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Berberine is an isoquinolone alkaloid present in a wide variety of plants. Other than Type 2 diabetes and hypertension it is also found to have an effect in lowering blood cholesterol levels. However, because of its poor oral bioavailability and substantial first pass hepatic metabolism it is consumed in higher dosage leading to side effects. To reduce dosage and avoid adverse effects, transdermal delivery is investigated using transethosomal gel as a carrier. Transethosomes are ethanolic nanocarriers that are specifically designed for the dermal or transdermal delivery route as it has enhanced permeation of the vesicles. In our study we have successfully investigated the potential use of berberine loaded transethosomal gel (BBR-TE) as a carrier for transdermal delivery. Three-level three-factorial Box Behnken Design was used to optimize BBR-TE (Opt-BBR-TE). The optimized formulation was further evaluated and found to have a particle size of 165.70 nm with entrapment efficiency of 79.60±4.07%. The in vitro drug release study suggested the non-Fickian transport mechanism. The ex vivo skin permeation was found to be 94.35±3.64% when compared to berberine conventional formulation. Berberine has also shown promising antioxidant activity when compared to the standard solution and was entrapped inside TE vesicles in non-crystalline form. The Opt-BBR-TE was converted into gel form. Various parameters of the gel such as pH, Drug Content, Spreadability and extrudability were found to have promising results. Present study data revealed that the developed transethosomal gel formulation was found to be a potentially useful drug carrier for transdermal delivery of berberine. [ABSTRACT FROM AUTHOR]

In an effort to tackle the skin reactions frequently observed with topical application of ivermectin (IVM), a study was conducted to develop and optimize transethosomes (TESMs) loaded with IVM for scabies treatment. A three-factor, two-level (23) full factorial design was employed. Soyabean phosphatidylcholine concentration (A), ethanol concentration (B) and Span 60 amount (C) were studied as independent factors, while entrapment efficiency (EE), particle size (PS), polydispersity index (PDI), zeta potential (ZP) and drug release after 6 h (Q6h) were characterized. The skin sensitivity of the optimized formulation was evaluated by skin irritation test and histopathological examination. The EE% ranged from 88.55 ± 0.576% to 94.13 ± 0.305%, PS was from 318.033 ± 45.61 nm to 561.400 ± 45.17 nm, PDI was from 0.328 ± 0.139 to 0.671 ± 0.103, ZP was from −54.13 ± 1.09 mV to −60.50 ± 2.34 mV and Q6h was from 66.20 ± 0.30% to 93.46 ± 0.86%. The IVM-loaded transethosomal cream showed lower skin irritation and a more intact epidermal layer with intact keratinocyte, compared to the marketed cream which showed severe destruction of the keratin layer. Therefore, patient compliance can be improved by encapsulating IVM within TESMs to minimize its skin reactions. [ABSTRACT FROM AUTHOR]

Atorvastatin calcium is an antihyperlipidemic agent with low bioavailability due to the first-pass metabolism after oral administration. To overcome the limitation, an alternative method for delivering drug molecules to the systemic circulation is needed, such as transethosomes produced for transdermal delivery. Therefore, this study aimed to produce atorvastatin calcium transethosomes with characteristics suitable for transdermal delivery using validated analytical method. Transethosomes formulations were prepared with different concentrations of soy lecithin and ethanol. All formulations were evaluated for particle size, zeta potential, polydispersity index (PDI), drug content, and deformability index. Validation of the analytical method of atorvastatin calcium was carried out using system suitability, selectivity, linearity, limit of detection (LOD), limit of quantification (LOQ), precision, accuracy, and robustness. The result showed that transethosomes had a small particle size of 123.90 nm-165.10 nm, high zeta potential values, acceptable PDI, the highest atorvastatin calcium content, and good deformability index. In addition, the system suitability test results were acceptable and there was no interference in the atorvastatin calcium area. Linearity showed r =0.9999 with LOD and LOQ values of 0.388 µg/mL and 1.176 µg/mL, respectively. The % RSD in the precision was < 2 and the recovery in the accuracy was 98.76%-101.04%. The method proved to be robust with respect to mobile phase pH changes. Based on the results, atorvastatin calcium-loaded transethosomes were suitable for transdermal delivery and could be effectively produced with a 3% soy lecithin and 30% ethanol concentration. The analytical method for determining drug content of atorvastatin calcium-loaded transethosomes could be effectively applied. [ABSTRACT FROM AUTHOR]

