Date of Award
Doctor of Philosophy in Pharmaceutical Sciences
Thomas E. Needham
The nasal administration of drugs, particularly peptides, is very beneficial but like other mucosal routes, suffers from low bioavailability for the higher molecular weight compounds. The nasal bioavailability of peptides and proteins is influenced by the dosage form as well as the devices used for administration. In the present study an effort was made to investigate the effect of formulation and device variables on the intranasal delivery and absorption of salmon calcitonin (sCT). The formulations were designed as nasal sprays with viscosity of 1 and 76 cps using methylcellulose as a viscosity enhancing agent at 0 and 1% w/w; tonicity of 100 mOsm, 300 mOsm and 600 mOsm using sodium chloride as a tonicity adjusting agent; an acidic phospholipid, Dimyristoylphosphatidylglycerol (DMPG), as an absorption enhancer at 1% w/w and chlorobutanol as the preservative. The formulations were investigated for viscosity by using a cone and plate viscometer and for droplet size distribution with a Malvern laser sizer. The selected formulations were delivered to the nasal cavity of healthy male New Zealand rabbits using a commercially available metered spray pump and a prototype device, nasal micron spray pump, to facilitate a uniform distribution of the spray in the nasal cavity. The components of the devices, mechanism of pump and actuator design were evaluated for dose accuracy as well as their ability to generate a uniform distribution of spray in the nasal cavity. A full factorial design with tonicity at three levels, viscosity at two levels and concentration of enhancer at two levels was used as the experimental design. Serum levels of sCT were determined using a double antibody radioimrnunoassay. The area under the curve (AUC) and bioavailability were determined using pharrnacokinetic software MKDATA. The pharmacodynamic effect of salmon calcitonin of lowering of calcium was measured, by complexation with arsenazo III, using a visible spectrophotometric technique at 650 nm. The data was analyzed using ANOVA and the comparisons among the treatments were performed using Scheffe's multiple comparison analysis and Fisher's least significance test. Deviation from isotonicity (300 mOsm) enhanced the intranasal bioavailability of sCT by 4-5 fold while the addition of DMPG at a concentration of 1% w/w doubled the bioavailability. Variation in the viscosity of formulations did not influence the bioavailability of salmon calcitonin. The data was interpreted using response surface methodology (RSM) with canonical analysis parameters demonstrating that optimum formulations could be designed.
Dua, Ramneik, "The Influence of Formulation and Device Variables on the Intransasal Absorption of Salmon Calcitonin" (1995). Open Access Dissertations. Paper 181.