Protective potential of frankincense essential oil and its loaded solid lipid nanoparticles against UVB-induced photodamage in rats via MAPK and PI3K/AKT signaling pathways; A promising anti-aging therapy.

Frankincense oil has gained increased popularity in skin care, yet its anti-aging effect remains unclear. The current study aimed to investigate the anti-photoaging effect of frankincense (Boswellia papyrifera (Del.) Hochst., Family Burseraceae) essential oil in an in vivo model. The oil was initially extracted by two methods: hydro-distillation (HD) and microwave-assisted hydro-distillation (MAHD). GC/MS analysis revealed the dominance of n-octyl acetate, along with other marker compounds of B. papyrifera including octanol and diterpene components (verticilla 4(20) 7, 11-triene and incensole acetate). Thereafter, preliminary investigation of the anti-collagenase and anti-elastase activities of the extracted oils revealed the superior anti-aging effect of HD-extracted oil (FO), comparable to epigallocatechin gallate. FO was subsequently formulated into solid lipid nanoparticles (FO-SLNs) via high shear homogenization to improve its solubility and skin penetration characteristics prior to in vivo testing. The optimimal formulation prepared with 0.5% FO, and 4% Tween® 80, demonstrated nanosized spherical particles with high entrapment efficiency percentage and sustained release for 8 hours. The anti-photoaging effect of FO and FO-SLNs was then evaluated in UVB-irradiated hairless rats, compared to Vitamin A palmitate as a positive standard. FO and FO-SLNs restored the antioxidant capacity (SOD and CAT) and prohibited inflammatory markers (IL6, NFκB p65) in UVB-irradiated rats via downregulation of MAPK (pERK, pJNK, and pp38) and PI3K/AKT signaling pathways, alongside upregulating TGF-ß expression. Subsequently, our treatments induced Procollagen I synthesis and downregulation of MMPs (MMP1, MMP9), where FO-SLNs exhibited superior anti-photoaging effect, compared to FO and Vitamin A, highlighting the use of SLNs as a promising nanocarrier for FO. In particular, FO-SLNs revealed normal epidermal and dermal histological structures, protected against UVß-induced epidermal thickness and dermal collagen degradation. Our results indicated the potential use of FO-SLNs as a promising topical anti-aging therapy.

Contemporary Techniques and Potential Transungual Drug Delivery Nanosystems for The Treatment of Onychomycosis.

The humanoid nail is considered an exceptional protective barrier that is formed mainly from keratin. Onychomycosis is the cause of 50% of nail infections that is generally caused by dermatophytes. Firstly, the infection was regarded as a cosmetic problem but because of the tenacious nature of onychomycosis and its relapses, these infections have attracted medical attention. The first line of therapy was the oral antifungal agents which were proven to be effective; nevertheless, they exhibited hepato-toxic side effects, alongside drug interactions. Following, the opportunity was shifted to the topical remedies, as onychomycosis is rather superficial, yet this route is hindered by the keratinized layers in the nail plate. A potential alternative to overcome the obstacle was applying different mechanical, physical, and chemical methods to boost the penetration of drugs through the nail plate. Unfortunately, these methods might be expensive, require an expert to be completed, or even be followed by pain or more serious side effects. Furthermore, topical formulations such as nail lacquers and patches do not provide enough sustaining effects. Recently, newer therapies such as nanovesicles, nanoparticles, and nanoemulsions have emerged for the treatment of onychomycosis that provided effective treatment with possibly no side effects. This review states the treatment strategies such as mechanical, physical, and chemical methods, and highlights various innovative dosage forms and nanosystems developed in the last 10 years with a focus on advanced findings regarding formulation systems. Furthermore, it demonstrates the natural bioactives and their formulation as nanosystems, and the most relevant clinical outcomes.

Standardization and quantitative analysis of Araucaria Heterophylla extract via an UPLC-MS/MS method and its formulation as an antibacterial phytonanoemulsion gel.

