Fabrication of Hybrid Coated Microneedles with Donepezil Utilizing Digital Light Processing and Semisolid Extrusion Printing for the Management of Alzheimer's Disease.

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.

Mesoporous silica coated spicules for photodynamic therapy of metastatic melanoma.

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.

The anti-inflammatory activity of flavonoids and alkaloids from Sophora flavescens alleviates psoriasiform lesions: Prenylation and methoxylation beneficially enhance bioactivity and skin targeting.

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.

A Nano-Based Approach to Deliver Satureja thymbra Essential Oil to the Skin: Formulation and Characterization.

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.

The Impact of Phospholipid-Based Liquid Crystals' Microstructure on Stability and Release Profile of Ascorbyl Palmitate and Skin Performance.

The drug delivery potential of liquid crystals (LCs) for ascorbyl palmitate (AP) was assessed, with the emphasis on the AP stability and release profile linked to microstructural rearrangement taking place along the dilution line being investigated by a set of complementary techniques. With high AP degradation observed after 56 days, two stabilization approaches, i.e., the addition of vitamin C or increasing AP concentration, were proposed. As a rule, LC samples with the lowest water content resulted in better AP stability (up to 52% of nondegraded AP in LC1 after 28 days) and faster API release (~18% in 8 h) as compared to the most diluted sample (29% of nondegraded AP in LC8 after 28 days, and up to 12% of AP released in 8 h). In addition, LCs exhibited a skin barrier-strengthening effect with up to 1.2-fold lower transepidermal water loss (TEWL) and 1.9-fold higher skin hydration observed in vitro on the porcine skin model. Although the latter cannot be linked to LCs' composition or specific microstructure, the obtained insight into LCs' microstructure contributed greatly to our understanding of AP positioning inside the system and its release profile, also influencing the overall LCs' performance after dermal application.

Development of Essential Oil-Loaded Polymeric Nanocapsules as Skin Delivery Systems: Biophysical Parameters and Dermatokinetics Ex Vivo Evaluation.

Essential oils (EOs) are natural antioxidant alternatives that reduce skin damage. However, EOs are highly volatile; therefore, their nanoencapsulation represents a feasible alternative to increase their stability and favor their residence time on the skin to guarantee their effect. In this study, EOs of Rosmarinus officinalis and Lavandula dentata were nanoencapsulated and evaluated as skin delivery systems with potential antioxidant activity. The EOs were characterized and incorporated into polymeric nanocapsules (NC-EOs) using nanoprecipitation. The antioxidant activity was evaluated using the ferric thiocyanate method. The ex vivo effects on pig skin were evaluated based on biophysical parameters using bioengineering techniques. An ex vivo dermatokinetic evaluation on pig skin was performed using modified Franz cells and the tape-stripping technique. The results showed that the EOs had good antioxidant activity (>65%), which was maintained after nanoencapsulation and purification. The nanoencapsulation of the EOs favored its deposition in the stratum corneum compared to free EOs; the highest deposition rate was obtained for 1,8-cineole, a major component of L. dentata, at 1 h contact time, compared to R. officinalis with a major deposition of the camphor component. In conclusion, NC-EOs can be used as an alternative antioxidant for skin care.

Investigation of piroctone olamine delivery to the skin from single, binary and ternary solvent systems.

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. CONCLUSION: 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.

OBJECTIF: 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. CONCLUSION: 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.

Effects of Sodium Salts of Fatty Acids and Their Derivatives on Skin Permeation of Cromolyn Sodium.

