Sterilization of gentamicin containing collagen/PLGA microparticle composites.

In order to achieve implants which provide sustained release of gentamicin, microparticles based on a 50/50 Resomer 503/Resomer 502H blend were combined with collagen in order to achieve their fixation and to utilize the favorable effect of collagen on wound healing. Ethylene oxide treatment as well as beta- and gamma-irradiation were tested for sterilization of the collagen/PLGA-microparticle composite. All methods resulted in a decrease of molecular weight and glass transition temperature of polymer raw material and microparticles. In addition, ethylene oxide treatment yielded aggregation of microparticles leading to a substantial increase in the initially liberated gentamicin dose. Furthermore, chemical changes of gentamicin after ethylene oxide sterilization could be identified using NMR spectroscopy. Despite a decrease in the molecular weight and glass transition temperature after irradiation, neither morphological changes of the composites nor changes regarding the gentamicin release profile from beta- and gamma-sterilized material were observed. Free radicals, which could only be detected in gentamicin drug substance and at marginal level in gentamicin-loaded MPs, disappeared within 4 weeks. Additional microbiological testing verified the microbiological activity of gentamicin liberated from beta-sterilized composites. Storage of beta-sterilized composite at 4 degrees C/35% r.h. for 3 months did not influence morphology, molecular weight, glass transition temperature, and release profiles of microparticles and composites. However, at 25 degrees C/60% r.h. and 40 degrees C/75% r.h. a marked decrease in molecular weight and glass transition temperature resulted. This effect was due to a higher humidity, water uptake into polymers, and subsequent hydrolysis of polymers and microparticles, which was more pronounced for RG 502H because of its hydrophilicity. Upon storage at 25 degrees C/60% r.h. and 40 degrees C/75% r.h. particles collapsed resulting in an increased gentamicin liberation. Thus, all sterilization techniques have their pros and cons, but based on drug release profile and chemical changes of gentamicin irradiation treatment appears to be more suitable for collagen/gentamicin-loaded PLGA microparticle composites.