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Effects of Formulation Variables on Lung Dosimetry of Albuterol Sulfate Suspension and Beclomethasone Dipropionate Solution Metered Dose Inhalers

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Abstract

The performance of pressurized metered dose inhalers (MDIs) is affected by formulation and device variables that impact delivered dose, aerodynamic particle size distribution, and consequently lung deposition and therapeutic effect. Specific formulation variables of relevance to two commercially available products—Proventil® HFA [albuterol sulfate (AS) suspension] and Qvar® [beclomethasone dipropionate (BDP) solution]—were evaluated to determine their influence on key performance attributes measured experimentally with in vitro cascade impaction studies. These commercial MDIs, utilized as model systems, provided mid-points for a design of experiments (DoE) plan to manufacture multiple suspension and solution MDI formulations. The experimental results were utilized as input variables in a computational dosimetry model to predict the effects of MDI formulation variables on lung deposition. For the BDP solution DoE MDIs, increased concentrations of surfactant oleic acid (0–2% w/w) increased lung deposition from 24 to 46%, whereas changes in concentration of the cosolvent ethanol (7–9% w/w) had no effect on lung deposition. For the AS suspension DoE MDIs, changes in oleic acid concentration (0.005–0.25% w/w) did not have significant effects on lung deposition, whereas lung deposition decreased from 48 to 26% as ethanol concentration increased from 2 to 20% w/w, and changes in micronized drug volumetric median particle size distribution (X50, 1.4–2.5 μm) increased deposition in the tracheobronchial airways from 5 to 11%. A direct correlation was observed between fine particle fraction and predicted lung deposition. These results demonstrate the value of using dosimetry models to further explore relationships between performance variables and lung deposition.

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Acknowledgements

Funding for this work was made possible, in part, by the Food and Drug Administration through grant 1U01FD004943-01. Views expressed in this publication do not necessarily reflect the official policies of the Department of Health and Human Services, nor does any mention of trade names, commercial practices, or organization imply endorsement by the US Government.

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Author notes

  1. Poonam Sheth

    Present address: Pearl Therapeutics, Durham, NC, USA

  2. Anthony J. Hickey

    Present address: RTI International, Research Triangle Park, NC, USA

  3. Jay T. Holt

    Present address: Aurobindo Pharma USA, Inc., Raleigh, NC, USA

  4. Bhawana Saluja

    Present address: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA

Authors and Affiliations

  1. Applied Research Associates, 8537 Six Forks Rd., Raleigh, NC, 27615, USA

    Jeffry D. Schroeter, Bahman Asgharian & Owen T. Price

  2. Cirrus Pharmaceuticals, Inc. (presently, Recipharm), Morrisville, NC, USA

    Poonam Sheth, Anthony J. Hickey & Jay T. Holt

  3. Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA

    Denise S. Conti & Bhawana Saluja

Authors
  1. Jeffry D. Schroeter
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  2. Poonam Sheth
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Correspondence to Jeffry D. Schroeter.

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Schroeter, J.D., Sheth, P., Hickey, A.J. et al. Effects of Formulation Variables on Lung Dosimetry of Albuterol Sulfate Suspension and Beclomethasone Dipropionate Solution Metered Dose Inhalers. AAPS PharmSciTech 19, 2335–2345 (2018). https://doi.org/10.1208/s12249-018-1071-7

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  • DOI: https://doi.org/10.1208/s12249-018-1071-7

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