A wearable iontophoresis enables dual-responsive transdermal delivery for atopic dermatitis treatment.

Atopic dermatitis is a chronic, inflammation skin disease that remains a major public health challenge. The current drug-loading hydrogel dressings offer numerous benefits with enhanced loading capacity and a moist-rich environment. However, their development is still limited by the accessibility of a suitable driven source outside the clinical environment for precise control over transdermal delivery kinetics. Here, we prepare a sulfonated poly(3,4-ethylenedioxythiophene) (PEDOT) polyelectrolyte hydrogel drug reservoir that responds to different stimuli-both endogenous cue (body temperature) and exogenous cue (electrical stimulation), for wearable on-demand transdermal delivery with enhanced efficacy. Functioned as both the drug reservoir and cathode in a Zn battery-powered iontophoresis patch, this dual-responsive hydrogel achieves high drug release efficiency (68.4 %) at 37 °C. Evaluation in hairless mouse skin demonstrates the efficacy of this technology by facilitating transdermal transport of 12.2 µg cm-2 dexamethasone phosphate when discharged with a 103 Ω external resistor for 3 h. The Zn battery-driven iontophoresis results in an effective treatment of atopic dermatitis, displaying reductions in epidermal thickness, mast cell infiltration inhibition, and a decrease in IgE levels. This work provides a new treatment modality for chronic epidermal diseases that require precise drug delivery in a non-invasive way.

Alleviating rheumatoid arthritis with a photo-pharmacotherapeutic glycan-integrated nanogel complex for advanced percutaneous delivery.

The prospective of percutaneous drug delivery (PDD) mechanisms to address the limitations of oral and injectable treatment for rheumatoid arthritis (RA) is increasing. These limitations encompass inadequate compliance among patients and acute gastrointestinal side effects. However, the skin's intrinsic layer can frequently hinder the percutaneous dispersion of RA medications, thus mitigating the efficiency of drug delivery. To circumvent this constraint, we developed a strontium ranelate (SrR)-loaded alginate (ALG) phototherapeutic hydrogel to assess its effectiveness in combating RA. Our studies revealed that this SrR-loaded ALG hydrogel incorporating photoelectrically responsive molybdenum disulfide nanoflowers (MoS2 NFs) and photothermally responsive polypyrrole nanoparticles (Ppy NPs) to form ALG@SrR-MoS2 NFs-Ppy NPs demonstrated substantial mechanical strength, potentially enabling delivery of hydrophilic therapeutic agents into the skin and significantly impeding the progression of RA. Comprehensive biochemical, histological, behavioral, and radiographic analyses in an animal model of zymosan-induced RA demonstrated that the application of these phototherapeutic ALG@SrR-MoS2 NFs-Ppy NPs effectively reduced inflammation, increased the presence of heat shock proteins, regulatory cluster of differentiation M2 macrophages, and alleviated joint degeneration associated with RA. As demonstrated by our findings, treating RA and possibly other autoimmune disorders with this phototherapeutic hydrogel system offers a distinctive, highly compliant, and therapeutically efficient method.

Prolonged Skin Retention of Luliconazole from SLNs Based Topical Gel Formulation Contributing to Ameliorated Antifungal Activity.

The development of effective therapy is necessary because the patients have to contend with long-term therapy as skin fungal infections usually relapse and are hardly treated. Despite being a potent antifungal agent, luliconazole (LCZ) has certain shortcomings such as limited skin penetration, low solubility in aqueous medium, and poor skin retention. Solid Lipid Nanoparticles (SLNs) were developed using biodegradable lipids by solvent injection method and were embodied into the gel base for topical administration. After in-vitro characterizations of the formulations, molecular interactions of the drug with excipients were analyzed using in-silico studies. Ex-vivo release was determined in contrast to the pure LCZ and the commercial formulation followed by in-vivo skin localization, skin irritation index, and antifungal activity. The prepared SLNs have an average particle size of 290.7 nm with no aggregation of particles and homogenous gels containing SLNs with ideal rheology and smooth texture properties were successfully prepared. The ex-vivo LCZ release from the SLN gel was lower than the commercial formulation whereas its skin deposition and skin retention were higher as accessed by CLSM studies. The drug reaching the systemic circulation and the skin irritation potential were found to be negligible. The solubility and drug retention in the skin were both enhanced by the development of SLNs as a carrier. Thus, SLNs offer significant advantages by delivering long lasting concentrations of LCZ at the site of infection for a complete cure of the fungal load together with skin localization of the topical antifungal drug.

