Liposomes and Other Nanocarriers for the Treatment of Acne Vulgaris: Improved Therapeutic Efficacy and Skin Tolerability.

Acne vulgaris is a common dermatologic disorder that affects approximately 85% of teenagers, which significantly impacts the quality of life in adolescents. It is a chronic disease of the sebaceous follicles that is multifactorial in etiology. Topical treatment is the first choice for mild and moderate acne, while systemic therapy is reserved for severe and certain moderate cases. Topical treatments include retinoids (e.g., tretinoin and adapalene), antibiotics (e.g., clindamycine), and other agents (e.g., benzoyl peroxide and azelaic acid), often applied in combination. The mechanisms of action include antimicrobial, anti-inflammatory, and keratolytic activities, as well as sebum secretion reduction, and the normalization of follicular keratinization. However, these topical agents commonly induce side effects, such as dryness, burning, stinging, peeling, redness, erythema, and photosensitivity. Therefore, there is a need to reduce the side effects of anti-acne drugs, while maintaining or enhancing their therapeutic effectiveness. This article aims to comprehensively outline nanotechnology strategies, particularly the use of phospholipid-based nanocarriers like liposomes and related vesicles, to enhance therapeutic efficacy, skin tolerability, and patient compliance in the treatment of acne vulgaris. In addition, novel active ingredients encapsulated in vesicles beyond those recommended in official guidelines are discussed.

Overcoming False-Negative Patch Tests: A Systematic Literature Review.

Exogenous allergens, found in cosmetic products, jewelry items, antiseptics and antibacterials, plants, and solvents, can cause clinical allergic contact dermatitis (ACD). To help identify and discern which allergen is causing ACD, clinicians use patch tests, but they can yield false-negative results at times. Examining potential reasoning for false negatives is particularly helpful when a patient's history and physical examination strongly suggest ACD, and the patch test is negative. A strong history and physical presentation suggestive of ACD warrants additional patch testing or other methods to verify a false-negative patch test result. We conducted a literature review to compile various reasonings and solutions for false-negative patch tests in suspected ACD patients. Utilizing EMBASE, Scopus, PubMed, and Google Scholars, 49 articles were included by using search terms such as "False negative patch test" or "False-negative patch test" and "allergic contact dermatitis," or "ACD." Common factors that led to false-negative patch test results include low allergen concentration, inadequate percutaneous penetration, technique error, immunosuppressive therapy, and ultraviolet exposure. Potential solutions include using different vehicles, concentration, increasing reading time, repeating the patch test, intradermal testing, and repeat open application testing. If a false-negative patch test is suspected, then intradermal testing can be administered to ensure the specificity of the patch test result. Considering the main contributing factors and solutions to false-negative patch tests, clinicians can accurately diagnose ACD and administer proper treatment plans.

Patch Testing With Nickel, Cobalt, and Chromium in Patients With Suspected Allergic Contact Dermatitis.

Background: Allergic contact dermatitis is frequently caused by metals, including multiple metals simultaneously. Objectives: To assess characteristics and associations of positive and clinically relevant patch test (PT) reactions with solitary and concurrent metal sensitization. Methods: A retrospective analysis of PT results for nickel, cobalt, and/or chromium from the North American Contact Dermatitis Group between 2001 and 2018 (n = 43,522). Results: 18.0% had a positive/allergic reaction to nickel sulfate hexahydrate, 7.3% to cobalt chloride hexahydrate, and 3.0% to potassium dichromate. 87.9% patients had a currently relevant reaction to 0, 9.4% to 1, and 2.7% to multiple metals tested. Patients with 1 versus no currently relevant reactions to metal were more likely to have a primary dermatitis site of trunk, feet, and ears; patients with currently relevant reactions to multiple metals had more dermatitis affecting the trunk and ears. Metal sources varied by co-reacting metal, especially for patients with cobalt and chromium allergy. Jewelry was the most commonly identified source of nickel and cobalt for both solitary and concurrent metal allergy. Conclusions: Sensitization to multiple metals occurred in 6% of patients. Allergen sources varied between patients with sensitivity to 1 metal versus those who had concurrent sensitivity to cobalt and/or chromium.

Topical Delivery Systems Effectively Transport Analgesics to Areas of Localized Pain via Direct Diffusion.

