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Olmesartan medoxomil (OLM) is an antihypertensive drug with low oral bioavailability due to extensive first-pass metabolism. This study aimed to prepare transetho somes (TEs) for enhancing the transdermal delivery of OLM to avoid its oral problems. TE formulae were prepared utilizing 51.31 full factorial design using various surfactants (SAAs) and different phospholipid-to-SAA ratios. The formulae were characterized regarding their entrapment efficiency percentage (EE%), particle size (PS), polydispersity index (PDI), zeta potential (ZP), and the amount of drug released after 6 hours (Q6h). Design Expert software was employed to select the optimum formula. The optimum formula (TE14) had an EE% of 58.50%±1.30%, PS of 222.60±2.50 nm, PDI of 0.11±0.06, ZP of -20.80±0.30 mV, and Q6h of 67.40%±0.20%. In addition, TE14 was compared to transferosomes (TFs) in terms of elasticity and was found to show higher deformability index. Further, evaluation of ex vivo permeation using both rat and shed snake skin showed higher permeability of TE14 compared to TFs and OLM suspension. Confocal laser scanning microscopy confirmed the capability of the fluorolabeled TE14 to penetrate deep within the skin, while the histopathological study confirmed its safety. TE14 successfully maintained normal blood pressure values of rats up to 24 hours. Moreover, TE14 showed superiority in dermatokinetic study when compared with drug suspension. Taken together, the obtained results confirmed the potential of employing TEs as a successful carrier for the transdermal delivery of OLM.

The intention of this work was to load olmesartan medoxomil (OLM), a sparsely water soluble antihypertensive bioactive with low oral bioavailability (26%), into PEGylated bilosomes (PBs) for augmenting its transdermal delivery. PBs contain PEGylated single chain edge activator besides the components of traditional bilosomes (Span 60, cholesterol and bile salts). The PEG gives further resilience to vesicle membrane and is speculated to augment both permeability and bioavailability of OLM. A 2 factorial experiment was constructed to inspect the impact of diverse variables on vesicles' features and sort out the optimal formula adopting Design Expert software utilizing thin film hydration technique. Vesicles' evaluation was done by finding out entrapment efficiency percent (EE%), particle size (PS), polydispersity index (PDI), zeta potential (ZP) and amount of drug released after 6 hrs (Q6h). The optimal formula was selected and characterized for further investigations. The optimal formula (PB15) showed spherical vesicles with EE% of 72.49±0.38%, PS of 559.30±10.70 nm, PDI of 0.57±0.15, ZP of -38.35±0.65 mV and Q6h of 59.60±0.24%. PB15 showed higher deformability index (28.39±5.71 g) compared to traditional bilosomes (5.88±0.90 g) and transethosomes (14.94±0.63 g). Further, PB15 showed superior skin permeation from rat's skin relative to the drug suspension. Moreover, confocal laser scanning microscopy examination revealed efficient penetration of the fluoro-labeled PB15 through skin. Histopathological study ensured the safety of PB15. In addition, in-vivo skin deposition studies showed higher OLM deposition in rat's skin from PB15 compared to transethosomes and OLM suspension. Furthermore, pharmacodynamic and pharmacokinetic studies performed using male Wistar rats and male Albino rabbits, respectively, showed the superiority of PB15 over oral tablets. PB15 was found to have significantly higher AUC and AUC relative to the oral tablets. As well, the relative bioavailability of PB15 was found to be 235.04%. Overall, the obtained results confirmed the creditable effect of PB15 for transdermal delivery.

