Transdermal Diffusion Research Articles

Solubility and in vitro transdermal diffusion of riboflavin assisted by PAMAM dendrimers

PAMAM dendrimers of full generation (Gn) and half generation (Gn.5) were used as solubility enhancers of riboflavin (B2 vitamin) in methanol. They were found to weakly enhance solubility of B2 (7.2–10.3 times) according to the order: G2≫G2.5>G3≫G3.5>G4. The homogeneous mixtures of Gn (or Gn.5) with B2 of 1:1 molar ratio were obtained by removal of methanol to form oily host-guest complexes. The complexes were released from o/w emulsions and the transdermal permeation of B2 through polyvinyldifluoride (PVDF) and pig ear skin (PES) membranes was estimated. PAMAM dendrimers were demonstrated to promote permeation of B2 according to the order: G2>G3≫G2.5>G3.5>G4 (none). The permeation of fluorescein labeled dendrimers is faster than B2; the diffusion of G2 dendrimer through PES was the slowest of all studied Gn dendrimers, presumably due to absorption inside the skin. On the other hand the G2 was the best permeation enhancer for B2. The water soluble PAMAM dendrimers G2 and G3 can be successfully applied in cosmetic and dermatologic emulsions for this weakly water soluble vitamin.

Characterization of porcine skin as a model for human skin studies using infrared spectroscopic imaging

Porcine skin is often considered a substitute for human skin based on morphological and functional data, for example, for transdermal drug diffusion studies. A chemical, structural and temporal characterization of porcine skin in comparison to human skin is not available but will likely improve our understanding of this porcine skin model. Here, we employ Fourier transform infrared (FT-IR) spectroscopic imaging to holistically measure chemical species as well as spatial structure as a function of time to characterize porcine skin as a model for human skin. Porcine skin was found to resemble human skin spectroscopically and differences are elucidated. Cryo-prepared fresh porcine skin samples for spectroscopic imaging were found to be stable over time and small variations are observed. Hence, we extended characterization to the use of this model for dynamic processes. In particular, the capacity and stability of this model in transdermal diffusion is examined. The results indicate that porcine skin is likely to be an attractive tool for studying diffusion dynamics of materials in human skin.

Combined strategies for enhancing the transdermal absorption of midazolam through human skin

Midazolam administration by intravenous or intramuscular injection produces pain and stress. For this reason, alternative methods of administration have been proposed. The transdermal administration of midazolam could improve patient comfort, which is especially important for children in the pre-operative period. We aimed to assess the effect of iontophoresis and chemical percutaneous enhancers applied individually and together, to determine if a synergistic effect is achieved when both enhancement techniques are simultaneously employed. This work reports the characterization of the passive diffusion of midazolam hydrochloride through human skin in vitro and evaluates the effect of iontophoresis application and chemical percutaneous enhancers on said diffusion when employed both individually and in combination. Percutaneous absorption assays demonstrated that the physical technique of iontophoresis, when applied alone, moderately increased midazolam hydrochloride permeation flux through human skin, producing a similar effect to that obtained with R-(+)-limonene chemical enhancer. Among the strategies assayed, it was observed that Azone produced the most pronounced enhancement effect when applied separately. The combination of pre-treatment with Azone and iontophoresis exhibited a higher capacity for enhancing the transdermal flux of midazolam through human skin than Azone alone. In conclusion, when applied individually, Azone exhibited the greatest enhancement effect on the transdermal diffusion of midazolam of the various strategies assayed. The combination of Azone and iontophoresis produce the highest transdermal steady-state flux of midazolam but no synergic effect was achieved when the two enhancement strategies were applied in combination, showing that although selecting the best conditions for iontophoresis application, it is less effective for augmenting the transdermal delivery of midazolam than the chemical enhancer Azone.

PAMAM dendrimers as solubilizers and hosts for 8-methoxypsoralene enabling transdermal diffusion of the guest

PAMAM dendrimers form host–guest complexes with 8-methoxypsoralene (8-MOP) – the photosensitizer for PUVA therapy. The stoichiometry of complexes was studied by 1H NMR spectroscopy in solution and by differential scanning calorimetry in neat mixtures containing 8-MOP and dendrimers of generations G2.5, G3, G3.5, and G4. The dendrimers showed solubilization effect for 8-MOP resulting in increase of 8-MOP concentration in methanol up to 15 molecules of 8-MOP per G2.5 and G3 and 30 molecules of 8-MOP per G3.5, and G4. Isolation of oily host–guest complexes containing 3 or 7 molecules of 8-MOP per G3 and G4, respectively corroborate well with DSC results; glass transition temperature of neat host–guest complexes increases with number of host molecules in comparison with G3 or G4, until the capacity of host is exceeded. The oily host–guest complexes of stoichiometry 3:1 and 7:1 of 8-MOP to G3 and G4, respectively are well soluble in water. The 3:1 host–guest complexes diffused slowly through polyvinyldifluoride and pig ear skin membranes, when released from o/w emulsion. The host–guest complex 8-MOP- G3 was proposed as convenient formulation for psoralene skin administration in PUVA therapy.

