Steady-state Permeability Coefficients Research Articles

A compartment model to predict in vitro finite dose absorption of chemicals by human skin

Dermal uptake is an important and complex exposure route for a wide range of chemicals. Dermal exposure can occur due to occupational settings, pharmaceutical applications, environmental contamination, or consumer product use. The large range of both chemicals and scenarios of interest makes it difficult to perform generalizable experiments, creating a need for a generic model to simulate various scenarios. In this study, a model consisting of a series of four well-mixed compartments, representing the source solution (vehicle), stratum corneum, viable tissue, and receptor fluid, was developed for predicting dermal absorption. The model considers experimental conditions including small applied doses as well as evaporation of the vehicle and chemical. To evaluate the model assumptions, we compare model predictions for a set of 26 chemicals to finite dose in-vitro experiments from a single laboratory using steady-state permeability coefficient and equilibrium partition coefficient data derived from in-vitro experiments of infinite dose exposures to these same chemicals from a different laboratory. We find that the model accurately predicts, to within an order of magnitude, total absorption after 24 h for 19 of these chemicals. In combination with key information on experimental conditions, the model is generalizable and can advance efficient assessment of dermal exposure for chemical risk assessment.

Influence of Permeant Lipophilicity on Permeation Across Human Sclera

The objectives of this study were to determine the effects of permeant lipophilicity on permeant uptake into and transport across human sclera for transscleral delivery. Model permeants with a wide range of lipophilicities were selected and studied with human sclera. Uptake experiments were carried out to measure permeant partitioning into the sclera. Transport experiments were performed in side-by-side diffusion cells, and the permeability coefficients and transport lag times of the permeants across the sclera were evaluated. Permeants with higher lipophilicity showed higher partition coefficients to human sclera, and the apparent transport lag time also increased significantly as the permeant lipophilicity increased. No correlation between the permeability coefficients and lipophilicity of the model permeants was observed in this study with human sclera. A hypothesis on the different findings between the present and previous studies was proposed. Permeants with higher lipophilicity exhibited stronger binding to human sclera and would therefore lead to larger permeant partitioning to the sclera and longer transport lag time. The steady-state permeability coefficients of the permeants were not significantly affected by permeant lipophilicity.

Alfuzosin hydrochloride transdermal films: evaluation of physicochemical, in vitro human cadaver skin permeation and thermodynamic parameters

The main objective of the investigation was to develop a transdermal therapeutic system for alfuzosin hydrochloride and to study the effects of polymeric system and loading dose on the in vitro skin permeation pattern. Principles of experimental design have been exploited to develop the dosage form. Ratio of ethyl cellulose (EC) and polyvinyl pyrrolidone (PVP) and loading dose were selected as independent variables and their influence on the cumulative amount of alfuzosin hydrochloride permeated per cm2 of human cadaver skin at 24 h (Q24), permeation flux (J) and steady state permeability coefficient (PSS) were studied using experimental design. Various physicochemical parameters of the transdermal films were also evaluated. Activation energy for in vitro transdermal permeation has been estimated. Ratio of EC and PVP was found to be the main influential factor for all the dependent variables studied. Drug loading dose was also found to influence the dependent variables but to a lesser extent. Physicochemical parameters of the prepared films were evaluated and found satisfactory. Activation energy for alfuzosin permeation has also been estimated and reported. The therapeutic system was found to be dermatologically non-irritant and hence, a therapeutically effective amount of alfuzosin hydrochloride can be delivered via a transdermal route.

CO2Permeability of Polystyrene Nanocomposites and Nanocomposite Foams

Steady state permeability coefficients P of carbon dioxide (CO2) in polystyrene (PS) and PS nanocomposites and their corresponding foams at 0.10 MPa (gauge pressure) and three different temperatures were measured. Permeability coefficients of foams are about 1 order of magnitude higher than those of corresponding plates. Three PS nanocomposites were used: PS + 5% 20A (treated nanoclay provided by Southern Clay), PS + 5% CNFs (carbon nanofibers), and PS + 5% MHABS (nanoclay treated with 2-methacryloyloxyethylhexadecyldimethylammonium bromide). For both plates and foams, the permeability coefficient decreases considerably with addition of nanoparticles. Foam structure is shown to play a more important role than nanoparticles in determining the permeability coefficient values for nanocomposite foams.

