Biorelevant Dissolution Models for a Weak Base To Facilitate Formulation Development and Overcome Reduced Bioavailability Caused by Hypochlordyria or Achlorhydria,Molecular Pharmaceutics

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Biorelevant Dissolution Models for a Weak Base To Facilitate Formulation Development and Overcome Reduced Bioavailability Caused by Hypochlordyria or Achlorhydria
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2017-09-08 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00593
Dawen Kou , Sudharsan Dwaraknath ₁ , Yannick Fischer ₂ , Daniel Nguyen , Myeonghui Kim ₃ , Hiuwing Yiu , Preeti Patel , Tania Ng , Chen Mao , Matthew Durk , Leslie Chinn , Helen Winter , Larry Wigman , Peter Yehl

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In this study, two dissolution models were developed to achieve in vitro–in vivo relationship for immediate release formulations of Compound-A, a poorly soluble weak base with pH-dependent solubility and low bioavailability in hypochlorhydric and achlorhydric patients. The dissolution models were designed to approximate the hypo-/achlorhydric and normal fasted stomach conditions after a glass of water was ingested with the drug. The dissolution data from the two models were predictive of the relative in vivo bioavailability of various formulations under the same gastric condition, hypo-/achlorhydric or normal. Furthermore, the dissolution data were able to estimate the relative performance under hypo-/achlorhydric and normal fasted conditions for the same formulation. Together, these biorelevant dissolution models facilitated formulation development for Compound-A by identifying the right type and amount of key excipient to enhance bioavailability and mitigate the negative effect of hypo-/achlorhydria due to drug–drug interaction with acid-reducing agents. The dissolution models use readily available USP apparatus 2, and their broader utility can be evaluated on other BCS 2B compounds with reduced bioavailability caused by hypo-/achlorhydria.

中文翻译：

弱碱的生物相关溶出模型，以促进制剂开发并克服由低氯酸或胃酸缺乏引起的生物利用度降低

在这项研究中，开发了两种溶出模型以实现化合物-A的速释制剂的体外-体内关系，该化合物是难溶性弱碱，具有pH依赖性溶解度，在低水合和无水患者中生物利用度低。设计溶出度模型以估计一杯水与药物一起摄入后的低/胃酸和正常禁食的胃部状况。来自两个模型的溶出度数据可预测体内相对值在相同的胃部条件下（低/无水或正常）的各种制剂的生物利用度。此外，溶出度数据能够估计在相同配方的低/无水和正常禁食条件下的相对性能。这些生物相关的溶出度模型一起，通过确定正确的类型和数量的关键赋形剂来促进化合物A的配方开发，从而增强生物利用度并减轻由于药物与降酸剂相互作用而引起的低/胃酸缺乏的负面影响。溶出度模型使用现成的USP设备2，其广泛的效用可以在其他BCS 2B化合物上得到评估，这些化合物的生物利用度降低，是由于低/胃酸缺乏引起的。

更新日期：2017-09-08

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