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01-12-2003 | Clinical Investigations

Intranasal Delivery of PEGylated Salmon Calcitonins: Hypocalcemic Effects in Rats

Authors: K. C. Lee, M. -O. Park, D. H. Na, Y. S. Youn, S. D. Lee, S. D. Yoo, H. S. Lee, P. P. DeLuca

Published in: Calcified Tissue International | Issue 6/2003

Abstract

To evaluate the hypocalcemic effect of polyethylene gtycol-conjugated salmon calcitonins (PEG-sCT) in rats, mono-PEGylated sCTs (mono-PEG-sCTs) and unmodified sCT were administered via the intranasal route and serum calcium levels were measured by colorimetric assay using o-cresolphthalein. Mono-PEG-sCTs were prepared with different sizes of succinimidyl succinate monomethoxy PEG molecules (PEG_2K, PEG_5K, PEG_12K) and characterized by HPLC and MALDI-TOF mass spectrometry. Nasal instillation of mono-PEG_2K-sCT at a dose of 2 IU/kg resulted in sustained reduction in serum calcium levels over 8 hr, with a maximum reduction (% max_d) of 13% after 6 hr of application. Whereas unmodified sCT showed a transient decrease in serum calcium levels with the maximum reduction (5%) observed after 30 min of administration. The overall reductions in serum calcium levels expressed as the net change in AUC relative to control in 8 hr were 11.9 ± 0.2, 4.6 ± 0.7, and 2.6 ± 0.7% for mono-PEG_2K-, mono-PEG_5K-, and mono-PEG_12K-sCT, respectively, compared to 3.2 ± 0.6% for unmodified sCT. The relative bioavailability of nasally administered 2 IU/kg of mono-PEG_2K-sCT was approximately 4-fold higher than nasally administrated unmodified sCT, and the absolute bioavailability was approximately 91% of intravenously injected sCT in 8 hr. It can be concluded that the intranasal absorption of mono-PEG-sCTs was inversely related to the molecular weights of the PEG attached. Of the PEGylated sCTs examined, mono-PEG_2K-sCT showed the most pronounced hypocalcemic effect. Therefore the intranasal application would probably be an alternative route of administration for mono-PEG-sCTs in achieving sustained calcium-lowering effects.

Chien, YW, Chang, SF 1987Intranasal drug delivery for systemic medications.Crit Rev Ther Drug Carrier Syst467194PubMed

Chien, YW, Su, KSE, Chang, SF 1989Intranasal delivery of peptide/protein drugs, intranasal delivery of nonpeptide molecules, intranasal delivery of diagnostic drugs.Chien, YWSu, KSEChang, SF eds. Nasal systemic drug delivery.Marcel DekkerNew York89298

Pontiroli, AE, Calderara, A, Pozza, G 1989Intranasal drug delivery: potential advantages and limitations from a clinical pharmacokinetics perspective.Clin Pharm17299307CrossRef

Illum, L 1992Nasal delivery of peptides, factors affecting nasal absorption.Crommelin, DJAMidha, KK eds. Topics in pharmaceutical sciencesMedpharm ScientificStuttgart7182

Eppstein, DA, Longenecker, JP 1988Alternative delivery systems for peptides and proteins as drugs.Crit Rev Ther Drug Carrier Syst599139PubMed

Lee, VHL, Yamamoto, A 1990Penetration and enzymic barriers to peptide and protein absorption.Adv Drug Deliv Rev4171207CrossRef

Banga, AK, Chien, YW 1988Systemic delivery of therapeutic peptides and proteins.Int J Pharm481550CrossRef

McMartin, C, Hutchinson, LEF, Hyde, R, Peters, DE 1987Analysis of structural requirement for the absorption of drugs and macromolecules from the nasal cavity.J Pharm Sci76535540CrossRefPubMed

Reginster, JY, Albert, A, Lecart, MP, Lambelin, P, Deroisy, R, Fontaine, MA, Franchimont, P 19871-Year controlled randomised trial of prevention of early post-menopausal bone loss by intranasal calcitonin.Lancet214811483CrossRefPubMed

10.

