The possibility of controlling periorbital hyperpigmentation disorders is one of the most important research goals in cosmetic preparations. In the current investigation, 1% vitamin K (Vit K) was incorporated into a Chitosan/alginate hydrogel which aimed to increase the dermal delivery and anti-pigmentation effect. The Vit K-hydrogel was evaluated using several different tests, including volume expansion/contraction analysis, differential scanning calorimetry (DSC), scanning electron microscopy (SEM), ultraviolet (UV) absorbance spectroscopy, and attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy. Vit K hydrogel\'s drug release profile showed a steady increase over time. Furthermore, the modified Vit K hydrogel formulations showed no harmful effects in an in vitro cytotoxicity study. The Vit K hydrogel was tested for dermal irritation on Wistar rats, and the hydrogel was found to be non-irritating. Furthermore, Vit K-hydrogel inhibited melanin formation (31.76 ± 1.14%) and was remarkably higher than free Vit K. In addition, Vit K-hydrogel inhibited L-dopa auto-oxidation to a greater extent (94.80 ± 2.41%) in comparison with Vit K solution (73.95 ± 1.62%). Vit K-hydrogel enhanced percutaneous transport of Vit K, according to in vitro percutaneous absorption findings, suggesting that this innovative formulation may provide new therapeutic options for periorbital hyperpigmentation.

Transdermal administration of chemo therapeutics into burn healing may be an effective treatment to reduce toxic side effects and improve patient compliance for burns. As a transdermal delivery system, Camelina lipid droplets (CLDs) have received great attention due to their biocompatibility, high drug payload, and rapid absorption. However, the absorbed-related mechanisms of Camelina lipid droplets have not yet been reported. Thus, this paper not only demonstrated that CLD can accelerate skin burn healing through promoting hFGF2 absorption, but also elucidated the mechanism between the skin tissue and keratinocytes using Franz, HE staining, DSC, FTIR spectroscopy, and atomic force microscopy with the presence of CLD-hFGF2 freeze-dried powder. We found that the cumulative release rate of CLD-hFGF2 freeze-dried powder was significantly higher than that of free hFGF2 freeze-dried powder into the skin. At the same time, CLD can change the structure and content of lipids and keratin to increase the permeability of hFGF2 freeze-dried powder in skin tissue. Unlike the free state of hFGF2, the biophysical properties of single cells, including height and adhesion force, were changed under CLD-hFGF2 freeze-dried powder treatment. Meanwhile, CLD-hFGF2 freeze-dried powder was more easily taken up through keratinocytes without damaging cell integrity, which provided a new viewpoint for understanding the absorption mechanism with the CLD system for cellular physiology characteristics. Overall, our findings demonstrated that CLD could break through the stratum corneum (SC) barrier and elucidated the transport mechanism of lipid droplets in skin tissue, which provides a crucial guideline in drug delivery applications for future engineering.

Psoriasis is a chronic inflammatory skin disease that is difficult to treat. Quercetin (QT) is a dietary flavonoid known for its anti-inflammatory effects and safe use in humans. However, the topical application of quercetin for psoriasis treatment presents a significant challenge due to its poor water solubility and low stability in semisolid preparations, where it tends to recrystallize. This work presents a novel liposome-in-gel formulation for the quercetin-based topical treatment of psoriasis. The quercetin-loading liposomes are stabilized by hydroxypropyl-β-cyclodextrin (HPCD), which interacts with phospholipids via hydrogen bonding to form a layer of an HPCD coating on the liposome interface, thus resulting in improved stability. Various analytical techniques, such as FTIR spectroscopy, Raman spectroscopy, and TEM, were used to characterize the molecular coordination patterns between cyclodextrin and liposomes. The results demonstrated that HPCD assisted the liposomes in interfacing with the matrix lipids and keratins of the stratum corneum, thereby enhancing skin permeability and promoting drug penetration and retention in the skin. The in vivo results showed that the topical QT HPCD-liposome-in-gel improved the treatment efficacy of psoriatic plaque compared to free QT. It alleviated the symptoms of skin thickening and downregulated proinflammatory cytokines, including TNF-α, IL-17A, and IL-1β. The results suggested that the HPCD-coordinated liposome-in-gel system could be a stable carrier for topical QT therapy with good potential in psoriasis treatment.

Plaque psoriasis is characterized by an abnormal thickening of the epidermis, which causes great difficulties for traditional topical drug delivery. Microneedles can pierce the thickened epidermis and deliver drugs to the skin for psoriasis treatment. Tacrolimus is a poorly water-soluble immunosuppressant used for the treatment of psoriasis. In this study, tacrolimus (TAC) nanocrystals (NCs) were produced using a bottom-up technique that dispersed TAC into a sodium hyaluronate-based microneedle patch (MNP), and its therapeutic efficacy was evaluated. The average particle size of the TAC NCs was 259.6 ± 2.3 nm. The mechanical strength of the microneedles was 0.41 ± 0.06 N/needle, which was sufficient to penetrate psoriatic skin. Microneedles were detached from the substrate 10 min after insertion into the psoriasis skin with an insertion depth of 258.8 ± 14.4 μm. The intradermal retention of the MNP (8.40 ± 0.33 μg/cm2) was six times that of the commercial ointment (1.40 ± 0.12 μg/cm2). In pharmacodynamic experiments, results indicated improvement in the phenotypic and histopathological features and reduction in the level of TNF-α, IL-17A, and IL-23 of psoriatic skin treated with TAC NCs MNP. Therefore, MNP loaded with TAC NCs may be a promising approach for psoriasis treatment.