Atopic dermatitis is a chronic inflammatory disorder with rising prevalence. The safety concerns over usually used steroids are driving the need for developing an effective atopic dermatitis treatment. The use of therapeutic agents such as cromolyn sodium (CS) is suggested. However, due to its physicochemical properties, CS permeation across the skin is a challenge. The aim of this study was to investigate the effect of sodium salts of fatty acids or their derivatives with varied carbon chain lengths as potential enhancers on the skin permeation of CS. These included sodium caprylate, salcaprozate sodium, sodium decanoate, sodium palmitate, and sodium oleate dissolved in propylene glycol along with CS (4% w/w). In vitro permeation of the formulations across the dermatomed porcine ear skin was investigated over 24 h using Franz Diffusion cells. The amount of CS permeation from propylene glycol was 5.54 ± 1.06 µg/cm2 after 24 h. Initial screening of enhancers (enhancer: drug::1:1) showed enhancement in permeation of CS using sodium oleate and sodium caprylate, which were then investigated in higher ratio of drug: enhancer (1:2). Among all the formulations tested, sodium oleate (enhancer: drug::1:2) was observed to significantly (p < 0.05) enhance the permeation of CS with the highest total delivery of 359.79 ± 78.92 µg/cm2 across skin in 24 h and higher drug retention in the skin layers (153.0 ± 24.93 µg/cm2) as well. Overall, sodium oleate was found to be the most effective enhancer followed by sodium caprylate for improving the topical delivery of CS.

Application of Confocal Raman Microscopy for the Characterization of Topical Semisolid Formulations and their Penetration into Human Skin Ex Vivo.

PURPOSE: The quality testing and approval procedure for most pharmaceutical products is a streamlined process with standardized procedures for the determination of critical quality attributes. However, the evaluation of semisolid dosage forms for topical drug delivery remains a challenging task. The work presented here highlights confocal Raman microscopy (CRM) as a valuable tool for the characterization of such products. METHODS: CRM, a laser-based method, combining chemically-selective analysis and high resolution imaging, is used for the evaluation of different commercially available topical acyclovir creams. RESULTS: We show that CRM enables the spatially resolved analysis of microstructural features of semisolid products and provides insights into drug distribution and polymorphic state as well as the composition and arrangement of excipients. Further, we explore how CRM can be used to monitor phase separation and to study skin penetration and the interaction with fresh and cryopreserved excised human skin tissue. CONCLUSION: This study presents a comprehensive overview and illustration of how CRM can facilitate several types of key analyses of semisolid topical formulations and of their interaction with their biological target site, illustrating that CRM is a useful tool for research, development as well as for quality testing in the pharmaceutical industry.

EthoLeciplex: a new tool for effective cutaneous delivery of minoxidil.

This work designates EthoLeciplex, a vesicular system consisting of phospholipid, CTAB, ethanol and water, as an innovative vesicular system for cutaneous/transfollicular minoxidil (MX) delivery. MX-loaded EthoLeciplex was fabricated by one-step fabrication process. Formulations were designed to study the effects of drug/phospholipid ratio, CTAB/phospholipid ratio, and ethanol concentration on vesicular size, PDI, surface charge and EE%. The optimized formulation was characterized by in vitro release, drug/excipient compatibility, ex vivo skin permeability and safety. A size of 83.6 ± 7.3 to 530.3 ± 29.4 nm, PDI of 0.214 ± 0.01 to 0.542 ± 0.08 and zeta potential of +31.6 ± 4.8 to +57.4 ± 12.5 mV were observed. Encapsulation efficiency was obtained in its maximum value (91.9 ± 16.2%) at the lowest drug/phospholipid ratio, median CTAB/phospholipid and the highest ethanol concentration. The optimized formulation was consisted of 0.3 as drug/lipid ratio, 1.25 as CTAB/lipid ratio and 30% ethanol concentration and showed responses' values in agreement with the predicted results. Differential scanning calorimetry studies suggested that EthoLeciplex existed in flexible state with complete incorporation of MX into lipid bilayer. The cumulative amount of MX permeated from EthoLeciplex, conventional liposome and ethanolic solution after 12 h were 36.3 ± 1.5 µg/ml, 21 ± 2.0 µg/ml and 55 ± 4.0 µg/ml respectively. Based on the remaining amount, the amount of MX accumulated in different skin layers can be predicted in descending order as follows; EthoLeciplex > conventional liposome > MX solution. EthoLeciplex produced marked disorder in the stratum corneum integrity and swelling with no features of skin toxicity. This new cationic system is a promising carrier for cutaneous/transfollicular drug delivery.

Microneedle-assisted transdermal delivery of amlodipine besylate loaded nanoparticles.