Transcutaneous Immunization of 1D Rod-Like Tobacco-Mosaic-Virus-Based Peptide Vaccine via Tip-Loaded Dissolving Microneedles.

Peptide vaccines induce specific neutralizing antibodies and are effective in disease prevention and treatment. However, peptide antigens have a low immunogenicity and are unstable, requiring efficient vaccine carriers to enhance their immunogenicity. Here, we develop a tobacco mosaic virus (TMV)-based peptide vaccine for transdermal immunization using a tip-loaded dissolving microneedle (MN) patch. TMV is decorated with the model peptide antigen PEP3. The prepared TMV-PEP3 promotes dendritic cell maturation and induces dendritic cells to overexpress MHC II, costimulatory factors, and pro-inflammatory factors. By encapsulation of TMV-PEP3 in the tips of a trehalose MN, TMV-PEP3 can be delivered by MN and significantly promote local immune cell infiltration. In vivo studies show that both subcutaneous injection and MN administration of TMV-PEP3 increase the production of anti-PEP3 IgG antibodies and the harvested serum can induce complement-dependent cytotoxicity. This work provides a promising strategy for constructing efficient and health-care-friendly peptide vaccines.

Assessment of the Vehicle for Roflumilast Cream Compared to a Ceramide-Containing Moisturizing Cream in Mild Eczema.

BACKGROUND: Inflammatory dermatologic conditions suitable for topical treatments benefit from a hydrating vehicle that improves the skin barrier without irritation. OBJECTIVE: This research was designed to assess skin barrier effects and aesthetic attributes of the vehicle for topical roflumilast cream (vehicle) vs a currently marketed ceramide-containing moisturizing cream (moisturizer). METHODS: This was a single-site, randomized, intraindividual, double-blind, controlled study conducted over 17 days. Patients (aged 18 years or older) with mild, symmetric asteatotic eczema of the lower extremities were enrolled to receive lower leg applications of the vehicle on one leg and moisturizer on the other. The primary efficacy endpoint was a change in transepidermal water loss (TEWL) from baseline to day 15. Secondary efficacy endpoints included change from baseline in TEWL at other study visits, change from baseline in hydration as assessed via corneometry, and patient- and investigator-rated assessments of the products. Safety and tolerability were also assessed. RESULTS: A total of 40 patients enrolled in the study. The primary efficacy endpoint was met for both treatments. A statistically significant difference in TEWL on day 1 favored the moisturizer, but no difference was seen between vehicle and moisturizer at any other timepoint. Both vehicle and moisturizer also met the secondary efficacy endpoint of change from baseline in hydration. LIMITATIONS: The sample size was small. CONCLUSIONS: The vehicle for roflumilast cream performed similarly to a leading, currently marketed, dermatologist-recommended, ceramide-containing moisturizer across all patient- and investigator-rated assessments of efficacy, tolerability, and aesthetic properties in patients with mild asteatotic eczema. J Drugs Dermatol. 2024;23(10):834-840. doi:10.36849/JDD.7958  .

Assessing Patient Preferences for Atopic Dermatitis Treatment: A Review Article of Discrete Choice Experiments.

