Kwok Philip Chi Lip, Chan Hak-Kim
Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR.
Curr Pharm Des. 2014;20(3):474-82. doi: 10.2174/13816128113199990400.
Many newly discovered drug molecules have low aqueous solubility, which results in low bioavailability. One way to improve their dissolution is to formulate them as nanoparticles, which have high specific surface areas, consequently increasing the dissolution rate and solubility. Nanoparticles can be produced via top-down or bottom-up methods. Top-down techniques such as wet milling and high pressure homogenisation involve reducing large particles to nano-sizes. Some pharmaceutical products made by these processes have been marketed. Bottom-up methods such as precipitation and controlled droplet evaporation form nanoparticles from molecules in solution. To minimise aggregation upon drying and promote redispersion of the nanoparticles upon reconstitution or administration, hydrophilic matrix formers are added to the formulation. However, the nanoparticles will eventually agglomerate together after dispersing in the liquid and hinders dissolution. Currently there is no pharmacopoeial method specified for nanoparticles. Amongst the current dissolution apparatus available for powders, the flow-through cell has been shown to be the most suitable. Regulatory and pharmacopoeial standards should be established in the future to standardise the dissolution testing of nanoparticles. More nanoparticle formulations of new hydrophobic drugs are expected to be developed in the future with the advancement of nanotechnology. However, the agglomeration problem is inherent and difficult to overcome. Thus the benefit of dissolution enhancement often cannot be fully realised. On the other hand, chemical strategies such as modifying the parent drug molecule to form a more soluble salt form, prodrug, or cyclodextrin complexation are well established and have been shown to be effective in enhancing dissolution. Thus the value of nanoformulations needs to be interpreted in the light of their limitations. Chemical approaches should also be considered in new product development.
许多新发现的药物分子水溶性低，导致生物利用度低。提高其溶出度的一种方法是将它们制成纳米颗粒，纳米颗粒具有高比表面积，从而提高溶出速率和溶解度。纳米颗粒可以通过自上而下或自下而上的方法制备。自上而下的技术，如湿磨和高压均质化，涉及将大颗粒减小到纳米尺寸。通过这些工艺生产的一些药品已经上市。自下而上的方法，如沉淀和控制液滴蒸发，从溶液中的分子形成纳米颗粒。为了使干燥时的聚集最小化，并促进纳米颗粒在重构或给药时的再分散，将亲水性基质形成剂添加到制剂中。然而，纳米颗粒在分散于液体中后最终会聚集在一起并阻碍溶解。目前没有针对纳米颗粒的药典方法。在目前可用于粉末的溶出装置中，流通池已被证明是最合适的。未来应建立监管和药典标准，以规范纳米颗粒的溶出度测试。随着纳米技术的进步，预计未来会开发出更多新的疏水性药物的纳米颗粒制剂。然而，聚集问题是固有的且难以克服。因此，溶出度提高的益处往往无法完全实现。另一方面，化学策略，如修饰母体药物分子以形成更易溶的盐形式、前药或环糊精络合，已经成熟并已被证明在提高溶出度方面有效。因此，需要根据纳米制剂的局限性来解释其价值。在新产品开发中也应考虑化学方法。
