Propellant Free Pressurized Spray System of Etodolac to Manage Acute Pain Conditions: In Vitro and In Vivo Evaluation.

This study aimed to develop a propellant-free topical spray formulation of Etodolac (BCS-II), a potent NSAID, which could be beneficial in the medical field for the effective treatment of pain and inflammation conditions. The developed novel propellant-free spray formulation is user-friendly, cost-effective, propellant-free, eco-friendly, enhances the penetration of Etodolac through the skin, and has a quick onset of action. Various formulations were developed by adjusting the concentrations of different components, including lecithin, buffering agents, film-forming agents, plasticizers, and permeation enhancers. The prepared propellant-free spray formulations were then extensively characterized and evaluated through various in vitro, ex vivo, and in vivo parameters. The optimized formulation exhibits an average shot weight of 0.24 ± 0.30 ml and an average drug content or content uniformity of 87.3 ± 1.01% per spray. Additionally, the optimized formulation exhibits an evaporation time of 3 ± 0.24 min. The skin permeation study demonstrated that the permeability coefficients of the optimized spray formulation were 21.42 cm/h for rat skin, 13.64 cm/h for mice skin, and 18.97 cm/h for the Strat-M membrane. When assessing its potential for drug deposition using rat skin, mice skin, and the Strat-M membrane, the enhancement ratios for the optimized formulation were 1.88, 2.46, and 1.92, respectively against pure drug solution. The findings from our study suggest that the propellant-free Etodolac spray is a reliable and safe topical formulation. It demonstrates enhanced skin deposition, and improved effectiveness, and is free from any skin irritation concerns.

Transdermal Delivery of Niacin Through Polysaccharide Films Ameliorates Cutaneous Flushing in Experimental Wistar Rats.

BACKGROUND: Niacin, an established therapeutic for dyslipidemia, is hindered by its propensity to induce significant cutaneous flushing when administered orally in its unmodified state, thereby constraining its clinical utility. OBJECTIVE: This study aimed to fabricate, characterize, and assess the in-vitro and in-vivo effectiveness of niacin-loaded polymeric films (NLPFs) comprised of carboxymethyl tamarind seed polysaccharide. The primary objective was to mitigate the flushing-related side effects associated with oral niacin administration. METHODS: NLPFs were synthesized using the solvent casting method and subsequently subjected to characterization, including assessments of tensile strength, moisture uptake, thickness, and folding endurance. Surface characteristics were analyzed using a surface profiler and scanning electron microscopy (SEM). Potential interactions between niacin and the polysaccharide core were investigated through X-ray diffraction experiments (XRD) and Fourier transform infrared spectroscopy (FTIR). The viscoelastic properties of the films were explored using a Rheometer. In-vitro assessments included drug release studies, swelling behavior assays, and antioxidant assays. In-vivo efficacy was evaluated through skin permeation assays, skin irritation assays, and histopathological analyses. RESULTS: NLPFs exhibited a smooth texture with favorable tensile strength and moisture absorption capabilities. Niacin demonstrated interaction with the polysaccharide core, rendering the films amorphous. The films displayed slow and sustained drug release, exceptional antioxidant properties, optimal swelling behavior, and viscoelastic characteristics. Furthermore, the films exhibited biocompatibility and non-toxicity towards skin cells. CONCLUSION: NLPFs emerged as promising carrier systems for the therapeutic transdermal delivery of niacin, effectively mitigating its flushing-associated adverse effects.

Integrating mathematical approaches (IMAS): Novel methodology for predicting dermal absorption rates of chemicals under finite dose conditions.

