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Special Issue "Transdermal Delivery Systems: Current Landscape and Trends"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (15 September 2016)

Special Issue Editor

Guest Editor
Prof. Dr. Yogeshvar Kalia

School of Pharmaceutical Sciences, University of Geneva, 30 Quai Ernest Ansermet, 1211 Geneva, Switzerland
Website | E-Mail
Interests: Prodrugs; microemulsions; polymeric micelles; iontophoresis; fractional laser ablation; transdermal delivery; topical delivery; dermatology

Special Issue Information

Dear Colleagues,

The perceived limitations of: (i) topical drug delivery to the skin for the targeted local treatment of disease; and (ii) transdermal drug delivery for systemic therapy, are being challenged by the development of new formulation strategies and delivery technologies. There is also an increased perception of the need to provide more targeted therapy and thereby to improve efficacy and to decrease the risk of side-effects: "the right drug, at the right place, at the right time". These drivers have led to considerable innovation, interest and progress in the field. Although, there is a general assumption as to the "optimal" physicochemical properties of a drug candidate for delivery into the skin, theory and practice can be very different. For example, locally acting therapeutics used to target dermatological diseases include aciclovir (log P −1.5) and adapalene (log P 8.2), an almost ten log unit difference in lipophilicity. The efficient, targeted delivery of such disparate molecules should require very different strategies. Peptides and proteins, including antibodies, have also been delivered into and across the skin using new technologies—these biomolecules are obviously very different from low molecular weight, lipophilic therapeutics which are the "conventional" candidates for transdermal delivery. The aim of this Special Issue is to provide a platform to present the latest developments in drug delivery and vaccination—in short, to show how the "impossible" is becoming possible.

Prof. Dr. Yogeshvar Kalia
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 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

  • transdermal delivery
  • topical delivery
  • formulation
  • drug delivery
  • follicular delivery
  • vaccination
  • chemical penetration enhancers
  • microneedles
  • iontophoresis
  • laser ablation
  • micelles
  • liposomes
  • nanocarriers
  • topical delivery

Published Papers (8 papers)

