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Fed- and Fasted-State Performance of Pretomanid Amorphous Solid Dispersions Formulated with an Enteric Polymer

[Image: see text] Weakly acid polymers with pH-responsive solubility are being used with increasing frequency in amorphous solid dispersion (ASD) formulations of drugs with low aqueous solubility. However, drug release and crystallization in a pH environment where the polymer is insoluble are not we...

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Autores principales: Nguyen, Hanh Thuy, Van Duong, Tu, Jaw-Tsai, Sarah, Bruning-Barry, Rebecca, Pande, Poonam, Taneja, Rajneesh, Taylor, Lynne S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10245392/
https://www.ncbi.nlm.nih.gov/pubmed/37220082
http://dx.doi.org/10.1021/acs.molpharmaceut.3c00174
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author Nguyen, Hanh Thuy
Van Duong, Tu
Jaw-Tsai, Sarah
Bruning-Barry, Rebecca
Pande, Poonam
Taneja, Rajneesh
Taylor, Lynne S.
author_facet Nguyen, Hanh Thuy
Van Duong, Tu
Jaw-Tsai, Sarah
Bruning-Barry, Rebecca
Pande, Poonam
Taneja, Rajneesh
Taylor, Lynne S.
author_sort Nguyen, Hanh Thuy
collection PubMed
description [Image: see text] Weakly acid polymers with pH-responsive solubility are being used with increasing frequency in amorphous solid dispersion (ASD) formulations of drugs with low aqueous solubility. However, drug release and crystallization in a pH environment where the polymer is insoluble are not well understood. The aim of the current study was to develop ASD formulations optimized for release and supersaturation longevity of a rapidly crystallizing drug, pretomanid (PTM), and to evaluate a subset of these formulations in vivo. Following screening of several polymers for their ability to inhibit crystallization, hypromellose acetate succinate HF grade (HPMCAS-HF; HF) was selected to prepare PTM ASDs. In vitro release studies were conducted in simulated fasted- and fed-state media. Drug crystallization in ASDs following exposure to dissolution media was evaluated by powder X-ray diffraction, scanning electron microscopy, and polarized light microscopy. In vivo oral pharmacokinetic evaluation was conducted in male cynomolgus monkeys (n = 4) given 30 mg PTM under both fasted and fed conditions in a crossover design. Three HPMCAS-based ASDs of PTM were selected for fasted-state animal studies based on their in vitro release performance. Enhanced bioavailability was observed for each of these formulations relative to the reference product that contained crystalline drug. The 20% drug loading PTM-HF ASD gave the best performance in the fasted state, with subsequent dosing in the fed state. Interestingly, while food improved drug absorption of the crystalline reference product, the exposure of the ASD formulation was negatively impacted. The failure of the HPMCAS-HF ASD to enhance absorption in the fed state was hypothesized to result from poor release in the reduced pH intestinal environment resulting from the fed state. In vitro experiments confirmed a reduced release rate under lower pH conditions, which was attributed to reduced polymer solubility and an enhanced crystallization tendency of the drug. These findings emphasize the limitations of in vitro assessment of ASD performance using standardized media conditions. Future studies are needed for improved understanding of food effects on ASD release and how this variability can be captured by in vitro testing methodologies for better prediction of in vivo outcomes, in particular for ASDs formulated with enteric polymers.
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spelling pubmed-102453922023-06-08 Fed- and Fasted-State Performance of Pretomanid Amorphous Solid Dispersions Formulated with an Enteric Polymer Nguyen, Hanh Thuy Van Duong, Tu Jaw-Tsai, Sarah Bruning-Barry, Rebecca Pande, Poonam Taneja, Rajneesh Taylor, Lynne S. Mol Pharm [Image: see text] Weakly acid polymers with pH-responsive solubility are being used with increasing frequency in amorphous solid dispersion (ASD) formulations of drugs with low aqueous solubility. However, drug release and crystallization in a pH environment where the polymer is insoluble are not well understood. The aim of the current study was to develop ASD formulations optimized for release and supersaturation longevity of a rapidly crystallizing drug, pretomanid (PTM), and to evaluate a subset of these formulations in vivo. Following screening of several polymers for their ability to inhibit crystallization, hypromellose acetate succinate HF grade (HPMCAS-HF; HF) was selected to prepare PTM ASDs. In vitro release studies were conducted in simulated fasted- and fed-state media. Drug crystallization in ASDs following exposure to dissolution media was evaluated by powder X-ray diffraction, scanning electron microscopy, and polarized light microscopy. In vivo oral pharmacokinetic evaluation was conducted in male cynomolgus monkeys (n = 4) given 30 mg PTM under both fasted and fed conditions in a crossover design. Three HPMCAS-based ASDs of PTM were selected for fasted-state animal studies based on their in vitro release performance. Enhanced bioavailability was observed for each of these formulations relative to the reference product that contained crystalline drug. The 20% drug loading PTM-HF ASD gave the best performance in the fasted state, with subsequent dosing in the fed state. Interestingly, while food improved drug absorption of the crystalline reference product, the exposure of the ASD formulation was negatively impacted. The failure of the HPMCAS-HF ASD to enhance absorption in the fed state was hypothesized to result from poor release in the reduced pH intestinal environment resulting from the fed state. In vitro experiments confirmed a reduced release rate under lower pH conditions, which was attributed to reduced polymer solubility and an enhanced crystallization tendency of the drug. These findings emphasize the limitations of in vitro assessment of ASD performance using standardized media conditions. Future studies are needed for improved understanding of food effects on ASD release and how this variability can be captured by in vitro testing methodologies for better prediction of in vivo outcomes, in particular for ASDs formulated with enteric polymers. American Chemical Society 2023-05-23 /pmc/articles/PMC10245392/ /pubmed/37220082 http://dx.doi.org/10.1021/acs.molpharmaceut.3c00174 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Nguyen, Hanh Thuy
Van Duong, Tu
Jaw-Tsai, Sarah
Bruning-Barry, Rebecca
Pande, Poonam
Taneja, Rajneesh
Taylor, Lynne S.
Fed- and Fasted-State Performance of Pretomanid Amorphous Solid Dispersions Formulated with an Enteric Polymer
title Fed- and Fasted-State Performance of Pretomanid Amorphous Solid Dispersions Formulated with an Enteric Polymer
title_full Fed- and Fasted-State Performance of Pretomanid Amorphous Solid Dispersions Formulated with an Enteric Polymer
title_fullStr Fed- and Fasted-State Performance of Pretomanid Amorphous Solid Dispersions Formulated with an Enteric Polymer
title_full_unstemmed Fed- and Fasted-State Performance of Pretomanid Amorphous Solid Dispersions Formulated with an Enteric Polymer
title_short Fed- and Fasted-State Performance of Pretomanid Amorphous Solid Dispersions Formulated with an Enteric Polymer
title_sort fed- and fasted-state performance of pretomanid amorphous solid dispersions formulated with an enteric polymer
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10245392/
https://www.ncbi.nlm.nih.gov/pubmed/37220082
http://dx.doi.org/10.1021/acs.molpharmaceut.3c00174
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