Quantitative structure permeation relationship (QSPR) models have gained prominence in recent years owing to their capacity to elucidate the influence of physicochemical properties on the dermal absorption of chemicals. These models facilitate the prediction of permeation coefficient (Kp) values, indicating the skin permeability of a chemical under infinite dose conditions. Conversely, obtaining dermal absorption rates (DAs) under finite dose conditions, which are crucial for skin product safety evaluation, remains a challenge when relying solely on Kp predictions from QSPR models. One proposed resolution involves using Kroes' methodology, categorizing DAs based on Kp values; however, refinement becomes necessary owing to discreteness in the obtained values. We previously developed a mathematical model using Kp values obtained from in vitro dermal absorption tests to predict DAs. The present study introduces a new methodology, Integrating Mathematical Approaches (IMAS), which combines QSPR models and our mathematical model to predict DAs for risk assessments without conducting in vitro dermal absorption tests. Regarding 40 chemicals (76.1 ≤ MW ≤ 220; -1.4 ≤ Log Ko/w ≤ 3.1), IMAS showed that 65.0% (26/40) predictions of DA values were accurate to within twofold of the observed values in finite dose experiments. Compared to Kroes' methodology, IMAS notably mitigated overestimation, particularly for hydrophilic chemicals with water solubility exceeding 57.0 mg/cm3. These findings highlight the value of IMAS as a tool for skin product risk assessments, particularly for hydrophilic compounds.

[Development of Transdermal Formulation Based on Nanotechnology and Elucidation of Its Drug Delivery Pathways].

Transdermal drug delivery is a formulation in which the drug is absorbed through the skin for systemic action. Its advantages include avoidance of first-pass effects, sustained drug supply, and ease of administration and discontinuation. Drugs administered transdermally transfer into the blood circulation through the stratum corneum, epidermis, and dermis. The stratum corneum on the skin surface plays a barrier function in skin absorption. Therefore, developing of transdermal drug delivery systems requires innovations that overcome the barrier function of the stratum corneum and improve skin permeation. This review examines the usefulness of transdermal formulations based on solid nanoparticles using raloxifene. Milled raloxifene was gelled with (mRal-NPs) or without menthol (Ral-NPs) using Carbopol. The drug release and transdermal penetration were measured using a Franz diffusion cell, and the therapeutic evaluation of osteoporosis was determined in an ovariectomized rat model. Although the raloxifene released from Ral-NPs remained in the nanoparticle state, the skin penetration of raloxifene nanoparticles was prevented by the stratum corneum in rat. The inclusion of menthol in the formulation attenuated the barrier function of the stratum corneum and permitted raloxifene nanoparticles to penetrate through the skin. Moreover, macropinocytosis relates to the formulation's skin penetration, including menthol (mRal-NPs). Applying mRal-NPs attenuated the decreases in calcium level and stiffness of bones of ovariectomized rats. This information can support future studies aimed at designing novel transdermal formulations.

Nanosuspension-Loaded Dissolving Microneedle Patches for Enhanced Transdermal Delivery of a Highly Lipophilic Cannabidiol.

Purpose: Transdermal Drug Delivery System (TDDS) offers a promising alternative for delivering poorly soluble drugs, challenged by the stratum corneum's barrier effect, which restricts the pool of drug candidates suitable for TDDS. This study aims to establish a delivery platform specifically for highly lipophilic drugs requiring high doses (log P > 5, dose > 10 mg/kg/d), to improve their intradermal delivery and enhance solubility. Methods: Cannabidiol (CBD, log P = 5.91) served as the model drug. A CBD nanosuspension (CBD-NS) was prepared using a bottom-up method. The particle size, polydispersity index (PDI), zeta potential, and concentration of the CBD-NS were characterized. Subsequently, CBD-NS was incorporated into dissolving microneedles (DMNs) through a one-step manufacturing process. The intradermal dissolution abilities, physicochemical properties, mechanical strength, insertion depth, and release behavior of the DMNs were evaluated. Sprague-Dawley (SD) rats were utilized to assess the efficacy of the DMN patch in treating knee synovitis and to analyze its skin permeation kinetics and pharmacokinetic performance. Results: The CBD-NS, stabilized with Tween 80, exhibited a particle size of 166.83 ± 3.33 nm, a PDI of 0.21 ± 0.07, and a concentration of 46.11 ± 0.52 mg/mL. The DMN loaded with CBD-NS demonstrated favorable intradermal dissolution and mechanical properties. It effectively increased the delivery of CBD into the skin, extended the action's duration in vivo, and enhanced bioavailability. CBD-NS DMN exhibited superior therapeutic efficacy and safety in a rat model of knee synovitis, significantly inhibiting TNF-α and IL-1ß compared with the methotrexate subcutaneous injection method. Conclusion: NS technology effectively enhances the solubility of the poorly soluble drug CBD, while DMN facilitates penetration, extends the duration of action in vivo, and improves bioavailability. Furthermore, CBD has shown promising therapeutic outcomes in treating knee synovitis. This innovative drug delivery system is expected to offer a more efficient solution for the administration of highly lipophilic drugs akin to CBD, thereby facilitating high-dose administration.

