DEVELOPMENT OF NEW BIORESORBABLE POLYMERS FOR THE HIGHLY EFFICIENT CONTROL OF DRUG-RELEASE

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This study deals with the synthesis, hydrolyis, and bioresorption of novel poly (alpha- hydroxy acids) comprising alpha-malic acid units, as well as with their use for the matrix materials on which a highly efficient release-control of drug isoestablished. The followings are principal findings.1. Preparation of Monomers: 3(S)-[(Benzyloxycarbonyl)methyll- (BMD) and 3(s)-[(ethoxy- carbonyl)methyl]-1.4-dioxane-2.5-diones (EMD) were prepared by lactonization of the coupling compounds of bromoacetyl chloride with beta-benzyl and beta-ethyl malates, respectively. NaHCO_3 was the only base for the successful de-hydobromination reaction.2. Polymerization and Copolymerization: Ring-opening polymerizations of both BMD and EMD were carried out in bulk with tin octylate as the catalyst to give poly(glycolic acid-co-alpha-malic acid esters). By the similar ring-opening copolymerizations of L-lactide with BMD and EMD, the terpolimers consisting of lactic acid (L), glycolic acid (G), and alpha-malic … More acid esters (M^*) were obtained. The copolymers comprising BMD units were subjected to hydrogenolytic deprotection in the presence of a Pd-C catalyst to obtain the alpha-malic acid (M)-containing copolyesters (L-G-M) having carboxy pendants.3. Hydrolyzability and Bioresorbability: The films of the L-G-M copolymers were immersed in a phosphate buffer, by which the hydrolyzability of alpha-malic acid-containing polyesters was found to be much higher than that of poly (lactic acid). The same films were implanted under the dorsal skin of rats to investigate their bioresorbability. The results indicated that the rate of degradation in vivo is comparable with that in vitro, that the resorption rate increases with increasing M ratio in the copolymers, and that the biocom- patibility of the copolymers are excellent without rejection symptoms observed in the sites of implantation. From the above results poly (alpha -hydroxy acids) comprising alpha-malic acid units were known to be used as the drug matrix, on which new drug delivery system is possibly to be developed. At present, the preparation of microspheres based on these copolymers is under way. Less