Effect of vehicles and sodium lauryl sulphate on xenobiotic permeability and stratum corneum partitioning in porcine skin

Dermal contact with potentially toxic agricultural and industrial chemicals is a common hazard encountered in occupational, accidental spill and environmental contamination scenarios. Different solvents and chemical mixtures may influence dermal absorption. The effects of sodium lauryl sulphate (SLS) on the stratum corneum partitioning and permeability in porcine skin of 10 agricultural and industrial chemicals in water, ethanol and propylene glycol were investigated. The chemicals were phenol, p-nitrophenol, pentachlorophenol, methyl parathion, ethyl parathion, chlorpyrifos, fenthion, simazine, atrazine and propazine. SLS decreased partitioning into stratum corneum from water for lipophilic compounds, decreased partitioning from propylene glycol and did not alter partitioning from ethanol. SLS effects on permeability were less consistent, but generally decreased permeability from water, increased permeability from ethanol and had an inconsistent effect on permeability from propylene glycol. It was concluded that, for the compounds tested, partitioning into the stratum corneum was determined by the relative solubility of the solute in the donor solvent and the stratum corneum lipids. Permeability, however, reflected the result of successive, complex processes and was not predictable from stratum corneum partitioning alone. Addition of SLS to solvents altered partitioning and absorption characteristics across a range of compounds, which indicates that partition coefficients or skin permeability from neat chemical exposure should be used with caution in risk assessment procedures for chemical mixtures.     

Cluster analysis of the dermal permeability and stratum corneum/solvent partitioning of ten chemicals in twenty-four chemical mixtures in porcine skin

Assumptions based on absorption from single solvent systems may be inappropriate for risk assessment when chemical mixtures are involved. We used K-means and hierarchical cluster analyses to identify clusters in stratum corneum partitioning and porcine skin permeability datasets that are distinct from each other based on mathematical indices of similarity and dissimilarity. Twenty-four solvent systems consisting of combinations of water, ethanol, propylene glycol, methyl nicotinate and sodium lauryl sulfate were used with 10 solutes, including phenol, p-nitrophenol, pentachlorophenol, methyl parathion, ethyl parathion, chlorpyrifos, fenthion, simazine, atrazine and propazine. Identifying the relationships between solvent systems that have similar effects on dermal absorption formed the bases for hypotheses generation. The determining influence of solvent polarity on the partitioning data structure supported the hypothesis that solvent polarity drives the partitioning of non-polar solutes. Solvent polarity could not be used to predict permeability because solvent effects on diffusivity masked the effects of partitioning on permeability. The consistent influence of the inclusion of propylene glycol in the solvent system supports the hypothesis that over-saturation due to solvent evaporation has a marked effect on permeability. These results demonstrated the potential of using cluster analysis of large datasets to identify consistent solvent and chemical mixture effects.     

Effect of chemical interactions in pentachlorophenol mixtures on skin and membrane transport.

Pentachlorophenol (PCP) has been widely used as a pesticide, and topical exposure to a chemical mixture can alter its dermal absorption. The purpose of this study was to evaluate the influence of single and binary solvent systems (ethanol, EtOH, and water), a surfactant (6% sodium lauryl sulfate, SLS), and a rubifacient/vasodilator (1.28% methyl nicotinate, MNA) on PCP membrane transport, and to correlate these effects with physiochemical characteristics of the PCP mixtures. Partitioning, diffusion, and absorption parameters of (14)C-PCP at low (4 microg/cm(2)) and high (40 microg/cm(2)) doses were assessed in porcine skin and silastic membranes in vitro. In these 8-h, flow-through diffusion studies, PCP was dosed with the following vehicles: 100% EtOH, 100% water, 40% EtOH + 60% water, 40% EtOH + 60% water + SLS, 40% EtOH + 60% water + MNA, and 40% EtOH + 60% water + SLS + MNA. PCP absorption ranged from 1.55-15.62% for the high dose and 0.43-7.20% for the low dose. PCP absorption, flux, and apparent permeability were influenced by PCP solubility, and PCP apparent permeability was correlated with log PC (r2 = 0.66). Although PCP was very soluble in pure ethanol (100%), this vehicle evaporated very rapidly, and PCP absorption in ethanol was the lowest with this vehicle when compared to pure water (100%) or aqueous ethanol mixtures in general. MNA had no significant effect on membrane absorption or relative permeability R(P) in aqueous ethanol solutions, but the presence of the surfactant, SLS, significantly reduced PCP absorption and R(P) in both membrane systems. In conclusion, these studies demonstrated that modification in mixture composition with either a solvent and/or a surfactant can influence PCP diffusion in skin. Physicochemical interactions between these mixture components on the skin surface and stratum corneum contributed significantly to PCP transport, and these interactions were identified by simultaneously assessing chemical diffusion in biological and inert membrane systems.     

