Transdermal Drug Permeation Research Articles

Enantioselective penetration enhancing effect of carvone on the in vitro transdermal permeation of nicorandil

The objective was to investigate the difference in penetration enhancing effect of R-carvone, S-carvone and RS-carvone on the in vitro transdermal drug permeation. In vitro permeation studies were carried out across neonatal rat epidermis from 2%w/v HPMC (hydroxypropyl methylcellulose) gel containing 4%w/v of nicorandil (a model drug) and a selected concentration (12%w/v) of either R-carvone, S-carvone or RS-carvone against a control. The stratum corneum (SC) of rats was treated with vehicle (70%v/v ethanol-water) or ethanolic solutions of 12%w/v R-carvone, S-carvone or RS-carvone. The enhancement ratio (ER) of R-carvone, S-carvone and RS-carvone when compared to control was about 37.1, 31.2 and 29.9, respectively indicating enantioselective penetration enhancing effect of carvone enantiomers. Furthermore, there was a significant decrease in the lag time required to produce a steady-state flux of nicorandil with S-carvone when compared to R-carvone and RS-carvone. DSC and FT-IR studies indicate that the investigated enantiomers of carvone exhibit a difference in their ability to affect the cellular organization of SC lipids and proteins thereby showing enantioselective transdermal drug permeation. It was concluded that R-carvone exhibited a higher penetration enhancing activity on transdermal permeation of nicorandil when compared to its S-isomer or racemic mixture.

Performance of transdermal therapeutic systems: Effects of biological factors

Transdermal drug delivery (TDD) is a technique that is used to deliver a drug into the systemic circulation across the skin. This mechanism of drug delivery route has many advantages, including steady drug plasma concentrations, improved patient compliance, elimination of hepatic first pass, and degradation in the gastrointestinal tract. Over the last 30 years, many transdermal products have been launched in the market. Despite the inherent advantages of TDD and the growing list of transdermal products, one of the major drawbacks to TDD is the occurrence of inter- and intraindividual variation in the absorption of the drug across the skin. A majority of these variations are caused by biological factors, such as gender, age, ethnicity, and skin hydration and metabolism. These factors affect the integrity and the barrier qualities of the skin, which subsequently result in the variation in the amount of drug absorbed. The main objective of this review article is to provide a concise commentary on the biological factors that contribute to the variation in transdermal permeation of drugs across human skin and the available transdermal therapeutic systems that may reduce the variations caused by biological factors.

Efficacy study of vesicular gel containing methotrexate and menthol combination on parakeratotic rat skin model

Methotrexate (MTX) is indicated in the symptomatic control of severe, recalcitrant, and disabling psoriasis. The oral or parenteral route of administration causes systemic toxicity. The topical route of delivery, though, reduces systemic toxicity and has limited applicability due to restricted permeability. Liposomal and niosomal MTX topical formulations have also been investigated with limited success to achieve drug localization in the skin. Menthol has been suggested in conditions of psoriasis, in addition to its skin-penetration–enhancing effect on drugs. The present work aimed at investigating the potential benefits of combining menthol with MTX in a vesicular gel base for not only improving the penetration and dermal availability of MTX, but also to render such a formulation more effective with greater patient acceptability. MTX liposomes were prepared by thin-film hydration, and the vesicles were characterized for drug-entrapment efficiency, size, and morphology. These liposomal vesicles were incorporated in a gel base, and this vesicular gel was evaluated for transdermal drug permeation and extent of drug accumulation in the skin, using a rat skin ex vivo model. Skin histology studies were carried out to investigate any structural changes caused by the permeation enhancers. Antipsoriatic efficacy of the formulations was tested in vivo, using the rat tail model. The results indicated that the vesicular gel containing menthol could cause maximum drug retention in the skin. The skin treated with menthol had a disrupted epidermis and microcavities. The in vivo studies also ascertained the effectiveness of the formulation in inducing a normal pattern of differentiation in the rat tail skin that initially showed parakeratosis, which is also characteristic of psoriatic epidermis. These results show the potential of vesicular gel containing MTX and menthol to improve penetration into the skin and cause drug retention in skin appendages.