Reginster, JY, Albert, A, Franchimont, P 1985Salmon-calcitonin nasal spray in Paget’s disease of bone: preliminary results in five patients.Calcif Tissue Int37577580CrossRefPubMed

11.

Lee, WA, Ennis, RD, Longenecker, JP, Bengtsson, P 1994The bioavailability of intranasal salmon calcitonin in healthy volunteers with and without a permeation enhancer.Pharm Res11747750CrossRefPubMed

12.

Overgaard, K, Agnusdei, D, Hansen, MA, Maioli, E, Christiansen, C, Gennari, C 1991Dose response bioactivity and bioavailability of salmon calcitonin in premenopausal and postmenopausal women.J Clin Endocrinol Metab72344349CrossRefPubMed

13.

Lee, KC, Moon, SC, Park, MO, Lee, JT, Na, DH, Yoo, SD, Lee, HS, DeLuca, PP 1999Isolation, characterization and stability of positional isomers of mono-PEGylated salmon calcitonins.Pharm Res16818823

14.

Lee, KC, Tak, KK, Park, MO, Lee, JT, Woo, BH, Yoo, SD, Lee, HS, DeLuca, PP 1999Preparation and characterization of polyethylene glycol modified salmon calcitonins.Pharm Devel Technol4269275CrossRef

15.

Lee, KC, Soltis, EE, Newman, PW, Burton, KW, Mehta, RC, DeLuca, PP 1991In vivo assessment of salmon calcitonin sustained release from biodegradable microspheres.J Control Rel17199206CrossRef

16.

Hirai, S, Yasbiki, T, Mima, H 1981Effect of surfactants to nasal absorption of insulin in rats.Int J Pharm9165172CrossRef

17.

Schipper, NG, Romeijn, SG, Verhoef, J, Merkus, FW 1994Hypocalcemic effect of salmon calcitonin following single and repeated nasal and intravenous administration in young rabbits.Calcif Tissue Int545055CrossRefPubMed

18.

Behl, CR, Pimplaskar, HK, Sileno, AP, Xia, WJ, deMeireles, JC, Romeo, VD 1998Optimization of systemic nasal drug delivery with pharmaceutical excipients.Adv Drug Del Rev29117133CrossRef

19.

Deftos, LJ, Nolan, JJ, Seely, BL, Clopton, PL, Cote, GJ, Whitham, CL, Florek, LJ, Christensen, TA, Hill, MR 1997Intrapulmonary drug delivery of salmon calcitonin.Calcif Tissue Int61345347CrossRefPubMed

20.

Azria, M 1989The calcitonins: physiology and pharmacology.KargerBasel

21.

Morimoto, K, Miyazaki, M, Kakemi, M 1995Effects of proteolytic enzyme inhibitors on nasal absorption of salmon calcitonin in rats.Int J Pharm11318CrossRef

22.

Lang, SR, Staudenmann, W, James, P, Manz, H-J, Kessler, R, Galli, B, Moser, H-P, Rummelt, A, Merkle, HP 1996Proteolysis of human calcitonin in excised bovine nasal mucosa: elucidation of the metabolic pathway by liquid secondary ionization mass spectrometry (LSIMS) and matrix-assisted laser desorption ionization mass spectrometry (MALDI).Pharm Res1316791685CrossRefPubMed

23.

Donovan, MD, Flynn, GL, Amidon, GL 1990Absorption of polyethylene glycols 600 through 2000: the molecular weight dependence of gastrointestinal and nasal absorption.Pharm Res7863868CrossRefPubMed

Title: Intranasal Delivery of PEGylated Salmon Calcitonins: Hypocalcemic Effects in Rats
Authors: K. C. Lee
M. -O. Park
D. H. Na
Y. S. Youn
S. D. Lee
S. D. Yoo
H. S. Lee
P. P. DeLuca
Publication date: 01-12-2003
Publisher: Springer New York
Published in: Calcified Tissue International / Issue 6/2003
Print ISSN: 0171-967X
Electronic ISSN: 1432-0827
DOI: https://doi.org/10.1007/s00223-002-0034-9

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