Skin infections are among the bacterial infections that present significant therapeutic challenges due to antibiotic resistance. Recently, herbal products clutched a significant attention as safe replacements for other medications but their low aqueous solubility and poor bioavailability are considered major challenges which could be circumvented via formulation. As a species of genera Araucaria, Araucaria Heterophylla possesses pharmacological activities such as antioxidant and antibacterial actions, and this study aimed to standardize the extract of the plant against 4'''methoxyamentoflavone (as a main component of the extract) through a validated UPLC-MS/MS method and evaluate its antibacterial activity, which was followed by loading the standardized extract into a nanoemulsion to form a phytonanoemulsion (PNE), where the design analysis and optimization were performed through a simplex lattice design. The optimized PNE (PNE 3) was then loaded into HPMC/Pluronic F-127 gel (in ratio 1:4) to sustain the release of the active constituent. The heightened penetrability of PNE 3 gel was visualized via confocal laser scanning microscopy, and its prolonged effect was proved thru an in vivo study conducted on male Wistar rats. A histopathological study revealed the safety of the formulation when applied topically. Thus, PNE gel could be a potentially broad-spectrum antibacterial drug delivery system.

A Cosmeceutical Topical Water-in-Oil Nanoemulsion of Natural Bioactives: Design of Experiment, in vitro Characterization, and in vivo Skin Performance Against UVB Irradiation-Induced Skin Damages.

Introduction: Damage to human skin occurs either chronologically or through repetitive exposure to ultraviolet (UV) radiation, where collagen photodegradation leads to the formation of wrinkles and skin imperfections. Consequently, cosmeceutical products containing natural bioactives to restore or regenerate collagen have gained a remarkable attention as an ameliorative remedy. Methods: This study aimed to develop and optimize collagen-loaded water-in-oil nanoemulsion (W/O NE) through a D-optimal mixture design to achieve an ideal multifunctional nanosystem containing active constituents. Vit E was included as a constituent of the formulation for its antioxidant properties to minimize the destructive impact of UV radiation. The formulated systems were characterized in terms of their globule size, optical clarity, and viscosity. An optimized system was selected and evaluated for its physical stability, in vitro wound healing properties, and in vivo permeation and protection against UV radiation. In addition, the effect of collagen-loaded NE was compared to Vit C-loaded NE and collagen-/Vit C-loaded NEs mixture as Vit C is known to enhance collagen production within the skin. Results: The optimized NE was formulated with 25% oils (Vit E: safflower oil, 1:3), 54.635% surfactant/cosurfactant (Span 80: Kolliphor EL: Arlasolve, 1:1:1), and 20.365% water. The optimized NE loaded with either collagen or Vit C exhibited a skin-friendly appearance with boosted permeability, and improved cell viability and wound healing properties on fibroblast cell lines. Moreover, the in vivo study and histopathological investigations confirmed the efficacy of the developed system to protect the skin against UV damage. The results revealed that the effect of collagen-/Vit C-loaded NEs mixture was more pronounced, as both drugs reduced the skin damage to an extent that it was free from any detectable alterations. Conclusion: NE formulated using Vit E and containing collagen and/or Vit C could be a promising ameliorative remedy for skin protection against UVB irradiation.

Span 80/TPGS modified lipid-coated chitosan nanocomplexes of acyclovir as a topical delivery system for viral skin infections.

