Nano-vesicular systems for melanocytes targeting and melasma treatment: In-vitro characterization, ex-vivo skin retention, and preliminary clinical appraisal.

Melasma represents an acquired melanogenesis disorder resulting in skin's hyperpigmentation effect. Although several approaches are adopted for melasma treatment, nanotechnology presents the most convenient one. Therefore, the present work aimed to formulate and characterize three nano-vesicular systems namely, liposomes, penetration enhancer containing vesicles (PEVs) and invasomes to enhance the topical delivery of the skin whitening agent; alpha arbutin (α-arbutin) for the treatment of melasma. Liposomes were prepared according to a 23 full factorial design and the selected formula was further employed for the preparation of PEVs and invasomes. Results showed that the three vesicular systems exhibited nano-sizes ranging from 151.95 to 672.5 nm, negative charges ranging from -12.50 to -28.20 mV, high entrapment efficiencies ranging from 80.59 to 99.53 %, good stability and prolonged-release of α-arbutin for 24 h after dispersion in hydrogel form. The deposition study from the vesicular hydrogel confirmed their effectiveness for the drug's accumulation in the skin reaching an average of 1.6-fold higher in the stratum corneum, 1.6-1.8-fold higher in the epidermis, and 1.6-1.8-fold higher in the dermis compared to the free drug dispersion in hydrogel. A preliminary clinical split-face study on patients suffering from melasma revealed that α-arbutin-loaded liposomes and PEVs in hydrogel forms showed better clinical outcomes compared to the free α-arbutin hydrogel as well as to the previously published α-arbutin encapsulated in chitosan nanoparticles and dispersed in hydrogel form. This delineates the aforementioned nano-vesicular systems as effective and clinically superior delivery means for melasma management.

In Vitro and in vivo characterization of nasal pH-Responsive in-situ hydrogel of Candesartan-loaded invasomes as a potential stroke treatment.

Candesartan (CDN) is a useful anti-stroke medication because it lowers blood pressure, inflammation, oxidative stress, angiogenesis and apoptosis. However, CDN has limited efficacy due to its low solubility and poor bioavailability. This study set out to develop nasal pH-responsive in situ hydrogel of CDN-loaded invasomes a (PRHCLI) for enhancing CDN's release, penetration, bioavailability, and effectiveness as a possible treatment for stroke. Based on the results of the pre-formulation investigation, the optimum CLI formulation for intravasomal delivery of CDN was determined to be 3% of phospholipid, 0.16% of cholesterol, 3% of ethanol, and 1% of cineole. The optimum formulation significantly enhanced CDN permeation and release by 2.06-fold and 59.06%, respectively. The CLI formulation was added to a mixture of chitosan (0.67%w/v) and glyceryl monooleate (0.27%v/v) to develop PRHCLI. The PRHCLI formulation enhanced the release and permeation of CDN relative to free CDN by 2.15 and 2.76 folds, respectively. An experimental rat stroke model was utilized for in vivo studies to evaluate the bioavailability, effectiveness, and toxicity of the PRHCLI formulation. The nasal PRHCLI drops increased the CDN's bioavailability by 3.20-fold compared to oral free CDN. Increased grip strength and decreased flexion, spontaneous motor activity, and Morris Water Maze scores in comparison to oral free CDN showed that nasal PRHCLI drops have better anti-stroke activity. The toxicity evaluation revealed the safety of nasal PRHCLI. Hence, nasal PRHCLI drops may represent a promising avenue as a stroke therapy.

Improving the targeting and therapeutic efficacy of anastrazole for the control of breast cancer: In vitro and in vivo characterization.