Synergistic enhancement of skin permeability by N-lauroylsarcosine and ethanol

To develop formulations for transdermal drug delivery, this study tested the hypothesis that the anionic surfactant, N-lauroylsarcosine (NLS), and ethanol synergistically increase skin permeability by increasing the fluidity of stratum corneum lipid structure. Skin permeability experiments showed that transdermal delivery of fluorescein across human cadaver epidermis was increased by up to 47-fold using formulations containing NLS in aqueous ethanol solutions. Skin permeability was increased by increasing NLS concentration in combination with 25-50% ethanol solutions. Skin permeability was shown to correlate with skin electrical conductivity measurements, changes in differential scanning calorimetry lipid transition peak temperature, and Fourier transform infrared spectroscopy CH stretching peak shifts indicative of stratum corneum lipid fluidization and changes in protein conformation. Evidence for lipid extraction was also evident, but did not appear to be responsible for the observed increases in skin permeability. We conclude that NLS in aqueous ethanol formulations can dramatically increase skin permeability by a mechanism involving synergistic lipid-fluidization activity in the stratum corneum.     

Effects of ionization on the percutaneous absorption of drugs: partitioning of nicotine into organic liquids and hydrated stratum corneum

To gain further insight into the disposition of ionizable drugs in the stratum corneum, the partitioning of nicotine as a function of pH was studied in excised, hydrated, human stratum corneum (SC) and the organic liquids n-butanol, n-octanol, isopropyl myristate, and Miglyol 812. Partitioning in n-octanol, isopropyl myristate, and Miglyol 812 was consistent with the pH-partition hypothesis, while partitioning in n-butanol agreed with agreed with a model for the partitioning of the free base and an ion pair which dissociates in the organic phase. The results in SC also suggested the partitioning of ion pairs. Binding studies indicated that neither the un-ionized nor the ionized species is bound significantly in the stratum corneum. Trichloroacetate (TCA) anion increased partitioning of ionized nicotine in n-butanol, but had no effect in stratum corneum. Delipidization of the stratum corneum decreased the partition coefficient for the free base, but had no effect on the ionized species. Thermodynamic parameters determined from van't Hoff plots were consistent with the entry of un-ionized nicotine into ordered lipids. These results suggest that the un-ionized form is found within the lipid regions of the stratum corneum, while the ionized form is located in aqueous regions.     

Ethanol and water sorption into stratum corneum and model systems

Sorption of ethanol and water into stratum corneum, delipidized stratum corneum, and triolein as a simple model lipid was investigated. Optima in ethanol sorption and flux are related to dehydration of keratins. There was no optimum for solubility in triolein; a linear cosolvency is observed with ethanol:triolein mixtures. A model is proposed which qualitatively predicts the key features of ethanol-enhanced skin permeation on the basis of these solubility phenomena and a constant diffusion coefficient.     

Heterogeneity Effects on Permeability–Partition Coefficient Relationships in Human Stratum Corneum

The relationship between the permeability of solutes undergoing transport via the lipid pathway of the stratum corneum and the degree to which the same solutes partition into the stratum corneum has been explored by measuring the permeability coefficients and stratum corneum/water partition coefficients of a series of hydrocortisone esters varying in lipophilicity. Isolated human stratum corneum, used in both the permeability and the uptake experiments, was shown to resemble full-thickness skin in its overall resistance and selectivity to solute structure. As with full-thickness skin, delipidization destroys the barrier properties of isolated stratum corneum. Although a linear relationship is frequently assumed to exist between permeability coefficients and membrane/water partition coefficients, a log–log plot of permeability coefficients versus the intrinsic stratum corneum/water partition coefficients for the series of hydrocortisone esters studied is distinctly nonlinear. This nonlinearity arises from the fact that the transport of these solutes is rate limited by a lipid pathway in the stratum corneum, while uptake reflects both lipid and protein domains. From the relative permeability coefficients of 21-esters of hydrocortisone varying in acyl-chain structure, group contributions to the free energy of transfer of solute into the rate-limiting barrier microenvironment of the stratum corneum lipid pathway are calculated for a variety of functional groups including the –CH_2–, –CONH₂, –CON(CH₃)₂, -COOCH₃, –COOH, and –OH groups. These are compared to contributions to the free energies of transfer obtained for the same functional groups in octanol/water, heptane/water, and stratum corneum/water partitioning experiments. The group contributions to transport for polar, hydrogen-bonding functional groups are similar to the values obtained from octanol/water partition coefficients. This similarity suggests that complete loss of hydrogen bonding does not occur in the transition state for passive diffusion via the lipid pathway.     

