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Pharmaceutics
Special Issues
Novel Approaches in Dermal Drug Delivery
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Novel Approaches in Dermal 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 (30 June 2020) | Viewed by 50576

Special Issue Editors

Prof. Dr. Sarah Hedtrich

E-Mail Website
Guest Editor
Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver Campus, 2405 Wesbrook Mall, Vancouver, BC, Canada
Interests: topical drug delivery; reconstruction of human-based organ (disease) models
Prof. Dr. Annika Vogt

E-Mail Website
Guest Editor
Clinical Research Center for Hair and Skin Science, Department of Dermatology and Allergy, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
Interests: skin barrier function and immunology; skin penetration; ex vivo skin models and translational clinical trials

Special Issue Information

Dear Colleagues,

The easy accessibility of human skin provides unique potential for topical applications. A variety of resident and migratory cell populations relevant for barrier and immune functions and tissue regeneration reside underneath a unique barrier architecture. In recent years, several novel approaches have been developed to overcome the skin barrier that could help to tackle existing challenges in the field, such as the effective delivery of biomacromolecules and targeting of specific tissue compartments or cell populations. Technical advances in in vitro and ex vivo skin models and the unique possibility for in vivo clinical assessment using non-invasive imaging and minimal-invasive assessment techniques provide ideal conditions for translational research.

This Issue aims to provide an up-to-date perspective on recent advancements in the field of topical drug delivery. This also includes a critical review of proposed and currently available approaches, including their translational potential, from the perspective of a basic scientist and a dermatologist.

Prof. Dr. Sarah Hedtrich
Prof. Dr. Annika Vogt
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • dermatotherapy
  • skin permeation and penetration enhancement
  • transcutaneous drug delivery systems
  • preclinical skin models
  • translational potential of novel dermal drug delivery approaches

Published Papers (9 papers)

