Solution stability of salmon calcitonin at high concentration for delivery in an implantable system

Salmon calcitonin solutions (50 mg/mL and 100 mg/mL) were placed on stability at 37 degrees C for 1 year in a variety of solvent systems including water, ethanol, glycerol, propylene glycol (PG) and dimethyl sulfoxide (DMSO). Calcitonin degradation was monitored by RP-HPLC and size-exclusion chromatography. DMSO and pH 3.3 solutions provided optimum stability. Conformational stability was also monitored by FTIR over the 1 year time course and compared with chemical and physical stability. After 12 months at 37 degrees C, four major conformations were observed: a beta-sheet conformation (pH 3.3, pH 5.0, 70% DMSO and 70% glycerol), an aggregate conformation (pH 7.0 water), a strong alpha-helical conformation (70% EtOH, 70% PG) and a weak alpha-helical conformation (100% DMSO). No correlation between structure and chemical stability was observed in which both the beta-sheet structure (pH 3.3, water) and a loose alpha-helical structure (100% DMSO) demonstrated good stability. However, some correlation was observed between structure and physical stability, where co-solvents inducing an alpha-helical structure resulted in a decrease in gelation. These two structural states associated with improved stability and minimal gelation, indicated that gelation can be reduced or eliminated by the use of pharmaceutically acceptable co-solvents. Finally, salmon calcitonin (50 mg/mL) was formulated in 100% DMSO and delivered from a DUROS implant over 4 months. Delivery at a target dose of 18 microg/day calcitonin at 37 degrees C was confirmed.