Anastrazole (ASZ) is an effective aromatase inhibitor that is used for breast cancer treatment. Nevertheless, ASZ's effectiveness is diminished due to its low water solubility, unregulated release, absence of targeting, and inadequate patient compliance. The goal of the research was to create a hydrogel formulation of ASZ-loaded invasomes (ALI) to enhance the solubility, permeability, targeting, and efficacy of ASZ while also sustaining its release for treatment of breast cancer. The optimized ALI formulation was determined to be 3%w/v phospholipid, 0.15%w/v cholesterol, 3%v/v ethanol, and 1 %v/v cineole based on the results of the pre-formulation study. After conducting in vitro characterization of the optimum formulation, it was combined with carbopol for in vivo examination of its anti-tumor efficacy in a rat model of 7, 12-dimethylbenzanthracene. Compared to free ASZ, ALI hydrogel increased its penetration by 10.67 times and prolonged its release by 64.02%. Compared to the control positive group, ALI hydrogel reduced tumor volume by 99.19% and mortality by 10.93%. The anti-tumor effect of the ALI hydrogel was demonstrated by its ability to accumulate more ASZ in tumors and reduce hypercellular tumors. Overall, transdermal ALI hydrogel shows potential as a promising approach for treating breast cancer.

Luteolin-loaded Invasomes Gel for Transdermal Delivery: Development, Optimization, in-vitro, and Preclinical Evaluation.

Luteolin (LN), is an herbal bioactive flavone and exhibits many pharmacological activities. However, the bioavailability of LN is limited due to its inadequate solubility and significant first-pass metabolism. The present study developed transdermal LN-loaded invasomes (IVM) gel to improve the therapeutic efficacy. The LN-IVM was prepared and optimized by 2 3 factorial designs. LN-IVM was characterized for physicochemical parameters. The optimized LN-IVM (LN-IVMopt) was incorporated into HPMC-K4M gel and evaluated for viscosity, spreadability, and irritation. Further LN-IVM gel was evaluated for drug release, ex-vivo permeation, pharmacokinetic and pharmacodynamics study. LN-IVMopt showed 300.8±2.67 nm of VS, 0.258 of PDI, 89.92±1.29% of EE, and a zeta potential of -18.2 mV. LN-IVM exhibited spherical morphology. FTIR and XRD results demonstrated that LN was encapsulated into IVM matrix. The optimized IVM gel (LN-IVMoptG2) exhibited excellent viscosity, spreadability, and sustained release of LN (91.32±2.95% in 24 h). LN-IVMoptG2 exhibited statistically significant (p < 0.05) higher flux (5.79 µg/h/cm2 ) than LN-gel (2.09 µg/h/cm2 ). The apparent permeability coefficient of plain LN gel and LN- IVMoptG was 1.15×10-5 cm/min and 3.22×10-5 cm/min respectively. LN-IVMoptG2 showed no irritation (score 0.0) throughout the study (60 min). The relative bioavailability of LN from LN-IVMopt-G2 (transdermal) was 2.38±0.19 fold as compared to LN-Sus (oral) and 1.81±0.15-fold than plain LN-gel (transdermal). The LN-IVMoptG2 showed a substantial lessening in the paw volume up to 12 h (17.48±1.94% swelling) than plain LN-gel (44.77±2.82% swelling). The finding concluded that the IVM gel is a novel, effective, and safe approach for the delivery of LN transdermally to improve its therapeutic efficacy.

Beyond Skin Deep: Phospholipid-Based Nanovesicles as Game-Changers in Transdermal Drug Delivery.

Transdermal administration techniques have gained popularity due to their advantages over oral and parenteral methods. Noninvasive, self-administered delivery devices improve patient compliance and control drug release. Transdermal delivery devices struggle with the skin's barrier function. Molecules over 500 Dalton (Da) and ionized compounds don't permeate through the skin. Drug encapsulation in phospholipid-based vesicular systems is the most effective skin delivery technique. Vesicular carriers include bi-layered liposomes, ultra-deformable liposomes, ethanolic liposomes, transethosomes, and invasomes. These technologies enhance skin drug permeation by increasing formula solubilization, partitioning into the skin, and fluidizing the lipid barrier. Phospholipid-based delivery systems are safe and efficient, making them a promising pharmaceutical and cosmeceutical drug delivery technique. Still, making delivery systems requires knowledge about the physicochemical properties of the drug and carrier, manufacturing and process variables, skin delivery mechanisms, technological advances, constraints, and regulatory requirements. Consequently, this review covers recent research achievements addressing the mentioned concerns.

pH-Sensitive In Situ Gel of Mirtazapine Invasomes for Rectal Drug Delivery: Protruded Bioavailability and Anti-Depressant Efficacy.

