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

Abstract

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(d,l-lactide) (PDLLA) or poly(d,l-lactide-co-glycolide) (PLGA) with a lactide/glycolide ratio of 50/50 or 75/25 and acid (A) or ester (E) end-capping in N-methyl-2-pyrrolidone at a polymer/solvent ratio of 20/80% (w/w). Mean in vitro drug release in 0.05 M phosphate buffer pH 7.4 with 1% (w/v) 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 (t1/2) 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% (v/v) (mean t1/2 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.

A long-acting formulation of rifabutin is effective for prevention and treatment of Mycobacterium tuberculosis

“…LA bedaquiline for prevention of LTBI reactivation is currently being developed 10,11 . Affordable LA formulations with generic anti-TB drugs would allow the use of this approach in low-income communities.…”

Investigation of Alogliptin-Loaded In Situ Gel Implants by 23 Factorial Design with Glycemic Assessment in Rats

“…Pharmaceutics 2022, 14, x FOR PEER REVIEW 25 of 34 formulation [19,99]. Besides, the internal structure of the ISGI formulation exhibited a slightly spongy appearance with the presence of some holes (Figure 8d), which could explain the release of alogliptin from the formulation [100].…”

“…After 1 day, the external surface presented some fissures and incisions which might reflect the increment of the thickness of the external shell of the formulation (Figure 8c). This could be due to the higher affinity of DMSO solvent to water producing a faster phase inversion and higher water uptake during the solvent exchange step leading to the overall expansion of the formulation [19,99]. Besides, the internal structure of the ISGI formulation exhibited a slightly spongy appearance with the presence of some holes (Figure 8d), which could explain the release of alogliptin from the formulation [100].…”

“…They can also protect the drug from degradation, enhance its absorption, and withstand physiological stress and biological stability [18]. In comparison to the required deep intramuscular injection, syringe clogging or possible stability troubles under certain conditions of such carriers, the long-acting injectable in situ gel implant (ISGI) systems are recognized as ideal substitutes for sustaining the release of drugs [15,19]. The ISGI systems are characterized by their minimally invasive administration, compatibility with several drugs, and simple inexpensive processing, including only dissolution or suspension of the drug in a polymeric solution [20,21].…”