注射用羟基喜树碱脂质体的研究
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摘要
羟基喜树碱(hydroxycampothecin,HCPT)是从中国喜树中提取的抗肿瘤药,它选择性的抑制拓扑异构酶I而干扰DNA的复制,具有高效低毒,广谱抗癌的特点,且与其他常用抗肿瘤药无交叉耐药性。临床用于膀胱癌、直肠癌、肝癌、胃癌、卵巢癌、白血病及头颈部肿瘤等,皆取得良好疗效。其优点还在于主要从胆汁中排泄,对泌尿系统刺激性小,对肾功能无影响。羟基喜树碱的a-羟基内脂环是活性的必需基团,临床上使用的是其内酯开环的钠盐注射液,该制剂不但疗效较低,而且会导致严重的副作用,因此需要改善临床剂型。脂质体作为一种新型药物载体,能提高被包裹药物的稳定性,并能使药物靶向定位于特定的组织,激活机体自身的免疫功能,减少或降低药物的毒性。
本文以羟基喜树碱为模型药物,首先将其制备成脂质体,有效改变该药物的稳定性,达到提高羟基喜树碱的生物利用度。再加入冻干保护剂,冻干,以提高脂质体的储存稳定性。
首先,经过载体和工艺的筛选,以氢化豆磷脂(HSPC)为载体,采用薄膜-超声分散法制备了羟基喜树碱脂质体,并对脂质体的制备工艺进行了优化,以包封率与外观性状为指标,最终确定影响因素为:羟基喜树碱与HSPC的摩尔比例、F68的浓度、磷酸缓冲液的浓度。每个因素取三个水平,选用L9(34)表,以羟基喜树碱脂质体的包封率为指标进行正交试验,最终确定最佳处方:羟基喜树碱:HSPC=1:10,F68的浓度为0.8%,磷酸缓冲液的浓度为0.05mol/L。
然后,经过考察制剂外观,分散性以及稳定性作为标准,考察了几种不同冻干支架剂以及不同用量的情况下,对制剂冻干的保护作用。最后采用差热分析法(DSC)、红外法(IR)、X-射线衍射等方法对羟基喜树
碱-HSPC脂质体的质量进行了鉴别和检查,结果表明羟基喜树碱在载体中以非晶形存在。
依照中国药典2005版二部附录有关要求,对实验室三批制剂进行了质量评价方法学和稳定性研究,制定出质量标准,为新药申报和工业生产提供了良好的临床前研究基础。
注射用羟基喜树碱脂质体的质量标准包括制剂的性状、鉴别、检查、含量测定以及稳定性试验等方面,其中含量和有关物质测定采用高效液相色谱法,经色谱条件的摸索和方法学的考察,能精密准确的测定样品含量,在此基础上制定了注射用羟基喜树碱脂质体的质量标准;按此标准对三批制剂进行了质量检查,各项指标均符合要求。
实验室三批制剂的稳定性考察包括:影响因素试验(高温、高湿、光照)加速试验和长期试验。影响因素试验结果表明注射用羟基喜树碱脂质体在高温、高湿条件下不稳定,应常温、干燥保存。
Hydroxycampothecin(HCPT) is a potent antitumor drug, isolated from Nyssaceae in China, it is the one of the DNA topoisomerase I inhibitors. It shows high antitumor activity in vitro and in vivo. It has excellence such as antitumor, low toxicity, broad-spectum anticancer, and it has no acrossing resistance with other antitumor drug. HCPT has been used to cure liver carcinoma, urinary bladder carcinoma, and colorectal cancer, etc. It also has excellence such as being exreted from choler, less effect to urinary system,no effect to kidney, Structure-activity studies have shown that successful inhibition of DNA topoisomerase I by HCPT requires an intact lactose E-ring. In clinical, the sodium injection with lactose E-ring open has low therapy effect, also has serious side-effect, so the research is to find advanced dosage and clinical uses. Liposomes have been used to be a new kind of carrier, they can improve the stability of the drug and carry the drug to the targeting place.
In this passage, the liposomes were prepared by HCPT and different supplementary metials, which improve the stability of HCPT and increase its bioavailability. Then, the freeze-dry liposomes were produced by adding lyoprotectetants, which improve the stability of storage.
Firstly, Hydrogenated Soy Phosphatidylcholine(HSPC) as carrier, HCPT liposmes were produced by flim-supersonic dispersion method after carrier choice and technique filter. According to the encapsulation efficiency, various factors were studied. The main variables were HCPT/HSPC ratio, F68 concentration, PBS concentration. Eventually employ the L9(34)orthogonal table. The optimized prescription of the HCPT liposomes was: HCPT:HSPC=1:10, F68 concentration 0.8%,PBS concentration 0.05mol/L.
Based on the optimized prescription, the protective function of different kinds of cryoprotectants and different quantities of them were examined by the standards of appearance, redispersity and encapsulation efficiency.
Then the formation of the inclusion was proved by Differential Scanning Calorimeters, IR, X-ray diffractometry and solubility before and after being liposomes.
According to the related request of the appendices of Chinese pharmacopoeia (2005 edition,Ⅱpart), we perfomed the quality analysis to HCPT-HSPC liposome injection including their characters, identification, inspection, quantification,etc. We use HPLC method to perform quantification, which was able to determie the content of methodology and precisely after the groupig chromatography condition and studying of methpdplogy. Then, we established the quality standard of HCPT-HSPC liposome injection. According to this quality standard, we performed quality analysis to laboratory preparations.
We investigated the stablity of the three block medium amplified preparation, including stressing testing (illumination, high temperature and high moisture), accelerated testing, long-testing. The results of stressing showed the HCPT-HSPC liposomes are unstable under high temperature and high moisture.
