Journal
PHARMACEUTICS
Volume 14, Issue 2, Pages -Publisher
MDPI
DOI: 10.3390/pharmaceutics14020300
Keywords
cocrystal screening; inhalable cocrystal; drug-drug cocrystal; antiviral cocrystal; reformulation; quality-by-design; SARS-CoV-2; improved pharmaceutical properties
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Funding
- Li Ka Shing Faculty of Medicine at the University of Hong Kong [202007002, 104006162]
- Health@InnoHK program of the Innovation and Technology Commission of the Hong Kong SAR government
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This study developed a carrier-free inhalable dry powder formulation containing a favipiravir-theophylline cocrystal via spray drying, providing an alternative treatment strategy for individuals with concomitant respiratory infections and chronic obstructive pulmonary disease/asthma. The optimized formulation showed suitable particle size for deep lung delivery with no in vitro cytotoxicity observed in cell experiments.
Formulating pharmaceutical cocrystals as inhalable dosage forms represents a unique niche in effective management of respiratory infections. Favipiravir, a broad-spectrum antiviral drug with potential pharmacological activity against SARS-CoV-2, exhibits a low aqueous solubility. An ultra-high oral dose is essential, causing low patient compliance. This study reports a Quality-by-Design (QbD)-guided development of a carrier-free inhalable dry powder formulation containing a 1:1 favipiravir-theophylline (FAV-THP) cocrystal via spray drying, which may provide an alternative treatment strategy for individuals with concomitant influenza infections and chronic obstructive pulmonary disease/asthma. The cocrystal formation was confirmed by single crystal X-ray diffraction, powder X-ray diffraction, and the construction of a temperature-composition phase diagram. A three-factor, two-level, full factorial design was employed to produce the optimized formulation and study the impact of critical processing parameters on the resulting median mass aerodynamic diameter (MMAD), fine particle fraction (FPF), and crystallinity of the spray-dried FAV-THP cocrystal. In general, a lower solute concentration and feed pump rate resulted in a smaller MMAD with a higher FPF. The optimized formulation (F1) demonstrated an MMAD of 2.93 mu m and an FPF of 79.3%, suitable for deep lung delivery with no in vitro cytotoxicity observed in A549 cells.
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