Advances in Topical and Transdermal Drug Delivery

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (10 September 2022) | Viewed by 76142

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Associate Professor, LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
Interests: medicinal chemistry; infectious, inflammatory and cancer diseases; nanotechnology and nanodelivery; development of “smart” drug systems; biophysics and drug-membrane interactions
Special Issues, Collections and Topics in MDPI journals
LAQV, REQUIMTE, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
Interests: cell culture; colloids; magnetic nanoparticles; marine polysaccharides; liposomes; lipid nanoparticles; photothermal therapy; polymeric nanoparticles
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
LAQV-REQUIMTE, Applied Chemistry Department, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
Interests: biochemistry; medicinal and pharmaceutical chemistry; drug delivery; nanotechnology; polymers; spectroscopy; fluorescence; metal ions; metallodrugs; skin; plants nutrition
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are pleasure to invite you to contribute a full article, short communication, or review article to a Special Issue entitled “Advances in Topical and Transdermal Drug Delivery”. The Issue aims to cover the most recent advances and newly developed approaches to improve skin drug delivery.

Skin is the biggest organ in human body, represents an important drug administration route, and is a place for the application of cosmetics and therapeutic agents. Transdermal drug delivery has attracted a great deal of attention as an alternative to the oral administration of drugs and hypodermic injections, mainly due to its many advantages like improved bioavailability, more uniform plasma levels, longer duration (and thus reduced dosing frequency), enhanced patient compliance, and reduced systemic side effects.

However, this organ represents a great challenge for drug delivery since it blocks the entry of most cutaneously administered drugs. Therefore, different approaches have been developed to surmount these limitations. In the present Special Issue, we expect to collect interesting solutions developed with the aim of overcoming the current drawbacks of skin drug delivery.

The knowledge obtained and the novel approaches will certainly contribute to improving the permeation of many active agents and therefore allow the treatment of several disorders and the implementation of anti-ageing solutions.

We would very much appreciate it if you would consider being one of our authors. We look forward to your contribution.

Prof. Dr. Salette Reis
Dr. Sofia Lima
Dr. Tânia Moniz
Guest Editors

Manuscript Submission Information

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Keywords

  • therapeutic agent
  • skin absorption
  • cosmetic application
  • skin mimetic models
  • nanoparticles
  • hydrogels
  • microneedles

Published Papers (22 papers)