Atopic dermatitis (AD) is one of the most prevalent inflammatory skin conditions, characterized by recurrent eczema with varying degrees of erythema, pruritus, xerosis, and pain. Although there are many treatment options for AD, efficacy is limited by poor adherence, especially for topical medications. Patient preferences for certain vehicle formulations and frequencies of administration, as well as patient aversion to certain adverse effects, can negatively impact adherence and treatment success. Discrete choice experiments (DCEs) are used to assess preferences in a manner comparable to clinical decision-making. Six discrete choice experiments on AD were analyzed to create a comprehensive data sheet of patient and physician preferences for medication. When choosing a medication, skin clearance, itch relief, and flexible treatments were most important to patients. J Drugs Dermatol. 2024;23(10):847-851.  doi:10.36849/JDD.8056.

Application Characteristics and Patient Preference of Triple-Combination vs Layered Topicals for Acne: Split-Face Study.

BACKGROUND: Although triple-combination therapies for acne are generally more efficacious than dual-combinations or topical monotherapy, this benefit may be offset by reduced adherence to a complicated treatment regimen. Clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide 3.1% (CAB; Cabtreo®, Ortho Dermatologics) gel is the first triple-combination topical approved for the treatment of acne. By delivering multiple active ingredients as a fixed-dose combination, CAB gel may improve ease of use, which can benefit both treatment adherence and efficacy. The objective of this study was to compare the application characteristics of CAB gel with the layered application of its 3 individual active ingredients. METHODS: In this split-face study, adults with acne-prone skin (N=25), self-applied CAB gel (0.3 cc) to 1 side of the face and layered benzoyl peroxide cream, adapalene gel, and clindamycin gel (0.1 cc each) on the opposite side. CAB and clindamycin gels were compounded with pyranine, which fluoresces under blue light. Photos taken under blue light were used to assess the uniformity of product application, and participants rated the evenness, speed, and ease of the 2 application regimens, as well as overall preference. RESULTS: Investigator-assessed evenness of application favored CAB gel over layered application in 100% of participants. All participants rated the application of CAB gel as more uniform, easier, and faster. Most (96%) preferred CAB gel for use at home. CONCLUSION: Fixed-dose CAB gel was applied more evenly than separate application of its 3 active ingredients. By addressing 3 of the main acne pathogenic pathways in a single, easy-to-apply formulation, CAB gel may improve the efficacy of and adherence to acne treatment. J Drugs Dermatol. 2024;23(10):857-861. doi:10.36849/JDD.8430.

INDIVIDUAL ARTCLE: Pathophysiologic Targets of Acne Treatment.

Acne vulgaris is an extremely common dermatologic condition. Individuals with acne present not only to dermatologists, but also to internists, family medicine physicians, pediatricians, estheticians, and beauty counters alike in search of a treatment. The diagnosis of acne is relatively straightforward, leading many to believe that acne is a simple condition. However, the pathophysiology of acne is anything but simple. Decades of research has ultimately revealed a complex interaction of pathogenic factors that lead to acne. This includes sebum production, C. acnes colonization, inflammation, and follicular hyperkeratinization. Understanding each of these features has been fundamental to the development of anti-acne medications. Topical agents are often used as an initial therapy given their safety and efficacy. While some topical therapies have been used for decades, new creams, gels, and lotions continue to be added to the list of approved acne treatments. Given the number of topical acne products on the market, we present an updated review of the current landscape of topical acne treatments and how each choice functions mechanistically to fight against acne. J Drugs Dermatol. 2024;23:10(Suppl 1):s4-11.

FULL SUPPLEMENT: Targeting Acne Pathogenesis with Topical Therapies.

We, as dermatologists, are exceedingly lucky.  We can watch our patients improve before our eyes. In clinical practice, we don't often track a quantitative metric to gauge success but rather measure the success of our treatment by the appearance of our patients' skin.

A Review of the Vitiligo Literature to Standardize Expression of Disease Severity.

