Gamma irradiation effects and EPR investigation on poly(lactide-co-glycolide) microspheres containing bupivacaine

The effects of radiation on the stability of microspheres made of a polylactide-co-glycolide 50:50 copolymer (PLGA) and
loaded with 40% bupivacaine (BU) were studied. The radiolysis mechanisms of BU and BU-loaded microspheres were investigated
by using electronic paramagnetic resonance (EPR) analysis. Microspheres were prepared by means of a spray drying method.
Irradiation was carried out in the open, at the dose of 25 kGy, by using a 60Co source. The stability of BU-loaded microspheres
was evaluated over a 1-year period on the basis of drug content and dissolution profile. Non-irradiated microspheres were stable
over the whole period under consideration. Immediately after irradiation the amount of BU released after 24 h from irradiated
microspheres increased from 17 to 25%; in the following 3 months of storage it increased to about 35%, and then it kept constant
for 1 year. Radicals generated by BU irradiation were identified by EPR analysis; the sensitivity to radiation of BU was about
four times lower than that of PLGA. Furthermore, the EPR spectra of loaded microspheres showed that the relative abundance
of BU radicals plus PLGA radicals was proportionate to the electronic fractions of the components; this implies that no spin
transfer BU/PLGA had occurred during irradiation.