The local treatment of kojic acid (KA) as a tyrosinase inhibitor results in inadequate skin absorption and a number of side effects. The current study aims to maximize KA skin delivery. To produce KA-hydrogel, 1% KA was injected into a Chitosan/alginate hydrogel. The impacts of biopolymer proportion on the KA-hydrogel preparations were investigated. Swelling analysis, weight loss analysis, differential scanning calorimetry (DSC), scanning electron microscopy (SEM), UV absorption spectroscopy, attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy were used to evaluate the KA-hydrogel. The swelling percentages of KA-hydrogel increased significantly after 4 h. After two weeks, up to 60% of the primary mass of the KA- hydrogel has been removed. By alternation in biopolymer proportion, the drug release profile of KA-hydrogel demonstrated a sustained pattern. According to the skin absorption experiment, KA-hydrogel had higher skin deposition (25.630 ± 3.350%) than KA-plain gel (5.170 ± 0.340%). Moreover, an in vitro cytotoxicity analysis for the modified KA-hydrogel preparations revealed no cytotoxic effects on HFF cell line (90%). Moreover, KA hydrogel had inhibitory effect on melanin synthesis and are comparable with KA. Furthermore, KA-hydrogel had higher inhibitory effect on L-dopa auto oxidation (94.84 ± 2.41%) in comparison KA solution (73.95 ± 3.28%). Also, the dermal irritation study on Wistar rat revealed that the hydrogel constituent used did not irritate the skin. These results revealed that the KA-hydrogel might be employed as KA local administration, thus opening up new prospects for the therapies of hyperpigmentation problems.

Psoriasis is an immune-mediated skin disorder that affects populations worldwide. Methotrexate (MTX) is a cytotoxic drug with powerful anti-proliferative and anti-inflammatory effects that has gained prominence in treating inflammatory diseases including psoriasis. However, low solubility and side effects through oral administration hinder its systemic application. In this study, we developed a novel niosomes based on ceramide (cerosomes) to co-deliver MTX and nicotinamide (NIC), i.e., MTX/NIC cerosomes, for topically treating psoriasis with the aim to enhancing the efficacy and reducing the toxicity. NIC significantly solublized MTX by forming hydrogen bonds with MTX. In vitro and in vivo permeation studies showed that the cerosomes significantly promoted drug permeation through and retention in the skin, and the enhancing mechanism was clarified by Fourier transform infraredand Raman spectroscopy. MTX/NIC cerosomes exhibited strong anti-proliferation effect on lipopolysaccharide- irritated HaCaT cells by arresting the cell cycle at S phase and inducing apoptosis. Importantly, compared to MTX oral administration, topical application of MTX/NIC cerosomes on imiquimod (IMQ)-induced psoriatic mouse model exhibited a superior performance in ameliorating skin lesions, reducing spleen index and epidermal thickness, and downregulating the mRNA expression levels of proinflammatory cytokines including TNFα, IL-23, IL-17A, IL-6, IL-1β, and IL-22. Taken together, MTX/NIC cerosomes is a promising approach for psoriasis topical treatment.

BACKGROUND: Methotrexate (MTX) is an antiproliferative drug widely used to treat inflammatory diseases and autoimmune diseases. The application of percutaneous administration is hindered due to its poor transdermal penetration. To reduce side effects and enhanced percutaneous delivery of MTX, novel methotrexate (MTX)-loaded micelles prepared with a amphiphilic cationic material, N,N-dimethyl-(N\',N\'-di-stearoyl-1-ethyl)1,3-diaminopropane (DMSAP), was designed.
METHODS: DMSAP was synthesized via three steps using simple chemical agents. H nuclear magnetic resonance and mass spectroscopy were used to confirm the successful synthesis of DMSAP. A safe and non-toxic phosphatidylcholine, soybean phosphatidylcholine (SPC), was added to DMSAP at different ratios to form P/D-micelles. Then, MTX-entrapped micelles (M/P/D-micelles) were prepared by electrostatic adsorption. The physicochemical properties and blood stability of micelles were examined thoroughly. In addition, the transdermal potential of the micelles was evaluated by permeation experiments.
RESULTS: In aqueous environments, DMSAP conjugates could self-assemble spontaneously into micelles with a low critical micelle concentration (CMC) of 0.056 mg/mL. Stable, spherical MTX-entrapped micelles (M/P/D-micelles) with a size of 100-120 nm and high zeta potential of +36.26 mV were prepared. In vitro permeation studies showed that M/P/D-micelles exhibited superior skin permeability and deposition of MTX in the epidermis and dermis compared with that of free MTX.
CONCLUSIONS: These special novel cationic M/P/D-micelles can enhance the permeability of MTX and are expected to be a promising percutaneous delivery system for therapy skin diseases.

