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This study aimed to overcome the poor solubility of pterostilbene (PTS) by developing promising reconstituted proethoniosomes (PENs). The reconstituted PENs loaded with PTS were fabricated according to a 23 factorial design by Design-Expert® software. The prepared ethoniosomes were assessed for entrapment efficiency (EE %) and % PTS released after 24 h (Q24h). According to the desirability criteria, the ethoniosomal formula (F4) was chosen as the optimized formulation with EE% of 93.19 ± 0.66 and Q24h of 75.10 ± 1.90%. The optimum ethoniosomal formulation was further coated with folic acid (FA) using bovine serum albumin (BSA) as a carrier and stabilizing agent and further evaluated for transmission electron microscopy (TEM), particle size, zeta potential, elasticity, Fourier transform infrared spectroscopy (FTIR), and stability. The targeted ethoniosomal formula appeared as spherical nanovesicles with a size of 144.05 ± 1.77 nm size and a zeta potential of -38.6 mV. The elasticity of the targeted ethoniosomal formula 19.27 ± 1.2 was higher than that of the corresponding niosome 1.48 ± 0.02. The targeted ethoniosomal formula showed high stability for three months. Fluorescence microscopy demonstrated an accumulation of FA-BSA-ethoniosomes in the cytoplasm of A549 cell lines. The observed therapeutic activity of the targeted ethoniosomal formula on lung cancer was explored by in vitro cytotoxicity on A549 lung cancer cells and in vivo animal models. The in vivo results were supported by histopathological analysis and immunohistochemical caspase-3 staining. FA-BSA-ethoniosomal formulation allowed specific targeting of cancer tissues overexpressing folate receptors. Overall, these results confirmed that the targeted ethoniosomal formula could be a promising nano-carrier for potential application as targeted cancer chemotherapy in clinical studies. Graphical Abstract

Comorbid conditions of heart and liver disorders added to HCV-induced hepatic steatosis make co-administration of statins, and direct-acting antivirals is common in clinical practice. This study aimed to evaluate the pharmacokinetic interaction of atorvastatin and fixed-dose combination of sofosbuvir/ledipasvir “FDCSL” with rationalization to the underlying mechanism. A randomized, three-phase crossover study that involves 12 healthy volunteers was performed. Participants received a single-dose of atorvastatin 80 mg alone, atorvastatin 80-mg plus tablets containing 400/90 mg FDCSL, or tablets containing 400/90 mg FDCSL alone. Plasma samples were analyzed using liquid chromatography–tandem mass spectrometry (LC–MS/MS) for atorvastatin, sofosbuvir, ledipasvir, and sofosbuvir metabolite “GS-331007,” and their pharmacokinetics parameters were determined. Compared to atorvastatin alone, the administration of FDCSL caused a significant increase in both areas under the concentration–time curve from time zero to infinity (AUC0−∞) and maximum plasma concentration (Cmax) of atorvastatin by 65.5% and 156.0%, respectively. Also, atorvastatin caused a significant increase in the AUC0−∞ and Cmax of sofosbuvir by 32.0% and 11.0%, respectively. Similarly, AUC0−∞ and Cmax of sofosbuvir metabolite significantly increased by 84.0% and 74.0%, respectively. However, ledipasvir AUC0−∞ showed no significant change after atorvastatin intake. The elimination rate in all drugs revealed no significant changes. After concurrent administration of FDCSL with atorvastatin, the AUC0−∞ of both atorvastatin and sofosbuvir were increased. Caution should be taken with close monitoring for possible side effects after co-administration of atorvastatin and FDCSL in clinical practice.

The study was conducted to evaluate the potential application of nanocapsules and nanospheres as topical drug delivery systems for indomethacin (as model drug). Both were prepared by nanoprecipitation using poly (ɛ-caprolactone) and hydroxypropyl β-cyclodextrin polymers and evaluated for morphology, particle size, zeta potential, EE% and in vitro drug release then incorporated in methylcellulose and Carbopol 940 gel bases and evaluated for in vitro release. The selected formulations and market product were evaluated for ex vivo human skin permeation and anti-inflammatory and analgesic activities by paw edema and hot plate methods respectively. Results showed that nanocapsules had slight higher EE% and larger particle sizes than nanospheres. In vitro release and zeta potential were nearly similar. Methylcellulose exhibited higher in vitro release than Carbopol 940 after 3 h (except NS2). Ex vivo skin permeation studies showed significant higher cumulative amount of IND (and flux) from NC1/MC and NS1/MC (1573.06 ± 14.23 µg/cm 2 and 1452.24 ± 23.18 µg/cm 2 respectively) than market product. They also showed enhancement ratio and permeability coefficient rate of ∼1.5 and ∼2 respectively. NC1/MC proved to be significantly higher pharmacodynamic effects than market product. All results showed that NC1/MC could provide a promising formula as a topical delivery of indomethacin.