Thymoquinone (TQ), a bioactive compound found in Nigella sativa seeds, possesses diverse therapeutic properties for skin conditions. However, formulating TQ presents challenges due to its hydrophobic nature and chemical instability, which hinder its skin penetration. Transethosomes, as a formulation, offer an environment conducive to enhancing TQ's solubility, stability, and skin permeation. To optimize TQ transethosomal formulations, we introduced a combination of ionic and nonionic surfactants, namely Tween 20 and sodium lauryl sulfate (SLS) or sodium lauroyl glutamate (SLG). Surfactants play a crucial role in stabilizing the formulation, reducing aggregation, improving biocompatibility, and minimizing potential toxicity. We fine-tuned the formulation composition and gained insights into its interfacial behavior using the Langmuir monolayer technique. This method elucidated the interfacial properties and behavior of phospholipids in ethosome and transethosome formulations. Our findings suggest that monolayer studies can serve as the initial step in selecting surfactants for nanocarrier formulations based on their interfacial dilational rheology studies. It was found that the addition of surfactant to the formulation increased the elasticity considering the capability of transethosomes to significantly decrease their radius when permeating the skin barrier. The results of the dilational rheology experiments were most relevant to drug permeation through the skin for the largest amplitude of deformation. The combination of Tween 20 and SLS efficiently modified the rheological behavior of lipids, increasing their elasticity. This conclusion was supported by in vitro studies, where formulation F2 composed of Tween 20 and SLS demonstrated the highest permeation after 24 h (300.23 µg/cm2). Furthermore, the F2 formulation showed the highest encapsulation efficiency (EE) of 94%, surpassing those of the control and ethosomal formulations. Additionally, this transethosomal formulation exhibited antimicrobial activity against S. aureus, with a zone of inhibition of 26.4 ± 0.3 mm. Importantly, we assessed the cytotoxicity of both ethosomes and transethosomes at concentrations ranging from 3.5 µM to 50 µM on HaCaT cell lines and found no cytotoxic effects compared to TQ hydroethanolic solution. These results suggest the potential safety and efficacy of TQ transethosomal formulations. [ABSTRACT FROM AUTHOR]

Atopic dermatitis is a skin condition characterized by lichenification (thickening and increased skin marking), eczematous lesions, dry skin, itching, and pruritus. Eugenol is an aromatic polyphenolic compound that has attracted the attention of researchers due to its anti-inflammatory, anti-oxidant, and anti-cancer properties. The primary goal of the present study was to develop and evaluate eugenol-loaded transethosomes for the treatment of AD. Eugenol-loaded transethosomes were formulated using the ethanol injection method and subsequently subjected to particle size analysis, zeta potential, entrapment efficiency, deformability index, and HRTEM analysis. Transethosomal gel was prepared by direct-dispersion method by using Carbopol 940®. Results showed transethosomes to be lipid bilayer structures with acceptable size, and high entrapment efficiency. Transethosomal formulation showed shear-thinning behavior. Eugenol-loaded transethosomal gel was significantly able to enhance the retention of the drug in the skin. Transethosomal gel was significantly able to reduce Ear thickness, DLC, TLC, and IL-6 levels in mice model of AD. These results indicate that the eugenol-loaded transethosomal gel could be a promising carrier for the topical administration of eugenol for the treatment of AD. [ABSTRACT FROM AUTHOR]

Abstract Background The objective of this current research was to enhance the topical delivery of Nadifloxacin (NDFX) by incorporating it into a transethosomal gel formulation. NDFX has limited penetration into the deep layer of the skin because it is poorly water soluble and it has a log p value of 2.47. To optimize the formulation, the “Box–Behnken design” was utilized. The independent variables included phosphatidylcholine 90, tween 80 and ethanol. The produced formulations underwent evaluation for entrapment efficiency, vesicle size and zeta potential. The optimized formulation was then incorporated into suitable gel bases and subjected to further investigation, including in vitro diffusion, ex vivo penetration, in vitro antimicrobial assay and in vivo anti-acne activity. Results The optimized formulation exhibited an entrapment efficiency of 80.12%, a vesicle size of 156.1 nm and a zeta potential of − 33.23 mV. TEM images confirmed the presence of encapsulated vesicles with a spherical shape. The in vitro diffusion study demonstrated that the transethosomal gel containing Carbopol 934 (1%) exhibited higher drug release compared to the HPMC K4M gels. Furthermore, the ex vivo permeation study revealed that the optimized transethosomal gel demonstrated increased permeation compared to the commercially available formulation. Conclusion The optimized transethosomal formulation displayed enhanced in vitro antimicrobial and in vivo anti-acne effects against Propionibacterium acnes in Wistar albino rats when compared to the marketed formulation.

