A Comparison of the Pulmonary Bioavailability of Powder and Liquid Aerosol Formulations of Salmon Calcitonin
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To compare the pulmonary pharmacokinetics and relative bioavailability of salmon calcitonin delivered as aqueous droplets, pH 6.6 and pH 4.8 with that of a spray dried powder in healthy volunteers.
Spray dried powders (1.6 μm [GSD 2.1]) containing 5% by wt. sCal, 6.25% human serum albumin, 73.55% mannitol and 15% citric acid/sodium citrate were prepared using a Buchi model 190 spray drier. Aqueous solutions were prepared by dissolving the spray dried powder at a sCal concentration of 1.25 mg/ml, pH was adjusted using 21 mM sodium hydroxide. Aerosols were delivered as part of a 4 way cross-over study to 16 healthy volunteers. The Nektar pulmonary delivery device was used to deliver the dry powder aerosol. A Salter nebulizer controlled by a Rosenthal dosimeter was used to deliver the aqueous aerosols. Miacalcin™ injection was used as the subcutaneous control. Dose delivered to the lung was estimated by gamma scintigraphy. Plasma concentrations of sCal were measured using a radioimmunoassay.
Aerosol size distributions were matched, 3.3 μm MMAD and ∼2.2 GSD. Inhaled flow rates were similar, although not equal, 5.8 and ∼9.8 l/min respectively for dry powder and liquid inhalations. Lung doses of sCal ranged from 53 to 88 μgm, peripheral lung doses from 25 to 51 μgm. Pharmacokinetic profiles and lung bioavailability relative to subcutaneous injection for all formulations were similar (not statistically significantly different p > 0.05), relative lung bioavailability ranged from 11% to 18%, estimates of relative bioavailability based on peripheral lung dose ranged from 20% to 33%.
The study showed no difference in pharmacokinetic profiles between the various aerosol dosage forms. pH of the aqueous solutions did not affect kinetics or relative bioavailability.
Key wordsaerosol bioavailability deposition dry powder nebulizer salmon calcitonin
area under the curve
dose content uniformity
geometric standard deviation
high pressure liquid chromatograph
mass median aerodynamic diameter
ratio, peripheral to central ratio
Nektar pulmonary delivery system
particle size distribution
united States Pharmacopeia
volume median diameter
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