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28 pages, 6946 KiB  
Article
New Ferulic Acid and Amino Acid Derivatives with Increased Cosmeceutical and Pharmaceutical Potential
by Ewa Janus, Luan Ramalho Pinheiro, Anna Nowak, Edyta Kucharska, Ewelina Świątek, Natalia Podolak, Magdalena Perużyńska, Katarzyna Piotrowska, Wiktoria Duchnik, Łukasz Kucharski and Adam Klimowicz
Pharmaceutics 2023, 15(1), 117; https://doi.org/10.3390/pharmaceutics15010117 - 29 Dec 2022
Cited by 3 | Viewed by 2581
Abstract
Ferulic acid (FA) has been widely used in the pharmaceutical and cosmetics industry due to its, inter alia, antioxidant, antiaging and anti-inflammatory effects This compound added to cosmetic preparations can protect skin because of its photoprotective activity. However, the usefulness of FA as [...] Read more.
Ferulic acid (FA) has been widely used in the pharmaceutical and cosmetics industry due to its, inter alia, antioxidant, antiaging and anti-inflammatory effects This compound added to cosmetic preparations can protect skin because of its photoprotective activity. However, the usefulness of FA as a therapeutic agent is limited due to its low solubility and bioavailability. The paper presents the synthesis, identification, and physicochemical properties of new FA derivatives with propyl esters of three amino acids, glycine (GPr[FA]), L-leucine (LPr[FA]), and L-proline (PPr[FA]). The NMR and FTIR spectroscopy, DSC, and TG analysis were used as analytical methods. Moreover, water solubility of the new conjugates was compared with the parent acid. Both ferulic acid and its conjugates were introduced into hydrogel and emulsion, and the resulting formulations were evaluated for stability. Additionally, in vitro penetration of all studied compounds from both formulations and for comparative purposes using Franz diffusion cells was evaluated from the solution in 70% (v/v) ethanol. Finally, cytotoxicity against murine fibroblasts L929 was tested. All of the analyzed compounds permeated pig skin and accumulated in it. LPr[FA] and PPr[FA] were characterized by much better permeability compared to the parent ferulic acid. Additionally, it was shown that all the analyzed derivatives are characterized by high antioxidant activity and lack of cytotoxicity. Therefore, they can be considered as an interesting alternative to be applied in dermatologic and cosmetic preparations. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)
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18 pages, 2736 KiB  
Article
Preparation and Evaluation of Vitamin D3 Supplementation as Transdermal Film-Forming Solution
by Majd Kittaneh, Moammal Qurt, Numan Malkieh, Hani Naseef and Ramzi Muqedi
Pharmaceutics 2023, 15(1), 39; https://doi.org/10.3390/pharmaceutics15010039 - 22 Dec 2022
Cited by 5 | Viewed by 2765
Abstract
Vitamin D3 is available in oral and injectable dosage forms. Interest in the transdermal route as an alternative to the oral and parenteral routes has grown recently. In this study, several film-forming solutions for the transdermal delivery of vitamin D3 were prepared. They [...] Read more.
Vitamin D3 is available in oral and injectable dosage forms. Interest in the transdermal route as an alternative to the oral and parenteral routes has grown recently. In this study, several film-forming solutions for the transdermal delivery of vitamin D3 were prepared. They contained 6000 IU/mL of vitamin D3 that formed a dry and acceptable film in less than 5 min after application. The formulations consisted of ethanol and acetone 80:20, and one or more of the following ingredients: Eudragit L100-55, PVP, PG, limonene, oleic acid, camphor, and menthol. Vitamin D3 release was studied from both the film-forming solution and pre-dried films using a Franz diffusion cell. The film-forming solution released a significant amount of vitamin D3 compared to the dry film, which is attributed mostly to the saturation driving force due to the evaporation of volatile solvents. In vitro permeation studies through artificial skin Strat M® membrane revealed that the cumulative amount of vitamin D3 permeated after 24 h under the experimental conditions was around 800 IU across 3.14 cm2. The cumulative permeation curve showed faster permeation in earlier stages. Young’s modulus, viscosity, and pH of the formulations were determined. Most of the formulations were stable for 3 weeks. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)
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15 pages, 3137 KiB  
Article
Advantageous Combinations of Nanoencapsulated Oregano Oil with Selected Antibiotics for Skin Treatment
by Maya Margaritova Zaharieva, Mila Kaleva, Alexander Kroumov, Marta Slavkova, Niko Benbassat, Krassimira Yoncheva and Hristo Najdenski
Pharmaceutics 2022, 14(12), 2773; https://doi.org/10.3390/pharmaceutics14122773 - 12 Dec 2022
Cited by 2 | Viewed by 1730
Abstract
The aim of the present study was to evaluate the antimicrobial activity of combinations between encapsulated oregano oil and the most commonly applied antibiotics (ciprofloxacin or gentamicin) against skin infections. In particular, chitosan-alginate nanoparticles loaded with oregano oil and the selected antibiotics were [...] Read more.
The aim of the present study was to evaluate the antimicrobial activity of combinations between encapsulated oregano oil and the most commonly applied antibiotics (ciprofloxacin or gentamicin) against skin infections. In particular, chitosan-alginate nanoparticles loaded with oregano oil and the selected antibiotics were included in methylcellulose hydrogels. Consistency, spreadability, pH of the hydrogel and in vitro release rate of the oil were considered appropriate for topical application. The combination of encapsulated oil and gentamicin in the hydrogel resulted in a synergistic effect against methicillin-sensitive (MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus strains. It was expressed in a fourfold reduction in the effective concentration of gentamicin and 98% inhibition of the bacterial metabolic activity. When ciprofloxacin was included in the combination instead of gentamicin, an additive effect with a two-fold decrease in the effective drug concentration and a 96% reduction in the bacterial metabolic activity were observed. Both combinations significantly inhibited the formation of MRSA biofilm by more than 90% when applied. In vivo application of the hydrogel containing the synergistic combination between the encapsulated oil and gentamicin did not induce irritation of the rabbit skin. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)
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9 pages, 1189 KiB  
Article
Effect of an Oxygen-Based Mechanical Drug Delivery System on Percutaneous Permeation of Various Substances In Vitro
by Anna-Lena Elksnat, Paula Zscherpe, Karina Klein, Jessika Maximiliane Cavalleri and Jessica Meißner
Pharmaceutics 2022, 14(12), 2722; https://doi.org/10.3390/pharmaceutics14122722 - 5 Dec 2022
Cited by 1 | Viewed by 1689
Abstract
Transdermal drug administration is an elegant method to overcome various side effects of oral or parenteral drug administration. Nevertheless, due to an effective skin barrier, which is provided by the stratum corneum, transdermal drug delivery is sometimes very slow and ineffective. Thus, [...] Read more.