BACKGROUND: The literature on vitiligo is heterogeneous with limited standardization in vitiligo disease severity reporting. OBJECTIVES: The IDEOM Vitiligo Workgroup initiated a project to develop an improved understanding of clinical reporting of vitiligo severity. METHODS: A medical librarian-developed literature review identified 50 clinical trials treating vitiligo topically using topical corticosteroids or topical tacrolimus that included adult and pediatric patients, with 10 or more patients, with grading by SORT criteria. RESULTS: Grading systems used included body surface area scoring (BSA) clinically or via photography and mapping. Most studies create a grading system of repigmentation including G0- no change, G1- 1-25%, G2- 26-50%, G3- 51-75%, G4- 75-99%, and G5- 100%. Variations include reporting success as thresholds >25% (G2-G5), >50% (G3-G5), and >75% (G4-G5) repigmentation. Vitiligo Area Scoring Index (VASI), Dermatology Life Quality Index (DLQI), patient satisfaction, and the vitiligo noticeability scale are all standardized scoring systems that have been used in clinical studies. Other metrics reported include onset and maintenance of response, treatment burden, side effects, and cost-effectiveness. CONCLUSIONS: BSA total and quartiles of improvement are the most commonly reported metrics in studies with high-level evidence. The addition of categories of no improvement, complete clearance, spontaneous improvement, and worsening appears to enhance information collection. Collection of data using photographs or computer-assisted BSA monitoring enhances data reproducibility. Thresholds of success should include 25%, 50%, 75%, and adding 90% and 100% repigmentation. VASI represents a validated collection method, which can be modified for 50%, 75%, and 90% improvement. Newer metrics including treatment burden and cost effectiveness are emerging metrics under evaluation. J Drugs Dermatol. 2024;23(10):842-846. doi:10.36849/JDD.8049.

Clindamycin Phosphate 1.2%/Adapalene 0.15%/Benzoyl Peroxide 3.1% Gel for Male and Female Acne: Phase 3 Analysis.

BACKGROUND: Clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide 3.1% gel (CAB) is the only fixed-dose triple-combination treatment approved for acne. This post hoc analysis assessed the impact of sex on efficacy and safety/tolerability of CAB. METHODS: In two multicenter, double-blind, phase 3 studies (NCT04214639 and NCT04214652), participants aged ≥9 years with moderate-to-severe acne were randomized (2:1) to 12 weeks of once-daily treatment with CAB or vehicle gel. Pooled data were analyzed by sex. Assessments included treatment success (≥2-grade reduction from baseline in Evaluator’s Global Severity Score and a score of 0 [clear] or 1 [almost clear]), inflammatory/noninflammatory lesion counts, Acne-Specific Quality of Life (Acne-QoL) questionnaire, treatment-emergent adverse events (TEAEs), and cutaneous safety/tolerability. RESULTS: At week 12, treatment success rates were significantly greater with CAB versus vehicle irrespective of sex (females: 53.7% vs 23.0%; males: 43.1% vs 24.6%; P<0.05, both). CAB-treated female and male participants both experienced greater reductions from baseline versus vehicle in inflammatory (females: 77.7% vs 57.9%; males: 77.5% vs 57.1%; P<0.001, both) and noninflammatory lesions (females: 72.5% vs 45.6%; males: 72.3% vs 49.6%; P<0.001, both). Acne-QoL improvements from baseline to week 12 were significantly greater with CAB than vehicle. No significant differences in any efficacy measures between CAB-treated males and females were observed. Most TEAEs were of mild-to-moderate severity; no sex-based trends for safety/tolerability were observed. CONCLUSIONS: CAB demonstrated comparable efficacy, quality-of-life improvements, and safety in female and male participants with moderate-to-severe acne. As the first fixed-dose, triple-combination topical formulation, CAB represents an important new treatment for acne. J Drugs Dermatol. 2024;23(10):873-881. doi:10.36849/JDD.8484.

Treatment of chronic hand eczema with topical anti-inflammatory drugs other than topical corticosteroids.

