An in-situ forming implant formulation of naltrexone with minimum initial burst release using mixture of PLGA copolymers and ethyl heptanoate as an additive: In-vitro, ex-vivo, and in-vivo release evaluation

Abstract

An in-situ forming implant formulation of naltrexone (NTX) was achieved based on a minimum initial burst release of NTX in the in-vitro release medium using a Box-Behnken design. Variables such as percent of copolymer by weight, copolymer composition (PLGA 756s: PLGA 504H), and percent ethyl heptanoate by weight as an additive in formulation were investigated. The in-vitro, ex-vivo, and in-vivo release of the optimized formulation was investigated. The rabbit-blood concentrations of the optimized formulation and Vivitrol were compared to ensure their equivalency. The initial burst release of the optimized formulation in the in-vitro release over the first 24 h, 6.18 ± 0.91%, was significantly (p < 0.05) lower than that of the formulation containing 100% of PLGA 504H (17.45 ± 1.07%) and 100% of PLGA 756s (11.82 ± 1.03%). The C max ® of NTX (21.06 ± 2.9 ng/mL) from the optimized formulation was close to that of Vivitrol® (21.11 ± 2.89 ng/mL). Also, the absolute bioavailability (F) and the range of serum concentration of NTX (C) of the ISFI formulation (F =18.29, C =6.18–22.84) were similar to Vivitrol ® (F =16.83, C =6.83–23.09). These results indicate that the optimized formulation can reach an effective therapeutic concentration for treating opioid and alcohol dependence.