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Research

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Open AccessArticle The Effect and Mechanism of Transdermal Penetration Enhancement of Fu’s Cupping Therapy: New Physical Penetration Technology for Transdermal Administration with Traditional Chinese Medicine (TCM) Characteristics
Molecules 2017, 22(4), 525; doi:10.3390/molecules22040525
Received: 15 December 2016 / Revised: 9 March 2017 / Accepted: 22 March 2017 / Published: 27 March 2017
Cited by 1 | PDF Full-text (13027 KB) | HTML Full-text | XML Full-text
Abstract
Background: In this paper, a new type of physical penetration technology for transdermal administration with traditional Chinese medicine (TCM) characteristics is presented. Fu’s cupping therapy (FCT), was established and studied using in vitro and in vivo experiments and the penetration effect and mechanism
[...] Read more.
Background: In this paper, a new type of physical penetration technology for transdermal administration with traditional Chinese medicine (TCM) characteristics is presented. Fu’s cupping therapy (FCT), was established and studied using in vitro and in vivo experiments and the penetration effect and mechanism of FCT physical penetration technology was preliminarily discussed. Methods: With 1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-ylacetic acid (indomethacin, IM) as a model drug, the establishment of high, medium, and low references was completed for the chemical permeation system via in vitro transdermal tests. Furthermore, using chemical penetration enhancers (CPEs) and iontophoresis as references, the percutaneous penetration effect of FCT for IM patches was evaluated using seven species of in vitro diffusion kinetics models and in vitro drug distribution; the IM quantitative analysis method in vivo was established using ultra-performance liquid chromatography-tandem mass spectrometry technology (UPLC-MS/MS), and pharmacokinetic parameters: area under the zero and first moment curves from 0 to last time t (AUC0–t, AUMC0–t), area under the zero and first moment curves from 0 to infinity (AUC0–∞, AUMC0–∞), maximum plasma concentration (Cmax) and mean residence time (MRT), were used as indicators to evaluate the percutaneous penetration effect of FCT in vivo. Additionally, we used the 3K factorial design to study the joint synergistic penetration effect on FCT and chemical penetration enhancers. Through scanning electron microscopy (SEM) and transmission electron microscope (TEM) imaging, micro- and ultrastructural changes on the surface of the stratum corneum (SC) were observed to explore the FCT penetration mechanism. Results: In vitro and in vivo skin permeation experiments revealed that both the total cumulative percutaneous amount and in vivo percutaneous absorption amount of IM using FCT were greater than the amount using CPEs and iontophoresis. Firstly, compared with the control group, the indomethacin skin percutaneous rate of the FCT low-intensity group (FCTL) was 35.52%, and the enhancement ratio (ER) at 9 h was 1.76X, roughly equivalent to the penetration enhancing effect of the CPEs and iontophoresis. Secondly, the indomethacin percutaneous ratio of the FCT middle-intensity group (FCTM) and FCT high-intensity group (FCTH) were 47.36% and 54.58%, respectively, while the ERs at 9 h were 3.58X and 8.39X, respectively. Thirdly, pharmacokinetic data showed that in vivo indomethacin percutaneous absorption of the FCT was much higher than that of the control, that of the FCTM was slightly higher than that of the CPE, and that of the FCTM group was significantly higher than all others. Meanwhile, variance analysis indicated that the combination of the FCT penetration enhancement method and the CPE method had beneficial effects in enhancing skin penetration: the significance level of the CPE method was 0.0004, which was lower than 0.001, meaning the difference was markedly significant; the significance level of the FCT was also below 0.0001 and its difference markedly significant. The significance level of factor interaction A × B was lower than 0.0001, indicating that the difference in synergism was markedly significant. Moreover, SEM and TEM images showed that the SC surfaces of Sprague-Dawley rats treated with FCT were damaged, and it was difficult to observe the complete surface structure, with SC pores growing larger and its special “brick structure” becoming looser. This indicated that the barrier function of the skin was broken, thus revealing a potentially major route of skin penetration. Conclusion: FCT, as a new form of transdermal penetration technology, has significant penetration effects with TCM characteristics and is of high clinical value. It is worth promoting its development. Full article
(This article belongs to the Special Issue Transdermal Delivery Systems: Current Landscape and Trends)
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Open AccessArticle Alkylglycerol Derivatives, a New Class of Skin Penetration Modulators
Molecules 2017, 22(1), 185; doi:10.3390/molecules22010185
Received: 16 September 2016 / Revised: 3 January 2017 / Accepted: 17 January 2017 / Published: 22 January 2017
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Abstract
