PEPTIDE DEGRADATION DURING PREPARATION AND IN-VITRO RELEASE TESTING OF POLY(L-LACTIC ACID) AND POLY(DL-LACTIC-CO-GLYCOLIC ACID) MICROPARTICLES

Biodegradable, tetracosactide-loaded microparticles were prepared by m eans of (i) spray drying, (ii) w/o/w solvent evaporation method (WOW) and (iii) by the aerosol solvent extraction system (ASES) using poly(L -lactic acid) (L-PLA) and poly(DL-lactic-co-glycolic acid) (DL-PLGA) o f varying monomer composition or molecular weight. In the absence of t he polymer the peptide did not degrade or aggregate irreversibly when in contact with methanol and methylene chloride or under the condition s used in the first step of WOW, as proven by HPLC, electrospray-mass spectrometry (MS) and circular dichroism (CD). During the extraction p rocess, used to isolate the peptide from the microparticles, tetracosa ctide was partially oxidised. The highest stability of the peptide dur ing microencapsulation was guaranteed with high molecular weight L-PLA , when using WOW or ASES, and with very low molecular weight PLGA, in the case of spray drying and WOW. The burst release of the micropartic les, during in vitro release testing, depended on the preparation meth od as well as on the nature of the polymer and increased in the order ASES < spray drying < WOW and with increasing hydrophilicity of the po lymer. Exceptionally, in the case of very low molecular weight PLGA, t o which tetracosactide showed a very strong affinity during the in vit ro adsorption study, no burst effect was observed. In addition, these microparticles released the peptide continuously, whereas for the othe rs, composed of high molecular weight PLA and PLGA, the burst release was followed by a lag phase. During in vitro release peptide degradati on increased with increasing polymer hydrophilicity but could be reduc ed by increasing drug loading. In polymer-free control solutions tetra cosactide degradation was always slower than in the presence of microp articles. Oxidation and hydrolysis were found to be the major degradat ion pathways. (C) 1998 Elsevier Science B.V. All rights reserved.