Transdermal drug administration is an elegant method to overcome various side effects of oral or parenteral drug administration. Nevertheless, due to an effective skin barrier, which is provided by the stratum corneum, transdermal drug delivery is sometimes very slow and ineffective. Thus, the effect of a medical device (DERMADROP TDA) for transdermal penetration of drugs in conjunction with a special vehicle emulsion on percutaneous permeation of several substances (with different physicochemical properties) was investigated in Franz-type diffusion cells with porcine skin over 28 h. This medical device disperses pharmaceutical agents via oxygen flow through an application system, which is used in conjunction with specially developed vehicle substances. Substance permeation of various substances with different physicochemical properties (diclofenac, enrofloxacin, flufenamic acid, indomethacin, and salicylic acid) was examined after application with a pipette and with the medical device. Therefore, acceptor media samples were collected up to 28 h after drug administration. Drug concentration in the acceptor medium was determined via high-performance liquid chromatography. Enhanced permeation was observed for diclofenac, enrofloxacin, flufenamic acid, indomethacin, and salicylic acid after oxygen-based administration. This correlates negatively with the molecular weight. Thus, drug administration can effectively be enhanced by a medical device using oxygen. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)
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13 pages, 3341 KiB  
Article
Efficacy and Safety of Ablative Fractional Laser-Assisted Delivery of Methotrexate in Adults with Localized Scleroderma: A Randomized and Controlled Clinical Trial
by Qing Guo, Mingjie He, Junjie Cen, Danqi Huang, Shaoyun Hao, Zengqi Tang and Hui Xiong
Pharmaceutics 2022, 14(11), 2261; https://doi.org/10.3390/pharmaceutics14112261 - 22 Oct 2022
Cited by 2 | Viewed by 1885
Abstract
Localized scleroderma (LS) is an autoimmune disease with sclerosis of the skin as the main manifestation. Currently, there is no specific treatment for LS. The effectiveness of ablative fractional laser (AFL) therapy for LS has been demonstrated in several studies. Combining ablative fractional [...] Read more.
Localized scleroderma (LS) is an autoimmune disease with sclerosis of the skin as the main manifestation. Currently, there is no specific treatment for LS. The effectiveness of ablative fractional laser (AFL) therapy for LS has been demonstrated in several studies. Combining ablative fractional Er:YAG laser therapy with topical methotrexate may yield therapeutic benefits for patients with LS. To compare the efficacy and safety of AFL-assisted delivery of methotrexate in adults with LS, we randomly divided patients into an AFL therapy group and an ablative fractional laser-assisted delivery of methotrexate (AFL+MTX) therapy group. Laser and assisted drug delivery treatment were given every four weeks for four months, and 22 patients completed the trial. Ultrasound measurements of dermal thickness and histological fibrosis degree and the Localized Scleroderma Cutaneous Assessment Tool (LoSCAT) score were used to assess therapeutic effects. Treatment results showed that both AFL and AFL-assisted methotrexate delivery were effective in treating LS, and the laser combined with methotrexate therapy was more effective in improving clinical appearance (p value = 0.042) and dermal thickness (p value = 0.016). No serious adverse reaction occurred in either group. In conclusion, AFL and assisted delivery of methotrexate are effective and safe treatments for LS. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)
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16 pages, 4304 KiB  
Article
Formulation and Evaluation of a Drug-in-Adhesive Patch for Transdermal Delivery of Colchicine
by Yaran Lei, Guobao Yang, Feng Du, Jiahe Yi, Liangzhu Quan, Hanhan Liu, Xun Zhou, Wei Gong, Jing Han, Yuli Wang and Chunsheng Gao
Pharmaceutics 2022, 14(10), 2245; https://doi.org/10.3390/pharmaceutics14102245 - 21 Oct 2022
Cited by 6 | Viewed by 2683
Abstract
Gout is one of the most prevalent rheumatic diseases, globally. Colchicine (COL) is the first-line drug used for the treatment of acute gout. However, the oral administration of COL is restricted, owing to serious adverse reactions. Therefore, this study aimed to develop a [...] Read more.
Gout is one of the most prevalent rheumatic diseases, globally. Colchicine (COL) is the first-line drug used for the treatment of acute gout. However, the oral administration of COL is restricted, owing to serious adverse reactions. Therefore, this study aimed to develop a drug-in-adhesive (DIA) patch to achieve transdermal delivery of COL. We investigated the solubility of COL in different pressure-sensitive adhesives (PSAs) using slide crystallization studies. The COL-DIA patches were optimized based on in vitro skin penetration studies and evaluated by in vivo pharmacokinetics and pharmacodynamics. The results showed that the optimized COL-DIA patch contained 10% COL, Duro-Tak 87-2516 as PSA, 5% oleic acid (OA) and 5% propylene glycol (PG) as permeation enhancer, exhibiting the highest in vitro cumulative penetration amount of COL (235.14 ± 14.47 μg∙cm−2 over 48 h). Pharmacokinetic studies demonstrated that the maximum plasma drug concentration (Cmax) was 2.65 ± 0.26 ng/L and the mean retention time (MRT) was 37.47 ± 7.64 h of the COL-DIA patch, effectively reducing the drug side effects and prolonging drug activity. In addition, pharmacodynamic studies showed the patch significantly decreased the expression levels of inflammatory factors of gouty rats and reduced pathological damage in the ankle joint of rats, making it an attractive alternative to the administration of COL for the treatment of gout. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)
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16 pages, 3831 KiB  
Article
Antifungal Nail Lacquer for Enhanced Transungual Delivery of Econazole Nitrate
by Vinam Puri, Riya Savla, Kevin Chen, Keyaara Robinson, Amitkumar Virani and Bozena Michniak-Kohn
Pharmaceutics 2022, 14(10), 2204; https://doi.org/10.3390/pharmaceutics14102204 - 16 Oct 2022
Cited by 6 | Viewed by 3288
Abstract
The fungal disease of the nail, onychomycosis, which is also the most prevalent nail disturbance, demands effective topical treatment options considering the possible adverse effects of systemic antifungal therapy. The current work is focused on development of an adhesive and resistant, drug-delivering and [...] Read more.
