Abstract
The synthesis of relatively low molecular weight copoly (D-lactic acid/L-lactic acid) was performed by direct polycondensation in the absence of catalysts. The in vivo degradation of the polymers, for example copoly (D-lactic acid/L-lactic acid, 50 : 50mol-%) with a number-average molecular weight (Mn) of 2, 200, was examined by implanting them subcutaneously into the backs of rats. This polymer led to an “S” type degradation pattern, which is characterized by degradation with initial lag time. An LH-RH agonist, [D-Leu6] -des Gly-NH210 LH-RH ethylamide (Leuprolide), was incorporated into a fine cylindrical polymer formulation by a so-called melt-pressing technique. The main purpose of this paper is to explain the effect of drug dispersion in the formulation on drug release and pharmacological activity through the degradation of the polymer. For this purpose, three polymer formulations with different structures of drug dispersion were prepared : (a) sandwich type, (b) blend type, and (c) molecular dispersion type.
The daily amount of drug released in vivo was strongly influenced by the difference in drug dispersion. Constant release for a longer period was maintained in the order of (c) > (b) > (a) formulation. Both (a) and (b) formulations showed an initial burst of drug release. In contrast, (c) formulation maintained constant release over a period of 12 weeks without the initial burst. The pharmacological activity of the drug released in vivo from the three formulations was evaluated by measuring the changes in weight of accessory sex organs of male adult Wistar rats. The organ weights were decreased rapidly after administration of the drug through controlled delivery until they reached up to those of castrate levels. The lost weight of the organ was regained up to the normal level soon after the complete cessation of the drug release. This response can be explained by the mode of drug release.