The absorption modulating activity of two alkylglycerol derivatives (batyl and chimyl alcohol) on skin barrier properties was evaluated. Biophysical tests such as transepidermal water loss (TEWL) and attenuated total reflectance–Fourier transform infrared (ATR-FTIR) spectroscopy, as well as in vitro skin permeation studies, were
[...] Read more.
The absorption modulating activity of two alkylglycerol derivatives (batyl and chimyl alcohol) on skin barrier properties was evaluated. Biophysical tests such as transepidermal water loss (TEWL) and attenuated total reflectance–Fourier transform infrared (ATR-FTIR) spectroscopy, as well as in vitro skin permeation studies, were performed in order to determine the effect of these compounds as chemical absorption modulators. Four drugs were used as models: three NSAIDS (diclofenac, naproxen, and piroxicam) and glycyrrhizic acid. The results showed that treatment of the skin with alkylglycerols caused (i) a reduction on the amount of drug permeated; (ii) a reduction in TEWL; and (iii) changes in the ATR-FTIR peaks of stratum corneum lipids, indicative of a more ordered structure. All of these findings confirm that alkyl glycerols have an absorption retarding effect on the drugs tested. Such effects are expected to give rise to important applications in the pharmaceutical and cosmetic sectors, in cases where it is desirable for the drug to remain in the superficial layers of the skin to achieve a local effect. Full article
(This article belongs to the Special Issue Transdermal Delivery Systems: Current Landscape and Trends)
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Open AccessArticle NO Exchange for a Water Molecule Favorably Changes Iontophoretic Release of Ruthenium Complexes to the Skin
Molecules 2017, 22(1), 104; doi:10.3390/molecules22010104
Received: 24 September 2016 / Revised: 16 December 2016 / Accepted: 3 January 2017 / Published: 8 January 2017
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Abstract
Ruthenium (Ru) complexes have been studied as promising anticancer agents. Ru nitrosyl complex (Ru-NO) is one which acts as a pro-drug for the release of nitric oxide (NO). The Ru-aqueous complex formed by the exchange of NO for a water molecule after NO
[...] Read more.
Ruthenium (Ru) complexes have been studied as promising anticancer agents. Ru nitrosyl complex (Ru-NO) is one which acts as a pro-drug for the release of nitric oxide (NO). The Ru-aqueous complex formed by the exchange of NO for a water molecule after NO release could also possess therapeutic effects. This study evaluates the influence of iontophoresis on enhancing the skin penetration of Ru-NO and Ru-aqueous and assesses its applicability as a tool in treating diverse skin diseases. Passive and iontophoretic (0.5 mA·cm−2) skin permeation of the complexes were performed for 4 h. The amount of Ru and NO in the stratum corneum (SC), viable epidermis (VE), and receptor solution was quantified while the influence of iontophoresis and irradiation on NO release from Ru-NO complex was also evaluated. Iontophoresis increased the amount of Ru-NO and Ru-aqueous recovered from the receptor solution by 15 and 400 times, respectively, as compared to passive permeation. Iontophoresis produced a higher accumulation of Ru-aqueous in the skin layers as compared to Ru-NO. At least 50% of Ru-NO penetrated the SC was stable after 4 h. The presence of Ru-NO in this skin layer suggests that further controlled release of NO can be achieved by photo-stimulation after iontophoresis. Full article
(This article belongs to the Special Issue Transdermal Delivery Systems: Current Landscape and Trends)
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Open AccessArticle Podophyllotoxin-Loaded Nanostructured Lipid Carriers for Skin Targeting: In Vitro and In Vivo Studies
Molecules 2016, 21(11), 1549; doi:10.3390/molecules21111549
Received: 27 September 2016 / Revised: 28 October 2016 / Accepted: 7 November 2016 / Published: 17 November 2016
Cited by 3 | PDF Full-text (7369 KB) | HTML Full-text | XML Full-text | Correction
Abstract
Nanostructured lipid carriers (NLC) exhibit high skin targeting efficiency and good safety. They are promising vehicles for topical drug delivery. This study aims to increase the skin distribution of podophyllotoxin (POD) by incorporating it into NLCs. Two kinds of POD-loaded NLCs (POD-NLCs)—POD-NLCformulation
[...] Read more.
Nanostructured lipid carriers (NLC) exhibit high skin targeting efficiency and good safety. They are promising vehicles for topical drug delivery. This study aims to increase the skin distribution of podophyllotoxin (POD) by incorporating it into NLCs. Two kinds of POD-loaded NLCs (POD-NLCs)—POD-NLCformulation 1 and POD-NLCformulation 2—were prepared and characterized. Their skin targeting efficiencies were compared by conducting in vitro and in vivo experiments. Obviously smaller mean particle size was observed for POD-NLCformulation 1 (106 nm) than POD-NLCformulation 2 (219 nm), whereas relatively low POD loadings (less than 0.5%) were observed for both POD-NLCformulation 1 (0.33%) and POD-NLCformulation 2 (0.49%). Significantly higher in vitro and in vivo rat skin deposit amounts of POD (p ˂ 0.01) were detected after the topical application of POD-NLCformulation 1 compared to POD-NLCformulation 2. To visualize the skin distribution behavior of hydrophobic active pharmaceutical ingredients (APIs) when NLCs were used as carriers, POD was replaced with Nile red (NR—a hydrophobic