The fungal disease of the nail, onychomycosis, which is also the most prevalent nail disturbance, demands effective topical treatment options considering the possible adverse effects of systemic antifungal therapy. The current work is focused on development of an adhesive and resistant, drug-delivering and permeation-enhancing polymeric film containing econazole nitrate (ECN) for topical antifungal treatment. The development of the lacquer formulation was guided by the Quality by Design approach to achieve the critical quality attributes needed to obtain the product of desired quality. Eudragit RSPO at 10% w/w was found to be the ideal adhesive polymer for the application and an optimal permeation-enhancing lacquer formulation was achieved by the optimization of other formulation excipients, such as plasticizer and the solvent system. Additionally, novel experimental enhancements introduced to the research included refined D50 drying time and drying rate tests for lacquer characterization as well as a multi-mechanism permeation-enhancing pre-treatment. Moreover, a practical implication was provided by a handwashing simulation designed to test the performance of the lacquer during actual use. In vitro drug release testing and ex vivo nail permeation testing demonstrated that the optimized nail lacquer performed better than control lacquer lacking the permeation enhancer by achieving a faster and sustained delivery of ECN. It can be concluded that this is a promising drug delivery system for topical antifungal treatment of onychomycotic nails, and the novel characterization techniques may be adapted for similar formulations in the future. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)
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12 pages, 1875 KiB  
Article
Topical Tirbanibulin, a Dual Src Kinase and Tubulin Polymerization Inhibitor, for the Treatment of Plaque-Type Psoriasis: Phase I Results
by Jin-Bon Hong, Po-Yuan Wu, Albert Qin, Yi-Wen Huang, Kuan-Chiao Tseng, Ching-Yu Lai, Wing-Kai Chan, Jane Fang, David L. Cutler and Tsen-Fang Tsai
Pharmaceutics 2022, 14(10), 2159; https://doi.org/10.3390/pharmaceutics14102159 - 11 Oct 2022
Cited by 1 | Viewed by 1605
Abstract
Plaque-type psoriasis is a common skin disorder. Tirbanibulin (KX01) is a new Src kinase inhibitor with potent antiproliferative activity against keratinocytes and has been approved for treatment of actinic keratosis. This Phase I study investigates the safety and activity of KX01 ointment in [...] Read more.
Plaque-type psoriasis is a common skin disorder. Tirbanibulin (KX01) is a new Src kinase inhibitor with potent antiproliferative activity against keratinocytes and has been approved for treatment of actinic keratosis. This Phase I study investigates the safety and activity of KX01 ointment in patients with plaque-type psoriasis. We recruited 28 patients from two medical centers in Taiwan. This study was performed in four stages. Double-blind treatments were randomized in stages I (KX01 0.01% + placebo, two rounds of two-week treatment) and II (KX01 0.1% + placebo, four weeks) and open-labelled in stages III (KX01 1%, five days) and IV (KX01 1%, five days weekly for four weeks). The safety, tolerability, KX01 concentration, target area score, physician global assessment, and disease relapse were determined. Most treatment-emergent adverse events were mild-to-moderate application site reactions. Three (50.0%) subjects from the stage IV group showed ≥50% reduction in the target area score (TAS50), while two subjects (33.3%) showed a clinically meaningful improvement in the physician global assessment score. KX01 0.01%, 0.1%, and 1% were safe and well-tolerated. KX01 1% at four weeks showed a promising activity for the treatment of plaque-type psoriasis. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)
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11 pages, 1645 KiB  
Article
Design of Liposomal Lidocaine/Cannabidiol Fixed Combinations for Local Neuropathic Pain Treatment
by Silvia Franzè, Liliana Angelo, Antonella Casiraghi, Paola Minghetti and Francesco Cilurzo
Pharmaceutics 2022, 14(9), 1915; https://doi.org/10.3390/pharmaceutics14091915 - 10 Sep 2022
Cited by 7 | Viewed by 2540
Abstract
The administration of drug fixed combinations by nanocarriers is a new attractive approach since it can allow improvements in both the skin penetration of cargo compounds and their synergistic effects. The cutaneous administration of lidocaine (LD) and cannabidiol (CBD) combination can be useful [...] Read more.
The administration of drug fixed combinations by nanocarriers is a new attractive approach since it can allow improvements in both the skin penetration of cargo compounds and their synergistic effects. The cutaneous administration of lidocaine (LD) and cannabidiol (CBD) combination can be useful for the local treatment of neuropathic pain. In fact, these drugs might exert a complementary effect on pain acting on sodium and calcium channels. In this study, the feasibility to deliver this combination in the deeper layers of the skin using deformable liposomes was studied. Based on a study of the drug affinity for lipid components performed by DSC, CBD was loaded in the lipid bilayer for limiting the leakage, while LD was loaded in the inner core by a pH gradient method (G-liposomes) or after previous encapsulation in micelle (DiMiL). The effect of the presence of Tween 80 in the liposome membrane was also evaluated. DiMiL increased both the skin permeation and the retention in the dermis of CBD and LD with respect to G-liposomes (R24dermis: 11.52 ± 2.4 against 4.51 ± 0.8 µg/cm2 for CBD; 19.6 ± 2.9 against 3.2 ± 0.1 µg/cm2 for LD). Moreover, both DiMiL and G-liposomes were more efficient than control formulations carrying free drugs in improving drug skin permeation. Interestingly, in the presence of a drug exerting a fluidizing effect such as CBD, the removal of Tween 80 from the composition led to an improved control of drug release and a higher extent of drug retention in the dermis layer. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)
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15 pages, 1975 KiB  
Article
Sugar-Triggered Burst Drug Releasing Poly-Lactic Acid (PLA) Microneedles and Its Fabrication Based on Solvent-Casting Approach
by Seongsu Kang, Ji Eun Song, Seung-Hyun Jun, Sun-Gyoo Park and Nae-Gyu Kang
Pharmaceutics 2022, 14(9), 1758; https://doi.org/10.3390/pharmaceutics14091758 - 23 Aug 2022
Cited by 13 | Viewed by 2829
Abstract
Microneedles have emerged as a novel transdermal delivery tool that enables the delivery of various products such as drugs, vaccines, or cosmetic ingredients. Although the demand for solid microneedles composed of biocompatible polymer is increasing, the manufacture of microneedles using poly-lactic acid (PLA) [...] Read more.
Microneedles have emerged as a novel transdermal delivery tool that enables the delivery of various products such as drugs, vaccines, or cosmetic ingredients. Although the demand for solid microneedles composed of biocompatible polymer is increasing, the manufacture of microneedles using poly-lactic acid (PLA) with rapid drug-releasing is yet to be established and the process is still in its infancy. Here, we propose a novel strategy for the fabrication of PLA solid microneedles which enable a drug to be burst-released based on a solvent-casting process. This approach offers extreme simplicity, broad geometric capability, cost-effectiveness, and scalability based on high fidelity-replicas. It was verified that microneedles of various heights (250–500 μm) could be fabricated with appropriate mechanical strength to penetrate the stratum corneum layer of skin. By adding sugar in the composition of PLA microneedle, it was observed that both hydrophilic and hydrophobic drugs can be rapidly released within 30 min. Our burst drug-releasing PLA microneedle having both characteristics of solid microneedle and soluble microneedle and its fabrication approach based on solvent-casting will contribute to getting microneedle technology close to commercialization and beyond existing technical limitations. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)
