Search Results (121)

A comprehensive two-dimensional liquid chromatography platform (LC × LC) was developed and validated for dermal permeability studies. In this implementation, the two separation dimensions were applied to mimic the layered structure of human skin: a ceramide-like stationary phase in the first dimension (¹D) to simulate the lipid-rich epidermis, and an immobilized artificial membrane (IAM) phase in the second (²D) to emulate the dermis. Experimental conditions were optimised to reflect the microenvironment of the in vivo skin. For validation purposes, 43 pharmaceutical and cosmetic compounds whose transdermal permeability coefficients (log K_p) were known from the scientific literature were selected as model solutes. A good degree of separation was achieved across the whole dataset, and affinity profiles correlated with transdermal passage properties, suggesting that retention within specific chromatographic ranges may be predictive of skin permeation. To complement this approach, mass diffusion measurements were also conducted using Permeapad^® 96-well plates and LC was performed on a narrow bore column in MS-friendly conditions. These log K_p values were compared against both in vivo and chromatographic retention data. The combined use of these techniques offers a strategic framework for profiling new chemical entities for their dermal absorption in a manner that is both ethically compliant and eco-sustainable. Full article

Dermal drug delivery is a promising alternate route of drug administration, offering localized therapeutic effects, reduced systemic effects, and improved patient compliance. However, the skin’s intricate configuration, especially the stratum corneum (SC), presents formidable barriers, restricting drug permeation. This review summarizes biological, synthetic, and methodological models employed to study dermal absorption and permeability. Ex vivo human skin is a reference point, but limited availability and ethical constraints necessitate reliance on animal models, including porcine, rodent, rabbit, monkey, and even snake skin, each with unique advantages and drawbacks. Synthetic substitutes, e.g., reconstructed human epidermis and Strat-M^® membranes, provide reproducibility and economic practicality, though none fully mimic the barrier functions of human skin. Innovative analytical methods, including diffusion cells, skin-PAMPA, tape stripping, and advanced imaging techniques, enable quantitative, semi-quantitative, and qualitative insights into drug transport. Collectively, these tools support formulation optimization and aid regulatory bioequivalence assessments. However, challenges remain in correlating in vitro, ex vivo, and in vivo outcomes and in replicating the skin’s dynamic physiology. This review highlights current opportunities and limitations, emphasizing the need for more physiologically relevant models to advance safe, effective, and innovative dermal drug delivery systems. Full article

(1) Background: Low-molecular-weight hyaluronic acid displays moisturizing and anti-aging properties and reduces UV-induced inflammation when applied topically. A 3 kDa sodium hyaluronate oligosaccharide (Extra-Low HA) was designed, and studies were performed to evaluate its safety for cosmetic applications. (2) Methods: The ability of the Extra-Low HA (ExLMW-HA) to penetrate skin was evaluated. Then, pro-inflammatory cytokines were quantified in the culture medium of skin explants following ExLMW-HA application with or without inflammation inducer (PMA). Finally, four predictive in vitro tests (Keratinosens^™, kDPRA, Ames’ test, micronucleus test) were conducted to assess the safety of ExLMW-HA. (3) Results: The molecule permeates skin down to the living epidermis and possibly interacts with the dermal compartment. The oligosaccharide did not induce TNF-α, IL-1β, IL-1α, CXCL2, CCL3, or IL-15, neither in basal nor in stressed conditions. ExLMW-HA is not predicted to be a skin sensitizer or a mutagenic or genotoxic substance. (4) Conclusions: This 3 kDA HA is considered safe for use in topical application at the tested dosage. Full article

Background/Objectives: Ultradeformable liposomes represent an established platform for topical delivery of antioxidant compounds, thanks to their structural flexibility and ability to enhance skin permeation, but standardized manufacturing protocols are still lacking. This study presents a microfluidic-based strategy for the scalable production of ultradeformable liposomes encapsulating Stellaria media extract, a polyphenol-rich phytocomplex with strong antioxidant activity. Methods: Liposomes were produced with a GMP-like microfluidic platform enabling fine control of formulation parameters and high reproducibility under conditions directly transferable to continuous manufacturing. Process optimization tested different total flow rates. Characterization included particle size and distribution, encapsulation efficiency, colloidal stability and kinetics of release. Permeation was assessed with Franz diffusion cells using human stratum corneum and epidermidis membranes. Results: Optimal conditions were a flow rate ratio of 3:1 and a total flow rate of 7 mL/min, yielding ultradeformable liposomes with a mean size of 89 ± 1 nm, a polydispersity index < 0.25, and high encapsulation efficiency (72%). The resulting formulation showed long-term colloidal stability and controlled release. Diffusion studies demonstrated a 2-fold increase in permeation rate compared to the free extract. Conclusions: These findings highlight the potential of microfluidics as a robust and scalable technology for the industrial production of ultradeformable liposomes designed to enhance the dermal delivery of bioactive phytocomplex for both pharmaceutical and cosmeceutical applications. Full article