Formulation and evaluation of miconazole lipogel for enhanced drug permeation.

Hydrophilic drugs could be incorporated into the skin surface by manes of Lipogel. This study aimed to prepare miconazole lipogel with natural ingredients to enhance drug permeability using dimethyl Sulfoxide (DMSO). The miconazole lipogels, A1 (without DMSO) and A2 (with DMSO) were formulated and evaluated for organoleptic evaluation, pH, viscosity, stability studies, freeze-thawing, drug release profile and drug permeation enhancement. Results had stated that prepared lipogel's pH falls within the acceptable range required for topical delivery (4 to 6) while both formulations show good results in organoleptic evaluation. The A2 formulation containing DMSO shows better permeation of miconazole (84.76%) on the artificial skin membrane as compared to A1 lipogel formulation (50.64%). In in-vitro drug release studies, A2 for-mulation showed 87.48% drug release while A1 showed just 60.1% drug release from lipogel. Stability studies were performed on model formulations under environmental conditions and both showed good spreadibility, stable pH, free of grittiness and good consistency in formulation. The results concluded that A2 formulation containing DMSO shows better results as compared to DMSO-free drug lipogel.

Assessment of human dermal absorption of flame retardant additives in polyethylene and polypropylene microplastics using 3D human skin equivalent models.

To overcome ethical and technical challenges impeding the study of human dermal uptake of chemical additives present in microplastics (MPs), we employed 3D human skin equivalent (3D-HSE) models to provide first insights into the dermal bioavailability of polybrominated diphenyl ether (PBDEs) present in MPs; and evaluated different factors influencing human percutaneous absorption of PBDEs under real-life exposure scenario. PBDEs were bioavailable to varying degrees (up to 8 % of the exposure dose) and percutaneous permeation was evident, albeit at low levels (≤0.1 % of the exposure dose). While the polymer type influenced the release of PBDEs from the studied MPs to the skin, the polymer type was less important in driving the percutaneous absorption of PBDEs. The absorbed fraction of PBDEs was strongly correlated (r2 = 0.88) with their water solubility, while the dermal permeation coefficient Papp of PBDEs showed strong association with their molecular weight and logKOW. More sweaty skin resulted in higher bioavailability of PBDEs from dermal contact with MPs than dry skin. Overall, percutaneous absorption of PBDEs upon skin contact with MPs was evident, highlighting, for the first time, the potential significance of the dermal pathway as an important route of human exposure to toxic additive chemicals in MPs.

Penetration pathways, influencing factors and predictive models for dermal absorption of exobiotic molecules: A critical review.

This review provides a comprehensive summary of the skin penetration pathways of xenobiotics, including metals, organic pollutants, and nanoparticles (NPs), with a particular focus on the methodologies employed to elucidate these penetration routes. The impacts of the physicochemical properties of exogenous substances and the properties of solvent carriers on the penetration efficiencies were discussed. Furthermore, the review outlines the steady-state and transient models for predicting the skin permeability of xenobiotics, emphasizing the models which enable realistic visualization of pharmaco-kinetic phenomena via detailed geometric representations of the skin microstructure, such as stratum corneum (SC) (bricks and mortar) and skin appendages (hair follicles and sebaceous gland units). Limitations of published research, gaps in current knowledge, and recommendations for future research are highlighted, providing insight for a better understanding of the skin penetration behavior of xenobiotics and associated health risks in practical application contexts.

QbD Based Formulation Development and Optimisation of Ozenoxacin Topical Nano-Emulgel and Efficacy Evaluation Using Impetigo Mice Model.