Chronic hand eczema is a fluctuating, inflammatory, pruritic disease of the hands and wrists that is commonly treated with topical corticosteroids and emollients. In a recent report in The Lancet, Bissonnette et al. demonstrated that delgocitinib cream showed superior efficacy versus a cream vehicle and was well tolerated over 16 weeks in adults with moderate to severe chronic hand eczema.

Transdermal iontophoresis versus high power pain threshold ultrasound in Mechanical Neck Pain: a randomized controlled trial.

BACKGROUND: The investigation aimed to assess the impacts of magnesium sulphate (MgSO4) iontophoresis and high-power pain-threshold ultrasound (HPPT-US) on pain, range of motion (ROM), and functional activity in physical therapy students suffering from mechanical cervical pain. METHODS: Typically, 75 males aged 19 to 30 years suffering from mechanical neck pain were enrolled in this investigation. Participants were divided at random into three groups. Group A received iontophoresis plus conventional physical therapy program, Group B received HPPTUS along with conventional therapy, and Group C received conventional therapy only. The outcomes were pain evaluated by visual analog scale (VAS) and Digital Electronic Pressure Algometer, cervical range of motion measured by Myrin gravity reference goniometer, and Arabic Neck disability index (ANDI) evaluate neck function. RESULTS: The differences within and between groups were detected utilizing a mixed-design multivariate analysis of variance (MANOVA). The within- and between-group analysis of all outcome measures revealed that there were statistically significant differences at post-intervention between high-power ultrasound and conventional group at all variables and also between iontophoresis and conventional group, but there was no statistically significant variation between high-power ultrasound and iontophoresis. CONCLUSION: MgSO4 iontophoresis and HPPT-US are effective in decreasing pain, improving neck function, and improving neck ROM in subjects with mechanical neck pain who have active myofascial trigger points (MTrPs) on the upper fibers of the trapezius with no superiority of one over the other. TRAIL REGISTRATION: The study was registered in the Clinical Trials Registry (registration no: NCT05474898) 26/7/2022.

A new approach to modeling transdermal ethanol kinetics.

Measurement of ethanol above the skin surface (supradermal) is used to monitor blood alcohol concentrations (BAC) in both legal and consumer settings. Previously, the relationship between supradermal alcohol concentration (SAC) and BAC was described using partial and ordinary differential equations (PDE model: J. Appl. Physiol. 100: 649-55, 2006). Using a range of BAC profiles by varying absorption times and peak concentrations, the PDE model accurately predicted experimental measures of SAC. Recently, other mathematical models have relied on the PDE model. This paper proposes a new approach to modeling transdermal ethanol kinetics using a mass transfer coefficient and only ordinary differential equations (ODE model). Using a range of BAC profiles, the ODE model performed very similarly to the PDE model. The ODE model had slightly slower washout rates and slightly slower times to peak SAC and to zero SAC. Similar to the PDE model, a sensitivity analysis on the ODE model showed changes in solubility and diffusivity within the stratum corneum, stratum corneum thickness, and the volume of gas above the skin affected model performance. This new model will streamline integration into larger physiologic models, reduce computation time, and decrease the time to transform skin alcohol measurements to blood alcohol concentrations.

Retinol semisolid preparations in cosmetics: transcutaneous permeation mechanism and behaviour.

Retinol is widely used to treat skin ageing because of its effect on cell differentiation, proliferation and apoptosis. However, its potential benefits appear to be limited by its skin permeability. Herein, we investigated the transcutaneous behavior of retinol in semisolid cosmetics, in both in vitro and in vivo experiments. In vitro experiments used the modified Franz diffusion cell combined with Raman spectroscopy. In in vivo experiments, the content of retinol in rat skin and plasma was detected with HPLC. Retinol in semisolid cosmetics was mainly concentrated in the stratum corneum in the skin of the three animal models tested, and in any case did not cross the skin barrier after a 24 h dermatologic topical treatment in Franz diffusion cells tests. Similar results were obtained in live mice and rats, where retinol did not cross the skin barrier and did not enter the blood circulation. Raman spectroscopy was used to test the penetration depth of retinol in skin, which reached 16 µm out of 34 µm in pig skin, whereas the skin of mouse and rat showed too strong bakground interference. To explore epidermal transport mechanism and intradermal residence, skin transcriptomics was performed in rats, which identified 126 genes upregulated related to retinol transport and metabolism, relevant to the search terms "retinoid metabolic process" and "transporter activity". The identity of these upregulated genes suggests that the mechanism of retinol action is linked to epidermis, skin, tissue and epithelium development.