Application of Eudragit RS to thermo-sensitive drug delivery systems: II. Effect of temperature on drug permeability through membrane consisting of Eudragit RS/PEG 400 blend polymers

The Eudragit RS and polyethylene glycol 400 (PEG 400) blend polymer (EPG) membranes were prepared by the solvent casting method to pioneer a novel application of Eudragit RS to a thermo-sensitive material. The EPG membranes containing 2.5–10% PEG 400 (2.5–10% EPG) showed the glass transition temperatures (Tgs) around the body temperature (32–42 °C). Drug permeation studies through the EPG membranes were carried out using acetaminophen (AAP) and aminopyrine (AMP) as the model drugs. The permeability of AAP and AMP through the EPG membranes has been shown to be a discontinuous function of temperature, that is, their permeability increased steeply above the Tg of the membranes. The amount of AMP permeated at 42 °C was nearly eight times as much as that at 36 °C. Arrhenius plots of the steady-state permeability coefficient ( P) of AAP indicated two straight lines that intersect at the Tg of the 10% EPG membrane. In the water uptake study for the 10% EPG membrane, the degree of the swelling for the membrane tended to increase with increasing temperature above the Tg of the membrane. The thermo-sensitive permeation mechanism for the EPG membranes might be based on the structure change of the membranes caused by the glass transition, so that the membranes could absorb more water. Considering the high biological safety of Eudragit RS and PEG 400, the EPG membranes might be used to develop a novel thermo-sensitive drug delivery system.

Percutaneous Absorption of Trihalomethanes, Haloacetic Acids, and Haloketones

Bathing in chlorinated drinking water causes significant exposure to potentially toxic disinfection by-products (DBPs). In the present studies, we measured the permeation coefficients ( K p) of three important classes of DBPs, trihalomethanes (THMs), haloketones (HKs), and haloacetic acids (HAAs), in aqueous solution across human skin using in vitro diffusion chambers. Linear mixed-effects model was utilized to calculate the steady-state permeability coefficients. The permeability coefficients of THMs ranged from 0.16 to 0.21 cm/h when the donor solution was at 25°C. Bromoform had the highest K p value, while chloroform was the least permeable through the skin. THMs were approximately 10 times more permeable than HKs, while the permeability of HAAs through the skin was very low (1 to 3 × 10 −3 cm/h, pH 7). The permeability of HKs tripled as the temperature was increased from room temperature (20°C) to bathing temperature (40°C). A direct relationship was found between the permeability of THMs, but not HKs and HAAs, and their octanol/water partition coefficients. The dermal dose from daily bathing activities was approximated for an average adult using U.S. EPA recommended methods and found to be 40–70% of the daily ingestion dose for the THMs, 10% of the ingestion dose for HKs, and an insignificant percentage of the ingestion dose for the HAAs. In addition to ingestion, dermal absorption is an important route of exposure to THMs and HKs and must be considered in models of risk assessment.

In vitro permeation of nickel salts through human stratum corneum.

Allergic contact dermatitis due to nickel salts is common. It is therefore important to measure the permeation of these salts through the stratum corneum (SC), the primary rate-limiting domain in skin. An advanced diffusion system and analytical techniques now enable better measurement of the flux than was possible in earlier experiments. Human SC was prepared by trypsinization of dermatomed cadaver leg skin. The diffusion system included diffusion cells with a spiral line. Aqueous solutions of nickel salts (Ni(NO3)2, NiSO4, NiCl2 and Ni(-OOCCH3)2 at 1% Ni2+ concentration) were used as the donor solution (400 microL/cell). The receptor fluid, pure water, was collected up to 96 h after application of the donor solutions. Nickel concentrations in the donor and receptor fluid, as well as in the SC, were analysed using inductively coupled plasma mass spectrometry (ICP-MS) with a confidence limit of 0.5 ppb. Based on the total recovery of nickel from the experiments, about 98% of the dose remained in the donor solution, whereas 1% or less was retained in SC and less than 1% was found in the receptor fluid. Following an early surge, nickel permeates slowly across SC. The steady-state permeability coefficients of nickel were calculated from the flux data (approximately 5.2-8.5 x 10(-7) cm/h) with no significant difference among the salts. The results concur in principle with earlier studies conducted using the full-thickness human skin in vitro, and suggest that in vivo nickel ions may permeate simultaneously by routes of diffusion such as the shunt pathway, apart from slow transcellular/intercellular diffusion alone.

Influence of temperature on the percutaneous absorption for lipophilic and hydrophilic drugs across the rat skin pretreated with oleic acid

The combined effect of pretreatment with oleic acid and temperature on the rat skin permeation of lipophilic and hydrophilic drugs was examined. Prednisolone was used as a lipophilic penetrant which would penetrate through the lipid route of the skin. On the other hand, glucose was used as a hydrophilic penetrant which would permeate through the polar pathway. The steady-state permeability coefficients ( P) of these penetrants were determined employing two-chamber diffusion cells in which excised rat abdominal skin was mounted. On skin pretreated with 3% oleic acid in 30% ethanol for 2 h, the P values of both penetrants abruptly increased with increase in temperature. On the other hand, these penetrants did not permeate through skin pretreated with 30% ethanol alone, even though a high temperature was applied.

