The physical characterization and biological activity of insulin immobilized to surface-modified nanocrystalline particles

The development and preparation of proteins for use as medicinal agents has become an integral part of the pharmaceutical industry. Unfortunately, proteins possess chemical and physical properties which present unique difficulties in the storage and delivery of these pharmaceutical agents. Novel drug delivery technologies have been developed to stabilize protein pharmaceuticals during the storage and administration of these agents. Using ideal properties established by current drug delivery approaches, a surface modified nanoparticulate drug delivery system was designed to stabilize protein pharmaceuticals immobilized to the surface of these biodegradable particles. The main focus of this dissertation examines the hypothesis that nanoparticulate drug carriers coated with surface modifiers comprised of stabilizing hydroxyl and carboxyl groups may reduce protein pharmaceutical inactivation following immobilization.; The first chapter of the dissertation describes the physical and chemical processes that may affect the stability of protein pharmaceuticals during storage and administration. Current drug delivery approaches and their advantages and limitations are introduced that may prevent pharmaceutical inactivation and loss of therapeutic value during storage and delivery. Ideal parameters for drug delivery systems are summarized. Chapter Two contains a detailed description of the components of the proposed Decoy Drug Delivery System. This novel system involves biodegradable, nanomeric calcium phosphate particles coated with stabilizing surface modifiers prior to pharmaceutical immobilization. Three candidate surface modifiers are described and insulin is established as the model protein pharmaceutical for the current investigation. The third chapter of the dissertation focuses on the physical characterization of the surface modified brushite particles with and without insulin immobilization. Various techniques were used to identify and determine the size and stability of the surface modified and unmodified brushite particles. All drug-carrier formulations were observed to be stable under physiological conditions and to bind significant amounts of insulin, with P5P and citrate modified carriers meeting several of the ideal delivery parameters established in Chapter 1.; The fourth chapter of the dissertation examines the biological activity of insulin immobilized to the various surface modified nanoparticulates when administered to non-diabetic rabbits and diabetic beagles. The results observed may indicate the requirement for surface modifier films to stabilize protein pharmaceuticals and prevent inactivation during storage and administration. Chapter five summarizes the experimental results with possible implications and focuses on future investigative directions.