Background: The objective of this current research was to enhance the topical delivery of Nadifloxacin (NDFX) by incorporating it into a transethosomal gel formulation. NDFX has limited penetration into the deep layer of the skin because it is poorly water soluble and it has a log p value of 2.47. To optimize the formulation, the "Box–Behnken design" was utilized. The independent variables included phosphatidylcholine 90, tween 80 and ethanol. The produced formulations underwent evaluation for entrapment efficiency, vesicle size and zeta potential. The optimized formulation was then incorporated into suitable gel bases and subjected to further investigation, including in vitro diffusion, ex vivo penetration, in vitro antimicrobial assay and in vivo anti-acne activity. Results: The optimized formulation exhibited an entrapment efficiency of 80.12%, a vesicle size of 156.1 nm and a zeta potential of − 33.23 mV. TEM images confirmed the presence of encapsulated vesicles with a spherical shape. The in vitro diffusion study demonstrated that the transethosomal gel containing Carbopol 934 (1%) exhibited higher drug release compared to the HPMC K4M gels. Furthermore, the ex vivo permeation study revealed that the optimized transethosomal gel demonstrated increased permeation compared to the commercially available formulation. Conclusion: The optimized transethosomal formulation displayed enhanced in vitro antimicrobial and in vivo anti-acne effects against Propionibacterium acnes in Wistar albino rats when compared to the marketed formulation. [ABSTRACT FROM AUTHOR]

Drug delivery through transdermal route is one of the effective methods for the application of drugs. It overcomes many drawbacks which are encountered with the oral route. Moreover, many drugs are not able to pass through the stratum corneum, which is the main barrier for the transdermal drug delivery. Formation of ultra-deformable vesicles (UDVs) is a novel technique for the transdermal applications of the drugs. Transethosomes (TEs), ethosomes, and transferosomes are all part of the UDV. Because of the presence of increased concentrations of ethanol, phospholipids, and edge activators, TEs provide improved drug permeation through the stratum corneum. Because of the elasticity of TEs, drug penetration into the deeper layer of skin also increases. TEs can be prepared using a variety of techniques, including the cold method, hot method, thin film hydration method, and the ethanol injection method. It increases patient adherence and compliance because it is a non-invasive procedure of administering drugs. Characterization of the TEs includes pH determination, size and shape, zeta potential, particle size determination, transition temperature, drug content, vesicle stability, and skin permeation studies. These vesicular systems can be utilized to deliver a variety of medications transdermally, including analgesics, antibiotics, antivirals, and anticancer and arthritis medications. This review aims to describe vesicular approaches that had been used to overcome the barrier for the transdermal delivery of drug and also describes brief composition, method of preparation, characterization tests, mechanism of penetration of TEs, as well as highlighted various applications of TEs in medicine. [ABSTRACT FROM AUTHOR]

In this study, Trifluralin (TRF) co-loaded with Miltefosine (MTF) in nano transfersomes (NTs) were prepared aiming their enhanced penetration topically with improved macrophage targeting and antileishmanial effects. Formulations were optimized in a series of experiments based on their particle size, polydispersity index (PDI), drug incorporation and deformability index. TEM analysis was performed to check morphology of NTs. TRF-MTF co-loaded NTs were further incorporated into chitosan gel to obtain better retention. In vitro release and Ex vivo permeation studies of the optimized TRF-MTF co-loaded NTs were conducted to check dissolution behavior and skin permeation of the developed formulation as compared to the drug solutions and TRF-MTF co-loaded NTs gel. Macrophage uptake and antileishmanial efficacy of the developed formulation was also investigated. The optimized formulation had a particle size of 188.5 nm with rounded morphology, PDI of 0.101, and deformability index of 0.987. The drug incorporation of TRF and MTF were respectively found as 91% and 88%. Controlled and significantly enhanced drug release and augmented skin penetration was observed from the TRF-MTF co-loaded NTs as compared to pure drugs. Significant uptake of the TRF-MTF co-loaded NTs by the macrophage proved greater intracellular infiltration via the skin barriers. In vitro anti-leishmanial study exhibited 6-folds and 5-folds decrease in the respective IC50 values of TRF-MTF co-loaded NTs when used against Leishmania (L.) tropica amastigotes and promastigotes. This study exhibited the efficacy of NTs when loaded with dual drugs for enhanced skin penetration and macrophage localization. [ABSTRACT FROM AUTHOR]