Combined effect of d-limonene pretreatment and temperature on the rat skin permeation of lipophilic and hydrophilic drugs.

The combined effect of d-limonene and temperature on the skin permeation of lipophilic and hydrophilic penetrants has been investigated in rats in vitro. Prednisolone was used as a lipophilic penetrant, and glucose and isoniazid were used as hydrophilic ones, respectively. When the skin was pretreated with 30% ethanol without d-limonene, the steady state permeability coefficient (P) of every penetrant through the skin was difficult to calculate because of very low permeability. On the other hand, the cumulative amount of each penetrant increased with an increase in temperature when the skin was pretreated with 1.5% d-limonene in 30% ethanol. The Arrhenius plots of P values for glucose and isoniazid showed a linear relationship, and the activation energies of skin permeation were estimated to be 87.6 and 66.5 kJ/mol, respectively. When prednisolone was used as penetrant, however, the Arrhenius plot of P values exhibited a convex curvature. This may suggest that the combined use of d-limonene and temperature effectively changes the barrier structure of the non-polar pathway in the stratum corneum, while no synergistic effect was observed on the polar pathway.

Combined effect of d-limonene and temperature on the skin permeation of ketoprofen

The effect of temperature on the enhancement action of d-limonene on percutaneous absorption of ketoprofen (KPF) was investigated in rats in vivo and in vitro. The apparent penetration rate ( R p ) of KPF absorbed from alcoholic hydrogels in rats was estimated based on a pharmacokinetic model, which was derived on the assumption of a constant penetration rate through the skin. The R p value increased sigmoidally with increase in the temperature applied, i.e., the R p value was almost constant at the lower temperatures, however, it increased abruptly at the critical temperature ( T c ) of applied heat. The T c value was significantly lowered by increasing the content of d-limonene in the hydrogel. The steady-state permeability coefficients ( P) of KPF through the skin was determined by employing two-chamber diffusion cells in which the excised rat abdominal skin was mounted. The combined effect of d-limonene and temperature on the P value was also clarified. The Arrhenius plots of P values showed a linear relationship when the skin was pretreated with 30% ethanol without d-limonene. The activation energy of permeation of KPF through the skin was estimated to be 6.49 kJ/mol. When the skin was pretreated with 1.5% d-limonene in 30% ethanol, the Arrhenius plots of P exhibited a convex curvature. Morphological changes of the skin surface were also observed microscopically. The application of heat, along with the synergistic effect of d-limonene, may effectively change the dense barrier structure of the stratum corneum.

Effect of ethanol on skin permeation of nonionized and ionized diclofenac

The effect of ethanol on the skin permeation of diclofenac (DF) was investigated using excised hairless rat abdominal skin in vitro. The steady-state flux of DF increased with increase in the pH of DF-suspended donor solution; this phenomenon demonstrated a close correspondence with enhancement in the solubility of DF in the donor solution. In constrast, the steady-state permeability coefficient ( P) of DF was inversely proportional to the change in pH of the donor solution, suggesting that the pattern of skin permeation of DF apparently obeyed the pH-partition theory, although the contribution of the ionized form of DF cannot be taken as being negligible. In order to determine the contribution of either the nonionized or ionized form on the skin permeation of DF, the permeability coefficients for each form (nonionized and ionized molecules) were calculated using the P values and the degree of ionization of DF in the donor solution. Addition of ethanol in the donor solution led to a marked decrease in the Pvalue of nonionized DF, whereas the P value of ionized DF was not greatly affected by ethanol. A large amount of ethanol might increase the extent of permeation of DF through the lipid pathway by affecting the dense barrier structure of the skin. The flux of the ionized form of DF was particularly enhanced due to the increase in solubility as a result of the addition of ethanol, since the partition coefficient (skin/donor solution) of the ionized form was not greatly decreased compared with that of the nonionized form.

Factors to be considered in the evaluation of bioavailability and bioequivalence of topical formulations.

In this paper, an attempt is made to find functional definitions of bioavailability and bioequivalence for topical products and to examine critical factors that influence topical bioavailability and bioequivalence. A physical model approach for quantifying the problem and increasing our understanding is presented here. The key assumptions are (1) that the target site is in the lower epidermis (basal layer) or in the dermis, and (2) that it is the thermodynamic activity (i.e., the free drug concentration, C*, of the active drug species) at the target site that is the true correlate of drug effectiveness. Studies initiated to implement the physical model approach involved first validating a 'three-tiered' model for finite dose drug uptake/transport in skin with experimentally determined input parameters (partition coefficient, K, and steady-state permeability coefficients, P, for the stratum corneum, viable epidermis, and dermis). Hydrocortisone was used as the model drug with hairless guinea pig skin as the model membrane. The physical model is used to show, via the C* concept, how formulation factors may influence bioavailability and bioequivalence. Finally, a method is presented for predicting the efficacy of topical formulations employing appropriate in vitro data and physical model calculations.

