【摘要】：目的： 納米粒作為新型藥物給藥載體,具有改善口服不穩(wěn)定或難溶性藥物的吸收、延長藥物體內(nèi)循環(huán)時間、增加藥物穿過生物膜屏障的能力,增加藥物靶向性等優(yōu)點,成為研究抗腫瘤藥物載體的熱點。而納米粒制劑在生產(chǎn)制備、運輸、貯存都可能發(fā)生粒子泄漏、害降解產(chǎn)物產(chǎn)生等問題。目前對納米粒制劑仍無規(guī)范統(tǒng)一的質(zhì)量標準,本文對注射用多西他賽納米粒制劑質(zhì)量控制技術進行研究,對納米粒理化性質(zhì)(包括納米粒外觀、粒度分布及Zeta電勢測定、酸值、過氧化值)、含量測定、包封率、體外釋放、殘留溶劑、有害雜質(zhì)溶血磷脂酰膽堿檢測方法進行系統(tǒng)考察,為納米粒制劑質(zhì)量控制提供參考依據(jù)。 方法： (1)對注射用多西他賽納米粒理化性質(zhì)進行考察； 檢查納米粒外觀；采用靜態(tài)光散射法和動態(tài)激光散射法測定納米粒粒度分布,測定納米粒Zeta電勢；考察納米粒酸值及過氧化值。 (2) HPLC法測定注射用多西他賽納米粒含量,并進行方法學研究； (3)測定納米粒包封率,對游離藥物與納米粒分離方法進行研究； 分別采用超速離心法、微柱離心法、葡聚糖凝膠柱層析法及動態(tài)透析法分離游離藥物及納米粒,并研究各方法對測定注射用多西他賽納米粒包封率結果的影響。 (4)注射用多西他賽納米粒體外釋放測定； 參照《中國藥典》2010版第二部附錄X C溶出度測定第三法將裝有注射用多西他賽納米�；鞈乙褐猛肝龃鼉�(nèi)并固定在溶出小槳上,根據(jù)累積釋放量探尋注射用多西他賽納米粒體外釋放緩釋規(guī)律。 (5)頂空氣相色譜法測定納米粒中殘留溶劑； (6)采用HPLC不同檢測器測定注射用多西他賽納米粒中有害雜質(zhì)溶血磷脂酰膽堿含量。 結果： 檢查注射液多西他賽納米粒外觀為白色凍干塊狀物,色澤均一；采用動態(tài)激光散射法測得納米粒平均粒徑為117.9028nm,大于200nm的粒子不超過5%,Zeta電勢為-3.54mV；納米粒酸值結果不大于2,過氧化值不大于3; HPLC法測定注射用多西他賽納米粒含量為9.94mg· g-1,動態(tài)透析-高效液相色譜法測定納米粒包封率為95.0%；初步考察注射用多西他賽納米粒體外釋放各級動力學模型擬合較好；頂空氣相色譜法測定納米粒中殘留溶劑乙醇含量為0.2%；超聲、離心提取磷脂組分, HPLC法紫外測定納米粒中溶血磷脂酰膽堿含量為0.24%, HPLC蒸發(fā)光檢測器未能檢出納米粒中溶血磷脂酰膽堿含量。 結論： 建立的注射用多西他賽納米粒制劑理化性質(zhì)檢查方法簡單、快速；HPLC法測定納米粒含量、動態(tài)透析-HPLC法測定納米粒包封率、溶出小杯法測定納米粒體外釋放、頂空氣相色譜法測定納米粒殘留溶劑、HPLC-UV及HPLC-ELSD法測定納米粒中有害雜質(zhì)溶血磷脂酰膽堿含量方法可行、可靠、可控,可為注射用多西他賽納米粒制劑建立質(zhì)量標準提供參考依據(jù)。
[Abstract]:Objective: as a new drug delivery carrier, nanoparticles have the ability to improve the absorption of unstable or insoluble drugs, prolong the internal circulation of drugs, and increase the ability of drugs to pass through the biofilm barrier. Increasing drug targeting has become a hot spot in the research of anti-tumor drug carriers. However, particle leakage and degradation products may occur in preparation, transportation and storage of nanoparticles. At present, there is still no standard and uniform quality standard for nanoparticles. In this paper, the quality control technology of doxetacemide granules for injection is studied, and the physicochemical properties of nanoparticles (including appearance, particle size distribution and Zeta potential determination, acid value, acid value) of nanoparticles are studied. Peroxide value), content determination, entrapment efficiency, in vitro release, residual solvent, harmful impurity lysophosphatidylcholine were systematically investigated, which provided reference for quality control of nanoparticles. Methods: (1) the physicochemical properties of doxetacernet for injection were investigated, the appearance of nanoparticles was examined, the particle size distribution was measured by static light scattering and dynamic laser scattering, and the Zeta potential of nanoparticles was measured. The acid value and peroxide value of nanoparticles were investigated. (2) HPLC method was used to determine the content of doxetacinamil for injection and the methodology was studied. (3) the entrapment efficiency of nanoparticles was determined and the method of separating free drugs from nanoparticles was studied. Free drugs and nanoparticles were separated by ultracentrifugation, microcolumn centrifugation, dextran gel column chromatography and dynamic dialysis, respectively. The effects of various methods on the determination of entrapment efficiency of doxetacernet for injection were studied. (4) in vitro release assay of doxetacernet for injection; With reference to Chinese Pharmacopoeia 2010 Edition, part II, appendix X C, the third method was used to determine the dissolution rate of a hemodialysis bag containing doxetacemide for injection and to fix it on a small dissolving paddle. According to the cumulative release amount, the release rule of doxetacemide for injection in vitro was investigated. (5) Headspace gas chromatography was used to determine the residual solvent in nanoparticles. (6) the content of lysophosphatidylcholine, a harmful impurity in doxetacemide granules for injection, was determined by HPLC detector. Results: the appearance of doxetacemide injection was white and the color was uniform, the average diameter of the nanoparticles was 117.9028 nm by dynamic laser scattering, and the particle size larger than 200nm was less than 5% Zeta potential (-3.54 MV), and the average particle size was 117.9028 nm by dynamic laser scattering (DLS). The acid value of nanoparticles was not more than 2, peroxide value was less than 3, the content of doxetacemide for injection was determined by HPLC method, and the entrapment efficiency was 95.0 by dynamic dialysation-high performance liquid chromatography. The kinetic models for in vitro release of doxetacemide for injection were well fitted, and the residual solvent ethanol content in nanoparticles was determined by headspace gas chromatography with 0.2% ethanol content. The content of lysophosphatidylcholine in nanoparticles was determined by HPLC method. The content of lysophosphatidylcholine in nanoparticles was not detected by HPLC evaporative light detector. Conclusion: the established method is simple to determine the physical and chemical properties of doxetasine granules for injection. The rapid HPLC method is used to determine the content of nanoparticles, the dynamic dialysation-HPLC method is used to determine the encapsulation efficiency of nanoparticles, and the dissolution cup method is used to determine the release of nanoparticles in vitro. The method of headspace gas chromatography for the determination of residual solvent HPLC-UV and HPLC-ELSD method for the determination of lysophosphatidylcholine in nanoparticles is feasible, reliable and controllable. It can provide a reference for the establishment of quality standard for doxetasine granules for injection.
【學位授予單位】：廣州中醫(yī)藥大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R943

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