Nanocarrier-Integrated Microneedles: Divulging the Potential of Novel Frontiers for Fostering the Management of Skin Ailments.

The various kinds of nanocarriers (NCs) have been explored for the delivery of therapeutics designed for the management of skin manifestations. The NCs are considered as one of the promising approaches for the skin delivery of therapeutics attributable to sustained release and enhanced skin penetration. Despite the extensive applications of the NCs, the challenges in their delivery via skin barrier (majorly stratum corneum) have persisted. To overcome all the challenges associated with the delivery of NCs, the microneedle (MN) technology has emerged as a beacon of hope. Programmable drug release, being painless, and its minimally invasive nature make it an intriguing strategy to circumvent the multiple challenges associated with the various drug delivery systems. The integration of positive traits of NCs and MNs boosts therapeutic effectiveness by evading stratum corneum, facilitating the delivery of NCs through the skin and enhancing their targeted delivery. This review discusses the barrier function of skin, the importance of MNs, the types of MNs, and the superiority of NC-loaded MNs. We highlighted the applications of NC-integrated MNs for the management of various skin ailments, combinational drug delivery, active targeting, in vivo imaging, and as theranostics. The clinical trials, patent portfolio, and marketed products of drug/NC-integrated MNs are covered. Finally, regulatory hurdles toward benchtop-to-bedside translation, along with promising prospects needed to scale up NC-integrated MN technology, have been deliberated. The current review is anticipated to deliver thoughtful visions to researchers, clinicians, and formulation scientists for the successful development of the MN-technology-based product by carefully optimizing all the formulation variables.

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.

Dermaplaning for Transdermal Drug Permeation Enhancement: A Qualitative and Quantitative Assessment.

In this study, we sought to investigate the effect of dermaplaning, a popular cosmeceutical skin rejuvenation technique on the permeation of drugs. Baclofen and diclofenac were used as hydrophilic and hydrophobic model drugs, respectively. A specific area of skin was treated with 4 strokes of a dermaplane device. Interindividual variability was assessed by having multiple users operate the device for the study. Dermaplaned skin was histologically evaluated and characterized for resistance drop and the depletion of the stratum corneum (SC). The effect of dermaplaning on drug permeation was investigated via in vitro permeation studies. Histology studies depicted the removal of SC and some parts of viable epidermis by dermaplaning. A significant drop in electrical resistance post skin dermaplaning was observed for all treatment groups, signifying the depletion of barrier properties of SC (p < 0.05). Consequently, significant drug flux and permeation were observed over 24 h for the model drugs across dermaplaned skin. However, varied absorption profile was observed in vitro for both drugs across dermaplaned skin. Dermaplaning displayed a better suitability for significantly enhancing the permeation of the hydrophilic drug, baclofen. Evidence of variation in results post dermaplaning was observed amidst multiple users as well (p < 0.05).

Adjuvants in cutaneous vaccination: A comprehensive analysis.

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

Iontophoresis-coupled rapidly dissolving polymeric microneedle patch of naloxone for its enhanced transdermal delivery.

The transdermal delivery of naloxone for opioid overdose emergency purposes is a challenge due to its poor rate of diffusion through the layers of skin. This results in delayed delivery of an insufficient amount of the drug within minimal time as is desired to save lives. The ability of dissolving polymeric microneedles to shorten the lag time significantly has been explored and shown to have prospects in terms of the transdermal delivery of naloxone. This is an option that offers critical advantages to the ongoing opioid crisis, including ease of distribution and easy administration, with little to no need for intervention by clinicians. Nonetheless, this approach by itself needs augmentation to meet pharmacokinetic delivery attributes desired for a viable clinical alternative to existing market dosage forms. In this study, we report the success of an optimized iontophoresis-coupled naloxone loaded dissolving microneedle patch which had facilitated a 12- fold increase in average cumulative permeation and a 6-fold increase in drug flux over a conventional dissolving microneedle patch within 60 min of application (p < 0.05). This translates to a 30 % decrease in dose requirement in a mechanistically predicted microneedle patch established to be able to achieve the desired early plasma concentration time profile needed in an opioid overdose emergency. Applying a predictive mathematical model, we describe an iontophoresis-coupled microneedle patch design capable of meeting the desired pharmacokinetic profile for a viable naloxone delivery form through skin.

