DRUG DISSOLUTION AS A CONTROLLABLE PROCESS

药物溶解是一个可控过程

• 批准号: 2185240
• 负责人: MARYLEE Z SOUTHARD
• 金额: $ 8.46万
• 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/2185240
• 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.

该项目是对化学过程的研究，可用于 改变药物分子的溶出速率。 使用实验和 数学研究，修改溶解的合理策略 中性和可电离分子的行为将得到发展。 将研究过程以控制位置为目标， 药物溶出的速率和化学机制，其中这些因素 影响其治疗价值。 许多口服药物的吸收率可能受到以下因素的限制： 它们在胃肠道 (GI) 内容物中的溶解速度缓慢 道。 对于水性差的药物尤其如此 溶解度。 对于其他试剂，溶解可能太快，导致 血浆浓度可能有毒或太短 在持续时间里。 此外，可电离药物在通过时会改变形式 通过胃和胃肠道环境的变化， 从可溶形式到不溶形式。 通常，会加入缓冲器 进入配方，尽管没有合理的使用基础 特定的药物。 此外，胃肠道液体含有表面活性剂，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。 标准 溶出度测试在体外条件下进行，快速 搅拌。 因为溶解速率受流体流量的影响 围绕药物片剂，该测试提供的信息很少 药片在体内的实际时间过程。 这笔赠款将尝试 确定中性和电离药物的关键特性 通过研究层流条件下的溶解来影响溶解 与胃肠道相似，并且具有不同的 pH 值和表面活性剂 浓度。 根据这些信息，它将调查使用情况 与固体药物共同压缩的缓冲液作为改变的手段 那个环境。 层流溶解的数学分析 将进行流动以确定影响因素 当两种成分溶解时药物和缓冲液之间的相互作用， 相互作用并被传送走。 目标是确定最优的 基于药物溶解度的缓冲剂的类型和比例 特征、它与胃肠道环境的相互作用以及它的期望 溶解率。 为了实现这一目标，将制定一项正式战略 开发利用药物的不良特性来设计缓冲 “定制”配方以优化其溶出率。