本文以羟基喜树碱为模型药物,首先将其制备成脂质体,有效改变该药物的稳定性,达到提高羟基喜树碱的生物利用度。再加入冻干保护剂,冻干,以提高脂质体的储存稳定性。
首先,经过载体和工艺的筛选,以氢化豆磷脂(HSPC)为载体,采用薄膜-超声分散法制备了羟基喜树碱脂质体,并对脂质体的制备工艺进行了优化,以包封率与外观性状为指标,最终确定影响因素为:羟基喜树碱与HSPC的摩尔比例、F68的浓度、磷酸缓冲液的浓度。每个因素取三个水平,选用L9(34)表,以羟基喜树碱脂质体的包封率为指标进行正交试验,最终确定最佳处方:羟基喜树碱:HSPC=1:10,F68的浓度为0.8%,磷酸缓冲液的浓度为0.05mol/L。
然后,经过考察制剂外观,分散性以及稳定性作为标准,考察了几种不同冻干支架剂以及不同用量的情况下,对制剂冻干的保护作用。最后采用差热分析法(DSC)、红外法(IR)、X-射线衍射等方法对羟基喜树
碱-HSPC脂质体的质量进行了鉴别和检查,结果表明羟基喜树碱在载体中以非晶形存在。
依照中国药典2005版二部附录有关要求,对实验室三批制剂进行了质量评价方法学和稳定性研究,制定出质量标准,为新药申报和工业生产提供了良好的临床前研究基础。
注射用羟基喜树碱脂质体的质量标准包括制剂的性状、鉴别、检查、含量测定以及稳定性试验等方面,其中含量和有关物质测定采用高效液相色谱法,经色谱条件的摸索和方法学的考察,能精密准确的测定样品含量,在此基础上制定了注射用羟基喜树碱脂质体的质量标准;按此标准对三批制剂进行了质量检查,各项指标均符合要求。
实验室三批制剂的稳定性考察包括:影响因素试验(高温、高湿、光照)加速试验和长期试验。影响因素试验结果表明注射用羟基喜树碱脂质体在高温、高湿条件下不稳定,应常温、干燥保存。
Hydroxycampothecin(HCPT) is a potent antitumor drug, isolated from Nyssaceae in China, it is the one of the DNA topoisomerase I inhibitors. It shows high antitumor activity in vitro and in vivo. It has excellence such as antitumor, low toxicity, broad-spectum anticancer, and it has no acrossing resistance with other antitumor drug. HCPT has been used to cure liver carcinoma, urinary bladder carcinoma, and colorectal cancer, etc. It also has excellence such as being exreted from choler, less effect to urinary system,no effect to kidney, Structure-activity studies have shown that successful inhibition of DNA topoisomerase I by HCPT requires an intact lactose E-ring. In clinical, the sodium injection with lactose E-ring open has low therapy effect, also has serious side-effect, so the research is to find advanced dosage and clinical uses. Liposomes have been used to be a new kind of carrier, they can improve the stability of the drug and carry the drug to the targeting place.
In this passage, the liposomes were prepared by HCPT and different supplementary metials, which improve the stability of HCPT and increase its bioavailability. Then, the freeze-dry liposomes were produced by adding lyoprotectetants, which improve the stability of storage.
Firstly, Hydrogenated Soy Phosphatidylcholine(HSPC) as carrier, HCPT liposmes were produced by flim-supersonic dispersion method after carrier choice and technique filter. According to the encapsulation efficiency, various factors were studied. The main variables were HCPT/HSPC ratio, F68 concentration, PBS concentration. Eventually employ the L9(34)orthogonal table. The optimized prescription of the HCPT liposomes was: HCPT:HSPC=1:10, F68 concentration 0.8%,PBS concentration 0.05mol/L.
Based on the optimized prescription, the protective function of different kinds of cryoprotectants and different quantities of them were examined by the standards of appearance, redispersity and encapsulation efficiency.
Then the formation of the inclusion was proved by Differential Scanning Calorimeters, IR, X-ray diffractometry and solubility before and after being liposomes.
According to the related request of the appendices of Chinese pharmacopoeia (2005 edition,Ⅱpart), we perfomed the quality analysis to HCPT-HSPC liposome injection including their characters, identification, inspection, quantification,etc. We use HPLC method to perform quantification, which was able to determie the content of methodology and precisely after the groupig chromatography condition and studying of methpdplogy. Then, we established the quality standard of HCPT-HSPC liposome injection. According to this quality standard, we performed quality analysis to laboratory preparations.
We investigated the stablity of the three block medium amplified preparation, including stressing testing (illumination, high temperature and high moisture), accelerated testing, long-testing. The results of stressing showed the HCPT-HSPC liposomes are unstable under high temperature and high moisture.
引文
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[3] Jung LL, Zamboni WC. Cellular, pharmacokinetic, and pharmacodynamic aspects of response to camptothecins: can we improve it? Drug Resistance Updates, 2001,4(3): 152-167.
[4]任中海,全运科,张成辉,等.羟基喜树碱抗癌谱的实验研究.肿瘤防治杂志,2002,9(1): 27-29.
[5]刘键,晋彬.羟基喜树碱类药物作用机制及在合并治疗中机理的研究.中国肿瘤临床,1998, 25(5): 392-389.
[6]周立新,王碧瑶,沈卫星,等。羟基喜树碱体外抗癌药敏的实验研究.中国肿瘤临床,2000, 27(9): 717-719.
[7]石星,杨坤禹.羟基喜树碱为主治疗原发性肝癌临床疗效观察.中国中西医结合消化杂志,2001, 9(3): 148-149.
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