To formulate and optimize Ozenoxacin nano-emulsion using Quality by Design (QbD) concept by means of Box-Behnken Design (BBD) and converting it to a gel to form Ozenoxacin nano-emulgel followed by physico-chemical, in-vitro, ex-vivo and in-vivo evaluation. This study demonstrates the application of QbD methodology for the development and optimization of an effective topical nanoemulgel formulation for the treatment of Impetigo focusing on the selection of appropriate excipients, optimization of formulation and process variables, and characterization of critical quality attributes. BBD was used to study the effect of "% of oil, % of Smix and homogenization speed" on critical quality attributes "globule size and % entrapment efficiency" for the optimisation of Ozenoxacin Nano-emulsion. Ozenoxacin loaded nano-emulgel was characterized for "description, identification, pH, specific gravity, amplitude sweep, viscosity, assay, organic impurities, antimicrobial effectiveness testing, in-vitro release testing, ex-vivo permeation testing, skin retention and in-vivo anti-bacterial activity". In-vitro release and ex-vivo permeation, skin retention and in-vivo anti-bacterial activity were found to be significantly (p < 0.01) higher for the nano-emulgel formulation compared to the innovator formulation (OZANEX™). Antimicrobial effectiveness testing was performed and found that even at 70% label claim of benzoic acid is effective to inhibit microbial growth in the drug product. The systematic application of QbD principles facilitated the successful development and optimization of a Ozenoxacin Nano-Emulsion. Optimised Ozenoxacin Nano-Emulgel can be considered as an effective alternative and found to be stable at least for 6 months at 40 °C / 75% RH and 30 °C / 75% RH.

Nanodiamond-based berberine aquasomes for enhancing penetration across epidermis to treat psoriasis.

The use of berberine hydrochloride (BCS class III) has limited application in psoriasis, when given as topical drug delivery systems, due to low permeability in the skin layer. Hence, berberine hydrochloride-loaded aquasome nanocarriers were developed for skin targeting, particularly epidermis (primary site of psoriasis pathophysiology) and enhance the skin permeability of berberine hydrochloride. Aquasomes were formulated using the adsorption method and characterized by structural morphology TEM, % drug adsorption, drug release profile (in-vitro and ex-vivo), in-vivo efficacy study and stability study. The reduced particle size and higher surface charge of SKF3 formulation (263.57 ± 27.78 nm and -21.0 ± 0.43 mV) showed improved stability of aquasomes because of the development of higher surface resistance to formation of aggregates. The adsorption of hydrophilic berberine and the non-lipidic nature of aquasomes resulted in % adsorption efficiency (%AE) of 94.46 ± 0.39 %. The controlled first-order release behavior of aquasomes was reported to be 52.647 ± 14.63 and 32.08 ± 12.78 % in in-vitro and ex-vivo studies, respectively. In-vivo studies demonstrated that topical application of berberine hydrochloride loaded aquasomes significantly alleviated psoriasis symptoms like hyperkeratosis, scaling and inflammation, due to the reduction in the inflammatory cytokines (IL-17 and IL-23). Therefore, aquasome formulation exhibits an innovative approach for targeted application of berberine hydrochloride in the management of psoriasis.

Eugenol-Loaded Transethosomal Gel for Improved Skin Delivery and Treatment of Atopic Dermatitis.

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.

Mathematical modeling of transdermal delivery of topical drug formulations in a dynamic microfluidic diffusion chamber in health and disease.

Mathematical models of epidermal and dermal transport are essential for optimization and development of products for percutaneous delivery both for local and systemic indication and for evaluation of dermal exposure to chemicals for assessing their toxicity. These models often help directly by providing information on the rate of drug penetration through the skin and thus on the dermal or systemic concentration of drugs which is the base of their pharmacological effect. The simulations are also helpful in analyzing experimental data, reducing the number of experiments and translating the in vitro investigations to an in-vivo setting. In this study skin penetration of topically administered caffeine cream was investigated in a skin-on-a-chip microfluidic diffusion chamber at room temperature and at 32°C. Also the transdermal penetration of caffeine in healthy and diseased conditions was compared in mouse skins from intact, psoriatic and allergic animals. In the last experimental setup dexamethasone, indomethacin, piroxicam and diclofenac were examined as a cream formulation for absorption across the dermal barrier. All the measured data were used for making mathematical simulation in a three-compartmental model. The calculated and measured results showed a good match, which findings indicate that our mathematical model might be applied for prediction of drug delivery through the skin under different circumstances and for various drugs in the novel, miniaturized diffusion chamber.

Culture insert device with perfusable microchannels enhancesin vitroskin model development and barrier function assessment.

