Pharmaceutical and Analytical R&D, AstraZeneca R&D Mölndal, Mölndal, Sweden.
Drug Dev Ind Pharm. 2009 Dec;35(12):1479-86. doi: 10.3109/03639040903025855.
The exposure of UG558 was not good enough using traditional microsuspensions.
The aim of this study was to find out whether nanosuspensions were a better choice compared with a microsuspension, for an acidic substance with a water solubility in the order of 2 microM (pH 6.8, small intestinal pH) and no permeability limitations.
UG558 was ground by a planetary ball mill. The particle size was measured by laser diffraction and the stability of the particle sizes was followed. The pharmacokinetic parameters of UG558 administered as nanosuspension have been compared with those from microsuspension using rat as in vivo specie. Both formulations were administered orally. The nanosuspension was also administered intravenously.
The particle size of the nanosuspensions was about 190 nm and about 12 microm for the microsuspensions. At the administered doses, solutions were no alternative (e.g. due to limited solubility). Already at the lowest dose, 5 micromol/kg (5 ml/kg), a significant difference was observed between the two suspensions. These results were further confirmed at a high dose (500 micromol/kg, 5 mL/kg). Thus, the study demonstrated a clear correlation between particle size and in vivo exposures, where the nanosuspensions provided the highest exposure. Furthermore, no adverse events were observed for the substance nor the nanosuspension formulations (i.e., the particles) in spite of the higher exposures obtained with the nanoparticles. To make it possible to calculate the bioavailability, 5 micromol/kg doses of the nanosuspensions (5 ml/kg) were also administered intravenously. No adverse events were observed.
The nanoparticles have a larger surface, resulting in faster in vivo dissolution rate, faster absorption, and increased bioavailability, compared to microparticles. The lower overall bioavailability observed at the high dose, compared with the low dose, was due to a combination of low dissolution rate, low solubility, and a narrow intestinal absorption window for UG558.
使用传统的微悬浮液，UG558 的暴露度不够好。
本研究旨在确定纳米混悬剂是否优于微悬浮液，对于水溶性在 2 microM 左右（pH6.8，小肠 pH）且不存在渗透限制的酸性物质。
UG558 通过行星球磨机进行粉碎。通过激光衍射测量粒径，并跟踪粒径的稳定性。使用大鼠作为体内物种，比较 UG558 纳米混悬剂和微混悬剂给药后的药代动力学参数。两种制剂均口服给药。纳米混悬剂也静脉给药。
纳米混悬剂的粒径约为 190nm，微混悬剂的粒径约为 12 微米。在所给剂量下，溶液不是替代物（例如，由于溶解度有限）。即使在最低剂量 5 微摩尔/千克（5 毫升/千克）时，两种混悬剂之间也观察到显著差异。在高剂量（500 微摩尔/千克，5 毫升/千克）下进一步证实了这些结果。因此，该研究表明粒径与体内暴露之间存在明显的相关性，其中纳米混悬剂提供了最高的暴露。此外，尽管纳米粒子的暴露量更高，但未观察到该物质或纳米混悬剂制剂（即粒子）出现不良反应。为了能够计算生物利用度，还静脉给予 5 微摩尔/千克的纳米混悬剂（5 毫升/千克）剂量。未观察到不良反应。
与微粒子相比，纳米粒子具有更大的表面积，导致体内溶解速率更快、吸收更快、生物利用度增加。与低剂量相比，高剂量时观察到的总生物利用度较低，这是由于 UG558 的溶解速率低、溶解度低以及小肠吸收窗口狭窄的综合作用。