Acyclovir (ACR) is considered the gold standard drug for the treatment of skin viral infections caused by the herpes simplex or varicella-zoster virus. However, topical therapy with ACR is hindered by its poor skin penetrability, thus necessitating high doses and frequent administrations. This study was proposed to formulate a modified lipid-coated chitosan nanocomplexes (LCNCs) of acyclovir (ACR), containing span 80 and TPGS, to boost the dermal delivery of ACR and improve the therapeutic outcomes. LCNCs were formulated through a self-assembly method, and the statistical analysis and the optimization were performed via a general 23 factorial design. Three formulation variables were selected; namely, the amount of chitosan (A), the amount of glyceryl monooleate (GMO) (B), and span 80: D-α-tocopheryl polyethylene glycol succinate (Vitamin ETPGSorTPGS) ratio (C). Four measured attributes were determined; viz., the particle size (PS) in nm, the polydispersity index (PDI), the zeta potential (ZP) in mV, and the entrapment efficiency percentages (EE%). The optimal formulation (LCNCs 8), formulated with 600 mg chitosan, 120 mg GMO, and 3:1 span 80: TPGS ratio, possessed PS of 177.50 ± 1.41 nm, PDI value of 0.28 ± 0.02, ZP of -10.70 ± 0.85 mV, and EE% of 77.20 ± 2.40 %, and was able to sustain ACR release over 24 h. Transmission electron microscopy displayed LCNCs architecture as a polymeric core of chitosan with a lipid coat of GMO, and the solid-state characterization results confirmed the dispersion of ACR in LCNCs. The ex vivo permeation study and the in vivo dermatokinetics profile verified the boosted accumulation of ACR in the skin via LCNCs, while the confocal laser scanning microscopy revealed the heightened penetrability of LCNCs. The topical application of LCNCs demonstrated a safe profile via the modified Draize test and histopathological examinations. Inclusively, ACR-loaded LCNCs could be a promising topical formulation with an advanced dermal delivery status for the treatment of skin viral infections.

Tailoring thixotropic mixed-lipid nanoconstructs of voriconazole for the management of Vulvovaginal candidiasis: Formulation, statistical optimization, in vitro characterization and in vivo assessment.

Vulvovaginal candidiasis is a pervasive gynecological condition among women worldwide due to infection recurrence and resistance to conventional drugs. This calls for a novel formulation of alternative medication and with enhanced efficacy. This study aimed to fabricate mixed-lipid nanoconstructs (MLNCs) of voriconazole (VCZ) with a low concentration of lipids applying high shear homogenization and ultrasonication to form a semisolid formulation. Tefose 63 and Gelot 64 were employed as emulsifiers that are specified for vaginal preparations; as per their mucoadhesive properties and their texture enhancing characters, although usually used as lipids in different lipid carriers. A 24 factorial design was established and the optimized formulation was prepared using 10% total lipids, in which solid lipids (Sterotex NF: Glyceryl monostearate) ratio was 1.92:1 and the oils percentage was 30% (Maisine: Glyceryl monooleate, in the ratio of 1:1), and the emulsifiers mixture (Tefose 63: Gelot 64) ratio was 1:1, as 10% of total formulation weight. The optimized formulation with a viscosity of 964.49 ± 57.99 cp showed spherical nanoparticles (322.72 ± 15.11 nm) that entrapped 67.16 ± 3.45% of VCZ and exhibited release of 70.08 ± 2.87% in 8 h. The optimized formulation with high bioadhesive potentials significantly reduced the fungal burden in female Wistar rats infected with vaginal candidiasis, compared to the aqueous VCZ suspension (p < .05). Furthermore, in vivo histopathological findings proved the effectiveness and the safety of the optimized MLNCs formulation after vaginal application. Inclusively, MLNCs formulation could be a promising vaginal delivery system of VCZ for the treatment of vulvovaginal candidiasis.

3D printed ocusert laden with ultra-fluidic glycerosomes of ganciclovir for the management of ocular cytomegalovirus retinitis.

Cytomegalovirus (CMV) retinitisis a vision-threatening disease that principally afflicts immunosuppressed patients. For the management of the disease, Ganciclovir (GCV) is usually administered systemically, where patients may suffer severe untoward effects. The ocularly-applied alternatives are either the intravitreal injections, which are frequently administered due to GCV short half-life, or the sustained-release implants, which require surgical removal upon drug depletion. Both therapies are invasive and should be completed by a medical expert. The objective of this research was to formulate a non-invasive alternative represented in GCV loaded ultra-fluidic glycerosomes (UFGs), which are glycerosomes containing sodium taurocholate as an edge activator (EA), then incorporating the optimal UFGs in polylactic acid (PLA)-based 3D printed ocusert to prolong the release of GCV. The experimental design, the statistical analysis, and the optimization were performed via Design-Expert® software. The optimal formulation (UFGs 6; composed of 600 mg Phosphatidylcholine (PC), 20 mg cholesterol, 0.1:1 weight molar ratio of EA: PC and 1 gm glycerol) possessed nanovesicles (441.70 ± 1.13 nm) that entrapped 69.33 ± 0.28 % of GCV, with zeta potential value of -37.00 ± 0.42 mV and deformability index value of 74.68 ± 0.71. The confocal microscopy results showed the supreme penetration power of UFGs through the rabbit's cornea, compared to edge-activated vesicles and conventional glycerosomes from the laden ocusert. Moreover, the topical application of the ocusert laden with the optimal GCV loaded UFGs to the rabbits' eyes evidenced their safety as per the histopathological findings. Furthermore, a pharmacokinetic study in the rabbit's aqueous humor demonstrated the sustained release of GCV from the ocusert laden with the optimal GCV loaded UFGs over 5 days. Inclusively, the ocusert laden with UFGs could be considered as a non-invasive sustaining drug delivery system of GCV for the management of CMV retinitis.