In this investigation, we focused on ceramide IIIB, a skin component whose depletion tends to augment multiple skin disorders and fungal infections. Ceramide IIIB was included into PEGylated surfactant-based vesicular phospholipid system to formulate 'PEGylated cerosomes' (PCs) loaded with fenticonazole nitrate (FTN). FTN is a potent antifungal agent adopted in the treatment of mixed mycotic and bacterial infections. The ceramide content of the vesicles may provide protective and regenerative skin activity whereas Brij ® ; the PEGylated surfactant, can enhance drug deposition and skin hydration. Both components are expected to augment the topical effect of FTN. PCs were prepared by thin-film hydration technique. A 2 3 full-factorial design was applied to study the effect of ceramide amount (X 1 ), Brij type (X 2 ) and Brij amount (X 3 ) on the physicochemical properties of the formulated PCs namely; entrapment efficiency (EE%;Y 1 ), particle size (PS;Y 2 ), polydispersity index (PDI;Y 3 ) and zeta potential (ZP;Y 4 ). The optimal formula was selected for further in-vivo dermatokinetic and histopathological study. The optimal FTN-loaded PC (PC6) showed nanosized cerosomes (551.60 nm) with high EE% (83.00%w/w), and an acceptable ZP value of 20.90 mV. Transmission electron micrographs of the optimal formula illustrated intertwined tubulation form deviated from the conventional spherical vesicles. Finally, the dermatokinetic study of PC6 showed higher drug concentration and localization of FTN in skin layers when compared with FTN suspension and the histopathological study confirmed its safety for topical application. The overall findings of our study verified the effectiveness of utilizing PEGylated cerosomes to augment the activity of FTN as a topical antifungal agent.

Aim: To compare the ability of both terpesomes (TPs) and leciplex (LPs) loaded moxifloxacin hydrochloride (MOX) for enhancing ocular drug conveyance. Methods: Two separate 21.31 full-factorial trials were established to determine the influence of multiple variables upon nanovesicles properties and select the optimized formulae using Design Expert[R] software. The thin-film hydration method was used to formulate TPs, while the single-step procedure was used for LPs. All formulae were characterized for their entrapment efficiency percent (EE%), particle size distribution (PS), polydispersity index (PDI), and zeta potential (ZP). Then, the optimized formulae were selected, evaluated, and compared for additional assessments. Results: The optimized formulae TP4 and LP1 showed EE% of 84.14[+ or -]0.21 and 78.47 [+ or -]0.17%, PS of 578.65[+ or -]5.65 and 102.41[+ or -]3.39 nm, PDI of 0.56[+ or -]0.04 and 0.28[+ or -]0.01, ZP of -12.50[+ or -]0.30 and 32.50[+ or -]0.50 mV, respectively. Further, LP1 showed enhanced corneal permeation across cow cornea compared to MOX solution and TP4. Besides, confocal laser scanning microscopy assessment 232viewed valuable infiltration from the fluoro-labeled LP through corneal layers compared to TP. LP1 showed spherical morphology and, its ability to adhere to mucus membranes was justified. Further, LP1 showed superiority over MOX solution in biofilm inhibition and eradication in addition to the treatment of infected mice with methicillin-resistant Staphylococcus aureus without any inflammatory response. Finally, the histopathological study verified the harmlessness and biocompatibility of the assembled LPs. Conclusion: The gained outcomes confirmed the capability of utilizing LPs as a successful nanovesicle for the ocular conveyance of MOX over TPs and MOX solution. Keywords: biofilm, confocal laser microscope, moxifloxacin hydrochloride, MRSA, leciplex, ocular drug conveyance, terpesomes

