Effect of ethanol pretreatment on skin permeation of drugs

It has been demonstrated that ethanol (EtOH) can enhance skin permeation of drugs when simultaneously applied with drugs. However, only a few studies have reported on the pretreatment effect of EtOH on skin permeations. In this study, the pretreatment effects of EtOH on skin permeation of drugs were investigated by measuring changes in skin permeation and electrical skin resistance. Permeabilities of deuterium oxide (D2O), isosorbide mononitrate (ISMN), isosorbide dinitrate (ISDN), calcein sodium (CA-Na), and fluorescein isothiocyanate-dextran 4?kDa (FD-4, 3.3-4.4?kDa) were evaluated through Yucatan micropig skin pretreated with different concentrations of EtOH solution. From the results, almost constant skin permeabilities of D2O and ISDN were observed independent of EtOH concentration. Skin permeabilities of ISMN, CA, and FD-4 increased with low concentrations of EtOH, but decreased with high concentrations of EtOH. At 99.5% EtOH pretreatment, skin permeabilities of hydrophilic compounds (ISMN, CA, and FD-4) decreased to non-detectable levels. In addition, low molecular ion transports were almost constant at any EtOH concentration. Since molecular (ion) sizes of ISMN, CA, and FD-4 are larger than Na⁺, Cl^－, and D2O, permeation pathway sizes for hydrophilic compounds in the skin barrier may be remarkably decreased by pretreatment with high concentrations of EtOH. However, the permeability coefficient of ISDN was not influenced by any EtOH concentration, since ISDN is a lipophilic, low-molecular compound that permeated through the lipophilic stratum corneum pathway. The present results show useful information for repeatedly and topically applied formulations containing EtOH, and also contribute to the effective use of alcohol formulations.     

Effect of positively and negatively charged liposomes on skin permeation of drugs

To clarify the effect of the surface charge of liposomes on percutaneous absorption, the permeation of liposomal drugs through rat skin was investigated in vitro and in vivo. Liposomes were prepared using egg yolk lecithin (EPC, phase transition temperature, -15 to -17 degrees C), cholesterol and dicetylphosphate (DP) or stearylamine (SA) (10:1:1, mol/mol). Also examined was the penetration behavior of positively and negatively charged liposomes, using a fluorescent probe (Nile Red). The in vitro penetration rate of melatonin (MT) entrapped in negatively charged liposomes was higher than that of positively charged ones (p<0.05). When the percutaneous absorption of ethosuximide (ES) encapsulated was estimated in vivo, the absorption of ES from negatively charged liposomes was slightly higher than that from positively charged liposomes. Additionally, the absorption of ES from both types of liposomes was superior to that from the lipid mixtures consisting of the same composition as the vesicles. The percutaneous absorption of betahistine (BH) from a gel formulation containing negatively charged liposomes of BH was much more than that from the formulation with positively charged ones, with 2-fold higher AUC (p<0.05). Histological studies revealed that the negatively charged liposomes diffused to the dermis and the lower portion of hair follicles through the stratum corneum and the follicles much faster than the positive vesicles at the initial time stage after application. Thus, the rapid penetration of negatively charged liposomes would contribute to the increased permeation of drugs through the skin.     

Effects of isopropyl palmitate on the skin permeation of drugs

The model penetrants oxaprozin, nimesulide, gliclazide, and ribavirin, because of their different lipophilicities, were selected to assess the enhancing activity of pre-treatment solutions consisting of isopropyl palmitate (IP) in ethanol (5%, 10%, 15%and 20%, w/w, respectively) across excised rat skin using Franz diffusion cells and HPLC detection. All pre-treatment solutions produced a significant increase in the flux and permeation of all four penetrants (p<0.001) and a relationship between penetrant lipophilicity and enhancement effect was observed. The general order of IP effectiveness at concentration was 20%>15%>10%>5% (w/w). The lag-time of drugs did not significantly change except for ribavirin.     

