Pharmaceutical Development, AstraZeneca R&D Mölndal, Sweden.
Drug Dev Ind Pharm. 2011 Mar;37(3):243-51. doi: 10.3109/03639045.2010.505927. Epub 2010 Aug 12.
The aim of the present study was to find out if nanosuspensions were a better choice compared with microsuspensions, for the present substances with water solubility in the order of 2-3 μM (pH 6.8, small intestinal pH) and no permeability limitations. The ambition was also to understand what the higher solubility in the stomach for BA99 means in terms of absorption properties of the substance.
The pharmacokinetic parameters of a poorly soluble acid (AC88) and a poorly soluble base (BA99) administered orally as nanosuspensions have been compared with those from microsuspensions using rat as in vivo species.
A significant difference was observed between the two suspensions for AC88 already at the lowest dose, 5 μmol/kg (the particle size of the nanosuspensions and the microsuspensions was about 200 nm and 14 μm, respectively). These results were further confirmed at a high dose (500 μmol/kg). However, for BA99, there were no significant differences between the two formulations at any dose investigated (the particle size of the nanosuspensions and the microsuspensions was about 280 nm and 12 μm, respectively).
The study demonstrated a clear correlation between particle size and in vivo exposures for an acidic compound, the nanosuspensions providing the highest exposure. For a basic compound, on the other hand, with the present properties and doses, a microsuspension was sufficient. In the latter case, the higher solubility at gastric pH, because of the basic pK(a), limits the need for particle reduction.
本研究旨在探讨对于水溶性在 2-3 μM 左右（pH6.8，小肠 pH）且不存在渗透限制的现有物质而言，纳米混悬剂是否优于微混悬剂。本研究还旨在了解 BA99 在胃中更高的溶解度对该物质吸收特性意味着什么。
使用大鼠作为体内物种，比较了口服给予纳米混悬剂和微混悬剂的一种难溶性酸（AC88）和一种难溶性碱（BA99）的药代动力学参数。
对于 AC88，两种混悬剂在最低剂量 5 μmol/kg 时就观察到显著差异（纳米混悬剂和微混悬剂的粒径约为 200nm 和 14μm）。在高剂量（500μmol/kg）时，这些结果得到了进一步证实。然而，对于 BA99，在所研究的任何剂量下，两种制剂之间均无显著差异（纳米混悬剂和微混悬剂的粒径分别约为 280nm 和 12μm）。
该研究表明，粒径与体内暴露之间存在明显相关性，对于酸性化合物，纳米混悬剂提供了最高的暴露量。对于碱性化合物，另一方面，根据目前的性质和剂量，微混悬剂就足够了。在后一种情况下，由于碱性 pKa，在胃 pH 下更高的溶解度限制了对粒径减小的需求。