Nanosuspension-based microneedle skin patch of baclofen for sustained management of multiple sclerosis-related spasticity.

Baclofen (BAC) is the first-line recommendation to treat spasticity in people with multiple sclerosis whose treatment goals include improving mobility or easing pain. The short half-life of BAC calls for multiple daily dosing which may be eliminated by the development of a transdermal system. This study aimed to assess the effect of transdermal microneedle patches on improving the skin permeation of BAC. Nanosuspension-loaded microneedle patch containing BAC was fabricated and characterized. In vitro permeation of BAC across intact and microneedle-treated dermatomed porcine ear skin was evaluated. In vitro passive permeation of BAC solution after 72 h was observed to be 92.56 ± 11.24 µg/cm2. A near 9-fold enhancement was observed when employing the strategy of microneedle-mediated delivery of the solution. To increase drug loading, two strategies, nanosizing and microneedle-mediated delivery, were combined and permeation of BAC after 72 h resulted to be 1951.95 ± 82.01 µg/cm2 (p < 0.05). Microneedle-mediated transdermal delivery of BAC holds potential for sustained management of multiple sclerosis-related spasticity. Nanosizing of BAC particles facilitated higher drug loading in MN patches and an eventual increase in cumulative drug permeation from the patches.

Transdermal delivery of naloxone hydrochloride using minimally invasive physical ablation techniques.

NAL's hydrophilicity and the inherent lipophilic properties of the stratum corneum hinders its capacity for immediate delivery through skin in opioid rescue cases. In this study, we had sought to investigate the feasibility of using minimally invasive physical ablative techniques including sonophoresis, laser, dermaplaning, microneedles, and microdermabrasion for systemically delivering NAL via the skin. These techniques reduced lag time to NAL delivery to about 3-12 min from 71.22 ± 9.62 min seen for passive delivery. Also, they all significantly enhanced the amount of NAL delivered in 1 h and over 24 h period of evaluation as compared to the passive group (p < 0.05). Sonophoresis and laser showed the greatest delivery in 1 h, followed by dermaplaning. The cumulative amount of drug delivered by these approaches in 1 h were 1277.95 ± 387.06, 83.33 ± 11.11, 30.66 ± 5.67 µg/cm2, respectively. Though the most remarkable, inconsistencies in in vitro permeation profile of NAL were observed with the 1 MHz ultrasound frequency used. With proper optimization of the conditions of use and design, the different approaches explored in this study can be potentially applied for the systemic delivery of naloxone in opioid overdose emergencies and opioid disaccustoming purposes.

In vitro percutaneous absorption studies of cannabidiol using human skin: Exploring the effect of drug concentration, chemical enhancers, and essential oils.

Cannabidiol, a non-psychoactive constituent of cannabis, has garnered much attention after United States Food and Drug Administration approved Epidiolex® for oral use. Although therapeutic effect of cannabidiol after systemic absorption has been investigated extensively, its therapeutic potential in treating skin disorders after local delivery still needs further exploration. Our study has investigated the effect of cannabidiol concentration, chemical enhancers, and essential oils on percutaneous absorption of cannabidiol. In vitro permeation tests were conducted on human skin. The 24 h study results suggest no significant difference in amount of drug absorbed into skin, between 5% (242.41 ± 12.17 µg/cm2) and 10% (232.79 ± 20.82 cm2) cannabidiol solutions. However, 1% delivered (23.02 ± 4.74 µg/cm2) significantly lower amount of drug into skin than 5% and 10%. Transcutol and isopropyl myristate did not enhance delivery of cannabidiol. However, oleic acid was found to be useful as chemical enhancer. Oleic acid (43.07 ± 10.11 µg/cm2) had significantly higher cannabidiol delivery into skin than the group without oleic acid (10.98 ± 3.40 µg/cm2) after a 4 h in vitro permeation study. Essential oils at concentrations tested had lower total cannabidiol delivery when compared to control. This study's findings will help guide future research on the pharmacological effect of percutaneously delivered cannabidiol on inflammatory skin disorders.

