Preparation and evaluation of biphenyl dimethyl dicarboxylate microemulsions for oral delivery

To improve the solubility and bioavailability of poorly water-soluble biphenyl dimethyl dicarboxylate (BDD), a drug used in treating liver diseases, a premicroemulsion concentrate composed of oil, surfactant, and cosurfactant for oral administration of BDD was prepared, and its physicochemical properties and the pharmacokinetic parameters of BDD were evaluated. Among the non-ionic surfactants and oils studied, Tween 80, which led to the highest solubility of BDD (109.7 mug/ml), and Neobee M-5(R) were chosen for preparing a premicroemulsion concentrate. At the 2:1 ratio of Tween 80 to Neobee M-5(R), the solubility of BDD increased 7-fold compared with that at the ratio of 1:4. The solubility of BDD was further improved by the addition of triacetin used as a cosurfactant. Droplet size of BDD microemulsion comprising Tween 80 and Neobee M-5(R) at the ratio of 2:1, and 35% of triacetin, was kept constant both in distilled water and artificial gastric fluid without pepsin (pH 1.2) throughout 120-min incubation period. BDD in premicroemulsion concentrate rapidly dissolved whereas the mixture of BDD and calcium-carboxymethylcellulose (Ca-CMC) (2:1) and BDD powder hardly dissolved during 120-min incubation. About 50% of BDD in premicroemulsion concentrate dissolved within 10 min. AUC(0-->24 h) and the mean maximum plasma level (C-max) of BDD after oral administration of premicroemulsion concentrate in rats were 5- and 9.8-fold higher, respectively, than those of BDD with Ca-CMC. These results demonstrate that premicroemulsion concentrate of BDD composed of Tween 80 and Neobee M-5(R) at the ratio of 2:1, and 35% of triacetin, greatly enhances the bioavailability of BDD after the dose, possibly due to the increase in solubility and immediate dispersion of drug in the gastrointestinal tract. Thus, this system may provide a useful dosage form for oral intake of a water-insoluble drug, BDD. (C) 2001 Elsevier Science B.V. All rights reserved.