The objective of this proposal is to define the optimal parameters for an enzymatically controlled polymeric insulin delivery system. In this system, glucose oxidase is immobilized to Sepharose beads or to the polymer backbone of the insulin delivery matrix. Lyophilized insulin is incorporated into the polymer matrix. THe release of insulin is controlled by its dissolution and diffusion rate. Preliminary experiments have shown that increasing the insulin dissolution rate results in an increased insulin release rate from the matrix. This change in insulin dissolution rate can be controlled by altering the pH of the microenvironment of the matrix. THis pH change can be mediated by the conversion of glucose the gluconic acid by the immobilized glucose oxidase. When glucose concentrations rise, the enzyme catalyzes the production of gluconic acid and lowers the microenvironmental pH of matrix. The lower pH response to changes in glucose concentration. The advantages to the diabetic of an insulin delivery system which more closely mimics physiologic insulin delivery include improved patient compliance and improved short and long term therapy. This enzyme mediated feedback controlled delivery system could be applied to the numerous new therapeutic proteins now being developed.