The aim of the current study was to load fenticonazole nitrate, a slightly water-soluble antifungal agent, into terpene-enriched phospholipid vesicles (terpesomes) as a potential delivery system for the management of ocular fungal infection. Thin film hydration method was used to prepare terpesomes according to a 3 full factorial design to inspect the effect of several variables on vesicles' features. The investigated factors were terpenes type (X ) and terpenes amount (X ) while the dependent responses were encapsulation efficiency percent (Y ), particle size (Y ) and polydispersity index (Y ). Design Expert program was used to chose the best achieved formula. The selected terpesomes were further optimized via incorporation of a positive charge inducer (stearylamine) to enhance adhesion to the negatively charged mucus covering the eye surface. The in vivo performance of the optimized fenticonazole nitrate-loaded terpesomes relative to drug suspension was evaluated by measuring the antifungal activity (against ) retained in the tear's fluid at different time intervals after ocular application in albino rabbits. The optimized terpesomes showed spherical vesicles with entrapment efficiency of 79.02±2.35%, particle size of 287.25±9.55 nm, polydispersity index of 0.46±0.01 and zeta potential of 36.15±1.06 mV. The in vivo study demonstrated significantly higher ocular retention of the optimized fenticonazole nitrate-loaded terpesomes relative to the drug suspension. Moreover, the histopathological studies proved the safety and biocompatibility of the prepared terpesomes. The obtained results verified the potential of the terpesomes for safe and effective ocular delivery of fenticonazole nitrate.

Objectives: In this study, we aimed to incorporate levocetirizine dihydrochloride (LVC) into electrospun nanovesicle-in-nanofiber (NF) scaffolds for combined management of atopic dermatitis and methicillin-resistant Staphylococcus Aureus skin infection, to sustain LVC release for continuous skin improvement. Methods: Firstly, LVC was encapsulated in cerosomes (CERs) by employing a thin-film hydration approach using a 21.31 factorial design. CERs were assessed by calculating entrapment efficiency (EE%), particle size (PS) and polydispersity index (PDI). In addition, the optimized CERs were further subjected to stability evaluation. After that, the optimized CERs were incorporated into polyurethane nanofibers (NFs) using a coaxial electrospinning technique. An in vitro release assay was used to calculate the amount of LVC released from the LVC-NFs and the optimized CERs-NFs. For morphological assessment of NFs, LVC-NFs and CERs-NFs were subjected to transmission electron microscopy, scanning electron microscopy, and confocal laser scanning microscopy. Atomic force microscopy was utilized to evaluate the roughness of CERs and both NFs. The optimum formulation was further subjected to in vivo study. Results: The optimum CERs exhibited an EE% of 65.03 ± 1.07%, a PS of 680.00 ± 39.50 nm, and a PDI of 0.51 ± 0.04. LVC was released in a sustained manner from CERs NFs. Further, a dermatokinetic study confirmed that CERs-NFs sustained the infiltration of LVC, compared with the other groups. Finally, a safety assessment showed that all formulations were safe when topically applied to rat skin. Conclusions: In conclusion, AD and MRSA skin infections may be cured by employing electrospun nanofiber-scaffold-loaded LVC CERs, which can thus be regarded as a promising system.

Metformin (MET), an antidiabetic drug, is emerging as a promising anticancer agent. This study was initiated to investigate the antitumor effects and potential molecular targets of MET in mice bearing solid Ehrlich carcinoma (SEC) as a model of breast cancer (BC) and to explore the potential of zein nanoparticles (ZNs) as a carrier for improving the anticancer effect of MET. ZNs were fabricated through ethanol injection followed by probe sonication method. The optimum ZN formulation (ZN8) was spherical and contained 5 mg zein and 30 mg sodium deoxycholate with a small particle size and high entrapment efficiency percentage and zeta potential. A stability study showed that ZN8 was stable for up to three months. In vitro release profiles proved the sustained effect of ZN8 compared to the MET solution. Treatment of SEC-bearing mice with ZN8 produced a more pronounced anticancer effect which was mediated by upregulation of P53 and miRNA-543 as well as downregulation of NF-κB and miRNA-191-5p gene expression. Furthermore, ZN8 produced a marked elevation in pAMPK and caspase-3 levels as well as a significant decrease in cyclin D1, COX-2, and PGE2 levels. The acquired findings verified the potency of MET-loaded ZNs as a treatment approach for BC.

