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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

Apigenin is a natural flavonoid which is claimed to have many pharmacological activities ranging from simple anti-inflammatory to anticancer action. However, poor dissolution slowed the advancement of this drug through the development pipelines. The objective of this work was to probe ethanol-aided kneading of apigenin with arginine as a new strategy for enhanced dissolution rate. The work was extended to develop rapidly disintegrating tablets of apigenin. Apigenin was mixed with increasing molar ratios of arginine before ethanol-aided kneading. The resulting products were examined using Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction in addition to probing the dissolution characteristics of apigenin. The analytical techniques highlighted the existence of new crystalline species with a possibility of salt formation. The recorded alterations in the crystalline properties were associated with a significant enhancement in the dissolution rate of apigenin. The presence of arginine did not have any negative effect of the cytotoxic power of apigenin. Optimum formulation was successfully prepared as rapidly disintegrating tablets which showed fast liberation of apigenin. The study introduced arginine as a potential excipient for enhanced dissolution of apigenin after ethanol-assisted kneading.

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.

Transdermal delivery of non-steroidal anti-inflammatory drugs (NSAIDs) is an effective route of drug administration, as it directs the drug to the inflamed site with reduced incidence of systemic adverse effects such as gastric hemorrhage and ulcers. Tenoxicam (TNX) is a member of NSAIDs that are marketed only as oral tablets due to very poor absorption through the skin. The current study intended to formulate and characterize a hydrogel loaded with nanostructured lipid carriers (NLCs) to enhance the transdermal delivery of TNX. Six formulations of TNX were formulated by slight modifications of high shear homogenization and ultrasonication method. The selected formula was characterized for their particle size, polydispersity index (PDI), zeta potential, entrapment efficiency (EE), in-vitro drug release and ex-vivo skin permeation studies. Moreover, the effectiveness of the developed formula was studied in-vivo using carrageenan-induced paw edema and hyperalgesia model in irradiated rats. Formula F4 was chosen from six formulations, as the average diameter was 679.4 ± 51.3 nm, PDI value of about 0.02, zeta potential of −4.24 mV, EE of 92.36%, globules nanoparticles without aggregations and absence of interactions in the developed formula. Additionally, the in-vivo study showed the efficacy of formula F4 (TNX-NLCs hydrogel) equivalent to oral TNX in reducing the exaggerated inflammatory response induced by carrageenan after irradiation. In conclusion, the present findings suggest that TNX-NLCs hydrogel could be a potential transdermal drug delivery system alternative to the oral formulation for the treatment of various inflammatory conditions.

Objectives: Enhance the dissolution rate of bicalutamide via co-crystallization with sucralose (sweetener), with the aim to develop rapidly disintegrating tablets with subsequent prompt dissolution. Significance: Bicalutamide is antiandrogenic agent for the treatment of prostate cancer but has low and variable oral bioavailability, mainly attributed to poor dissolution. Co-crystallization with benign excipients is promising for dissolution enhancement with the additive serving dual functions. The benefit will become greater if dissolution enhancement is associated with the development of orodispersible tablets which is suitable for elderly patients who are the most vulnerable for prostate cancer. Methods: Bicalutamide was dissolved in acetone in the presence of increasing molar ratios of sucralose. The solvent was evaporated while mixing to deposit crystals that were subjected to wet co-grinding until drying. The developed solids were characterized using Fourier transform infrared spectroscopy, differential thermal analysis and X-ray diffraction in addition to monitoring bicalutamide dissolution. Results: Instrumental analysis provided evidences for co-crystallization which was initiated at 1:1 molar ratio of bicalutamide to sucralose with complete co-crystallization at 1:4 molar ratio. The co-crystals provided faster bicalutamide dissolution compared with the unprocessed drug and that recrystalized from acetone in the absence of sucralose. The formulation containing bicalutamide with sucralose at 1:4 molar ratio was selected for tablet formulation into which superdisintegrants were included. The developed tablets exhibited flash disintegration with subsequent fast dissolution of bicalutamide. Conclusions: The study introduced co-crystallization of bicalutamide with sucralose as an efficient tool to enhance the dissolution rate and to develop rapidly dissolving tablets for intraoral administration.

Dyphylline, xanthine derivatives, is used to manage asthma, cardiac dyspnea, chronic bronchitis, and emphysema. This work aimed to develop controlled release matrix tablets of Dyphylline using different types of polymers, and different preparation techniques such as direct compression, wet granulation, and hot melt methods. The prepared matrix tablets were evaluated by Infrared spectral analysis, differential thermal analysis, evaluation which included hardness, friability, content uniformity, and the in-vitro drug release. Kinetic analysis of the release profiles was investigated using different kinetic orders. All Dyphylline formulae obey Higuchi’s diffusion model. The diffusion is the mechanism of Dyphylline release from its controlled matrix tablets. IR and DSC revealed no incompatibility between Dyphylline and the polymers used in the prepared formulae. The obtained results revealed that the wet granulation technique using water as the granulating liquid is the best method for the formulation of Dyphylline hydrophilic matrix tablets compared with the other techniques. The high content of polymers led to the high value of T1/2, and a decrease in Dyphylline's extent due to the improvement of the retention of drug release. A synergistic effect was obtained using PVP-K-25 in the hydrophilic matrix tablets, which led to the retention of the drug release.