Topical delivery systems (TDSs) enable the direct transport of analgesics into areas of localized pain and thus minimize the side effects of administration routes that rely on systemic drug distribution. For musculoskeletal pain, clinicians frequently prescribe topical products containing lidocaine or diclofenac. This study assessed whether drug delivery from a TDS into muscle tissue occurs mainly via direct diffusion or systemic transport. An investigational TDS containing 108 mg lidocaine (SP-103, 5.4% lidocaine), a commercially available TDS containing 36 mg lidocaine (ZTlido®, 1.8% lidocaine), and a topical pain relief gel (Pennsaid®, 2% diclofenac) were tested. Using open flow microperfusion (OFM), interstitial fluid from the dermis, subcutaneous adipose tissue (SAT), and muscle was continuously sampled to assess drug penetration in all tissue layers. Ex vivo and in vivo experiments showed a higher diffusive transport of lidocaine compared to diclofenac. The data showed a clear contribution of diffusive transport to lidocaine concentration, with SP-103 5.4% resulting in a significantly higher lidocaine concentration in muscle tissue than commercially available ZTlido® (p = 0.008). These results indicate that SP-103 5.4% is highly effective in delivering lidocaine into muscle tissue in areas of localized pain for the treatment of musculoskeletal pain disorders (e.g., lower back pain).

Efficacy and safety of combinational therapy using topical minoxidil and microneedling for the treatment of androgenetic alopecia: a systematic review and meta-analysis.

Androgenetic alopecia is a widespread condition that is the most common type of hair loss affecting approximately 58% and 40% of men and women by the age of 50, respectively. Patients have been known to experience severe distress due to androgenetic alopecia, including anxiety, low self-esteem, and depression. The objective of this study was to conduct a systematic review and meta-analysis to determine the efficacy of combination therapy using topical minoxidil and microneedling compared to topical minoxidil alone. This systematic review of randomized controlled trials was carried out using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. The literature search was performed using Scopus, Cochrane, Embase, and the National Institutes of Health's United States National Library of Medicine from inception through January 20, 2023. Randomized controlled trials examining the efficacy of combinational therapy and monotherapy using microneedling and minoxidil on patients with clinically diagnosed androgenetic alopecia were included after screening titles, abstracts, and full texts. Two independent reviewers selected studies, extracted data, and appraised the risk of bias using the Cochrane risk of bias assessment tool. Ten randomized controlled trials, including 466 patients, were selected for this review and eight studies were ultimately included in the meta-analysis. All eight studies displayed a statistically significant increase in total hair count [standard mean difference (SMD) 1.76; 95% CI 1.26-2.26; P < 0.00001]; however, the evidence did not support a statistically significant increase in hair diameter (SMD 0.82; 95% CI - 0.01 to 1.65; P = 0.05). No scarring nor serious adverse events were reported in any of the studies. The findings of this meta-analysis strongly support the utilization of a multimodal therapeutic approach of minoxidil and microneedling for hair growth in patients with androgenetic alopecia. However, variations in factors such as rating scale measurements, microneedling methods, and areas of treatment may have resulted in confounding. Further randomized controlled, large-sample trials employing rigorous methodologies are needed to gain a more comprehensive understanding regarding treatment efficacy, namely the impact of combinational therapy on hair diameter.Clinical trial registrations This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and is registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42023391164) and the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY) database (INPLASY202310031).

Unmasking Racial Disparity in the Diagnosis and Treatment of Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a chronic, profoundly incapacitating disease predominantly affecting the apocrine gland-rich areas of the human body. Although it affects 0.05% to 4% of the general population, there exists a significant racial disparity, with people of color, particularly Black individuals, experiencing a notably higher prevalence. Despite this disparity, the current literature lacks comprehensive analyses of HS concerning race and ethnicity, revealing a systemic blind spot in understanding and addressing the disease's racially disproportionate impacts. In this commentary, we aim to shed light on these racial disparities, focusing specifically on the stark inequities related to the timely diagnosis and subsequent dermatological care of HS in the United States. This commentary explores the racial bias in HS prevalence, severity, diagnostic delay, access to specialized care, and underrepresentation in clinical trials. By emphasizing the urgent need to address these disparities, we seek to foster an inclusive dialogue and drive proactive efforts toward achieving equitable care and research representation for all populations affected by this debilitating condition. Through this discussion, we aim to pave the way for a healthcare landscape that acknowledges and addresses the racial disparities inherent in HS, ensuring that advancements in the management of the disease cater to the needs of all populations, irrespective of their racial or ethnic background.

Non-invasive skin measurement methods and diagnostics for vitiligo: a systematic review.

