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

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.

Improvement in Inhalation Properties of Theophylline and Levofloxacin by Co-Amorphization and Enhancement in Its Stability by Addition of Amino Acid as a Third Component

“…56 Recent research on inhalable dry powder formulations developed multicomponent formulations with various prom-inent merits. 57,58 In particular, inhalable co-crystal formulations are expected to simultaneously deliver multicomponent drugs to the same position in the lungs. 59 The deposited proportion of THE and LEV on each stage in Figure 7b displays similar patterns between THE and LEV.…”

“…Although carrier-based methods were commonly considered normal inhalable formulations, it is difficult to simultaneously deliver multiple drugs to the same position in the lungs using this method . Recent research on inhalable dry powder formulations developed multicomponent formulations with various prominent merits. , In particular, inhalable co-crystal formulations are expected to simultaneously deliver multicomponent drugs to the same position in the lungs . The deposited proportion of THE and LEV on each stage in Figure b displays similar patterns between THE and LEV.…”

Discovery of new cocrystals beyond serendipity: lessons learned from successes and failures

“…In the context of cocrystallization, these techniques have recently emerged as promising strategies for fabricating kinetically stable and energetic cocrystals, 18,[99][100][101][102] which excel in light of their simplicity, scalability, and capability to achieve precise control over particle attributes for inhaled drug delivery purposes. [103][104][105][106] Remarkably, Alhalaweh et al serendipitously discovered a 1 : 1 urea-succinic acid cocrystal using spray drying in either water or 2-propanol, where the cocrystal formation was kinetically mediated by the amorphous state of the materials. 107,108 The urea-succinic acid cocrystal exhibits stoichiometric diversity that could exist in both 1 : 1 and 2 : 1 molar ratios.…”

Pulmonary drug delivery: an effective and convenient delivery route to combat COVID-19

“…Focused on increasing drug solubility and reducing the dose, a co crystal of favipiravir and theophylline was produced by spray drying method. MMAD and FPF were suitable for pulmonary delivery and the crystals presented no toxic effects on A549 cell line [ 58 ]. There is also a hypothesis that combined pulmonary delivery of favipiravir and tocilizumab (antibody against interleukin-6 receptor that will be covered in the next pages) in a mucoadhesive nanostructured carrier would prolong drug retention in the alveolar region and control drug release in the disease site leading to higher efficacy [ 59 ].…”