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15 pages, 4194 KiB  
Article
Micromolding of Amphotericin-B-Loaded Methoxyethylene–Maleic Anhydride Copolymer Microneedles
by Sina Azizi Machekposhti, Alexander K. Nguyen, Lyndsi Vanderwal, Shane Stafslien and Roger J. Narayan
Pharmaceutics 2022, 14(8), 1551; https://doi.org/10.3390/pharmaceutics14081551 - 26 Jul 2022
Cited by 11 | Viewed by 2065
Abstract
Biocompatible and biodegradable materials have been used for fabricating polymeric microneedles to deliver therapeutic drug molecules through the skin. Microneedles have advantages over other drug delivery methods, such as low manufacturing cost, controlled drug release, and the reduction or absence of pain. The [...] Read more.
Biocompatible and biodegradable materials have been used for fabricating polymeric microneedles to deliver therapeutic drug molecules through the skin. Microneedles have advantages over other drug delivery methods, such as low manufacturing cost, controlled drug release, and the reduction or absence of pain. The study examined the delivery of amphotericin B, an antifungal agent, using microneedles that were fabricated using a micromolding technique. The microneedle matrix was made from GantrezTM AN-119 BF, a benzene-free methyl vinyl ether/maleic anhydride copolymer. The GantrezTM AN-119 BF was mixed with water; after water evaporation, the polymer exhibited sufficient strength for microneedle fabrication. Molds cured at room temperature remained sharp and straight. SEM images showed straight and sharp needle tips; a confocal microscope was used to determine the height and tip diameter for the microneedles. Nanoindentation was used to obtain the hardness and Young’s modulus values of the polymer. Load–displacement testing was used to assess the failure force of the needles under compressive loading. These two mechanical tests confirmed the mechanical properties of the needles. In vitro studies validated the presence of amphotericin B in the needles and the antifungal properties of the needles. Amphotericin B GantrezTM microneedles fabricated in this study showed appropriate characteristics for clinical translation in terms of mechanical properties, sharpness, and antifungal properties. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)
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22 pages, 4096 KiB  
Article
Compritol-Based Nanostrucutured Lipid Carriers (NLCs) for Augmentation of Zolmitriptan Bioavailability via the Transdermal Route: In Vitro Optimization, Ex Vivo Permeation, In Vivo Pharmacokinetic Study
by Doaa H. Hassan, Joseph N. Shohdy, Doaa Ahmed El-Setouhy, Mohamed El-Nabarawi and Marianne J. Naguib
Pharmaceutics 2022, 14(7), 1484; https://doi.org/10.3390/pharmaceutics14071484 - 18 Jul 2022
Cited by 14 | Viewed by 2464
Abstract
Migraine is a severe neurovascular disease manifested mainly as unilateral throbbing headaches. Triptans are agonists for serotonin receptors. Zolmitriptan (ZMP) is a biopharmaceutics classification system (BCS) class III medication with an absolute oral bioavailability of less than 40%. As a result, our research [...] Read more.
Migraine is a severe neurovascular disease manifested mainly as unilateral throbbing headaches. Triptans are agonists for serotonin receptors. Zolmitriptan (ZMP) is a biopharmaceutics classification system (BCS) class III medication with an absolute oral bioavailability of less than 40%. As a result, our research intended to increase ZMP bioavailability by developing transdermal nanostructured lipid carriers (NLCs). NLCs were prepared utilizing a combination of hot melt emulsification and high-speed stirring in a 32 full factorial design. The studied variables were liquid lipid type (X1) and surfactant type (X2). The developed NLCs were evaluated in terms of particle size (Y1, nm), polydispersity index (Y2, PDI), zeta potential (Y3, mV), entrapment efficacy (Y4, %) and amount released after 6 h (Q6h, Y5, %). At 1% Mygliol as liquid lipid component and 1% Span 20 as surfactant, the optimized formula (NLC9) showed a minimum particle size (138 ± 7.07 nm), minimum polydispersity index (0.39 ± 0.001), acceptable zeta potential (−22.1 ± 0.80), maximum entrapment efficiency (73 ± 0.10%) and maximum amount released after 6 h (83.22 ± 0.10%). The optimized formula was then incorporated into gel preparation (HPMC) to improve the system stability and ease of application. Then, the pharmacokinetic study was conducted on rabbits in a cross-over design. The calculated parameters showed a higher area under the curve (AUC0–24, AUC0–∞ (ng·h/mL)) of the developed ZMP-NLCs loaded gel, with a 1.76-fold increase in bioavailability in comparison to the orally administered marketed product (Zomig®). A histopathological examination revealed the safety of the developed nanoparticles. The declared results highlight the potential of utilizing the proposed NLCs for the transdermal delivery of ZMP to improve the drug bioavailability. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)
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22 pages, 6156 KiB  
Article
Polymeric Microneedles for Transdermal Delivery of Rivastigmine: Design and Application in Skin Mimetic Model
by Tânia M. T. Guimarães, Tânia Moniz, Cláudia Nunes, Maya Margaritova Zaharieva, Mila Kaleva, Krassimira Yoncheva, Hristo Najdenski, Sofia A. Costa Lima and Salette Reis
Pharmaceutics 2022, 14(4), 752; https://doi.org/10.3390/pharmaceutics14040752 - 30 Mar 2022
Cited by 6 | Viewed by 2715
Abstract
In the last years, microneedles (MNs) have been considered a valuable, painless, and minimally invasive approach for controlled transdermal drug delivery (TDD). Rivastigmine (RV), a drug administered to patients suffering from dementia, is currently delivered by oral or transdermal routes; however, both present [...] Read more.
In the last years, microneedles (MNs) have been considered a valuable, painless, and minimally invasive approach for controlled transdermal drug delivery (TDD). Rivastigmine (RV), a drug administered to patients suffering from dementia, is currently delivered by oral or transdermal routes; however, both present limitations, mainly gastrointestinal adverse symptoms or local skin irritation and drug losses, respectively, for each route. Given this, the objective of the present work was to develop and evaluate the potential of polymeric MNs for RV transdermal delivery in a controlled manner. Polymeric MNs with two needle heights and different compositions were developed with calcein as a fluorescent model molecule. Morphology and mechanical characterisation were accessed. Skin permeation experiments showed the ability of the devices to deliver calcein and confirmed that the arrays were able to efficiently pierce the skin. To obtain a new TDD anti-dementia therapeutic solution, RV was loaded in 800 µm polymeric MNs of alginate and alginate/k-carrageenan MNs. In the presence of RV, the MN’s morphology was maintained; however, the presence of RV influenced the compression force. Skin permeation studies revealed that RV-loaded MNs allowed a more efficient controlled release of the drug than the commercial patch. In vivo, skin irritation tests in rabbits revealed that the developed MNs were innocuous upon removal, in contrast with the evidence found for Exelon®, the commercial patch, which caused slight mechanical damage to the skin. The herein-produced MNs demonstrated a more controlled release of the drug, being the more suitable option for the transdermal delivery of RV. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)