Background/Objectives: This study presents the development and characterization of a novel thermoresponsive hydrogel composed of hyaluronic acid (HA), poloxamer 407, cannabidiol (CBD), and colloidal silver (Ag), designed for topical antimicrobial therapy. Methods: The Ag-CBD complex was first synthesized and subsequently incorporated into a HA–poloxamer gel matrix to produce a stable, sprayable formulation with suitable physicochemical properties for dermal applications. Results: The HA-Ag-CBD hybrid gel exhibited a physiological pH, a gelation temperature compatible with skin surface conditions, and favorable rheological behavior, including thixotropy and shear thinning—critical for uniform application and retention under dynamic conditions. Release studies confirmed a sustained delivery profile, supporting prolonged local activity of CBD and colloidal Ag. Antimicrobial assays demonstrated that the HA-Ag-CBD hybrid gel retained potent activity against Staphylococcus aureus and Candida albicans, with minimum inhibitory and bactericidal concentrations (MIC/MBC) statistically comparable to those of the unencapsulated Ag-CBD complex. Against E. coli, the HA-Ag-CBD hydrogel exhibited primarily bacteriostatic activity, with a low MIC (9.24 μg/mL) but a substantially higher MBC (387.35 μg/mL), consistent with the intrinsic structural resistance of Gram-negative bacteria. In contrast, bactericidal activity was more pronounced against Gram-positive strains, reflecting differential susceptibility related to bacterial envelope properties. CBD consistently demonstrated superior antimicrobial efficacy to colloidal Ag, while the Ag-CBD combination produced slightly enhanced, mainly additive effects, likely due to complementary membrane disruption and intracellular Ag⁺ ion activity. Cytotoxicity assays on normal human dermal fibroblasts confirmed that the HA-Ag-CBD hybrid gel maintained >70% cell viability at therapeutically relevant concentrations, in accordance with ISO 10993-5:2009 guidelines, and effectively mitigated the inherent cytotoxicity of the Ag-CBD complex. Conclusions: The HA-Ag-CBD hybrid gel demonstrates strong potential as a biocompatible, multifunctional topical formulation for the treatment of infected wounds and skin lesions. Future work will focus on in vivo evaluation, assessment of skin permeation, and further development to support translational applications. Full article

Background: Skin injuries, such as chronic wounds and inflammatory skin diseases, often face limitations in treatment efficacy due to the low efficiency of transdermal drug delivery and insufficient local concentrations. Curcumin (CUR), a natural compound with anti-inflammatory and antioxidant properties, has demonstrated potential in the repair of skin damage; however, its clinical application is hindered by its physicochemical characteristics. This study constructs a novel nanocomposite drug delivery system: CUR-loaded micellar nanocomposite gel (CUR-M-DMNs-Gel). A composite system is used to achieve the efficient solubilization and enhanced transdermal permeation of CUR, thereby providing a novel formulation approach for the treatment of skin diseases. Methods: CUR-loaded micellar (CUR-M) utilizes CUR as the core active ingredient, which possesses multiple pharmacological effects including anti-inflammatory and antioxidant properties. TPGS serves as a micellar carrier that not only enhances the solubility and stability of CUR through its amphiphilic structure but also facilitates drug absorption and transport within the body. In dissolvable microneedles (DMNs), PVP K30 forms a stable three-dimensional network structure through entanglement of polymer chains, ensuring sufficient mechanical strength for effective penetration of the skin barrier. Meanwhile, PVP K90, with its higher molecular weight, enhances the backing’s support and toughness to prevent needle breakage during application. The incorporation of hyaluronic acid (HA) improves both the moisture retention and adhesion properties at the needle tips, ensuring gradual dissolution and release of loaded CUR-M within the skin. In CUR-loaded micellar gel (CUR-M-Gel), PVP K30 increases both adhesive and cohesive forces in the gel through chain entanglement and hydrogen-bonding interactions. Tartaric acid precisely regulates pH levels to adjust crosslinking density; glycerol provides a long-lasting moisturizing environment for the gel; aluminum chloride enhances mechanical stability and controlled drug-release capabilities; NP-700 optimizes dispersion characteristics and compatibility within the system. Results: In vitro experiments demonstrated that the CUR-M-DMNs-Gel composite system exhibited enhanced transdermal penetration, with a cumulative transdermal efficiency significantly surpassing that of single-component formulations. In the mouse skin defect model, CUR-M-DMNs-Gel facilitated collagen deposition and effectively inhibited the expression of inflammatory cytokines (TNF-α, IL-6, and IL-1β). In the mouse skin photoaging model, CUR-M-DMNs-Gel markedly reduced dermal thickness, alleviated damage to elastic fibers, and suppressed inflammatory responses. Conclusions: The CUR-M-DMNs-Gel system can enhance wound healing through subcutaneous localization, achieving long-term sustained efficacy. This innovative approach offers new insights into the treatment of skin injuries. Full article

