Toward physiologically relevant in vitro release testing of PLGA microspheres for subcutaneous administration

Despite nearly 40 years of clinical use, PLGA microspheres (MS) still lack reliable in vitro methods to predict drug release, limiting rational development of new subcutaneous (SubQ) formulations or generics. This study investigated how components of the SubQ environment (e.g. proteins, glycosaminoglycans, and lipids) influence drug release from PLGA microspheres containing flurbiprofen or naltrexone. Four independent SubQ-relevant release media of increasing complexity were designed based on the reported SubQ tissue composition. Drug release was evaluated using the sample-and-separate method and, for the first time with PLGA microspheres, the SubCutaneous Injection Site SimulatOR (SCISSOR) containing different extracellular matrix cartridges. Medium composition affected release in a drug- and formulation-dependent manner. For flurbiprofen-loaded microspheres, differences were mainly confined to the initial burst, with limited effects on the overall release. Naltrexone release from the MS varied markedly among media and was faster and more extensive in albumin-containing media than in electrolyte- containing medium. With the SCISSOR method, flurbiprofen release from the PLGA microspheres was comparable between cartridges, reaching approximately 25% after 7 days, whereas naltrexone release from the microspheres remained below 5% after 4 days. These findings indicate that SubQ tissue components may influence PLGA microsphere performances supporting their inclusion in in vitro release methods.