Effect of Ethanol Pretreatment on Skin Permeation of Drugs

Abstract

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 (D 2 O), 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 D 2 O 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 D 2 O, 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.Key words skin permeation; ethanol; pretreatment; electrical skin resistance; enhancer; permeation route Ethanol (EtOH) is well known as an ingredient of alcoholic beverages and has been utilized as a medicine for humans with different efficacies since ancient times. Currently, several skin disinfectants containing EtOH are frequently utilized in hospitals and public facilities for preventive purposes against viral infections. EtOH is a commonly used solvent just like water in pharmaceutical formulations, and is applied as a skin permeation enhancer, a skin disinfectant, and a solubilizer for poorly-soluble drugs. Tinctures, lotions, gels and liniments are dosage forms containing EtOH. Transdermal drug delivery systems and topical formulations often have the problem of low skin permeation of active ingredients. The skin barrier is mainly constituted by the outermost layer of skin, the stratum corneum, which dramatically restricts skin permeability of drugs. EtOH in topical formulations greatly enhances skin permeation of drugs. Estradiol and fentanyl dermal patches are typical examples developed using EtOH to enhance their transdermal deliveries.1-3) It has been proposed that the mechanisms of EtOH effects on the stratum corneum are extraction of lipids, increases in lipid...

Analysis of the Pretreatment Effect of Ethanol on the Stratum Corneum- and Hair Follicular-Penetration of Drugs Using the Hair Follicle-Plugging Method

“…The decreasing ratio in the skin permeation of FD-4 obtained in the present study was higher than our previous findings for the permeation of calcein (molecular weight (MW); 645) after a pretreatment with a high concentration of EtOH. 25) On the other hand, the reciprocal of electrical skin resistance 34) obtained in the present study suggests that ion transport through skin was detected under all conditions independently of the EtOH concentration. The low reciprocal of skin resistance of ionized LC has been attributed to low ion concentrations in the buffered solution (we used 1/30 mM PB instead of PBS) in the donor compartment, and the relationship between skin resistance and the EtOH concentration was similar to that of the other drugs.…”

“…25) Our findings demonstrated that the skin permeation of hydrophilic drugs was increased and decreased by pretreatments with low and high concentrations of EtOH, respectively. We then speculated that EtOH may have affected the permeation pathway of these drugs.…”

“…Moreover, the permeability coefficients of lipophilic compounds were estimated from our previously reported results in which EtOH did not have a significant effect on the skin permeation of isosorbide dinitrate (MW; 236, Log K ow ; 1.22). 25) The reason why different behaviors were observed between ionized LC and FL, which have similar molecular weights and Log K ow , was attributed to the existence of different permeation pathways dependent on the different physicochemical properties of penetrants such as the electrical charge or functional group. Thus, EtOH could affect both aqueous pathways to change the permeability coefficients of hydrophilic drugs.…”

Spray-on transdermal drug delivery systems

“…Typically, TSS contains a volatile alcohol as a carrier solvent. Volatile alcohol impact on skin permeation from volatile transdermal products is minimal due to its rapid evaporation; for alcohol to enhance skin permeation alcohol--skin contact time is critical [56][57][58]. In a recent study to assess alcohol enhanced skin permeation from disinfectant formulations, it was concluded that alcohol did not induce clinically relevant dermal absorption enhancement within 1 h after disinfectant application.…”

High-Throughput Screening of Potential Skin Penetration-Enhancers Using Stratum Corneum Lipid Liposomes: Preliminary Evaluation for Different Concentrations of Ethanol

“…However, the permeation of caffeine decreased at the highest ethanol concentration, because highly concentrated ethanol dehydrates the skin membrane and reduces the skin permeation of drugs [21]. Our previous study also found that the skin permeability of hydrophilic drugs was increased but inversely decreased by low and high concentration of ethanol, respectively [22]. In addition, X-ray diffraction data confirmed that low concentrations of ethanol disturbed the short lamellar structure of SC lipids, but the high concentration caused an aligned structure [23].…”