Exploitation of Design-of-Experiment Approach for Design and Optimization of Fast-Disintegrating Tablets for Sublingual Delivery of Sildenafil Citrate with Enhanced Bioavailability Using Fluid-Bed Granulation Technique.

Amer S Alali,Ismail A Walbi,Ahmed Alalaiwe,Mohammed F Aldawsari,Ramadan Al-Shdefat,Bjad K Almutairy,Mohamed H Fayed

doi:10.3390/pharmaceutics13060870

Abstract

Sildenafil citrate undergoes first-pass metabolism, resulting in poor oral bioavailability at 25–41% of the administered dose. This study aimed to design and optimize fast-disintegrating tablets for the sublingual delivery of sildenafil citrate to improve bioavailability and facilitate rapid onset of action. The design-of-experiment (DoE) approach using 32 full factorial design was conducted to develop a new formulation of sildenafil fast-disintegrating sublingual tablets (FDSTs) using the fluid-bed granulation technique. The levels of partially pre-gelatinized starch (5–15%) and microcrystalline cellulose (10–60%) were selected as independent formulation variables. The prepared FDSTs were investigated for physical properties. Further, the optimum formulation was chosen for in vivo study in rabbits. Regression analysis showed that independent variables have a significant (p < 0.05) influence on critical attributes of FDSTs. The optimized formulation showed acceptable mechanical strength (friability < 1.0%) with very fast disintegration (14.561 ± 0.84 s) and dissolution (94.734 ± 2.76% after 15 min). Further, the optimized formulation demonstrated a significant increase (p < 0.01) in Cmax and AUC0–∞ with short tmax compared to the market product (Viagra®). Based on these results, using the DoE approach, a high level of assurance was achieved for FDSTs’ product quality and performance.

Highlights

Erectile dysfunction (ED) is the consistent or recurrent failure to obtain and/or maintain a penile erection necessary for adequate sexual performance [1]
The present study proves that fluid-bed granulation is an efficient technology for the improvement of dissolution rate, thereby leading to an improvement in the bioavailability of sildenafil citrate, without the use of other formulation strategies to enhance dissolution properties
The fluid-bed granulation technique could be useful for the development of fast-disintegrating sublingual tablets (FDSTs) that are applied for sublingual delivery

Summary

Introduction

Erectile dysfunction (ED) is the consistent or recurrent failure to obtain and/or maintain a penile erection necessary for adequate sexual performance [1]. Of men between the ages of 40 and 70 years suffered from ED [3]. It causes deep negative influence on an individual’s social life and prosperity [1]. Sildenafil “phosphodiesterase-5 inhibitors” is indicated as the first line treatment of ED [4]. Sildenafil is only administered by the oral route. Oral administration of sildenafil has several drawbacks. The absolute bioavailability of sildenafil in humans following oral administration of 50 mg was 41%. A late onset of action was observed. The onset of action usually started after 30–45 min [5,6]

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