Sustained drug delivery strategies for treatment of common substance use disorders: Promises and challenges.

Substance use disorders (SUDs) are a leading cause of death and other ill health effects in the United States and other countries in the world. Several approaches ranging from detoxification, behavioral therapy, and the use of antagonists or drugs with counter effects are currently being applied for its management. Amongst these, drug therapy is the mainstay for some drug abuse incidences, as is in place specifically for opioid abuse or alcohol dependence. The severity of the havocs observed with the SUDs has triggered constant interest in the discovery and development of novel medications as well as suitable or most appropriate methods for the delivery of these agents. The chronic need of such drugs in users warrants the need for their prolonged or sustained systemic availability. Further, the need to improve patient tolerance to medication, limit invasive drug use and overall treatment outcome are pertinent considerations for embracing sustained release designs for medications used in managing SUDs. This review aims to provide an overview on up-to-date advances made with regards to sustained delivery systems for the drugs for treatment of different types of SUDs such as opioid, alcohol, tobacco, cocaine, and cannabis use disorders. The clinical relevance, promises and the limitations of deployed sustained release approaches along with future opportunities are discussed.

Characterization of microneedles and microchannels for enhanced transdermal drug delivery.

Microneedle (MN)-based technologies are currently one of the most innovative approaches that are being extensively investigated for transdermal delivery of low molecular weight drugs, biotherapeutic agents and vaccines. Extensive research reports, describing the fabrication and applications of different types of MNs, can be readily found in the literature. Effective characterization tools to evaluate the quality and performance of the MNs as well as for determination of the dimensional and kinetic properties of the microchannels created in the skin, are an essential and critical part of MN-based research. This review paper provides a comprehensive account of all such tools and techniques.

Transdermal Route: A Viable Option for Systemic Delivery of Antidepressants.

The high rise in the population suffering from depression depicts the need for improved and highly effective treatment options for this condition. Efforts to develop existing drugs into user-friendly dosage forms with a number of advantages in major depressive states, including but not limited to: sustained drug release, reduced drug dosing frequency, improved tolerance and adherence, suitability for use in diverse populations and different treatment scenarios, as well as less central nervous system side effects are required. One such non-invasive drug delivery route that could provide the aforementioned benefits in the treatment of depression is the transdermal route. A number of conventional and emerging transdermal delivery strategies have been investigated for some potent antidepressants and results depict the potential of this route as a viable means for systemic delivery of therapeutically relevant doses of the tested agents, with Emsam®, the commercially available patch of selegiline, being an evidence for the same. The investigated approaches include the formulation of transdermal patches, use of vesicular drug carriers, pro-drug approach, microemulsification, chemical as well as physical enhancement technologies. This review provides a comprehensive account of the rationale, developments made till date, scope and future prospects of delivering antidepressants via the transdermal1 route of administration.

Delivering therapeutic cannabinoids via skin: Current state and future perspectives.

Adequate evidence exists in the literature indicating a relatively positive shift with regards to the legal acceptance of cannabis and cannabis-derived products for medicinal purposes in some countries. Concomitantly, scientists are showing renewed interest in cannabis-related research work. Over the years, clinical and preclinical studies have demonstrated the therapeutic significance of cannabinoids for diverse indications. Additionally, efforts are being made to develop cannabis-related products into acceptable prescription products. FDA authorization for the commercial use of four cannabinoid-derived products, available as oral dosage forms is a significant progress already. However, there are certain drawbacks associated with the conventional delivery forms of cannabinoids. These include low oral bioavailability due to hepatic degradation, gastric instability, poor water solubility, and the side effects experienced upon the use of high doses of psychotropic cannabinoids associated with heightened plasma concentrations of the drug. These are however, limitable with the aid of transcutaneous drug delivery. Emerging topical and transdermal strategies could be exploited for the successful development of highly effective delivery systems for cannabinoids. This review discusses the feasibility of delivering therapeutic cannabinoids via skin and provides a comprehensive account of the supporting research studies that have been reported in the literature till date.