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.