Development of a Sildenafil Citrate Microemulsion-Loaded Hydrogel as a Potential System for Drug Delivery to the Penis and Its Cellular Metabolic Mechanism

Abstract

Sildenafil citrate is used to treat mild to moderate erectile dysfunction and premature ejaculation. However, it has low oral bioavailability, numerous adverse effects, and delayed onset of action. These problems may be resolved by transdermal delivery to the penis. Hence, sildenafil citrate was formulated as a microemulsion system using isopropyl myristate, Tween 80, PEG400, and water (30:20:40:10). The hydrogel used in the microemulsion was 2% w/w poloxamer 188. The sildenafil microemulsion-loaded hydrogels were characterised for their appearance, particle size, pH, spreadability, swelling index, viscosity, sildenafil drug content, membrane permeation, epithelial cell cytotoxicity, and in vitro drug metabolism. The optimised formulated microemulsion showed the lowest droplet size and highest solubility of sildenafil citrate. The in vitro skin permeation of the sildenafil citrate microemulsion-loaded hydrogel was significantly higher than that of the sildenafil suspension, with a 1.97-fold enhancement ratio. The formulated microemulsion exhibited a 100% cell viability, indicating its safety for skin epithelial cells. The major metabolic pathway of sildenafil citrate loaded in the microemulsion formulation was hydroxylation. Furthermore, loading sildenafil in the microemulsion reduced the drug metabolite by approximately 50% compared to the sildenafil in aqueous suspension. The sildenafil citrate-loaded isopropyl myristate-based microemulsion hydrogels were physically and chemically stable over 6 months of storage. The sildenafil citrate microemulsion-loaded hydrogel showed in vitro results suitable for used as a transdermal drug delivery system.

Advanced hydrogels: New expectation for the repair of organic erectile dysfunction

“…In the mentioned treatment options, oral PDE5Is and topical/intraurethral alprostadil are still arguably the two most important approaches. Topical administration can be an alternative to oral administration due to the disadvantages of oral drugs, such as high systemic side effects, low bioavailability, and delayed onset of action [ 15 ]. However, topical administration also suffers from local discomfort and insufficient transdermal rates, and the use of hydrogel supports the optimization of this mode of delivery.…”

“…Currently available strategies to treat primary organic ED include oral pharmacotherapy, topical/intraurethral alprostadil, shockwave therapy, hormonal treatment, vacuum erection devices (VEDs), intracavernous injection therapy, vascular surgery, and penile prostheses [ 5 ]. However, these strategies suffer from the following weaknesses: low bioavailability, high systemic adverse effects, poor patient experience, invasiveness, and limited application [ 5 , 14 , 15 ]. Most importantly, ED is hardly cured by these therapies [ 5 ].…”

Review: The Discovery and Development of Sildenafil Citrate

“…At high doses, sildenafil citrate can cause persistent retinal toxicity in certain individuals 32 . Sildenafil citrate is reported to have low oral absorption, multiple side effects, and delayed onset of action 33 . The two most common side effects are headache and flushing which are brief and easily treatable 18 .…”

“…[111] CODEN (USA): AJPRHS conditions in healthy Chinese men, thus offering a convenient alternative method of oral administration 36 . Sildenafil citrate hydrogel containing microemulsion showed in vitro results that were suitable for use as a transdermal drug delivery system 33 .…”

Development and In Vitro Evaluation of Controlled Release Viagra® Containing Poloxamer-188 Using Gastroplus™ PBPK Modeling Software for In Vivo Predictions and Pharmacokinetic Assessments

“…Only a few studies have been carried out on developing non-oral sustained release SDF dosage forms using polymers, for example, lung-delivered, controlled release formulations of SDF with poloxamer-407 (P-407) [ 8 ] or a vaginal controlled release suppository of SDF containing EVAC 210 polymer [ 9 ]. In addition, some SDF formulations were prepared with polymers, such as SDF nano-dispersion inhalers incorporating poloxamer-188 (P-188) [ 10 ], SDF solid lipid nanoparticles formulated with gelucire 44/14 [ 11 ], SDF spray-dried microparticle inhalers formed by using sodium carboxymethylcellulose, sodium alginate, and sodium hyaluronate [ 12 ], SDF-loaded polymeric microparticles based on poly(lactide-co-glycolide) [ 13 ], and an SDF microemulsion-loaded hydrogel [ 14 ].…”