Biphasic flux profiles of melatonin: The Yin–Yang of transdermal permeation enhancement mediated by fatty alcohol enhancers

This study investigates physicochemical processes responsible for the biphasic transdermal flux profiles of melatonin in the presence of saturated fatty alcohols (SFAL) and unsaturated fatty alcohols (USFAL). The first phase melatonin flux (J1st) in the presence of USFAL enhancers increased with increase in the number of double bonds and reached a limiting value with two double bonds in the molecule. In case of SFAL enhancers, J1st increased with enhancer chain length and log formulation/skin partition coefficients (log Ps), which were calculated using the solubility parameters of various formulation components. But, melatonin flux in the second phase decreased with increase in the enhancer chain length and log P values. On the other hand, the transepidermal water loss (TEWL) from the SFAL treated skin increased drastically in the second phase and correlated with log P value of the enhancer. High TEWL value, indicative of a severely disrupted SC, may help the polar formulation components to accumulate in the SC. As a consequence, the SC polarity could change significantly and reduce the partitioning of lipophilic enhancer and/or melatonin in the second phase. This study demonstrated that an optimal level of barrier disruption enhances the transdermal permeation of drugs, whereas, a drastic barrier disruption impedes transdermal transport. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:209–218, 2010

A two-layer diffusive model for describing the variability of transdermal drug permeation

There is mounting evidence that the permeability coefficients ( k p ) that describe any given transdermal drug permeation process generally follow some form of positively skewed, non-symmetrical distribution rather than a simple normal distribution. Yet a suitable theoretical treatment of this area has not been undertaken to date. In this paper, we describe a two-layer model that can explain five drugs’ k p variabilities as measured in two previously published papers. The model shows why rapidly permeating drugs would tend to exhibit more symmetrical k p distributions while progressively more slowly permeating drugs would tend to exhibit progressively more positively skewed k p distributions. Future research should take this effect into account when comparing the flux variabilities of hydrophilic and lipophilic drugs.

Electret Enhances Transdermal Drug Permeation

Electrets are polymeric discs that carry semi permanent electrostatic charge. These provide electrostatic potentials in the range of 500 to 3,000 V. In the current work, the effect of electret exposure on the skin permeability was investigated. Transdermal transport studies were carried out across porcine epidermis in Franz diffusion cells. Salicylic acid, fluorescein labeled dextrans (FD) and propofol were used as test diffusants. The ability of electret to enhance the transdermal permeation of salicylic acid was studied in vivo in Sprague Dawley rats. Electret enhanced the permeability of porcine epidermis to salicylic acid. The enhancement factor increased with the surface voltage, however it was independent of the nature of charge (+ or -). The enhancement by electret was cut-off at 1 kDa, as interpreted by studying the transport of FD. The electrets decreased the permeability of skin to propofol, a lipophilic diffusant. Pretreatment of porcine epidermis enhanced the iontophoretic transport of salicylic acid, whereas the same did not enhance the transport of salicylic acid by electroporation. It is most likely that electret exposure renders the lipid domains of stratum corneum more permeable to polar molecules and in turn hampers the diffusion of nonpolar diffusant.

An Extended Model Based on the Modified Nernst–Planck Equation for Describing Transdermal Iontophoresis of Weak Electrolytes

An extended model for iontophoretic enhancement of transdermal drug permeation under constant voltage is described based on the previously modified Nernst-Planck equation, which included the effect of convective solvent flow. This model resulted in an analytical expression for the enhancement factor as a function of applied voltage, convective flow velocity due to electroosmosis, ratio of lipid to aqueous pathway passive permeability, and weighted average net ionic valence of the permeant in the aqueous epidermis domain. The shift of pH in the epidermis compared to bulk caused by the electrical double layer at the lipid-aqueous domain interface was evaluated using the Poisson-Boltzmann equation. This was solved numerically for representative surface charge densities and yielded pH differences between bulk and epidermal aqueous domain between 0.05 and 0.4 pH units. The developed model was used to analyze the experimental enhancement of an amphoteric weak electrolyte measured in vitro using human cadaver epidermis and a voltage of 250 mV at different pH values. Parameter values characterizing the involved factors were determined that yielded the experimental enhancement factors and passive permeability coefficients at all pH values. The model provided a very good agreement between experimental and calculated enhancement and passive permeability. The deduced parameters showed (i) that the pH shift in the aqueous permeation pathway had a notable effect on the ionic valence and the partitioning of the drug in this domain for a high surface charge density and depending on the pK(a) and pI of the drug in relation to the bulk pH; (ii) the magnitude and the direction of convective transport due to electroosmosis typically reflected the density and sign, respectively, of surface charge of the tissue and its effect on enhancement was substantial for bulk pH values differing from the pI of epidermal tissue; (iii) the aqueous pathway predominantly determined passive permeability of the studied compound despite its measurable lipophilicity and therefore the lipid pathway did not notably affect enhancement. Hence, the proposed model can provide a good quantitative insight into the interplay between different phenomena and permeant properties influencing iontophoresis and can potentially be used as a predictive tool of the process.

