Comparative Analysis of Percutaneous Absorption Enhancement by d-Limonene and Oleic Acid Based on a Skin Diffusion Model

Percutaneous absorption-enhancing effects of d-limonene and oleic acid were investigated using three model drugs with different lipophilicities in in vitro diffusion experiments with guinea pig skin. Pretreatment of the skin with d-limonene resulted in a large penetration enhancement for the lipophilic butylparaben (BP) and amphiphilic 6-mercaptopurine (6-MP) but had little effect on the hydrophilic mannitol (MT). Oleic acid caused a large effect only on 6-MP penetration. The penetration profiles were analyzed with a two-layer skin diffusion model consisting of stratum corneum with polar and nonpolar routes and viable epidermis plus dermis. Through curve-fitting, six parameters corresponding to drug diffusivity and partitioning in these three regions of the skin were obtained, and the mechanisms of enhancers were assessed in comparison with those of l-geranylazacycloheptan-2-one (GACH) reported previously. Increased penetration was caused mainly by modification of the barrier property of the nonpolar route in the stratum corneum in all cases. In the nonpolar route, d-limonene increased mainly drug diffusivity, while GACH enhanced predominately drug partitioning. On the other hand, oleic acid moderately increased both parameters.     

In Vivo Evaluation of Acyclovir Prodrug Penetration and Metabolism Through Rat Skin Using a Diffusion/Bioconversion Model

Purpose. In order to evaluate the in vivo penetration of prodrugs which undergo metabolism in skin, we analyzed thein vivo penetration profiles of acyclovir prodrugs based on a two-layer skin diffusion model in consideration of metabolic process. Methods. Acyclovir prodrugs (e.g., valerate, isovalerate and pivarate) were used as model prodrugs and the amounts excreted in urine were measured after percutaneous application. In vivo penetration profiles were then estimated by employing a deconvolution method and the penetration of acyclovir prodrugs was analyzed using a diffusion model. Subsequently, diffusion, partitioning and metabolic parameters were compared under in vitro and in vivo conditions. Results. Although total penetration amounts at the end of the experiment were similar for the three prodrugs, the ratio of intact prodrug to total penetration amount differed significantly. Moreover, the excretion and absorption profiles were also very different for each prodrug. Enzymatic hydrolysis rate constants calculated under in vivo conditions were considerably larger than those obtained in the skin homogenate and in vitro penetration experiments. Conclusions. The present skin diffusion/bioconversion model combined with computer analysis enables us to comprehensively account for diffusion, partitioning and metabolism during in vivo percutaneous absorption. Nevertheless, different enzymatic hydrolysis rate constants obtained under bothin vivo and in vitro conditions demonstrate the difficulty of obtaining accurate values for in vivo enzymatic activity from related in vitro experiments.     

Reverse Hexagonal Phase Nanodispersion of Monoolein and Oleic Acid for Topical Delivery of Peptides: in Vitro and in Vivo Skin Penetration of Cyclosporin A

Purpose To obtain and characterize reverse hexagonal phase nanodispersions of monoolein and oleic acid, and to evaluate the ability of such system to improve the skin penetration of a model peptide (cyclosporin A, CysA) without causing skin irritation. Methods The nanodispersion was prepared by mixing monoolein, oleic acid, poloxamer, and water. CysA was added to the lipid mixture to obtain a final concentration of 0.6% (w/w). The nanodispersion was characterized; the skin penetration of CysA was assessed in vitro (using porcine ear skin mounted in a Franz diffusion cell) and in vivo (using hairless mice). Results The obtainment of the hexagonal phase nanodispersion was demonstrated by polarized light microscopy, cryo-TEM and small angle X-ray diffraction. Particle diameter was 181.77 ± 1.08 nm. At 0.6%, CysA did not change the liquid crystalline structure of the particles. The nanodispersion promoted the skin penetration of CysA both in vitro and in vivo. In vitro, the maximal concentrations (after 12 h) of CysA obtained in the stratum corneum (SC) and in the epidermis without stratum corneum (E) + dermis (D) were ∼2 fold higher when CysA was incorporated in the nanodispersion than when it was incorporated in the control formulation (olive oil). In vivo, 1.5- and 2.8-times higher concentrations were achieved in the SC and [E+D], respectively, when the nanodispersion was employed. No histopathological alterations were observed in the skin of animals treated with the nanodispersion. Conclusion These results demonstrate that the hexagonal phase nanodispersion is effective in improving the topical delivery of peptides without causing skin irritation.     