Transdermal drug delivery has been developed to increase drug bioavailability and improve patient compliance. The current study was carried out to formulate and evaluate a transdermal delivery system loaded with biodegradable polymeric nanoparticles for sustained delivery of amlodipine besylate (AMB). For this purpose, AMB was incorporated into CS nanoparticles that were prepared via the ionic gelation method. Three formulations containing different blends of CS and tripolyphosphate were investigated for the preparation of the nanoparticles and evaluated for particle size (PS), zeta potential (ZP), loading capacity (LC), encapsulation efficiency (EE), scanning electron microscope (SEM), and drug release kinetics. The smallest observed particle size was 321.14 ± 7.21 nm (NP-3). Across all formulations, the highest observed EE% was 87.2 ± 0.12% (NP-2), and the highest observed LC% was 60.98 ± 0.08% (NP-2). Microneedles were formed by using 15% polyvinylalcohol (PVA) (F1), 15% PVA with 1% propylene glycol (PG) (F2), and 15% PVA with 5% PG (F3). On investigating drug release rates, it was observed that drug permeation and steady-state flux (Jss) both increased proportionally with increasing PG concentration. Nanomedicine, when combined with physical techniques, has opened new opportunities for the growth and development of transdermal delivery systems in the pharmaceutical industry. In conclusion, biodegradable polymeric nanoparticles loaded in hydrogel microneedles served as a potential system for the transdermal delivery of AMB in a controlled manner.

Skin permeability, a dismissed necessity for anti-wrinkle peptide performance.

BACKGROUND: The skin offers various benefits and potential for peptide delivery if its barrier performance can be reduced temporarily and reversibly. As peptides possess high molecular weight, hydrophilic nature (in most cases), and ionizable groups in the structure, their skin delivery is highly challenging. Apart from this, they are susceptible to the proteolytic enzymes in the skin. Anti-wrinkle peptides, like other peptides, suffer from insufficient skin permeability, while most of them must penetrate deep in the skin to present their efficacy. Although the cellular studies indicate the effectiveness of such peptides, without the ability to permeate the skin sufficiently, this efficacy is useless. Poor skin permeability of anti-wrinkle peptides has led to ongoing research for finding feasible and noninvasive enhancement methods that would be desirable for consumers of cosmetic products. METHOD: In this paper, the possibility of skin permeation of anti-wrinkle peptides as well as the chemical, physical, and encapsulation approaches that have been employed to date to increase permeability of these difficult molecules are thoroughly reviewed. RESULTS: Most anti-wrinkle peptides are not appropriate candidates for skin permeation and the use of enhancement methods is essential to increase their permeability. To do so, only some permeability enhancement approaches have been applied so far, including chemical modification with hydrophobic moieties or cell penetrating peptides, metal complexation, chemical permeation enhancers, iontophoresis, microneedles, and encapsulation in nanocarriers. The results of studies published on the skin permeability of anti-wrinkle peptides carnosine, GHK, PKEK, GEKG, GQPR, and KTTKS indicate that the skin permeability of these peptides can be successfully increased. CONCLUSION: Although the skin permeability of most anti-wrinkle peptides is not high enough and most anti-wrinkle peptides might not reach their targets in the skin at right concentrations, their permeability can be increased to therapeutic concentrations using various enhancement approaches.

