Microneedle (MN) patches are gaining increasing attention as a cost-effective technology for delivering drugs directly into the skin. In the present study, two different 3D printing processes were utilized to produce coated MNs, namely, digital light processing (DLP) and semisolid extrusion (SSE). Donepezil (DN), a cholinesterase inhibitor administered for the treatment of Alzheimer\'s disease, was incorporated into the coating material. Physiochemical characterization of the coated MNs confirmed the successful incorporation of donepezil as well as the stability and suitability of the materials for transdermal delivery. Optical microscopy and SEM studies validated the uniform weight distribution and precise dimensions of the MN arrays, while mechanical testing ensured the MNs\' robustness, ensuring efficient skin penetration. In vitro studies were conducted to evaluate the produced transdermal patches, indicating their potential use in clinical treatment. Permeation studies revealed a significant increase in DN permeation compared to plain coating material, affirming the effectiveness of the MNs in enhancing transdermal drug delivery. Confocal laser scanning microscopy (CLSM) elucidated the distribution of the API, within skin layers, demonstrating sustained drug release and transcellular transport pathways. Finally, cell studies were also conducted on NIH3T3 fibroblasts to evaluate the biocompatibility and safety of the printed objects for transdermal applications.

This study aimed to develop chitosan alginate nanoparticles (CANPs) for enhanced stability for dermal delivery of protein hydrolysate from Acheta domesticus (PH). CANPs, developed using ionotropic pre-gelation followed by the polyelectrolyte complex technique, were characterized for particle size, polydispersity index (PDI), and zeta potential. After the incorporation of PH into CANPs, a comprehensive assessment included encapsulation efficiency, loading capacity, morphology, chemical analyses, physical and chemical stability, irritation potential, release profile, skin permeation, and skin retention. The most optimal CANPs, comprising 0.6 mg/mL sodium alginate, 1.8 mg/mL calcium chloride, and 0.1 mg/mL chitosan, exhibited the smallest particle size (309 ± 0 nm), the narrowest PDI (0.39 ± 0.01), and pronounced negative zeta potential (-26.0 ± 0.9 mV), along with an encapsulation efficiency of 56 ± 2%, loading capacity of 2.4 ± 0.1%, release of 40 ± 2% after 48 h, and the highest skin retention of 12 ± 1%. The CANPs induced no irritation and effectively enhanced the stability of PH from 44 ± 5% of PH remaining in a solution to 74 ± 4% after three-month storage. Therefore, the findings revealed the considerable potential of CANPs in improving PH stability and skin delivery, with promising applications in cosmetics and related fields.

We report on the fabrication of mesoporous silicon dioxide coated Haliclona sp. spicules (mSHS) to enhance the delivery of the insoluble photosensitizer protoporphyrin IX (PpIX) into deep skin layers and mediate photodynamic therapy for metastatic melanoma in mice. The mSHS are dispersed sharp edged and rod-like micro-particles with a length of approximate 143.6 ± 6.4 μm and a specific surface area of 14.9 ± 3.4 m2/g. The mSHS can be topically applied to the skin, adapting to any desired skin area and lesion site. The insoluble PpIX were incorporated into the mesoporous silica coating layers of mSHS (mSHS@PpIX) with the maximum PpIX loading capacity of 120.3 ± 3.8 μg/mg. The mSHS@PpIX significantly enhanced the deposition of PpIX in the viable epidermis (5.1 ± 0.4 μg/cm2) and in the dermis (0.5 ± 0.2 μg/cm2), which was 154 ± 11-fold and 22 ± tenfold higher than those achieved by SHS, respectively. Topical delivery of PpIX using mSHS (mSHS@PpIX) completely eradicated the primary melanoma in mice in 10 days without recurrence or metastasis over 60 days. These results demonstrate that mSHS can be a promising topical drug delivery platform for the treatment of diverse cutaneous diseases, such as metastatic melanoma.

