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At least 469 records · Page 26Linked to original sources
PubMed1994

A model membrane approach to the epidermal permeability barrier.

The permeability barrier of mammalian skin is found in unusual intercellular domains in the upper layers of the epidermis, and is composed mainly of three lipid classes: ceramide, cholesterol, and free fatty acid. These are organized as lamellae, but the details of lipid organization are not precisely known. To examine the relationship between lipid composition and phase behavior, aqueous dispersions of bovine brain ceramide, cholesterol, and perdeuterated palmitic acid were examined by 2H NMR and compared to analogous systems in which sphingomyelin replaced ceramide. The sphingomyelin systems give rise as expected to a stable fluid lamellar signal over the temperature range 20-75 degrees C and pH 5.2-7.4, whereas the ceramide dispersions show complex polymorphism as a function of both temperature and pH. Prominent features of the ceramide dispersions containing cholesterol are phase coexistence and the presence of a "solid" phase in which molecular motion is more inhibited than in a classical phospholipid gel phase: T1z measurements indicate that lateral diffusion of the palmitic acid probe effectively does not occur. In the absence of cholesterol, a fluid lamellar signal is not observed, but the appearance of a "solid" signal is also influenced by the pH. In the presence of cholesterol, a fluid lamellar signal is present at 50 degrees C, and the 2H NMR order parameter profile is very similar to that derived from the analogous sphingomyelin dispersions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Stratum corneum lipid phase transitions and water barrier properties.

In mammals, the outer skin layer, the stratum corneum, is the ultimate barrier to water loss. In order to relate barrier function to stratum corneum structure, samples from porcine skin were investigated by using differential scanning calorimetry (DSC), infrared (IR) spectroscopy, and water permeability techniques. Results of DSC and IR studies show that stratum corneum lipids undergo thermal transitions between 60 and 80 degrees C similar to lipid thermotropic transitions seen in a variety of synthetic and biological membranes. Results of water flux experiments performed under conditions similar to those of the DSC and IR studies show an abrupt change in permeability at about 70 degrees C. At low temperatures, water flux values are similar to those obtained for human skin in vivo, yielding an activation energy of 17 kcal/mol, in excellent agreement with values obtained for water flux through a variety of lipid biomembranes. In contrast, at temperatures above about 70 degrees C, water flux is characterized by an activation energy only slightly higher than that of free diffusion, suggesting that the stratum corneum offers little diffusional resistance under these conditions. These combined results suggest that increased disorder in stratum corneum lipid structure, brought about by thermotropic transitions, results in dramatically altered diffusional resistance of this tissue to water flux. Thus, as found for numerous biological membranes, water flux and lipid order in porcine stratum corneum are inversely related.

Animals↗
PubMed1997

Evaluation of transdermal penetration enhancers using a novel skin alternative.

A novel alternative to animal skin models was developed in order to aid in the screening of transdermal penetration enhancers. The skin alternative consists of a dermal layer containing human fibroblasts dispersed in a collagen matrix and an epidermal layer of differentiated and stratified human keratinocytes. Skin alternatives were placed in modified Franz diffusion cells (receptor volume 12 mL, donor area 3.14 cm2, n = 5) and enhancer solution (0.4 M in propylene glycol (PG)) was applied. Following 1 h of pretreatment, 10 microL of saturated hydrocortisone (HC) solution in PG was applied, and the cells were occluded with Parafilm. Samples were removed from the receptor compartment over 24 h, replaced with fresh receptor solution, and analyzed for steroid content using HPLC. Skin HC content was also determined. Receptor concentration at 24 h (Q24) for full-thickness skin alternative (control) was 28.6 +/- 13.7 microM and permeability (P) was 8.3 x 10(-4) +/- 5.5 x 10(-4) cm h-1. Azone (1) produced a Q24 of 105.0 +/- 36.1 microM and a P of 11.3 x 10(-4) +/- 1.8 x 10(-4) cm h-1, while the novel penetration enhancer 1-dodecyl-2-pyrrolidinone (2) produced a Q24 of 164.8 +/- 61.2 microM and a P of 33.3 x 10(-4) +/- 6.6 x 10(-4) cm h-1. Compound 3 produced the highest values for all permeability parameters tested with a P of 48.0 +/- 36.8 cm h-1 and a Q24 of 186.1 +/- 45.1 microM. When compared to the control, compound 1 gave an enhancement ratio (ER) of 3.7 for Q24 and 1.4 for P. Compound 2 gives an ER 5.8 for Q24 and 4.0 for P. These enhancement ratios are similar to those found using HC and human skin.

