Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA.
Adv Healthc Mater. 2016 Aug;5(15):1960-8. doi: 10.1002/adhm.201600266. Epub 2016 Jun 1.
Although roughly 40% of pharmaceuticals being developed are poorly water soluble, this class of drugs lacks a formulation strategy capable of producing high loads, fast dissolution kinetics, and low energy input. In this work, a novel bottom-up approach is developed for producing and formulating nanocrystals of poorly water-soluble active pharmaceutical ingredients (APIs) using core-shell composite hydrogel beads. Organic phase nanoemulsion droplets stabilized by polyvinyl alcohol (PVA) and containing a model hydrophobic API (fenofibrate) are embedded in the alginate hydrogel matrix and subsequently act as crystallization reactors. Controlled evaporation of this composite material produces core-shell structured alginate-PVA hydrogels with drug nanocrystals (500-650 nm) embedded within the core. Adjustable loading of API nanocrystals up to 83% by weight is achieved with dissolution (of 80% of the drug) occurring in as little as 30 min. A quantitative model is also developed and experimentally validated that the drug release patterns of the fenofibrate nanocrystals can be modulated by controlling the thickness of the PVA shell and drug loading. Thus, these composite materials offer a "designer" drug delivery system. Overall, our approach enables a novel means of simultaneous controlled crystallization and formulation of hydrophobic drugs that circumvents energy intensive top-down processes in traditional manufacturing.
尽管大约 40%的正在开发的药物的水溶性较差，但这一类药物缺乏一种能够生产高负载、快速溶解动力学和低能量输入的制剂策略。在这项工作中，使用核壳复合水凝胶珠，开发了一种生产和配制难溶性活性药物成分（API）纳米晶体的新型自下而上方法。由聚乙烯醇（PVA）稳定的有机相纳米乳液液滴，含有模型疏水性 API（非诺贝特），嵌入藻酸盐水凝胶基质中，随后充当结晶反应器。通过控制这种复合材料的蒸发，产生具有药物纳米晶体（500-650nm）的核壳结构的藻酸盐-PVA 水凝胶，这些纳米晶体嵌入在核中。通过控制 PVA 壳的厚度和药物负载，可以实现高达 83%重量的 API 纳米晶体的可调负载，并且在 30 分钟内即可实现 80%的药物溶解。还开发并实验验证了一个定量模型，即通过控制 PVA 壳的厚度和药物负载，可以调节非诺贝特纳米晶体的药物释放模式。因此，这些复合材料提供了一种“设计”的药物输送系统。总的来说，我们的方法为同时控制疏水性药物的结晶和制剂提供了一种新的方法，避免了传统制造中能量密集的自上而下过程。