The study focused on formulation of carmellose sodium hydrogels and nonionic microemulsions with 5% and 10% of levetiracetam and investigation of drug concentration influence on their physicochemical characteristics and in-use stability as well as influence of drug concentration and carrier type on in vitro drug release and in vivo antihyperalgesic/antiedematous activity in a rat model of localized (intraplantar) carrageenan-induced inflammation. Hydrogels were pseudoplastic semisolids with thixotropy and pH 7.37-7.58. Microemulsions were low viscous Newtonian nanodispersions of oil droplets (13.11-15.11 nm) in water, with pH 4.01-4.64. Physical stability of the investigated systems was preserved over the 3-month storage under ambient conditions. Levetiracetam release followed zero order and Korsmeyer-Peppas models (R2 ≥ 0.99) reflecting the combined effects of drug concentration and carrier viscosity. All levetiracetam-loaded formulations produced significant reduction of hyperalgesia and paw swelling induced by carrageenan (p < 0.001). Their efficacy in exerting antihyperalgesic activity was significantly higher than that observed with the reference 5% ibuprofen hydrogel preparation (up to 6 h) (p < 0.001), while antiedematous activity was comparable with the reference product. No erythema and visible blood vessels were observed in a rat ear test. The study demonstrated percutaneous delivery of levetiracetam as useful and safe therapeutic option for localized inflammatory pain with potential to overcome the insufficient efficacy of topically applied nonsteroidal anti-inflammatory drugs in the form of a hydrogel. Graphical abstract.

Background: Topical application of tacrolimus (FK506) was effective in treating atopic dermatitis (AD); however, the therapeutic efficiency is hampered by its poor penetration into the skin and local side effects of transient irritation symptoms with a burning sensation, a feeling of warmth or heat. Menthol and camphor have been widely used in topical compound formulations for adjunctive pharmacotherapy for antipruritics and analgesics owing to their cool nature, and both present skin penetration enhancing effects. Moreover, they can form a liquid eutectic oil to solubilize hydrophobic drugs. Purpose: Taking advantages of menthol/camphor eutectic (MCE), this work aims to integrate FK506 into MCE to construct a microemulsion system, i.e., FK506 MCE ME, which simultaneously enhances the percutaneous delivery and treatment efficacy, while reduces the side effects of FK506. Methods: The formulation of FK506 MCE ME was optimized and characterized. Different formulations containing FK506 were topically administered to treat 1-chloro-2, 4-dinitrobenzene (DNCB)-induced murine AD. Results: MCE solubilized FK506. FK506 in MCE ME penetrated skin in vitro more than in the commercial ointment, and MCE predominantly exerted the enhancing effects in MCE ME. FK506 MCE ME or FK506 MCE ME gel had greater effects on clinical symptoms, histological analysis, and IgE than did commercial FK506. The anti-pruritic and down-regulation of substance P effects of MCE ME vehicle mitigated the side effects of FK506 application. Conclusion: MCE ME presented the excellent properties of simultaneously enhancing the percutaneous delivery and treatment efficacy, while reducing the side effects of FK506 for AD. Therefore, MCE ME is a promising nanoscale system for FK506 to effectively treating AD with low irritation and high medication adherence. Chemical compounds studied in this article: Tacrolimus (PubChem CID: 445643); menthol (PubChem CID: 1254); camphor (PubChem CID: 2537).

Gold nanoparticles functionalized with 3-mercapto-1-propansulfonate (AuNPs-3MPS) have been prepared and loaded with Methotrexate (MTX), an immunosuppressive agent used in the systemic treatment of moderate-severe inflammatory diseases. The effects of the AuNPs-3MPS@MTX topically administered in vitro on skin model and in vivo on imiquimod-induced psoriasis-like mice model, have been studied. Clinical response, epidermal thickness, cell proliferation rate and inflammation were tested. AuNPs-3MPS@MTX treated mice showed a decreasing of scaling and erythema score, reduction of epidermal thickness, parakeratosis and hyperkeratosis, compared to AuNPs-3MPS treated mice. Immunohistochemistry analysis staining displayed that Ki67, K6 CD3 and CD8 stainings were reduced in AuNPs-3MPS@MTX treated mice. Blood evaluation showed no differences in blood count and in ALT and AST levels before and after AuNPs-3MPS or AuNPs-3MPS@MTX treatment. Topical AuNPs-3MPS@MTX treatment is able to induce a reduction of keratinocytes hyperproliferation, epidermal thickness and also inflammatory infiltrate in vivo on imiquimod-induced psoriasis like mice model.