Synthesis and Enhancing Effect of Transkarbam 12 on the Transdermal Delivery of Theophylline, Clotrimazole, Flobufen, and Griseofulvin

Dodecyl-6-aminohexanoate (DDEAC) is a transdermal permeation enhancer with excellent activity, low toxicity, and no dermal irritation. We hypothesized that DDEAC reacts with air CO2 to form a two-chain ammonium carbamate--Transkarbam 12 (T12)--which is responsible for the enhancing effect. DDEAC and T12 were synthesized, their structures were confirmed by spectral methods, and their enhancing activity was studied using the Franz diffusion cell and human skin. A high-performance liquid chromatography method was developed for determination of T12, and its biodegradability was evaluated using porcine esterase. Only the carbamate salt T12 was responsible for the high enhancing activity; DDEAC tested under argon to avoid reaction with CO2 was inactive. T12 enhanced transdermal permeation of drugs covering a wide range of physicochemical properties, including theophylline (enhancement ratio up to 55.6), clotrimazole (7.7), flobufen (5.0), and griseofulvin (24). The activity was pH-dependent, further confirming the importance of the carbamate structure. The metabolization of T12 followed a second-order kinetics with t(1/2) = 31 min. Our results indicate that T12 is a promising biodegradable permeation enhancer for a wide range of drugs, and the structurally novel group of carbamate enhancers warrants further investigation.

Transdermal iontophoresis

Iontophoresis is a technique used to enhance the transdermal delivery of compounds through the skin via the application of a small electric current. By the process of electromigration and electro-osmosis, iontophoresis increases the permeation of charged and neutral compounds, and offers the option for programmed drug delivery. Interest in this field of research has led to the successful delivery of both low (lidocaine) and high molecular drugs, such as peptides (e.g., luteinising hormone releasing hormone, nafarelin and insulin). Combinations of iontophoresis with chemical enhancers, electroporation and sonophoresis have been tested in order to further increase transdermal drug permeation and decrease possible side effects. In addition, rapid progress in the fields of microelectronics, nanotechnology and miniaturisation of devices is leading the way to more sophisticated iontophoretic devices, allowing improved designs with better control of drug delivery. Recent successful designing of the fentanyl E-TRANS® iontophoretic system have provided encouraging results. This review will discuss basic concepts, principles and applications of this delivery technique.

Estimation of Transdermal Permeation Parameters in Non-stationary Diffusion Experiments. Application to Pre-treatment Studies with Terpenes

To estimate the applicability of transdermal drug permeation parameters in a finite-dose model for skin pre-treated with terpenes and to evaluate the enhancing effect of some terpene formulations on alprazolam permeation. In vitro enhancement of alprazolam human skin permeation was investigated using a pretreatment with different terpene solutions. Vertical diffusion, Franz-type cells were used. Intrinsic drug permeation was also investigated. Transdermal permeation parameters were estimated from the permeation tabulates using different theoretical approaches for their calculation. Two groups of permeation parameters were calculated: modelistic (diffusion of a finite-dose of drug model) and parameters nondependent of a diffusional model. In control experiments, all approaches of data treatment satisfactorily described the experimental permeation profiles. When skin pre-treatment was investigated, the fitting of a mathematical sigmoid function was much better than the diffusional approach. Pre-treatment of the skin with Limonene dissolved in ethanol / propylene glycol and Menthol dissolved in propylene glycol increased 15 and 10 times respectively the permeation parameters of alprazolam. Using enhancers that are rapidly cleared from the skin, skin permeability does not remain constant during the permeation experiment and therefore it is not possible to calculate parameters that are usually true coefficients or definite values. In this case, non-modelistic parameters can be used to estimate an enhancing effect.

