کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
8513552 1556497 2018 23 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Automated Supersaturation Stability Assay to Differentiate Poorly Soluble Compounds in Drug Discovery
ترجمه فارسی عنوان
تست پایداری خودکار فوقانی اشباع برای جداسازی ترکیبات نامناسب در کشف مواد مخدر
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی اکتشاف دارویی
چکیده انگلیسی
Increasingly, in vitro assays evaluate a compound's tendency to maintain supersaturation toward improving oral absorption. Throughput remains a challenge and only small sets of compounds are evaluated in reported studies. The present work describes an automated workflow and data analysis approach to determine supersaturation stability after 16 min. Eight increasing concentrations were targeted and supernatant concentration was measured following solvent shift in fasted-state simulated intestinal fluid. The effect of dimethyl sulfoxide both on equilibrium solubility and on induced supersaturation was addressed, whereas the change in concentration was evaluated over time. Our sample set included 24 commercial compounds, along with comparison to literature results. To demonstrate in vivo relevance of in vitro supersaturation, classification of supersaturation stability was proposed based on the target concentration achieved and the percentage of area under the curve dose proportionality in 42 preclinical and clinical studies. Eighty-one percent of low supersaturation stability compounds (target concentrations ≤50 μM) had proportionality <0.8, whereas 100% of high supersaturation stability compounds (target concentrations ≥200 μM) demonstrated proportionality ≥0.8. The robust, automated assay and its impact on dose proportionality downstream make this approach applicable in drug discovery where low-soluble compounds with otherwise attractive properties may be differentiated on the basis of supersaturation stability.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 107, Issue 1, January 2018, Pages 84-93
نویسندگان
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