热熔挤出技术制备苯氧乙酸吡嗪酯类化合物FC固体分散体的研究

发布时间：2019-03-11 18:19

【摘要】：FC是苯氧乙酸吡嗪酯类化合物,是以川芎嗪醇和非诺贝特酸成酯而成,具有降血脂的作用,同时又可降低血液粘度。属于创新药的范畴,目前还未上市。本次课题研究的是使用热熔挤出技术将难溶性药物FC制备成固体分散体,考察该技术在制备固体分散体,提高难溶性药物的溶出度以及含FC固体分散体在动物体内药代动力学方面的作用。参考相关文献,并通过平衡溶解度的测定,选取1.0%SDS溶液作为溶出介质,建立了紫外分光光度法来对FC进行体外溶出度的测定,该方法学经过验证,快捷方便,安全可靠。另外,用HPLC进行有关物质检测,通过照电位法进行含量测定。利用化学基团贡献法计算出了FC的溶解度参数为22.82MPa1/2,并计算出常用的一些载体的溶解度参数,选择出相容性好的PEG6000、PVPK30、Poloxamer188作为载体,用于下一步进行的热熔挤出操作。本课题研究的重点是使用热熔挤出技术制备出不同的固体分散体。首先考察的是当药物与载体的比例均为1:4时,药物的溶出度情况。结果表明,将FC做成固体分散体后,其溶出度明显高于原料药、药物和载体的物理混合物。接下来对这三种载体分别进行了考察,依次考察了载药量、挤出温度不同时,药物的溶出情况。通过DSC和X-衍射分析对分散体进行物相鉴别,进而分析药物FC在不同的载体中的存在状态。接着进一步考察了Poloxamer188和PVPK30这两种固体分散体的稳定性,选择的评价指标是含量、外观状态以及溶出度。将固体分散体于室温和40℃、RH75%的加速条件下进行放置,并考察了不同的放样时间对稳定性的影响,结果发现以PVPK30作为载体时,固体分散体的稳定性较好。选择稳定性较好的FC-PVPK30固体分散体(1:4)进行进一步的处理,以微晶纤维素作为填充剂,20%的交联羧甲基纤维素钠和硬脂酸镁作为崩解剂和润滑剂,制备出溶出度较高的含FC固体分散体的片剂。最后建立了HPLC法来测定SD大鼠体内的FC浓度,经过方法学验证,该方法简便可行,准确可靠。动物灌胃给药后,对各取血点的动物血液进行药物浓度测定,用DAS 2.0版统计软件药代动力学程序对所测的数据进行处理。结果知:大鼠在灌胃后,对照组在(2.333±0.517)h达到(1.612±0.152)mg/L的峰值浓度,受试组在(2±0)h达到(1.628±0.171)mg/L的峰值浓度,受试组的相对生物利用度为103.37±63.31%,未得到显著的提高,并对其原因进行了分析。
[Abstract]:FC is a kind of pyrazinates of phenoxyacetate. It is made from ligustrazine alcohol and fenofibrate. It has the function of lowering blood lipid and reducing blood viscosity at the same time. Belongs to the category of innovative drugs, is not yet on the market. The purpose of this study is to prepare the insoluble drug FC into solid dispersion by hot melt extrusion, and investigate the application of this technology in the preparation of solid dispersion. The dissolution of insoluble drugs and the pharmacokinetics of FC-containing solid dispersions in animals were improved. Referring to the relevant literatures, and through the determination of equilibrium solubility, the 1.0%SDS solution was selected as the dissolution medium, and the ultraviolet spectrophotometry was established to determine the dissolution of FC in vitro. The methodology was verified, rapid and convenient. Safe and reliable. In addition, HPLC was used to detect the related substances and the content was determined by potentiometric method. The solubility parameters of FC were calculated by chemical group contribution method, and the solubility parameters of some commonly used carriers were calculated. The PEG6000,PVPK30,Poloxamer188 with good compatibility was selected as the carrier. For the next hot melt extrusion operation. In this paper, different solid dispersions were prepared by hot melt extrusion. First, the dissolution of the drug was investigated when the ratio of drug to carrier was 1: 4. The results showed that the dissolution rate of FC was significantly higher than that of the physical mixture of drug, drug and carrier when it was made into solid dispersion. Then the three kinds of carriers were investigated, in turn, the dissolution of the drug was investigated at different extrusion temperature. The dispersion was identified by DSC and X-ray diffraction, and then the state of existence of drug FC in different carriers was analyzed. The stability of two solid dispersions, Poloxamer188 and PVPK30, was further investigated. The evaluation indexes were content, appearance and dissolution. The solid dispersion was placed at room temperature and 40 鈩，

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