AAPS PharmSciTech

, 20:137 | Cite as

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

  • Donglei LengEmail author
  • Eric Ofosu Kissi
  • Korbinian Löbmann
  • Kaushik Thanki
  • Elias Fattal
  • Thomas Rades
  • Camilla Foged
  • Mingshi Yang
Research Article Theme: Paul Myrdal Memorial Issue - Pharmaceutical Formulation and Aerosol Sciences
Part of the following topical collections:
  1. Theme: Paul Myrdal Memorial Issue - Pharmaceutical Formulation and Aerosol Sciences


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.


pulmonary administration spray drying inhalable dry powder 2-fluid nozzle 3-fluid nozzle 



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.

Supplementary material

12249_2019_1344_MOESM1_ESM.docx (66 kb)
ESM 1 (DOCX 66 kb)


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Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Donglei Leng
    • 1
    Email author
  • Eric Ofosu Kissi
    • 2
  • Korbinian Löbmann
    • 1
  • Kaushik Thanki
    • 1
  • Elias Fattal
    • 3
  • Thomas Rades
    • 1
  • Camilla Foged
    • 1
  • Mingshi Yang
    • 1
    • 4
  1. 1.Department of Pharmacy, Faculty of Health and Medical ScienceUniversity of CopenhagenCopenhagenDenmark
  2. 2.Department of PharmacyUniversity of OsloOsloNorway
  3. 3.Institut Galien Paris-Sud, UMR CNRS 8612, Faculté de PharmacieUniv Paris-SudChâtenay-Malabry CedexFrance
  4. 4.Wuya College of InnovationShenyang Pharmaceutical UniversityShenyangChina

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