A physical method to enhance transdermal delivery of a tissue optical clearing agent: Combination of microneedling and sonophoresis

Various physical methods, such as microneedling, laser ablation, sonophoresis, and sandpaper, have been widely studied to enhance the transdermal delivery of tissue optical clearing (TOC) agents. A previous study demonstrated that the microneedling method could effectively enhance the permeability of a TOC agent through the skin barrier. In this study, we introduce a new physical combination method which utilizes both microneedling and sonophoresis to further enhance the transdermal delivery of a TOC agent, glycerol. Porcine skin samples were divided into a control group treated only with the microneedle roller and a test group treated with both the microneedle roller and sonophoresis. Glycerol was applied topically after microneedling. The optimal concentration and transdermal delivery efficacy of glycerol were quantitatively evaluated. A 70% glycerol solution was determined to be the optimal concentration for the combination method. The combination method resulted in approximately a 2.3-fold higher transdermal diffusion rate of glycerol when compared to the microneedling method alone. The combination method and optimal glycerol concentration effectively enhanced transdermal delivery of glycerol by accelerating the diffusion rate through the skin barrier.

Quantification of porcine skin permeability in transdermal diffusion with a numerical model

Transdermal drug delivery system (TDDS) finds a variety of applications in drug delivery nowadays and is viewed as a potential method in controlled release of drug. Commonly known as a chemical enhancer in TDDS, urea alters the structure and composition of corneocyte and intracellular lipids, thus makes it easier for molecules to penetrate through stratum corneum, the major and outmost barrier layer of skin. In this research, however, urea itself is employed as a tracer diffusing through whole porcine skin in vitro. The diffusion process is recorded as the specific conductivity variation in time course. Concentration of urea is easily converted from its specific conductivity with aid of standard curves predetermined. Experimental results show the accumulation of tracer quantity diffusing through the skin sample as time proceeds. In parallel, a simple diffusion model is developed, attempting to describe this mass transport process in mathematical point of view. Output of the comparison between model data and experimental results generates the effective permeability of the whole skin, and quantifies the molecular mobility of the diffusing tracer. Permeability determined in this work is validated against literature data and discussed from molecular viewpoint theoretically. This study describes a combination of experiments and theory aiming at quantifying the transdermal permeation. Good agreement between model and experiment supports the efficacy of the approach and thus builds up a quantitative base for the upcoming researches seeking improvement of TDDS.

In-vivo dynamic characterization of microneedle skin penetration using optical coherence tomography

The use of microneedles as a method of circumventing the barrier properties of the stratum corneum is receiving much attention. Although skin disruption technologies and subsequent transdermal diffusion rates are being extensively studied, no accurate data on depth and closure kinetics of microneedle-induced skin pores are available, primarily due to the cumbersome techniques currently required for skin analysis. We report on the first use of optical coherence tomography technology to image microneedle penetration in real time and in vivo. We show that optical coherence tomography (OCT) can be used to painlessly measure stratum corneum and epidermis thickness, as well as microneedle penetration depth after microneedle insertion. Since OCT is a real-time, in-vivo, nondestructive technique, we also analyze skin healing characteristics and present quantitative data on micropore closure rate. Two locations (the volar forearm and dorsal aspect of the fingertip) have been assessed as suitable candidates for microneedle administration. The results illustrate the applicability of OCT analysis as a tool for microneedle-related skin characterization.