Effect of abrasion induced by a rotating brush on the skin permeation of solutes with varying physicochemical properties.

A transient reduction in the barrier nature of the skin can be a pre-requisite for successful (trans)dermal delivery of some drugs. The aim of this present study was to investigate and effect of a dermal abrading "rotating brush" device on percutaneous absorption and skin integrity. In vitro experiments were conducted using excised human epidermal membrane. The effect of device parameters (bristle type, treatment duration and applied pressure) on skin permeability of model solutes (methyl paraben, butyl paraben, caffeine, acyclovir and angiotensin II) with varying physicochemical properties was examined and compared to established methods of skin penetration enhancement (positive controls). The device parameter which was found to have the most marked effect on permeability of the compounds was bristle type. Profound changes (2- to 100-fold increase) were observed in the epidermal permeability of the hydrophilic penetrants (caffeine, acyclovir and angiotensin II), when the brush device was employed compared to positive controls (ethanol enhancement, delipidisation, iontophoresis and tape-stripping). Findings from this present study support the effectiveness of a rotating brush applied to the skin in enhancing epidermal permeability. Further optimization of operational parameters is required to exploit this simple and effective delivery device.     

Effect of menthone and related compounds on skin permeation of drugs with different lipophilicity and molecular organization of stratum corneum lipids

The objective of this article was to investigate the enhancing effect of menthone, menthol and pulegone on the transdermal absorption of drugs with different lipophilicity and probe their mechanisms of action at molecular level. Five model drugs, namely osthole, tetramethylpyrazine, ferulic acid, puerarin and geniposide, which were selected based on their lipophilicity denoted by logK_o/w, were tested using in vitro permeation studies in which Franz diffusion cells and rat skin were employed. Infrared spectroscopy and molecular dynamic simulation were used to investigate the effect of these enhancers on the stratum corneum (SC) lipids, respectively. Three compounds could effectively promote the transdermal absorption of drugs with different lipophilicity, and the overall promoting capacities were in the following increasing order: pulegone?<?menthol?<?menthone. The penetration enhancement ratio was roughly in parabolic curve relationships with the drug lipophilicity after treatment with menthol or menthone, while the penetration enhancement effect of pulegone hardly changed with the alteration of the drug lipophilicity. The molecular mechanism studies suggested that menthone and menthol enhanced the skin permeability by disordering the ordered organization of SC lipids and extracted part of SC lipids, while pulegone appeared to promote drug transport across the skin only by extracting part of SC lipids.     

Effect of pH on skin permeation enhancement of acidic drugs by l-menthol-ethanol system

The effect of pH on the skin permeation enhancement of three acidic drugs by the l-menthol-ethanol system was investigated. The total flux of acidic drugs from the system remarkably varied over the pH range 3.0-8.0, and the permeation enhancement factor depended on the system pH and drug. A skin permeation model, which consists of two permeant (unionized and ionized) species, two system (oily and aqueous) phases, and two permeation (lipid and pore) pathways, was developed. The assumptions were made that only the unionized species can distribute to the oily phase and transport via the lipid pathway. The model explained the relationship between the concentration of drug in the aqueous phase and system pH. The skin permeability data were also described by the model and permeability coefficients corresponding to the physicochemical properties of permeant were calculated for the lipid and pore pathways. The model simulation showed that the permeation of acidic drugs occurred from the aqueous phase and the oily phase acted as a reservoir. Whether the total flux increased with increase of pH was dependent on the lipophilicity of drug. These results suggest that the pH of l-menthol-ethanol system should be given attention to elicit the maximum permeation enhancement.     

