Cl. Stevenson et Mm. Tan, Solution stability of salmon calcitonin at high concentration for deliveryin an implantable system, J PEPT RES, 55(2), 2000, pp. 129-139
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.