Multiscale Modeling Framework of Transdermal Drug Delivery

This study addresses the modeling of transdermal diffusion of drugs to better understand the permeation of molecules through the skin, especially the stratum corneum, which forms the main permeation barrier to percutaneous permeation. In order to ensure reproducibility and predictability of drug permeation through the skin and into the body, a quantitative understanding of the permeation barrier properties of the stratum corneum (SC) is crucial. We propose a multiscale framework of modeling the multicomponent transdermal diffusion of molecules. The problem is divided into subproblems of increasing length scale: microscopic, mesoscopic, and macroscopic. First, the microscopic diffusion coefficient in the lipid bilayers of the SC is found through molecular dynamics (MD) simulations. Then, a homogenization procedure is performed over a model unit cell of the heterogeneous SC, resulting in effective diffusion parameters. These effective parameters are the macroscopic diffusion coefficients for the homogeneous medium that is "equivalent" to the heterogeneous SC, and thus can be used in finite element simulations of the macroscopic diffusion process. The resulting drug flux through the skin shows very reasonable agreement to experimental data.

Electrospun cellulose acetate fiber mats containing asiaticoside or Centella asiatica crude extract and the release characteristics of asiaticoside

Ultra-fine cellulose acetate (CA; Mw≈30,000Da; degree of acetyl substitution≈2.4) fiber mats containing asiaticoside (AC) from the plant Centella asiatica L. either in the form of pure substance (PAC) or a crude extract (CACE) were fabricated by electrospinning. Incorporation of either PAC or CACE (40wt.% based on the weight of CA) in the neat CA solution (17% w/v in 2:1 v/v acetone/dimethylacetamide) did not affect the morphology of the obtained fibers, as both the neat and the herb-loaded CA fibers were smooth. The average diameters of these fibers ranged between 301 and 545nm. Determination of the release characteristics of AC from the herb-loaded CA fiber mats was carried out by the total immersion and the transdermal diffusion through a pigskin method in acetate or phosphate buffer solution that contained methanol (hereafter, A/B/M or P/B/M medium) at either 32 or 37°C, respectively. In the total immersion method, the maximum amounts of the AC released from the PAC- and the CACE-loaded CA fiber mats into the A/B/M medium were ∼24 and ∼10% (based on the weight of the specimens), while those of the AC released into the P/B/M medium were ∼26 and ∼12%, respectively. Considerably lower values were, however, obtained when the materials were placed on top of a piece of pigskin. Lastly, the herb-loaded CA fiber mats released no substance that was harmful to normal human dermal fibroblasts, rending their potential for use as topical/transdermal or wound dressing patches.

Navigating transdermal diffusion with multiphoton fluorescence lifetime imaging

We demonstrate the potential of fluorescence lifetime imaging by time-correlated single-photon counting as a method for monitoring the transdermal diffusion pathway and diffusion rate of pharmaceuticals in human skin. The current application relies on observing subtle changes in the fluorescence lifetime of the intrinsic fluorophores present in the intracellular region between corneocytes of the stratum corneum. We have comprehensively characterized the measured fluorescence lifetimes from intracorneocyte junctions in three skin section types (dermatomed skin, epidermal membranes and stratum corneum) revealing statistically significant differences of the short lifetime component between each of the types, which we attribute to the sample preparation and imaging method. We show using epidermal membrane sections that application of a drug/solvent formulation consisting of ethinyl estradiol and spectroscopic grade ethanol to the surface gives rise to a slight but statistically significant shortening of the fluorescence lifetime of the long-lived emitting species present in the sample, from approximately 2.8 ns to 2.5 ns. The method may be useful for future studies where the kinetics and pathways of a variety of applied formulations could be investigated.

Prodrugs and codrugs as strategies for improving percutaneous absorption

Although the advent of marketed transdermal drug-delivery products is nearing three decades, considerable strides in this noninvasive route of administration have been slow compared with its intravenous and oral counterparts, primarily due to the extreme barrier capabilities of the skin. The development of prodrug and codrug systems provides opportunity to enhance drug flux through the skin and thereby create highly desirable and efficacious treatment. The pharmacologically inactive prodrug is synthesized to increase or maximize its transdermal diffusion capabilities and then metabolized in vivo to the active compound. Similarly, codrugs are mutual prodrugs that are linked together in order to improve the drug-delivery properties of one or both drugs. This article reviews the current advances in prodrug and codrug transdermal therapy and their respective mechanisms for improvement in percutaneous absorption.