Skin is the body\'s largest organ and serves as a protective barrier from physical, thermal, and mechanical environmental challenges. Alongside, the skin hosts key immune system players, such as the professional antigen-presenting cells (APCs) like the Langerhans cells in the epidermis and circulating macrophages in the blood. Further, the literature supports that the APCs can be activated by antigen or vaccine delivery via multiple routes of administration through the skin. Once activated, the stimulated APCs drain to the associated lymph nodes and gain access to the lymphatic system. This further allows the APCs to engage with the adaptive immune system and activate cellular and humoral immune responses. Thus, vaccine delivery via skin offers advantages such as reliable antigen delivery, superior immunogenicity, and convenient delivery. Several preclinical and clinical studies have demonstrated the significance of vaccine delivery using various routes of administration via skin. However, such vaccines often employ adjuvant/(s), along with the antigen of interest. Adjuvants augment the immune response to a vaccine antigen and improve the therapeutic efficacy. Due to these reasons, adjuvants have been successfully used with infectious disease vaccines, cancer immunotherapy, and immune-mediated diseases. To capture these developments, this review will summarize preclinical and clinical study results of vaccine delivery via skin in the presence of adjuvants. A focused discussion regarding the FDA-approved adjuvants will address the experiences of using such adjuvant-containing vaccines. In addition, the challenges and regulatory concerns with these adjuvants will be discussed. Finally, the review will share the prospects of adjuvant-containing vaccines delivered via skin.

Essential oils are well known for their biological properties, making them useful for the treatment of various diseases. However, because of their poor stability and high volatility, their potential cannot be fully exploited. The use of nanoformulations to deliver essential oils can solve these critical issues and amplify their biological activities. We characterized an essential oil from Satureja thymbra via GC-MS and HPLC-DAD to provide qualitative and quantitative data. The essential oil was formulated in phospholipid vesicles which were characterized for size, surface charge, and storage stability. The entrapment efficiency was evaluated as the quantification of the major monoterpenoid phenols via HPLC-DAD. The morphological characterization of the vesicles was carried out via cryo-TEM and SAXS analyses. The essential oil\'s antioxidant potential was assayed via two colorimetric tests (DPPH• and FRAP) and its cytocompatibility was evaluated in HaCaT skin cell cultures. The results showed that the nanoformulations developed for the loading of S. thymbra essential oil were below 100 nm in size, predominantly unilamellar, stable in storage, and had high entrapment efficiencies. The vesicles also displayed antioxidant properties and high cytocompatibility. These promising findings pave the way for further investigation of the therapeutic potential of S. thymbra nanoformulations upon skin application.

Several drugs can be used for treating inflammatory skin pathologies like dermatitis and psoriasis. However, for the management of chronic and long-term cases, topical administration is preferred over oral delivery since it prevents certain issues due to systemic side effects from occurring. Cyclosporin A (CsA) has been used for this purpose; however, its high molecular weight (1202 Da) restricts the diffusion through the skin structure. Here, we developed a nano-in-micro device combining lipid vesicles (LVs) and dissolving microneedle array patches (DMAPs) for targeted skin delivery. CsA-LVs allowed the effective incorporation of CsA in the hydrophilic DMAP matrix despite the hydrophobicity of the drug. Polymeric matrix composed of poly (vinyl alcohol) (5% w/v), poly (vinyl pyrrolidine) (15% w/v) and CsA-LV dispersion (10% v/v) led to the formation of CsA-LVs@DMAPs with adequate mechanical properties to penetrate the stratum corneum barrier. The safety and biocompatibility were ensured in an in vitro viability test using HaCaT keratinocytes and L929 fibroblast cell lines. Ex vivo permeability studies in a Franz-diffusion cell setup showed effective drug retention in the skin structure. Finally, CsA-LVs@DMAPs were challenged in an in vivo murine model of delayed-type hypersensitivity to corroborate their potential to ameliorate skin inflammatory conditions. Different findings like photon emission reduction in bioluminescence study, normalisation of histological damage and decrease of inflammatory cytokines point out the effectivity of CsA-LVs@DMAPs to treat these conditions. Overall, our study demonstrates that CsA-LVs@DMAPs can downregulate the skin inflammatory environment which paves the way for their clinical translation and their use as an alternative to corticosteroid-based therapies.

