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 ± 0.2 μg/mL at 24 h (5-FU-loaded PLGA 50/50 MS), 2.5 ± 0.1 μg/mL at 48 h (5-FU-loaded PLGA 75/25 MS), and 2.3 ± 0.1 μg/mL at 24 h (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.