【摘要】：FC是苯氧乙酸吡嗪酯類化合物,是以川芎嗪醇和非諾貝特酸成酯而成,具有降血脂的作用,同時又可降低血液粘度。屬于創(chuàng)新藥的范疇,目前還未上市。本次課題研究的是使用熱熔擠出技術(shù)將難溶性藥物FC制備成固體分散體,考察該技術(shù)在制備固體分散體,提高難溶性藥物的溶出度以及含F(xiàn)C固體分散體在動物體內(nèi)藥代動力學(xué)方面的作用。參考相關(guān)文獻(xiàn),并通過平衡溶解度的測定,選取1.0%SDS溶液作為溶出介質(zhì),建立了紫外分光光度法來對FC進(jìn)行體外溶出度的測定,該方法學(xué)經(jīng)過驗(yàn)證,快捷方便,安全可靠。另外,用HPLC進(jìn)行有關(guān)物質(zhì)檢測,通過照電位法進(jìn)行含量測定。利用化學(xué)基團(tuán)貢獻(xiàn)法計(jì)算出了FC的溶解度參數(shù)為22.82MPa1/2,并計(jì)算出常用的一些載體的溶解度參數(shù),選擇出相容性好的PEG6000、PVPK30、Poloxamer188作為載體,用于下一步進(jìn)行的熱熔擠出操作。本課題研究的重點(diǎn)是使用熱熔擠出技術(shù)制備出不同的固體分散體。首先考察的是當(dāng)藥物與載體的比例均為1:4時,藥物的溶出度情況。結(jié)果表明,將FC做成固體分散體后,其溶出度明顯高于原料藥、藥物和載體的物理混合物。接下來對這三種載體分別進(jìn)行了考察,依次考察了載藥量、擠出溫度不同時,藥物的溶出情況。通過DSC和X-衍射分析對分散體進(jìn)行物相鑒別,進(jìn)而分析藥物FC在不同的載體中的存在狀態(tài)。接著進(jìn)一步考察了Poloxamer188和PVPK30這兩種固體分散體的穩(wěn)定性,選擇的評價指標(biāo)是含量、外觀狀態(tài)以及溶出度。將固體分散體于室溫和40℃、RH75%的加速條件下進(jìn)行放置,并考察了不同的放樣時間對穩(wěn)定性的影響,結(jié)果發(fā)現(xiàn)以PVPK30作為載體時,固體分散體的穩(wěn)定性較好。選擇穩(wěn)定性較好的FC-PVPK30固體分散體(1:4)進(jìn)行進(jìn)一步的處理,以微晶纖維素作為填充劑,20%的交聯(lián)羧甲基纖維素鈉和硬脂酸鎂作為崩解劑和潤滑劑,制備出溶出度較高的含F(xiàn)C固體分散體的片劑。最后建立了HPLC法來測定SD大鼠體內(nèi)的FC濃度,經(jīng)過方法學(xué)驗(yàn)證,該方法簡便可行,準(zhǔn)確可靠。動物灌胃給藥后,對各取血點(diǎn)的動物血液進(jìn)行藥物濃度測定,用DAS 2.0版統(tǒng)計(jì)軟件藥代動力學(xué)程序?qū)λ鶞y的數(shù)據(jù)進(jìn)行處理。結(jié)果知:大鼠在灌胃后,對照組在(2.333±0.517)h達(dá)到(1.612±0.152)mg/L的峰值濃度,受試組在(2±0)h達(dá)到(1.628±0.171)mg/L的峰值濃度,受試組的相對生物利用度為103.37±63.31%,未得到顯著的提高,并對其原因進(jìn)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，

本文編號：2438503