The present research emphasizes fabrication alongside the assessment of an innovative nano-vesicular membranous system known as invasomes (NVMs) laden with Mirtazapine for rectal administration. This system could circumvent the confines of orally administered counterparts regarding dose schedules and bioavailability. Mirtazapine invasomes were tailored by amalgamating phospholipid, cineole, and ethanol through a thin-film hydration approach rooted in the Box-Behnken layout. Optimization of composition parameters used to fabricate desired NVMs' physicochemical attributes was undertaken using the Design-Expert® program. The optimal MRZ-NVMs were subsequently transformed to a pH-triggered in situ rectal gel followed by animal pharmacodynamic and pharmacokinetic investigations relative to rectal plain gel and oral suspension. The optimized NVMs revealed a diameter size of 201.3 nm, a z potential of -28.8 mV, an entrapment efficiency of 81.45%, a cumulative release within 12 h of 67.29%, and a cumulative daily permeated quantity of 468.68 µg/cm2. Compared to the oral suspension, pharmacokinetic studies revealed a 2.85- and 4.45-fold increase in calculated rectal bioavailability in circulation and brain, respectively. Pharmacodynamic and immunohistopathology evaluations exposed superior MRZ-NVMs attributed to the orally administered drug. Consequently, rectal MRZ-NVMs can potentially be regarded as a prospective nanoplatform with valuable pharmacokinetics and tolerability assets.

Terpene-based novel invasomes: pioneering cancer treatment strategies in traditional medicine.

Health care workers have faced a significant challenge because of the rise in cancer incidence around the world during the past 10 years. Among various forms of malignancy skin cancer is most common, so there is need for the creation of an efficient and safe skin cancer treatment that may offer targeted and site-specific tumor penetration, and reduce unintended systemic toxicity. Nanocarriers have thus been employed to get around the issues with traditional anti-cancer drug delivery methods. Invasomes are lipid-based nanovesicles having small amounts of terpenes and ethanol or a mixture of terpenes and penetrate the skin more effectively. Compared to other lipid nanocarriers, invasomes penetrate the skin at a substantially faster rate. Invasomes possess a number of advantages, including improved drug effectiveness, higher compliance, patient convenience, advanced design, multifunctionality, enhanced targeting capabilities, non-invasive delivery methods, potential for combination therapies, and ability to overcome biological barriers,. These attributes position invasomes as a promising and innovative platform for the future of cancer treatment. The current review provides insights into invasomes, with a fresh organizational scheme and incorporates the most recent cancer research, including their composition, historical development and methods of preparation, the penetration mechanism involving effect of various formulation variables and analysis of anticancer mechanism and the application of invasomes.

Transdermal application of diacerin loaded-terpene enriched invasomes: an approach to augment anti-edema and nociception inhibition activity.

