In Vitro Evaluation of Poly(lactide-co-glycolide) In Situ Forming Gels for Bedaquiline Fumarate Salt and Pharmacokinetics Following Subcutaneous Injection in Rats
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-varian...
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doaj-2a963148dce44c2a8f2e1c01e20930bf2021-08-26T14:13:07ZengMDPI AGPharmaceutics1999-49232021-08-01131231123110.3390/pharmaceutics13081231In Vitro Evaluation of Poly(lactide-co-glycolide) In Situ Forming Gels for Bedaquiline Fumarate Salt and Pharmacokinetics Following Subcutaneous Injection in RatsSandy Van Hemelryck0Rani Wens1Hannelore van Poppel2Milou Luijks3Koosha Shahidi4Marcin Marczak5Ariane Kahnt6René Holm7Erik Mannaert8Peter Langguth9Clinical Pharmacology and Pharmacometrics, Janssen Research and Development, Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, BelgiumClinical Pharmacology and Pharmacometrics, Janssen Research and Development, Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, BelgiumClinical Pharmacology and Pharmacometrics, Janssen Research and Development, Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, BelgiumClinical Pharmacology and Pharmacometrics, Janssen Research and Development, Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, BelgiumClinical Pharmacology and Pharmacometrics, Janssen Research and Development, Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, BelgiumAnalytical Development, Janssen Research and Development, Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, BelgiumBioanalysis, Janssen Research and Development, Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, BelgiumDrug Product Development, Janssen Research and Development, Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, BelgiumClinical Pharmacology and Pharmacometrics, Janssen Research and Development, Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, BelgiumPharmaceutical Technology and Biopharmaceutics, Johannes Gutenberg University, Staudingerweg 5, 55128 Mainz, GermanyThis 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<sub>1/2</sub>) 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<sub>1/2</sub> 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.https://www.mdpi.com/1999-4923/13/8/1231in situ forming gelsinjectablebedaquilinein vitro releasepharmacokineticssustained release |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sandy Van Hemelryck Rani Wens Hannelore van Poppel Milou Luijks Koosha Shahidi Marcin Marczak Ariane Kahnt René Holm Erik Mannaert Peter Langguth |
spellingShingle |
Sandy Van Hemelryck Rani Wens Hannelore van Poppel Milou Luijks Koosha Shahidi Marcin Marczak Ariane Kahnt René Holm Erik Mannaert Peter Langguth In Vitro Evaluation of Poly(lactide-co-glycolide) In Situ Forming Gels for Bedaquiline Fumarate Salt and Pharmacokinetics Following Subcutaneous Injection in Rats Pharmaceutics in situ forming gels injectable bedaquiline in vitro release pharmacokinetics sustained release |
author_facet |
Sandy Van Hemelryck Rani Wens Hannelore van Poppel Milou Luijks Koosha Shahidi Marcin Marczak Ariane Kahnt René Holm Erik Mannaert Peter Langguth |
author_sort |
Sandy Van Hemelryck |
title |
In Vitro Evaluation of Poly(lactide-co-glycolide) In Situ Forming Gels for Bedaquiline Fumarate Salt and Pharmacokinetics Following Subcutaneous Injection in Rats |
title_short |
In Vitro Evaluation of Poly(lactide-co-glycolide) In Situ Forming Gels for Bedaquiline Fumarate Salt and Pharmacokinetics Following Subcutaneous Injection in Rats |
title_full |
In Vitro Evaluation of Poly(lactide-co-glycolide) In Situ Forming Gels for Bedaquiline Fumarate Salt and Pharmacokinetics Following Subcutaneous Injection in Rats |
title_fullStr |
In Vitro Evaluation of Poly(lactide-co-glycolide) In Situ Forming Gels for Bedaquiline Fumarate Salt and Pharmacokinetics Following Subcutaneous Injection in Rats |
title_full_unstemmed |
In Vitro Evaluation of Poly(lactide-co-glycolide) In Situ Forming Gels for Bedaquiline Fumarate Salt and Pharmacokinetics Following Subcutaneous Injection in Rats |
title_sort |
in vitro evaluation of poly(lactide-co-glycolide) in situ forming gels for bedaquiline fumarate salt and pharmacokinetics following subcutaneous injection in rats |
publisher |
MDPI AG |
series |
Pharmaceutics |
issn |
1999-4923 |
publishDate |
2021-08-01 |
description |
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<sub>1/2</sub>) 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<sub>1/2</sub> 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. |
topic |
in situ forming gels injectable bedaquiline in vitro release pharmacokinetics sustained release |
url |
https://www.mdpi.com/1999-4923/13/8/1231 |
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