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Design of Inhalable Solid Dosage Forms of Budesonide and Theophylline for Pulmonary Combination Therapy

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  • Theme: Paul Myrdal Memorial Issue - Pharmaceutical Formulation and Aerosol Sciences
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Abstract

Corticosteroid resistance poses a major challenge to effective treatment of chronic obstructive pulmonary diseases. However, corticosteroid resistance can be overcome by co-administration of theophylline. The aim of this study was to formulate the corticosteroid budesonide with theophylline into inhalable dry powders intended for pulmonary combination therapy. Four types of spray-dried powders were prepared: (i) budesonide and theophylline co-dissolved and processed using a 2-fluid nozzle spray drier, (ii) budesonide nanocrystals and dissolved theophylline co-dispersed and processed using a 2-fluid nozzle spray drier, (iii) dissolved budesonide and dissolved theophylline processed using a 3-fluid nozzle spray drier, and (iv) budesonide nanocrystals and dissolved theophylline processed using a 3-fluid nozzle spray drier. Spray drying from the solutions resulted in co-amorphous (i) and partially amorphous powders (iii), whereas spray drying of the nanosuspensions resulted in crystalline products (ii and iv). Even though budesonide was amorphous in (i) and (iii), it failed to exhibit any dissolution advantage over the unprocessed budesonide. In contrast, the dissolution of budesonide from its nanocrystalline formulations, i.e., (ii) and (iv), was significantly higher compared to a physical mixture or unprocessed budesonide. Furthermore, the spray-dried powders obtained from the 2-fluid nozzle spray drier, i.e., (i) and (ii), exhibited co-deposition of budesonide and theophylline at the same weight ratio in the aerodynamic assessment using the New Generation Impactor. In contrast, the depositions of budesonide and theophylline deviated from the starting weight ratio in the aerodynamic assessment of spray-dried powders obtained from the 3-fluid nozzle spray drier, i.e., (iii) and (iv). Based on these results, the powders spray-dried from the suspension by using the 2-fluid nozzle spray drier, i.e., (ii), offered the best formulation properties given the physically stable crystalline solid-state properties and the co-deposition profile.

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Acknowledgments

The study was funded by a PhD stipend of the Faculty of Health and Medical Sciences, University of Copenhagen, Denmark, and the National Natural Science Foundation of China (No. 81573380). We acknowledge the Core Facility for Integrated Microscopy, Faculty of Health and Medical Sciences, University of Copenhagen, for the morphology study of the spray-dried particles. We thank the Danish Agency for Science, the Technology and Innovation for funding the Zetasizer Nano ZS and Novo Nordisk for supporting the Next Generation Impactor. We gratefully acknowledge PhD students Junwei Wang and Yongquan Li from the University of Copenhagen for valuable scientific discussion and technical support.

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Authors and Affiliations

  1. Department of Pharmacy, Faculty of Health and Medical Science, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark

    Donglei Leng, Korbinian Löbmann, Kaushik Thanki, Thomas Rades, Camilla Foged & Mingshi Yang

  2. Department of Pharmacy, University of Oslo, P.O. Box 1068, Blindern, N-0316, Oslo, Norway

    Eric Ofosu Kissi

  3. Institut Galien Paris-Sud, UMR CNRS 8612, Faculté de Pharmacie, Univ Paris-Sud, 5 rue J.B. Clément, 92296, Châtenay-Malabry Cedex, France

    Elias Fattal

  4. Wuya College of Innovation, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang, 110016, China

    Mingshi Yang

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  1. Donglei Leng
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Correspondence to Donglei Leng.

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Leng, D., Kissi, E.O., Löbmann, K. et al. Design of Inhalable Solid Dosage Forms of Budesonide and Theophylline for Pulmonary Combination Therapy. AAPS PharmSciTech 20, 137 (2019). https://doi.org/10.1208/s12249-019-1344-9

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