The ever-stricter regulations on animal experiments in the field of cosmetic testing have prompted a surge in skin-related research with a special focus on recapitulation of thein vivoskin structurein vitro. In vitrohuman skin models are seen as an important tool for skin research, which in recent years attracted a lot of attention and effort, with researchers moving from the simplest 2-layered models (dermis with epidermis) to models that incorporate other vital skin structures such as hypodermis, vascular structures, and skin appendages. In this study, we designed a microfluidic device with a reverse flange-shaped anchor that allows culturing of anin vitroskin model in a conventional 6-well plate and assessing its barrier function without transferring the skin model to another device or using additional contraptions. Perfusion of the skin model through vascular-like channels improved the morphogenesis of the epidermis compared with skin models cultured under static conditions. This also allowed us to assess the percutaneous penetration of the tested caffeine permeation and vascular absorption, which is one of the key metrics for systemic drug exposure evaluation.

Formulation characterization of lecithin organogel as topical drug delivery system for psoriasis: In-vitro permeation and preclinical evaluation.

Psoriasis is a chronic inflammatory and proliferative skin disease that causes pathological skin changes and has a substantial impact on the quality of patient life. Apremilast was approved by the US Food and Drug Administration as an oral medication for psoriasis and is beneficial in mild to moderate conditions for chronic usage. However, 5%-7% of withdrawals were reported due to severe side effects. To address the issue, a localized drug delivery strategy via the topical route may be a viable approach. However, poor physicochemical properties make it vulnerable to passing through the skin, requiring a specialized drug delivery system to demonstrate its full potential via a topical route like lecithin organogel. The formulation was optimized by screening the suitable lecithin type and non-polar solvents based on the gel formation ability of lecithin and the solubility of apremilast in the solvent. The pseudo-ternary diagram was used to optimize the water content required to form the gel. The optimized gel was found to be shear thinning characterized for rheological parameters, in-vitro diffusion studies, and in-vitro skin distribution studies. Preclinical studies in Imiquimod-induced mice showed a better reduction in severity index, cytokine levels, and epidermal hyperplasia from the lecithin organogel group compared to the apremilast oral administration and marketed standard topical gel group. Based on these results, lecithin organogel can be considered a promising approach to deliver molecules like apremilast by topical route in psoriatic-like conditions.

Safety assessment of Paeonia lactiflora root extract for a cosmetic ingredient employing the threshold of toxicological concern (TTC) approach.

Botanical extracts, widely used in cosmetics, pose a challenge to safety assessment due to their complex compositions. The threshold of toxicological concern (TTC) approach, offering a safe exposure level for cosmetic ingredients, proves to be a promising solution for ensuring the safety of cosmetic ingredients with low exposure level. We assessed the safety of Paeonia lactiflora root extract (PLR), commonly used in skin conditioning products, with the TTC. We identified 50 constituents of PLR extract from the USDA database and literature exploration. Concentration of each constituent of PLR extract was determined with the information from USDA references, literature, and experimental analysis. The genotoxicity of PLR and its constituents was assessed in vitro and in silico respectively. Cramer class of the constituents of the PLR extract was determined with Toxtree 3.1 extended decision tree using ChemTunes®. Systemic exposure of each constituent from leave-on type cosmetic products containing PLR at a 1% concentration was estimated and compared with respective TTC threshold. Two constituents exceeding TTC threshold were further analyzed for dermal absorption using in silico tools, which confirmed the safety of PLR extract in cosmetics. Collectively, we demonstrated that the TTC is a useful tool for assessing botanical extract safety in cosmetics.

Mechanisms of the Drug Penetration Enhancer Propylene Glycol Interacting with Skin Lipid Membranes.

