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

Citation
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
Citations number
49
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF PEPTIDE RESEARCH
ISSN journal
1397002X → ACNP
Volume
55
Issue
2
Year of publication
2000
Pages
129 - 139
Database
ISI
SICI code
1397-002X(200002)55:2<129:SSOSCA>2.0.ZU;2-B
Abstract
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.