Abstract
Purpose. Salmon Calcitonin (sCT) is used to treat hypercalcemia resulting from Paget's disease and osteoporosis. sCT is available either in a sterile injectable form or nasal spray. Alternative and more cost-effective dosage forms for the delivery of calcitonin are needed. We sought to deliver sCT transmucosally using a previously reported mucoadhesive bilayer thin-film composite (TFC) via the buccal route.
Methods. Forty micrograms of salmon calcitonin (200-IU) was loaded on preformed TFCs. In vitro release of sCT from TFCs was monitored in phosphate-buffered saline (10 mM, pH 7.4) at 37°C. Female New Zealand White rabbits (n = 6) were dosed with 40 μg of sCT either by injection via the ear vein or by applying sCT-loaded TFCs directly on the buccal pouch. Blood was collected at various times, and the plasma sCT and calcium concentrations were quantified. WinNonlin® was used to determine the relevant pharmacokinetic parameters.
Results. In vitro, over 80% of sCT was released from the TFCs within 240 min. Super Case-II transport was indicated as the primary release mechanism. Rabbits injected intravenously had C max, Cls, Vss, and AUC0-inf values of 75.1 ± 6.5 ng/mL, 20.7 ± 3.3 mL/min, 637 ± 141 mL, and 1925 ± 237 ng*min/mL, respectively. Rabbits dosed via the buccal route had C max, Cls, and AUC0-400 min values of 4.6 ± 1.6 ng/mL, 22.0 ± 5.9 mL/min, and 842.9 ± 209.7 ng*min/mL, respectively. The relative bioavailability for rabbits treated with the TFCs was 43.8 ± 10.9% with a CV of 24.9%. The reductions in plasma calcium levels after administration of sCT by both the intravenous and buccal route were comparable.
Conclusions. The TFCs effectively delivered therapeutically efficacious amounts of sCT across the buccal mucosa in rabbits.
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REFERENCES
L. E. Wehren. The role of the primary care physician in diagnosis and management of osteoporosis. Int. J. Fertil. Womens Med. 47:116–122 (2002).
M. Zaidi, A. M. Inzerillo, B. S. Moonga, P. J. R. Bevis, and C. L. H. Huang. Forty years of calcitonin-where are we now? A tribute to the work of Iain Macintyre, FRS. Bone 30:655–663 (2002).
J. R. Potts. Chemistry of calcitonin. Bone Mineal. 16:169–173 (1992).
D. J. Hosking and O. L. M. Bijvoet. Therapeutic uses of calcitonin. In J. A. Parsons (ed.), Endocrinology of Calcium Metabolism. Raven Press, New York, 1982 pp. 485–535.
L. J. Deftos. Calcitonin in clinical medicine. Adv. Intern. Med. 23:159–193 (1978).
M. Azria, D. H. Copp, and J. M. Zanelli. 25 years of salmon calcitonin: From synthesis to therapeutic use. Calcif. Tissue Int. 57:407–408 (1995).
Mosby's Drug Consult Top 200. http://www.mosbydrugconsult-.com/DrugConsult/Top_200/.
J. Y. Reginster and P. Franchimon. Side effects of synthetic salmon calcitonin given by intranasal spray compared with intramuscular injection. Clin. Exp. Rheumatol. 3:155–157 (1985).
W. A. Lee, R. D. Ennis, J. P. Longenecker, and P. Bengtsson. The bioavailability of intranasal salmon calcitonin in healthy volunteers with and without a permeation enhancer. Pharm. Res. 11: 747–750 (1994).
K. Morimoto, J. Katsumata, T. Yabuta, and K. Iwanaga, M Kakemi, Y. Tabata, and Y. Ikada. Gelatin microspheres as a pulmonary delivery system: Evaluation of salmon calcitonin absorption. J. Pharm. Pharmacol. 52:611–617 (2000).