This study employed a sol–gel route to fabricate mesoporous silica (MS) carriers capable of simultaneously encapsulating two widely utilized UV absorbers—benzophenone-3 (BP-3) and octyl methoxycinnamate (OMC)—resulting in the composite sunscreen agent S4M1B1. Comprehensive characterization using FTIR, TGA, UV–vis spectroscopy, DSC, SEM, and standard photoprotective indices (SPF and UVA-PF) confirmed the successful immobilization of both active ingredients within the MS porous structure, achieving a notably high loading of up to 72 wt%. Sunscreen formulations incorporating the encapsulated composite demonstrated superior photoprotective performance, exhibiting SPF and UVA-PF values approximately 40% higher than equivalent physical mixtures of the same actives. Additionally, the MS encapsulation significantly enhanced the photostability of BP-3 and OMC, effectively maintaining their UV-protective efficacy after prolonged simulated solar exposure. Franz glass diffusion cell assays further revealed that encapsulation markedly reduced the in vitro skin permeation of both BP-3 and OMC by over 55%, substantially diminishing transdermal absorption risks. The dual benefits of enhanced UV-protection efficiency and reduced dermal penetration underscore the composite’s potential as a safer and more effective active ingredient in cosmetic sunscreen products, with promising applications in advanced skincare and cosmeceutical formulations. Full article

This study investigates the valorisation of sour orange (Citrus aurantium L.) flowers using supercritical antisolvent fractionation (SAF) with CO₂ as an antisolvent. SAF was applied to selectively recover bioactive compounds from ethanolic extracts, using supercritical CO₂ to induce precipitation. Response Surface Methodology (RSM) was employed to optimize operational conditions across a pressure range of 8.7–15 MPa and CO₂ flow rates of 0.6–1.8 kg/h, at a constant temperature of 40 °C. Pressure showed a statistically significant positive effect on precipitate yield, while higher CO₂ flow rates led to reduced recovery. High-performance liquid chromatography (HPLC) analysis identified naringin (33.7%), neohesperidin (21.6%), and synephrine (9.0%) as the main components of the enriched fractions. SAF enabled the selective concentration of these compounds, supporting its application as a green separation technique. As a complementary evaluation, preliminary in silico predictions of ADMET properties and skin permeability were performed. The results indicated favourable absorption, low predicted toxicity, and limited dermal permeation for the major flavonoids. These findings are consistent with available experimental and regulatory safety data. Overall, the study demonstrates the potential of SAF as an effective green technology for the selective extraction and enrichment of high-value bioactive compounds derived from Citrus aurantium flowers, with promising applications in cosmetic, nutraceutical, and pharmaceutical formulations. Full article

Background/Objectives: Adapalene is a synthetic retinoid used as a treatment for acne vulgaris. In this study, we attempted to evaluate the dermal pharmacokinetics of adapalene utilizing experimental and in silico tools. Methods: We utilized three over the counter (OTC) adapalene gels to evaluate local dermal pharmacokinetics. A data-driven, robust, mechanistic dermal physiologically based pharmacokinetic (PBPK) model was developed by integrating the physicochemical properties of adapalene, the formulation attributes of the gels, and the biophysical aspects of dermal absorption. The dermal PBPK model was validated against experimental data using in vitro release studies and in vitro permeation studies with human cadaver skin. A clinical study was performed to evaluate the effects of adapalene from the three gel formulations. The impact of adapalene delivery from three gels on the stratum corneum (SC) thickness, pilosebaceous unit area, keratinocyte number, and epidermal thickness was captured using a non-invasive technique, line-field confocal optical coherence tomography (LC–OCT). These responses were evaluated using an Emax model. Results: The dermal PBPK model has successfully predicted adapalene penetration profiles across different gel formulations. The model accuracy, in predicting drug release and permeation characteristics, was confirmed using the experimental data. Clinical evaluation revealed formulation-dependent differences in adapalene’s effects on measured skin parameters, with distinct pharmacodynamic profiles observed for each gel formulation. Conclusions: The overall study gave us a detailed insight into potential effects of formulation on the dermal pharmacokinetics and pharmacodynamics of adapalene using three marketed gels. Full article

