Enhancement of transdermal delivery of theophylline using microemulsion vehicle
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.
Section snippets
Materials
Theophylline was obtained from Shanghai Wandai Corporation (batch no. A031213, Shanghai, China). Oleic acid was purchased from Shanghai Chemical Reagent Corporation (Shanghai, China). PEG-8 glycol caprylate (Labrasol) was kindly donated by Gattefossé, France. Polyoxyl 40 hydrogenated castor oil (Cremophor RH40) was donated by BASF, Germany. Water was deionized and filtered in our lab. All other chemical and solvent were analytical reagent grade.
Screening of oils and surfactants for microemulsion
In order to find out appropriate oils and
Screening of oils and surfactants for microemulsion
The solubility of theophylline was highest in oleic acid, followed by ethyllinoleate, olive oil, castor oil, salad oil and sesame oil. Theophylline also had a higher solubility in Labrasol and Cremophor RH40 followed by Cremophor EL35, tween-80 and propanediol, but had a less solubility in lecithin and span-80. Kanikkannan (Kanikkannan et al., 2000) had reported that oleic acid could increase fluidity of lipid portion of the stratum corneum which resulted in a permeation enhancing effect, and
Conclusion
The theophylline microemulsion was formulated for transdermal application. The different microemulsion formulations were selected using the construction of pseudo-ternary phase diagram. Optimum formulation of the microemulsion was obtained by in vitro permeation studies. The addition of menthol to the microemulsion increased the permeation rate of theophylline via the skin. The permeation rate of theophylline from microemulsion accorded with the Fick's first law. The result of in vivo
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