In-vitro, ex-vivo, and in-vivo evaluation of buprenorphine HCl release from an in situ forming gel of PLGA-PEG-PLGA using N-methyl-2-pyrrolidone as solvent

An in situ forming gel (ISFG) of buprenorphine (BP) was prepared using PLGA-PEG-PLGA (triblock) and N-methyl-2-pyrrolidone as solvent for decreasing the initial burst release. Supercritical CO2 method was used for ring opening polymerization of triblock. The optimum formulation of ISFG was achieved based on a minimum initial burst release of BP in the in-vitro release media using Box-Behnken design. In-vitro, ex-vivo, and in-vivo studies of ISFG were compared with an in situ forming implant (ISFI) composed of copolymer PLGA 504H (similar to RBP-6000). The initial burst release from in vitro media for the ISFG (6.19 +/- 0.31%) was significantly lower than that for the ISFI (13.45 +/- 1.14%) because the thermosensitive property of the triblock and hydrogen bonding between the NMP molecules and the PEG of the triblock prevented the NMP from diffusing rapidly into the release medium. The C-max of BP (6.95 +/- 0.98 ng/mL) from the ISFG was significantly (p < 0.05) lower than those from the ISFI (8.19 +/- 1.02). Furthermore, the AUC, the range of serum concentration (C) of BP for the ISFG (AUC = 2721.38 +/- 69, C = 1.87-7.12) formulation were similar to those for ISFI (AUC = 2727.36 +/- 71, C = 1.75-10). The results suggest that the ISFG can be used as a new type of sustained-release injection formulation with a smaller initial burst release than the ISFI.