Effect of chitosan on the intranasal absorption of salmon calcitonin in sheep.
The effects of a chitosan-based delivery system on the pharmacokinetics of intranasally administered salmon calcitonin (sCT) were investigated in a sheep model. In particular, the feasibility of producing a formulation with a comparable or improved bioavailability and/or less variability than the currently marketed nasal product (Miacalcin nasal spray, Novartis Pharmaceuticals) was assessed. A comparator (control) formulation comprising sCT solution was also tested. Sheep (n=6) were dosed intranasally according to a randomized crossover design. The intranasal sCT dose was 1100 IU (equivalent to approximately 17 IU kg-1). After completion of the nasal dosing legs, five of the sheep received 300 IU sCT (equivalent to approximately 5 IU kg-1) by subcutaneous injection to estimate relative bioavailability. After intranasal or subcutaneous dosing, serial blood samples were taken and plasma separated by centrifugation before measuring sCT concentrations by ELISA. Pharmacokinetic (non-compartmental) and statistical (analysis of variance or non-parametric alternative) analyses were performed. No systemic or local adverse effects were observed following intranasal or subcutaneous administration of sCT. The mean relative bioavailability of sCT from the chitosan solution was improved twofold compared with Miacalcin nasal spray and threefold compared with sCT control solution. Inter-animal variability in sCT absorption appeared to be lower with use of the chitosan-based solution compared with the control solution or commercial product. Based on the reported sheep data, a chitosan delivery system could offer the potential to significantly improve the intranasal absorption of sCT and reduce the variability in absorption. In the clinical setting, this may allow relatively lower doses of the drug to be given intranasally and/or lead to improvements in the efficacy or quality of intranasal therapy.
Hinchcliffe
Michael
M
Archimedes Development Ltd, Albert Einstein Centre, Nottingham Science & Technology Park, University Boulevard, Nottingham NG7 2TN, UK. michael.hinchcliffe@archimedespharma.com
Jabbal-Gill
Inderjit
I
Smith
Alan
A
D000277:Adjuvants, Pharmaceutic / Q000494:pharmacology*; D000281:Administration, Intranasal; D000818:Animals; D001682:Biological Availability; D002116:Calcitonin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D048271:Chitosan / Q000494:pharmacology*; D018592:Cross-Over Studies; D004797:Enzyme-Linked Immunosorbent Assay; D008297:Male; D009297:Nasal Mucosa / Q000378:metabolism*; D012756:Sheep
D000277:Adjuvants, Pharmaceutic; C028815:salmon calcitonin; D002116:Calcitonin; D048271:Chitosan