Trehalosomes: Colon targeting trehalose-based green nanocarriers for the maintenance of remission in inflammatory bowel diseases.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) in inflammatory bowel diseases (IBDs) are contradictory between their beneficial effect in alleviating inflammation, and injurious outcomes in aggravating the symptoms of colitis. The study aimed to formulate trehalosomes (THs); innovative green trehalose-based nanocarriers, to alleviate the inflammation symptoms that might be provoked by NSAIDs in IBDs; as trehalose was proved to lighten the inflammation and the oxidative stress response, besides its resistance to the acidic conditions that rises its potentiality as a means for colon targeting. THs were fabricated using L-α-phosphatidylcholine (PL), trehalose, and transcutol, in a single step circumventing the incorporation of any organic solvent and loaded with Tenoxicam (TXM) as a model anti-inflammatory medication. A full 23 factorial design, using Design-Expert® software, was established to optimize the formulation variables. The optimized formulation composed of trehalose: PL at a weight ratio of 1:1, 377.72 mg transcutol, and sonicated for 4 min, possessed a spherical shape with a size of 268.61 nm and EE% of 97.83% and released 70.22% of its drug content over 24 h. The supreme protective action of TXM loaded THs compared to TXM suspension and drug-free THs was revealed by the suppression of the inflammatory biomarkers and the improved histopathology of the colonic tissue in male New Zealand rabbits. IL-1ß, IL-6, and TNF-alpha levels were notably dampened with TXM loaded THs, and oxidative stress markers, measured as GSH and MDA, were significantly altered. The study indicates the successful role of green THs in colon targeting and its anti-inflammatory characteristics in protecting against possible NSAIDs-driven exacerbation of colitis.

LC-MS/MS quantitation of phytocannabinoids and their metabolites in biological matrices.

Marijuana (i.e., cannabis) and its derivatives are considered the most commonly used of illicit drugs. Within the last two decades, phytocannabinoids and their synthetic analogues have emerged as potential medicines for the treatment of various disorders via targeting of the endocannabinoid system. Recently, some countries have legalized (medicinal/recreational) cannabis, which now allows for more research to be conducted. Accordingly, sensitive and specific analytical assays are required to identify and quantify these compounds in different human matrices. These analytical approaches were developed using mass spectrometric detection, where LC-MS/MS specifically has become the mainstay for the quantitative analysis of tetrahydrocannabinol and other cannabinoids. This is due to its superior selectivity and sensitivity, and ability to determine free and conjugate analytes within the same analysis. This tabular review of such methods is prefaced by a short overview of the major cannabinoids and some of their physiological actions.

Enhanced Permeation of Methotrexate via Loading into Ultra-permeable Niosomal Vesicles: Fabrication, Statistical Optimization, Ex Vivo Studies, and In Vivo Skin Deposition and Tolerability.