This study aimed to formulate diacerein loaded terpene-enriched invasomes (DCN-TINV) to fulfill a fruitful management of osteoarthritis. A 23 factorial design was adopted, including A: cholesterol concentration (%w/v), B: ethanol volume (mL) and C: phosphatidylcholine: drug ratio as the studied factors. Invasomes were constructed using the thin film hydration technique. Herein, percent entrapment efficiency (EE%), particle size (PS), poly-dispersity index (PDI) and zeta potential (ZP) were statistically analyzed using Design-Expert® software to select the optimum formula. The selected criteria for detecting the optimum formula were restricting PS (<350 nm), dismissing PDI, magnifying ZP (as absolute value) and EE%. The selected formula was further scrutinized through multiple in-vitro studies, including Fourier-transform infrared spectroscopy, differential scanning calorimetry, pH measurement, stability study, release profile and transmission electron microscopy. Furthermore, the ex-vivo performance was evaluated through ex-vivo skin permeation and deposition. Finally, it was subjected to an array of in-vivo tests, namely Draize test, histopathology, In-vivo skin penetration, edema size, and nociception inhibition measurements. The optimum formula with desirability (0.913) demonstrated EE% (89.21% ± 2.12%), PS (319.75 ± 10.11 nm), ZP (-55 ± 3.96 mV) and a prolonged release profile. Intriguingly, revamped skin permeation (1143 ± 32.11 µg/cm2), nociception inhibition (77%) and In-vivo skin penetration (144 µm) compared to DCN suspension (285 ± 21.25 µg/cm2, 26% and 48 µm, respectively) were displayed. The optimum DCN-TINV exhibited plausible safety and stability profiles consolidated with auspicious efficacy for better management of osteoarthritis.

Improving the bioavailability and therapeutic efficacy of felodipine for the control of diabetes-associated atherosclerosis: In vitro and in vivo characterization.

Felodipine has proven to be effective as an atherosclerosis therapy because it increases blood flow to the vessel wall. However, the poor solubility, low bioavailability, and hepatic first-pass metabolism of oral felodipine compromise its therapeutic effectiveness. The study's goal is to create a nasal pH-sensitive hydrogel of felodipine-loaded invasomes (IPHFI) that will improve felodipine's release, permeation, bioavailability, and efficacy as a potential diabetes-associated atherosclerosis therapy. According to the pre-formulation study, the felodipine-loaded invasomes formulation composed of phospholipid (3%w/v), cholesterol (0.16%w/v), ethanol (3%v/v) and cineole (1%v/v) was chosen as the optimum formulation. The optimum formulation was characterized in vitro and then mixed with a mixture of chitosan and glyceryl monooleate to make the IPHFI formulation. The IPHFI formulation enhanced the release and permeation of felodipine by 2.99 and 3-fold, respectively. To assess the efficacy and bioavailability of the IPHFI formulation, it was studied in vivo using an experimental atherosclerosis rat model. Compared to oral free felodipine, the nasal administration of the IPHFI formulation increased the bioavailability by 3.37-fold and decreased the serum cholesterol, triglycerides, LDL, and calcification score by 1.56, 1.53, 1.80, and 1.18 ratios, respectively. Thus, nasal IPHFI formulation may represent a promising diabetes-associated atherosclerosis therapy.

Liposomes and Other Nanocarriers for the Treatment of Acne Vulgaris: Improved Therapeutic Efficacy and Skin Tolerability.

Acne vulgaris is a common dermatologic disorder that affects approximately 85% of teenagers, which significantly impacts the quality of life in adolescents. It is a chronic disease of the sebaceous follicles that is multifactorial in etiology. Topical treatment is the first choice for mild and moderate acne, while systemic therapy is reserved for severe and certain moderate cases. Topical treatments include retinoids (e.g., tretinoin and adapalene), antibiotics (e.g., clindamycine), and other agents (e.g., benzoyl peroxide and azelaic acid), often applied in combination. The mechanisms of action include antimicrobial, anti-inflammatory, and keratolytic activities, as well as sebum secretion reduction, and the normalization of follicular keratinization. However, these topical agents commonly induce side effects, such as dryness, burning, stinging, peeling, redness, erythema, and photosensitivity. Therefore, there is a need to reduce the side effects of anti-acne drugs, while maintaining or enhancing their therapeutic effectiveness. This article aims to comprehensively outline nanotechnology strategies, particularly the use of phospholipid-based nanocarriers like liposomes and related vesicles, to enhance therapeutic efficacy, skin tolerability, and patient compliance in the treatment of acne vulgaris. In addition, novel active ingredients encapsulated in vesicles beyond those recommended in official guidelines are discussed.

