Formulation and Delivery

B iotechnology has created many therapeutic proteins to treat diseases that were incurable 10 years ago (Table 1). Formulating protein delivery systems so that the drugs maintain stability and remain within safe and efficacious target doses remains a challenge. Two general approaches have been used in addressing the delivery of protein therapeutics: • One has focused on noninvasive means of transporting therapeutic proteins into patient’s bodies. Two oral peptide products and three nasal products are approved in the United States. Several pulmonary insulin products are in clinical trials. • The second technology set aimed at increasing the in vivo half-life of proteins. Several extended-release poly(lactide-co-glycolide) (PLGA) low–molecular-weight peptide products are marketed today. There are also several chemically altered protein products that have reached the market using technologies such as amino acid substitution and PEGylation. The limited successes in protein drug delivery so far ref lect the difficulty of these research and development efforts. Thus, the hypodermic needle and syringe still remains the most practical route for protein delivery despite many attempts to develop noninvasive systems or reduced-frequency administration. Early on it was apparent that protein biopharmaceutical development was significantly more difficult than that for traditional pharmaceuticals. Molecular sizes of proteins are orders of magnitude larger than classical drugs, and their secondary and tertiary structures make them very susceptible to physical and chemical degradation. Proteins are easily denatured by heat or by agitation and often go through structural changes when exposed to water and organic solvents. So they often must be maintained at refrigerated temperatures, with stabilizing additives for long-term storage. Proteins also need sterile packaging.