The skin's protective mechanisms, in some cases, are not able to counteract the destructive effects induced by UV radiations, resulting in dermatological diseases, as well as skin aging. Nutlin-3, a potent drug with antiproliferative activity in keratinocytes, can block UV-induced apoptosis by activation of p53. In the present investigation, ethosomes and transethosomes were designed as delivery systems for nutlin-3, with the aim to protect the skin against UV damage. Vesicle size distribution was evaluated by photon correlation spectroscopy and morphology was investigated by cryogenic transmission electron microscopy, while nutlin-3 entrapment capacity was evaluated by ultrafiltration and HPLC. The in vitro diffusion kinetic of nutlin-3 from ethosomes and transethosomes was studied by Franz cell. Moreover, the efficiency of ethosomes and transethosomes in delivering nutlin-3 and its protective role were evaluated in ex vivo skin explants exposed to UV radiations. The results indicate that ethosomes and transethosomes efficaciously entrapped nutlin-3 (0.3% w/w). The ethosome vesicles were spherical and oligolamellar, with a 224 nm mean diameter, while in transethosome the presence of polysorbate 80 resulted in unilamellar vesicles with a 146 nm mean diameter. The fastest nutlin-3 kinetic was detected in the case of transethosomes, with permeability coefficients 7.4-fold higher, with respect to ethosomes and diffusion values 250-fold higher, with respect to the drug in solution. Ex vivo data suggest a better efficacy of transethosomes to promote nutlin-3 delivery within the skin, with respect to ethosomes. Indeed, nutlin-3 loaded transethosomes could prevent UV effect on cutaneous metalloproteinase activation and cell proliferative response. [ABSTRACT FROM AUTHOR]

The objective of this study was to develop and evaluate a novel vesicular formulation of luliconazole (LUL) for the management of Candida albicans infection through a topical route. LUL-loaded transethosomes (LUL-TE) were prepared by the film hydration method and various independent and dependent variables were optimized using the Box–Behnken design. Selected critical material attributes were the content of phospholipids (X1), concentration of ethanol (X2), and amount of sodium cholate (X3). Formulated LUL-TE were characterized for percent entrapment efficiency, percent drug loading, vesicle size, and polydispersity index (PDI) and were incorporated into the carbomer gel base and further evaluated for gel characterizations. The prepared transethosomal gel (LUL-TE-CHG) was evaluated for pH, spreadability, viscosity, antifungal activity, and in vitro study. From the observed results, it was evident that the prepared LUL-TE-CHG was in the desired pH (6.2 ± 0.45), spreadability [8.3 ± 0.42 g/(cm·s)], viscosity (236.1–19.2.26 mPa·s), nanovesicle size (252 ± 9.82), entrapment efficiency (85% ± 5.24%), zeta potential (−34.05 ± 3.52 mV), and PDI (0.233 ± 0.002). The zone of inhibition results suggested that the LUL-TE-CHG formulation has the highest antifungal activity, that is, 5.83 ± 0.15 mm3. The in vitro results showed that drug release within 2 h was 18.1% ± 2.0% and after that sustained release action, 83.2% ± 1.7% within 8 h. Finally, to confirm the therapeutic efficacy of the developed formulation, fungal infection was induced by using C. albicans in Wistar rats. In vivo, skin irritation study and histopathology studies were performed in the disease-induced model. Animal experiments revealed that LUL-TE-CHG has significantly improved the diseased condition in Wistar rats. The results observed from the skin permeation and skin deposition profile ensure that the prepared novel LUL-loaded TE system had a higher permeation rate and increased retention time compared with LUL-CHG. The hydrogel incorporated with LUL could be a novel approach with safe and effective fungal treatment. [ABSTRACT FROM AUTHOR]