Nanovesicular ultraflexible invasomes and invasomal gel for transdermal delivery of phytopharmaceuticals.

Tweetable abstract Invasomes and invasomal gel are ultraflexible, soft vesicular, phospholipid based nanocarriers with deeper skin penetration ability for transdermal applications of drugs and phytopharmaceuticals.

Design, optimization, and in vivo evaluation of invasome-mediated candesartan for the control of diabetes-associated atherosclerosis.

Atherosclerosis is an inflammatory disease characterized by the accumulation of arterial plaque. Diabetes mellitus stands out as a major risk factor for atherosclerosis. Candesartan is a potent angiotensin II receptor antagonist that enhances arterial blood flow and reduces insulin resistance. However, oral candesartan has limited activity because of its low bioavailability, water solubility, hepatic first-pass degradation, and efficacy. The current study aims to develop nasal candesartan-loaded invasome (CLI) drops to improve candesartan's permeation, release, and bioavailability as a potential treatment for diabetes-associated atherosclerosis. Design expert software was used to prepare various CLI formulations to determine the impact of the concentrations of ethanol, cineole, and phospholipid. The desirability index was used to estimate the optimized formulation composition to maximize entrapment efficiency and minimize vesicle size. The optimized formulation had a 1% ethanol concentration, a 1.5% cineole concentration, and a 2.32% phospholipid concentration. The selected optimized formulation was then tested in a rat model of diabetes and atherosclerosis to evaluate its activity. The results showed that nasal CLI drops significantly raised serum HDL levels by a ratio of 1.42 and lowered serum glucose, cholesterol, triglycerides, LDL, and VLDL levels by 69.70%, 72.22%, 36.52%, 58.0%, and 65.31%, respectively, compared with diabetic atherosclerotic rats, throwing an insight on the potential for promising anti-diabetic and anti-atherosclerotic activities. Additionally, atherosclerotic lesions were improved in rats treated with CLI, as shown in histopathology. In conclusion, the results of this investigation showed that treatment with nasal CSN-loaded invasome formulation drops prevented the initiation and progression of diabetes-associated atherosclerosis.

Effect of invasome composition on membrane fluidity, vesicle stability and skin interactions.

Invasomes have been widely exploited to enhance the percutaneous permeation of drugs. On the other hand, few studies have been dedicated to evaluating how their composition impacts the interaction with the skin, vesicle rigidity and stability, which was the focus of this investigation. Light scattering and spectroscopic techniques were considered for vesicle characterization. The addition of cholesterol (CHOL) into the phosphatidylcholine (PC) vesicles led to increased membrane rigidity (from PC:CHOL 5:0.5) and a concentration-dependent disorder effect on skin domains. Nevertheless, these vesicles were showed to be less stable. Ethanol, in turn, resulted in larger and more flexible vesicles, which can be attributed to its preferential distribution in headgroups of PC. The effect of limonene on membrane rigidity was dependent on the vesicle composition. It reduced the rigidity when few constituents were considered, but an opposite effect was observed for vesicles containing PC, CHOL, ethanol and limonene. Competitive effects of limonene and CHOL by the same domains in PC could explain these findings. Limonene was crucial to obtaining more monodisperse vesicles and it showed a synergistic action with CHOL in the disruption of lipid domains in the skin. Invasomes were more stable than liposomes. CHOL-free invasomes showed to be stable for up to 40 days at room temperature.

Development of Soft Luliconazole Invasomes Gel for Effective Transdermal Delivery: Optimization to In-Vivo Antifungal Activity.