Effect of l-menthol and 1,8-cineole on phase behavior and molecular organization of SC lipids and skin permeation of zidovudine

The aim of this investigation was to study the effect of 1,8-cineole and l-menthol on phase behavior and molecular organization of Stratum corneum (SC) lipids and permeation of zidovudine (AZT) across human cadaver skin (HCS). Permeation studies were conducted across HCS using Franz diffusion cells at 37 °C. Differential scanning calorimetry (DSC) and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) were employed to understand the effect of terpenes on phase behavior and molecular organization of a model SC lipid system consisting of an equimolar mixture of ceramide, palmitic acid and cholesterol. Both 1,8-cineole and l-menthol applied at 5% w/v in 66.6% ethanol as a vehicle significantly enhanced the pseudosteady state flux of AZT across HCS. The vehicle reduced the number of endothermic transitions observed in the DSC thermogram of a hydrated model SC lipid system from three to two with a lowered midtransition temperature ( T m), while the inclusion of terpenes resulted in a single but very broad endothermic transition for the model SC lipid system. Correspondingly, ATR-FTIR studies revealed that both 1,8-cineole and l-menthol increased CH 2 stretching frequencies on either side of lipid transition in addition to lowering the T m of model SC lipid system by ∼2–8 °C. The alterations observed in the amide-I frequencies of model SC lipid system after the inclusion of terpenes suggest that they disrupt the interlamellar hydrogen-bonding network at the polar head group region. Further, terpenes also increased the hydration levels of the lipid system probably by forming new aqueous channels. These results indicate that terpenes enhance transdermal permeation of AZT and other drugs by transforming SC lipids from a highly ordered orthorhombic perpendicular subcellular packing to a less ordered hexagonal subcell packing.

Mechanism of Enhancement Effect of Dendrimer on Transdermal Drug Permeation through Polyhydroxyalkanoate Matrix

Mechanism of Enhancement Effect of Dendrimer on Transdermal Drug Permeation through Polyhydroxyalkanoate Matrix

Drug Adsorption in Human Skin: A Streaming Potential Study

The objective of this study was to investigate the drug adsorption process in human skin using in vitro streaming potential measurements. Streaming potential is an electrokinetic phenomenon, which reflects both the charge density and the pore size of a membrane. Thus, the adsorption of charged solutes on the pore walls can be detected as a change of streaming potential, viz., as a change in the slope ΔE/ΔP. In these streaming potential measurements, hydrophilic nadolol and luteinizing hormone‐releasing hormone, and lipophilic propranolol and Nafarelin were used as model drugs. As could be expected, the hydrophilic drugs did not change the slope. The more lipophilic propranolol and Nafarelin, instead, changed the slope. Propranolol changed the slope gradually from negative to positive when the concentration was increased from 1 to 10 mM. With Nafarelin, a straight line with a slope of about 0 was obtained at pH 7.3 and an ascending curve at pH 4.2. These results indicate that the negative charges on the pore walls of human skin are blocked by adsorption of the lipophilic cations. The adsorption of lipophilic cations in the skin alters the permselectivity of the skin, which, in turn, may lead to the inhibition of electroosmotic flow across the skin during iontophoresis and to the shut down of transdermal drug permeation of higher molecular weight drugs. © 2003 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:2366–2372, 2003

In-vitro release and transdermal fluxes of a highly lipophilic drug and of enhancers from matrix TDS

