Demonstrated solid-state stability of parathyroid hormone PTH(1-34) coated on a novel transdermal microprojection delivery system.

ABSTRACT

PURPOSE: This study assessed conditions necessary for at least a 2-year, ambient temperature storage stability of the peptide parathyroid hormone 1-34, or PTH(1-34), coated on a novel transdermal microprojection delivery system, or ZP-PTH. METHODS: Liquid coating characterization of high concentration PTH(1-34) formulations (>20% w/w) was assessed by viscosity and contact angle measurements along with RP-HPLC and SEC-HPLC. Solid-state coating morphology of PTH(1-34) on microprojection arrays was determined by SEM, and stability on storage was assessed after dissolution and testing with stability indicating assays. Internal vapor analysis was performed to detect and quantify volatile organics released by patch components into the headspace inside the final package. RESULTS: Aggregation and oxidation were the primary degradation mechanisms for solid-state PTH(1-34) in this transdermal delivery system. Although these two degradation pathways can be retarded by appropriate stabilizers and use of foil pouch packaging (nitrogen purged and desiccant), the solid-state drug formulation's compatibility with patch components, particularly the plastic retainer ring, surprisingly dictated PTH(1-34) stability. Internal vapor analysis demonstrated that PTH(1-34) was particularly vulnerable to vapors such as moisture, oxygen, and outgassed formaldehyde, and each of these volatiles played a unique and significant role in PTH(1-34)'s degradation mechanism. CONCLUSIONS: Identifying degradation mechanisms of volatile compounds on solid-state PTH(1-34) peptide stability allowed for the rationale for selection of final formulation, system components and packaging conditions. A >2-yr, ambient temperature storage stability was demonstrated for solid-state drug coated on a novel transdermal microprojection delivery system. This system was successfully tested in a Phase 2 clinical trial for the treatment of post-menopausal women with osteoporosis.