Rational Development of a Carrier-Free Dry Powder Inhalation Formulation for Respiratory Viral Infections via Quality by Design: A Drug-Drug Cocrystal of Favipiravir and Theophylline.

Si Nga Wong,Ruipeng Chen,Shing Fung Chow,Nicholas Blagden,Jingwen Weng,Richard Lakerveld,Ignatius Ip,Ian J Scowen,Richard Telford

doi:10.3390/pharmaceutics14020300

Abstract

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 μm and an FPF of 79.3%, suitable for deep lung delivery with no in vitro cytotoxicity observed in A549 cells.

Highlights

The pandemic caused by coronavirus 2 (SARS-CoV-2), which results in a severe acute respiratory syndrome, has raised an unprecedentedly high level of awareness towards influenza viral infections in history and resulted in over 2.6 million deaths according to the WHO as of March 2021 [1]
The cocrystals remained stable at 60 °C for 1 month, without phase transformation detected during storage based on the Differential scanning calorimetry (DSC) thermogram (Figure S2)
The novelty of this work lies in demonstrating that spray drying is a robust particle engineering technique for producing cocrystal as an inhalable FAV-THP dry powder formulation

Summary

Introduction

The pandemic caused by coronavirus 2 (SARS-CoV-2), which results in a severe acute respiratory syndrome, has raised an unprecedentedly high level of awareness towards influenza viral infections in history and resulted in over 2.6 million deaths according to the WHO as of March 2021 [1]. [2], individuals with certain underlying medical conditions, chronic lung diseases (e.g., chronic obstructive pulmonary disease (COPD) and asthma), have been identified to show higher risk of being infected with SARS-CoV-2 and developing more severe pneumonia and acute respiratory failure, which are likely to be the leading causes of death. The impaired lung function and marked airway inflammation induced by COPD/asthma are considered as poor prognostic factors when SARS-CoV-2 infection is presented [13]. Stabilizing such conditions is a crucial treatment strategy to minimize the infection risk. These highlight an urgent need to establish an effective pharmacological intervention in preventing and treating viral respiratory infections for these vulnerable patient groups

Objectives

Methods

Results

Conclusion