Using the method of homogenization to calculate the effective diffusivity of the stratum corneum with permeable corneocytes

The stratum corneum is the outermost layer of the skin, which acts as a barrier membrane against the penetration of molecules into and out of the body. It has a biphasic structure consisting of keratinized cells (corneocytes) that are embedded in a lipid matrix. The macroscopic transport properties of the stratum corneum are functions of its microstructure and the transport properties of the corneocytes and the lipid matrix, and are of considerable interest in the context of transdermal drug delivery and quantifying exposure to toxins, as well as for determining the relation of skin disorders to disruption of the stratum corneum barrier. Due to the complexity of the tissue and the difference in length scales involved in its microstructure, a direct analysis of the mass transport properties of the stratum corneum is not feasible. In this study, we undertake an approach where the macroscopic diffusion tensor of the stratum corneum is obtained through homogenization using the method of asymptotic expansions. The biphasic structure of the stratum corneum is fully accounted for by allowing the corneocytes to be permeable and considering the partitioning between the corneocytes and the lipid phases. By systematically exploring the effect of permeable corneocytes on the macroscopic transport properties of the stratum corneum, we show that solute properties such as lipophilicity and relative permeabilities in the two phases have large effects on its transdermal diffusion behavior.

Use of Transdermal Drug Formulations in the Elderly

Transdermal drug delivery systems are pharmaceutical forms designed to administer a drug through the skin to obtain a systemic effect. They ensure a constant rate of drug administration and a prolonged action. Several different types of transdermal delivery devices are available on the market. They are either matrix or reservoir systems and their main current uses are to treat neurological disorders, pain and coronary artery disease, and as hormone replacement therapy. Transdermal drug administration has a number of advantages compared with the oral route: it avoids gastrointestinal absorption and hepatic first-pass metabolism, minimizes adverse effects arising from peak plasma drug concentrations and improves patient compliance. Compared with the parenteral route, transdermal administration entails no risk of infection. For elderly people, who are often polymedicated, transdermal drug delivery can be a good alternative route of administration. Transdermal absorption depends on passive diffusion through the different layers of the skin. As skin undergoes many structural and functional changes with increasing age, it would be useful to know whether these alterations affect the transdermal diffusion of drugs. Studies have shown that age-related changes in hydration and lipidic structure result in an increased barrier function of the stratum corneum only for relatively hydrophilic compounds. In practice, no significant differences in absorption of drugs from transdermal delivery systems have been demonstrated between young and old individuals. The need for dose adaptation in elderly patients using transdermal drug delivery systems is therefore not related to differences in skin absorption but rather to age-related cardiovascular, cerebral, hepatic and/or renal compromise, and to ensuing geriatric pharmacokinetic and pharmacodynamic changes.

Book Review

The objective of the present study was to investigate the effect of various terpenes, including a diterpene, forskolin (FSK; a putative penetration enhancer), on skin permeation of valsartan. Permeation studies were carried out with Automated Transdermal Diffusion Cells Sampling System (SFDC 6, LOGAN Instruments Corp., NJ, USA) through rat skin and human cadaver skin (HCS) using ethanol: IPB (pH 7.4) (40:60) as vehicle. The efficacy of the study terpenes for permeation of valsartan across rat skin and human cadaver skin was found in the order of cineole > d-limonene > l-menthol > linalool > FSK and cineole > d-limonene > linalool > l-menthol > FSK, respectively. No apparent skin irritation (erythema, edema) was observed on treatment of skin with terpenes including FSK. FT-IR, DSC, and histopathological studies revealed that FSK enhanced the skin permeation of the active drug by disruption and extraction of lipid bilayers of SC in consonance with other terpenes.

Electrospun cellulose acetate fiber mats containing curcumin and release characteristic of the herbal substance

Ultra-fine cellulose acetate (CA; Mw≈30,000Da; degree of acetyl substitution≈2.4) fiber mats containing curcumin from the plant Curcuma longa L., widely known for its anti-tumor, antioxidant, and anti-inflammatory properties, were fabricated, for the first time, from the neat CA solution (17% w/v in 2:1 v/v acetone/dimethylacetamide) containing curcumin in various amounts (i.e., 5–20wt.% based on the weight of CA powder) by electrospinning. Incorporation of curcumin in the neat CA solution did not affect the morphology of the resulting fibers, as both the neat and the curcumin-loaded CA fibers were smooth. The average diameters of the curcumin-loaded CA fibers ranged between ∼314 and ∼340nm. The integrity of the as-loaded curcumin in the curcumin-loaded CA fiber mats was intact as indicated by the 1H nuclear magnetic resonance spectrometric results and the ability of the as-loaded curcumin in maintaining its free radical scavenging ability. Investigation of the release characteristic of curcumin from the curcumin-loaded CA fiber mats was carried out by the total immersion and the transdermal diffusion through a pig skin method in the acetate buffer solution containing Tween 80 and methanol or the B/T/M medium at 37°C. In the total immersion method, almost all of the curcumin loaded in the curcumin-loaded CA fiber mat specimens was released into the medium (∼90 to ∼95%), while considerably lower values were obtained when the curcumin-loaded CA fiber mats were placed on top of a piece of pig skin. Lastly, the curcumin-loaded CA fiber mats were proven non-toxic to normal human dermal fibroblasts.