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Research

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16 pages, 4144 KiB  
Article
Development of an Oil-in-Water Self-Emulsifying Microemulsion for Cutaneous Delivery of Rose Bengal: Investigation of Anti-Melanoma Properties
by Farzaneh Forouz, Maryam Dabbaghi, Sarika Namjoshi, Yousuf Mohammed, Michael S. Roberts and Jeffrey E. Grice
Pharmaceutics 2020, 12(10), 947; https://doi.org/10.3390/pharmaceutics12100947 - 05 Oct 2020
Cited by 12 | Viewed by 2955
Abstract
The topical delivery route is proposed as an alternative or adjunctive approach to melanoma treatment, since the target site for melanoma treatment—the epidermal basal layer—is potentially accessible by this route. Microemulsion systems are effective delivery vehicles for enhanced, targeted skin delivery. This work [...] Read more.
The topical delivery route is proposed as an alternative or adjunctive approach to melanoma treatment, since the target site for melanoma treatment—the epidermal basal layer—is potentially accessible by this route. Microemulsion systems are effective delivery vehicles for enhanced, targeted skin delivery. This work investigated the effect of Rose Bengal (RB) and RB-loaded self-emulsifying microemulsions (SEMEs) on growth inhibition of human melanoma and normal skin cell monolayers, the safety of the excipients incorporated in SEMEs on human cell lines, and the in-vitro human skin penetration of RB delivered in SEMEs and control solution. Cellular toxicity was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the growth inhibitory mechanism of RB was investigated by flow cytometry using PI staining. Unloaded SEMEs caused reduced cellular toxicity compared to the surfactant excipient, Labrasol®. RB-loaded SEMEs increased cell growth inhibition compared to the RB aqueous solution. Flow cytometry revealed apoptotic cells after treatment with RB-loaded SEMEs, indicating that apoptosis may be one of the mechanisms of cell death. Preliminary results of multiphoton microscopy with fluorescence lifetime imaging (MPM-FLIM) analysis showed deeper penetration with greater skin concentrations of RB delivered from SEMEs compared to the RB aqueous solution. This study highlights the enhanced skin penetration and antimelanoma effects of RB loaded in a SEME system. Full article
(This article belongs to the Special Issue Novel Approaches in Dermal Drug Delivery)
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27 pages, 5905 KiB  
Article
Formulation of Sodium Valproate Nanospanlastics as a Promising Approach for Drug Repurposing in the Treatment of Androgenic Alopecia
by Farid. A. Badria, Hassan A. Fayed, Amira K. Ibraheem, Ahmed F. State and Eman A. Mazyed
Pharmaceutics 2020, 12(9), 866; https://doi.org/10.3390/pharmaceutics12090866 - 11 Sep 2020
Cited by 24 | Viewed by 4437
Abstract
Sodium valproate (SV) is an antiepileptic drug that is widely used in the treatment of different seizure disorders. The topical SV has a hair regenerative potential through activating the Wnt/β-catenin pathway and anagen phase induction. The aim of the current investigation was to [...] Read more.
Sodium valproate (SV) is an antiepileptic drug that is widely used in the treatment of different seizure disorders. The topical SV has a hair regenerative potential through activating the Wnt/β-catenin pathway and anagen phase induction. The aim of the current investigation was to fabricate nanospanlastics of SV for improving its dermal delivery by providing prolonged drug effect and increasing its permeability for treatment of androgenic alopecia (AGA). SV-loaded nanospanlastics were formulated according to 23 factorial design by ethanol injection method using a non-ionic surfactant (Span 60) and edge activators (EAs), such as Tween 80 and Cremophor RH 40, to explore the influence of different independent variables on entrapment efficiency (EE%) and percentage drug released after 12 h (Q12h) in order to choose the optimized formula using Design-Expert software. The optimized formula (F8) appeared as spherical deformable vesicles with EE% of 90.32 ± 2.18% and Q12h of 90.27 ± 1.98%. F8 exhibited significant improvement of ex vivo permeation than free SV. The clinical study exhibited no comparable difference between F8 and marketed minoxidil lotion. However, F8 demonstrates less adverse effects than minoxidil lotion. Nanospanlastics could be a safe and effective method for improving the topical delivery of SV in the management of AGA. Full article
(This article belongs to the Special Issue Novel Approaches in Dermal Drug Delivery)
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15 pages, 1849 KiB  
Article
Serine Protease-Mediated Cutaneous Inflammation: Characterization of an Ex Vivo Skin Model for the Assessment of Dexamethasone-Loaded Core Multishell-Nanocarriers
by Janna Frombach, Fiorenza Rancan, Katharina Kübrich, Fabian Schumacher, Michael Unbehauen, Ulrike Blume-Peytavi, Rainer Haag, Burkhard Kleuser, Robert Sabat, Kerstin Wolk and Annika Vogt
Pharmaceutics 2020, 12(9), 862; https://doi.org/10.3390/pharmaceutics12090862 - 10 Sep 2020
Cited by 8 | Viewed by 3122
Abstract
Standard experimental set-ups for the assessment of skin penetration are typically performed on skin explants with an intact skin barrier or after a partial mechanical or chemical perturbation of the stratum corneum, but they do not take into account biochemical changes. Among [...] Read more.
