CONTROLLED RELEASE OF MACROMOLECULES

描述（改编自研究者摘要）：这是一个赠款 高分子药物控释研究的延续申请 重量（MW > 1，000道尔顿）药物，如多肽。 的成因 这项工作可以追溯到1979年，涉及系统的研究， 化学方法来实现大分子的控制释放。期间 最近的补助期（1989-91），调查人员综合， 研究了一类新的聚合物--非酰胺连接的聚氨基酸 键，并启动了蛋白质失活的基础研究， 治疗相关的条件。蛋白质灭活工作涉及 三种模型蛋白，胰岛素（MW 6，000）、RNA酶（MW 14，000）和血红蛋白 (MW 68，000），并研究了由于润湿而导致的聚集问题， 添加剂对润湿时蛋白质不溶解程度的影响， 并评估润湿后蛋白质的物理化学变化。 的 本发明旨在研究：1）治疗性蛋白质的稳定性， 固态;和2）治疗性蛋白质在溶液中的稳定性。 了解蛋白质在这些细胞中的基本机制， 有两个条件是制造和使用受控的 蛋白质药物的释放系统。这些机制研究将有助于 通过数学建模，特别是蛋白质折叠和展开， 将提供关于稳定性/不稳定性的驱动力的见解， 这些代理人。具体而言，这项工作将审查：1）在 蛋白质溶液，和2）固态稳定性。

DESCRIPTION (adapted from investigator's abstract): This is a grant renewal application for the study of controlled release of high molecular weight (MW > 1,000 Daltons) drugs such as polypeptides. The genesis of this work dates to 1979 and involves a systematic study of physical and chemical methods to achieve controlled release of large molecules. During the most recent grant period (1989-91) the investigators synthesized and examined a new class of polymers-poly amino acids linked by non-amide bonds, and initiated fundamental studies of protein inactivation under therapeutically relevant conditions.The protein inactivation work involved three model proteins, insulin (MW 6,000), RNAase (MW 14,000) and hemoglobin (MW 68,000) and examined the issues of aggregation due to wetting, the effect of additives on the extent of protein insolubilization upon wetting, and evaluated the physico-chemical changes in proteins upon wetting. The present proposal intends to study:1) stability of therapeutic proteins in the solid state; and 2) stability of therapeutic proteins in solution. Understanding the fundamental mechanism of how proteins inactivate in these two conditions is fundamental to the fabrication and use of controlled release systems for protein drugs. These mechanistic studies will be aided by mathematical modelling, especially of protein folding and unfolding and will provide insight as to the driving forces for stability/instability of these agents. Specifically the work will examine: 1) aggregation in protein solutions, and 2) solid state stability.