Luliconazole (LZ) is a good candidate for the treatment of fungal infection topically but has limitations, i.e., poor solubility and poor permeability to skin. Due to these limitations, multiple administrations for a long time are required to treat the inflection. The aim of the present study was to develop the invasomes (IVS) gel of LZ to improve the topical antifungal activity. The IVS was prepared by the thin-film hydration method and optimized by Box-Bhekhen design software. The optimized LZIVS (LZIVSopt) has 139.1 ± 4.32 nm of vesicle size, 88.21 ± 0.82% of entrapment efficiency, 0.301 ± 0.012 of PDI, and 19.5 mV (negative) of zeta potential. Scanning microscopy showed a spherical shape of the vesicle. FTIR spectra showed there is no interaction between the drug and lipid. Thermogram showed that the LZ is encapsulated into the LZIVS matrix. LZIVSopt gel (LZIVSopt-G3) exhibited optimum viscosity (6493 ± 27 cps) and significant spreadability (7.2 g·cm/s). LZIVSopt-G3 showed 2.47-fold higher permeation than pure LZ-gel. LZIVSopt-G3 did not show any edema or swelling in the skin, revealing that the developed formulation is non-irritant. LZIVSopt-G3 exhibited significant inhibition of the fungus infection (C. albicans) in the infected rats. The finding concluded that IVS gel is a good carrier and an attractive approach for the enhancement of topical delivery of LZ to treat the fungal infection.

Linalool-Incorporated Synergistically Engineered Modified Liposomal Nanocarriers for Enhanced Transungual Delivery of Terbinafine against Onychomycosis.

This work investigates the synthesis of linalool-containing invasomes for terbinafine (TBF-IN) in order to increase the solubility, bioavailability, and nail permeability of terbinafine (TBF) for transungual administration. TBF-IN was created utilising the thin-film hydration technique, and with the Box-Behnken design (BBD), optimisation was carried out. TBF-INopt were investigated for vesicle size, zeta potential, PDI (Polydispersity index), entrapment efficiency (EE) and in vitro TBF release. In addition, nail permeation analysis, TEM (transmission electron microscopy), and CLSM (confocal scanning laser microscopy) were performed for further evaluation. The TBF-INopt exhibited spherical as well as sealed vesicles with a considerably small size of 146.3 nm, an EE of 74.23 per cent, a PDI of 0.1612, and an in vitro release of 85.32 per cent. The CLSM investigation revealed that the new formulation had better TBF nail penetration than the TBF suspension gel. The antifungal investigation demonstrated that the TBF-IN gel has superior antifungal activity against Trichophyton rubrum and Candida albicans compared to the commercially available terbinafine gel. In addition, an investigation of skin irritation using Wistar albino rats indicates that the TBF-IN formulation is safe for topical treatment. This study confirmed that the invasomal vesicle formulation is an effective vehicle for the transungual delivery of TBF for the treatment of onychomycosis.

Augmented Transdermal Delivery of Curcumin for the Effective Management of Plaque Psoriasis - Design, Formulation, Characterisation, and In Vivo Studies.

Psoriasis is a recurrent, life-threatening anti-inflammatory condition that affects nearly 1-3% of the global population. It is an autoimmune illness distinguished by hyperplasia of skin cells or fast skin cell development, resulting in abnormally irritating scales and skin patches. Curcumin, as a selective phosphorylase kinase inhibitor, actively suppresses inflammation and keratinocyte proliferation in psoriasis. However, limited solubility in water and poor skin permeability poses a significant hurdle in curcumin's topical effectiveness in psoriasis. The present study focuses on enhancing the solubility and skin permeability of curcumin for better transdermal application. Curcumin-loaded invasomes were formulated, and a factorial design was applied to study the effect of the type of terpenes and their concentrations on the properties of prepared invasomes. A topical gel was formulated using the optimised invasomal formulation which was further evaluated for anti-psoriatic potential in BALB/c mice. The optimised formulation showed 85.84 ± 0.56% entrapment efficiency and a vesicle size of 302.33 ± 1.53 nm. The invasomal gel of the optimised formulation showed a permeation flux of 3 times greater than the plain gel. In vivo studies demonstrated that the invasomal gel of curcumin promoted faster and earlier recovery in psoriatic mice than conventional curcumin gel.