Standard experimental set-ups for the assessment of skin penetration are typically performed on skin explants with an intact skin barrier or after a partial mechanical or chemical perturbation of the stratum corneum, but they do not take into account biochemical changes. Among the various pathological alterations in inflamed skin, aberrant serine protease (SP) activity directly affects the biochemical environment in the superficial compartments, which interact with topically applied formulations. It further impacts the skin barrier structure and is a key regulator of inflammatory mediators. Herein, we used short-term cultures of ex vivo human skin treated with trypsin and plasmin as inflammatory stimuli to assess the penetration and biological effects of the anti-inflammatory drug dexamethasone (DXM), encapsulated in core multishell-nanocarriers (CMS-NC), when compared to a standard cream formulation. Despite a high interindividual variability, the combined pretreatment of the skin resulted in an average 2.5-fold increase of the transepidermal water loss and swelling of the epidermis, as assessed by optical coherence tomography, as well as in a moderate increase of a broad spectrum of proinflammatory mediators of clinical relevance. The topical application of DXM-loaded CMS-NC or DXM standard cream revealed an increased penetration into SP-treated skin when compared to untreated control skin with an intact barrier. Both formulations, however, delivered sufficient amounts of DXM to effectively suppress the production of interleukin-6 (IL-6), interleukin-8 (IL-8) and Thymic Stromal Lymphopoietin (TSLP). In conclusion, we suggest that the herein presented ex vivo inflammatory skin model is functional and could improve the selection of promising drug delivery strategies for anti-inflammatory compounds at early stages of development. Full article
(This article belongs to the Special Issue Novel Approaches in Dermal Drug Delivery)
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18 pages, 7138 KiB  
Article
Advanced Characterization of Imiquimod-Induced Psoriasis-Like Mouse Model
by Mehwish Jabeen, Anne-Sophie Boisgard, Alix Danoy, Naima El Kholti, Jean-Paul Salvi, Roselyne Boulieu, Bérengère Fromy, Bernard Verrier and Myriam Lamrayah
Pharmaceutics 2020, 12(9), 789; https://doi.org/10.3390/pharmaceutics12090789 - 20 Aug 2020
Cited by 55 | Viewed by 6808
Abstract
Many autoimmune disorders such as psoriasis lead to the alteration of skin components which generally manifests as unwanted topical symptoms. One of the most widely approved psoriasis-like animal models is the imiquimod (IMQ)-induced mouse model. This representation mimics various aspects of the complex [...] Read more.
Many autoimmune disorders such as psoriasis lead to the alteration of skin components which generally manifests as unwanted topical symptoms. One of the most widely approved psoriasis-like animal models is the imiquimod (IMQ)-induced mouse model. This representation mimics various aspects of the complex cutaneous pathology and could be appropriate for testing topical treatment options. We perform a thorough characterization of this model by assessing some parameters that are not fully described in the literature, namely a precise description of skin disruption. It was evaluated by transepidermal water loss measurements and analyses of epidermis swelling as a consequence of keratinocyte hyperproliferation. The extent of neo-angiogenesis and hypervascularity in dermis were highlighted by immunostaining. Moreover, we investigated systemic inflammation through cytokines levels, spleen swelling and germinal centers appearance in draining lymph nodes. The severity of all parameters was correlated to IMQ concentration in skin samples. This study outlines new parameters of interest useful to assess this model. We highlight the skin barrier disruption and report a systemic inflammatory reaction occurring at distance both in spleen and lymph nodes. These newly identified biological endpoints could be exploited to investigate the efficacy of therapeutic candidates for psoriasis and more extensively for several other skin inflammatory diseases. Full article
(This article belongs to the Special Issue Novel Approaches in Dermal Drug Delivery)
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24 pages, 1444 KiB  
Article
Development of a Self-Emulsifying Drug Delivery System for Optimized Topical Delivery of Clofazimine
by Daniélle van Staden, Jeanetta du Plessis and Joe Viljoen
Pharmaceutics 2020, 12(6), 523; https://doi.org/10.3390/pharmaceutics12060523 - 08 Jun 2020
Cited by 28 | Viewed by 4124
Abstract
A quality-by-design and characterization approach was followed to ensure development of self-emulsifying drug delivery systems (SEDDSs) destined for topical delivery of the highly lipophilic clofazimine. Solubility and water-titration experiments identified spontaneous emulsification capacity of different excipient combinations and clofazimine. After identifying self-emulsification regions, [...] Read more.
A quality-by-design and characterization approach was followed to ensure development of self-emulsifying drug delivery systems (SEDDSs) destined for topical delivery of the highly lipophilic clofazimine. Solubility and water-titration experiments identified spontaneous emulsification capacity of different excipient combinations and clofazimine. After identifying self-emulsification regions, check-point formulations were selected within the self-emulsification region by considering characteristics required to achieve optimized topical drug delivery. Check-point formulations, able to withstand phase separation after 24 h at an ambient temperature, were subjected to characterization studies. Experiments involved droplet size evaluation; size distribution; zeta-potential; self-emulsification time and efficacy; viscosity and pH measurement; cloud point assessment; and thermodynamic stability studies. SEDDSs with favorable properties, i.e., topical drug delivery, were subjected to dermal diffusion studies. Successful in vitro topical clofazimine delivery was observed. Olive oil facilitated the highest topical delivery of clofazimine probably due to increased oleic acid levels that enhanced stratum corneum lipid disruption, followed by improved dermal clofazimine delivery. Finally, isothermal microcalometric experiments studied the compatibility of excipients. Potential interactions were depicted between argan oil and clofazimine as well as between Span®60 and argan-, macadamia- and olive oil, respectively. However, despite some mundane incompatibilities, successful development of topical SEDDSs achieved enhanced topical clofazimine delivery. Full article
