvacca was dissolved in 100 ml methanol at 50 ° c . and 5 ml of 50 % sulfuric acid was slowly added dropwise over 30 minutes during agitation . after 30 to 80 minutes , the product was filtered off , extracted for 5 hours in a soxhlet device and dried . a white product was obtained that had a degree of saponification of 50 to 90 % depending on the reaction time . 28 g d , l - lactide ( la ), 22 g glycolide ( ga ) and 0 . 5 g pvacca were introduced into a 100 ml nitrogen flask , scavenged with nitrogen and heated to 150 - 200 ° c ., depending on the degree of hydrolysis , in an oil bath under a nitrogen atmosphere until the monomers melted . 200 mg of tin octoate was then injected into the melt during continuous agitation and the reaction first run for a half - hour at 170 ° c . and then for 3 . 5 hours at 150 ° c . after cooling to room temperature the product was dissolved in 100 ml methylene chloride and washed three times with distilled water to eliminate pvacca residues . the polymer solution was then filtered through a glass suction filter (# 3 ), the product precipitated in ethanol and dried to constant weight for a few days in vacuum . the produced esters were dissolved in cdcl 3 and characterized by nmr spectroscopy at 25 ° c . with addition of tetramethylsilane ( tms ) as a reference . d = 1 . 5 - 1 . 7 h atom of the -- ch 3 group of the lactyl unit d = 3 . 8 - 4 . 7 four peaks of equal intensity : h atoms on the dextran sulfate ring the fifth h atom is covered by the glycolyl ch 2 peak d = 4 . 7 - 4 . 9 h atom of the ch 2 group of the glycolyl unit d = 5 . 3 h atom of the -- ch 2 oso 3 na , covered by the -- ch of the lactyl unit ( lies at d = 3 . 0 for dextran , i . e ., for -- ch 2 oh ) d = 1 . 2 - 1 . 4 h atom of the -- ch 3 group of the deae residue d = 3 . 1 - 4 . 0 series of peaks : four h atoms on the dextran ring , 10 h atoms on the -- ch 2 group in the deae residue and on the dextran ring d = 4 . 9 h atom on cl in the dextran ring covered by the -- ch 2 peak of the glycolyl unit the molecular weights of the produced esters were determined by gel permeation chromatography in methylene chloride . the determination was carried out in a temperature - controlled column combination ( lichrogel ps mix and lichrogel ps 40 , 10 μm , merck ) at 25 ° c . using a differential refractometer ( merck hitachi ri - 71 ). polystyrene standards were used for calibration ( merck , mw 3250 ; 5100 ; 19 , 600 ; 34 , 500 and 87 , 000 ). to investigate the degradation behavior of the polymers according to the invention , 10 % ( w / v ) polymer solutions in methylene chloride were produced . these were cast onto teflon - coated plates and the solvent eliminated first for 48 hours at room temperature then in vacuum at room temperature . after drying to constant weight , 100 - 200 μm thick films were obtained that were cut into 20 mm × 10 mm pieces . four to 6 of the polymer film pieces produced in this manner were introduced into 50 ml of distilled water , the temperature of which was controlled at 37 ° c ., removed after established time intervals , dried to constant weight in vacuum at room temperature and investigated by gel permeation chromatography with respect to changes in molecular weight . fig1 depicts the molecular weight degradation of polymer films produced from polymers 2 and 3 . the weight loss was determined gravimetrically . for this purpose , a polymer film piece was introduced into a nylon gauze and this was sealed by heating and transferred to a shaker bath filled with distilled water , thermostated to 37 ° c . after fixed time intervals , the gauze was removed , dried to constant weight in vacuum at room temperature and the remaining weight determined . fig2 shows a graph of the polymer weight remaining after the corresponding time intervals of polymer films produced from polymers 5 and 13 ( table 1 ). the polymers according to the invention exhibit significantly increased molecular weight degradation in comparison with ordinary linear polylactide - coglycolides , which is accompanied by an also significant weight loss of the polymer . microparticles were produced from polymers 5 and 13 ( table 1 ) by solvent evaporation . for this purpose a bsa solution ( 25 %) was introduced into a 20 % polymer solution ( methylene chloride ) during intense homogenization with a toothed - rim dispersal rod so that bsa and polymer were in a weight ratio of 10 %. this emulsion was injected under agitation into a 0 . 