Design and establishment of a biodegradable device from a sustained and adjustable rate of release of bioactive protein drugs

Protein drugs are the most rapidly growing segment of the biopharmaceutical drug market in this decade. For therapeutic proteins that are secreted locally and have a short in vivo half-life, it would be highly desirable to develop a protein drug delivery device that can provide the proper dosage at a controlled rate in the vicinity of the target area, without distributing the drugs in systemic circulation. The main objective of this study was to design a biodegradable polymeric device for delivering bioactive proteins at a constant rate, and at a concentration within its therapeutic window. The three proteins that have been chosen in this work, vascular endothelial growth factor (VEGF), interleukin2 (IL-2), and interferon-gamma (IFN-gamma), represent a class of therapeutic proteins that are highly potent and all of which require a sustained and localized delivery in nano-molar concentrations. Through this thesis, it has been demonstrated that constant protein release can be achieved by using two mechanisms: one is by utilizing the electrostatic interaction formed between alginate and the encapsulated protein; the other mechanism by distributing therapeutic protein and excipients as solid particles within a rubbery matrix and relying on the excipient's osmotic pressure to drive it from the matrix. In the first approach, VEGF was encapsulated in calcium alginate microspheres. Sustained VEGF release at a rate of 6.2 ng/day for 14 days was achieved by masking the electrostatic interaction between alginate and VEGF with 500 mM of CaCl2 in the release media. In the second approach, VEGF, IFN-gamma and IL-2 were each co-lyophilized with bovine serum albumin and trehalose as excipients, then embedded into a photo-cross-linked elastomer matrix. Using the optimum formulation, over 90% of the embedded protein can be released at a constant rate in the range of 20∼30 ng/day for up to 18 days. Manipulating the geometries and mechanical properties of the elastomer device changed the rate of protein release, but did not alter the zero order nature of the release kinetics. Cell based bioactivity assays showed the release proteins were highly bioactive during the first two weeks of the release study. The elastomer delivery device degraded via hydrolysis in three months in phosphate buffered saline. The formulations designed and developed in this study demonstrate promising potential as sustained protein drug delivery vehicles for localized delivery applications.