کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8513308 | 1556493 | 2018 | 40 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Oral Delivery of Highly Lipophilic, Poorly Water-Soluble Drugs: Self-Emulsifying Drug Delivery Systems to Improve Oral Absorption and Enable High-Dose Toxicology Studies of a Cholesteryl Ester Transfer Protein Inhibitor in Preclinical Species
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کلمات کلیدی
DSCSEDDSCETPSMEDDSAUC - AUCSolubility - انحلال پذیریAbsorption - جذبSelf-emulsifying - خود امولسیونSelf-emulsifying drug delivery systems - خود تحریک کننده سیستم های تحویل داروییIntravenous - داخل وریدیGastrointestinal tract - دستگاه گوارشGI tract - دستگاه گوارشSelf-microemulsifying drug delivery systems - سیستم های تحویل دارویی خودمراقبتیPharmacokinetics - فارماکوکینتیکBioavailability - فراهم زیستیLipid-based formulations - فرمول های مبتنی بر لیپیدnot determined - مشخص نشدهarea under the curve - منطقه تحت منحنیcholesteryl ester transfer protein - پروتئین انتقال پروتئین کلسترول استDifferential scanning calorimetry - کالریمتری روبشی افتراقی
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
BMS-A is an inhibitor of cholesteryl ester transfer protein and is a highly lipophilic compound (clogP 10.5) with poor aqueous solubility (<0.0001 mg/mL at pH 6.5). The compound exhibits low oral exposure when dosed as cosolvent solution formulations. The purpose of this study was to evaluate lipid-based formulations for enabling high-dose toxicology studies and enhancing toxicology margins of BMS-A in preclinical studies in nonrodent species. The solubility of BMS-A was screened in lipid and cosolvent/surfactant excipients, and prototype formulations were developed. In vitro tests showed that fine/microemulsions were formed after aqueous dilution of lipid formulations, and BMS-A was transferred from oil phase to aqueous phase with enhanced solubility following lipid digestion. When dosed in dogs at 200 mg/kg, a Gelucire-based formulation exhibited more than 10-fold higher exposure compared to the solution formulation and was thus selected for toxicology studies in dogs. For monkeys, an olive oil formulation was developed, and the exposure was about 7-fold higher than that from the solution. In summary, lipid-based drug delivery could be applied in early stages of drug discovery to enhance oral exposure and enable preclinical toxicology studies of highly lipophilic compounds, while facilitating the candidate selection of a molecule which is more specifically designed for bioperformance in a lipid-based drug delivery strategy.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 107, Issue 5, May 2018, Pages 1352-1360
Journal: Journal of Pharmaceutical Sciences - Volume 107, Issue 5, May 2018, Pages 1352-1360
نویسندگان
Xue-Qing Chen, Theresa Ziemba, Christine Huang, Ming Chang, Carrie Xu, Jennifer X. Qiao, Tammy C. Wang, Heather J. Finlay, Mark E. Salvati, Leonard P. Adam, Olafur Gudmundsson, Michael J. Hageman,