Investigation of drug dissolution from cochleates applying transdermal diffusion cell

Investigation of drug dissolution from cochleates applying transdermal diffusion cell

Effect of cross-linking on properties and release characteristics of sodium salicylate-loadedelectrospun poly(vinyl alcohol) fibre mats

Cross-linking of electrospun (e-spun) fibre mats (beaded fibre morphologywith the average diameter of the fibre segments between beads being∼108 nm) of poly(vinyl alcohol) (PVA) containing sodium salicylate (SS), used as the model drug,was achieved by exposing the fibre mats to the vapour from 5.6 M aqueous solution of eitherglutaraldehyde or glyoxal for various exposure time intervals, followed by a heat treatmentin a vacuum oven. With increasing the exposure time in the cross-linking chamber, themorphology of the e-spun fibre mats gradually changed from a porous to dense structure.Both the degree of swelling and the percentage of weight loss of the cross-linked fibre mats(i.e. ∼200–530% and ∼15–57%, respectively) were lower than those of the untreated ones(i.e. ∼610% and ∼67%, respectively). Cross-linking was also responsible for the monotonic increase in the storagemoduli of the cross-linked SS-loaded e-spun PVA fibre mats with increasing exposure timein the cross-linking chamber. The release characteristic of the model drug fromthe SS-loaded e-spun PVA fibre mats both before and after cross-linking wasassessed by the transdermal diffusion through a pig skin method. The cumulativerelease of the drug from these matrices could be divided into two stages: 0–4 and4–72 h, in which the amount of SS released in the first stage increased very rapidly,while it was much slower in the second stage. Cross-linking slowed down therelease of SS from the drug-loaded fibre mats appreciably and both the rate ofrelease and the total amount of the drug released were decreasing functions ofthe exposure time interval in the cross-linking chamber. Lastly, the cross-linkedSS-loaded e-spun PVA fibre mats were non-toxic to normal human dermal fibroblasts.

Memory formalism in the passive diffusion across highly heterogeneous systems

In this note, we present an extension of the Fick’s second law by introducing a memory formalism based on derivatives of fractional order to take into account the passive diffusion process across two different membranous systems, i.e., a biological membrane, where its structural complexity suggests the introduction of a space-dependent diffusion constant, and a heterogeneous highly porous system at a macroscopic level, composed of an impenetrant matrix and pores across which the solute diffuse. This approach has been employed to describe some recent experimental results concerning the transdermal diffusion of drugs through human stratum corneum and the flux of water observed across a sand layer under a constant hydrostatic pressure difference. Despite the two examples we report concern with deeply different heterogeneous systems at a different scale length, a reasonable good agreement is obtained in both the two cases.

High-performance liquid chromatographic determination of sumatriptan after in vitro transdermal diffusion studies

A simple, accurate, precise and rapid HPLC method with UV detection has been validated in order to determine the in vitro transdermal absorption of sumatriptan succinate. The HPLC method is a modification of that described by Nozal et al. [M.J. Nozal, J.L. Bernal, L. Toribio, M.T. Martín, F.J. Diez, J. Pharm. Biomed. Anal. 30 (2002) 285–291]. Separation was carried out on a 250 mm Kromasil C18 column at room temperature. The detector response, at 282.7 nm, was found to be linear in a concentration range between 0.145 and 145 μM. The limit of detection (LOD) was 0.019 μM and the limit of quantification (LOQ) was 0.145 μM.

Sniffing a human sex-steroid derived compound affects mood and autonomic arousal in a dose-dependent manner

The effects of sniffing different concentrations of the human sex-steroid derived compound 4,16-androstadien-3-one (AND) on autonomic nervous system function and mood were measured in 60 subjects. The effects were sex-specific and concentration-dependent. Only high concentrations of AND (0.00625 M) increased positive mood ( p<0.03) and decreased negative mood ( p<0.05) in women compared to men, and had sympathetic-like effects in women ( p<0.003), and parasympathetic-like effects in men ( p<0.05). These findings further implicate AND in chemical communication between humans, but pose questions as to the path by which AND is transduced, whether through chemical sensing or transdermal diffusion.