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14 pages, 1510 KiB  
Article
Deep Eutectic Solvents for Improving the Solubilization and Delivery of Dapsone
by Sonia Trombino, Carlo Siciliano, Debora Procopio, Federica Curcio, Annarita S. Laganà, Maria Luisa Di Gioia and Roberta Cassano
Pharmaceutics 2022, 14(2), 333; https://doi.org/10.3390/pharmaceutics14020333 - 30 Jan 2022
Cited by 24 | Viewed by 4099
Abstract
Owing to a growing awareness toward environmental impact, the use of safer and eco-friendly solvents like deep eutectic solvents (DESs), has recently undergone important growth in the pharmaceutical field, with regard to their application as non-aqueous liquid administration vehicles, since they do not [...] Read more.
Owing to a growing awareness toward environmental impact, the use of safer and eco-friendly solvents like deep eutectic solvents (DESs), has recently undergone important growth in the pharmaceutical field, with regard to their application as non-aqueous liquid administration vehicles, since they do not carry the same risks of toxicity and handling as traditional organic solvents. Major attention has been given to the development of advantageous transdermal drug delivery systems, because of their ease of use and better acceptability. Here, we report the use of two different DESs, based on choline chloride, used as hydrogen bond acceptor (HBA), and ascorbic acid or propylene glycol, used as hydrogen bond donors (HBDs), able to enhance the solubility and the topical delivery of dapsone, representing a class IV drug. The interactions between the DESs’ components and the drug were studied by performing DSC, FT-IR, and NMR analysis of the eutectic systems and the pure drug, confirming the establishment of H-bonds between the drug and the DESs’ components. Diffusion and permeability studies, carried out in a Franz cell, showed an increase in permeability, highlighting the great potential of DESs as dissolution and permeation enhancers in the development of novel and more effective drug delivery systems in topical administration. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)
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20 pages, 11414 KiB  
Article
Formulation, Preparation, Characterization, and Evaluation of Dicarboxylic Ionic Liquid Donepezil Transdermal Patches
by Linh Dinh, Soohun Lee, Sharif Md Abuzar, Heejun Park and Sung-Joo Hwang
Pharmaceutics 2022, 14(1), 205; https://doi.org/10.3390/pharmaceutics14010205 - 16 Jan 2022
Cited by 8 | Viewed by 4297
Abstract
Donepezil (DPZ) is generally administered orally to treat Alzheimer’s disease (AD). However, oral administration can cause gastrointestinal side effects. Therefore, to enhance compliance, a new way to deliver DPZ from transdermal patch was developed. Ionic bonds were created by dissolving dicarboxylic acid and [...] Read more.
Donepezil (DPZ) is generally administered orally to treat Alzheimer’s disease (AD). However, oral administration can cause gastrointestinal side effects. Therefore, to enhance compliance, a new way to deliver DPZ from transdermal patch was developed. Ionic bonds were created by dissolving dicarboxylic acid and DPZ in ethanol, resulting in a stable ionic liquid (IL) state. The synthesized ILs were characterized by differential scanning calorimetry, optical microscope, Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy. The DPZ ILs were then transformed to a suitable drug-in-adhesive patch for transdermal delivery of DPZ. The novel DPZ ILs patch inhibits crystallization of the IL, indicating coherent design. Moreover, DPZ ILs and DPZ IL patch formulations performed excellent skin permeability compared to that of the DPZ free-base patch in both in vitro and ex vivo skin permeability studies. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)
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16 pages, 2565 KiB  
Article
Development and Evaluation of Novel Water-Based Drug-in-Adhesive Patches for the Transdermal Delivery of Ketoprofen
by Kwanputtha Arunprasert, Chaiyakarn Pornpitchanarong, Theerasak Rojanarata, Tanasait Ngawhirunpat, Praneet Opanasopit, Porawan Aumklad and Prasopchai Patrojanasophon
Pharmaceutics 2021, 13(6), 789; https://doi.org/10.3390/pharmaceutics13060789 - 25 May 2021
Cited by 9 | Viewed by 3463
Abstract
The objective of this study was to develop novel water-based drug-in-adhesive pressure-sensitive adhesives (PSAs) patches for the transdermal delivery of ketoprofen, employing poly(N-vinylpyrrolidone-co-acrylic acid) copolymer (PVPAA) and poly(methyl vinyl ether-alt-maleic anhydride) (PMVEMA) as the main components. The polymers were crosslinked with [...] Read more.
The objective of this study was to develop novel water-based drug-in-adhesive pressure-sensitive adhesives (PSAs) patches for the transdermal delivery of ketoprofen, employing poly(N-vinylpyrrolidone-co-acrylic acid) copolymer (PVPAA) and poly(methyl vinyl ether-alt-maleic anhydride) (PMVEMA) as the main components. The polymers were crosslinked with tartaric acid and dihydroxyaluminium aminoacetate using various polymer ratios. Ketoprofen was incorporated into the PVPAA/PMVEMA PSAs during the patch preparation. The physicochemical properties, adhesive properties, drug content, release profile, and skin permeation of the patches were examined. Moreover, the in vivo skin irritation and skin adhesion performance in human volunteers were evaluated. The patches prepared at a weight ratio of PVPAA/PMVEMA of 1:1 presented the highest tacking strength, with desirable peeling characteristics. The ketoprofen-loaded PVPAA/PMVEMA patches exhibited superior adhesive properties, compared to the commercial patches, because the former showed an appropriate crosslinking and hydrating status with the aid of a metal coordination complex. Besides, the permeated flux of ketoprofen through the porcine skin of the ketoprofen-loaded PVPAA/PMVEMA patches (4.77 ± 1.00 µg/cm2/h) was comparable to that of the commercial patch (4.33 ± 0.80 µg/cm2/h). In human studies, the PVPAA/PMVEMA patches exhibited a better skin adhesion performance, compared with the commercial patches, without skin irritation. In addition, the patches were stable for 6 months. Therefore, these novel water-based PSAs may be a potential adhesive for preparing drug-in-adhesive patches. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)
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Review

