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Improving Dissolution Behavior and Oral Absorption of Drugs with pH-Dependent Solubility Using pH Modifiers: A Physiologically Realistic Mass Transport Analysis
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2021-08-24 , DOI: 10.1021/acs.molpharmaceut.1c00262
Niloufar Salehi 1 , Gislaine Kuminek 2, 3 , Jozef Al-Gousous 2, 4 , David C Sperry 3 , Dale E Greenwood 3 , Nicholas M Waltz 2, 5 , Gordon L Amidon 2 , Robert M Ziff 1 , Gregory E Amidon 2
Affiliation  

Orally dosed drugs must dissolve in the gastrointestinal (GI) tract before being absorbed through the epithelial cell membrane. In vivo drug dissolution depends on the GI tract’s physiological conditions such as pH, residence time, luminal buffers, intestinal motility, and transit and drug properties under fed and fasting conditions (Paixão, P. et al. Mol. Pharm.2018 and Bermejo, et al. M. Mol. Pharm.2018). The dissolution of an ionizable drug may benefit from manipulating in vivo variables such as the environmental pH using pH-modifying agents incorporated into the dosage form. A successful example is the use of such agents for dissolution enhancement of BCS class IIb (high-permeability, low-solubility, and weak base) drugs under high gastric pH due to the disease conditions or by co-administration of acid-reducing agents (i.e., proton pump inhibitors, H2-antagonists, and antacids). This study provides a rational approach for selecting pH modifiers to improve monobasic and dibasic drug compounds’ dissolution rate and extent under high-gastric pH dissolution conditions, since the oral absorption of BCS class II drugs can be limited by either the solubility or the dissolution rate depending on the initial dose number. Betaine chloride, fumaric acid, and tartaric acid are examples of promising pH modifiers that can be included in oral dosage forms to enhance the rate and extent of monobasic and dibasic drug formulations. However, selection of a suitable pH modifier is dependent on the drug properties (e.g., solubility and pKa) and its interplay with the pH modifier pKa or pKas. As an example of this complex interaction, for basic drugs with high pKa and intrinsic solubility values and large doses, a polyprotic pH modifier can be expected to outperform a monoacid pH modifier. We have developed a hierarchical mass transport model to predict drug dissolution of formulations under varying pH conditions including high gastric pH. This model considers the effect of physical and chemical properties of the drug and pH modifiers such as pKa, solubility, and particle size distribution. This model also considers the impact of physiological conditions such as stomach emptying rate, stomach acid and buffer secretion, residence time in the GI tract, and aqueous luminal volume on drug dissolution. The predictions from this model are directly applicable to in vitro multi-compartment dissolution vessels and are validated by in vitro experiments in the gastrointestinal simulator. This model’s predictions can serve as a potential data source to predict plasma concentrations for formulations containing pH modifiers administered under the high-gastric pH conditions. This analysis provides an improved formulation design procedure using pH modifiers by minimizing the experimental iterations under both in vitro and in vivo conditions.

中文翻译:

使用 pH 调节剂改善具有 pH 依赖性溶解度的药物的溶解行为和口服吸收:生理上真实的传质分析

口服药物在通过上皮细胞膜吸收之前必须溶解在胃肠道 (GI) 中。体内药物溶解取决于胃肠道的生理条件,例如 pH 值、停留时间、管腔缓冲液、肠道蠕动以及进食和禁食条件下的转运和药物特性(Paixão, P. et al. Mol. Pharm. 2018 and Bermejo,等人, M. Mol. Pharm. 2018)。可电离药物的溶解可能受益于体内操作变量,例如环境 pH 值,使用掺入剂型的 pH 值调节剂。一个成功的例子是在胃部 pH 值较高的情况下,或通过联合使用降酸剂来增强 BCS IIb 类(高渗透性、低溶解度和弱碱)药物的溶出度。IE、质子泵抑制剂、H2 拮抗剂和抗酸剂)。本研究为选择 pH 调节剂以提高一元和二元药物化合物在高胃 pH 溶出条件下的溶出速率和程度提供了一种合理的方法,因为 BCS II 类药物的口服吸收可能受到溶解度或溶出速率的限制取决于初始剂量数。甜菜碱氯化物、富马酸和酒石酸是有前景的 pH 调节剂的例子,它们可以包含在口服剂型中,以提高一元和二元药物制剂的速率和范围。然而,合适的 pH 调节剂的选择取决于药物特性(例如溶解度和 p Ka)及其与 pH 调节剂 p Ka相互作用或 p K a s。作为这种复杂相互作用的一个例子,对于具有高 p K a和固有溶解度值和大剂量的碱性药物,可以预期多元 pH 调节剂优于单酸 pH 调节剂。我们开发了一种分级传质模型来预测在不同 pH 条件下(包括高胃液 pH)下制剂的药物溶出。该模型考虑了药物的物理和化学性质和 pH 调节剂(如 p K a )的影响、溶解度和粒度分布。该模型还考虑了生理条件的影响,例如胃排空率、胃酸和缓冲液分泌、在胃肠道中的停留时间和水腔体积对药物溶解的影响。该模型的预测直接适用于体外多室溶出容器,并通过胃肠模拟器的体外实验进行验证。该模型的预测可以作为潜在的数据源来预测在高胃 pH 条件下给药的含有 pH 调节剂的制剂的血浆浓度。该分析通过最小化两种体外实验迭代,提供了一种使用 pH 调节剂的改进配方设计程序。体内条件。
更新日期:2021-09-06
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