Improved oral absorption profile of itraconazole in hypochlorhydria by self-micellizing solid dispersion approach

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• 作者：Yoshiki Kojo ; Saori Matsunaga ; Hiroki Suzuki ; Hideyuki Sato ; Yoshiki Seto ; Satomi Onoue ; ^{onoue@u-shizuoka-ken.ac.jp}
• 关键词：ADI ; acceptable daily intake ; AUC ; area under the curve of blood concentration vs. time ; DLS ; dynamic light scattering ; DMEM ; Dulbecco's modified Eagle's medium ; DMSO ; dimethyl sulfoxide ; DSC ; differential scanning calorimetry ; GI ; gastrointestinal ; IEC6 cell ; intestinal epithelioid cell line No.6 derived from neonatal rat ileum ; ITZ ; itraconazole ; LD50 ; lethal dose 50% ; LDH ; lactate dehydrogenase ; NaPB ; sodium phosphate buffer ; PLM ; polarized light microscopy ; PXRD ; powder X-ray diffraction ; RH
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：97
• 期：Complete
• 页码：55-61
• 全文大小：768 K
• 卷排序：97

文摘

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 127 nm. The degradation of ITZ in SMSD/ITZ was negligible after storage under accelerated conditions at 40 °C or 40 °C/75%RH for 4 weeks. 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.