CONTEXTE: La peau offre divers avantages et a la faculté de recevoir des peptides si l'on parvient à réduire temporairement et de manière réversible sa capacité à fonctionner comme une barrière. Comme les peptides ont un poids moléculaire élevé, une nature hydrophile (dans la plupart des cas) et possèdent des groupes ionisables dans leur structure, il est très difficile d'en faire bénéficier la peau. En outre, ils sont sensibles aux enzymes protéolytiques de la peau. Les peptides antirides, comme d'autres peptides, souffrent d'une capacité insuffisante de perméation de la peau ; or, la plupart d'entre eux doivent y pénétrer profondément pour avoir une efficacité. Bien que les études cellulaires indiquent l'efficacité de ces peptides, s'ils sont incapables de pénétrer suffisamment la peau, cette efficacité est inopérante. Face à cette perméabilité médiocre de la peau aux peptides antirides, des recherches sont menées actuellement pour trouver des méthodes d'amélioration à la fois réalisables et non invasives, qui soient attractives pour les consommateurs de produits cosmétiques. MÉTHODE: Dans cet article, nous étudions de manière approfondie la possibilité de perméation des peptides antirides à travers l'épiderme, ainsi que les approches chimiques, physiques et d'encapsulation utilisées à ce jour pour augmenter l'aptitude à la perméation de ces molécules difficiles. RÉSULTATS: La plupart des peptides antirides ne sont pas de bons candidats à la perméation de l'épiderme, et il est essentiel d'avoir recours à des méthodes de renforcement pour augmenter leur capacité de pénétration. Pour ce faire, seules certaines approches de renforcement de la perméation ont été appliquées jusqu'à présent : une modification chimique avec des fractions hydrophobes ou des peptides pénétrants la cellule ; la complexation métallique ; les amplificateurs de perméation chimique ; l'iontophorèse ; les micro-aiguilles et l'encapsulation dans les nano supports. Les résultats des études publiées sur la perméabilité de l'épiderme aux peptides antirides que sont la carnosine, le GHK, le PKEK, le GEKG, le GQPR et le KTTKS indiquent que l'augmentation de la capacité de perméation de l'épiderme de ces peptides est possible et donne de bons résultats. CONCLUSION: Bien que la capacité de perméation de la plupart des peptides antirides ne soit pas suffisamment élevée et qu'ils n'atteignent pas leurs cibles dans la peau aux bonnes concentrations, cette capacité peut être augmentée jusqu'à des concentrations thérapeutiques en recourant à diverses approches de renforcement.

Thermosensitive gel based on cellulose derivative for topical delivery of propolis in acne treatment.

Thermosensitive bioadhesive formulations can display increased retention time, skin permeation, and improve the topical therapy of many drugs. Acne is an inflammatory process triggered by several factors like the proliferation of the bacteria Propionibacterium acnes. Aiming for a new alternative treatment with a natural source, propolis displays great potential due to its antibiotic, anti-inflammatory, and healing properties. This study describes the development of bioadhesive thermoresponsive platform with cellulose derivatives and poloxamer 407 for propolis skin delivery. Propolis ethanolic extract (PES) was added to the formulations with sodium carboxymethylcellulose (CMC) or hydroxypropyl methylcellulose (HPMC) and poloxamer 407 (Polox). The formulations were characterized as rheology, bioadhesion, and mechanical analysis. The selected formulations were investigated as in vitro propolis release, cytotoxicity, ex vivo skin permeation by Fourier Transform Infrared Photoacoustic Spectroscopy, and the activity against P. acnes. Formulations showed suitable sol-gel transition temperature, shear-thinning behavior, and texture profile. CMC presence decreased the cohesiveness and adhesiveness of formulations. Polox/HPMC/PES system displayed less cytotoxicity, modified propolis release governed by anomalous transport, skin permeation, and activity against P. acnes. These results indicate important advantages in the topical treatment of acne and suggest a potential formulation for clinical evaluation.

Nanoencapsulation of Tea Catechins for Enhancing Skin Absorption and Therapeutic Efficacy.

Tea catechins are a group of flavonoids that show many bioactivities. Catechins have been extensively reported as a potential treatment for skin disorders, including skin cancers, acne, photoaging, cutaneous wounds, scars, alopecia, psoriasis, atopic dermatitis, and microbial infection. In particular, there has been an increasing interest in the discovery of cosmetic applications using catechins as the active ingredient because of their antioxidant and anti-aging activities. However, active molecules with limited lipophilicity have difficulty penetrating the skin barrier, resulting in low bioavailability. Nevertheless, topical application is a convenient method for delivering catechins into the skin. Nanomedicine offers an opportunity to improve the delivery efficiency of tea catechins and related compounds. The advantages of catechin-loaded nanocarriers for topical application include high catechin loading efficiency, sustained or prolonged release, increased catechin stability, improved bioavailability, and enhanced accumulation or targeting to the nidus. Further, various types of nanoparticles, including liposomes, niosomes, micelles, lipid-based nanoparticles, polymeric nanoparticles, liquid crystalline nanoparticles, and nanocrystals, have been employed for topical catechin delivery. These nanoparticles can improve catechin permeation via close skin contact, increased skin hydration, skin structure disorganization, and follicular uptake. In this review, we describe the catechin skin delivery approaches based on nanomedicine for treating skin disorders. We also provide an in-depth description of how nanoparticles effectively improve the skin absorption of tea catechins and related compounds, such as caffeine. Furthermore, we summarize the possible future applications and the limitations of nanocarriers for topical delivery at the end of this review article.