Very few drugs have the necessary physicochemical properties to cross the skin's main permeability barrier, the stratum corneum (SC), in sufficient amounts. Propylene glycol (PG) is a chemical penetration enhancer that could be included in topical formulations in order to overcome the barrier properties of the skin and facilitate the transport of drugs across it. Experiments have demonstrated that PG increases the mobility and disorder of SC lipids and may extract cholesterol from the SC, but little is known about the molecular mechanisms of drug permeation enhancement by PG. In this work, we have performed molecular dynamics (MD) simulations to investigate the molecular-level effects of PG on the structure and properties of model SC lipid bilayers. The model bilayers were simulated in the presence of PG concentrations over the range of 0-100% w/w PG, using both an all-atom and a united atom force field. PG was found to localize in the hydrophilic headgroup regions at the bilayer interface, to occupy the lipid-water hydrogen-bonding sites, and to slightly increase lipid tail disorder in a concentration-dependent manner. We showed with MD simulation that PG enhances the permeation of small molecules such as water by interacting with the bilayer interface; the results of our study may be used to guide the design of formulations for transdermal drug delivery with enhanced skin permeation, as well as topical formulations and cosmetic products.

Transdermal Delivery of Pramipexole Using Microneedle Technology for the Potential Treatment of Parkinson's Disease.

Parkinson's disease (PD) is a debilitating neurodegenerative disease primarily impacting neurons responsible for dopamine production within the brain. Pramipexole (PRA) is a dopamine agonist that is currently available in tablet form. However, individuals with PD commonly encounter difficulties with swallowing and gastrointestinal motility, making oral formulations less preferable. Microneedle (MN) patches represent innovative transdermal drug delivery devices capable of enhancing skin permeability through the creation of microconduits on the surface of the skin. MNs effectively reduce the barrier function of skin and facilitate the permeation of drugs. The work described here focuses on the development of polymeric MN systems designed to enhance the transdermal delivery of PRA. PRA was formulated into both dissolving MNs (DMNs) and directly compressed tablets (DCTs) to be used in conjunction with hydrogel-forming MNs (HFMNs). In vivo investigations using a Sprague-Dawley rat model examined, for the first time, if it was beneficial to prolong the application of DMNs and HFMNs beyond 24 h. Half of the patches in the MN cohorts were left in place for 24 h, whereas the other half remained in place for 5 days. Throughout the entire 5 day study, PRA plasma levels were monitored for all cohorts. This study confirmed the successful delivery of PRA from DMNs (Cmax = 511.00 ± 277.24 ng/mL, Tmax = 4 h) and HFMNs (Cmax = 328.30 ± 98.04 ng/mL, Tmax = 24 h). Notably, both types of MNs achieved sustained PRA plasma levels over a 5 day period. In contrast, following oral administration, PRA remained detectable in plasma for only 48 h, achieving a Cmax of 159.32 ± 113.43 ng/mL at 2 h. The HFMN that remained in place for 5 days demonstrated the most promising performance among all investigated formulations. Although in the early stages of development, the findings reported here offer a hopeful alternative to orally administered PRA. The sustained plasma profile observed here has the potential to reduce the frequency of PRA administration, potentially enhancing patient compliance and ultimately improving their quality of life. This work provides substantial evidence advocating the development of polymeric MN-mediated drug delivery systems to include sustained plasma levels of hydrophilic pharmaceuticals.

Nanocarrier-Integrated Microneedles: Divulging the Potential of Novel Frontiers for Fostering the Management of Skin Ailments.

The various kinds of nanocarriers (NCs) have been explored for the delivery of therapeutics designed for the management of skin manifestations. The NCs are considered as one of the promising approaches for the skin delivery of therapeutics attributable to sustained release and enhanced skin penetration. Despite the extensive applications of the NCs, the challenges in their delivery via skin barrier (majorly stratum corneum) have persisted. To overcome all the challenges associated with the delivery of NCs, the microneedle (MN) technology has emerged as a beacon of hope. Programmable drug release, being painless, and its minimally invasive nature make it an intriguing strategy to circumvent the multiple challenges associated with the various drug delivery systems. The integration of positive traits of NCs and MNs boosts therapeutic effectiveness by evading stratum corneum, facilitating the delivery of NCs through the skin and enhancing their targeted delivery. This review discusses the barrier function of skin, the importance of MNs, the types of MNs, and the superiority of NC-loaded MNs. We highlighted the applications of NC-integrated MNs for the management of various skin ailments, combinational drug delivery, active targeting, in vivo imaging, and as theranostics. The clinical trials, patent portfolio, and marketed products of drug/NC-integrated MNs are covered. Finally, regulatory hurdles toward benchtop-to-bedside translation, along with promising prospects needed to scale up NC-integrated MN technology, have been deliberated. The current review is anticipated to deliver thoughtful visions to researchers, clinicians, and formulation scientists for the successful development of the MN-technology-based product by carefully optimizing all the formulation variables.