Background/Objectives. Chronic inflammatory skin disorders, such as atopic dermatitis and psoriasis, require safe and effective topical treatments. This study aimed to develop and evaluate a novel anti-inflammatory emulsion enriched with menthol, capsaicin, amino acids (glycine, arginine, histidine), and boswellic acid. Methods. Three formulations were prepared: a control (E1), a partial (E2), and a comprehensive formulation (E3). Physicochemical analyses included texture profiling, rheological behavior, pH stability, moisture content, and particle size distribution. Results. E3 demonstrated superior colloidal stability, optimal pH (5.75–6.25), and homogenous droplet size (<1 µm), indicating favorable dermal delivery potential. Ex vivo permeation studies revealed effective skin penetration of menthol and amino acids, with boswellic acid remaining primarily in the epidermis, suggesting localized action. Under oxidative stress conditions, E3 significantly improved fibroblast viability, indicating synergistic cytoprotective effects of combined active ingredients. While individual compounds showed limited or dose-dependent efficacy, their combination restored cell viability to near-control levels. Conclusions. These findings support the potential of this multi-component emulsion as a promising candidate for the topical management of inflammatory skin conditions. Full article

Prunus leaf extracts are rich in phenolic and flavonoid compounds like rutin, and they are known for their antioxidant potential. This study compares the bioactivity and stability of leaf extracts from Prunus domestica L. (EL), Prunus salicina Lindl. (JL), and Prunus cerasifera Ehrh. (CL) and evaluates the dermal safety of a cream containing the extract with the most favorable in vitro properties for potential cosmetic use. Ethanolic extracts were assessed for total phenolic and condensed tannin contents, as well as antioxidants, using DPPH assay and lipid peroxidation inhibitory activities. The CL extract exhibited moderate total phenolic content, the highest condensed tannin content, and strong antioxidant (IC₅₀ = 22.1 ± 3.1 µg/mL) and anti-lipid peroxidation (62.3 ± 1.0%) activities. Based on these results, CL was incorporated into a cream formulation (CCL), which was then evaluated for physicochemical properties, antioxidant retention, and in vitro skin permeation using Franz diffusion cells. The formulation remained physically stable under ambient conditions and retained antioxidant activity above 74.5% under thermal cycling conditions. Rutin from the CCL formulation was retained within the Strat-M™ membrane (4.0 ± 1.1%), which was 5.7-fold higher than that of the control (0.7 ± 0.6%) over 8 h; however, it was not detected in the receptor chamber under these in vitro conditions. A semi-open patch test conducted on 26 healthy volunteers under double-blind conditions revealed no signs of irritation, confirming the formulation’s dermal safety. Overall, the findings support the feasibility of using P. cerasifera extract as a stable antioxidant component in topical skincare formulations. Full article

In this study, we designed an injectable skin-rejuvenating formulation based on polyethylene glycol–polycaprolactone–polyethylene glycol (PEG-PCL-PEG) copolymers to provide a synergistic combination of biocompatibility, antioxidative capacity, and regenerative potential. Through the systematic optimization of the precursor molar ratio and molecular weight, well-defined PEG-PCL-PEG copolymers were synthesized and structurally characterized using gel permeation chromatography (GPC), proton nuclear magnetic resonance (¹H-NMR), and Fourier transform infrared (FT-IR) spectroscopy. An optimized precipitation and drying protocol effectively reduced residual solvents, as confirmed by gas chromatography (GC). Idebenone was incorporated as an antioxidant to prevent skin aging, while hyaluronic acid (HA), L-arginine, and glycerin were included to promote collagen regeneration. In vitro assays demonstrated that idebenone-loaded samples exhibited prolonged intracellular antioxidant activity with low cytotoxicity. The collagen-promoting formulation, containing HA, glycerin, and L-arginine, enhanced the expression of transforming growth factor-β (TGF-β) and type III collagen (COL3) while suppressing inflammatory genes, suggesting a favorable environment for extracellular matrix remodeling. In vivo evaluation corroborated these outcomes, showing angiogenesis, collagen reorganization, and progressive dermal thickness. Histological analysis further confirmed sustained matrix regeneration and tissue integration. These results highlight the potential of PEG-PCL-PEG-based injectables as a multifunctional platform for collagen regeneration, offering a promising strategy for both cosmetic and clinical applications. Full article

