Improved oral absorption profile of itraconazole in hypochlorhydria by self-micellizing solid dispersion approach.
The present study was aimed to evaluate the applicability of a self-micellizing solid dispersion (SMSD) system of itraconazole (ITZ) with the use of Soluplus®to achieve improved dissolution and stable oral absorption of ITZ under hypochlorhydric conditions. The SMSD of ITZ (SMSD/ITZ) was prepared by the freeze-drying method. Physicochemical properties of SMSD/ITZ were assessed in terms of morphology, crystallinity, particle size, thermal behavior, dissolution profile, and stability. The pharmacokinetic profile of SMSD/ITZ was evaluated in both normal rats and omeprazole-treated rats as a hypochlorhydric model. From the crystallinity assessment, ITZ in SMSD/ITZ might exist in an amorphous state. The dissolution behavior of SMSD/ITZ was markedly improved under both acidic and neutral conditions through the formation of nano-micelles with a diameter of 127nm. The degradation of ITZ in SMSD/ITZ was negligible after storage under accelerated conditions at 40°C or 40°C/75%RH for 4weeks. Under light exposure, ca. 33% of ITZ in SMSD/ITZ was degraded, suggesting the need for protection from light. Although the oral absorption of crystalline ITZ was negligible, SMSD/ITZ showed an improved pharmacokinetic profile in normal rats, with an absolute bioavailability (BA) of 2.9%, and even 6.3% in the hypochlorhydric model. From these findings, SMSD technology could be beneficial for improving the absorption profiles of weak basic drugs, even in hypochlorhydric patients.
Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Yoshiki
Y
Kojo
Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Saori
S
Matsunaga
Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Hiroki
H
Suzuki
Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Hideyuki
H
Sato
Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Yoshiki
Y
Seto
Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. Electronic address: onoue@u-shizuoka-ken.ac.jp.
Satomi
S
Onoue
D000126:Achlorhydria / Q000188:drug therapy / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D065546:Drug Liberation / Q000187:drug effects / Q000502:physiology; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D017964:Itraconazole / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D008823:Micelles; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D011145:Polyvinyls / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014961:X-Ray Diffraction
D000935:Antifungal Agents; D008823:Micelles; D011145:Polyvinyls; C572167:polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; D017964:Itraconazole; D011092:Polyethylene Glycols
Dissolution; Hypochlorhydric model animal; Itraconazole; Self-micellizing; Solid dispersion