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

Salmon calcitonin solutions (50 mg/mL and 100 mg/mL) were placed on stabili ty at 37 degrees C for 1 year in a variety of solvent systems including wat er, ethanol, glycerol, propylene glycol (PG) and dimethyl sulfoxide (DMSO). Calcitonin degradation was monitored by RP-HPLC and size-exclusion chromat ography. DMSO and pH 3.3 solutions provided optimum stability. Conformation al stability was also monitored by FTIR over the 1 year time course and com pared 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 wat er), a strong alpha-helical conformation (70% EtOH, 70% PG) and a weak alph a-helical conformation (100% DMSO). No correlation between structure and ch emical 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 ph ysical stability, where co-solvents inducing an alpha-helical structure res ulted in a decrease in gelation. These two structural states associated wit h improved stability and minimal gelation, indicated that gelation can be r educed or eliminated by the use of pharmaceutically acceptable co-solvents. Finally, salmon calcitonin (50 mg/mL) was formulated in 100% DMSO and deli vered from a DUROS(R) implant over 4 months. Delivery at a target dose of 1 8 mu g/day calcitonin at 37 degrees C was confirmed.