(This article belongs to the Special Issue Novel Approaches in Dermal Drug Delivery)
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19 pages, 3086 KiB  
Article
Highly Elastic and Water Stable Zein Microfibers as a Potential Drug Delivery System for Wound Healing
by Alma Akhmetova, Georg-Marten Lanno, Karin Kogermann, Martin Malmsten, Thomas Rades and Andrea Heinz
Pharmaceutics 2020, 12(5), 458; https://doi.org/10.3390/pharmaceutics12050458 - 18 May 2020
Cited by 18 | Viewed by 4113
Abstract
The development of biomaterials for wound healing applications requires providing a number of properties, such as antimicrobial action, facilitation of cell proliferation, biocompatibility and biodegradability. The aim of the present study was to investigate morphological and mechanical properties of zein-based microfibers, ultimately aimed [...] Read more.
The development of biomaterials for wound healing applications requires providing a number of properties, such as antimicrobial action, facilitation of cell proliferation, biocompatibility and biodegradability. The aim of the present study was to investigate morphological and mechanical properties of zein-based microfibers, ultimately aimed at creating an environment suitable for wound healing. This was achieved through co-axial electrospinning of core–shell microfibers, with zein protein in the core and polyethylene oxide (PEO) in the shell. Small amounts of PEO or stearic acid were additionally incorporated into the fiber core to modify the morphology and mechanical properties of zein fibers. The presence of PEO in the core was found to be essential for the formation of tubular fibers, whereas PEO in the shell enhanced the stability of the microfibers in water and ensured high elasticity of the microfiber mats. Tetracycline hydrochloride was present in an amorphous form within the fibers, and displayed a burst release as a result of pore-formation in the fibers. The developed systems exhibited antimicrobial activity against Staphylococcus aureus and Escherichia coli, and showed no cytotoxic effect on fibroblasts. Biocompatibility, antimicrobial activity and favorable morphological and mechanical properties make the developed zein-based microfibers a potential biomaterial for wound healing purposes. Full article
(This article belongs to the Special Issue Novel Approaches in Dermal Drug Delivery)
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18 pages, 1999 KiB  
Article
Nanocrystals for Improved Drug Delivery of Dexamethasone in Skin Investigated by EPR Spectroscopy
by Silke B. Lohan, Siavash Saeidpour, Miriam Colombo, Sven Staufenbiel, Michael Unbehauen, Amanuel Wolde-Kidan, Roland R. Netz, Roland Bodmeier, Rainer Haag, Christian Teutloff, Robert Bittl and Martina C. Meinke
Pharmaceutics 2020, 12(5), 400; https://doi.org/10.3390/pharmaceutics12050400 - 27 Apr 2020
Cited by 17 | Viewed by 2976
Abstract
Nanocrystals represent an improvement over the traditional nanocarriers for dermal application, providing the advantages of 100% drug loading, a large surface area, increased adhesion, and the potential for hair follicle targeting. To investigate their advantage for drug delivery, compared to a base cream [...] Read more.
Nanocrystals represent an improvement over the traditional nanocarriers for dermal application, providing the advantages of 100% drug loading, a large surface area, increased adhesion, and the potential for hair follicle targeting. To investigate their advantage for drug delivery, compared to a base cream formulation, dexamethasone (Dx), a synthetic glucocorticoid frequently used for the treatment of inflammatory skin diseases, was covalently linked with the paramagnetic probe 3-(carboxy)-2,2,5,5-tetramethyl-1-pyrrolidinyloxy (PCA) to DxPCA. To investigate the penetration efficiency between these two vehicles, electron paramagnetic resonance (EPR) spectroscopy was used, which allows the quantification of a spin-labeled drug in different skin layers and the monitoring of the drug release. The penetration behavior in excised healthy and barrier-disrupted porcine skin was monitored by EPR, and subsequently analyzed using a numerical diffusion model. As a result, diffusion constants and free energy values in the different layers of the skin were identified for both formulations. Dx-nanocrystals showed a significantly increased drug amount that penetrated into viable epidermis and dermis of intact (factor 3) and barrier-disrupted skin (factor 2.1) compared to the base cream formulation. Furthermore, the observed fast delivery of the spin-labeled drug into the skin (80% DxPCA within 30 min) and a successive release from the aggregate unit into the viable tissue makes these nanocrystals very attractive for clinical applications. Full article
(This article belongs to the Special Issue Novel Approaches in Dermal Drug Delivery)
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Review

