A systematic approach to develop and characterize a compositionally equivalent buprenorphine in situ forming implant (Sublocade®)

Sublocade® is a PLGA-based in situ forming implant designed for the sustained delivery of buprenorphine, a partial mu-opioid receptor agonist, with a monthly dosing regimen for the treatment of moderate to severe opioid use disorder (OUD). Unlike other suspension-based in situ forming implants, where the drug crystals are dispersed within the Atrigel® system, Sublocade® is a true solution-based in situ forming implant, as buprenorphine is fully dissolved in the Atrigel® system. The heterogeneous nature of PLGA and the lack of compendial in vitro release testing methods present challenges for the development of generic alternatives, limiting treatment accessibility during the opioid crisis. This study focuses on the comprehensive characterization of Sublocade® and the development of a compositionally equivalent, reverse-engineered buprenorphine in situ forming implant (BUP-ISFI). Advanced analytical methods were employed to establish key PLGA attributes, including molecular weight, lactide/glycolide (L/G) ratio, end group, and blockiness from Sublocade®, which was key in developing reverse-engineered BUP-ISFI. Solid-state characterization techniques revealed a heterogeneous distribution of precipitated drug crystals within the solidified implant. An in-house PVA thin-film-assisted cylindrical adapter in UPS 2 dissolution apparatus achieved a reproducible drug release and was able to discriminate any changes in formulation with different PLGA molecular weight, end group and L/G ratio. Sublocade® and reverse-engineered BUP-ISFI had similar in vitro drug release profiles and demonstrated similar pharmacokinetic profile and drug absorption. This study provides valuable insights into PLGA purification, characterization and in vitro/in vivo evaluation of solution-based in situ forming implants, which is essential for the development of generic products.