Department of Pharmaceutics and Drug Delivery, The University of Mississippi, University, Mississippi, 38677, USA.
College of Pharmacy, The University of Texas at Austin, Austin, Texas, 78712, USA.
AAPS PharmSciTech. 2021 Feb 19;22(3):79. doi: 10.1208/s12249-021-01945-8.
Fenofibrate is an effective lipid-lowering drug; however, its poor solubility and high log p (5.2) result in insufficient absorption from the gastrointestinal tract, leading to poor bioavailability. In this study, a one-step continuous twin-screw melt granulation process was investigated to improve the solubility and dissolution of fenofibrate using Gelucire® 48/16 and Neusilin® US2 as the solubilizer and surface adsorbent, respectively. The formulations (granules) were prepared at different ratios of fenofibrate, Gelucire® 48/16, and Neusilin® US2 based on phase-solubility studies and characterized using dissolution, differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy analyses and studies on flow properties. In the phase-solubility studies, a linear relation was observed between Gelucire® 48/16 concentration and the amount of fenofibrate dissolved. In contrast, the dissolution rate of the prepared formulations was independent of the fenofibrate: Gelucire® 48/16 ratio and dependent on the Neusilin® US2 levels in the formulation. Increasing Neusilin® US2 levels decreased the rate of dissolution of the granules but improved the stability of the tablets under storage at accelerated stability conditions. Interestingly, higher Gelucire® 48/16 levels in the granules resulted in tablets with a hard matrix, which slowed disintegration and dissolution. All formulations exhibited improved dissolution compared to pure fenofibrate.
非诺贝特是一种有效的降脂药物；然而，其较差的溶解度和高 log p（5.2）导致其在胃肠道中的吸收不足，从而导致生物利用度较差。在这项研究中，使用 Gelucire® 48/16 和 Neusilin® US2 作为增溶剂和表面吸附剂，研究了一步连续双螺杆熔融造粒工艺来提高非诺贝特的溶解度和溶解速率。根据相溶解度研究，以不同的非诺贝特、Gelucire® 48/16 和 Neusilin® US2 比例制备了制剂（颗粒），并通过溶解、差示扫描量热法、粉末 X 射线衍射和扫描电子显微镜分析以及流动性能研究进行了表征。在相溶解度研究中，观察到 Gelucire® 48/16 浓度与溶解的非诺贝特量之间存在线性关系。相比之下，制备的制剂的溶解速率与非诺贝特：Gelucire® 48/16 比例无关，而与制剂中 Neusilin® US2 水平有关。增加 Neusilin® US2 水平会降低颗粒的溶解速率，但会提高在加速稳定性条件下储存时片剂的稳定性。有趣的是，颗粒中较高的 Gelucire® 48/16 水平会导致片剂具有硬基质，从而减缓崩解和溶解。与纯非诺贝特相比，所有制剂的溶解性能均有所提高。
