Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Int J Pharm. 2019 Jun 10;564:39-47. doi: 10.1016/j.ijpharm.2019.04.033. Epub 2019 Apr 11.
We investigated the effect of variation in the molecular weight of hypromellose (HPMC) on the oral absorption of fenofibrate (FFB) nanocrystal. Four types of HPMC with different molecular weights and sodium dodecyl sulfate (SDS) were used as dispersion stabilizers for FFB nanocrystal suspension. Wet-milling of FFB crystal with HPMC and SDS formed diamond-shaped FFB nanocrystals with approximately 150 nm diameter. HPMC was strongly adsorbed onto the FFB nanocrystal interface, and the amount of HPMC adsorbed was not dependent on the molecular weight of HPMC. However, the decrease in the molecular weight of adsorbed HPMC led to an improvement in the permeability of FFB nanocrystal through the mucin layer. The decrease in molecular weight of HPMC enhanced the flexibility of FFB nanocrystal interface and effectively inhibited its interaction with mucin. This led to faster diffusion of FFB nanocrystal through mucin. In vivo oral absorption studies showed rapid FFB absorption from FFB nanocrystal formulations using HPMC of low molecular weights. The present study revealed that the molecular weight of the dispersion stabilizer for drug nanocrystal formulation should be taken into consideration to achieve improved absorption of poorly water-soluble drugs after oral administration.
我们研究了羟丙甲纤维素（HPMC）分子量的变化对非诺贝特（FFB）纳米晶体口服吸收的影响。使用四种不同分子量的 HPMC 和十二烷基硫酸钠（SDS）作为 FFB 纳米晶体悬浮液的分散稳定剂。用 HPMC 和 SDS 对 FFB 晶体进行湿磨，形成了具有约 150nm 直径的菱形 FFB 纳米晶体。HPMC 被强烈吸附在 FFB 纳米晶界面上，吸附的 HPMC 量与 HPMC 的分子量无关。然而，吸附 HPMC 的分子量降低导致 FFB 纳米晶体通过粘蛋白层的渗透性提高。HPMC 分子量的降低增强了 FFB 纳米晶界面的柔韧性，并有效地抑制了其与粘蛋白的相互作用。这导致 FFB 纳米晶体通过粘蛋白的扩散更快。体内口服吸收研究表明，使用低分子量 HPMC 的 FFB 纳米晶体制剂可快速吸收 FFB。本研究表明，在药物纳米晶体制剂中，分散稳定剂的分子量应该被考虑在内，以实现口服后改善难溶性药物的吸收。
