Abstract
Purpose. This study was done to prepare, characterize, and evaluate salmon calcitonin (sCT) microspheres (ms) in vivo using a low molecular weight, hydrophilic 50∶50 poly (D,L-lactide-co-glycolide) polymer (PLGA).Methods. sCT ms were prepared by a dispersion/solvent extraction/evaporation process and characterized for drug content, particle size, surface morphology, and structural integrity of encapsulated peptide. Peptide stability and binding to the polymer was studied in 0.1 M phosphate buffer (PB), pH 7.4, and 0.1 M acetate buffer (AB), pH 4.0. Serum sCT levels were monitored for 2 weeks after subcutaneous injection of sCT ms to rats.Results. sCT ms were essentially free of discernible surface pores with a particle size distribution in the range of 16 to 89 mm and mean particle size of 51 and 53 mm for 2 batches. Fourier Transform Matrix-assisted Laser Desorption mass spectrometry of the extracted peptide showed that the encapsulation process did not alter its chemical structure. The peptide was substantially more stable in AB than in PB. Peptide binding to the polymer was dependent on pH and was markedly higher in PB than in AB. In vivo study proved that elevated serum sCT levels could be sustained for at least 10 days after administration of sCT ms to rats at a dose of 1.0 mg/kg.Conclusions. It was demonstrated that sCT could be incorporated into polymeric ms prepared from a low molecular weight, hydrophilic PLGA using a dispersion technique without altering molecular structure. A 2-week formulation was prepared at a dose of 1.0 mg/kg.
Keywords: Salmon calcitzzonin (sCT), microspheres, PLGA, peptide interaction
Full Text
The Full Text of this article is available as a PDF (117.5 KB).
References
- 1.Gennari C, Agnusdei D, Montagnani M, Gonnelli S, Civitelli R. An effective regimen of intranasal salmon calcitonin in early postmenopausal bone loss. Calcif Tissue Int. 1992;50:381–383. doi: 10.1007/BF00301638. [DOI] [PubMed] [Google Scholar]
- 2.MacIntyre I, Stevenson JC, Whitehead MI, Wimalawansa SJ, Banks LM, Healy MJR. Calcitonin for prevention of postmenopausal bone loss. Lancet. 1988;1(8591):900–902. doi: 10.1016/S0140-6736(88)91712-6. [DOI] [PubMed] [Google Scholar]
- 3.Mazzuoli GF, Tabolli S, Bigi F, et al. Effects of salmon calcitonin on the bone loss induced by ovariectomy. Calcif Tissue Int. 1990;47:209–214. doi: 10.1007/BF02555921. [DOI] [PubMed] [Google Scholar]
- 4.Bonucci E, Ballanti P, Ramires PA, Richardson JL, Benedetti LM. Prevention of ovariectomy osteopenia in rats after vaginal administration of hyaff 11 microspheres containing salmon calcitonin. Calcif Tissue Int. 1995;56:274–279. doi: 10.1007/BF00318046. [DOI] [PubMed] [Google Scholar]
- 5.McSheehy PM, Farina C, Airaghi R, et al. Pharmacologic evaluation of the calcitonin analogue SB 205614 in models of osteoclastic bone resorption in vitro and in vivo: comparison with salmon calcitonin and elcatonin. Bone. 1995;16:435–444. doi: 10.1016/8756-3282(95)90189-2. [DOI] [PubMed] [Google Scholar]
- 6.Wronski TJ, Yen CF, Burton KW, et al. Skeletal effects of calcitonin in ovariectomized rats. Endocrinology. 1991;129:2246–2250. doi: 10.1210/endo-129-4-2246. [DOI] [PubMed] [Google Scholar]
- 7.Huwyler R, Born W, Ohnhaus EE, Fischer JA. Plasma kinetics and urinary excretion of exogenous human and salmon calcitonin in man. Am J Physiol. 1979;236:E15–E19. doi: 10.1152/ajpendo.1979.236.1.E15. [DOI] [PubMed] [Google Scholar]
- 8.Millest AJ, Evans JR, Young JJ, Johnstone D. Sustained release of salmon calcitonin in vivo from lactide:glycolide copolymer depots. Calcif Tissue Int. 1993;52:361–364. doi: 10.1007/BF00310200. [DOI] [PubMed] [Google Scholar]
- 9.Jeyanthi R, Mehta RC, Thanoo BC, DeLuca PP. Effect of processing parameters on the properties of peptide-containing PLGA microspheres. J Microencapsulation. 1997;14(2):163–174. doi: 10.3109/02652049709015330. [DOI] [PubMed] [Google Scholar]
- 10.Lee KC, Lee YJ, Song HM, Chun CJ, DeLuca PP. Degradation of synthetic salmon calcitonin in aqueous solution. Pharm Res. 1992;9:1521–1523. doi: 10.1023/A:1015839719618. [DOI] [PubMed] [Google Scholar]
- 11.Tsai T, Mehta RC, DeLuca PP. Adsorption of peptides to poly (D,L-lactide-co-glycolide): 2. Effect of solution properties on the adsorption. Int J Pharm. 1996;127:43–52. doi: 10.1016/0378-5173(95)04112-5. [DOI] [Google Scholar]