Stereoselective skin permeation of organic nitrates: application of partitioning and porous transport theories

The effect of the stereochemistry of organic nitrates on rat skin permeability was investigated. Skin permeabilities significantly differed between dinitrates and mononitrates, and also among their diastereomers. The maximum flux and permeability coefficient of dinitrate diastereomers from water were dependent on the solubility in octanol and the octanol/water partition coefficient, respectively. On the other hand, the key parameters determining the maximum flux and permeability coefficient of mononitrate isomers were the aqueous solubility and diffusivity. These results suggest that dinitrate diastereomers permeate across skin via the lipid domain of the stratum corneum according to a partitioning mechanism, and that skin permeation of mononitrate isomers occurs via an aqueous domain by a porous mechanism. Factors raising stereoselectivity in skin permeation of organic nitrates were closely related with stereostructure, especially the functional groups at the exo position, of diastereomers. The interaction between the functional groups and surrounding molecules thus causes the differences in physicochemical properties and skin permeability of stereoisomers.     

The influence of water mixtures on the dermal absorption of glycol ethers

Glycol ethers are solvents widely used alone and as mixtures in industrial and household products. Some glycol ethers have been shown to have a range of toxic effects in humans following absorption and metabolism to their aldehyde and acid metabolites. This study assessed the influence of water mixtures on the dermal absorption of butoxyethanol and ethoxyethanol in vitro through human skin. Butoxyethanol penetrated human skin up to sixfold more rapidly from aqueous solution (50%, 450 mg/ml) than from the neat solvent. Similarly penetration of ethoxyethanol was increased threefold in the presence of water (50%, 697 mg/ml). There was a corresponding increase in apparent permeability coefficient as the glycol ether concentration in water decreased. The maximum penetration rate of water also increased in the presence of both glycol ethers. Absorption through a synthetic membrane obeyed Fick's Law and absorption through rat skin showed a similar profile to human skin but with a lesser effect. The mechanisms for this phenomenon involves disruption of the stratum corneum lipid bilayer by desiccation by neat glycol ether micelles, hydration with water mixtures and the physicochemical properties of the glycol ether-water mixtures. Full elucidation of the profile of absorption of glycol ethers from mixtures is required for risk assessment of dermal exposure. This work supports the view that risk assessments for dermal contact scenarios should ideally be based on absorption data obtained for the relevant formulation or mixture and exposure scenario and that absorption derived from permeability coefficients may be inappropriate for water-miscible solvents.     

Effect of ethanol/propylene glycol on the in vitro percutaneous absorption of aspirin, biophysical changes and macroscopic barrier properties of the skin.

The effect of the solvent systems ethanol (EtOH), propylene glycol (PG) and combinations thereof was examined on the in vitro percutaneous absorption of the antithrombotic, aspirin, through porcine epidermis. Biophysical changes in the stratum corneum lipids were studied through the use of Fourier transform infrared (FTIR) spectroscopy. Macroscopic barrier properties of the epidermis were examined through the use of in vitro transepidermal water loss (TEWL). The flux of aspirin increased with increasing concentrations of EtOH in the solvent systems. The maximum flux of aspirin was achieved by 80% EtOH in combination with 20% PG beyond which (i.e. 100% EtOH) there was no increase in the flux. FTIR spectroscopic study was enacted in order to determine the biophysical properties of the stratum corneum when the solvents were applied. The FTIR spectra of the stratum corneum treated with 80% EtOH/20% PG showed a maximum decrease in absorbance for the asymmetric and symmetric C&z. sbnd;H peaks, which suggests a greater loss of the lipids in the stratum corneum layers. In vitro TEWL studies allowed an investigation into the macroscopic barrier integrity properties of the stratum corneum. The TEWL results indicated that each of the solvent systems significantly enhanced (P<0.05) in vitro TEWL in comparison to the control. In conclusion, 80% EtOH/20% PG enhanced the percutaneous absorption of aspirin by perturbing the macroscopic barrier integrity of the stratum corneum and through a loss of stratum corneum lipids. Copyright     

