Pharmacokinetic analysis and formulation development of therapeutic proteins
Hill, Kimberley Temeca
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Overcoming the challenges of protein drug delivery requires an integrated partnership between well-established concepts in drug delivery and a bit of the avant-garde, with the mutual goal of developing an efficient strategy that maintains protein stability and clinical effectiveness. In pursuit of this objective, the central purpose of this investigation was to examine two approaches for improving the physiological disposition of proteins, (1) chemical modification and (2) controlled drug release systems. Pharmacokinetic (PK) analysis of model polypeptides (galanin, glucagon, and motilin) following intravenous administration to male Sprague-Dawley rats revealed PK properties typically associated with this class of molecules, i.e. short biological half-life, and rapid clearance, which are often attributed to extensive proteolytic cleavage. Incorporation of protease resistant motifs into the primary structure of glucagon produced an obvious change in the physiological disposition of the derivatives, in comparison to the parent compound, in terms of the rate and the extent of tissue distribution. However, pharmacokinetic analysis indicated that the motif had a limited stabilizing effect, resulting in no statistically significant difference in biological half-lives. As a viable alternative to structural redesign, particulate drug delivery systems offer several advantages to protein drug delivery including controlled release and presumably structural protection. Therefore, the microencapsulation process must permit maintenance of the native protein structure during fabrication of and release from the protein-encapsulated particulate delivery device. To evaluate the effect of protein stabilizers on stress-induced protein unfolding during microencapsulation, primary emulsification studies were used to screen potential formulations. The water-soluble polymer polyvinylpyrrolidone was effective in increasing soluble protein recovery and retaining structural integrity of the protein. Protein encapsulated microsphere formulations containing stabilizing excipients were prepared by double emulsion-solvent evaporation. The presence of excipients in the internal aqueous phase of the double emulsion influenced particle size, encapsulation efficiency, and protein release from the final product.