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Determination of the Relative Bioavailability of Salbutamol to the Lungs Following Inhalation from Dry Powder Inhaler Formulations Containing Drug Substance Manufactured by Supercritical Fluids and Micronization

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Abstract

Purpose

The relative lung bioavailability of salbutamol sulfate particles produced using supercritical fluids (SEDS™) and delivered by dry powder inhaler (DPI) was compared with the performance of a conventional micronized drug DPI using the same device design (Clickhaler™, Innovata Biomed).

Materials and Methods

Twelve healthy volunteers and 11 mild asthmatic patients completed separate four-way randomised cross-over studies, assessing the relative bioavailability of salbutamol sulfate (urinary excretion method), formulated as SEDS™ particles (three batches) and micronized particles (Asmasal™ inhaler, UCB Pharma Ltd). Post-treatment improvements in patient lung function were assessed by measuring FEV1. Physicochemical evaluation of the three SEDS™ batches revealed inter-batch differences in particle size and shape.

Results

There was no significant difference in the relative lung bioavailability of salbutamol and its bronchodilator response between the best performing SEDS™ formulation and the Asmasal™ inhaler in volunteers and patients, respectively. SEDS™ salbutamol sulfate showing wafer like morphology gave greater fine particle dose, relative lung bioavailability and enhanced bronchodilation compared to other SEDS™ batches containing elongated particles.

Conclusions

Active Pharmaceutical Ingredient (API) manufactured using supercritical fluids and delivered by DPI can provide similar lung bioavailability and clinical effect to the conventional micronized commercial product. Product performance is however notably influenced by inter-batch differences in particle characteristics.

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Abbreviations

ACI:

Andersen cascade impactor

ANOVA:

Analysis of variance

API:

Active pharmaceutical ingredient

DPI (s):

Dry powder inhaler(s)

FEV1 :

Forced expiratory volume in 1 s

FPD:

Fine particle dose

GSD:

Geometric standard deviation

HPLC:

High performance liquid chromatography

MMAD:

Mass median aerodynamic diameter

RSD:

Relative standard deviation

SD:

Standard deviation

SEDS™:

Solution enhanced dispersion by supercritical fluids

SEM:

Scanning electron microscopy

TOF:

Time of flight

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Acknowledgements

The authors would like to thank the Engineering and Physical Sciences Research Council (EPSRC) in the UK for funding this research jointly through a case award with GlaxoSmithKline (GSK). We would also like to thank DMV, GSK, Nektar Therapeutics, ML Laboratories and Medeva Pharmaceutical Ltd for supply of materials and componentry.

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Author notes

  1. Ian Wong

    Present address: School of Pharmacy, University of London, 29/39 Brunswick Square, London, WC1N 1AX, UK

Authors and Affiliations

  1. Institute of Pharmaceutical Innovation, University of Bradford, Bradford, BD7 1DP, UK

    Catherine H. Richardson, Marcel de Matas & Henry Chrystyn

  2. School of Pharmacy, University of Bradford, Bradford, BD7 1DP, UK

    Catherine H. Richardson, Ian Wong & Henry Chrystyn

  3. Airedale General Hospital, Keighley, BD20 6TD, UK

    Harold Hosker & Rahul Mukherjee

Authors
  1. Catherine H. Richardson
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  2. Marcel de Matas
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  3. Harold Hosker
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  4. Rahul Mukherjee
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  5. Ian Wong
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  6. Henry Chrystyn
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Correspondence to Marcel de Matas.

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Richardson, C.H., de Matas, M., Hosker, H. et al. Determination of the Relative Bioavailability of Salbutamol to the Lungs Following Inhalation from Dry Powder Inhaler Formulations Containing Drug Substance Manufactured by Supercritical Fluids and Micronization. Pharm Res 24, 2008–2017 (2007). https://doi.org/10.1007/s11095-007-9328-y

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  • DOI: https://doi.org/10.1007/s11095-007-9328-y

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