Nanoemulsions (NEs) have emerged as effective drug delivery systems over the past few decades due to their multifaceted nature, offering advantages such as enhanced bioavailability, protection of encapsulated compounds, and low toxicity. In the present review, we focus on advancements in drug delivery over the last five years across (trans)dermal, oral, ocular, nasal, and intra-articular administration routes using NEs. Rational selection of components, surface functionalization, incorporation of permeation enhancers, and functionalization with targeting moieties are explored for each route discussed. Additionally, apart from NEs, we explore NE-based drug delivery systems (e.g., NE-based gels) while highlighting emerging approaches such as vaccination and theranostic applications. The growing interest in NEs for drug delivery purposes is reflected in clinical trials, which are also discussed. By summarizing the latest advances, exploring new strategies, and identifying critical challenges, this review focuses on developments for efficient NE-based therapeutic approaches. Full article

Background/Objectives: This study investigates the use of natural deep eutectic solvents (NADESs) in enhancing the solubility and skin permeation of a lidocaine base, a lipophilic form, in hydrogel systems. The aim was to develop an environmentally sustainable and biocompatible alternative to conventional lidocaine formulations, improving the dermal permeation and therapeutic efficacy. Methods: The lidocaine base was dissolved in a hydrophilic NADES system composed of choline chloride and citric acid, facilitating enhanced solubility, likely through new molecular interactions. Then, pH-adjusted hydrogels were formulated and optimized by employing a 3² full factorial design. Raman and nuclear magnetic resonance (NMR) spectroscopy were applied to evaluate the stability of lidocaine in the optimal formulation. The biopharmaceutical properties were investigated using in vitro drug release and skin permeation studies. In vivo tests assessed physiological skin parameters such as the hydration and transepidermal water loss. Results: The developed NADES-containing hydrogel significantly improved the solubility and stability of lidocaine. Skin permeation studies demonstrated enhanced dermal permeation compared with conventional hydrogel and ointment. These improvements, namely the enhanced solubility of lidocaine in the formulation and its increased permeation, were attributed to the dual effect of the NADES. Conclusions: NADES-containing hydrogels represent a promising green technology for formulating lidocaine-containing dermal preparations. This approach offers a biocompatible, natural-based alternative that can enhance the bioavailability and efficacy of topical anesthetics. Full article

The genitourinary syndrome of menopause (GSM) is a prevalent condition impacting a substantial number of women globally. Presently, the management of GSM typically entails the administration of estrogen via oral, dermal, or vaginal routes for a prolonged period of time. This study involves the development of a polymer-based hollow cylindrical delivery system loaded with estradiol hemihydrate (E2) for prolonged delivery to the uterine cavity (EPHCD) combined with a norethindrone acetate (NETA)-loaded polymeric matrix (NLPM), with both units placed onto an intra-uterine device to form a multi-component drug delivery system for the management of GSM (MCDDS). In developing EPHCD, a central composite design (CCD) was employed to evaluate and optimize the impact of formulation factors on EPHCD release and unit weight loss. The optimized EPHCD was further assessed for its chemical integrity, surface morphology, hydration characteristics, release behavior, ex vivo permeation and cytocompatibility. The optimized EPHCD, which featured a high drug load (10%) and low ethyl cellulose-to-polycaprolactone ratio (EC-to-PCL, 10%), demonstrated favorable attributes with a cumulative drug release and weight loss of 23.78 ± 0.84% and 2.09 ± 0.21%, respectively, over a 4-week testing period. The release kinetics were further noted to obey the Peppas–Sahlin model. Evaluation of MCDDS revealed an in vitro drug release comparable to the individual units, with permeation studies displaying an initial increase in the rate of flux for both drugs during the first 2 h, followed by a subsequent decrease. Moreover, the MCDDS components showed good cytocompatibility against NIH/3T3 cells, with cell viability of more than 70%. Upon evaluation of the MCDDS system, the results of this study highlight its potential as a viable sustained-release intrauterine platform for the treatment of GSM. Full article