Effect of 1-alkyl- or 1-alkenylazacycloalkanone derivatives on the penetration of drugs with different lipophilicities through guinea pig skin

The percutaneous penetration-enhancing effects of 1-dodecyl- (azone), l-geranyl-, and 1-farnesylazacycloheptan-2-one were investigated using seven penetrants having a wide range of n-octanol-water partition coefficients. The penetration of the drugs from water vehicle (aqueous system) and ethanol vehicle (ethanolic system) through excised guinea pig skin was increased by pretreatment with the enhancers. Large enhancement was observed for the drugs, such as 5-fluorouracil and 6-mercaptopurine, with n-octanol-water partition coefficients of approximately unity. The penetration profiles were analyzed based on a one-layer skin model. Two parameters corresponding to the drug diffusivity and partitioning into the skin were obtained. In the aqueous system, the partitioning of drugs into the skin was increased by pretreatment with the enhancers. This led to an increase in drug penetration and accumulation in the skin; diffusivities were little affected. From these parameters, the drug amounts in the vehicle and the skin were well estimated for drugs having partition coefficients of less than 1. In the ethanolic system, the enhancement was far less than that observed in the aqueous system.     

Liposome–skin interactions and their effects on the skin permeation of drugs

The aim of the study was to evaluate the interaction of phospholipid liposomes with skin and stratum corneum lipid liposomes (SCLLs). The influence of phospholipid liposomes on the skin permeability of model drugs was also studied. The transdermal flux of the drugs applied in various phospholipid containing formulations through human epidermis was studied in diffusion chambers. Liposomes in water solutions did not enhance the skin permeability of the drugs, but when ethanol (32% w/v) was present in the donor with EPC (egg yolk lecithin), permeabilities of some model drugs were substantially increased. Confocal microscopy studies revealed that EPC do not penetrate into the skin from water solutions, while from ethanol solutions, EPC penetrates deeply into the stratum corneum. Also, resonance energy transfer between different liposome compositions and the release of calcein from SCLLs showed that interactions between phospholipid liposomes and SCLLs increased with increasing ethanol concentration in the liposome solutions.     

Studies of the skin permeation of lipophilic drugs: paclitaxel

The objective of this investigation was to develop and validate skin permeation methodology for a highly lipophilic drug with respect to sink conditions and intactness of barrier during the course of experiment, using water permeation and trans epidermal water loss as tools.     

Effect of permeation enhancers and organic acids on the skin permeation of indapamide

The aim of present study was to investigate the transdermal properties of indapamide and to explore the efficacy of various permeation enhancers and organic acids with regard to the percutaneous absorption of indapamide. Permeation experiments were performed in vitro, using rat abdominal skin as a barrier. In the permeation studies, 2-chamber diffusion cells were used. The results obtained indicate that N-dodecylazepan-2-one, N-methyl-2-pyrrolidone, menthol and oleic acid had a strong enhancing effect on the permeation of indapamide and N-dodecylazepan-2-one exhibited the most potent enhancing effect. All eight of the organic acids chosen had a potent enhancing effect on the permeation of indapamide across rat abdominal skin. Among the organic acids examined, lactic acid had the greatest enhancing effect. The formation of an ion-pair between indapamide and organic acids may be responsible for the enhanced skin permeation of indapamide. Although the exact reason remains unknown, it is worth carrying out further investigations.     

The effects of terpene enhancers on the percutaneous permeation of drugs with different lipophilicities