Administration, Cutaneous↗
PubMed1998

Skin electroporation: rapid measurements of the transdermal voltage and flux of four fluorescent molecules show a transition to large fluxes near 50 V.

Large molecular fluxes and tight control are highly desired for transdermal drug delivery, which motivated this study of molecular transport due to high voltage pulsing. We used a flow-through sampling system (time resolution of approximately 14 s) to measure the response of human skin in vitro to a series of exponential pulses (time constant of 1 ms; peak transdermal voltages [Uskin,0] of 0 V to approximately 300 V, one pulse every 5.6 s). Four negatively charged, hydrophilic fluorescent tracer molecules were employed: sulforhodamine, lucifer yellow, cascade blue, and calcein (molecular weights of 450 to 625 Da). Although differences in their molecular transport profiles were observed, all four molecules exhibited a transition from small to large fluxes at Uskin,0 approximately 50 V. This behavior may reflect a transition from electroporation of the skin's appendages to electroporation of the multilamellar bilayer membranes within the stratum corneum.

Electroporation↗
PubMed2001

Influence of drug treatment on the microacidity in rat and human skin--an in vitro electron spin resonance imaging study.

PURPOSE: The possibilities of the noninvasive examination of microacidity (5) in different depths of the skin in vitro was explored, and the impact of drug treatment on the pH inside the skin was studied. METHODS: Spectral-spatial electron spin resonance imaging (ss-ESRI) and pH-sensitive nitroxides were used to obtain a pH map of rat and human skin in vitro. RESULTS: The dermal application of therapeutically used acids, such as salicylic acid and azelaic acid, caused a plain change of microacidity (pH) inside the skin. Species-linked differences between rat and human skin samples with respect to penetration and microacidity were found. CONCLUSIONS: ESRI has been shown to be a new and completely noninvasive method to monitor microacidity in different skin layers and on the skin surface. This nondestructive method allows serial measurements on skin samples to be performed without any preparatory steps.

Animals↗
PubMed2002

High throughput screening of transdermal formulations.

PURPOSE: Applications of transdermal drug delivery are limited by low skin permeability. Many chemicals have been used to enhance skin permeability, however, only a handful are actually used in practice. Combinations of chemicals are likely to be more efficient in enhancing skin permeability compared to individual enhancers. However, identification of efficient enhancer combinations is quite challenging because many chemical enhancers interact with each other and with the skin in a complex manner. In the absence of a fundamental knowledge of such interactions, we need to rely on rapid methods to screen various enhancer combinations for their effectiveness. In this paper, we report a novel high throughput (HTP) method that is at least 50-fold more efficient in terms of skin utilization and up to 30-fold more efficient in terms of holdup times than the current methods for formulation screening (Franz diffusion cells). METHODS: A high throughput method was developed based on skin conductivity and mannitol penetration into the skin. This method was used to perform at least 100 simultaneous tests per day. Detailed studies were performed using two model enhancers, sodium lauryl sulfate (SLS) and dodecyl pyridinium chloride (DPC). The predictions of the high throughput method were validated using Franz diffusion cells. RESULT: High throughput screening revealed that mixtures of SLS and DPC are significantly more effective in enhancing transdermal transport compared to each of them alone. Maximum efficiency was observed with near-equimolar mixtures of SLS: DPC. The predictions of the HTP method compared well against those made using Franz diffusion cells. Specifically, the effect of surfactant mixtures on skin conductivity and mannitol permeability measured using Franz cells also showed a maximum at near-equimolar mixtures of SLS: DPC. CONCLUSIONS: The novel HTP method allows rapid screening of enhancer formulations for transdermal applications. This method can be used to discover new and effective enhancer mixtures. At the same time, these data may also broaden our understanding of the effect of enhancers on skin permeability.