Jump to: Research, Other

35 pages, 4503 KiB  
Review
Microneedle-Mediated Transdermal Delivery of Biopharmaceuticals
by Hiep X. Nguyen and Chien N. Nguyen
Pharmaceutics 2023, 15(1), 277; https://doi.org/10.3390/pharmaceutics15010277 - 13 Jan 2023
Cited by 17 | Viewed by 7597
Abstract
Transdermal delivery provides numerous benefits over conventional routes of administration. However, this strategy is generally limited to a few molecules with specific physicochemical properties (low molecular weight, high potency, and moderate lipophilicity) due to the barrier function of the stratum corneum layer. Researchers [...] Read more.
Transdermal delivery provides numerous benefits over conventional routes of administration. However, this strategy is generally limited to a few molecules with specific physicochemical properties (low molecular weight, high potency, and moderate lipophilicity) due to the barrier function of the stratum corneum layer. Researchers have developed several physical enhancement techniques to expand the applications of the transdermal field; among these, microneedle technology has recently emerged as a promising platform to deliver therapeutic agents of any size into and across the skin. Typically, hydrophilic biomolecules cannot penetrate the skin by passive diffusion. Microneedle insertion disrupts skin integrity and compromises its protective function, thus creating pathways (microchannels) for enhanced permeation of macromolecules. Microneedles not only improve stability but also enhance skin delivery of various biomolecules. Academic institutions and industrial companies have invested substantial resources in the development of microneedle systems for biopharmaceutical delivery. This review article summarizes the most recent research to provide a comprehensive discussion about microneedle-mediated delivery of macromolecules, covering various topics from the introduction of the skin, transdermal delivery, microneedles, and biopharmaceuticals (current status, conventional administration, and stability issues), to different microneedle types, clinical trials, safety and acceptability of microneedles, manufacturing and regulatory issues, and the future of microneedle technology. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)
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30 pages, 3837 KiB  
Review
A Review of 3D-Printing of Microneedles
by Michael Olowe, Santosh Kumar Parupelli and Salil Desai
Pharmaceutics 2022, 14(12), 2693; https://doi.org/10.3390/pharmaceutics14122693 - 1 Dec 2022
Cited by 25 | Viewed by 7338
Abstract
Microneedles are micron-sized devices that are used for the transdermal administration of a wide range of active pharmaceutics substances with minimally invasive pain. In the past decade, various additive manufacturing technologies have been used for the fabrication of microneedles; however, they have limitations [...] Read more.
Microneedles are micron-sized devices that are used for the transdermal administration of a wide range of active pharmaceutics substances with minimally invasive pain. In the past decade, various additive manufacturing technologies have been used for the fabrication of microneedles; however, they have limitations due to material compatibility and bioavailability and are time-consuming and expensive processes. Additive manufacturing (AM), which is popularly known as 3D-printing, is an innovative technology that builds three-dimensional solid objects (3D). This article provides a comprehensive review of the different 3D-printing technologies that have the potential to revolutionize the manufacturing of microneedles. The application of 3D-printed microneedles in various fields, such as drug delivery, vaccine delivery, cosmetics, therapy, tissue engineering, and diagnostics, are presented. This review also enumerates the challenges that are posed by the 3D-printing technologies, including the manufacturing cost, which limits its viability for large-scale production, the compatibility of the microneedle-based materials with human cells, and concerns around the efficient administration of large dosages of loaded microneedles. Furthermore, the optimization of microneedle design parameters and features for the best printing outcomes is of paramount interest. The Food and Drug Administration (FDA) regulatory guidelines relating to the safe use of microneedle devices are outlined. Finally, this review delineates the implementation of futuristic technologies, such as artificial intelligence algorithms, for 3D-printed microneedles and 4D-printing capabilities. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)
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11 pages, 997 KiB  
Review
Spotlight on Calcipotriol/Betamethasone Fixed-Dose Combination in Topical Formulations: Is There Still Room for Innovation?
by Francesca Selmin, Silvia Franzè, Antonella Casiraghi and Francesco Cilurzo
Pharmaceutics 2022, 14(10), 2085; https://doi.org/10.3390/pharmaceutics14102085 - 29 Sep 2022
Cited by 3 | Viewed by 2189
Abstract
Psoriasis is a lifelong disease which requires treatment adherence for successful management. Considering the complexity of this pathology, the combination of active pharmaceutical ingredients with a synergistic mechanism of action can improve the safety and efficacy of the treatment with respect to the [...] Read more.
Psoriasis is a lifelong disease which requires treatment adherence for successful management. Considering the complexity of this pathology, the combination of active pharmaceutical ingredients with a synergistic mechanism of action can improve the safety and efficacy of the treatment with respect to the conventional monotherapy. Moreover, a fixed dose of therapeutic agents in a topical formulation offers the possibility to simplify administration, reduce the doses of each active ingredient, and improve patient’s compliance. Among the first-line treatments in mild to moderate psoriasis, the formulation of calcipotriol (Cal) and betamethasone dipropionate (BD) in a single vehicle is challenging due to their chemical incompatibility in an aqueous environment and the formation of degradation products. Based on these considerations, this review aims to provide an overview on the biopharmaceutical properties of Cal/BD fixed-dose combination products available on the market (namely ointment, oleogel, foam, and O/W cream), highlighting also the novel approaches under evaluation. The main differences among topical formulations are discussed considering the different features of the anatomic districts involved in psoriasis and the patient’s adherence. Moreover, since in vitro experiments are fundamental to evaluate the skin permeation profile during the development of an efficacious medicinal product, special emphasis is given to models proposed to mimic psoriatic lesions. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)
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16 pages, 2093 KiB  
Review
The Transdermal Delivery of Therapeutic Cannabinoids
by Haleh Mahmoudinoodezh, Srinivasa Reddy Telukutla, Sukhvir Kaur Bhangu, Ava Bachari, Francesca Cavalieri and Nitin Mantri
Pharmaceutics 2022, 14(2), 438; https://doi.org/10.3390/pharmaceutics14020438 - 18 Feb 2022
Cited by 23 | Viewed by 8227
Abstract
Recently, several studies have indicated an increased interest in the scientific community regarding the application of Cannabis sativa plants, and their extracts, for medicinal purposes. This plant of enormous medicinal potential has been legalised in an increasing number of countries globally. Due to [...] Read more.
Recently, several studies have indicated an increased interest in the scientific community regarding the application of Cannabis sativa plants, and their extracts, for medicinal purposes. This plant of enormous medicinal potential has been legalised in an increasing number of countries globally. Due to the recent changes in therapeutic and recreational legislation, cannabis and cannabinoids are now frequently permitted for use in clinical settings. However, with their highly lipophilic features and very low aqueous solubility, cannabinoids are prone to degradation, specifically in solution, as they are light-, temperature-, and auto-oxidation-sensitive. Thus, plant-derived cannabinoids have been developed for oral, nasal-inhalation, intranasal, mucosal (sublingual and buccal), transcutaneous (transdermal), local (topical), and parenteral deliveries. Among these administrations routes, topical and transdermal products usually have a higher bioavailability rate with a prolonged steady-state plasma concentration. Additionally, these administrations have the potential to eliminate the psychotropic impacts of the drug by its diffusion into a nonreactive, dead stratum corneum. This modality avoids oral administration and, thus, the first-pass metabolism, leading to constant cannabinoid plasma levels. This review article investigates the practicality of delivering therapeutic cannabinoids via skin in accordance with existing literature. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)
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19 pages, 1478 KiB  
Review
An Insight into Biomolecules for the Treatment of Skin Infectious Diseases
by Helena P. Felgueiras
Pharmaceutics 2021, 13(7), 1012; https://doi.org/10.3390/pharmaceutics13071012 - 2 Jul 2021
Cited by 13 | Viewed by 3162
Abstract
In assigning priorities, skin infectious diseases are frequently classified as minor when compared to infectious diseases of high mortality rates, such as tuberculosis or HIV. However, skin infections are amongst the most common and prevalent diseases worldwide. Elderly individuals present an increased susceptibility [...] Read more.
In assigning priorities, skin infectious diseases are frequently classified as minor when compared to infectious diseases of high mortality rates, such as tuberculosis or HIV. However, skin infections are amongst the most common and prevalent diseases worldwide. Elderly individuals present an increased susceptibility to skin infections, which may develop atypical signs and symptoms or even complicate pre-existing chronic disorders. When the skin fails to correct or inhibit the action of certain pathogenic microorganisms, biomolecules endowed with antimicrobial features are frequently administered topically or systemically to assist or treat such conditions. (1) Antibiotics, (2) antimicrobial peptides, or (3) natural extracts display important features that can actively inhibit the propagation of these pathogens and prevent the evolution of infectious diseases. This review highlights the properties and mechanisms of action of these biomolecules, emphasizing their effects on the most prevalent and difficult to treat skin infections caused by pathogenic bacteria, fungi, and viruses. The versatility of biomolecules’ actions, their symbiotic effects with skin cells and other inherent antimicrobial components, and their target-directed signatures are also explored here. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)
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Other

