Special Issue "Transdermal Drug Delivery"

Guest Editor
Prof. Dr. Bozena B. Michniak-Kohn
Pharmaceutics, Ernest Mario School of Pharmacy; Center for Dermal Research (CDR) & Laboratory for Drug Delivery (LDD), NJ Center for Biomaterials, Life Sciences Building, Rutgers-The State University of New Jersey, 145, Bevier Road, Piscataway, NJ 08854, USA
E-Mail: michniak@biology.rutgers.edu
Phone: +1 732 445 3589
Fax: +1 732 445 5006
Interests: topical; transdermal; percutaneous drug delivery; skin transport pathways; skin carrier systems; skin formulations; skin drug delivery; human skin equivalents; skin models

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• topical
• transdermal
• percutaneous drug delivery
• skin transport pathways
• skin carrier systems
• skin formulations
• skin drug delivery
• human skin equivalents
• skin models

Title: Effect of Duration and Amplitude of Direct Current when Lidocaine is Delivered by Iontophoresis
Authors: S. Saliba, C. Teeter, P. McKeon, C. Ingersoll and E. Saliba
Abstract: Dosage for the galvanic stimulation during iontophoresis
treatments are typically described in milliamp min (mA^.min). There are no clinical guidelines for manipulation of either the length of time or the amplitude of current to improve iontophoresis effectiveness. Objective: To compare the anaesthetic effects of lidocaine HCL(2%) using a long duration, low electrical amplitude treatment to a short duration, high amplitude treatment. Design: Double-blinded, crossover design. Setting: Clinical Research Laboratory. Patients or Other Participants: 21 subjects volunteered (8 females; 13 males). Age: 21.2 ± 4.25, height 170.7 ± 10.29 cm, mass 82.1 ± 19.24 kg. All participants were healthy with no lidocaine or adhesive allergy and no skin abnormalities. Intervention(s): Three treatments using a Phoresor II®; 2mL, 2% lidocaine HCL in standard iontophoresis electrodes were administered to each subject in a random order on the volar aspect of the right forearm. (1) HASD (40 mA^.min): High amplitude (4 mA), short duration (10 min); (2) LALD (40 mA^.min): Low amplitude (2 mA), long duration (20 min); (3) Sham condition (0 mA, 20 min). All treatments were separated by at least 48 hours. Main Outcome Measures: Semmes-Weinstein monofilament scores were taken pre and post intervention to measure sensation changes in the area designated for the treatment electrode. Two-way ANOVA with repeated measures was used to compare sensation scores. Post hoc pair-wise comparisons were performed to explain significant interactions. Results: Both iontophoresis treatments: LALD (4.2 ± 0.32 mm) and HASD (4.2 ± 0.52 mm) significantly increased Semmes-Weinstein monofilament scores, indicating an increase in anaesthesia in these conditions compared to the sham condition (3.6 ± 0.06 mm) p < 0.05. Neither LALD nor HASD was more effective than the other. There was no difference in anaesthesia with the sham condition. Conclusions: Lidocaine delivered via iontophoresis is effective in reducing cutaneous sensation when applied at 40 mA^.min. However, there was no benefit in either a high amplitude, short duration or low amplitude, long duration treatment at this treatment dose for cutaneous anaesthesia.
Keywords: percutaneous drug delivery; physical therapy; transdermal; electrical stimulation

Title: A Computational Procedure for Assessing the Dynamic Performance of Diffusion-Controlled Transdermal Delivery Devices
Author: Laurent Simon
Affiliation: Otto H. York Department of Chemical, Biological and Pharmaceutical Engineering, New Jersey Institute of Technology, Newark NJ 07102, USA
Abstract: Monolithic matrices are among the most inexpensive systems used to control the release of drugs. In these structures, the active pharmaceutical ingredients are encapsulated within a polymeric material using fabrication methods, such as hot melt extrusion and solvent casting techniques. The rate of drug delivery is controlled by the properties of the membrane barrier. Despite their popularity, to tailor the properties of the polymer and additives to specific release characteristics can be challenging and time-consuming. The heuristic approaches often adopted to select the vehicle formulation provide limited insight into key transport mechanisms, which makes it difficult to predict the device performance. Several theoretical methods have been proposed to design efficient two-layer systems (e.g., membrane and skin) and guide experimental research in the area. Although mathematical modeling has made it possible to simulate the release behaviors of medications and estimate diffusion coefficients necessary to meet an objective, these efforts have focused mainly on building a device that satisfies a steady-state performance criterion of attaining the desired flux. The time to reach this target is seldom addressed. This contribution suggests the use of an effective time constant in developing an optimum design strategy.