The current investigation aimed for loading fenticonazole nitrate (FTN), an antifungal agent with low aqueous solubility, into trans-novasomes (TNs) for management of tinea corporis topically. TNs contain Brij ® as an edge activator besides the components of novasomes (cholesterol, Span 60, and oleic acid) owing to augment the topical delivery of FTN. TNs were fabricated applying ethanol injection method based on D-optimal experiment. TNs were evaluated with regard to entrapment efficiency percent (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP). Further explorations were conducted on the optimum formulation (F7). F7 showed spherical appearance with EE%, PS, PDI, and ZP of 100.00 ± 1.10%, 358.60 ± 10.76 nm, 0.51 ± 0.004, and −30.00 ± 0.80 mV, respectively. The in silico study revealed the ability of the FTN-cholesterol complex to maintain favorable interactions throughout the molecular dynamics simulation (MDS) study. Moreover, Trichophyton mentagrophytes growth was inhibited effectively by F7 than by FTN suspension applying 2,3-bis(2-methyloxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction assay. Furthermore, a clinical appraisal on patients with tinea corporis fungal lesions confirmed the superiority of F7 compared to Miconaz ® cream in the magnitude of clinical cure of tinea corporis. Thereby, TNs could be considered as promising vesicles for enhancing the antifungal potential of FTN for the topical management of tinea corporis.

Titanium dioxide nanoparticles (TiO 2 -NPs) have found wide applications in medical and industrial fields. However, the toxic effect of various tissues is still under study. In this study, we evaluated the toxic effect of TiO 2 -NP on stomach, liver, and kidney tissues and the amelioration effect of clove oil nanoemulsion (CLV-NE) against DNA damage, oxidative stress, pathological changes, and the apoptotic effect of TiO 2 -NPs. Four groups of male mice were subjected to oral treatment for five consecutive days including, the control group, the group treated with TiO 2 -NPs (50 mg/kg), the group treated with (CLV-NE) (5% of the MTD), and the group treated with TiO 2 -NPs plus CLV-NE. The results revealed that the treatment with TiO 2 -NPs significantly caused DNA damage in the liver, stomach, and kidney tissues due to increased ROS as indicated by the reduction of the antioxidant activity of SOD and Gpx and increased MDA level. Further, abnormal histological signs and apoptotic effect confirmed by the significant elevation of p53 expression were reported after TiO 2 -NPs administration. The present data reported a significant improvement in the previous parameters after treatment with CLV-NE. These results showed the collaborative effect of the oils and the extra role of nanoemulsion in enhancing antioxidant effectiveness that enhances its disperse-ability and further promotes its controlled release. One could conclude that CLV-NE is safe and can be used as a powerful antioxidative agent to assess the toxic effects of the acute use of TiO 2 -NPs.

Fenticonazole nitrate (FTN) is a potent antifungal drug adopted in the treatment of vaginal candidiasis. It has inadequate aqueous solubility hence, novel ultra-deformable liposomes 'Terpesomes' (TPs) were developed that might prevail over FTN poor solubility besides TPs might abstain the obstacles of mucus invasion. TPs were assembled by thin-film hydration then optimized by Box Behnken design utilizing terpenes ratio (X 1 ), sodium deoxycholate amount (X 2 ), and ethanol concentration (X 3 ) as independent variable, whereas their impact was inspected for entrapment efficiency (Y 1 ), particle size (Y 2 ), and polydispersity index (Y 3 ). Design Expert ® was bestowed to select the optimal TP for more studies. The optimal TP had entrapment efficiency of 62.18 ± 1.39%, particle size of 310.00 ± 8.16 nm, polydispersity index of 0.20 ± 0.10, and zeta potential of −10.19 ± 0.2.00 mV. Elasticity results were greater in the optimal TP related to classical bilosomes. Further, ex vivo permeation illustrated tremendous permeability from the optimal TP correlated to classical bilosomes, and FTN suspension. Besides, in vivo assessment displayed significant inhibition effect in rats from FTN-TPs gel compared to FTN gel. The antifungal potency with undermost histopathological variation was detected in rats treated with FTN-TPs gel. Overall, the acquired findings verified the potency of utilizing FTN-TPs gel for treatment of vaginal candidiasis.