Percutaneous penetration of para-substituted phenols in vitro

The percutaneous penetration of 11 para-substituted phenols has been measured across full-thickness hairless mouse skin in vitro. The phenols, which spanned more than a 1000-fold range in octanol/water partition coefficient ( P), were applied ( 14C-radiolabeled) to the skin surface in a small volume of volatile organic solvent. Permeation kinetics were continuously monitored and were characterized by the maximum observed flux ( J max). The linear correlation of log J max with log P was very poor. However, inclusion of molecular volume (MV) in a multiple regression analysis considerably improved the relationship between the measured transport parameter and the physicochemical descriptors. Furthermore, significant parabolic (log J max = −0.18 + 1.35 · log P − 0.30 · [log P] 2) and bilinear (log J max = −0.17 + 1.08 · log P − 1.95 · [log( β · 10 log P + 1)]) dependencies were obtained, suggesting a change in the rate-limiting transport step (for compounds of high log P) from diffusion across the stratum corneum (SC) to partitioning at the SC-viable epidermis interface. Addition of a term in MV (or molar refractivity) further improved the absolute correlations, but with marginal statistical significance. A wider range of molecular size is necessary to unequivocally define the role of permeant dimensions in percutaneous permeability for this group of compounds. The quadratic log J max correlation with log P was compared to the previously reproted steady-state permeability coefficients ( K p) of a different set of phenol analogs through human epidermis. Despite the different methodologies, different compounds, and different skin membranes employed, the patterns of behavior in the two data sets were consistent, and suggest that the form of this correlation may be a suitable description of phenol permeability under a range of experimental conditions.

Percutaneous Penetration of para-Substituted Phenols in Vitro

Percutaneous Penetration of para-Substituted Phenols in Vitro HINZ, R. S., LORENCE, C. R., HODSON, C. D., HANSCH, C., HALL, L. L., AND Guy, R. H. (1991). Fundam Appl Toxicol 17, 575–583. The percutaneous penetration of II para-substituted phenols has been measured across full-thickness hairless mouse skin in vitro The phenols, which spanned more than a 1000-fold range in octanol/water partition coefficient (P), were applied (14C-radiolabeled) to the skin surface in a small volume of volatile organic solvent. Permeation kinetics were continuously monitored and were characterized by the maximum observed flux (Jmax). The linear correlation of log Jmax with log P was very poor. However, inclusion of molecular volume (MV) in a multiple regression analysis considerably improved the relationship between the measured transport parameter and the physicochemical descriptors. Furthermore, significant parabolic (log Jmax = −0.18 + l.35 log P − 0.30.[log P]2) and bilinear(log Jmax, −0.17 + 1.08·log P − 1.95·[log(β·10log P + 1)]) dependencies were obtained, suggesting a change in the rate-limiting transport step (for compounds of high log P) from diffusion across the stratum corneum (SC) to partitioning at the SC-viable epidermis interface. Addition of a term in MV (or molar refractivity) further improved the absolute correlations, but with marginal statistical significance. A wider range of molecular size is necessary to unequivocally define the role of permeant dimensions in percutaneous permeability for this group of compounds. The quadratic log Jmax correlation with log P was compared to the previously reported steady-state permeability coefficients (Kp) of a different set of phenol analogs through human epidermis. Despite the different methodologies, different compounds, and different skin membranes employed, the patterns of behavior in the two data sets were consistent, and suggest that the form of this correlation may be a suitable description of phenol permeability under a range of experimental conditions.

Transport of sulphur dioxide in polymers

Studies were made of the permeation, solution, and diffusion of sulphur dioxide in polyethylene, polyamide (Nylon 11), and polycarbonate at 25 °C and at pressures up to one atmosphere. The steady-state permeability coefficients of sulphur dioxide in all three polymers were pressure-dependent, and the effect of pressure on the solution and diffusion processes, which together govern the overall permeation process, account for the observed relations. Solution and diffusion in the two glassy polymers, polyamide and polycarbonate, were strongly pressure-dependent whereas in polyethylene diffusion was pressure-dependent but solution obeyed Henrys law. The vapour pressure isotherms of the glassy polymers obeyed a modified Langmuir expression suggesting that two concurrent sorption mechanisms were operative, the filling of microvoids within the polymer structures and ordinary Henrys law solution. Kinetic sorption-desorption studies showed that diffusion was “Fickian” in polyethylene and polyamide over the entire pressure range. It was also “Fickian” in polycarbonate at pressures up to approximately 25 cm Hg, but “non-Fickian” at higher levels. For each polymer, diffusion coefficients were determined by steady-state permeation and transient sorption-desorption methods, and the separate methods gave similar values.