THE INFLUENCE OF TERMINAL GAMMA-STERILIZATION ON CAPTOPRIL CONTAINING POLY(D,L-LACTIDE-CO-GLYCOLIDE) MICROSPHERES

Captopril microspheres from different biodegradable polyesters of the general structure poly (D,L-lactide-co-glycolide) (PLG), were prepared by a spray drying technique and the effects of gamma-irradiation both on the model drug substance and the polymers were investigated. Captopril, polymers and captopril microspheres were irradiated with doses of 6.9, 15.0, 27.7 and 34.8 kGy, using a Co-60 source. Microencapsulated captopril was partially oxidized to its disulfide, and probably coupled to PLG. The drug substance itself showed no oxidation under the same gamma-irradiation conditions. The weight average molecular weights of polymers (M(w)) decreased with increasing irradiation dose. The extent of M(w)-degradation was more pronounced with high initial M(w). The polydispersity indices (I=M(w)/M(n)) were nearly unchanged, indicating that random chain cleavage was a likely degradation mechanism and not the previously postulated unzipping reaction. DSC- and in-vitro release studies demonstrate, that interactions between drug and polymer during gamma-irradiation are of critical importance. In-vitro release is affected both by the initial polymer molecular weight and the irradiation dose. With low M(w) PLG (M(w) 16 500) a dose dependent acceleration of captopril release is seen, whereas for PLG (M(w) 51 500) the release decreases. A significant increase of captopril release rate due to faster polymer degradation is observed with high (M(w) 66 000) captopril microspheres, which can be rationalized on the basis of drastic changes in mechanical properties. Our studies demonstrate that gamma-sterilization of parenteral delivery systems from biodegradable polyesters is by no means a straightforward process step, but requires careful optimization of PLG molecular weights. The stability of the drug against high energy radiation is also influenced by polymer properties and the distribution of drug in the device. Solid solution type microspheres appear to be exceptionally sensitive towards gamma-irradiation.