Adjuvants, Pharmaceutic↗
PubMed1990

DC electrical properties of frozen, excised human skin.

DC current-voltage relationships and sodium ion transport measurements for human allograft skin immersed in saline buffers have been determined using a four terminal potentiometric method and diffusion cells of our own design. About three-fourths of the skin samples were deemed suitable for study on the basis of their high resistivities and similar j-V characteristics. Most of these samples yielded sodium ion permeability coefficients less than or equal to those reported for human skin in vivo. The current-voltage relationship in these tissues was time dependent, highly nonlinear, and slightly asymmetric with respect to the sign of the applied potential. Skin resistance decreased as current or voltage increased. For current densities less than 15 microA/cm2 and exposure times of 10-20 min, this decrease was almost completely reversible; at higher current densities, both reversible and irreversible effects were observed. The overall dependence of current on voltage was nearly exponential and was satisfactorily described by an equation of the form j approximately sinh V. Diffusion potentials, sodium ion membrane transference numbers, and sodium ion flux enhancement factors during iontophoresis were measured for skin immersed both in normal saline solutions and in saline solutions of differing concentrations. The sign of the diffusion potentials and the value of the sodium ion transference number (0.51 in normal saline at pH 7.4) indicated a weak permselectivity of the skin for transport of sodium ion versus chloride. At a current density of 71 microA/cm2 and transmembrane potentials in the range of 1.1-1.6 V, the flux enhancement for sodium ion was three to five times greater than that predicted for an uncharged homogeneous membrane according to electrodiffusion theory. For transmembrane potentials less than 0.17 V, agreement of this theory with the data was better but still incomplete.

Diffusion↗
PubMed1992

Cutaneous metabolism of nitroglycerin in vitro. II. Effects of skin condition and penetration enhancement.

The effects of skin storage, skin preparation, skin pretreatment with a penetration enhancer, and skin barrier removal by adhesive tape-stripping on the concurrent cutaneous transport and metabolism of nitroglycerin (GTN) have been studied in vitro using hairless mouse skin. Storing the skin for 10 days at 4 degrees C did not alter barrier function to total nitrate flux [GTN + 1,2-glyceryl dinitrate (1,2-GDN) + 1,3-glyceryl dinitrate (1,3-GDN)]. However, metabolic function was significantly impaired and suggested at least fivefold loss of enzyme activity. Heating skin to 100 degrees C for 5 min appreciably damaged hairless mouse skin barrier function. The ability to hydrolyze GTN was still present, however, and remained constant over the 10-hr experimental period, in contrast to the "control," which showed progressively decreasing enzymatic function with time. Pretreatment of hairless mouse skin in vivo (prior to animal sacrifice, tissue excision, and in vitro transport/metabolism studies) with 1-dodecylazacycloheptan-2-one (Azone), a putative penetration enhancer, significantly lowered the skin barrier to nitrate flux (relative to the appropriate control). Again, barrier perturbation resulted in essentially constant metabolic activity over the observation period. The ratio of metabolites formed (1,2-GDN/1,3-GDN) was increased from less than unity to slightly above 1 by the Azone treatment. Adhesive tape-stripping gradually destroyed skin barrier function by removal of the stratum corneum. The effects of 15 tape-strips were identical to those of Azone pretreatment: a greatly enhanced flux, a constant percentage formation of metabolites over 10 hr (once again), and an increase in the 1,2-GDN/1,3 GDN ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed1990

Enhancement of the in vitro skin permeability of azidothymidine (AZT) via iontophoresis and chemical enhancer.

Azidothymidine (AZT) was used as a model drug to study the effect of iontophoresis on the skin permeation of a neutral compound. The rate of in vitro permeation across hairless rat skin was low and highly variable. With iontophoresis treatment the permeation rate was two- to threefold greater than by passive diffusion. The addition of varying amounts of sodium chloride to the donor enhanced the iontophoretic permeation rate an additional two- to threefold possibly due to convective forces. The addition of N-decylmethyl sulfoxide (C10MSO) to the donor increased the permeation rate by several hundred-fold over passive diffusion for hairless rat skin and approximately 75-fold for human skin. No additional enhancement was observed with the combination of C10MSO and iontophoresis treatment at constant current or constant voltage. It may be that the presence of C10MSO lowers the zeta potential of the skin, thus enhancement due to convective flow is minimized.

