in-vitro iontophoretic permeation study of nicotine through rat skin

Nicotine transdermal systems are being used as an aid to smoking cessation programs. As the kinetics of nicotine delivery is important in success of a smoking cessation program, rapid and high input of nicotine is required, which is not possible by passive methods and requires enhancement strategies such as iontophoresis. Iontophoretic permeation, of nicotine looks promising, based on published data on human skin. However, to optimize this method, permeation pathways should be known and further parameters have to studied, which are the subject of the present investigation. In this study iontophoretic permeation of nicotine through rat skin was performed and the effects of different variables on this phenomenon were studied. Anodic iontophoresis of nicotine from a solution at pH 2.8, using a 0.5 mA/cm[2] current density resulted in a considerable enhancement [about 3-fold] of nicotine absorption through rat skin. Nicotine concentration and current density showed a directly increasing effect on permeation of the drug, but the effect of concentration was not linear. Pulsatile current delivery was more effective in permeation of nicotine than the continuous method. Anodic iontophoresis was around 2-fold more effective than the cathodic method in increasing the flux. Post iontophoretic permeation studies showed good reversibility of the membrane barrier properties. Results were in good agreement with the reported human data and might be considered as an evidence of the ability of rat skin to model human skin and also the importance of intercellular pathway of the stratum corneum in iontophoretic delivery of nicotine and possibly other drugs. Donor's pH showed no effect on permeation of nicotine under the studied conditions, pH values of <3. Results also showed that the electr-osmotic flow could occur at pH values lower than 4. Finally, this study show that by controlling the effective parameters of iontophoretic delivery, a more effective nicotine transdermal delivery method would achievable

Stereoselective permeation of tretinoin and isotretinoin through enhancer-treated rat skin. II. Effects of lipophilic penetration enhnacers

Many properties of chemicals depend on their stereochemistry. Among these, the effects of stereoisomerism on percutaneous absorption of drugs are not well studied. We have previously shown that permeation of tretinoin and isotretinoin [two geometric isomers] through hydrophilic enhancers-treated rat skin is stereoselective. As, depending on their lipophilicity, penetration enhancers can change permeation pathway of drugs, it was decided here to investigate permeation of the same stereoisomers through lipophilic enhancer-treated skin. Oleic acid, that mainly affects stratum corneum intercellular lipids, was chosen as the lipophilic penetration enhancer for this study. Permeation of retinoids through untreated and enhancer-treated rat skin was studied at room temperature. These studies employed static diffusion cells, saturated drugs in propylene glycol:water mixture [75:25, v/v] as the donor phase and aqueous solution of Tween20 as the receptor phase. Permeation of retinoids through untreated skin was too low to be detected in the receptor phase even by the used HPLC method with sensitivity of 10 ng ml-1. Oleic acid increased the permabilities of retinoids to measurable values. In oleic acid-treated skin, tretinoin permeated by about 1.3 times faster than isotretinoin [P<0.0001]. However, permeability coefficients, that are concentration-normalized fluxes, showed a reverse order. Permeability coefficient of isotretinoin through the same membrane was significantly [P=0.0002] higher than that of tretinoin. On the other hand, the difference between permeation lag-times of retinoids was not that significant [P=0.062]. These data show that stereoselctive permeation of these retinoids through oleic acid-treated rat skin is mainly a partitioning-related phenomenon. Diffusion coefficient might play only a minor role. Present results are partly different from those of our previous study on hydrophilic enhancers and clearly show that the type of enhancer and its mode of action can affect stereoselective permeation of drugs through the skin