Jump to: Research, Review

24 pages, 807 KiB  
Systematic Review
Laser-Assisted Drug Delivery: A Systematic Review of Safety and Adverse Events
by William Hao Syuen Ng and Saxon D. Smith
Pharmaceutics 2022, 14(12), 2738; https://doi.org/10.3390/pharmaceutics14122738 - 7 Dec 2022
Cited by 5 | Viewed by 2033
Abstract
Laser-assisted drug delivery (LADD) is an increasingly studied and applied methodology for drug delivery. It has been used in a wide variety of clinical applications. Given the relatively low barrier to entry for clinicians as well as ongoing research in this area, the [...] Read more.
Laser-assisted drug delivery (LADD) is an increasingly studied and applied methodology for drug delivery. It has been used in a wide variety of clinical applications. Given the relatively low barrier to entry for clinicians as well as ongoing research in this area, the authors aimed to review outcomes relating to safety in laser-assisted drug delivery. A systematic review was conducted, with the databases PubMed, Medline and Embase searched in September 2022. Included articles were those that mentioned laser-assisted drug delivery in human subjects that also reported adverse effects or safety outcomes. There were no language-based exclusions. Conference abstracts and literature reviews were excluded. The results were then tabulated and categorized according to the application of LADD. In total, 501 articles were obtained. Following deduplication, screening, and full text review 70 articles of various study designs were included. Common findings were erythema, oedema, pain, and crusting following LADD. Several notably more severe adverse effects such as generalized urticaria, infection, scarring and dyspigmentation were noted. However, these events were varied depending on the clinical use of LADD. Relevant negatives were also noted whereby no studies reported life-threatening adverse effects. Limitations included limited details regarding the adverse effects within the full texts, lack of follow-up, and risk of bias. In conclusion, there were multiple adverse effects that clinicians should consider prior to carrying out LADD, where treatment goals and patient tolerability should be considered. Further evidence is needed to quantitatively determine these risks. Full article
(This article belongs to the Special Issue Advances in Topical and Transdermal Drug Delivery)
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