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A Comparison of the Pulmonary Bioavailability of Powder and Liquid Aerosol Formulations of Salmon Calcitonin

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Abstract

Purpose

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.

Methods

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.

Results

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%.

Conclusion

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.

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Abbreviations

ACI:

Andersen impactor

AUC:

area under the curve

BAV:

bioavailability

C:

central

DCU:

dose content uniformity

GSD:

geometric standard deviation

HPLC:

high pressure liquid chromatograph

MMAD:

mass median aerodynamic diameter

P:

peripheral

P/C:

ratio, peripheral to central ratio

PDS:

Nektar pulmonary delivery system

PSD:

particle size distribution

sCal:

salmon calcitonin

SD:

standard deviation

USP:

united States Pharmacopeia

VMD:

volume median diameter

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Authors and Affiliations

  1. Nektar Therapeutics, San Carlos, CA, 94070, USA

    Andrew Clark & Mei-chang Kuo

  2. Pharmaceutical Profiles Ltd., Nottingham, England

    Stephen Newman, Peter Hirst, Gary Pitcairn & Matt Pickford

  3. Scientific Consultant, Nottingham, England

    Stephen Newman

  4. Vectura Group plc, Nottingham, England

    Peter Hirst

  5. Pfizer Global R&D, Sandwich, Kent

    Gary Pitcairn

  6. AstraZeneca, Loughborough, England

    Matt Pickford

Authors
  1. Andrew Clark
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  2. Mei-chang Kuo
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  3. Stephen Newman
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  4. Peter Hirst
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  5. Gary Pitcairn
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  6. Matt Pickford
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Correspondence to Andrew Clark.

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Clark, A., Kuo, Mc., Newman, S. et al. A Comparison of the Pulmonary Bioavailability of Powder and Liquid Aerosol Formulations of Salmon Calcitonin. Pharm Res 25, 1583–1590 (2008). https://doi.org/10.1007/s11095-008-9547-x

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  • DOI: https://doi.org/10.1007/s11095-008-9547-x

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