The aim of this study was to incorporate methotrexate (MTX) into ultra-permeable niosomal vesicles, containing cremophor RH40 as an edge activator (EA) and polyvinyl alcohol (PVA) as a stabilizer to enhance the drug permeation. Formulae were prepared by ethanol injection method following a Box-Behnken design in order to optimize the formulation variables (EA%, stabilizer %, and sonication time). To investigate the role of both cremophor RH40 and PVA, conventional MTX niosomes and MTX niosomes containing PVA only were fabricated. Drug entrapment efficiency percent (EE%), particle size (PS) analysis, zeta potential (ZP) measurements, and transmission electron microscopy (TEM) were conducted to characterize the vesicles. Cell viability studies and ex vivo permeation experiments of the optimized formula were conducted. Lastly, in vivo skin deposition of MTX from both the optimized formula and MTX solution was performed in rats. Besides, histopathological changes in rat skin were assessed. The optimized MTX ultra-permeable niosomal formula demonstrated spherical morphology, with an EE% of 65.16% and a PS of 453.6 nm. The optimized formula showed better physical stability in comparison with that of the same composition but lacking PVA. The cell viability studies verified the superior cytotoxicity of the optimized formula, and the ex vivo permeation studies revealed its ability to improve the drug permeation. The optimized formula demonstrated a significant deposition of MTX in rat dorsal skin, and histopathological evaluation confirmed the tolerability of the optimized formula in rats upon topical application. Accordingly, ultra-permeable noisomes, as a stable nanosystem, could be promising for effective delivery of MTX.

Mucoadhesive olaminosomes: A novel prolonged release nanocarrier of agomelatine for the treatment of ocular hypertension.

Mucoadhesive olaminosomes are novel nanocarriers designed to control agomelatine release and enhance its bioavailability. Olaminosomes were prepared using oleic acid, oleylamine and sorbitan monooleate adopting thin film hydration technique. Chitosan HCl was added to impart the mucoadhesive properties to the olaminosomes. Mucoadhesive olaminosomes were characterized for their particle size, in-vitro drug release and irritation potentiality in rabbit eyes. The reduction in intraocular pressure (IOP) through 8 h in male New Zealand Albino rabbits was measured after administration of the selected formulations. Histopathological changes in rabbits' eye were also evaluated. Results revealed that increasing the amount of the added oleylamine decreased the particle size of the resulted vesicles and increased the drug release rate. Olaminosomes showed enhanced drug absorption, hence more reduction in IOP was observed. Moreover, using chitosan HCl might increase the residence time of the formulation in the eye and hence improved the absorption of the drug. No histopathological changes in rabbits' eye were detected after the application of mucoadhesive olaminosomes concluding their safety on the ocular tissues. In conclusion, mucoadhesive olaminosomes succeeded in enhancing agomelatine bioavailability in rabbits' eyes confirming the development of a novel ocular nanocarrier for insoluble drugs.

Fabrication of levofloxacin polyethylene glycol decorated nanoliposomes for enhanced management of acute otitis media: Statistical optimization, trans-tympanic permeation and in vivo evaluation.

Acute otitis media (AOM), an infection in the middle ear, is usually treated through systemic administration of antibiotics because the stratum corneum of the intact tympanic-membrane (TM) possesses low permeability that holds against the ototopical antibiotics use. Therefore, the objective of this work was to encapsulate levofloxacin (LFX) into polyethylene glycol 400 (PEG 400) decorated nanoliposomes (PNLs) as an approach for drug delivery through the intact tympanic-membrane. LFX loaded-PNLs were primed by ethanol injection technique. A 23 full factorial design, using Design-Expert® software, was developed to optimize formulation variables. Particle size, polydispersity index, zeta potential and entrapment efficiency percent of the formulae were determined. The optimal formulation (F7, prepared using 30:1 phospholipid to drug weight ratio, 30 mg cholesterol and 125 mg PEG 400) exhibited improved ex vivo trans-tympanic permeation compared to nanoliposomes lacking PEG 400 and drug solution. In addition, F7 showed greater extent of in vivo deposition of LFX in the intact TM compared to drug solution. Furthermore, in vivo histopathological examination proved the tolerability of the PNLs after ototopical application. Overall, the obtained results revealed that PNLs could be promising for LFX delivery through intact TM providing means for the ototopical drug application for treatment of acute middle ear infections.

Ameliorative and protective effects of ginger and its main constituents against natural, chemical and radiation-induced toxicities: A comprehensive review.

