Combined effects of iontophoretic and chemical enhancement on drug delivery. II. Transport across human and murine skin.

This paper reports measurements of the release characteristics of the model drug salbutamol from a liquid crystalline vehicle across both human and hairless murine skin in vitro. The use of oleic acid and iontophoresis as penetration enhancement techniques, used separately and simultaneously, was also investigated. Over a period of 12h, salbutamol base did not diffuse from the vehicle across excised human skin while, in contrast, over a period of 2h, the drug passively transported across hairless murine skin. The diffusion co-efficient for the drug in this tissue was estimated to be 4.54+/-0.60x10(-9)cm(2)s(-1) with a permeability co-efficient of 7.03+/-0.83x10(-7)cms(-1). A current of density of 0.39mAcm(-2) facilitated a significant transport of salbutamol from the liquid crystalline vehicle across excised human skin but with a small (<0.1) transport number. The quantity of salbutamol transported across excised hairless murine skin under the same conditions was significantly greater with a transport number of 0.68. The alteration of the permeability of the tissue was less than that of the human skin and a full recovery of the pre-iontophoretic permeability of murine skin was consistently observed. The incorporation of either oleic or lauric acid into the monoglyceride component of the vehicle at a concentration of 0.1M had a marked effect on the transport of salbutamol across both human and murine skin. The initial passive permeation of the drug across the skin was not affected but the rate of drug delivery during iontophoresis was typically observed to increase by a factor greater than two. The post-iontophoretic transport of salbutamol across either tissue was also substantially enhanced in the presence of the fatty acid. The analogous use of stearic acid did not significantly influence the iontophoretic or the post-iontophoretic transport of salbutamol across excised human skin. The investigation also revealed a synergistic combination of the fatty acid and anodal iontophoresis to enhance the in vitro transport of other drug substances, including nicotine and diltiazem hydrochloride across murine skin. Oleic acid increased both the iontophoretic and post-iontophoretic transport of nicotine, so that the enhancement of drug delivery was greater than that caused by the current alone. The investigation also indicated that the barrier properties of the skin recover following the constant current iontophoresis in the presence of oleic or lauric acids.

Modelling skin permeability in risk assessment--the future.

The modelling of skin permeability is important for transdermal drug delivery, in the cosmetic industry and for risk assessment attendant on dermal exposure to toxic substances. The two principal methods currently used are quantitative structure-activity relationships (QSARs), used in the main to predict permeability coefficients, and mathematical modelling based on analytical or numerical solutions to the relevant partition and transport equations and used to predict the amount of a substance permeating through the skin. This paper will assess recent progress in this area and suggest what will be needed for future advancements. The considerable effort invested in the development of QSARs during the past decade has resulted in only rather modest progress. Further significant improvement in our ability to predict percutaneous permeability is likely to require the measurement of new data under carefully controlled conditions and its fitting to new QSAR equations. Reliable assessments of risks following dermal exposures will demand new integrated mathematical models that include the variables associated with the exposure and penetration processes as well as the factors that control the subsequent passage of the penetrant into the systemic system.

Iontophoretic and chemical enhancement of drug delivery. Part I: across artificial membranes.

This paper reports on measurements of the release characteristics of the model drug salbutamol base from a liquid crystalline vehicle across a non-rate limiting synthetic membrane. The measured passive release rates were compared with analogous behaviour: (i) when a penetration enhancer such as oleic acid was incorporated into the vehicle; (ii) when the release was iontophoretically assisted; and (iii) when the penetration enhancer and iontophoretic assistance were used simultaneously. The effects of using isotonic phosphate buffer solution as the aqueous domain of the vehicle and in the receptor were also separately assessed. The passive release from the standard system was consistent with matrix diffusion control. The addition of oleic acid indicated association of the drug with the fatty acid so that its release into an aqueous medium was significantly retarded. With buffer ions present in the vehicle the release rate increased consistent with reduced association, and when phosphate buffer was used as a receptor medium the release rate exceeded that of the standard vehicle due to an ion exchange process. The delivery of salbutamol from the fatty acid containing systems was substantially enhanced by iontophoresis and the rates were shown to be approximately proportional to the assisting currents. The data clearly indicate the iontophoretic process to be significantly less efficient in the presence of buffer ions but with the iontophoretic delivery rates being enhanced by the presence of a fatty acid.

An investigation of the adsorption of C5-C12 hydrocarbons in the ppmv and ppbv ranges on Carbotrap B.

The effects of concentration and temperature on the breakthrough volumes (Vb) of 23 volatile organic compounds on Carbotrap B have been determined using the frontal chromatography method. From the measured Vb, original isotherms have been produced and adsorption parameters based on the Langmuir, Freundlich, and Dubinin-Polyani adsorption models have been calculated. The calculated adsorption parameters describe the behavior of these VOC on Carbotrap B under the experimental conditions and are useful data for VOC sampling applications including adsorption modeling of pumped and diffusive sampling. Each of the adsorption models give similar results and are in good agreement with the experimental data in the ppmv concentration range. It will be shown that contrary to previous assumptions the Langmuir adsorption parameters obtained at ppmv concentrations cannot be used to predict Vb at ppbv concentrations and the calculated parameter mmax does not represent the maximum adsorbent capacity. The Freundlich and Dubinin-Polyani models are shown to be more successful in describing the adsorption behavior of the VOC at ppbv levels where Vb is independent of concentration. The isosteric heats of adsorption (-delta Hst) for some of the compounds have been determined using the Van't Hoff equation which can be used to predict the effect of temperature on Vb.

Percutaneous penetration studies for risk assessment.

During the last few years the general interest in the percutaneous absorption of chemicals has increased. It is generally accepted that there is very few reliable quantitative and qualitative data on dermal exposure to chemicals in the general population and in occupationally exposed workers. In order to predict the systemic risk of dermally absorbed chemicals and to enable agencies to set safety standards, data is needed on the rates of percutaneous penetration of important chemicals. Standardization of in vitro tests and comparison of their results with the in vivo data could produce internationally accepted penetration rates and/or absorption percentages very useful for regulatory toxicology. The work of the Percutaneous Penetration Subgroup of EC Dermal Exposure Network has been focussed on the standardization and validation of in vitro experiments, necessary to obtain internationally accepted penetration rates for regulatory purposes. The members of the Subgroup analyzed the guidelines on percutaneous penetration in vitro studies presented by various organizations and suggested a standardization of in vitro models for percutaneous penetration taking into account their individual experiences, literature data and guidelines already in existence. During the meetings of Percutaneous Penetration Subgroup they presented a number of short papers of up to date information on the key issues. The objective was to focus the existing knowledge and the gaps in the knowledge in the field of percutaneous penetration. This paper is an outcome of the meetings of the Percutaneous Penetration Subgroup and reports the presentations on the key issues identified throughout the 3-year duration of the Dermal Exposure Network (1997-1999).

Transdermal delivery of nicotine in normal human volunteers: a single dose and multiple dose study.

The absorption of nicotine delivered by a transdermal delivery system (TDS) was investigated in two separate studies, (A) a dose proportionality study and (B) a multiple dose study. In the dose range of 15-60 mg nicotine, the AUC and Cmax values were proportional to the dose. The levels achieved were in the same range as reported in smokers, following absorption from nicotine chewing gum. The TDS used in the present study produced sustained levels of nicotine for 24 h. No significant accumulation of nicotine was evident as a result of multiple dose administration using a 30-mg nicotine patch. Absorption of nicotine from the TDS was 80-90% and the rate of delivery was similar during both studies.