Four model drugs were selected based on their lipophilicity denoted as log P (nicardipine hydrochloride log P -0.99 +/- 0.1, hydrocortisone log P 1.43 +/- 0.47, carbamazepine log P 2.67 +/- 0.38, and tamoxifen log P 7.87 +/- 0.75). The enhancing activities of four terpene enhancers (fenchone log P 2.13 +/- 0.30, thymol log P 3.28 +/- 0.20, D-limonene log P 4.58 +/- 0.23, and nerolidol log P 5.36 +/- 0.38) were tested in vitro across full thickness hairless mouse skin with each of the evaluated drugs formulated in hydroxypropyl cellulose gel formulations. The relationships between lipophilicity (log P) of the terpene enhancers and model drugs and efficacy (represented by the enhancement ratio of flux ER(flux)) of the drugs when coadministered with the enhancers were examined using linear regression. Terpene enhancers had significant effect on the percutaneous permeation of the model drugs. Nerolidol (highest lipophilicity) provided the highest increase in the flux of the evaluated model drugs. The flux of nicardipine hydrochloride increased by approximately 135-fold, hydrocortisone by 33-fold, carbamazepine 8-fold, and tamoxifen 2-fold. The lowest increase in the flux was observed with fenchone. Linear relationships were generated between the ER(flux) of nicardipine hydrochloride, hydrocortisone, carbamazepine, and tamoxifen and the log P of the terpene enhancers [r = 0.951, (P = 0.049), r = 0.977, (P = 0.023), r = 0.942, (P = 0.057), and r = 0.874, (P = 0.126), respectively]. Furthermore, the four terpene enhancers produced linear relationships, indicating that they were more effective at enhancing the penetration of hydrophilic drugs rather than lipophilic drugs r=-0.824 (P=0.176) for fenchone, r = -0.891 (P = 0.109) for thymol, r = -0.846 (P = 0.154) for limonene, and r = -0.769 (P = 0.232) for nerolidol.     

Mechanistic and empirical modeling of skin permeation of drugs

The skin forms a barrier to the external environment, maintaining body fluids within our system and excluding harmful substances, while the skin is a site of administration of drugs for topical and systemic chemotherapy. It is an important issue to predict the rate at which drugs or other xenobiotics penetrate the skin. In this article, we review modeling approaches for predicting skin permeation of compounds, including both mechanistic and empirical approaches. Mechanistic approaches can give us much information on understanding of skin permeation of the compounds, such as structure-permeability relationship, contribution of each barrier step, mechanism of penetration enhancers, and in vivo-in vitro relationship. On the other hand, empirical modeling can overcome any inaccuracies of mechanistic models caused by the existence of uncertainties and, therefore, give us better predictions from the practical point of view. Artificial neural networks are being available for empirical modeling of complex skin transport phenomenon.     

Effect of different terpene-containing essential oils on permeation of estradiol through hairless mouse skin

Purpose of the present investigation was to evaluate six terpene-containing essential oils for their capacity to promote permeation of estradiol (ES) through hairless mouse skin in vitro. Tests on cajuput, cardamom, melissa, myrtle, niaouli and orange oil, all used at the 10% w/w concentration in propylene glycol (PG), evidenced niaouli oil (NIA) as the best permeation promoter for ES. Tests on the main terpene components of NIA (1,8 cineole, alpha-pinene, alpha-terpineol and D-limonene), evaluated neat (10% w/w in PG) or in admixture, confirmed the better promoting activity of whole NIA. The present data point to the validity of complex terpene mixtures, such as that composing NIA, as transdermal penetration enhancers for moderately lipophilic drugs like ES.     

离子导入对降纤酶经皮渗透的影响

目的研究离子导入对降纤酶经皮渗透的影响。方法利用水平式扩散池，对降纤酶进行离子导入透过大鼠皮肤和人尸表皮的渗透性试验，对电极极性、渗透介质的pH以及离子强度等影响进行考察。结果离子导入阳极转运时，在pH 6.4的磷酸盐缓冲介质中，降纤酶的表观经皮渗透系数为（1.2±0.4）×10^-4 cm·h^-1，明显高于阴极转运［（4.3±1.4）×10^-5 cm·h^-1］；在pH 7.4磷酸盐缓冲介质中，降纤酶阳极离子导入经皮渗透量为（25±5）×10^-14 mol·cm^-2高于pH 6.4介质经皮渗透量［(15±4)×10^-14 mol·cm^-2］。结论离子导入阳极转运能够促进降纤酶的经皮渗透，电渗作用有重要影响。     

DEET-loaded solid lipid particles for skin delivery: in vitro release and skin permeation characteristics in different vehicles