fluorescent probe), and the distribution behavior of NR-NLCformulation 1 and NR-NLCformulation 2 in rat skin in vivo was observed using confocal laser scanning microscopy (CLSM). Higher fluorescent intensity was observed in rat skin after the topical application of NR-NLCformulation 1 than NR-NLCformulation 2, suggesting that higher skin targeting efficiency might be obtained when NLCs with smaller mean particle size were used as carriers for hydrophobic APIs. This result was in accordance with those of skin distribution evaluation experiments of POD-NLCs. Skin irritation property of POD-NLCformulation 1 was investigated and no irritation was observed in intact or damaged rabbit skin, suggesting it is safe for topical use. Our results validated the safety of NLCs when applied topically. More importantly, mean particle size might be an important parameter for formulation optimization when NLCs are used as carriers for hydrophobic APIs for topical application, considering that their loading is relatively low. Full article
(This article belongs to the Special Issue Transdermal Delivery Systems: Current Landscape and Trends)
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Open AccessArticle Fractional CO2 Laser Pretreatment Facilitates Transdermal Delivery of Two Vitamin C Derivatives
Molecules 2016, 21(11), 1547; doi:10.3390/molecules21111547
Received: 19 July 2016 / Revised: 28 October 2016 / Accepted: 10 November 2016 / Published: 16 November 2016
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Abstract
Background: Topical vitamin C derivatives have been used to treat melasma and used as a skin whitener. The aim of this study was to compare skin histology and permeation of l-ascorbic acid 2-phosphate sesquimagnesium salt (MAP-1) and magnesium l-ascorbic acid-2-phosphate (MAP-2)
[...] Read more.
Background: Topical vitamin C derivatives have been used to treat melasma and used as a skin whitener. The aim of this study was to compare skin histology and permeation of l-ascorbic acid 2-phosphate sesquimagnesium salt (MAP-1) and magnesium l-ascorbic acid-2-phosphate (MAP-2) after fractional CO2 laser pretreatment. Methods: The effect of fractional laser treatment on porcine skin was examined by scanning electron microscopy and confocal laser scanning electron microscopy. The effect of fractional CO2 laser treatment of different fluencies and pass numbers on transdermal flux of the two vitamin C derivatives through porcine skin was examined in vitro using a Franz diffusion chamber. Results: Fluxes of MAP-1 and MAP-2 across fractional CO2 laser-treated (5 W) skin were eight- to 13-fold, and 20- to 22-fold higher, respectively, than the fluxes of these compounds across intact skin. Fluxes of MAP-1 and MAP-2 across fractional CO2 laser-treated (9 W) skin were 14- to 19-fold, and 30- to 42-fold higher, respectively, than their fluxes across intact skin. Conclusion: Fractional CO2 laser treatment is an effective way of delivering vitamin C derivatives into the skin. Full article
(This article belongs to the Special Issue Transdermal Delivery Systems: Current Landscape and Trends)
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Open AccessArticle Flow and Thixotropic Parameters for Rheological Characterization of Hydrogels
Molecules 2016, 21(6), 786; doi:10.3390/molecules21060786
Received: 21 April 2016 / Revised: 6 June 2016 / Accepted: 13 June 2016 / Published: 16 June 2016
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Abstract
The goal of this paper was to design several sodium carboxymethylcellulose hydrogels containing a BCS class II model drug and to evaluate their flow and thixotropic properties. The rheological measurements were performed at two temperatures (23 °C and 37 °C), using a rotational
[...] Read more.
The goal of this paper was to design several sodium carboxymethylcellulose hydrogels containing a BCS class II model drug and to evaluate their flow and thixotropic properties. The rheological measurements were performed at two temperatures (23 °C and 37 °C), using a rotational viscometer. The hydrogels were stirred at different time intervals (10 s, 2, 5, 10 and 20 min at 23 °C, and 10 s, 2 and 5 min at 37 °C), with a maximum rotational speed of 60 rpm, and the corresponding forward and backward rheograms were recorded as shear stress vs. shear rate. For all hydrogels, the rheological data obtained at both temperatures showed a decrease of viscosity with the increase of the shear rate, highlighting a pseudoplastic behaviour. The flow profiles viscosity vs. shear rate were quantified through power law model, meanwhile the flow curves shear stress vs. shear rate were assessed by applying the Herschel-Bulkley model. The thixotropic character was evaluated through different descriptors: thixotropic area, thixotropic index, thixotropic constant and destructuration thixotropic coefficient. The gel-forming polymer concentration and the rheological experiments temperature significantly influence the flow and thixotropic parameters values of the designed hydrogels. The rheological characteristics described have an impact on the drug release microenvironment and determine the stasis time at the application site. Full article
(This article belongs to the Special Issue Transdermal Delivery Systems: Current Landscape and Trends)
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Review