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31 pages, 4179 KiB  
Review
Skin Barriers in Dermal Drug Delivery: Which Barriers Have to Be Overcome and How Can We Measure Them?
by Christian Gorzelanny, Christian Mess, Stefan W. Schneider, Volker Huck and Johanna M. Brandner
Pharmaceutics 2020, 12(7), 684; https://doi.org/10.3390/pharmaceutics12070684 - 20 Jul 2020
Cited by 100 | Viewed by 8421
Abstract
Although, drugs are required in the various skin compartments such as viable epidermis, dermis, or hair follicles, to efficiently treat skin diseases, drug delivery into and across the skin is still challenging. An improved understanding of skin barrier physiology is mandatory to optimize [...] Read more.
Although, drugs are required in the various skin compartments such as viable epidermis, dermis, or hair follicles, to efficiently treat skin diseases, drug delivery into and across the skin is still challenging. An improved understanding of skin barrier physiology is mandatory to optimize drug penetration and permeation. The various barriers of the skin have to be known in detail, which means methods are needed to measure their functionality and outside-in or inside-out passage of molecules through the various barriers. In this review, we summarize our current knowledge about mechanical barriers, i.e., stratum corneum and tight junctions, in interfollicular epidermis, hair follicles and glands. Furthermore, we discuss the barrier properties of the basement membrane and dermal blood vessels. Barrier alterations found in skin of patients with atopic dermatitis are described. Finally, we critically compare the up-to-date applicability of several physical, biochemical and microscopic methods such as transepidermal water loss, impedance spectroscopy, Raman spectroscopy, immunohistochemical stainings, optical coherence microscopy and multiphoton microscopy to distinctly address the different barriers and to measure permeation through these barriers in vitro and in vivo. Full article
(This article belongs to the Special Issue Novel Approaches in Dermal Drug Delivery)
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28 pages, 3474 KiB  
Review
Microneedle-Based Delivery: An Overview of Current Applications and Trends
by Antonio José Guillot, Ana Sara Cordeiro, Ryan F. Donnelly, M. Carmen Montesinos, Teresa M. Garrigues and Ana Melero
Pharmaceutics 2020, 12(6), 569; https://doi.org/10.3390/pharmaceutics12060569 - 19 Jun 2020
Cited by 129 | Viewed by 12895
Abstract
Microneedle arrays (MNA) are considered as one of the most promising resources to achieve systemic effects by transdermal delivery of drugs. They are designed as a minimally invasive, painless system which can bypass the stratum corneum, overcoming the potential drawbacks of subcutaneous [...] Read more.
Microneedle arrays (MNA) are considered as one of the most promising resources to achieve systemic effects by transdermal delivery of drugs. They are designed as a minimally invasive, painless system which can bypass the stratum corneum, overcoming the potential drawbacks of subcutaneous injections and other transdermal delivery systems such as chemical enhancers, nano and microparticles, or physical treatments. As a trendy field in pharmaceutical and biomedical research, its applications are constantly evolving, even though they are based on very well-established techniques. The number of molecules administered by MNA are also increasing, with insulin and vaccines administration being the most investigated. Furthermore, MNA are being used to deliver cells and applied in other organs and tissues like the eyes and buccal mucosae. This review intends to offer a general overview of the current state of MNA research, focusing on the strategies, applications, and types of molecules delivered recently by these systems. In addition, some information about the materials and manufacturing processes is presented and safety data is discussed. Full article
(This article belongs to the Special Issue Novel Approaches in Dermal Drug Delivery)
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