Efficient Drug Delivery into Skin Using a Biphasic Dissolvable Microneedle Patch with Water-Insoluble Backing.

Dissolvable microneedle patches (MNPs) enable simplified delivery of therapeutics via the skin. However, most dissolvable MNPs do not deliver their full drug loading to the skin because only some of the drug is localized in the microneedles (MNs), and the rest remains adhered to the patch backing after removal from the skin. In this work, biphasic dissolvable MNPs are developed by mounting water-soluble MNs on a water-insoluble backing layer. These MNPs enable the drug to be contained in the MNs without migrating into the patch backing due to the inability of the drugs to partition into the hydrophobic backing materials during MNP fabrication. In addition, the insoluble backing is poorly wetted upon MN dissolution in the skin, which significantly reduces drug residue on the MNP backing surface after application. These effects enable a drug delivery efficiency of >90% from the MNPs into the skin 5 min after application. This study shows that the biphasic dissolvable MNPs can facilitate efficient drug delivery to the skin, which can improve the accuracy of drug dosing and reduce drug wastage.

The vitamin A ester retinyl propionate has a unique metabolic profile and higher retinoid-related bioactivity over retinol and retinyl palmitate in human skin models.

Human skin is exposed daily to environmental stressors, which cause acute damage and inflammation. Over time, this leads to morphological and visual appearance changes associated with premature ageing. Topical vitamin A derivatives such as retinol (ROL), retinyl palmitate (RPalm) and retinyl propionate (RP) have been used to reverse these changes and improve the appearance of skin. This study investigated a stoichiometric comparison of these retinoids using in vitro and ex vivo skin models. Skin biopsies were treated topically to compare skin penetration and metabolism. Treated keratinocytes were evaluated for transcriptomics profiling and hyaluronic acid (HA) synthesis and treated 3D epidermal skin equivalents were stained for epidermal thickness, Ki67 and filaggrin. A retinoic acid receptor-alpha (RARα) reporter cell line was used to compare retinoid activation levels. Results from ex vivo skin found that RP and ROL have higher penetration levels compared with RPalm. RP is metabolized primarily into ROL in the viable epidermis and dermis whereas ROL is esterified into RPalm and metabolized into the inactive retinoid 14-hydroxy-4,14-retro-retinol (14-HRR). RP treatment yielded higher RARα activation and HA synthesis levels than ROL whereas RPalm had a null effect. In keratinocytes, RP and ROL stimulated similar gene expression patterns and pathway theme profiles. In conclusion, RP and ROL show a similar response directionality whereas RPalm response was inconsistent. Additionally, RP has a consistently higher magnitude of response compared with ROL or RPalm.

Ethosomes as Nanocarriers for the Development of Skin Delivery Formulations.

The use of nanotechnology has been extensively explored for developing efficient drug delivery systems towards topical and transdermal applications. Ethosomes constitute a vesicular nanocarrier containing a relatively high concentration of ethanol (20-45%). Ethanol is a well-known permeation enhancer, which confers ethosomes unique features, including high elasticity and deformability, allowing them to penetrate deeply across the skin and enhance drug permeation and deposition. The improved composition of ethosomes offer, thereby, significant advantages in the delivery of therapeutic agents over particularly the conventional liposomes regarding different pathologies, including acne, psoriasis, alopecia, skin infections, hormonal deficiencies, among others. This review provides a comprehensive overview of the ethosomal system and an assessment of its potential as an efficient nanocarrier towards the skin delivery of active ingredients. Special attention is given to the composition of ethosomes and the mechanism of skin permeation, as well as their potential applications in different pathologies, particularly skin pathologies (acne, psoriasis, atopic dermatitis, skin cancer and skin infections). Some examples of ethosome-based formulations for the management of skin disorders are also highlighted. Besides the need for further studies, particularly in humans, ethosomal-based formulations hold great promise in the skin delivery of active ingredients, which increasingly asserts oneself as a viable alternative to the oral route.