Analysis of in vivo skin penetration enhancement by oleic acid based on a two-layer diffusion model with polar and nonpolar routes in the stratum corneum

The enhancement effect of oleic acid on the in vivo percutaneous absorption of mannitol, 6-mercaptopurine, and butylparaben was evaluated in rats. A deconvolution method was applied to estimate skin permeation from urinary excretion profiles of drugs. Oleic acid markedly increased skin permeation of mannitol and 6-mercaptopurine, while it slightly increased the permeation of butylparaben at the low dose but decreased it at the high dose. To elucidate the mechanism of enhancement of skin permeation by oleic acid, the estimated in vivo penetration profiles were analyzed based on a two-layer skin diffusion model with polar and nonpolar routes in the stratum corneum. With respect to the polar route, oleic acid did not change the diffusion parameter but increased the partition parameter, suggesting that it increased hydration of the stratum corneum and enlarged the aqueous pore pathway. On the other hand, oleic acid increased both the diffusion and partition parameters of 6-mercaptopurine in the nonpolar route. The mechanism of action of oleic acid was compared to those determined in a previous in vitro study using guinea pig skin. It was revealed that the basic mechanism of oleic acid for enhancing drug permeation was comparable between the present and previous studies, and that the difference in the apparent enhancement effect of oleic acid was due to the in vitro-in vivo difference in the degree of hydration of the stratum corneum and the diffusion length of the dermis layer.     

Drug Distribution in Human Skin Using Two Different In Vitro Test Systems: Comparison with In Vivo Data

Purpose. Two in vitro test systems used to study drug penetration into human skin—the Franz diffusion cell (FD-C) and the Saarbruecken penetration model (SB-M)—were evaluated, and the results were compared with data gained under analogous in vivo conditions. Methods. Excised human skin was used in all in vitro experiments. Flufenamic acid dissolved in wool alcohols ointment, was chosen as a model drug, and the preparation was applied using infinite dose conditions. To acquire quantitative information about the drug penetration, the skin was segmented into surface parallel sections at the end of each experiment, first by tape stripping the stratum corneum (SC), and second by cutting the deeper skin layers with a cryomicrotome. The flufenamic acid was extracted from each sample and assayed by high performance liquid chromatography (HPLC). For in vivo experiments, only the tape stripping technique was used. Results. a) Drug penetration into the SC: In both in vitro test systems the total drug amounts detected in the SC were found to increase over the different incubation times. Similar conditions were obtained in vivo, but on a lower level. Using Michaelis-Menten kinetics, the m_max value was calculated for the skin of two donors. The relations of the m_max values for the FD-C and the SB-M closely correspond (1.26 [donor 1] and 1.29 [donor 2]). A direct linear correlation of the drug amount in the SC and the time data were found for in vivo with both in vitro test systems.%b) Drug penetration into the deeper skin layers: The detected drug amounts in the deeper skin layers continuously increased with the incubation time in the SB-M, while in the FD-C, only very small drug amounts were observed after incubation times of 30 and 60 minutes. It was also noticed, that the drug amounts rose steeply at time points 3 and 6 hours. Additional studies showed a remarkable penetration of water into the skin from the basolateral acceptor compartment in the FD-C. This could explain the different drug transport into the deeper skin layers between the two in vitro test systems. Conclusions. Both in vitro models showed comparable results for the drug penetration into the SC and a robust correlation with in vitro data. Different results were obtained for the deeper skin layers. Whether a correlation between in vitro and in vivo data is also possible here has to be investigated by further experiments.     