In this study, the amphiphilic N-palmitoyl-KTTKS peptide was integrated in the bilayer of egg-derived phosphatidylcholine (PC) vesicles using two different preparation methods, namely thin-film evaporation (TLE) and reverse-phase evaporation (REV). Both the REV and TLE methods allowed for the formation of homogeneous liposome dispersions (PdI < 0.20) with mean hydrodynamic diameters of <100 nm and <200 nm, respectively, a net negative surface charge and a percentage of structured phospholipids higher than 90%. The inclusion of the amphiphilic N-palmitoyl-KTTKS peptide within phospholipid-based vesicles could improve peptide stability and skin delivery. Therefore, the obtained liposomes were evaluated via experiments assessing the synthesis of collagen and the ECM in 3T3-NIH fibroblasts. The obtained results showed that, when delivered with PC liposomes, pal-KTTKS stimulated collagen production more than free pentapeptide and 1 mM ascorbic acid, used as a positive control.

The objective of this study was to investigate the cutaneous delivery of cannabidiol (CBD) from aqueous formulations developed for the targeted local treatment of dermatological conditions. CBD was formulated using a proprietary colloidal drug delivery system (VESIsorb®) into an aqueous colloidal solution at 2% (ACS 2%) and two colloidal gels (CG 1% and CG 2%, which contained 1% and 2% CBD, respectively). Two basic formulations containing CBD (5% in propylene glycol (PG 5%) and a 6.6% oil solution (OS 6.6%)) and two marketed CBD products (RP1 and RP2, containing 1% CBD) were used as comparators. Cutaneous delivery and cutaneous biodistribution experiments were performed using human abdominal skin (500-700 µm) under infinite- and finite-dose conditions with 0.5% Tween 80 in the PBS receiver phase. The quantification of CBD in the skin samples was performed using a validated UHPLC-MS/MS method and an internal standard (CBD-d3). The cutaneous deposition of CBD under finite-dose conditions demonstrated the superiority of CG 1%, CG 2%, and ACS 2% over the marketed products; CG 1% had the highest delivery efficiency (5.25%). Cutaneous biodistribution studies showed the superiority of the colloidal systems in delivering CBD to the viable epidermis, and the upper and lower papillary dermis, which are the target sites for the treatment of several dermatological conditions.

The herb Sophora flavescens displays anti-inflammatory activity and can provide a source of antipsoriatic medications. We aimed to evaluate whether S. flavescens extracts and compounds can relieve psoriasiform inflammation. The ability of flavonoids (maackiain, sophoraflavanone G, leachianone A) and alkaloids (matrine, oxymatrine) isolated from S. flavescens to inhibit production of cytokine/chemokines was examined in keratinocytes and macrophages. Physicochemical properties and skin absorption were determined by in silico molecular modeling and the in vitro permeation test (IVPT) to establish the structure-permeation relationship (SPR). The ethyl acetate extract exhibited higher inhibition of interleukin (IL)-6, IL-8, and CXCL1 production in tumor necrosis factor-α-stimulated keratinocytes compared to the ethanol and water extracts. The flavonoids demonstrated higher cytokine/chemokine inhibition than alkaloids, with the prenylated flavanones (sophoraflavanone G, leachianone A) led to the highest suppression. Flavonoids exerted anti-inflammatory effects via the extracellular signal-regulated kinase, p38, activator protein-1, and nuclear factor-κB signaling pathways. In the IVPT, prenylation of the flavanone skeleton significantly promoted skin absorption from 0.01 to 0.22 nmol/mg (sophoraflavanone G vs. eriodictyol). Further methoxylation of a prenylated flavanone (leachianone A) elevated skin absorption to 2.65 nmol/mg. Topical leachianone A reduced the epidermal thickness in IMQ-treated mice by 47%, and inhibited cutaneous scaling and cytokine/chemokine overexpression at comparable levels to a commercial betamethasone product. Thus, prenylation and methoxylation of S. flavescens flavanones may enable the design of novel antipsoriatic agents.