Vitiligo is a multifaceted autoimmune depigmenting disorder affecting around 0.5 to 2.0% of individuals globally. Standardizing diagnosis and therapy tracking can be arduous, as numerous clinical evaluation methods are subject to interobserver variability and may not be validated. Therefore, there is a need for diagnostic tools that are objective, dependable, and preferably non-invasive. Aims: This systematic review provides a comprehensive overview of the non-invasive objective skin measurement methods that are currently used to evaluate the diagnosis, severity, and progression of vitiligo, as well as the advantages and limitations of each technique. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist was used for the systematic review. Scopus, Embase, Cochrane Library, and Web of Science databases were comprehensively searched for non-invasive imaging and biophysical skin measuring methods to diagnose, evaluate the severity of, or monitor the effects of vitiligo treatment. The risk of bias in included articles was assessed using the QUADAS-2 quality assessment scale. Results: An extensive literature search resulted in 64 studies for analysis, describing eight imaging techniques (reflectance confocal microscopy, computer-aided imaging analysis, optical coherence tomography, infrared photography, third-harmonic generation microscopy, multiphoton microscopy, ultraviolet light photography, and visible light/digital photograph), and three biophysical approaches (dermoscopy, colorimetry, spectrometry) used in diagnosing and assessing vitiligo. Pertinent information about functionality, mechanisms of action, sensitivity, and specificity was obtained for all studies, and insights into the strengths and limitations of each diagnostic technique were addressed. Methodological study quality was adequate; however, statistical analysis was not achievable because of the variety of methods evaluated and the non-standardized reporting of diagnostic accuracy results. Conclusions: The results of this systematic review can enhance clinical practice and research by providing a comprehensive overview of the spectrum of non-invasive imaging and biophysical techniques in vitiligo assessment. Studies with larger sample sizes and sound methodology are required to develop verified methods for use in future practice and research. Systematic review registration: (PROSPERO) database, (CRD42023395996).

Enigma of Intramuscular Triamcinolone Acetonide (Kenalog®) Efficacy.

Triamcinolone acetonide is a glucocorticosteroid used in standard clinical practice for its anti-inflammatory properties. Although it can be given via different routes of administration, the intramuscular route is unique compared with other corticosteroids-its effects remain potent over a longer period of time. We summarize the existing literature on the pharmacokinetic and pharmacodynamic mechanisms of intramuscular triamcinolone acetonide (Kenalog®). The fascinating nature of the purported efficacy of triamcinolone acetonide may be attributed to differing binding mechanisms, low solubility in blood, a low renal clearance rate, and various metabolites and other yet defined effects on skin. The enigma of the purported efficacy of triamcinolone acetonide may lie in the fact that it has a unique nature of having a long-term effect on dermatologic disease using a seemingly low dose compared with other routes of administration and other corticosteroids. Possible reasons for this may be binding differences at the intramuscular site, low solubility due to acetonide esters, a slow rate of absorption from the injected site, and a low renal clearance rate. There is still much to be learned about its mechanism of action, which may be of clinical and therapeutic significance.

Assessing the risk of a clinically significant infection from a Microneedle Array Patch (MAP) product.

Microneedle Array Patches (MAPs) are an emerging dosage form that creates transient micron-sized disruptions in the outermost physical skin barrier, the stratum corneum, to facilitate delivery of active pharmaceutical ingredients to the underlying tissue. Numerous MAP products are proposed and there is significant clinical potential in priority areas such as vaccination. However, since their inception scientists have hypothesized about the risk of a clinically significant MAP-induced infection. Safety data from two major Phase 3 clinical trials involving hundreds of participants, who in total received tens of thousands of MAP applications, does not identify any clinically significant infections. However, the incumbent data set is not extensive enough to make definitive generalizable conclusions. A comprehensive assessment of the infection risk is therefore advised for MAP products, and this should be informed by clinical and pre-clinical data, theoretical analysis and informed opinions. In this article, a group of key stakeholders identify some of the key product- and patient-specific factors that may contribute to the risk of infection from a MAP product and provide expert opinions in the context of guidance from regulatory authorities. Considerations that are particularly pertinent to the MAP dosage form include the specifications of the finished product (e.g. microbial specification), it's design features, the setting for administration, the skill of the administrator, the anatomical application site, the target population and the clinical context. These factors, and others discussed in this article, provide a platform for the development of MAP risk assessments and a stimulus for early and open dialogue between developers, regulatory authorities and other key stakeholders, to expedite and promote development of safe and effective MAP products.

Can Continuous Manufacturing of Topical Semisolids by Hot Melt Extrusion Soon Be a Reality?