Oxide terpenes as human skin penetration enhancers of haloperidol from ethanol and propylene glycol and their modes of action on stratum corneum

In this study, two terpenes with the same functional group; limonene oxide and pinene oxide were used at 5% w/v concentration in 50% v/v ethanol and 100% v/v propylene glycol (PG) to enhance the in vitro permeation of haloperidol (HP) through the human epidermis (or stratum corneum, SC). The enhancement mechanism of terpenes from both solvents was elucidated with HP-SC binding studies, Fourier transform infrared spectroscopy and differential scanning calorimetry. The enhancement activity of these terpenes was higher in 50% v/v ethanol than in 100% v/v PG. These terpenes in 50% v/v ethanol were predicted to provide the required therapeutic plasma concentration and daily-permeated amounts of the drug. Limonene oxide showed higher enhancement in both solvents, which was attributed to its less bulky structure. The terpenes in both solvents did not increase the partition of HP. Instrumental studies showed that these terpenes in 50% v/v ethanol extracted the SC lipids, disrupted the bilayer packing and partially fluidised the lipids. Limonene oxide in 100% v/v PG possibly disrupted the lipid bilayer, whilst leaving the overall bilayer structure intact and pinene oxide in the same vehicle fluidised the lipids within the ordered environment. This study showed that the mode of interactions of terpenes with SC were different in two solvent systems.     

Modified water containing hydrophilic ointment with suspended hydrocortisone-21-acetate--the influence of the microstructure of the cream on the in vitro drug release and in vitro percutaneous penetration.

Water containing hydrophilic ointment DAB 1997 was modified by the incorporation of ethanol and the effects of ethanol on the evaporation, the drug liberation and the permeation through human excised stratum corneum were investigated. Creams with 10%, 20%, 30% (v/v) and without ethanol were produced. As a model drug 2% (w/w) hydrocortisone-21-acetate was suspended in the o/w cream. The evaporation of the creams decreased with an increasing amount of ethanol which was unexpected because the vapor pressure of ethanol is higher than that of water. From this result it was concluded that ethanol might be interlamellarly fixed in the mixed crystal of the polyhydrate of the emulsifier to a higher extent than it is distributed within the aqueous bulk phase. In context with the liberation studies, ethanol decreased the drug liberation from the cream. This is in accordance with the above hypothesis of the ethanol partitioning within the cream, because the solubility of the drug in ethanol is higher than that in water. Therefore the interlamellar drug concentration should be higher than the solubility of the drug in the bulk phase, with the assumption that the gel network of the emulsifier polyhydrate is finally responsible for the delay in drug liberation. The permeation through stratum corneum showed no significant differences between the alcohol-free and the alcohol-loaded formulations. Obviously the decrease in drug liberation by ethanol was compensated for by the penetration enhancing effect.     

Effects of ethanol/l-menthol on the dynamics and partitioning of spin-labeled lipids in the stratum corneum.

The interaction of ethanol as well as ethanol/L-menthol mixtures with the uppermost layer of epidermis, the stratum corneum, was investigated by electron paramagnetic resonance (EPR) spectroscopy utilizing spin-labeled analogs of androstanol (ASL), stearic acid (5-DSA) and methyl stearate (5-DMS). The EPR spectra of these spin probes structured in stratum corneum tissue of neonatal rat are characterized by the coexistence of two spectral components indicating the presence of two classes of spin labels with very different states of mobility. Probably, one class of spin labels is H-bonded to the polar surface of the membrane and another class corresponds to spin labels more deeply inserted in the hydrophobic core. EPR results showed that in the ethanol range 0-70% neither fluidity in stratum corneum membranes nor the relative fractions of these two components changes were observed. Instead, ethanol only caused a selective extraction of spin labels. The removal of the steroid ASL began at 30% ethanol, reaching extraction levels over 50% at ethanol concentrations of 60-70%, whereas the more hydrophobic 5-DMS was partially removed only with 70% ethanol. Addition of 5% L-menthol to the solvent containing 20% ethanol increases both the mobility and the fraction of those spin labels situated in the hydrophobic core (more mobile spectral component). Altogether, these findings suggest that the L-menthol stabilizes mainly in the central region of stratum corneum membranes attracting the membrane lipids and causing hydrogen bond ruptures in the polar membrane interface.     