Synthesis of Carvacrol-Loaded Invasomes Nanoparticles Improved Acaricide Efficacy, Cuticle Invasion and Inhibition of Acetylcholinestrase against Hard Ticks.

Carvacrol is a monoterpenoid phenol found in many essential oils that has antibacterial, antifungal and antiparasitic activities. Drug loaded-invasome systems are used to deliver drugs utilizing nanoparticles to improve bioavailability, efficacy, and drug release duration. As a result, the present study developed carvacrol-loaded invasomes and evaluated their acaricidal effect against Rhipicephalus annulatus (cattle tick) and Rhipicephalus sanguineus (dog tick). Carvacrol loaded-invasome (CLI) was prepared and characterized using UV/Vis spectrophotometer, zeta potential measurements, Scanning Transmission Electron Microscopy (STEM), Fourier Transform Infrared (FT-IR) Spectroscopy, and Differential Scanning Calorimetry Analysis. CLI (5%) induced significant mortality (100%) in R. annulatus adult ticks with LC50 of 2.60%, whereas the LC50 of pure carvacrol was 4.30%. Carvacrol and CLI were shown to have a significant larvicidal action on both tick species, with LC50s of 0.24 and 0.21% against R. annulatus and 0.27 and 0.23% against R. sanguineus, respectively. Carvacrol and CLI (5%) induced significant repellent activities for 24 h against R. annulatus and R. sanguineus, as evidenced by the rod method and the petri-dish selective area choice method, respectively. High-performance liquid chromatography (HPLC) demonstrated that the CLI form had 3.86 times the permeability of pure carvacrol. Moreover, carvacrol and CLI inhibited acetylcholinesterase activity and decreased glutathione and malonedealdehyde levels in the treated ticks. In conclusion, invasomes significantly improved adulticidal and repellency activities of carvacrol against both tick species.

The deleterious effect of xylene-induced ear edema in rats: Protective role of dexketoprofen trometamol transdermal invasomes via inhibiting the oxidative stress/NF-κB/COX-2 pathway.

Pain and inflammation could have a negative impact on a patient's quality of life and performance, causing them to sleep less. Dexketoprofen trometamol (DKT) is a water-soluble, nonselective NSAIDs. Because DKT is quickly eliminated in the urine after oral delivery, its efficacy is limited and must be taken repeatedly throughout the day. The main ambition of this work is to develop and characterize the potential of invasomes to enhance the transdermal transport of DKT to achieve efficient anti-inflammatory and pain management. The optimum formulation (C1) showed the least %RE (53.29 ± 2.68 %), the highest %EE (86.51 ± 1.05 %), and spherical nanosized vesicles (211.9 ± 0.57 nm) with (PDI) of 0.353 ± 0.01 and (ZP) of -19.15 ± 2.45 mV. DKT flux and deposition in stratum corneum, epidermal, and dermal skin layers were significantly augmented by 2.6 and 3.51 folds, respectively, from the optimum invasomal gel formulation (C1-G) compared to DKT conventional gel (DKT-G). The anti-inflammatory activity of C1-G was evaluated using a model of xylene-induced ear edema in rats. Xylene exposure upregulated the ear expression of COX-2 level and MPO activity. Xylene also significantly increased the ear NF-κB p65, TNF-α, IL-Iß, and MDA levels. Furthermore, xylene induced oxidative stress, as evidenced by a significant decrease in ear GSH and serum TAC levels. These impacts were drastically improved by applying C1-G compared to rats that received DKT-G and plain invasomal gel formulation (plain C1-G). The histopathological findings imparted substantiation to the biochemical and molecular investigations. Thereby, C1-G could be a promising transdermal drug delivery system to improve the anti-inflammatory and pain management of DKT.