For more than five decades, pharmaceutical manufacturers have been relying heavily on batch manufacturing that is a sequential, multistep, laborious, and time-consuming process. However, late advances in manufacturing technologies have prompted manufacturers to consider continuous manufacturing (CM) is a feasible manufacturing process that encompasses fewer steps and is less tedious and quick. Global regulatory agencies are taking a proactive role to facilitate pharmaceutical industries to adopt CM that assures product quality by employing robust manufacturing technologies encountering fewer interruptions, thereby substantially reducing product failures and recalls. However, adopting innovative CM is known to pose technical and regulatory challenges. Hot melt extrusion (HME) is one such state-of-the-art enabling technology that facilitates CM of diverse pharmaceutical dosage forms, including topical semisolids. Efforts have been made to continuously manufacture semisolids by HME integrating the principles of Quality by Design (QbD) and Quality Risk Management (QRM) and deploying Process Analytical Technologies (PAT) tools. Attempts have been made to systematically elucidate the effect of critical material attributes (CMA) and critical process parameters (CPP) on product critical quality attributes (CQA) and Quality Target Product Profiles (QTPP) deploying PAT tools. The article critically reviews the feasibility of one of the enabling technologies such as HME in CM of topical semisolids. The review highlights the benefits of the CM process and challenges ahead to implement the technology to topical semisolids. Once the CM of semisolids adopting melt extrusion integrated with PAT tools becomes a reality, the process can be extended to manufacture sterile semisolids that usually involve more critical processing steps.

In vitro percutaneous penetration test overview.

Skin is a detailed, organized, and intricate niche in the human body. Topical and transdermal drugs are unique, in that their absorption is quite different from other routes of administration (oral, intramuscular, intravenous, etc.,.). A robust amount of research is required to approve the use of a drug-in vivo, in vitro, and ex vivo studies collectively help manufacturers and government agencies with approval of various compounds. Use of human and animal studies poses ethical and financial concerns, making samples difficult to use. In vitro and ex vivo methods have improved over the past several decades-results show relevance when compared to in vivo methods. The history of testing is discussed, followed by a detailed account of known complexities of skin and the current state of percutaneous penetration.

Patch Testing With Cobalt in Adults: A North American Contact Dermatitis Group Experience, 2001-2018.

Background: Cobalt is a recognized cause of allergic contact dermatitis (ACD); however, detailed information on patient characteristics, sites, and sources is lacking. Objective: The aim of the study is to assess trends in patch test reactions to cobalt and associated patient characteristics, common sources, and body sites affected. Methods: The study used a retrospective analysis of adult patients who were patch tested to cobalt by the North American Contact Dermatitis Group between 2001 and 2018 (n = 41,730). Results: Overall, 2986 (7.2%) and 1362 (3.3%) had allergic or currently relevant patch test reaction to cobalt, respectively. Patients with versus without an allergic patch test reaction to cobalt were more likely to be female, employed, have a history of eczema or asthma, be Black, Hispanic, or Asian, and have occupational-related dermatitis. The most commonly identified sources of cobalt in allergic patients included jewelry, belts, and cement, concrete, and mortar. Affected body site(s) varied by cobalt source among patients with currently relevant reactions. Occupational relevance was found in 16.9% of patients with positive reactions. Conclusions: Positive patch test reactions to cobalt were common. The most common body sites were the hands, and affected site varied by the source of cobalt.

Quantification methods comparing in vitro and in vivo percutaneous permeation by microneedles and passive diffusion.

Microneedles (MNs) are needles with a tip diameter ranging from 10 to 100 um and a length ranging up to 1 mm. The first patent for drug delivery device for percutaneous administration filed by Alza corporation dates back to 1976 (Gerstel and Place, 1976), and in between 1989 and 2021 the filed patents for MNs are >4500 [1]. These devices can potential overcome some drawbacks of traditional needles, such as the pain generated during insertion, requirement for trained personnel to manipulate syringes, and difficulty of performing injections in elderly and obese patients. MNs and MN arrays are emerging as a convenient method to deliver compounds and extract blood without causing any pain. A promising application is the use of MNs as alternative solution to topical creams (TC) and transdermal patches (TP) for transdermal drug delivery. The external layer of human skin, the epidermis, offers a major barrier to transdermal drug delivery, thanks to the stratum corneum (SC). Exposed to the external environment, SC ultimately protects the human body from UV light radiation, heat, water loss, bacteria, fungi and viruses, and it is the barrier that controls diffusion rate for almost all compounds. TC and TP applications are limited by the skin permeability to lipophilic compounds and small molecules, and by the slow delivery rate of some compounds. MNs have been around for >35 year now, and it is a general opinion that MNs increase delivery compared to passive diffusion, thanks to the feature of penetrating the SC and reaching the dermis. This review recollects the existing studies that compare MN delivery of drugs with passive diffusion of the same drugs in alive organisms, giving an overview of what are the type of MNs, the chemical delivered and the methods employed to quantify drug delivery into skin and/or in the bloodstream. The final aim is to quantify the enhancement factor of MNs with respect to passive diffusion, and establish a possible standard on how tests can be performed in order to compare different data.