Thymol-loaded PLGA nanoparticles: an efficient approach for acne treatment.

BACKGROUND: Acne is a common skin disorder that involves an infection inside the hair follicle, which is usually treated with antibiotics, resulting in unbalanced skin microbiota and microbial resistance. For this reason, we developed polymeric nanoparticles encapsulating thymol, a natural active compound with antimicrobial and antioxidant properties. In this work, optimization physicochemical characterization, biopharmaceutical behavior and therapeutic efficacy of this novel nanostructured system were assessed. RESULTS: Thymol NPs (TH-NP) resulted on suitable average particle size below 200 nm with a surface charge around - 28 mV and high encapsulation efficiency (80%). TH-NP released TH in a sustained manner and provide a slow-rate penetration into the hair follicle, being highly retained inside the skin. TH-NP possess a potent antimicrobial activity against Cutibacterium acnes and minor effect towards Staphylococcus epidermis, the major resident of the healthy skin microbiota. Additionally, the stability and sterility of developed NPs were maintained along storage. CONCLUSION: TH-NP showed a promising and efficient alternative for the treatment of skin acne infection, avoiding antibiotic administration, reducing side effects, and preventing microbial drug resistance, without altering the healthy skin microbiota. Additionally, TH-NP enhanced TH antioxidant activity, constituting a natural, preservative-free, approach for acne treatment.

A comparison of the in vitro permeation of 3-O-ethyl-l-ascorbic acid in human skin and in a living skin equivalent (LabSkin™).

OBJECTIVES: The safety assessment of personal care products often entails determining dermal absorption of their ingredients. Such experiments are typically performed in human or animal skin in vitro; however, ethical and safety considerations are associated with obtaining these tissues. Several human skin equivalent models (HSEs) have been developed as alternatives to human tissue. The barrier function of such models however, is normally less developed than human skin. Here, we examine the permeability of the HSE LabSkinTM to a model compound, 3-O-ethyl-l-ascorbic acid (EA) compared with human skin. METHODS: Skin uptake and permeation of EA was investigated in vitro using heat-separated human epidermis and LabSkinTM . Finite dose (5 µL cm-2 ) Franz-diffusion studies were conducted using 2 % (w/w) EA in a ternary solvent mixture comprising propylene glycol (PG), propylene glycol monolaurate (PGML), and isopropyl myristate (IPM). These excipients are commonly used in cosmetic products and they have been reported to promote permeation of EA in a different model, namely porcine skin. RESULTS: Permeation of EA through LabSkinTM was evident from 2 h; however, EA permeation in human skin was not detected until 5 h. Similar amounts of EA permeated through the two membranes at time points 8, 10, 12 and 24 h (p > 0.05). The cumulative amounts of EA delivered through LabSkinTM at 24 h were 41.3 ± 2.0 µg cm-2 , corresponding to 55.1 ± 1.8 % of the applied dose. Similar amounts permeated across human skin, 49.4 ± 4.1 µg cm-2 , accounting for 58.0 ± 4.2 % of the dose applied (p > 0.05). CONCLUSION: The permeation of EA in LabSkinTM compared well with results for human epidermis in terms of the permeation profiles and the cumulative amounts of EA that permeated. The data suggest that the skin barrier of the two models was similar with regard to their overall permeability to the hydrophilic active EA. The findings are promising for the use of LabSkinTM as a surrogate for human skin in permeability testing. Future studies will focus on exploring the reproducibility and robustness of LabSkinTM for delivery of other actives that span a range of physicochemical properties.

