In Vitro Evaluation of Poly(lactide-co-glycolide) In Situ Forming Gels for Bedaquiline Fumarate Salt and Pharmacokinetics Following Subcutaneous Injection in Rats

• Main Authors: Sandy Van Hemelryck, Rani Wens, Hannelore van Poppel, Milou Luijks, Koosha Shahidi, Marcin Marczak, Ariane Kahnt, René Holm, Erik Mannaert, Peter Langguth
• Format: Article
• Language: English
• Published: MDPI AG 2021-08-01
• Series: Pharmaceutics
• Subjects: in situ forming gels; injectable; bedaquiline; in vitro release; pharmacokinetics; sustained release
• Online Access: https://www.mdpi.com/1999-4923/13/8/1231

This study evaluated in vitro and in vivo drug release of bedaquiline from in situ forming gels (ISGs) containing 200 mg eq./g bedaquiline fumarate salt prepared with four different grades of poly(<span style="font-variant: small-caps;">d</span>,<span style="font-variant: small-caps;">l</span>-lactide) (PDLLA) or poly(<span style="font-variant: small-caps;">d</span>,<span style="font-variant: small-caps;">l</span>-lactide-co-glycolide) (PLGA) with a lactide/glycolide ratio of 50/50 or 75/25 and acid (A) or ester (E) end-capping in <i>N</i>-methyl-2-pyrrolidone at a polymer/solvent ratio of 20/80% (<i>w</i>/<i>w</i>). Mean in vitro drug release in 0.05 M phosphate buffer pH 7.4 with 1% (<i>w</i>/<i>v</i>) sodium lauryl sulphate was 37.3, 47.1, 53.3, and 62.3% within 28 days for ISGs containing PLGA5050A, PDLLA, PLGA7525A, and PLGA7525E, respectively. The data suggested that drug release was primarily controlled by precipitated drug redissolving, rather than polymer erosion. In vivo pharmacokinetic profiles after subcutaneous injections in rats were comparable for all ISGs (mean half-lives (t_1/2) ranged from 1411 to 1695 h) and indicated a sustained drug release when compared to a solution of bedaquiline fumarate salt in polyethylene glycol 400/water 50/50% (<i>v</i>/<i>v</i>) (mean t_1/2 of 895 h). In conclusion, PLGA or PDLLA-based ISGs have shown potential for parenteral sustained delivery of bedaquiline, suggesting further preclinical and clinical studies. From a formulation point of view, this case example highlights the importance of the interplay between drug solubility in biological media and dissolution of drug precipitates, which, in addition to the incorporation of diffusion controlling polymers, governs the release of the active drug.