Transfersomes for transdermal drug delivery

Transfersomes^® (Idea AG) are a form of elastic or deformable vesicle, which were first introduced in the early 1990s. Elasticity is generated by incorporation of an edge activator in the lipid bilayer structure. The original composition of these vesicles was soya phosphatidyl choline incorporating sodium cholate and a small concentration of ethanol. Transfersomes are applied in a non-occluded method to the skin and have been shown to permeate through the stratum corneum lipid lamellar regions as a result of the hydration or osmotic force in the skin. They have been used as drug carriers for a range of small molecules, peptides, proteins and vaccines, both in vitro and in vivo. It has been claimed by Idea AG that intact Transfersomes penetrate through the stratum corneum and the underlying viable skin into the blood circulation. However, this has not been substantiated by other research groups who have extensively probed the mechanism of penetration and interaction of elastic vesicles in the skin. Structural changes in the stratum corneum have been identified, and intact elastic vesicles visualised within the stratum corneum lipid lamellar regions, but no intact vesicles have been ascertained in the viable tissues. Using the principle of incorporating an edge-activator agent into a bilayer structure, a number of other elastic vesicle compositions have been evaluated. This review describes the research into the development and evaluation of Transfersomes and elastic vesicles as topical and transdermal delivery systems.     

Hair follicles contribute significantly to penetration through human skin only at times soon after application as a solvent deposited solid in man

AIMS

The aim of this study was to define the underlying relative penetration of caffeine through hair follicles and through intact stratum corneum with time in vivo through pharmacokinetic modelling.

METHODS

Caffeine plasma concentration–time profiles after topical application into skin with or without hair follicle blocking were modelled using the Wagner–Nelson method or a compartmental model with first order absorption and elimination. Pharmacokinetic parameters describing absorption rate and extent of absorption through hair follicles or the stratum corneum were determined separately and compared with each other.

RESULTS

The obtained pharmacokinetic parameters from the two methods were similar. The absorption rate constant of caffeine for hair follicles was nearly 10 times higher than that for the stratum corneum and the percentage of absorption from hair follicles was more than half of that of the stratum corneum. In addition, the absorption from the stratum corneum showed an approximately 10 min delay while there was no delay for absorption from hair follicles. All caffeine absorbed by hair follicles occurs within 30 min of application and accounts for 10.5 to 33.8% of the total amount absorbed across the skin for all subjects, whereas absorption of caffeine through the stratum corneum can occur over several hours.

CONCLUSION

Hair follicles contribute significantly to percutaneous absorption of caffeine after topical application in man in vivo only at times soon after application.     

Quantification of human skin barrier function and susceptibility to quantum dot skin penetration

Abstract

In this study, we utilize in vivo human skin and a viable ex-vivo human skin model to investigate the effect of a commercial depilatory agent on barrier function. Tape stripping was used as a positive control. The magnitude of skin barrier was quantified by measuring transepidermal water loss values on in vivo human skin and transepithelial electrical resistance measurements and tissue histology on ex vivo skin. The susceptibility to carboxylated quantum dot penetration through ex vivo skin was investigated using fluorescent microcopy analysis of microtomed skin sections and flow cytometry to quantify quantum dot association with live epidermal cells. Results show that depilatory treatment modifies the outside-in barrier sufficiently to allow quantum dots to penetrate the stratum corneum but to a lesser extent than tape stripping. The implications of these finding are discussed.     

Effects of Sucrose Oleate and Sucrose Laureate on in Vivo Human Stratum Corneum Permeability

Purpose. The purpose of this work was to 1) investigate the effect of sucrose esters (sucrose oleate and sucrose laureate in water or in Transcutol®, TC) on the stratum corneum (SC) barrier properties in vivo and 2) examine the impact of these surfactant-like molecules on the in vivo percutaneous penetration of a model penetrant 4-hydroxybenzonitrile (4-HB). Methods. Attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy and transepidermal water loss measurements were used to evaluate the sucrose oleate- and sucrose laureate-induced biophysical changes in SC barrier function in vivo. In addition, the effect of the enhancers on 4-HB penetration was monitored in vivo using ATR-FTIR spectroscopy in conjunction with tape-stripping of the treated site. Results. Treatment of the skin with 2% sucrose laureate or sucrose oleate in TC significantly increased the extent of 4-HB penetration relative to the control. Furthermore, when skin treated with these formulations was examined spectroscopically, the C-H asymmetric and symmetric stretching bands of the lipid methylene groups were characterized by 1) decreased absorbances and 2) frequency shifts to higher wavenumbers. These effects on the SC lipids and 4-HB penetration were more pronounced for sucrose laureate when combined with TC. Conclusions. A combination of sucrose esters (oleate or laureate) and TC is able to temporally alter the stratum corneum barrier properties, thereby promoting 4-HB penetration. These molecules are worthy of further investigation as potential candidates for inclusion in transdermal formulations as penetration enhancers.     

