Enhancement of transdermal delivery of theophylline using microemulsion vehicle

Abstract

A microemulsion vehicle had been studied as a possible matrix for transdermal delivery of theophylline. The existence of microemulsion regions were investigated in pseudo-ternary phase diagrams, and various microemulsion formulations were prepared using oleic acid, Cremophor RH40/Labrasol (1:2) and water. The optimal formulation of the microemulsion was evaluated in vitro using Franz diffusion cells. The droplet size of microemulsion was characterized by photo correlation spectroscopy. Pharmacokinetic study in vivo was conducted using rabbits, and the results indicated that AUC_0→∞ of transdermal administration was 1.65-fold higher than that of oral solution administration. These studies showed that microemulsion system of theophylline might be promising vehicles for the transdermal delivery of theophylline.

Introduction

Theophylline (Fig. 1), a potent methylxanthine drug, which acted as a bronchiolar smooth muscle relaxant and a suppressor of non-bronchodilator response of airways, and whose bronchodilator mechanism was through the inhibition of phosphodiesterase by increasing cAMP, had been widely used for the treatment of asthma and chronic obstructive pulmonary disease by oral or intravenous route clinically (Choi et al., 1988). But theophylline had a low therapeutic index. In general, therapeutic serum theophylline concentrations ranged from 5 to 15 μg/ml. Small changes in plasma levels might result in therapeutic failure or adverse effects, such as nausea, vomiting, tachycardia, headache, seizure and agitation, therefore, the clinical use of theophylline was limited (Paloucek and Rodvold, 1988, Stavric, 1988, Minton and Henry, 1996).

Microemulsion system, composed of oil phase, aqueous phase, surfactant and co-surfactant at appropriate ratios, had a droplet size between 10 and 100 nm, possessed specific physicochemical properties such as transparency, optical isotropy, low viscosity and thermodynamic stability (Gasco, 1997, Tenjarla, 1999, Lawrence and Rees, 2000).

Three main mechanisms had been proposed to explain the advantages of microemulsion for the transdermal delivery of drugs. First, the high solubility potential for both lipophilic and hydrophilic drugs of microemulsion systems might increase thermodynamic activity towards the skin. Second, ingredients of microemulsion, acting as permeation enhancers, might destroy the structure of stratum corneum and increase the flux of drug via skin. Third, the drug from microemulsion might be increased because the affinity of a drug to the internal phase could be modified easily (Delgado-Charro et al., 1997, Baroli et al., 2000, Kreilgaard, 2002). Recently many drugs such as ketoprofen, triptolide, apomorphine, lidocaine and estradiol using microemulsion for transdermal delivery had been reported (Kreilgaard et al., 2000, Peira et al., 2001, Rhee et al., 2001, Peltola et al., 2003, Chen et al., 2004, Sintov and Shapiro, 2004).

In transdermal delivery, choice of an appropriate vehicle for the transdermal delivery was an effective method to maximize the flux through the skin into systemic circulation (Berner and John, 1994, Hilton et al., 1994). The objective of this study was to find a stable microemulsion vehicle for theophylline transdermal delivery. A system consisting of oleic acid, Cremophor RH40, Labrasol and water was prepared, and its physicochemical properties and transdermal ability of theophylline in vitro and in vivo were evaluated.