Pulmonary Delivery of Favipiravir Formulation Using Soft-Mist Inhaler For COVID-19
Ayca Yildiz-Pekoz1, Ozlem Akbal-Dagistan1, Hanan Fael1, Meltem Culha1, Aybige Erturk1,9, Nur Sena Basarir1, Gokben Sahin1,10, Mustafa Sevim2, Semiha Leyla Sen2, Mert Kaskal3, Muge Serhatli5, Gamze Cakirca5,6, Saban Tekin5,7, Lutfiye Mulazimoglu Durmusoglu8, Berrak Yegen2
1Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Istanbul, Türkiye
2Marmara University, School of Medicine, Basic Medical Sciences, Department of Physiology, Istanbul, Türkiye
3Marmara University, School of Medicine, Internal Medical Sciences, Department of Medical Pharmacology, Istanbul, Türkiye
4TUBITAK Marmara Research Center-MRC, Life Sciences, Medical Biotechnology (Marmara Research Center (MRC), 41470, Gebze-Kocaeli, Türkiye
5Molecular Biology and Genetics, Institute of Natural and Applied Sciences, Gebze Technical University, 41400, Gebze, Kocaeli, Türkiye
6University of Health Sciences, Hamidiye Faculty of Medicine, Department of Basic Medical Sciences, Medical Biology, Istanbul, Türkiye
7Marmara University, School of Medicine, Department of Infectious Diseases, Istanbul, Türkiye
8Istinye University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Istanbul, Türkiye
9Trakya University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Istanbul, Türkiye
Summary
Favipiravir, an RNA-dependent RNA polymerase (RdRp) inhibitor, is one of the repurposed drugs that were used for patients in the COVID-19 pandemic. Although favipiravir was shown to be effective against SARS-CoV-2 virus, the expected performance was not achieved in the clinic. This was mainly due to the poor accumulation of favipiravir in the lung tissue following conventional administration. For our study, we proposed a theory that favipiravir is an ideal candidate for pulmonary delivery and developed the first suitable oral inhalation formulation with a high reduction in the dosage using soft-mist inhalers. Local lung targeting through inhalation of favipiravir is not only expected to overcome the low bioavailability of oral administration, but also aims to achieve a higher drug concentration in the lung tissues. Favipiravir pH-solubility profile was constructed and the impact of cyclodextrin additives on its solubility was investigated through phase solubility diagram. Preclinical studies were carried out on both sexes of rats, showing significant local lung accumulation and safe oxidative stress parameters. Ex vivo studies were carried out with xCELLigence RTCA MP device and proved that an inhalation dose of 2 mg/ml of favipiravir to be an effective dose against COVID-19 virus when given with soft-mist inhalers. These studies are noteworthy in terms of developing an alternative dosage form to the product available in the market for treatment of diseases caused not only by SARS-CoV-2, but also other airborne viruses.
Key Message
The significance of the research performed here is the output of a drug candidate that can be marketed within a short time span. Furthermore, we have shown that the favipiravir drug molecule was abandoned too early and the potential of this molecule lies within inhalation formulation.