OBJECTIFS: L'évaluation de la sécurité des produits de soins personnels implique souvent de déterminer l'absorption cutanée de leurs ingrédients. Ces expérimentations sont généralement réalisées in vitro sur la peau humaine ou animale ; cependant, des considérations éthiques et de sécurité sont associées à l'obtention de ces tissus. Plusieurs modèles équivalents de peau humaine (Human Skin Equivalent, HSE) ont été développés comme alternatives au tissu humain. La fonction barrière de ces modèles est cependant normalement moins développée que la peau humaine. Ici, nous examinons la perméabilité du HSE LabSkin™ à un composé modèle, l'acide 3-O-éthyl-l-ascorbique (EA) en le comparant à la peau humaine. MÉTHODES: L'absorption cutanée et la perméation de l'EA ont été étudiées in vitro à l'aide d'épiderme humain séparé par la chaleur et de LabSkin™. Des études de diffusion de Franz à dose limitée (5 µL cm-2 ) ont été réalisées en utilisant 2 % (p/p) d'EA dans un mélange de solvant ternaire contenant du propylène glycol (PG), du propylène glycol monolaurate (PGML) et du myristate d'isopropyle (IPM). Ces excipients sont fréquemment utilisés dans les produits cosmétiques et il a été rapporté qu'ils favorisent la perméation de l'EA dans un modèle différent, à savoir la peau porcine. RÉSULTATS: La perméation de l'EA par LabSkin™ était évidente dès 2 h ; cependant, la perméation de l'EA dans la peau humaine n'a pas été détectée avant 5 h. Des quantités similaires d'EA ont pénétré les deux membranes aux points temporels 8, 10, 12 et 24 h (p > 0,05). Les quantités cumulées d'EA délivrées par LabSkin™ à 24 h étaient de 41,3 ± 2,0 µg cm-2 , correspondant à 55,1 ± 1,8 % de la dose appliquée. Des quantités similaires ont pénétré la peau humaine, 49,4 ± 4,1 µg cm-2 , représentant 58,0 ± 4,2 % de la dose appliquée (p > 0,05). CONCLUSION: La perméation de l'EA dans LabSkin™ a bien soutenu la comparaison quant aux résultats concernant l'épiderme humain en termes de profils de perméation et de quantités cumulées d'EA qui ont pénétré. Les données suggèrent que la barrière cutanée des deux modèles était similaire en ce qui concerne leur perméabilité globale à l'EA hydrophile actif. Les résultats sont prometteurs pour l'utilisation de LabSkin™ en tant que substitut de la peau humaine dans les tests de perméabilité. Les études futures se concentreront sur l'exploration de la reproductibilité et de la robustesse de LabSkin™ pour la délivrance d'autres principes actifs qui couvrent un éventail de propriétés physicochimiques.

Development of erianin-loaded dendritic mesoporous silica nanospheres with pro-apoptotic effects and enhanced topical delivery.

BACKGROUND: Psoriasis is a malignant skin disease characterized as keratinocyte hyperproliferation and aberrant differentiation. Our previous work reported that a bibenzyl compound, erianin, has a potent inhibitory effect on keratinocyte proliferation. To improve its poor water-solubility, increase anti- proliferation activity, and enhance the skin delivery, erianin loaded dendritic mesoporous silica nanospheres (E/DMSNs) were employed. RESULTS: In this work, DMSNs with pore size of 3.5 nm (DMSN1) and 4.6 nm (DMSN2) were fabricated and E/DMSNs showed pore-size-dependent, significantly stronger anti-proliferative and pro-apoptotic effect than free erianin on human immortalized keratinocyte (HaCaT) cells, resulting from higher cellular uptake efficiency. In addition, compared to free erianin, treatment with E/DMSNs was more effective in reducing mitochondrial membrane potential and increasing cytoplasmic calcium levels, which were accompanied by regulation of mitochondria and endoplasmic reticulum stress (ERS) pathway. Porcine skin was utilized in the ex vivo accumulation and permeation studies, and the results indicated higher drug retention and less drug penetration in the skin when administered as the E/DMSNs-loaded hydrogel compared to the erianin-loaded hydrogel. Conlusions This work not only illustrated the further mechanisms of erianin in anti-proliferation of HaCaT cells but also offer a strategy to enhance the efficiency of erianin and the capacity of skin delivery through the DMSNs drug delivery systems.