Curcumin is a natural compound that has many medical applications. However, its low solubility and poor stability could impede its clinical applications. The present study aimed to formulate dry proniosomes to overcome these pitfalls and improve the therapeutic efficacy of Curcumin. Curcumin-loaded proniosomes were fabricated by the slurry method according to 32 factorial design using Design-Expert software to demonstrate the impact of different independent variables on entrapment efficiency (EE%) and % drug released after 12 h (Q12h). The optimized formula (F5) was selected according to the desirability criteria. F5 exhibited good flowability and appeared, after reconstitution, as spherical nanovesicles with EE% of 89.94 &plusmn, 2.31% and Q12h of 70.89 &plusmn, 1.62%. F5 demonstrated higher stability and a significant enhancement of Q12h than the corresponding niosomes. The docking study investigated the ability of Curcumin to bind effectively with the active site of DNA polymerase of Herpes simplex virus (HSV). The antiviral activity and the safety of F5 were significantly higher than Curcumin. F5 improved the safety of Acyclovir (ACV) and reduced its effective dose that produced a 100% reduction of viral plaques. Proniosomes could be promising stable carriers of Curcumin to be used as a safe and efficient antiviral agent.

Candesartan Cilexetil (CC) is a prodrug widely used in the treatment of hypertension and heart failure, but it has some limitations, such as very poor aqueous solubility, high affinity to P-glycoprotein efflux mechanism, and hepatic first-pass metabolism. Therefore, it has very low oral bioavailability. In this study, glyceryl monostearate (GMS) and Capryol&trade, 90 were selected as solid and liquid lipids, respectively, to develop CC-NLC (nanostructured lipid carrier). CC was successfully encapsulated into NLP (CC-NLC) to enhance its oral bioavailability. CC-NLC was formulated using a hot homogenization-ultrasonication technique, and the physicochemical properties were characterized. The developed CC-NLC formulation was showed in nanometric size (121.6 &plusmn, 6.2 nm) with high encapsulation efficiency (96.23 &plusmn, 3.14%). Furthermore, it appeared almost spherical in morphology under a transmission electron microscope. The surgical experiment of the designed CC-NLC for absorption from the gastrointestinal tract revealed that CC-NLC absorption in the stomach was only 15.26% of that in the intestine. Otherwise, cellular uptake study exhibit that CC-NLCs should be internalized through the enterocytes after that transported through the systemic circulation. The pharmacokinetic results indicated that the oral bioavailability of CC was remarkably improved above 2-fold after encapsulation into nanostructured lipid carriers. These results ensured that nanostructured lipid carriers have a highly beneficial effect on improving the oral bioavailability of poorly water-soluble drugs, such as CC.

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.

Acetazolamide (ACZ) is a potent carbonic anhydrase inhibitor that is used for the treatment of glaucoma. Its oral administration causes various undesirable side effects. This study aimed to formulate transgelosomes (TGS) for enhancing the ocular delivery of ACZ. ACZ-loaded transfersomes were formulated by the ethanol injection method, using phosphatidylcholine (PC) and different edge activators, including Tween 80, Span 60, and Cremophor RH 40. The effects of the ratio of lipid to surfactant and type of surfactant on % drug released after 8 h (Q8h) and entrapment efficiency (EE%) were investigated by using Design-Expert software. The optimized formula was formulated as TGS, using poloxamers as gelling agents. In vitro and in vivo characterization of ACZ-loaded TGS was performed. According to optimization study, F8 had the highest desirability value and was chosen as the optimized formula for preparing TGS. F8 appeared as spherical elastic nanovesicles with Q8h of 93.01 ± 3.76% and EE% of 84.44 ± 2.82. Compared to a free drug, TGS exhibited more prolonged drug release of 71.28 ± 0.46% after 8 h, higher ex vivo permeation of 66.82 ± 1.11% after 8 h and a significant lowering of intraocular pressure (IOP) for 24 h. Therefore, TGS provided a promising technique for improving the corneal delivery of ACZ.

Thymoquinone (TQ), obtained from black cumin (Nigella sativa), is a natural product with anti-oxidant, anti-inflammatory, and hepatoprotective effects but unfortunately with poor bioavailability. Aiming to improve its poor oral bioavailability, TQ-loaded nanostructured lipid carriers (NLCs) were prepared by high-speed homogenization followed by ultrasonication and evaluated in vitro. Bioavailability and pharmacodynamic studies were also performed. The resultant NLCs showed poor physical homogeneity in Compritol 888 ATO Pluronic F127 system which consequently produced larger particle size and polydispersity index, smaller zeta potential values, and lower short-term (30 days) physical stability than other systems. Encapsulation efficiency percentage (EE%) lied between 84.6 ± 5% and 96.2 ± 1.6%. TQ AUC0–t values were higher in animals treated with NLCs, with a relative bioavailability of 2.03- and 3.97-fold (for F9 and F12, respectively) higher than TQ suspension, indicating bioavailability enhancement by NLC formulation. Hepatoprotective effects of F12 showed significant (P