DEET (N,N-diethyl m-toluamide) is a lipophilic compound which has a common use as an insect repellent and causes not only skin irritation but also systemic side effects at high concentrations in long-term skin application. In this study, DEET is incorporated into solid lipid particles, a colloidal drug delivery system, in order to reduce the percutaneous permeation and avoid toxic effects and also maintain drug effectiveness on the skin surface for a long duration of insect repellence. Solid lipid particles were prepared based on emulsion systems at different concentrations and after the characterization studies, the formulation with 20% lipid phase and 1:1 drug:lipid ratio was carried to in vitro release and skin permeation studies. Solid lipid particles with DEET were compared to free DEET using cream and hydrophilic gel vehicles. Results showed that incorporation of DEET into solid lipid particles reduced the release rate and skin permeation of DEET. Imaging studies using scanning electron microscopy showed that there were still solid lipid particles on skin surface after 2 h indicating that DEET could be present for a longer time on the application site.     

Effect of selected fluorinated drugs in a "ringing" gel on rheological behaviour and skin permeation.

The purpose of the present study was to investigate the influence of different drugs exhibiting different solubility on the viscoelastic properties and on the skin diffusion profile of a ringing gel. In a preliminary rheology study with the placebo gel predominating elastic properties were confirmed and a temperature influence was indicated. Fluconazole, fludrocortisone-acetate, flumethasone-pivalate, flutamide and flufenamic-acid each 1% (w/w) were incorporated into the preparation and oscillatory measurements were performed at temperatures of 25, 28, 32 and 37 degrees C. In all drug containing formulations a high elastic G' value predominated the viscous G' value. The highest G' value could be obtained with the incorporated flumethasone-pivalate. Additionally in almost all cases the G' values decreased with increasing temperature compared to the placebo gel. Additionally in vitro standard diffusion experiments using Franz-type cells and porcine skin were performed. Following rank order of the cumulative drug release after 48 h was obtained: fluconazole>flufenamic-acid>flumethasone-pivalate>flutamide>fludrocortisone-acetate. Furthermore an excellent chemical stability of all incorporated drugs was confirmed over 10 weeks.     

Promoting mechanism of menthol derivative, 1-O-ethyl-3-buthylcyclohexanol, on the percutaneous absorption of ketoprofen

Menthol derivatives were synthesized and evaluated for their promoting activity on the percutaneous absorption of ketoprofen and skin irritation in vivo, choosing O-ethylmenthol (MET) as the mother compound. The compound having a C-3 positionned n-butyl group (1-O-ethyl-3-n-buthylcyclohexanol, OEBC) indicated the most promoting activity and caused relatively little skin irritation. In order to understand enhancement mechanism of OEBC an in vitro permeation study of ketoprofen was performed. The time course of the cumulative amounts of drug permeated through the rat skin exhibited a linear relation after an initial lag time. This was analyzed in membrane diffusion model and the diffusion and partition parameters of ketoprofen were estimated. Both parameters were remarkably enhanced when a hydrogel containing a small quantity of OEBC (0.5%) was applied. Furthermore, to clarify the site of action of OEBC, we also investigated in vitro permeation study of ketoprofen employing different skins of state, reversed skin and stratum corneum stripped skin. When OEBC was added to the hydrogels which were applied to the reversed and stripped skins, almost no changes of the flux were observed compared with the control (without OEBC). These results suggested that the site of action of OEBC was stratum corneum. Morphological changes of the stratum corneum surface were microscopically observed with 0-2% OEBC. The spaces between the stratum corneum cells treated with 0.5-2% OEBC became extended and the shape of each cell became clear. This may suggest that the site of action of OEBC was the intercellular of stratum corneum. Furthermore, an electron spin resonance study was performed to investigate the effect of OEBC on the intercellular lipid bilayer fluidity of the stratum corneum and the rotational correlation times were calculated. 2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO) and 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) were used as the spin label. In use of OEBC, the fluidity of TEMPO labeled the stratum corneum lipid increased as the addition of OEBC. The results suggested that OEBC promote the penetration of drugs by enhancing fluidity of the local lipid bilayers around TEMPO.