Cellular response of keratinocytes to the entry and accumulation of nanoplastic particles.

Plastic accumulation in the environment is rapidly increasing, and nanoplastics (NP), byproducts of environmental weathering of bulk plastic waste, pose a significant public health risk. Particles may enter the human body through many possible routes such as ingestion, inhalation, and skin absorption. However, studies on NP penetration and accumulation in human skin are limited. Loss or reduction of the keratinized skin barrier may enhance the skin penetration of NPs. The present study investigated the entry of NPs into a human skin system modeling skin with compromised barrier functions and cellular responses to the intracellular accumulations of NPs. Two in vitro models were employed to simulate human skin lacking keratinized barriers. The first model was an ex vivo human skin culture with the keratinized dermal layer (stratum corneum) removed. The second model was a 3D keratinocyte/dermal fibroblast cell co-culture model with stratified keratinocytes on the top and a monolayer of skin fibroblast cells co-cultured at the bottom. The penetration and accumulation of the NPs in different cell types were observed using fluorescent microscopy, confocal microscopy, and cryogenic electron microscopy (cryo-EM). The cellular responses of keratinocytes and dermal fibroblast cells to stress induced by NPs stress were measured. The genetic regulatory pathway of keratinocytes to the intracellular NPs was identified using transcript analyses and KEGG pathway analysis. The cellular uptake of NPs by skin cells was confirmed by imaging analyses. Transepidermal transport and penetration of NPs through the skin epidermis were observed. According to the gene expression and pathway analyses, an IL-17 signaling pathway was identified as the trigger for cellular responses to internal NP accumulation in the keratinocytes. The transepidermal NPs were also found in co-cultured dermal fibroblast cells and resulted in a large-scale transition from fibroblast cells to myofibroblast cells with enhanced production of α-smooth muscle actin and pro-Collagen Ia. The upregulation of inflammatory factors and cell activation may result in skin inflammation and ultimately trigger immune responses.

Development of a hydrogel containing bisabolol-loaded nanocapsules for the treatment of atopic dermatitis in a Balb/c mice model.

α-Bisabolol (αBIS), a plant-derived compound with anti-inflammatory properties, is potentially a therapeutic agent for Atopic dermatitis. However, its poor water solubility and photoinstability limit its topical application. Therefore, the present study, aimed to develop cationic polymeric nanocapsules of αBIS to improve its skin delivery, photostability, and therapeutic efficacy. The αBIS-loaded nanocapsules were prepared using the solvent displacement technique. A Box-Behnken (BB) design was employed to statistically optimize formulation variables and αBIS-loaded nanocapsules characterized by particle size, surface charge and encapsulation efficiency. The optimal formulation was selected, and the spherical shape of the nanocapsules was confirmed by scanning electron microscopy (SEM). Furthermore, hydrogel containing αBIS-loaded nanocapsules was prepared by thickening of nanocapsule suspension with Carbopol 934 and evaluated for rheology, in vitro drug release and skin permeation. Furthermore, a mice model of atopic dermatitis was used to evaluate the anti-inflammatory potential of the hydrogels. The optimal formulation displayed a spherical morphology under scanning electron microscopy (SEM) with an optimum particle size of 133.00 nm, polydispersity index (PDI) of 0.12, high EE% of 93 %, and improved optical stability of αBIS in the prepared nanocapsules compared to the free drug. The nano-based hydrogels demonstrated non-Newtonian pseudoplastic behavior and an increased αBIS in vitro release profile without causing skin irritation in rabbits. Drug retention within the dermis and epidermis layers significantly surpassed that of drug-free hydrogel. Moreover, in vivo histopathological studies and myeloperoxidase (MPO) enzyme activity, revealed that hydrogel containing bisabolol nanocapsules exhibited The best anti-inflammatory effect. The results showed that hydrogels containing bisabolol nanocapsules markedly alleviated dermatitis-related inflammation and reduced skin thickness in Balb/c mice. Our findings support nanocapsules as an effective drug delivery system to enhance αBIS stability, bioavailability, and therapeutic efficacy in AD treatment.