Comparison of in-situ forming composite using PLGA-PEG-PLGA with in-situ forming implant using PLGA: In-vitro, ex-vivo, and in-vivo evaluation of naltrexone release

Abstract

An in-situ forming composite (ISFC) of naltrexone (NTX) was prepared using PLGA-PEG-PLGA (triblock) and N-methyl-2-pyrrolidone (NMP) for decreasing the initial burst release. The supercritical CO2 method was used to achieve the ring-opening polymerization of the triblock. The Box-Behnken design was used to achieve the minimal initial burst release of NTX in the in-vitro release medium. In-vitro, ex-vivo, and in-vivo studies of the ISFC were compared with an in-situ forming implant (ISFI) composed of copolymer PLGA 504H. The equivalency of ISFC and Vivitrol® were compared by sampling the concentration of NTX in rabbit blood. The results of the in-vitro release evaluation showed that the initial burst release for the ISFC (5.69 ± 0.27%) was significantly lower than that for the ISFI (17.45 ± 1.07%). The Cmax of NTX (15.16 ± 2.46 ng/mL) from the ISFC was significantly (p < 0.05) lower than that of the ISFI (24.46 ± 2.9 ng/mL) and Vivitrol® (21.11 ± 2.89 ng/mL). The bioavailability and the range of serum concentration of NTX for the ISFC formulation was similar to that of Vivitrol®. The results suggested that the ISFC could be used as a new type of sustained-release formulation with a smaller initial burst release than the ISFI.