In Vitro Skin Permeation and Bioassay of Chlorhexidine Phosphanilate,a New Antimicrobial Agent

An in vitro technique was developed to study the permeation and antimicrobial activity of graded concentrations of a new antibacterial agent, chlorhexidine phosphanilate (CHP), in cream formulations using Franz diffusion cells. Formulations containing from 0.2 to 2% CHP were quantitatively applied to intact excised skin and to skin from which the stratum corneum and partial epidermis had been enzymatically removed. Receptor fluids from diffusion cells were sampled over time and assayed by HPLC methods for chlorhexidine and phosphanilic acid; 24- and 48-hr samples of the diffusate from studies with damaged skin were also bioassayed using clinical isolates of appropriate microbial species. Through intact skin almost no permeation of CHP was observed over 48 hr. The failure of CHP to penetrate intact human skin suggests that normal stratum corneum is the rate-limiting barrier to penetration by this antimicrobial agent. In damaged skin lacking stratum corneum barrier, the release of CHP from the formulation becomes the rate-determining step. Coincident with penetrating damaged skin, CHP dissociates, and the molar ratio of the chlorhexidine and phosphanilate moieties in the diffusate changes to favor phosphanilic acid. The extent of changes in the permeation rates of both moieties of CHP was directly related to the CHP concentration in cream. Both CHP moieties were found to reach equilibrium in the dermis within 24 hr after application. It was also observed that CHP creams down to 0.2% concentration yielded diffusates with activity exceeding the minimum inhibitory concentration of all test microorganisms within 24 hr.     

Percutaneous and Systemic Disposition of Hexamethylene Lauramide and Its Penetration Enhancement Effect on Hydrocortisone in a Rat Sandwich Skin-Flap Model

The percutaneous absorption and distribution profile of hexamethylene lauramide (hexahydro-1-lauroyl-lH-azepine) were examined using a rat skin-flap model. After a topical dose to the skin flap, the drug concentrations in the vasculature at the site of drug application and in the systemic blood were monitored simultaneously. Hexamethylene lauramide penetrated the skin and reached a steady state in stratum corneum, viable epidermis, dermis, and cutaneous blood in 3 hr. Its concentration in the skin was much higher than that in the blood. Its apparent concentration in the epidermis was 19 times that in the dermis and about 3000 times that in the cutaneous blood. The percutaneous absorption of ¹⁴C-hexamethylene lauramide resulted in ascending systemic blood concentrations throughout the experimental period, whereas the cutaneous blood levels remained steady. The topically absorbed hexamethylene lauramide was quantitatively recovered in urine (85%) and feces (13%). The half-lives of urinary and fecal excretion of ¹⁴C-hexamethylene lauramide were 17 and 30 hr, respectively. Hexamethylene lauramide, when topically coadministered in an experimental formulation, enhanced the skin penetration of hydrocortisone with increased drug contents in the stratum corneum (2-fold) and with increased hydrocortisone concentrations in the cutaneous blood (3.4-fold) and the systemic blood (3.5-fold). The results indicated that the high concentration and retention of hexamethylene lauramide in stratum corneum and viable epidermis may contribute to its penetration enhancement effect in the skin. A steady state in percutaneous tissues was observed before the drug reached distribution equilibrium systemically. The systemic blood concentration of a topically applied agent therefore may not reflect its percutaneous kinetic processes before a systemic distribution equilibrium is reached. Temporal profiles of a topical penetration enhancer in the skin and in the body are important information for the development of dematologic preparations for the treatment of skin disorders.     