Mechanism of skin penetration-enhancing effect by laurocapram.

In order to clarify the mechanism of action of laurocapram (Azone) on the skin permeation of drugs, the following experiments were done. First, the effect of Azone on the skin components was compared with that of other penetration enhancers. Azone markedly fluidized liposomal lipids (as a model lipid system) compared with other enhancers. Ethanol extracted large amounts of the stratum corneum lipids, whereas Azone did not. These results suggest that the effect of Azone on the lipids in the stratum corneum is not the same as that of ethanol. In addition, ethanol increased the amount of free sulfhydryl (SH) group of keratin in the stratum corneum, whereas Azone did not directly affect the stratum corneum protein. Azone increased water content in the stratum corneum, as measured by skin conductance. This effect might be a reason for the action of Azone. For further understanding, the enhancing effects of Azone on the skin permeation of several model compounds (alcohols, sugars, and inorganic ions) were compared with the effects of pretreatment with distilled water, which was thought to increase water-holding capacity, and pretreatment with ethanol, which was thought to affect the lipids and protein in the skin barrier (i.e., stratum corneum). Pretreatment with water or ethanol enhanced skin permeation of hydrophilic compounds, whereas they decreased that of octanol, a hydrophobic compound. The tendency of Azone to increase or decrease the skin permeation rate of most compounds was similar to that of pretreatment with water or ethanol. However, the effect of Azone on the skin permeation of inorganic ions was relatively low, whereas that of pretreatment with water or ethanol was high.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dermal Disposition of Triazine in Cutting Fluid Mixtures

Triazine is often added as a biocide/preservative to cutting fluids formulations that are used in the metal machine industry. Workers involved in metal machining are not only exposed to components in these cutting fluids, but also to biocides such as triazine that have been implicated in occupational irritant dermatitis. Very little is known about how these cutting fluids and their ingredients influence the dermal disposition of triazine. The purpose of this study was to assess ¹⁴C‐triazine membrane transport when topically applied to inert silastic membranes and porcine skin in an in vitro flow‐through diffusion cell system as aqueous mineral oil (MO) or aqueous polyethylene glycol (PEG) mixtures. ¹⁴C‐triazine mixtures were formulated with three commonly used cutting fluid additives; namely, 0% or 5% linear alkylbenzene sulfonate (LAS), 0% or 5% triethanolamine (TEA), and 0% or 5% sulfurized ricinoleic acid (SRA). Triazine partitioning from the formulation into the stratum corneum (SC) was reduced significantly by the presence of LAS, while SRA significantly reduced the pH of the formulation. Triazine absorption ranged from 2.2% to 3.9% dose in porcine skin and 12.6% to 18.6% dose in silastic membranes. In silastic membranes, the complete mixture reduced triazine absorption significantly in MO‐based mixtures, while in PEG‐based mixtures triazine absorption and apparent permeability were significantly increased. In porcine skin, triazine permeability was significantly increased for both MO‐ and PEG‐based complete mixtures with a trend towards greater triazine absorption in more complex PEG‐based mixtures. Interestingly, SRA + TEA significantly increased triazine permeability absorption in MO‐ and PEG‐based mixtures, but this interaction appears to be more additive than synergistic. Although the physicochemical experiments suggest otherwise, triazine readily permeates a homogenous lipid membrane such as the SC, while triazine permeability was significantly enhanced by the complete mixture, especially in PEG‐based mixtures.     

The Role of Protein and Lipid Domains in the Uptake of Solutes by Human Stratum Corneum

The uptake of a series of hydrocortisone esters varying in lipophilicity from water into untreated and delipidized human stratum corneum has been determined. The partition coefficients of solutes into fully hydrated stratum corneum are postulated to represent the separate contributions of three structurally distinct domains—the extractable lipids, protein, and the solvent domain. The solvent domain was assumed to have the properties of bulk water. The relative affinities of the protein and lipid domains of stratum corneum for solutes varying in structure were determined by comparing solute uptake in untreated and delipidized stratum corneum. Partitioning into the extracted lipids was also examined. Solute uptake into stratum corneum may be governed by the protein domain, the lipid domain, or a combination of the two, depending on solute lipophilicity. Due to differences in the selectivity of the two domains, a change in uptake mechanism occurs with increasing solute lipophilicity from protein-dominated uptake for hydrophilic solutes to lipid domain-dominated uptake for lipophilic solutes. The stratum corneum lipid content, which varies dramatically from individual to individual (3–46% in this study), is an important determinant of the affinity of the stratum corneum for highly lipophilic solutes but has no effect on the uptake of hydrophilic solutes.Prakash V. Raykar: In partial fulfillment of the Ph.D. degree of pharmaceutics, College of Pharmacy, University of Utah.     