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Open AccessReview Nanoparticle-Enabled Transdermal Drug Delivery Systems for Enhanced Dose Control and Tissue Targeting
Molecules 2016, 21(12), 1719; doi:10.3390/molecules21121719
Received: 24 October 2016 / Revised: 28 November 2016 / Accepted: 9 December 2016 / Published: 15 December 2016
Cited by 9 | PDF Full-text (593 KB) | HTML Full-text | XML Full-text
Abstract
Transdermal drug delivery systems have been around for decades, and current technologies (e.g., patches, ointments, and creams) enhance the skin permeation of low molecular weight, lipophilic drugs that are efficacious at low doses. The objective of current transdermal drug delivery research is to
[...] Read more.
Transdermal drug delivery systems have been around for decades, and current technologies (e.g., patches, ointments, and creams) enhance the skin permeation of low molecular weight, lipophilic drugs that are efficacious at low doses. The objective of current transdermal drug delivery research is to discover ways to enhance skin penetration of larger, hydrophilic drugs and macromolecules for disease treatment and vaccination. Nanocarriers made of lipids, metals, or polymers have been successfully used to increase penetration of drugs or vaccines, control drug release, and target drugs to specific areas of skin in vivo. While more research is needed to identify the safety of nanocarriers, this technology has the potential to expand the use of transdermal routes of administration to a wide array of therapeutics. Here, we review the current state of nanoparticle skin delivery systems with special emphasis on targeting skin diseases. Full article
(This article belongs to the Special Issue Transdermal Delivery Systems: Current Landscape and Trends)
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Open AccessReview Treatment Modalities for Acne
Molecules 2016, 21(8), 1063; doi:10.3390/molecules21081063
Received: 9 June 2016 / Revised: 26 July 2016 / Accepted: 8 August 2016 / Published: 13 August 2016
Cited by 5 | PDF Full-text (528 KB) | HTML Full-text | XML Full-text
Abstract
Acne is a common inflammatory skin disease which affects the pilosebaceous units of the skin. It can have severe psychological effects and can leave the patient with severe skin scarring. There are four well-recognized pathological factors responsible for acne which is also the
[...] Read more.
Acne is a common inflammatory skin disease which affects the pilosebaceous units of the skin. It can have severe psychological effects and can leave the patient with severe skin scarring. There are four well-recognized pathological factors responsible for acne which is also the target for acne therapy. In this review, different treatment options are discussed, including topical (i.e., retinoids, and antibiotics) and systemic (i.e., retinoids, antibiotics, and hormonal) treatments. Since the general public has been showing an increasing interest in more natural and generally safer treatment options, the use of complementary and alternative medicines (CAM) for treating acne was also discussed. The use of physical therapies such as comedone extraction, cryoslush therapy, cryotherapy, electrocauterization, intralesional corticosteroids and optical treatments are also mentioned. Acne has been extensively researched with regards to the disease mechanism as well as treatment options. However, due to the increasing resistance of Propionibacterium acnes towards the available antibiotics, there is a need for new treatment methods. Additionally, the lack of necessary evidence on the efficacy of CAM therapies makes it necessary for researchers to investigate these treatment options further. Full article
(This article belongs to the Special Issue Transdermal Delivery Systems: Current Landscape and Trends)
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