lontophoretic Delivery of Apomorphine I: In Vitro Optimization and Validation

Purpose. To investigate the feasibility of transdermal iontophoretic delivery of apomorphine in patients with Parkinson's disease, transdermal transport rates were optimized and validated across human stratum corneum and freshly dermatomed human skin in vitro. Methods. In all experiments R-apomorphine hydrochloride was applied in the anodal compartment. The effect on the flux of the following parameters was studied, using a flow through transport cell: current density, pH, concentration, ionic strength, osmolarity, buffer strength, temperature and skin type. Results. Transdermal transport of apomorphine was directly controlled by the presence or absence of current. Passive delivery was minimal and no depot effect was observed. A linear relationship was found between current density and steady-state flux. At room temperature the lag time was 30 to 40 minutes. A maximal steady-state flux was obtained when the donor concentration approached maximum solubility. By increasing the temperature of the acceptor chamber to 37°C, the steady-state flux was increased by a factor of 2.3 and the lag time decreased to ± 3 minutes. No effect of osmolarity and buffer strength, and only a small effect of ionic strength and pH on the transport rate were observed. The flux through dermatomed human skin was decreased compared to stratum corneum. This effect was shown not to be caused by skin metabolism. Conclusions. The results obtained in vitroindicate that the iontophoretic delivery of apomorphine can be controlled and manipulated accurately by the applied current. The in vitro flux furthermore depends on the donor composition, temperature and skin type. Under optimized conditions, transport rates resulting in therapeutically effective plasma concentrations are feasible, assuming a one to one in vitro/in vivo correlation.     

Stratum corneum reservoir as a predictive method for in vitro percutaneous absorption

Interaction between drug and proteins and lipids in stratum corneum (SC) is an important pharmacokinetic parameter in early steps of absorption. Previous in vivo studies showed that the total amount of compound, regardless of properties, penetrating over a 96 h period could be predicted by the amount present in SC 30 min after application by a linear relationship. Validating this linear relationship through in vitro study would facilitate testing of transdermal drug delivery platforms. We aimed to determine in vitro penetration behavior across SC of humans by determining the relationship between quantity present in SC reservoir 30 min after application with 24 h skin absorption and penetration. In this study, use of the SC reservoir effect to predict absorption and penetration of topical compounds is reaffirmed with in vitro models involving human skin. These results indicate the amount in short‐term (30 min) SC reservoir predict long‐term (24 h) skin absorption and penetration, as characterized by statistically significant linear relationships determined via regression. This may be explained by the fact that SC is a rate‐limiting barrier to percutaneous drug transport. After molecules diffuse through SC barrier, passage into deeper dermal layers and systemic uptake occur relatively quickly. These results enable one to measure quantity in SC reservoir shortly after topical application as a proxy for absorption and penetration over longer periods. With respect to drug development and risk assessment of toxic substances, this may simplify assays attempting to quantitate penetration capacity. Further investigation with a larger range of compounds is needed to clarify the observations recorded here. Copyright © 2015 John Wiley & Sons, Ltd.     

Oleic Acid as Optimizer of the Skin Delivery of 5-Aminolevulinic Acid in Photodynamic Therapy

Purpose In photodynamic therapy (PDT), topically applied aminolevulinic acid (5-ALA) is converted to protoporphyrin IX (PpIX), which upon light excitation induces tumor destruction. To optimize 5-ALA-PDT via improving the highly hydrophilic 5-ALA limited penetration into the skin, we propose the use of the known skin penetration enhancer, oleic acid (OA). Methods In vitro skin penetration and retention of 5-ALA (1% w/w) were measured in the presence or absence of OA (2.5, 5.0, and 10.0% w/w) in propylene glycol (PG) using porcine ear skin as the membrane. In vivo accumulation of PpIX, 4 h after application, was determined fluorometrically in healthy mice skin by chemical extracton of skin samples. In vivo PpIX fluorescence kinetics was also investigated by noninvasive techniques using an optical fiber probe, for 30 min up to 24 h after topical application of 1.0% 5-ALA + 10.0% OA in PG on hairless mice skins. Results The flux and in vitro retention of 5-ALA in viable epidermis increased in the presence of 10.0% (w/w) OA. The amounts of PpIX, evaluated both by chemical tissue extractions and in vivo measurements by an optical fiber probe, increased after applying 5-ALA formulations containing 5.0 or 10.0% OA. Moreover, in vivo kinetic studies showed an increase in skin PpIX accumulation when formulations containing 10% OA were used; PpIX accumulation was also maintained longer compared to controls. Conclusions Both in vitro and in vivo results show the OA potential as an optimizer of 5-ALA skin delivery.     

