Sildenafil 4.0-Integrated Synthetic Chemistry, Formulation and Analytical Strategies Effecting Immense Therapeutic and Societal Impact in the Fourth Industrial Era.

Andreas Ouranidis,Catherine K Markopoulou,Constantinos K Zacharis,Anastasia Tsiaxerli,Nikolaos Kostomitsopoulos,Elisavet Vardaka,Ioannis Nicolaou,Anna-Bettina Haidich,Dimitris Hatzichristou,Kyriakos Kachrimanis

doi:10.3390/ph14040365

Abstract

Sildenafil is a potent selective, reversible inhibitor of phosphodiesterase type 5 (PDE5) approved for the treatment of erectile dysfunction and pulmonary arterial hypertension. Whilst twenty years have passed since its original approval by the US Food and Drug Administration (USFDA), sildenafil enters the fourth industrial era catalyzing the treatment advances against erectile dysfunction and pulmonary hypertension. The plethora of detailed clinical data accumulated and the two sildenafil analogues marketed, namely tadalafil and vardenafil, signify the relevant therapeutic and commercial achievements. The pharmacokinetic and pharmacodynamic behavior of the drug appears complex, interdependent and of critical importance whereas the treatment of special population cohorts is considered. The diversity of the available formulation strategies and their compatible administration routes, extend from tablets to bolus suspensions and from per os to intravenous, respectively, inheriting the associated strengths and weaknesses. In this comprehensive review, we attempt to elucidate the multi-disciplinary elements spanning the knowledge fields of chemical synthesis, physicochemical properties, pharmacology, clinical applications, biopharmaceutical profile, formulation approaches for different routes of administration and analytical strategies, currently employed to guide the development of sildenafil-based compositions.

Highlights

IntroductionFrom a serendipitous discovery involving an experimental hypertension and angina medication to the first oral treatment indication of erectile dysfunction, the development of sildenafil (widely recognized by the name of its commercial blockbuster formulationViagra® ), is unique
From a serendipitous discovery involving an experimental hypertension and angina medication to the first oral treatment indication of erectile dysfunction, the development of sildenafil, is unique
In the case of ritonavir the plasma concentration of sildenafil and area under the curve (AUC) was increased by 300% and 11-fold respectively, a combinatory effect attributed to the parallel inhibition of CYP3A4 and CYP2C9 metabolic routes

Summary

Introduction

From a serendipitous discovery involving an experimental hypertension and angina medication to the first oral treatment indication of erectile dysfunction, the development of sildenafil (widely recognized by the name of its commercial blockbuster formulationViagra® ), is unique. From a serendipitous discovery involving an experimental hypertension and angina medication to the first oral treatment indication of erectile dysfunction, the development of sildenafil Sildenafil is a potent selective, reversible inhibitor of phosphodiesterase type 5 (PDE5) repurposed for the treatment of pulmonary arterial hypertension (PAH). Pharmaceuticals 2021, 14, 365 expression in the lung tissue and the proven vasodilatory activity of sildenafil, researchers rationally considered the drug’s possible therapeutic effect against pulmonary fibrosis, a complication of the COVID-19 disease [2,3,4]. The major metabolite derived by N-demethylation, is N-desmethylsildenafil (UK-103,320) and exhibits approximately 50% in vitro activity in PDE5 inhibition, constituting the 40%

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