Biodistribution of the photosensitizer temoporfin after in vivo topical application of temoporfin-loaded invasomes in mice bearing subcutaneously implanted HT29 tumor.

Temoporfin (mTHPC) has a great potential for the topical photodynamic therapy. However, it presents a highly hydrophobic second generation photosensitizer with low percutaneous penetration. In order to use mTHPC for dermal/transdermal delivery it is necessary to employ some of the penetration enhancement methods. In this study invasomes were used as a highly effective drug nanocarrier system to enhance its skin penetration, being composed of non-hydrogenated soybean lecithin (10% w/v), ethanol (3.3%w/v), a mixture of terpenes (1% w/v of the mixture cineole:citral:d-limonene = 45:45:10 v/v) and phosphate buffer saline up to 100% w/v. A pharmacokinetic/biodistribution study was performed in mice bearing s.c. implanted human colorectal tumor HT29 upon the application of mTHPC-loaded invasomes onto the skin above the underlying tumor. The aim was to obtain the biodistribution profile of mTHPC i.e. to gain data on mTHPC-distribution in the body (tumor, treated skin, muscle, blood, liver and untreated skin) of mice after the topical application of mTHPC-loaded invasomes. The results revealed that a significant mTHPC-amount was found in treated skin already after 2 h of incubation time. As to the tumor, significant amounts were found after 12 h, while the highest mTHPC-amount was found after 24 h. This study showed that invasomes applied onto the skin may deliver mTHPC to the tumor being necessary for PDT. Since mTHPC was also found in blood and liver, transdermal mTHPC delivery was confirmed. In conclusion, mTHPC-invasomes could be used for topical PDT of cutaneous and subcutaneous lesions, however with general photoxicity induced by systemic apsorption of mTHPC lasting only for 2 weeks. Additionally, due to systemic absorption of mTHPC after invasomes application onto the skin, they could be used transdermally for the PDT treatment of diseases, which need systemic drug absorption. However, it should be emphasized that mice were used in the study, differing in the skin properties compared to human skin. Thus, additional studies should be conducted.

Utilization of propranolol hydrochloride mucoadhesive invasomes as a locally acting contraceptive: in-vitro, ex-vivo, and in-vivo evaluation.

It was found that propranolol hydrochloride (PNL), which is a beta-blocker used for hypertension treatment, has a potent spermicidal activity through local anesthetic activity or beta-blocking effect on sperm cells subsequently it could be used as a contraceptive remedy. This study aimed to entrap PNL into invasomes (INVs) and then formulate it as a locally acting contraceptive gel. PNL-loaded mucoadhesive INVs were prepared via the thin-film hydration technique. The D-optimal design was utilized to fabricate INVs employing lipid concentration (X1), terpenes concentration (X2), terpenes type (X3), and chitosan concentration (X4) as independent variables, while their impact was observed for entrapment efficiency percent (Y1; EE%), particle size (Y2; PS), zeta potential (Y3; ZP), and amount of drug released after 6 h (Y4; Q6h). Design Expert® was bestowed to nominate the desired formula. The selected INV was subjected to further studies and formulated into a mucoadhesive gel for ex-vivo and in-vivo investigations. The optimum INV showed a spherical shape with EE% of 65.01 ± 1.24%, PS of 243.75 ± 8.13 nm, PDI of 0.203 ± 0.01, ZP of 49.80 ± 0.42 mV, and Q6h of 53.16 ± 0.73%. Differential scanning calorimetry study asserted the capability of INVs to entrap PNL. Permeation studies confirmed the desired sustained effect of PNL-loaded INVs-gel compared to PNL-gel, INVs, and PNL solution. Sperm motility assay proved the potency of INVs-gel to inhibit sperm motility. Besides, the histopathological investigation verified the tolerability of the prepared INVs-gel. Taken together, the gained data justified the efficacy of PNL-loaded INVs-gel as a potential locally acting contraceptive.