Assessment of the percutaneous penetration of cisplatin: The effect of monoolein and the drug skin penetration pathway

It was intended to examine the in vitro penetration of cisplatin (CIS) through porcine skin in the presence of different concentrations of monoolein (MO) as well as to verify the main barrier for CIS skin penetration. In vitro skin penetration of CIS was studied from propylene glycol (PG) solutions containing 0%, 5%, 10%, and 20% of MO using Franz-type diffusion cell and porcine ear skin. Pretreatment experiments with MO and experiments with skin without stratum corneum (SC) were also carried out. Skin penetration studies of CIS showed that the presence of MO doubled the drug permeation through the intact skin. However, permeation studies through the skin without SC caused only a small enhancement of CIS permeation compared to intact skin. Moreover, pretreatment of skin with MO formulations did not show any significant increase in the flux of the drug. In conclusion, MO did not act as a real penetration enhancer for CIS, but it increased the drug partition to the receptor solution improving CIS transdermal permeation. The absence of improvement in drug permeation by MO pretreatment and by the removal of SC indicates that the SC is not the main barrier for the permeation of the metal coordination compound.     

Percutaneous Absorption of Benzoic Acid Across Human Skin. I. In Vitro Experiments and Mathematical Modeling

The percutaneous absorption of benzole acid across human skin in vitro was experimentally and mathematically modeled. Skin partition coefficients were measured over a range of benzoic acid concentrations in both saline and distilled water. The permeation of benzoic acid was measured across isolated stratum corneum, stratum corneum and epidermis, and split-thickness skin. These experiments demonstrated that the stratum corneum was the rate-limiting barrier and that the flux is proportional to the concentration of the undissociated species. The permeation data were analyzed with a comprehensive non-steady-state mathematical model of diffusion across skin. Two adjustable parameters, the effective skin thickness and diffusivity, were fit to the permeation data by nonlinear regression.     

Effect of Concentration and Degree of Saturation of Topical Fluocinonide Formulations on In Vitro Membrane Transport and In Vivo Availability on Human Skin

Purpose. The thermodynamic acitvity of drugs in topical vehicles is considered to significantly influence topical delivery. In vitro diffusion across a synthetic membrane was shown to be correlated to the degree of saturation of the drug in the applied vehicle and therefore offers a potential for increased topical drug delivery. Fluocinonide a topical corticosteroid, was chosen as a model compound to investigate in vitro and in vivo availability from formulations with different degrees of saturation. Methods. Sub-, as well as, supersaturated drug solutions were prepared using PVP as an antinucleant agent. In vitro membrane diffusion experiments across silicone membrane and in vivo pharmacodynamic activity assessments, using the human skin blanching assay, were carried out. Results. Over the concentration range studied, the in vitro membrane transport of fluocinonide was proportional to the degree of saturation of the respective formulations. The in vivo pharmacodynamic response in the human skin blanching assay was related to the concentration of the drug in the vehicle irrespective of the degree of saturation. Conclusions. From the membrane permeation experiment it can be concluded, that the drug flux might be increased supra-proportionally with increasing donor concentration, drug (super-)saturation (proportional), beyond what would be anticipated based on ideal donor concentration and partition coefficient considerations only. These findings could not be confirmed in the in vivo investigation, probably due to additional vehicle effects (e.g., enhancement, irritation, drug binding) which have to be expected and could have altered the integrity of the stratum corneum and therewith topical bioavailability of the drug.     

Analysis of Drug Penetration Through the Skin by the Two-Layer Skin Mode

A diffusion model for the skin penetration of drug in the finite-dose system was developed considering the skin to be composed of two layers, the outermost layer (stratum corneum) and the lower layer (viable epidermis and dermis). Based on this skin model, the Laplace transforms of the equations for the drug amounts in the receptor, the vehicle, and the skin were derived. The penetration profiles of 6-mercaptopurine (6-MP) through the intact and stripped guinea pig skin were obtained from in vitro diffusion experiments. The computer fitting of those profiles to the Laplace-transformed equations by a nonlinear least-squares program based on a fast inverse Laplace transform algorithm [MULTI-(FILT)] gave parameters such as diffusion coefficients of 6-MP and thicknesses of both layers. The mean transit time (MTT) for each diffusion process was defined based on statistical moment concept and calculated using the obtained parameters. Under the present condition, the process to move from the vehicle to the stratum corneum is demonstrated to have the longest mean time in overall processes of 6-MP penetration.     