5 % pva solution from which the formed microparticles were filtered off after 3 hours of agitation . after drying ( in vacuum at room temperature ) the microparticles were stored at 5 ° c . the bsa degree of loading of the microparticles was determined photometrically at 278 nm after dissolution in acetonitrile and extraction with water . the particle size was determined by laser light scattering . the obtained results are summarized in table 2 . about 100 mg of microparticles ( accurately weighed ) was transferred to sealable reagent test tubes ( 20 ml ) and mixed with 5 ml phosphate buffer solution ( ph 7 . 2 ). the sealed test tubes were agitated at 37 ° c . in a rotating metal block thermostat ( rotatherm ) at 15 rpm . after predetermined time intervals the microparticles were centrifuged at 4000 rpm for 30 minutes , 3 ml of sample solution was taken , replaced with fresh phosphate buffer solution ( ph 7 . 2 ) and liberation continued . the bsa concentration in the sample solution was determined photometrically at 278 nm . fig3 shows the results of the liberation investigations . it is obvious that the increase in percentage of dextran sulfate sodium in the polymer leads to a reduction in the initially increased liberation and this occurs almost constantly over the entire liberation period . this is in distinct contrast to the generally two - phase liberation behavior of linear polylactide - coglycolides , which is marked by a high burst effect and delayed active ingredient liberation . a comparison of the liberation behavior of the polymers according to the invention with their weight loss ( cf . fig2 ) also shows that the former runs essentially parallel to the latter . the liberation behavior therefore appears to be largely controlled by the weight degradation of the matrix polymer . the polymers according to the invention are therefore particularly suited for formulation of depot forms . table 1__________________________________________________________________________ monomer tin octoate / dss . sup . a / mno . backbone la : ga ( mol / mol / mol ) t (° c .) t ( h ) mw mw / mn__________________________________________________________________________1 dex -- so . sub . 3 na 50 / 50 2 . 3 / 14 / 1000 170 24 32 . 000 2 . 332 dex -- so . sub . 3 na 50 / 50 5 . 3 / 14 / 1000 200 8 33 . 000 2 . 803 dex -- so . sub . 3 na 50 / 50 1 . 8 / 14 / 1000 170 24 44 . 000 2 . 224 dex -- so . sub . 3 na 50 / 50 1 . 2 / 14 / 1000 170 12 48 . 000 2 . 475 dex -- so . sub . 3 na 50 / 50 1 . 8 / 14 / 1000 170 12 39 . 100 2 . 486 dex -- so . sub . 3 na 50 / 50 0 . 42 / 7 . 2 / 1000 170 4 43 . 000 2 . 157 dex -- so . sub . 3 na 50 / 50 0 . 85 / 3 . 0 / 1000 170 4 62 . 000 1 . 938 dex -- so . sub . 3 na 50 / 50 0 . 85 / 1 . 5 / 1000 170 4 76 . 000 1 . 689 dex -- so . sub . 3 na 50 / 50 0 . 85 / 4 . 4 / 1000 170 4 54 . 000 2 . 1510 dex -- so . sub . 3 na 50 / 50 1 . 8 / 1 . 5 / 1000 170 4 94 . 000 1 . 4011 dex -- so . sub . 3 na 75 / 25 1 . 3 / 7 . 5 / 1000 170 4 38 . 000 1 . 8412 dex -- so . sub . 3 na 100 / 0 1 . 3 / 7 . 6 / 1000 170 4 37 . 000 1 . 8713 deae -- dex 50 / 50 1 . 8 / 12 / 1000 150 12 42 . 500 2 . 1914 deae -- dex 50 / 50 1 . 8 / 14 / 1000 150 12 40 . 000 2 . 0615 deae -- dex 75 / 25 1 . 8 / 7 . 8 / 1000 150 4 77 . 000 2 . 4716 deae -- dex 100 / 0 1 . 8 / 7 . 8 / 1000 150 4 87 . 000 2 . 67__________________________________________________________________________ . sup . a or deae -- dex ., referred to one ring unit . table 2______________________________________ la / ga bsa average diameter fieldno . * ( mol ) ( wt %) ( μm ) (%) ______________________________________5 50 / 50 6 . 3 40 8613 50 / 50 6 . 0 40 89______________________________________ * same numbering as table 1 .
the invention relates to new polyesters of a polyol containing substituents with electrolyte properties with polymeric hydroxycarboxylic esters , their method of preparation and their use . the polyesters are particularly suitable for use in the preparation of sustained - release drugs .