Proniosomal Gel-Loaded Phosphodiesterase Inhibitors (Sildenafil, Vardenafil, and Tadalafil): Prospects for Topical Penile Therapy of Tadalafil for Treatment of Erectile Dysfunction

Abstract

Oral phosphodiesterase inhibitors have emerged as a game changer for the treatment of erectile dysfunction (ED) since attaining FDA approval for its first member, sildenafil, in 1998. Topical penile therapy could be a viable replacement for oral medication that would transform the treatment of ED for many decades to come. This innovative idea could offer a safer topical alternative with less vision and cardiovascular side effects than the oral route. This work aims at developing proniosomal gels for three selected members (sildenafil, vardenafil, and tadalafil) and investigating the proniosomal gels on a rodent model. Niosomes derived from the parent proniosomal gels were characterized for entrapment efficiency (EE%), size, polydispersity index (PDI), zeta potential, and morphology. Proniosomal gels were evaluated for skin permeation, in vivo mating behaviors, and biochemical assays of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) post penile topical administrations. The optimized proniosomes loaded with tadalafil (F1-T) were compared with oral tablets (Cialis®). Proniosomal gels demonstrated significant enhancement of skin penetration by up to 5.5-fold, compared to control topical suspension. Tadalafil-loaded proniosomes showed superior skin permeability over sildenafil- and vardenafil-loaded proniosomes. In addition, significant improvement was noticed regarding intromission number, intromission ratio, NO, and cGMP for the proniosomal gel F1-T, compared to the untreated control. No statistically significant (p > 0.05) differences in sexual performance or biochemical parameters (NO and cGMP levels) were recorded among orally and topically (tadalafil proniosomal gel) administered groups. These findings support tadalafil topical penile therapy as a promising alternative to the oral route.

Sildenafil Citrate Induces Prostatic Hyperplasia in BPH Model Rats and Aged Rats

“…Speci cally, in penile tissue, the regulatory role of cGMP is terminated by PDE5, which destroys its phosphodiester bond, a process not shared by PDEs in other cellular contexts 9 . The inhibitory impact of PDE5 on cGMP can be effectively countered by PDE5i, wherein these inhibitors occupy the catalytic site, impeding direct interaction with cGMP 16,17 . Owing to additional molecular interactions with the catalytic site, the synthetic PDE5i exhibits an a nity approximately 1000-5000 times higher than that of cGMP [18][19][20] .…”

“…Currently, four PDE5i drugs have been approved by the Food and Drug Administration (FDA), namely sildena l, tadala l, vardena l, and avana l 17 . Sildena l citrate, recognized as the rst approved, safe and e cacious oral drug for ED 8 , obtained FDA approval in April 1998, marking its global introduction to the market 21 .…”