In Vitro Percutaneous Absorption of Arildone,a Highly Lipophilic Drug,and the Apparent No-Effect of the Penetration Enhancer Azone in Excised Human Skin

Purpose. Arildone, a novel lipophilic antiviral drug when evaluated in Clinical Trials showed limited skin absorption and antiviral efficacy. These studies were conducted to explain the apparent poor absorption characteristics and attempt to promote skin absorption by using Azone, a penetration enhancer. Methods. Standard in vitro skin permeation methods using excised human skin were employed to characterise the absorption of Arildone. ¹⁴C-Arildone was used to estimate the distribution in skin layers by scintigraphic and autoradiographic procedures. Results. The aqueous solubility and distribution constant values for Arildone were 2 µg ml^–1 and 5 × 10⁵ (isopropyl myristate/water), respectively. Absorption through full thickness skin or stratum corneum-viable epidermal membranes (diffusional resistant dermis removed), from a propylene glycol vehicle, was slow and the addition of Azone had no effect on the permeation rate. Distribution studies showed accumulation of Arildone in the stratum corneum. The concentration of Arildone in the viable epidermis was estimated from sectioning the skin and was found to be in sufficient amounts (400 µg cm^–3) to have potential antiviral activity. Conclusions. The apparent accumulation of Arildone in the stratum corneum suggested that the hydrophilic skin region presented the main barrier to permeation. Azone which affected the permeability of the stratum corneum was therefore not effective at enhancing Arildone absorption. Vehicles which readily permeate and enhance the transfer of lipophilic drugs from the stratum corneum into the viable epidermis were recommended.     

Do partition coefficients (liphophilicity/hydrophilicity) predict effects of occlusion on percutaneous penetration in vitro: a retrospective review

Abstract

Context: Skin occlusion influences percutaneous penetration by limiting penetrant evaporation, but also through impeding loss of water from skin and increasing the hydration state of the stratum corneum, thus dramatically altering the physiological nature of the stratum corneum. In general, occlusion is widely utilized to enhance penetration of applied drugs in clinical practice; however, occlusion does not increase the percutaneous absorption of all chemicals.

Objective: We focus on what effect occlusion has on the in vitro percutaneous absorption of compounds of varying lipophilicities/hydrophilicities.

Methods: Studies and prior reviews of the effects of occlusion on the in vitro percutaneous penetration of penetrants of varying lipophilicities/hydrophilicities were identified in the MEDLINE, PubMED, Embase and Science Citation Index databases using the terms occlusive, occluded, occlusion, in vitro, skin and percutaneous absorption/penetration to generate as broad of a search as possible. From the results generated, abstracts were subsequently scrutinized to identify articles dealing primarily with in vitro models of the skin involving occlusion. Moreover, after the identification of relevant articles, their references were examined to find additional sources of information.

Results: After examining the research articles generated by the search results, five original research articles were obtained that used in vitro occlusion models and provided insight regarding the role of partition coefficients in predicting occlusion’s effects on percutaneous penetration; articles that dealt with occlusion and percutaneous penetration but did not shed light on how the lipophilicity/hydrophilicity of a compound could affect occlusion efficacy were excluded. Some of the studies bolster the notion that occlusion-enhanced hydration of the stratum corneum increases the percutaneous absorption of lipophilic molecules more than hydrophilic molecules, which seems to confirm some in vivo studies. However, this effect was not consistent; many studies reviewed did not find that the penetrant’s liphophilicity/hydrophilicity reliably predicted occlusion’s effect on penetration. In these studies, lipophilic compounds did not demonstrate increased percutaneous absorption under occlusion.

Conclusion: Thus, it does not seem that partition coefficients can reliably predict the effect of occlusion on percutaneous penetration in vitro. This suggests skin occlusion may be more complex than previously thought.