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DRUG DISSOLUTION AS A CONTROLLABLE PROCESS

药物溶解是一个可控过程

基本信息

批准号：
2459451
负责人：
MARYLEE Z SOUTHARD
金额：
$ 9万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
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/2459451
关键词：
acidity /alkalinity buffers chemical models drug delivery systems drug interactions gastrointestinal drug absorption pharmacokinetics solubility surfactant

项目摘要

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.

这个项目是一个化学过程的研究，可用于改变药物分子的溶解速率。使用实验和数学研究，修改溶解的合理策略将发展中性和可电离分子的行为。将以控制位置为目标研究过程，药物溶出速率和化学机制，其中这些因素影响其治疗价值。许多口服给药药物的吸收速率可能受到以下因素的限制：它们在胃肠道（GI）内容物中的缓慢溶出速率道。这对于水性差的药物尤其如此，溶解度对于其他药剂，溶解可能太快，导致在血浆中的浓度可能有毒或太短持续时间。此外，可电离的药物可以改变形式，因为他们通过通过改变胃和胃肠道的环境，从可溶到不溶的形式。通常，加入缓冲液虽然没有合理的依据，特殊的药物。此外，胃肠道液体含有表面活性剂，提高或降低特定药物的吸收率;因此，胃肠道的组成可以影响药物溶出。标准溶出速率试验在体外条件下进行，搅拌的情况下因为溶解的速度受到流体流动的影响在药物片剂周围，该测试提供的信息很少。药片在体内的实际时间过程。这份补助金将尝试确定中性和可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类似于胃肠道中的，并且在不同的pH和表面活性剂中浓度的根据这些信息，它将调查与固体药物共压缩的缓冲液作为改变这种环境。层流溶解的数学分析将进行流程，以确定药物和缓冲液之间的相互作用，相互作用并被传送走。目标是确定最佳的基于药物溶解度的缓冲液类型和比例特征，其与GI环境的相互作用，以及其所需的溶出速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 “量身定制”配方，以优化其溶解速率。