In an effort to tackle the skin reactions frequently observed with topical application of ivermectin (IVM), a study was conducted to develop and optimize transethosomes (TESMs) loaded with IVM for scabies treatment. A three-factor, two-level (23) full factorial design was employed. Soyabean phosphatidylcholine concentration (A), ethanol concentration (B) and Span 60 amount (C) were studied as independent factors, while entrapment efficiency (EE), particle size (PS), polydispersity index (PDI), zeta potential (ZP) and drug release after 6 h (Q6h) were characterized. The skin sensitivity of the optimized formulation was evaluated by skin irritation test and histopathological examination. The EE% ranged from 88.55 ± 0.576% to 94.13 ± 0.305%, PS was from 318.033 ± 45.61 nm to 561.400 ± 45.17 nm, PDI was from 0.328 ± 0.139 to 0.671 ± 0.103, ZP was from −54.13 ± 1.09 mV to −60.50 ± 2.34 mV and Q6h was from 66.20 ± 0.30% to 93.46 ± 0.86%. The IVM-loaded transethosomal cream showed lower skin irritation and a more intact epidermal layer with intact keratinocyte, compared to the marketed cream which showed severe destruction of the keratin layer. Therefore, patient compliance can be improved by encapsulating IVM within TESMs to minimize its skin reactions.

Thymoquinone (TQ), a bioactive compound found in Nigella sativa seeds, possesses diverse therapeutic properties for skin conditions. However, formulating TQ presents challenges due to its hydrophobic nature and chemical instability, which hinder its skin penetration. Transethosomes, as a formulation, offer an environment conducive to enhancing TQ’s solubility, stability, and skin permeation. To optimize TQ transethosomal formulations, we introduced a combination of ionic and nonionic surfactants, namely Tween 20 and sodium lauryl sulfate (SLS) or sodium lauroyl glutamate (SLG). Surfactants play a crucial role in stabilizing the formulation, reducing aggregation, improving biocompatibility, and minimizing potential toxicity. We fine-tuned the formulation composition and gained insights into its interfacial behavior using the Langmuir monolayer technique. This method elucidated the interfacial properties and behavior of phospholipids in ethosome and transethosome formulations. Our findings suggest that monolayer studies can serve as the initial step in selecting surfactants for nanocarrier formulations based on their interfacial dilational rheology studies. It was found that the addition of surfactant to the formulation increased the elasticity considering the capability of transethosomes to significantly decrease their radius when permeating the skin barrier. The results of the dilational rheology experiments were most relevant to drug permeation through the skin for the largest amplitude of deformation. The combination of Tween 20 and SLS efficiently modified the rheological behavior of lipids, increasing their elasticity. This conclusion was supported by in vitro studies, where formulation F2 composed of Tween 20 and SLS demonstrated the highest permeation after 24 h (300.23 µg/cm2). Furthermore, the F2 formulation showed the highest encapsulation efficiency (EE) of 94%, surpassing those of the control and ethosomal formulations. Additionally, this transethosomal formulation exhibited antimicrobial activity against S. aureus, with a zone of inhibition of 26.4 ± 0.3 mm. Importantly, we assessed the cytotoxicity of both ethosomes and transethosomes at concentrations ranging from 3.5 µM to 50 µM on HaCaT cell lines and found no cytotoxic effects compared to TQ hydroethanolic solution. These results suggest the potential safety and efficacy of TQ transethosomal formulations.

