From Oral to Sublingual: A Redefined Avanafil Tablet with a Breakthrough in Bioavailability and First-Pass Metabolism Avoidance

Abstract

Introduction

Avanafil (AVA) is a very efficient phosphodiesterase type 5 inhibitor for the treatment of erectile dysfunction. However, it has limited bioavailability when taken orally and considerable first-pass metabolism. Enhancing its solubility and choosing an alternative delivery route may enhance its effectiveness and duration of action.

Methods

Eight complex formulations were elaborated and analyzed at various ratios using different polyethylene glycols and hydroxypropyl-beta-cyclodextrin (HP-β-CD). Sublingual tablets containing AVA were designed and optimized using the Quality-bydesign approach. The tablets’ pre-compression and post-compression properties were evaluated. The in-vivo pharmacokinetic behavior of the optimized tablet was assessed and compared with that of the commercial oral tablets in human volunteers.

Results

The HP-β-CD–AVA inclusion complex (1:1 molar ratio) showed an optimum solubilization capacity with an amount suitable for incorporation into sublingual tablets. The total amounts of superdisintegrants and Plasdone XL and the percentage of starch significantly influenced the length of time it took for 80% of the AVA to be released from the sublingual tablets, the tablet hardness, and the length of time for tablet disintegration. The optimized AVA sublingual tablet exhibited a 5.98-fold increase in the AVA mean residence time over the commercial tablet, with greater plasma exposure over 72 hours and 1356.42% relative bioavailability.

Conclusion

The sublingual tablets of the solubility-enhanced HP-β-CD–AVA inclusion complex represent a promising strategy to improve AVA bioavailability and bypass the first-pass effect. Furthermore, their extended activity offers potential clinical benefits, particularly for ED patients, such as ease of administration and reduced side effects.

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Materials

AVA was purchased from Jinlan Pharm-Drugs Technology Co., Ltd. (Hangzhou, China), while the Spectrum Chemical Manufacturing Corporation (Gardena, CA, USA) was the source of polyethylene glycol 4000 (PEG 4000). HP-β-CD, mannitol, PEG 2000, PEG 6000, and starch were purchased from Sigma-Aldrich (St. Louis, MO, USA). Explotab (sodium starch glycolate) was obtained from JRS Pharma (Rosenberg, Germany). Plasdone XL (homopolymer of N-vinylpyrrolidone) was provided by ISP (Baar, Switzerland). Whittaker Clark and Daniels (South Plainfield, NJ, USA) and Winlab Laboratory Chemical Reagents (Leicestershire, UK) were the sources of talc powder and magnesium stearate. Acetonitrile, ethanol, and methanol were obtained from Merck (Darmstadt, Germany). Honeywell Riedel-de Haën AG (Seelze, Germany) supplied the other solvents used in this work.

Turky Omar Asar, Omar D Al-Hejaili, Hossam S El-Sawy, Fathy I Abd-Allah, Abdelsattar M Omar, Tarek A Ahmed, Khalid M El-Say, From Oral to Sublingual: A Redefined Avanafil Tablet with a Breakthrough in Bioavailability and First-Pass Metabolism Avoidance, Drug Design, Development and Therapy, Dovepress Taylor & Francis Group