Transdermal systems (TDS) are a well-known application form for small, moderately lipophilic molecules. The aim of this study was to investigate the possibility of applying a highly lipophilic drug, the antiestrogen AE (log P=5.82) transdermally by polyacrylate-based matrix TDS. For this purpose, two effects of both drug and enhancer concentration in TDS were investigated: in-vitro release and transdermal permeation of drug and enhancers. In the TDS investigated, in-vitro release as well as in-vitro permeation of AE through excised skin of hairless mice was found to be independent of concentrations of both drug and enhancers. The steady-state fluxes observed were low (about 50–100 ng cm −2 h −1). But skin pretreatment with permeation enhancers resulted in a markedly enhanced permeability (1400 ng cm −2 h −1). Therefore, the permeation of this highly lipophilic drug seems to be limited by the stratum corneum barrier function. In contrast, the transdermal permeation of the enhancers was dependent on the TDS composition. Increase in enhancer content resulted in a higher permeation of enhancers, whereas skin pretreatment did not. In conclusion, it was shown that the highly lipophilic antiestrogen can be administered transdermally by pretreating the skin with the fluid permeation enhancer combination propylene glycol–lauric acid (9+1) and then applying a matrix TDS.

Transdermal delivery of highly lipophilic drugs: in vitro fluxes of antiestrogens, permeation enhancers, and solvents from liquid formulations.

Highly lipophilic basic drugs, the antiestrogens AE 1 (log P = 5.82) and AE 2 (log P = 7.8) shall be delivered transdermally. Transdermal permeation of drugs, enhancers, and solvents from various fluid formulations were characterized by in-vitro permeation studies through excised skin of hairless mice. Furthermore, differential scanning calorimetry (DSC) measurements of skin lipid phase transition temperatures were conducted. Transdermal flux of highly lipophilic drugs was extraordinarily enhanced by the unique permeation enhancer combination propylene glycol-lauric acid (9 + 1): steady-state fluxes of AE 1 and AE 2 were as high as 5.8 microg x cm(-2) x h(-1) and 3.2 microg x cm(-2) x h(-1), respectively. This dual enhancer formulation also resulted in a marked increase in the transdermal fluxes of the enhancers. Furthermore, skin lipid phase transition temperatures were significantly reduced by treatment with this formulation. Transdermal delivery of highly lipophilic drugs can be realized by using the permeation enhancer combination propylene glycol-lauric acid. The extraordinary permeation enhancement for highly lipophilic drugs by this formulation is due to mutual permeation enhancement of these two enhancers and their synergistic lipid-fluidising activity in the stratum corneum.

In vitro transdermal iontophoretic transport of timolol maleate: effect of age and species

Transdermal iontophoresis would be a promising method for the systemic delivery of water soluble and ionic drugs of relatively high molecular size, including peptides. In the present study, the effect of biological parameters such as age of the animal and species variation (rat, rabbit, mouse, guinea pig and human) on the transdermal iontophoretic transport was studied using timolol maleate (TM) as a model drug. The iontophoretic transport of TM across the skins obtained from the rats of different age groups was found to be similar. The results of the present study suggest that the age of the animal (Wistar rats: 1–8 months) did not appear to influence the transdermal iontophoretic transport of TM significantly. The amount of TM transported during iontophoresis (2 h) was significantly different among the different skin species. But the total amount of TM transported up to 24 h (2 h iontophoresis+22 h post-iontophoretic passive diffusion) was not significantly different among the different species studied. The present study provides further evidence that iontophoresis technique reduces the interspecies differences in the transdermal permeation of drugs, which is normally observed in passive diffusion of drugs. However, it must be noted that excised skins have been used in the present study to investigate the role of age and species variation on the iontophoretic transport of TM. The influence of these parameters under in vivo conditions might be different considering the physiological differences in different species and in the animals of different age groups.

A lamellar matrix model for stratum corneum intercellular lipids IV. Effects of terpene penetration enhancers on the permeation of 5-fluorouracil and oestradiol through the matrix

It is widely accepted that the intercellular lipid domain of the stratum corneum (SC) is the main barrier to transdermal permeation of most drugs. Previously, we reported a lamellar lipid matrix capable of modelling the structural properties of the SC intercellular lipids and its barrier performance toward oestradiol (OE) and 5-fluorouracil (5-FU). To investigate the ability of the matrix in modelling the effects of terpene penetration enhancers on the barrier performance of the SC, permeation of model drugs (OE and 5-FU) through cineole or limonene treated matrices were investigated here. Results revealed that the matrix is able to model the effects of cineole and limonene on the permeability coefficients of OE through the SC. The effects of cineole on the permeability coefficient of 5-FU through the SC seem to be underestimated by the model matrix; the difference was attributed to the effects of cineole on the SC intracellular proteins or to differences in the hydrophilicities of the SC lipids and the matrix. The matrix failed to model the enhancement effect of limonene toward permeation of 5-FU through the SC which might indicate that limonene increases the permeation of 5-FU in part through interactions with SC proteins which are not modelled in the matrix.

