Aqueous Solubilizing Systems for Parenteral Formulation Development—Proteins

Abstract

Protein solubility ranges from low micrograms per ml to several hundreds of milligrams per ml, and is very compound-specific. Most antibodies are known to reach solubilities of hundreds of mg per ml whereas beta amyloid protein has very low solubility. Small structural changes could lead to significant changes in solubility, for example, cryo-immunoglobulins may be almost insoluble. The dose and route of administration may demand a higher concentration than possible in simple formulations, posing a challenge to the development of a clinically or commercially viable product. One important challenge is that proteins are typically administered via injections due to poor bioavailability by other delivery modes (See review articles in book edited by Audus and Raub, 1993; Pharmaceutical Business Review website, 2005), which restricts the types and levels of excipients (FDA website; Powell et al., 1998; Strickley, 1999, 2000). Further constraints are imparted by the small volume of administration appropriate for subcutaneous and intramuscular delivery routes which need to be consistent with patient compliance and ease of delivery. This can be very different from the volume/ concentration constraints of intravenous administration. For therapeutic doses in the mg/kg levels, the less than approximately 1.2 mL acceptable volume for subcutaneous delivery may necessitate formulations containing hundreds of mg/mL protein. Moreover, toxicological studies may assess approximately 10- fold higher doses than those planned for clinical studies in order to establish a safety window. This necessitates even higher concentrations for non-clinical formulations than for clinical formulations.