Preparation and evaluation of celecoxib nanosuspensions for bioavailability enhancement
Preparation and evaluation of celecoxib nanosuspensions for bioavailability enhancement
复制标题
塞来昔布纳米混悬剂的制备及生物利用度评价
DOI：
10.1039/c6ra28676c
复制
发表时间：
2017-01-01
期刊：
影响因子：
3.9
通讯作者：
Ding, Yang
中科院分区：
文献类型：
--
作者：
He, Jiali;Han, Yue;Ding, Yang
塞来昔布（CLX）是一种选择性的环氧合酶-2（考克斯-2）抑制剂，但由于其水溶性差、口服生物利用度低而影响了其应用。本研究旨在开发一种纳米技术来克服这些问题。以D-α-生育酚聚乙二醇1000琥珀酸酯（TPGS）为稳定剂，采用高压均质法制备塞来昔布纳米混悬液（CLX-NS），并冻干成固体粉末。采用透射电子显微镜（TEM）、差示扫描量热法（DSC）、X射线粉末衍射（XRD）和傅立叶变换红外光谱（FT-IR）等方法对CLX-NS冻干粉的理化性质和药理学性质进行表征。进行体外溶出度、原位单向肠灌注研究和体内药代动力学研究以进行进一步研究。纳米悬浮液的颗粒为短棒状（约388 nm），并且保持与CLX粗粉末相同的结晶状态。在体外溶出度试验中，CLX-NS的溶出度（60 min内90.8%）高于CLX粗粉组（47.9%）和物理混合物组（52.9%）。在体肠灌流研究表明，CLX-NS在全肠吸收良好，主要吸收部位为十二指肠。在药代动力学分析中，CLX-NS的Cmax和AUC 0-t得到显著改善，与CLX粗粉相比，相对生物利用度增加245.8%。本研究表明，纳米混悬制剂可能是影响CLX胃肠道吸收、改善难溶性药物溶出度和口服生物利用度的一种有前景的策略。
Celecoxib (CLX) is a selective cyclooxygenase-2 (COX-2) inhibitor; however, the application of CLX is compromised due to its poor aqueous solubility and low oral bioavailability. This study aims to develop a nanotechnology to overcome these issues. Celecoxib nanosuspensions (CLX-NS) were formulated using D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) as stabilizer via high pressure homogenization (HPH) and then freeze-dried to solid powder. Transmission electron microscopy (TEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR) were employed to characterize the physicochemical and pharmaceutical properties of CLX-NS lyophilization. In vitro dissolution, an in situ single-pass intestinal perfusion study, and in vivo pharmacokinetic studies were performed for further investigation. Particles of the nanosuspensions were short-rod shaped (∼388 nm) and remained in the same crystalline state as CLX coarse powder. In the test of in vitro dissolution, CLX-NS displayed a higher dissolution amount (90.8% during 60 minutes) compared to groups of CLX coarse powder (47.9%) and physical mixture (52.9%). Moreover, in situ single-pass intestinal perfusion study indicated that CLX-NS could be well absorbed in the whole intestine with the main absorption site being the duodenum. Significant improvements in Cmax and AUC0–t of CLX-NS were obtained in pharmacokinetic analyses with a 245.8% increase in relative bioavailability compared to CLX coarse powder. This study showed that nanosuspension preparations could be a promising strategy in influencing CLX absorption in gastrointestinal tract, and improving dissolution and oral bioavailability of poorly water-soluble drugs.