Title: SKIN-CAD Simulator for Transdermal Drug Delivery
Authors: Daisuke Mori and Kakuji Tojo
Affiliation: Biocom Systems, Inc.
Abstract: Mathematical model and simulation software, SKIN-CAD, were developed to predict clinical performance of transdermal drug delivery systems. The theoretical approach consists of matrix system/skin diffusion model and whole body pharmacokinetic/pharmacodynamic model. SKIN-CAD can numerically solve a set of differential equations derived from the modeling of transdermal absorption. Numerical simulations were carried out to demonstrate skin permeation and blood concentration profiles under various pharmaceutical and clinical conditions. This in silico methodology can be used for optimum design of transdermal drug delivery systems. Using this computer model, SKIN-CAD, we may be able to reduce significantly the clinical trials by designing a rational and effective protocol for clinical studies.

Type of Paper: Article
Title: The Application of Discriminant Analysis and Machine Learning Methods As Tools to Identify and Classify Compounds with Potential As Transdermal Enhancers
Authors: W. J. Pugh ¹, Y. Sun ², N. Davey ², R. G. Adams ² and G. P. Moss ³
Affiliations: ¹ Welsh School of Pharmacy, Cardiff University, Cardiff, UK
² School of Engineering & Information Science, University of Hertfordshire, Hatfield, UK
³ School of Pharmacy, Keele University, Keele, UK; E-Mail: g.p.j.moss@meme.keele.ac.uk (G.P.M.)
Abstract: Discriminant analysis (DA) has previously been shown to allow the proposal of simple guidelines for the classification of 73 chemical enhancers of percutaneous absorption. Pugh et al. (2005) employed DA to classify such enhancers into simple categories, based on the physicochemical properties of the enhancer molecules. While this approach provided a reasonable accuracy of classification it was unable to provide a consistently reliable estimate of enhancement ratio (ER, defined as the amount of hydrocortisone transferred after 24h, relative to control). Gaussian Process (GP) methods have recently been employed in the prediction of percutaneous absorption of exogenous chemicals (Moss et al., 2009; Lam et al., 2010; Sun et al., 2011), and have shown that they provide more accurate predictions of this phenomena. In this study GP methods, including several machine learning processes including the K-nearest-neighbour (KNN) approach, were applied to the enhancer dataset used previously by Pugh et al. (2005). The SMOTE sampling method was used to oversample chemical compounds with ER > 10 in each training set in order to improve estimation and classification accuracy. Results show that GP methods based on a number of physicochemical parameters (log P, log S, MW, MB and CC), and and K-nearest-neighbours (KNN) based on three physicochemical descriptors (MW, CC and HB) not only provided accurate estimates of ER, but also provided better classification results than the DA approach. GP regression analysis correctly assigned 8 of the 12 “good” (ER > 10) enhancers and 56 of the 59 “poor” enhancers (ER < 10), whereas the KNN approach, for example, correctly assigned 10/12 (83.3%) good and 54 / 59 (91.5%) poor enhancers. Overall success rates were similar (DA 86.0%; GP 87.3%; KNN 87.3%). Use of the SMOTE oversampling method further improved the accuracy of prediction of the GP method, from 87.3% to 90.14%. GP methods give the best results in terms of statistical precision, as determined by the mean squared error, correlation coefficient and normalised log loss. Therefore, the GP and KNN methods show slight improvements, both statistically and in terms of precision of prediction, over DA, but resulted in fewer misclassifications and provides a simple method of predicting the activity of novel skin penetration enhancers.
Keywords: transdermal enhancers; discriminant analysis; Gaussian Process Regression; percutaneous absorption

