Department of Chemical Engineering and Applied Chemistry , University of Toronto , 200 College Street , Toronto , Ontario M5S 3E5 , Canada.
Institute of Biomaterials and Biomedical Engineering, University of Toronto , 164 College Street , Toronto , Ontario M5S 3G9 , Canada.
ACS Chem Biol. 2019 Apr 19;14(4):751-757. doi: 10.1021/acschembio.9b00032. Epub 2019 Mar 12.
Colloidal drug aggregates have been a nuisance in drug screening, yet, because they inherently comprise drug-rich particles, they may be useful in vivo if issues of stability can be addressed. As the first step toward answering this question, we optimized colloidal drug aggregate formulations using a fluorescence-based assay to study fulvestrant colloidal formation and stability in high (90%) serum conditions in vitro. We show, for the first time, that the critical aggregation concentration of fulvestrant depends on media composition and increases with serum concentration. Excipients, such as polysorbate 80, stabilize fulvestrant colloids in 90% serum in vitro for over 48 h. Using fulvestrant and an investigational pro-drug, pentyloxycarbonyl-( p-aminobenzyl) doxazolidinylcarbamate (PPD), as proof-of-concept colloidal formulations, we demonstrate that the in vivo plasma half-life for stabilized colloids is greater than their respective monomeric forms. These studies demonstrate the potential of turning the nuisance of colloidal drug aggregation into an opportunity for drug-rich formulations.
胶态药物聚集体一直是药物筛选中的一个难题，但由于它们本质上包含药物丰富的颗粒，如果能够解决稳定性问题，它们在体内可能是有用的。作为回答这个问题的第一步，我们使用基于荧光的测定法优化了胶态药物聚集体配方，以研究氟维司群胶态形成和在高（90%）血清条件下的体外稳定性。我们首次表明，氟维司群的临界聚集浓度取决于介质组成，并随血清浓度的增加而增加。赋形剂，如聚山梨醇酯 80，可使氟维司群胶体在 90%的血清中稳定超过 48 小时。使用氟维司群和一种研究性前药，戊氧基羰基-（对氨基苄基）恶唑烷二酮基氨基甲酸酯（PPD）作为胶体制剂的概念验证，我们证明了稳定胶体的体内血浆半衰期大于其各自的单体形式。这些研究表明，将胶态药物聚集的麻烦转化为富含药物的制剂的机会是可行的。