Y. H. Lee and P. J. Sinko. Oral delivery of salmon calcitonin. Adv. Drug Deliv. Rev. 42:225–238 (2000).
Y. Nakada, N. Awata, C. Nakamichi, and S. Goto. The effects of additives on the oral mucosal absorption of human calcitonin in rats. J. Pharmacobio-Dyn. 11:395–401 (1988).
S. J. Heiber, C. D. Ebert, S. C. Dave, K. Smith, S. W. Kim, and D. Mix. In-vivo buccal delivery of calcitonin. J. Control. Release 28:269–271 (1994).
H. H. Alur, J. D. Beal, S. I. Pather, A. K. Mitra, and T. P. Johnston. Evaluation of a novel, natural oligosaccharide gum as a sustained-release and mucoadhesive component of calcitonin buccal tablets. J. Pharm. Sci. 88:1313–1319 (1999).
T. Ogiso, M. Iwaki, T. Tanino, and T. Paku. Effectiveness of the elcatonin transdermal system for the treatment of osteoporosis and the effect of the combination of elcatonin and active vitamin D3 in rat. Biol. Pharm. Bull. 16:895–898 (1993).
E. Bonucci, P. Ballanti, P. A. Ramires, J. L. Richardson, and L. M. Benedetii. Prevention of ovariectomy osteopenia in rats after vaginal administration of Hyaff 11 microspheres containing salmon calcitonin. Calcif. Tissue Int. 56:274–279 (1995).
M. Baluom, D. I. Friedman, and A. Rubinstein. Absorption of calcitonin in the rat intestine by carbopol-containing submicron emulsions. Int. J. Pharm. 154:235–243 (1997).
N. N. Aldini, P. Caliceti, S. Lora, M. Fini, G. Giavaresi, M. Rocca, P. Torricelli, R. Giardino, and F. M. Veronese. Calcitonin release system in the treatment of experimental osteoporosis: Histomorphometric evaluation. J. Orthop. Res. 19:955–961 (2001).
H. E. Junginger, J. A. Hoogstraate, and J. C. Verhoef. Recent advances in buccal drug delivery and absorption-in vitro and in vivo studies. J. Control. Release 62:149–159 (1999).
Z. Cui and R. J. Mumper. Bi-layer disks for mucosal (genetic) immunization via the buccal route in rabbits. AAPS PharmSci 3(3) (2001).
Z. Cui and R. J. Mumper. Bilayer films for mucosal (genetic) Buccal Delivery of Calcitonin Using Thin Films 1905 immunization via the buccal route in rabbits. Pharm. Res. 19:947–953 (2002).
S. Jay, W. Fountain, Z. Cui, and R. J. Mumper. Transmucosal delivery of testosterone in rabbits using novel bi-layer mucoadhesive wax-film composite disks. J. Pharm. Sci. 91:2016–2024 (2002).
P. L. Ritger and N. A. Peppas. A simple equation for description of solute release II: Fickian and anomalous release from swellable devices. J. Control. Release 5:37–42 (1987).
P. J. Sinko, C. L. Smith, L. T. McWhorter, W. Stern, E. Wagner, and J. P. Gilligan. Utility of pharamacodynamic measures for assessing the oral bioavailability of peptides. 1. Administration of recombinant salmon calcitonin in rats. J. Pharm. Sci. 84:1374–1378 (1995).
R. S. Langer and N. A. Peppas. Present and future applications of biomaterials in controlled drug delivery systems. Biomaterials 2: 201–213 (1981).
A. Wade and P. J. Weller. Handbook of Pharmaceutical Excipients, 2nd ed., American Pharmaceutical Association, Washington, and The Pharmaceutical Press, London, 1994.
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Cui, Z., Mumper, R.J. Buccal Transmucosal Delivery of Calcitonin in Rabbits Using Thin-Film Composites. Pharm Res 19, 1901–1906 (2002). https://doi.org/10.1023/A:1021462012442
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DOI: https://doi.org/10.1023/A:1021462012442