Animals↗
PubMed1990

Electrical analysis of fresh, excised human skin: a comparison with frozen skin.

Samples of human allograft skin prepared without freezing ("fresh skin") were found to have electrical and sodium ion transport properties which differed only slightly from those of skin which had been similarly treated but stored frozen ("frozen skin"). The fresh skin samples were less permeable to sodium ions during passive diffusion and less conductive than frozen skin at low current levels. They were more permselective for sodium versus chloride during constant-current iontophoresis and showed slightly more asymmetry in their current-voltage properties. Overall, the electrical behavior of the two tissues was similar enough to support the use of frozen tissue in iontophoresis studies. However, caution should be exercised when considering the use of frozen skin for applications, such as those based on electroosmosis, where the observed differences could have a major impact on the results.

Diffusion↗
PubMed1988

The relationship of pKa and acute skin irritation in man.

The relationship between pKa and skin irritation in man is studied for a homologous series of benzoic acid derivatives, which permeate through human skin at comparable rates (15-88 micrograms/cm2/hr). Skin irritation and pKa are correlated for pKa less than or equal to 4. Laser Doppler velocimetric assessment of skin blood flow, color meter readings, erythema, edema, and the primary irritation index are all linearly correlated and related to pKa; erythema at 24 hr appears to be the most sensitive parameter to variation in pKa when pKa less than or equal to 4.

Adult↗
PubMed1989

Transdermal dual-controlled delivery of contraceptive drugs: formulation development, in vitro and in vivo evaluations, and clinical performance.

Several transdermal contraceptive device (TCD) formulations were developed to provide a dual-controlled transdermal delivery of levonorgestrel (LN), a potent progestin, and 17 beta-estradiol (E2), a natural estrogen. Using a sensitive HPLC method, the in vitro release and skin permeation profiles of LN and E2 from various TCD formulations were simultaneously characterized in the hydrodynamically well-calibrated Valia-Chien skin permeation cells and both were found to follow zero-order kinetics. The rates of drug release and skin permeation were observed to vary significantly depending upon some formulation parameters. Six-month stability studies were performed on seven formulations at room and elevated temperatures (37 and 45 degrees C), and two (Formulations 4 and 5) were found to be acceptable, based on drug recovery, release rate, and skin permeation rate data. Judging from the 6-month accelerated stability studies, it is projected these two formulations will have shelf-life of at least 2 years. As a result of development of an efficient manufacturing process, Formulation 4 was selected for further evaluation. One-week primary skin irritation evaluation in 6 rabbits indicated that Formulation 4 is nonirritating, and it was thus selected for Phase I clinical bioavailability/dose proportionality studies in 12 healthy female volunteers of child-bearing age. Results of pharmacokinetic and pharmacodynamic analyses demonstrated that it is capable of achieving and maintaining a steady-state serum level of LN throughout the 3-week treatment period by weekly applications of one or two TCD patches (10 or 20 cm2). A dose proportionality was obtained in the serum drug levels, daily dose delivered, and contraception efficacy. An excellent correlation was obtained for the rates of transdermal delivery determined by the in vitro studies using human cadaver skin, the in vivo studies in rabbits, and the clinical studies in living subjects.

Adhesives↗
PubMed1995

The electrical characteristics of human skin in vivo.

PURPOSE: The objectives of this study were to investigate the impedance properties of human skin in vivo and to examine the effect of iontophoresis upon them. METHODS: Having established the intra- and inter-individual variation in basal values of skin impedance, the effect of varying iontophoretic current density, ionic strength and counter-ion on the rate of recovery of skin impedance after iontophoresis was investigated. RESULTS: Passage of an iontophoretic current caused a significant reduction in the magnitude of the skin impedance. Increasing the current density caused an even greater reduction in the value of the skin impedance and slowed the rate of recovery. Reduction of the ionic strength resulted in an increase in the rate of recovery following iontophoresis. A significant increase in the rate of recovery was observed when CaCl2 replaced NaCl as the electrolyte. Although visual inspection revealed the presence of greater erythema when CaCl2 was used, there was an absence of the mild sensation experienced by volunteers when using NaCl. The last part of the study established a correlation between transepidermal water loss and impedance analysis as complementary methods for probing skin barrier function in vivo. The data were fitted to an equivalent circuit consisting of a resistor in parallel with a constant-phase element and a mechanistic model proposed to explain the electrical properties of the skin. CONCLUSIONS: The first comprehensive investigation of the effect of iontophoresis on the electrical properties of human skin in vivo has been described. It would appear from the results, and from their interpretation, that impedance spectroscopy may be an effective method to quantify the impact of iontophoresis on the skin, and to determine the extent to which proposed drug delivery regimens will perturb skin barrier function.