The skin’s protective mechanisms, in some cases, are not able to counteract the destructive effects induced by UV radiations, resulting in dermatological diseases, as well as skin aging. Nutlin-3, a potent drug with antiproliferative activity in keratinocytes, can block UV-induced apoptosis by activation of p53. In the present investigation, ethosomes and transethosomes were designed as delivery systems for nutlin-3, with the aim to protect the skin against UV damage. Vesicle size distribution was evaluated by photon correlation spectroscopy and morphology was investigated by cryogenic transmission electron microscopy, while nutlin-3 entrapment capacity was evaluated by ultrafiltration and HPLC. The in vitro diffusion kinetic of nutlin-3 from ethosomes and transethosomes was studied by Franz cell. Moreover, the efficiency of ethosomes and transethosomes in delivering nutlin-3 and its protective role were evaluated in ex vivo skin explants exposed to UV radiations. The results indicate that ethosomes and transethosomes efficaciously entrapped nutlin-3 (0.3% w/w). The ethosome vesicles were spherical and oligolamellar, with a 224 nm mean diameter, while in transethosome the presence of polysorbate 80 resulted in unilamellar vesicles with a 146 nm mean diameter. The fastest nutlin-3 kinetic was detected in the case of transethosomes, with permeability coefficients 7.4-fold higher, with respect to ethosomes and diffusion values 250-fold higher, with respect to the drug in solution. Ex vivo data suggest a better efficacy of transethosomes to promote nutlin-3 delivery within the skin, with respect to ethosomes. Indeed, nutlin-3 loaded transethosomes could prevent UV effect on cutaneous metalloproteinase activation and cell proliferative response.

Colchicine (COL) is the primary medication for treating an acute gout attack, however, it has a narrow therapeutic index and can cause mild to severe gastrointestinal side effects when administered orally. To address this, transethosomes (TEs) were developed as a transdermal drug delivery vehicle for COL in order to promote permeability. Studies have shown that TEs can disrupt the multilamellar and organized lipid domains of the skin, alter the structure of keratin, and increase the fluidity of the stratum corneum (SC), which facilitates the penetration of COL into the deeper layers of the skin. Additionally, ethanol has been found to play a role in the infiltration process, but is not the sole driving force. Results have demonstrated that COL-TEs have higher transdermal efficiency, increased drug permeability, longer skin retention time, and better biocompatibility than the COL water solution and the 40% ethanol COL-solution. Furthermore, the drug was found to effectively reduce inflammatory cytokine levels, thus providing the expected therapeutic effects. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Adding a suitable surfactant can enhance the transdermal permeability of transethosomes while also leveraging its functionality as a functional material. In this study, transethosomes were prepared using D-α-tocopherol acid polyethylene glycol succinate (TPGS) as edge activators for transdermal delivery of curcumin (Cur)., Methods: The TPGS-mediated curcumin-loaded transethosomes (Cur@TES) were prepared and formulated optimally, and the optimized formulations were characterized for their morphology, particle size, entrapment efficiency (EE) and drug loading (DL). The stability and deformability of Cur@TES were investigated, while the transdermal delivery of Cur@TES was investigated through in vitro transdermal assays and fluorescence imaging. A mouse ear swelling model was performed to determine the anti-inflammatory effect of Cur@TES., Results: Cur@TES appeared round or elliptical in shape. The particle size, EE and DL for the optimized formulation were observed as 131.2 ± 7.2 nm, 97.68 ± 2.26%, and 6.58 ± 0.62%, respectively. X-ray diffraction analysis confirmed the formation of disordered structures in the inner core of the vesicles. Moreover, Cur@TES system demonstrated better stability and deformability compared to the curcumin-loaded ethosomes (Cur@ES). In-vitro transdermal experiments demonstrated that Cur@TES significantly increased the amount of drug retained in the skin (P＜0.05). Fluorescence imaging confirmed that the skin distribution were distinctly enhanced with the delivery by TPGS mediated transethosomes. In addition, Cur@TES showed a significant inhibitory effect on Inflammatory swelling in the mouse ear-swelling model., Conclusion: TPGS-mediated transethosomes exhibit significant transdermal advantages and enhanced anti-inflammatory effects, providing a new perspective for the transdermal delivery of curcumin., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Transethosomes, a fusion of transferosomes and ethosomes, combine the advantageous attributes of both vesicular systems to enhance deformability and skin permeation. While skin delivery is effective for drug transport, overcoming the skin barrier remains a significant challenge, particularly for plant-based products with poor permeability. Transethosomes offer a promising solution, but their low viscosity and retention on skin surfaces led to the development of transethosomal gels. These gels can entrap unstable and high molecular weight herbal extracts, fractions and bioactive compounds, facilitating enhanced drug delivery to the inner layers of the skin. This review focuses on the superior performance of transethosomes compared with conventional lipid-based nanovesicular systems, offering an advanced approach for transdermal delivery of plant-based drugs with improved permeability and stability.