Harmon Paul, Galipeau Kendra, Xu Wei, Brown Chad, Wuelfing W Peter
Analytical Sciences, Merck Research Laboratories, Merck & Co., Inc. , West Point, Pennsylvania 19486, United States.
Formulation Sciences, Merck Research Laboratories, Merck & Co., Inc. , West Point, Pennsylvania 19486, United States.
Mol Pharm. 2016 May 2;13(5):1467-81. doi: 10.1021/acs.molpharmaceut.5b00863. Epub 2016 Apr 11.
Amorphous solid dispersions (ASDs) have been increasingly used to maximize human exposures from poorly soluble drug candidates. One well-studied advantage of ASDs is the increased amorphous drug solubility compared to crystalline forms. This provides more rapid dissolution rates. An additional advantage of ASDs is that the dissolution process of the ASD particle may also rapidly transform much of the drug present in the ASD particle to small (<1 μm) amorphous drug nanoparticles which will have fast dissolution rates. This work examines the mechanism by which this nanoparticle formation occurs by studying an ASD consisting of 70-80% copovidone, 20% anacetrapib (a low solubility lipophilic drug), and 0-10% TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate, a surfactant). Nanoparticle formation is found to derive from a rapid amorphous drug domain formation within the ASD particle, driven by copovidone dissolution from the particle. The role of surfactant in the ASD particle is to prevent an otherwise rapid, local drug domain aggregation event, which we term "hydrophobic capture". Surfactant thus allows the amorphous drug domains to escape hydrophobic capture and diffuse to bulk solution, where they are reported as nanoparticles. This view of surfactant and nanoparticle formation is compared to the prevailing view in the literature. The work here clarifies the different roles that surfactant might play in increasing nanoparticle yields and extending the useful drug loading ranges in copovidone-based ASDs.
无定形固体分散体（ASDs）已越来越多地用于使难溶性候选药物的人体暴露量最大化。ASDs一个经过充分研究的优势是，与结晶形式相比，无定形药物的溶解度有所提高。这使得溶解速度更快。ASDs的另一个优势是，ASD颗粒的溶解过程还可能迅速将ASD颗粒中存在的大部分药物转化为小尺寸（<1μm）的无定形药物纳米颗粒，这些纳米颗粒将具有快速的溶解速度。本研究通过研究一种由70 - 80%共聚维酮、20%阿那曲匹（一种低溶解度的亲脂性药物）和0 - 10% TPGS（d-α-生育酚聚乙二醇1000琥珀酸酯，一种表面活性剂）组成的ASD，来探究这种纳米颗粒形成的机制。研究发现，纳米颗粒的形成源于ASD颗粒内快速形成的无定形药物区域，这是由共聚维酮从颗粒中的溶解所驱动的。表面活性剂在ASD颗粒中的作用是防止原本会迅速发生的局部药物区域聚集事件，我们将其称为“疏水捕获”。因此，表面活性剂使无定形药物区域能够逃脱疏水捕获并扩散到本体溶液中，在那里它们以纳米颗粒的形式被报道。本文将这种关于表面活性剂和纳米颗粒形成的观点与文献中的主流观点进行了比较。这项工作阐明了表面活性剂在提高纳米颗粒产率和扩展基于共聚维酮的ASDs中有用药物载量范围方面可能发挥的不同作用。
