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 microg/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.
Kim
C K
CK
College of Pharmacy, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea. ckkim@plaza.snu.ac.kr
Cho
Y J
YJ
Gao
Z G
ZG
D000284:Administration, Oral; D000818:Animals; D004149:Dioxoles / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D004655:Emulsions; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013501:Surface-Active Agents / Q000494:pharmacology
D004149:Dioxoles; D004655:Emulsions; D013501:Surface-Active Agents; C041398:7,7'-dimethoxy-(4,4'-bi-1,3-benzodioxole)-5,5'-dicarboxylic acid dimethyl ester