OBJECTIVE: Disruption of the protective stratum corneum barrier increases the skin\'s vulnerability to microorganisms and facilitates conditions such as dandruff. Dandruff is a disorder of the scalp that causes increased scaling of the SC and is associated with Malassezia fungus. Consequently, many anti-dandruff commercial products use anti-fungal active ingredients such as piroctone olamine also known as Octopirox (OPX). OPX is an active ingredient used in a number of topical preparations for the management of dandruff. The characterization of the physicochemical properties of OPX was previously reported. The aim of the present work was to investigate a range of solvent systems for their effects on OPX interaction with human skin.
METHODS: The solvents used in this study were propylene glycol (PG), diethylene glycol monoethyl ether or Transcutol® (TC), PG monolaurate (PGML), isopropyl myristate (IPM), caprylic/capric triglyceride or Labrafac™ Lipophile WL 1349 (LAB), PG caprylate or Capryol® 90 (CAP), isostearyl isostearate (ISIS) and Plurol® Oleique CC 497 (PIOI). The single solvent systems evaluated were PG, TC, PGML, IPM, ISIS and CAP. For the binary solvent systems, PG and TC were examined. Ternary solvent systems consisted of: PG, TC and LAB; PG, PGML and LAB; and PG, TC and IPM. The concentration of OPX used was 1% (w/v). Heat-separated human epidermis was used for 24 h permeation experiments performed under finite dose conditions; mass balance studies were also conducted.
RESULTS: For the six single solvents examined no permeation was evident. Skin permeation of OPX was observed for binary and ternary solvent systems. The highest permeation for all PG:TC binary solvent system ratios tested was from the PG:TC (75:25) system. For the ternary solvent systems investigated, highest cumulative permeation of OPX was observed for PG:PGML:LAB (60:30:10). Considering all systems, PG:TC (75:25) delivered the greatest amount of OPX through the skin. Although OPX is deposited in the skin following the application of neat solvents, higher skin retention values were generally observed for binary and ternary systems.
CONCLUSIONS: To our knowledge, this is the first study to examine the permeation behaviour of OPX for a range of single, binary and ternary solvent systems.
OBJECTIVE: La perturbation de la barrière protectrice de la couche cornée augmente la vulnérabilité de la peau aux micro‐organismes et facilite des affections telles que les pellicules. Les pellicules sont un trouble du cuir chevelu qui provoque une augmentation de la desquamation de la couche cornée et qui est associé au champignon Malassezia. Par conséquent, de nombreux produits commerciaux antipelliculaires utilisent des principes actifs antifongiques, tels que la piroctone olamine, également appelée Octopirox (OPX). L’OPX est un principe actif utilisé dans un certain nombre de préparations topiques pour la prise en charge des pellicules. La caractérisation des propriétés physicochimiques de l’OPX a été précédemment rapportée. L’objectif de ce travail était d’étudier un éventail de systèmes de solvants pour leurs effets sur l’interaction de l’OPX avec la peau humaine. MÉTHODES: Les solvants utilisés dans cette étude étaient le propylène glycol (PG), l’éther monoéthylique de diéthylèneglycol ou Transcutol® (TC), le monolaurate de propylène glycol (PGML), le myristate d’isopropyle (IPM), le triglycéride caprylique/caprique ou Labrafac™ lipophile WL 1349 (LAB), le caprylate de propylène glycol ou Capryol® 90 (CAP), l’isostéarate d’isostéaryle (ISIS) et Plurol® Oleique CC 497 (PIOI). Les systèmes à solvant unique évalués étaient le PG, le TC, le PGML, l’IPM, l’ISIS et le CAP. Pour les systèmes de solvants binaires, le PG et le TC ont été examinés. Les systèmes de solvants ternaires comprenaient : PG, TC et LAB ; PG, PGML et LAB ; et PG, TC et IPM. La concentration d’OPX utilisée était de 1 % (p/v). L’épiderme humain séparé par la chaleur a été utilisé pour des expériences de perméation de 24 heures réalisées dans des conditions de dose finie ; des études d’équilibre de masse ont également été menées. RÉSULTATS: Pour les six solvants uniques examinés, aucune perméation n’était manifeste. Une perméation cutanée de l’OPX a été observée pour les systèmes de solvants binaires et ternaires. La perméation la plus élevée pour tous les rapports du système de solvant binaire PG:TC testés a été obtenue avec le système PG:TC (75:25). Pour les systèmes de solvants ternaires étudiés, la perméation cumulée la plus élevée d’OPX a été observée pour PG:PGML:LAB (60:30:10). Parmi tous les systèmes, PG:TC (75:25) a délivré la plus grande quantité d’OPX à travers la peau. Bien que l’OPX se dépose dans la peau après l’application de solvants purs, des valeurs de rétention cutanée plus élevées ont généralement été observées pour les systèmes binaire et ternaire.
CONCLUSIONS: À notre connaissance, il s’agit de la première étude visant à examiner le comportement de perméation de l’OPX pour un éventail de systèmes de solvants uniques, binaires et ternaires.