Type of Paper: Article
Title: Effect of Poloxamers on Lidocaine Transport and Skin Retention During Iontophoresis
Authors: B. Vietti ^1,2, F. Marra ^1,3 and P. Santi ¹
Affiliations: ¹ Department of Pharmacy, University of Parma, viale G.P. Usberti, 43124 Parma, Italy; E-Mail: santipat@unipr.it (P.S.)
² current affiliation: GlaxoSmithKline, San Polo di Torrile, Italy
³ current affiliation: Bouty S.p.A., S.S. n° 11 Padana Superiore Km 160, 20060 Cassina de' Pecchi, Italy
Abstract: The aim of this work was to explore the use of poloxamer micelles as carriers for transdermal delivery. In particular, we investigated the combined effect of iontophoresis and poloxamer 188 or poloxamer 407 on lidocaine permeation and skin retention.
Polymeric micelles were prepared according to the Schmolka cold method, i.e. by dissolving 5% (w/v) of poloxamer in 25 mM HEPES solution. Lidocaine was incorporated at 1% and the pH was adjusted to 7.4. After physico-chemical characterization, these polymeric solutions were used for transdermal iontophoresis experiments. At the end of permeation experiments, the skin was extracted to evaluate the amount of lidocaine accumulated.
Only poloxamer 407 exhibited self-assembling behaviour, resulting in micelles with a size ranging from 19.3 nm to 26.0 nm, depending on buffer composition and temperature (25 °C or 32 °C). Iontophoresis enhanced lidocaine transport across the skin, but the simultaneous presence of poloxamer 407 micelles gave a lower flux if compared to the reference solution. Poloxamer 188 was effective as permeation enhancer only when competing ions (Na+) were not present in the donor solution. Accumulation of lidocaine in both epidermal and dermal layers of the skin was enhanced by iontophoresis. Even if poloxamer 407 micelles decreased lidocaine flux skin retention was slightly higher. The use of iontophoresis is favourable not only for increasing lidocaine skin permeation, but also for delivering the drug in the skin in higher amounts. Furthermore, polymeric micelles reduced lidocaine skin permeation, but not skin retention. In this way it would be possible to obtain a prolonged release, without decreasing the amount of lidocaine delivered to the site of action, and to reduce systemic toxicity. Poloxamer 188 acts as a chemical enhancer when used simultaneously with iontophoresis, promoting lidocaine permeation in the absence of competing ions.
Keywords: transdermal; lidocaine; Poloxamer; micelle

Type of Paper: Article
Title: Effect of Penetration Enhancer Containing Vesicles on the (Trans)Dermal Delivery of Quercetin through New Born Pig Skin
Authors: M. Chessa, D. Valenti, C. Caddeo, M. Manconi *, C. Sinico, and A.M. Fadda
Affiliations: Dipartimento Farmaco Chimico Tecnologico, University of Cagliari, Via Ospedale 72, Cagliari, Italy; E-Mail: manconi@unica.it (M.M.)
Abstract: Quercetin, 3,3′,4′,5,7-pentahydroxyflavone, is a bioflavonoid most present in nature in plant food sources. It exerts multiple pharmacological effects, including potent anti-oxidant activity in vivo, induction of apoptosis, modulation of cell cycle, anti-mutagenesis, inhibition of angiogenesis, and anti-inflammatory effect. Recently, it has been reported that the topical application of quercetin inhibits oxidative skin damage and the inflammatory processes induced by the solar UV radiation. The quercetin molecule was successfully encapsulated into liposomes [1] and solid lipid nanoparticles to improve its intranasal and oral bioavability [2].
In this work, quercetin (2 mg/mL) was loaded in new vesicular carriers, Penetration Enhancer containing Vesicles (PEVs) prepared using a commercial mixture of lipids (Phospholipon^® 50, P50, 60 mg/ml) and one of four selected hydrophilic a penetration enhancers (PEs): Transcutol^® (Trc), propylene glycol (PG), polyethylene glycol 400 (PEG400), and Labrasol^® (Lab). All the PEs were used at the same concentration (40% of water phase). A solution of quercetin in PG/water mixture at the same concentration were also prepared and tested as a control. Photon Correlation Spectroscopy results showed a mean diameter of vesicles around 50 nm, except for Lab-PEVs (approximately 180 nm). All formulations showed a negative surface charge and an encapsulation efficiency in the range 45-85%. Transmission Electron Microscopy confirmed that size and morphology varied as a function of the used PE.
The influence of PEVs on ex vivo quercetin (trans)dermal delivery was evaluated using Franz-type diffusion cells, new born pig skin, and phosphate saline buffer (pH 7.0) as receptor fluid. Results showed that drug delivery is affected by the penetration enhancer used in the PEVs' formulation.
References:

1. Priprem, A.; Watanatorn, J.; Sutthiparinyanont, S.; Phachonpai, W.; Muchimapura, S. Anxiety and cognitive effects of quercetin liposomes in rats. Nanomed.-Nanotechnol. Biol. Med. 2008, 4, 70-78.
2. Li, H.; Zhao, X.; Ma, Y.; Zhai, G.; Li, L.; Lou, H. Enhancement of gastrointestinal absorption of quercetin by solid lipid nanoparticles. J. Control. Release 2009, 133, 238-244.