Simvastatin (SIM) is a HMG-CoA reductase inhibitor employed in the management of hyperlipidemia. However, its low bioavailability limits its clinical efficacy. The objective of this study was to overcome the poor bioavailability of SIM via the transdermal application of a SIM-loaded niosomal gel. Niosomes loaded with SIM were fabricated by means of the thin-film hydration method and optimized through a 3³-factorial design utilizing Design Expert^® software. The prepared niosomes were evaluated for entrapment efficiency (EE%), zeta potential, vesicle size, and cumulative percentage of drug release. The optimum niosomal formulation was loaded on the gel and evaluated for physical properties such as color, clarity, and homogeneity. It was also evaluated for spreadability, and the cumulative % drug release. The best niosomal gel formula was appraised for ex vivo permeation as well as pharmacokinetic study. The SIM-loaded niosomes showed EE% between 66.7–91.4%, vesicle size between 191.1–521.6 nm, and zeta potential ranged between −0.81–+35.6 mv. The cumulative percentage of drug released was ranged from 55% to 94% over 12 h. SIM-loaded niosomal gels were clear, homogenous, spreadable, and the pH values were within the range of physiological skin pH. Furthermore, about 73.5% of SIM was released within 24 h, whereas 409.5 µg/cm² of SIM passed through the skin over 24 h in the ex vivo permeation study. The pharmacokinetic study revealed higher AUC_0–∞ and Cmax with topical application of SIM-loaded niosomal gel compared to topical SIM gel or oral SIM suspension. The topical application of SIM-loaded niosomal gel ascertained the potential percutaneous delivery of SIM.

Psychological and emotional sexual conditions in men include premature ejaculation. Premature Ejaculation (PE) has 4%–66% worldwide effects on self-esteem, relationships, and quality of life. Poor sexual confidence, anxiety, and sadness may worsen the issue. For this disease, dapoxetine HCl (DH) is used. In normal and streptozotocin (STZ)-induced diabetic rats, DH-loaded poly (lactic-co-glycolic acid) PLGA NP intranasal (IN) therapy was compared to standard lidocaine for DH release, entrapment efficiency, behavioural analysis, histopathological and immunohistochemistry expression, as neuroprotection inspection and proto-oncogene c-Fos (FOS) protein sequence expression. Also, in silico brain serotonin and FOS protein analyses were performed. Double-emulsion-solvent evaporation produced DH-loaded PLGA NP for IN quick-acting PE. Safe, controlled release, and effectiveness were investigated in PE rats using DH-PLGA NP. The brain’s FOS protein expression, mount, intromission, post-ejaculatory, and Ejaculation frequencies were estimated. Optimized spherical NPs were 174 nm in size, − 69.45 mV zeta potential, 98.04% entrapment efficiency, and 78.61% release after 8 h. The brain’s ejaculation centre’s rapid-acting DH prolongs intra-ejaculation, lowers FOS protein density, and normalizes hippocampus neurons. Histology and immunohistochemistry confirmed behavioural results of lower FOS protein expression and delayed ejaculation. Docking revealed that the DH ligand binds more strongly to brain protein active sites involved in premature ejaculation via rapid brain delivery bypassing the BBB via IN dosing, confirmed by behavioural analysis, histopathology, and immunohistochemistry. Using DH acutely decreased rapid ejaculation and changed contextual neuronal activity in ejaculatory network brain regions. Our results improve PE neurobiology and pharmacology research. Expression of FOS protein in DH nanoformula IN protects normal and diabetic rats in normal and diabetic premature ejaculated rats. Graphical Abstract