Microorganism microneedle micro-engine depth drug delivery.

As a transdermal drug delivery method, microneedles offer minimal invasiveness, painlessness, and precise in-situ treatment. However, current microneedles rely on passive diffusion, leading to uncontrollable drug penetration. To overcome this, we developed a pneumatic microneedle patch that uses live Enterobacter aerogenes as microengines to actively control drug delivery. These microbes generate gas, driving drugs into deeper tissues, with adjustable glucose concentration allowing precise control over the process. Our results showed that this microorganism-powered system increases drug delivery depth by over 200%, reaching up to 1000 µm below the skin. In a psoriasis animal model, the technology effectively delivered calcitriol into subcutaneous tissues, offering rapid symptom relief. This innovation addresses the limitations of conventional microneedles, enhancing drug efficiency, transdermal permeability, and introducing a creative paradigm for on-demand controlled drug delivery.

Assessment of basic pharmacokinetic parameters of dapagliflozin in TTS formulations in male minipigs.

Given the extended time over which diabetes treatment is administered, the transdermal delivery system is anticipated to be a more suitable option for older individuals who may experience difficulty swallowing. The continuous delivery of dapagliflozin and more stable plasma levels are anticipated to reduce the incidence of side effects and the frequency of dosing. The objectives of the study were to determine the safety and plasma pharmacokinetics of dapagliflozin in male minipigs following application of the ointment and skin patch. In the initial phase of the study, the potential for transdermal permeation of dapagliflozin from ointment and transdermal patch to blood plasma of 15 male Göttingen minipigs was investigated. In the subsequent phase, the efficacy of utilising patches of varying strengths and sizes was assessed. The LC/MS method was employed to quantify the concentration of the active substance. The transportation of the studied API to the general circulation and accumulation in tissues were confirmed. The maximum drug concentration (122.99 ng/mL) in plasma was observed on the fourth day of application. The highest calculated Cmax was 131.91 ng/mL with a mean AUC0-last of 6620.7 ng h/mL. Following transdermal administration, dapagliflozin is excreted in the urine. The trend between urinary dapagliflozin 3-O-glucuronide levels and urinary glucose excretion was also observed. The transdermal patch has been demonstrated to be an effective drug delivery system for dapagliflozin.

[Efficacy of topical tirbanibulin in treating grade 2 actinic keratosis.] / Efficacia della tirbanibulina topica nel trattamento della cheratosi attinica di grado 2.

Actinic keratoses (AK) are common precancerous lesions usually arising on chronic sun-exposed areas. Field of cancerization (FC) is a chronically UV-exposed area in which subclinical multifocal AKs are found. Therapeutic choice is mainly made according to the Olsen grade of AKs. We report the case of a 76-year-old man with numerous AKs of the face and scalp. The patient had undergone numerous topical physical and medical therapies with poor results. On the left cheek, grade I and grade II AKs were found in a large FC, so he was prescribed topical therapy with tirbanibulin 1% ointment. After 10 days erythema and crusts were objectified and a burning sensation was reported on the area of application and on surrounding areas. At 8 weeks follow-up, the patient had total resolution of disease and no residual local side effects. Although tirbanibulin 1% ointment has indication for type I AKs of face and scalp, this case reported its efficacy and benefit also on type II AKs, demonstrating safety and a minimal and manageable degree of discomfort caused to the patient. Therefore, it fits fully among the treatments of grade I AKs but numerous still may be its indications as demonstrated in our case, where efficacy, safety and compliance were combined.