Electric Impedance↗
PubMed1993

Electrochemical characterization of human skin by impedance spectroscopy: the effect of penetration enhancers.

The electrochemical properties of human cadaver skin were studied in a diffusion cell with impedance spectroscopy as a function of time in the absence and presence of penetration enhancers dodecyl N,N-dimethylamino acetate and Azone. An improved electrochemical model of skin is presented, and combining the novel model with modern fractal mathematics, the effect of enhancers on the surface of skin is demonstrated. The enhancers appeared to open new penetration routes and increase the ohmic resistance, capacitive properties, and fractal dimension of skin, which means a rougher or more heterogeneous surface.

Administration, Cutaneous↗
PubMed1994

Estimation of skin target site acyclovir concentrations following controlled (trans)dermal drug delivery in topical and systemic treatment of cutaneous HSV-1 infections in hairless mice.

The use of controlled transdermal delivery of acyclovir (ACV) in the treatment of cutaneous herpes simplex virus type 1 infections in hairless mice was investigated. Using an in vivo animal model (A. Gonsho, et al. Int. J. Pharm. 65:183-194 (1990)) made it possible to quantify both, the topical and the systemic antiviral efficacy of ACV transdermal patches as a function of the drug delivery rate of the patches. Drug delivery rates required to attain systemic efficacy were found to be higher than the rates required to attain the same magnitude of topical efficacy. The ACV concentrations in the basal cell layer of the epidermis for 50% topical efficacy and 50% systemic efficacy were estimated. The basal epidermis layer was considered to be the site of antiviral drug activity (skin target site). Systemic plasma levels were obtained from pharmacokinetic studies and were used to estimate the ACV concentration achieved systemically in the basal epidermis layer. A computational model for drug permeation across skin was employed to estimate the ACV concentration achieved topically in the basal epidermis layer. Equal topical and systemic efficacies were found to correspond to equal drug concentrations at the site of antiviral activity. The length of the effective diffusion pathway of drug molecules in the dermis prior to entering the blood circulation was assumed to be approximately equal to 1/20 of the anatomical dermis thickness because of dermis vascularization.

Acyclovir↗
PubMed2003

Effects of fatty acids and iontophoresis on the delivery of midodrine hydrochloride and the structure of human skin.

PURPOSE: The purpose of this work was to investigate if fatty acids can increase the iontophoretic delivery of midodrine hydrochloride through human dermatomed skin and to observe the effects of iontophoresis and fatty acids on skin using SEM. METHODS: After prehydration for 1 h, human dermatomed skin was treated with 0-0.3 M fatty acids (oleic acid, linoleic acid, decanoic acid, and lauric acid) in propylene glycol (PG) for 1 h. Then the fatty acid solution was replaced by 1% midodrine hydrochloride aqueous solution, and 0.1 mA/cm2 constant current was applied. Samples were taken over 24 h and analyzed by HPLC. After the treatments outlined above, the epidermis was separated, fixed with glutaraldehyde, and dehydrated for SEM. RESULTS: SEM studies revealed that only 1 h of treatment with fatty acids opened up the tightly compact stratum corneum cell layer, and the permeation study showed a significant increase of the permeability of skin to midodrine hydrochloride after fatty acid treatment. CONCLUSIONS: Using 5% oleic acid pretreatment, with the electrical current offset at 0.1 mA/cm2, the daily delivery of midodrine hydrochloride can provide an adequate clinical application. The enhancement of passive and iontophoretic delivery by fatty acids may be occurring through the same mechanism.

Adjuvants, Pharmaceutic↗