Protein delivery from biodegradable microspheres.

The key components to the successful development of a biodegradable microsphere formulation for the delivery of proteins are polymer chemistry, engineering, and protein stability. These areas are intricately related and require a thorough investigation prior to embarking on the encapsulation of proteins. While each of these components is important for the development of a biodegradable microsphere formulation for protein delivery, other critical issues should also be considered. In particular, preclinical studies in the appropriate animal model are usually necessary to assess the potential feasibility of a continuous-release dosage form. These studies should be performed at the earliest possible stage of development to validate the feasibility of a controlled release formulation. After the utility of a controlled release formulation has been demonstrated, the polymer matrix should be chosen and bench-scale production of microspheres initiated. The only polymers presently approved for human use for controlled delivery are the polylactides [poly(lactic acid), poly(glycolic acid), and poly(lactic-coglycolic) acid]. These polymers require multiphase processes involving several steps to produce microspheres containing the desired protein. A thorough review of previous work on encapsulation with these polymers should provide some insight into conditions to be assessed in developing a process. Once a process is chosen, it must be optimized to provide the highest possible yield of microspheres with the desired characteristics (e.g., loading, release, size, etc.). Finally, the final aseptic process should be validated and methods generated to assess the final product. The clinical studies should then start upon approval of the IND application. In the future, the biotechnology industry, and the pharmaceutical industry in general, will be seeking new methods to improve the delivery of therapeutic agents such as proteins and peptides. Formulations like biodegradable microspheres significantly reduce health-care costs since fewer administrations are needed, and they provide a competitive advantage in markets with several competing products (e.g., LHRH agonist market). Further, many new indications such as neurological diseases may require a long-term delivery system. The future success of biodegradable microsphere formulations will primarily depend on the commitment of the pharmaceutical and biotechnology industries to the development of this technology.