Comparison of the effect of ultrasound and of chemical enhancers on transdermal permeation of caffeine and morphine through hairless mouse skin in vitro

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Abstract

The effect of ultrasound (US) on permeation of two model drugs, caffeine (CAF) and morphine (MOR), through hairless mouse skin in vitro was compared with that of three chemical enhancers. Low-frequency (40 KHz), low-power (<0.5 W/cm2) US was used; the effect of high-frequency US (1.5–3.0 MHz) was also evaluated in the case of CAF. The chemical enhancers, tested in combination with propylene glycol (PG), were benzalkonium chloride (BAC) oleyl alcohol (OA) and α-terpineol (TER). The high-frequency US enhancement of CAF transdermal flux was not statistically significant, while low frequency produced a small but significant increase of the enhancement factor. The effect of US on CAF permeation, however, was lower than that produced by chemical enhancers, in particular OA. The effect of low-frequency US on permeation of MOR was significantly greater (about 10-fold) when compared, on the same frequency and intensity basis, with the effect on CAF. The most active chemical enhancer for MOR, OA, had practically the same effect as low-frequency US. Sonicated skin, although showing slight histological changes, recovered its original low permeability characteristics after turning off sonication. Within the tested system, chemical enhancement appears to offer some advantages over low-frequency US.

Introduction

The constantly increasing commercial interest of transdermal products, and the recognition of the poor permeability characteristics of the skin have stimulated a great deal of research, aimed at enhancing transdermal drug delivery in a reproducible and reliable manner. The methods that have been explored to enhance transdermal penetration can be divided into two major categories: physical and chemical (Shah, 1994).

Among the physical methods, sonophoresis (or phonophoresis), that can be defined as ultrasonically-facilitated transport of drugs through the skin, has attracted in recent years the attention of several investigators (Skauen and Zentner, 1986, Brucks et al., 1989, Tyle and Agrawala, 1989, Bommannan et al., 1992a, Bommannan et al., 1992b, McElnay et al., 1993, Meidan et al., 1995, Mitragotri et al., 1995, Mitragotri et al., 1996). The most commonly used conditions for sonophoresis correspond to therapeutic/diagnostic US (frequency range, 1–10 MHz, intensity range, 0.2–3 W/cm2): the typical enhancement of transdermal drug transport observed in this frequency/intensity range is less than 10-fold, although in many circumstances no or scarce enhancement has been detected. Low-frequency (20 KHz, 0.125 W/cm2) pulsed US has been reported to be more effective, particularly in the case of proteins and hydrophilic drugs (Mitragotri et al., 1995, Mitragotri et al., 1996) and of clobetasol 17-propionate (Fang et al., 1999).

A wide body of literature, on the other hand, deals with chemical enhancers (or absorption promoters): these act mainly by transiently altering the permeability characteristics of the stratum corneum, which forms the rate-limiting lipophilic skin barrier (Hsieh, 1994, Finnin and Morgan, 1999).

Aim of the present investigation was to compare the effect of US and of chemical enhancers on permeation of two model drugs, caffeine (CAF) and morphine (MOR), through hairless mouse skin in vitro. Low-frequency (40 KHz), low-power (<0.5 W/cm2) US was used; the effect of high-frequency US (1.5–3.0 MHz) was also evaluated in the case of CAF. The chemical enhancers, tested in combination with propylene glycol (PG), were representative of three main categories: surfactants (benzalkonium chloride, BAC), fatty alcohols (oleyl alcohol, OA) and terpenes (α-terpineol, TER). The investigation included a histological study aimed at verifying possible damages produced by low-frequency US to the treated skin.

Section snippets

Materials

The following chemicals were used as received: caffeine (CAF, m.p.=238 °C); benzalkonium chloride (BAC); propylene glycol (PG) (Carlo Erba, Milano, Italy), morphine hydrochloride trihydrate (MOR, m.p.≈200 °C, SALARS, Como, Italy); oleyl alcohol (OA, Novol, Croda Italia srl, Pavia, Italy); α-terpineol (TER, Sigma Chemical Co, St. Louis, MO, USA). All other chemicals and reagents were of analytical grade.

Determination of octanol-buffer partition coefficients of CAF and MOR

The apparent partition coefficients of CAF and MOR were determined at 37 °C by equilibrating

Effect of ultrasound

The steady-state flux, J (given by Q/A×t, where Q is the amount of permeant diffusing across the area A in time t) was calculated by linear regression analysis of permeation data. The enhancing effect of sonication on drug permeation was expressed as US enhancement factor (E), calculated from the ratio Jb/Ja, where Ja and Jb are the average fluxes in the absence and in presence of US, respectively. The skin permeation parameters (flux, lag time, enhancement factor) calculated for CAF and MOR in

Discussion

CAF, considered a relatively hydrophilic, poorly skin-permeable molecule, is a widely used model drug for transdermal permeation studies. The influence of high- and low-frequency US on its transdermal transport has been investigated (Machluf and Kost, 1993, Mitragotri et al., 1995).

Some investigations have also dealt with transdermal administration of MOR. Attempts at improving the poor skin permeation properties of this drug, attributed to its high hydrophilicity (Roy and Flynn, 1988, Roy and

Acknowledgements

The authors wish to thank Professor M.F. Saettone for useful discussions.

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