Effect of penetration enhancers on the permeation of mannitol, hydrocortisone and progesterone through human skin

Mannitol, hydrocortisone and progesterone were selected as model penetrants to assess the mode of action of eight potential penetration enhancers in human skin. Their partition coefficients, octanol: water and stratum corneum: water were measured and correlated with their postulated routes of penetration through human skin. The results suggest that mannitol penetrated via a polar route, hydrocortisone by a mainly lipid route and progesterone via a lipid pathway but its penetration rate was probably affected by aqueous layers. From permeation studies through cadaver skin in which an in-vivo mimic method was used, it was concluded that the penetration enhancers fell into three main categories: solvents which enhanced permeation of polar and non-polar compounds e.g. 2-pyrrolidone, N-methylpyrrolidone, N-methylformamide and propylene glycol plus Azone; enhancers which preferentially affected the polar route e.g. propylene glycol plus decylmethylsulphoxide, and accelerants which mainly modified the non-polar route e.g. propylene glycol plus oleic acid, propylene glycol alone and, to a limited extent, water.     

Mixture additives inhibit the dermal permeation of the fatty acid, ricinoleic acid

Ricinoleic acid (RA) like many of the ingredients in machine cutting fluids and other industrial formulations are potential dermal irritants, yet very little is known about its permeability in skin. 3H-ricinoleic acid mixtures were formulated with three commonly used cutting fluid additives; namely, triazine (TRI), linear alkylbenzene sulfonate (LAS), and triethanolamine (TEA) and topically applied to inert silastic membranes and porcine skin in vitro as aqueous mineral oil (MO) or polyethylene glycol (PEG) mixtures. These additives significantly decreased ricinoleic acid partitioning from the formulation into the stratum corneum (SC) in PEG-based mixtures. Except for LAS, all other additives produced a more basic formulation (pH = 9.3-10.3). In silastic membranes and porcine skin, individual additives or combination of additives significantly reduced ricinoleic permeability. This trend in ricinoleic acid disposition in both membranes suggests that the mixture interaction is more physicochemical in nature and probably not related to the chemical-induced changes in the biological membrane as may be assumed with topical exposures to potentially irritant formulations.     

The influence of ethanol on permeation behaviour of the porous pathway in the stratum corneum

Relationship between in vitro percutaneous penetration of baclofen, a model zwitterion, and ethanol concentration in the vehicle was studied. In comparison with water, 95% ethanol increases the permeability coefficient of baclofen by a factor of 10, which suggests rapid and maximal pore formation in the stratum corneum. A slow time-dependent increase of penetration rate was observed for lower ethanol concentrations. For ethanol concentrations in the range 0–70%, solubility of baclofen in the vehicle is a dominant factor influencing the penetration rate. The reasons for an unexpectedly small effect of 70° ethanol on the process of pore formation in the stratum corneum are discussed.     

Etude des facteurs conditionnant l'absorption percutanee des alcools incorpores dans des melanges eau-monooleate de sorbitanne polyoxyethylene-myristate d'isopropyle

Percutaneous absorption of ethanol, butanol and octanol is studied in vitro on skin of hairless rats. Alcohols are introduced in various vehicles prepared with water-isopropyl myristate-polyoxyethylene sorbitan monooleate (Tween 80).In aqueous or isopropyl myristate solution, the permeability constant of alcohols increases in the same way as their partition coefficient, stratum corneum/vehicle. The addition of Tween 80 to the aqueous or isopropyl myristate solutions reduces the permeability constant of alcohols when they are initially poorly soluble in the pure solvent. The intensity of the effect is proportional to the quantity of surface-active agent added to the solvent and decreases with the stratum corneum/vehicle partition coefficient.In ternary systems with an external aqueous phase, results are similar to those obtained with water-Tween 80 solution. So percutaneous absorption of alcohols in a two phase mixture seems to be a function of the affinity of alcohols for the aqueous phase which are in contact with the stratum corneum.Absorption of alcohols is not modified by the viscosity of the various vehicles studied.