A new self-emulsifying formulation of itraconazole with improved dissolution and oral absorption.
To enhance the dissolution and oral absorption of poorly water-soluble itraconazole, self-emulsifying drug delivery system (SEDDS) composed of oil, surfactant and cosurfactant for oral administration of itraconazole was formulated, and its physicochemical properties and pharmacokinetic parameters of itraconazole were evaluated. Among the surfactants and oils studied, Transcutol, Pluronic L64 and tocopherol acetate were chosen that showed the maximal solubility to itraconazole. The solubility of itraconazole was further improved by the addition of hydrochloric acid. Droplet size of itraconazole emulsion was kept constant both in simulated gastric fluid without pepsin (pH 1.2) and simulated intestinal fluid (pH 6.8) throughout 120-min incubation period. Itraconazole in the SEDDS rapidly dissolved in every dissolution medium whereas the Sporanox showed different dissolution patterns during the 120-min incubation according to the dissolution media. In fasted and fed normal diet group, AUC(0-->24 h) and the mean maximum plasma level (Cmax) of itraconazole after oral administration of SEDDS in rats were comparable to those of itraconazole after oral dose of Sporanox. However, in fed lipidic diet group, AUC and Cmax after oral administration of SEDDS in rats were 3.7- and 2.8-fold higher, respectively, compared with those of Sporanox. These results demonstrate that the SEDDS of itraconazole composed of Transcutol, Pluronic L64 and tocopherol acetate greatly enhanced the bioavailability of itraconazole after the dose, particularly not influenced by food intake or not. Thus, this system may provide a useful dosage form for oral water-insoluble drug without food effect.
Hong
Ji-Yeon
JY
College of Pharmacy, Seoul National University, San 56-1, Sillim-dong, Gwanak-gu, Seoul, 151-742, Republic of Korea.
Kim
Jin-Ki
JK
College of Pharmacy, Seoul National University, San 56-1, Sillim-dong, Gwanak-gu, Seoul, 151-742, Republic of Korea.
Song
Yun-Kyoung
YK
College of Pharmacy, Seoul National University, San 56-1, Sillim-dong, Gwanak-gu, Seoul, 151-742, Republic of Korea.
Park
Jeong-Sook
JS
College of Pharmacy, Chungnam National University, 220, Gung-dong, Yuseong-gu, Daejeon, 305-764, Republic of Korea.
Kim
Chong-Kook
CK
College of Pharmacy, Seoul National University, San 56-1, Sillim-dong, Gwanak-gu, Seoul, 151-742, Republic of Korea. Electronic address: ckkim@plaza.snu.ac.kr.
D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D019540:Area Under Curve; D001682:Biological Availability; D002214:Capsules; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D004655:Emulsions; D005026:Ethylene Glycols; D018565:Food-Drug Interactions; D006851:Hydrochloric Acid; D007408:Intestinal Absorption; D017964:Itraconazole / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D009821:Oils; D010316:Particle Size; D020442:Poloxamer; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013501:Surface-Active Agents; D024505:Tocopherols; D024502:alpha-Tocopherol / Q000031:analogs & derivatives
D000935:Antifungal Agents; D002214:Capsules; D004655:Emulsions; D005026:Ethylene Glycols; D009821:Oils; D013501:Surface-Active Agents; D020442:Poloxamer; D017964:Itraconazole; C010111:carbitol; D024502:alpha-Tocopherol; D006851:Hydrochloric Acid; D024505:Tocopherols