Fatal unintentional poisoning is widespread upon human exposure to toxic agents such as pesticides, heavy metals, environmental pollutants, bacterial and fungal toxins or even some medications and cosmetic products. In this regards, the application of the natural dietary agents as antidotes has engrossed a substantial attention. One of the ancient known traditional medicines and spices with an arsenal of metabolites of several reported health benefits is ginger. This extended literature review serves to demonstrate the protective effects and mechanisms of ginger and its phytochemicals against natural, chemical and radiation-induced toxicities. Collected data obtained from the in-vivo and in-vitro experimental studies in this overview detail the designation of the protective effects to ginger's antioxidant, anti-inflammatory, and anti-apoptotic properties. Ginger's armoury of phytochemicals exerted its protective function via different mechanisms and cell signalling pathways, including Nrf2/ARE, MAPK, NF-ƙB, Wnt/ß-catenin, TGF-ß1/Smad3, and ERK/CREB. The outcomes of this review could encourage further clinical trials of ginger applications in radiotherapy and chemotherapy regime for cancer treatments or its implementation to counteract the chemical toxicity induced by industrial pollutants, alcohol, smoking or administered drugs.

Formulation and in vivo assessment of terconazole-loaded polymeric mixed micelles enriched with Cremophor EL as dual functioning mediator for augmenting physical stability and skin delivery.

The aim of the current study was to formulate terconazole (TCZ) loaded polymeric mixed micelles (PMMs) incorporating Cremophor EL as a stabilizer and a penetration enhancer. A 23 full factorial design was performed using Design-Expert® software for the optimization of the PMMs which were formulated using Pluronic P123 and Pluronic F127 together with Cremophor EL. To confirm the role of Cremophor EL, PMMs formulation lacking Cremophor EL was prepared for the purpose of comparison. Results showed that the optimal PMMs formulation (F7, where the ratio of total Pluronics to drug was 40:1, the weight ratio of Pluronic P123 to Pluronic F127 was 4:1, and the percentage of Cremophor EL in aqueous phase was 5%) had a high micellar incorporation efficiency (92.98 ± 0.40%) and a very small micellar size (33.23 ± 8.00 nm). Transmission electron microscopy revealed that PMMs possess spherical shape and good dispersibility. The optimal PMMs exhibited superior physical stability when compared with the PMMs formulation of the same composition but lacking Cremophor EL. Ex vivo studies demonstrated that the optimal PMMs formula markedly improved the dermal TCZ delivery compared to PMMs lacking Cremophor EL and TCZ suspension. In addition, it was found that the optimal PMMs exhibited a greater extent of TCZ deposition in the rat dorsal skin relative to TCZ suspension. Moreover, histopathological studies revealed the safety of the optimal PMMs upon topical application to rats. Consequently, PMMs enriched with Cremophor EL, as a stable nano-system, could be promising for the skin delivery of TCZ.

Fabrication of novel ultradeformable bilosomes for enhanced ocular delivery of terconazole: In vitro characterization, ex vivo permeation and in vivo safety assessment.

The objective of this work was to encapsulate terconazole (TCZ), a water insoluble antifungal drug, into novel ultradeformable bilosomes (UBs) for achieving enhanced ocular delivery. In addition to the constituents of the conventional bilosomes; namely, Span 60, cholesterol, and the bile salts, UBs contain an edge activator which imparts extra elasticity to the vesicles and consequently hypothesized to result in improved corneal permeation. In this study, TCZ loaded UBs were prepared utilizing ethanol injection method according to 23 full factorial design. The investigation of the influence of different formulation variables on UBs properties and selection of the optimum formulation was done using Design-Expert® software. The selected UBs formulation (UB1; containing 10mg bile salt and 5mg Cremophor EL as an edge activator) showed nanosized spherical vesicles (273.15±2.90nm) and high entrapment efficiency percent (95.47±2.57%). Results also revealed that the optimum UBs formulation exhibited superior ex vivo drug flux through rabbit cornea when compared with conventional bilosomes, niosomes, and drug suspension. Furthermore, in vivo ocular tolerance and histopathological studies conducted using male albino rabbits proved the safety of the fabricated UBs after topical ocular application. Overall, the obtained results confirmed that UBs could be promising for ocular drug delivery.