DRUG DISSOLUTION AS A CONTROLLABLE PROCESS

药物溶解是一个可控过程

• 批准号: 2185239
• 负责人: MARYLEE Z SOUTHARD
• 金额: $ 8.18万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2185239
• 关键词: acidity /alkalinity; buffers; chemical models; drug delivery systems; drug interactions; gastrointestinal drug absorption; pharmacokinetics; solubility; surfactant

This project is a study of the chemical processes that can be used to modify the dissolution rates of drug molecules. Using experimental and mathematical studies, a rational strategy for modifying the dissolution behavior of neutral and ionizable molecules will be developed. Processes will be studied with the goal of controlling the location, rate and chemical mechanism of drug dissolution where these factors affect its therapeutic value. The absorption rate of many orally-administered drugs can be limited by their slow dissolution rate in the contents of the gastrointestinal (GI) tract. this is true especially for drugs having poor aqueous solubility. For other agents, dissolution may be too rapid, resulting in blood plasma concentrations that are potentially toxic or too short in duration. Further, ionizable drugs can change form as they pass through the changing environment of the stomach and GI tract, shifting from soluble to insoluble forms. Frequently, a buffer is incorporated into the formulation, although without a rational basis for its use with the particular drug. Also, the GI fluids contain surfactants which can enhance or reduce the rate of absorption of particular drugs; thus the composition of the GI tract can influence drug dissolution. Standard dissolution rate tests are conducted in in vitro conditions with rapid stirring. Because the rate of dissolution is affected by the fluid flow surrounding the drug tablet, that test gives little information on the actual time course of the tablet in the body. This grant will attempt to identify the critical properties of neutral and ionizable drugs which affect dissolution by studying dissolution under laminar flow conditions similar to that in the GI tract, and in varied pH and surfactant concentrations. Based on this information, it will investigate the use of a buffer co-compressed with the solid drug as a means of altering that environment. The mathematical analysis of dissolution in laminar flow will be conducted to determine the dominant factors in the interaction between the drug and the buffer as both components dissolve, interact and are transported away. The goal is to determine the optimal type and proportion of buffer based on the drug solubility characteristics, its interaction with the GI milieu, and its desired dissolution rate. In accomplishing this goal, a formal strategy will be developed to use the undesirable properties of drugs to design buffered formulations "tailor-made" to optimize their dissolution rates.

这个项目研究的是可以用来 修改药物分子的溶出度。使用实验和 数学研究--修正溶解的合理策略 中性和可电离分子的行为将被开发出来。 将研究过程，以控制位置为目标， 药物溶解速率和化学机制，其中这些因素 影响其治疗价值。 许多口服药物的吸收速度受到以下因素的限制 其在胃肠道内容物中的缓慢溶出率(GI) 一条小路。这是真的，特别是对于含水较差的药物 溶解度。对于其他药剂来说，溶解可能太快，结果 具有潜在毒性或太短的血浆浓度 在持续时间上。此外，可电离药物在通过时会改变其形态。 通过不断变化的胃和胃肠道环境，转移 从可溶到不可溶的形式。通常，会合并一个缓冲区 纳入到公式中，尽管没有合理的基础来与 一种特殊的药物。此外，胃肠液含有表面活性剂，可以 提高或降低特定药物的吸收率；因此 胃肠道的组成会影响药物的溶出度。标准 溶出度试验是在体外条件下进行的 激动人心。因为溶解速度受流体流动的影响 围绕着药片，这项测试几乎没有提供关于 药片在体内的实际时间进程。此拨款将尝试 确定中性和可电离药物的关键特性 层流条件下溶出度研究对溶出度的影响 与胃肠道相似，并在不同的pH和表面活性物质中 浓度。根据这些信息，它将调查使用 与固体药物共压缩的缓冲液作为改变的手段 那种环境。层流中溶解的数学分析 将进行流程，以确定在 当两种成分溶解时药物和缓冲液之间的相互作用， 相互作用，然后被运走。目标是确定最优的 基于药物溶解度的缓冲液的类型和比例 特点，它与GI环境的相互作用，以及它所期望的 溶出度。为了实现这一目标，正式的战略将是 开发利用药物的不良特性来设计缓冲 配方“量身定做”，以优化其溶出度。