Transdermal permeation-enhancing activities of some inorganic anions

Effects of sodium salts of various monovalent inorganic anions on transdermal permeation of salicylic acid were investigated. In in-vitro experiment using a Franz-type diffusion cell and excised mouse skin, the permeation-enhancing activities of the sodium salts of inorganic anions were roughly proportional to lyotropic Hofmeister swelling abilities of the anions; F−<SO42−<Cl− <ClO4−<NO3 <SCN− <Br <I−, i.e. l, Br and SCN increased the flux of drugs through the mouse skin, while F−, SO42−, Cl−, ClO4− and NO3− decreased or did not affect the flux. In invivo experiment using the rabbit as the test animal, the plasma concentration of salicylic acid of the rabbit to which 10%-salicylic acid ointment containing 5%-Nal or NaBr was applied was significantly higher than that of the rabbit to which the ointment without the electrolytes was applied. The amounts of sterol leached out of stratum corneum sheet when the sheet was immersed in aqueous solutions of Nal, NaBr, or NaSCN were much more than that of stratum corneum immersed in aqueous solutions of the other inorganic anions. The FTIR/ATR spectroscopy showed that the peaks at 2853 cm−1 and 2924 cm−1 in the IR absorption spectrum of the stratum corneum sheet of the mouse were shifted to higher frequencies by the anions which enhanced the transdermal drug permeation, while not shifted by the anions which did not have any permeation-enhancing activities or have permeation-reducing activities. These results suggest that sodium salts of some anions such as iodide, bromide and thiocyanate enhance transdermal permeation of salicylic acid through swelling and perturbation of the skin structure by these anions.

Enhancement of Percutaneous Absorption of Propranolol Hydrochloride by Iontophoresis

AbstractIontophoresis is defined as the migration of ions when an electric current passes through a solution containing ionized species. When applied transdermally, iontophoresis may reduce the barrier porperties of skin and may enhance the transdermal permeation of drugs. This research work was aimed at exploring the factors which influence the effectiveness of iontophoresis facilitated transport of ionized species across the skin, and comparing it with that by passive diffusion. Propranolol hydrochloride was selected as the model drug, and rat abdominal skin as the in-vitro animal model. Pulse dc was applied, at 2.16/3/6/9 mA/cm2; 1:1 or 4:1 duty cycle and 20 KHz frequency for 15/25 minutes. Factors which modify the iontophoretic drug delivery, such as drug concentration, current density, duty-cycle of pulse dc, and duration of iontophoresis, were also evaluated. It was found that iontophoresis causes a significant increase in transdermal permeation of Propranolol hydrochloride in-vitro through rat abdo...

On the non-Gaussian distribution of human skin permeabilities

Human skin demonstrates considerable inter- and intra-donor variability to transdermal drug permeation. In the past, for a given permeant, replicate measurements of diffusional parameters have been (at least tacitly) assumed to provide a normal distribution with a wide degree of dispersion. We have monitored the permeability of human abdominal skin in vitro to model hydrophilic (5-fluorouracil, 5-FU) and lipophilic (oestradiol, ES) drugs. Drug permeation from a saturated aqueous solution was assessed using stainless-steel diffusion cells with an aqueous flow-through receptor solution. Diffusion was characterised by evaluation of drug permeability coefficients at steady-state flux. The variability of drug permeability coefficients for 644 determinations of 5-FU from 71 skin specimens and 221 replicates of ES from 28 specimens did not follow a normal distribution. Our data show that permeability coefficients tor both drugs followed more closely log-normal distributions. Additionally, our results indicate that the specimen population of cadavers may be comprised of two subgroups; those with higher than expected permeability, and the majority providing ‘ordinary’ permeability. No relationship was evident between specimen age, sex or storage time and drug permeability coefficient. When data are found to be log-normally distributed the appropriate measure of central tendency is the geometric mean, since the arithmetic mean tends to he artificially increased because of the nature and degree of a skewed distribution.