5-Fluorouracil plasma levels and biodegradation of subcutaneously injected drug-loaded microspheres prepared by spray-drying poly(D,L-lactide) and poly(D,L-lactide-co-glycolide) polymers.

Microspheres (MS) of 5-fluorouracil-loaded poly(D,L-lactide) (PLA), poly(D,L-lactide-co-glycolide) 75/25 (PLGA 75/25) and poly(D,L-lactide-co-glycolide) 50/50 (PLGA 50/50) prepared by the spray-drying technique were subcutaneously injected in the back of Wistar rats in order to evaluate the 5-fluorouracil (5-FU) release and the biodegradation characteristics. Determination of plasma 5-FU concentration by HPLC with analysis of data using a non-compartmental model showed drug in plasma between 9 and 14 days after administration of drug-loaded PLGA 50/50 or PLA and PLGA 75/25 microspheres, respectively, with a maximum drug concentration of 2.4+/-0.2microg/mL at 24h (5-FU-loaded PLGA 50/50 MS), 2.5+/-0.1microg/mL at 48h (5-FU-loaded PLGA 75/25 MS), and 2.3+/-0.1microg/mL at 24h (5-FU-loaded PLA MS). Pharmacokinetically, a significant increase of AUC (up to 50 times) and MRT (up to 196 times) of 5-FU with regard to the administration of the drug in solution was observed. Scanning electron microscopy and histological studies indicated that a small fibrous capsule was observed around the microspheres in the site of injection. One month after the injection of PLGA 50/50 MS and 2 months after the injection of PLGA 75/25 and PLA MS, masses of polymers, instead of single microspheres, were observed. Close to them, macrophagic cells were present, and blood vessels were observed in the connective tissue. Total absence of fibrous capsule and injected microspheres was observed after 2 (for PLGA 50/50 MS) or 3 (PLGA 75/25 and PLA MS) months.

Degradation behaviour of microspheres prepared by spray-drying poly(D,L-lactide) and poly(D,L-lactide-co-glycolide) polymers.

Polymeric microsphere degradation must be taken into account in the design of drug delivery systems to be injected in in vivo systems, thus a prior analysis of in vitro degradation behaviour of microspheres appears to be necessary. In this study degradation characteristics of poly(lactide-co-glycolide) (PLGA) and poly(D,L-lactide) (PLA) microspheres prepared by the spray-drying technique have been examined. It was found that a slow decrease in molecular weight took place during the first stage of degradation, and the value of the rate constant decreased with the increase of the percentage of lactic acid of the polymer in a linear way. Thus, the period of time of this first stage decreased with the increase of content of glycolidyl units of the polymer, and it was the unique stage observed in PLA microspheres after 5 months of study. During this period of time, significant mass loss was not observed in the microspheres. The second stage of degradation of PLGA microspheres showed a larger rate constant, whose value increased with the content of glycolidyl units of the polymer. Mass loss was observed from number-average molecular weight about 6000. A sharp decrease of glass transition temperature (T(g)) was observed coinciding with the start of mass loss. This fact was accompanied by a physical change of the samples, fusion of microspheres to form large particles, which also fusion to form a unique mass of polymer; moment from that the degradation process was quicker.