熊果酸缓释片的研究
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摘要
熊果酸(Ursolic Acid, UA),为五环三萜类化合物,资源广、毒性低、具有广泛的生物活性。有抗肿瘤、抗氧化、抗肝炎、抗炎抑菌、降血脂、抗溃疡等作用,尤其抗肿瘤、抗氧化、抗肝炎作用显著,有望成为抗肿瘤、抗肝炎新药。近年来,在基础研究、工业化提取分离、现代制剂形式和临床应用方面熊果酸研究都有了十分重要的进展。
目前,有关熊果酸的制剂研究只有利用β-环糊精制成包合物添加于食物中使用以及制成冻干粉针剂作为肝靶向制剂的相关报道,且受到生物利用度低的限制,熊果酸所具有的生物活性并未得到充分、广泛的应用。本实验从提高其疗效及安全度,降低血浓峰谷现象,方便病人服药考虑,研制熊果酸的亲水凝胶骨架型缓释片,增加其临床剂型。
本论文对UA缓释片的处方工艺,体外释放度影响因素,质量标准和稳定性进行了研究。
采用正交设计法优选熊果酸缓释片,以熊果酸为主药,以HPMC为缓释材料,加入一定比例的淀粉和乳糖作填充剂,首先通过预实验考察影响缓释性能的各项因素,最后确定影响熊果酸缓释片缓释效果的四因素为HPMC用量、粘合剂的种类、淀粉与乳糖比例以及压片硬度。每个因素取三个水平,选用L9(34)表,以熊果酸的释放度为指标进行正交实验,最终确定最佳处方:亲水凝胶骨架材料为HPMC(K4M),用量为20%,淀粉与乳糖的比例为2:1,片剂硬度为5kg/mm2。
最优处方确定后,分别考察了制备工艺、释放介质、pH、不同方法、转速等因素对熊果酸缓释片体外释放度的影响。确定了实验室放大生产工艺为等量递增分级过筛;释放条件:介质为0.5%的十二烷基硫酸钠(磷酸盐调节pH=7.00±0.05),转速为100rpm,方法为转篮法。
依照中国药典2005版二部附录有关要求,确定出可行的质量评价方法进行质量分析,制定出质量标准,并对生产的三批中试制剂进行了质量标准的分析和稳定性考察,为新药申报和工业生产提供了良好的临床前研究基础。
熊果酸缓释片质量分析包括制剂的性状、鉴别、检查、含量测定等方面,其中含量和释放度测定采用高效液相色谱法,经色谱条件摸索和方法学考察,能精密准确地测定样品含量;在此基础上制定了熊果酸缓释片的质量标准;按此质量标准对中试三批制剂进行的质量检查,各项指标均符合要求,体外释放规律拟合符合Higuich方程,12小时累积释放度达90%以上,具有良好的缓释性能。
中试三批制剂稳定性考察包括: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熊果酸缓释片对高温、光照稳定,在高湿条件下释放度略有加快,故在高湿条件下确定包装材料。实验结果显示加速试验和长期试验各项指标均符合要求。
试验结果表明,熊果酸缓释片各项指标均较理想,体外释放具有良好的缓释性能。但是在体内能否得到类似的缓释效果,还有待于进一步试验证明。
Ursolic Acid (UA) is pentacyclic triterpenoid compound, which has wide resources. It has such functions as less poison, against tumour, against oxidate, against hepatitis, against ulcer and diabetes. It also has the functions of protecting liver and reducing hyperlipema. It has rich resource and can be a new medicine against tumour and hepatitis. It can also be used as the product for skin care. It has wide prospects for development. In recent years, the research of ursolic acid had obtained more important findings about basic studies, the methods of extraction and isolation for industry, advanced dosage forms and clinical uses.
At present, the praeparatum of ursolic acid were reported on the itsβ-cyclodextrin inclusion compound which used in foods and the freeze injectable powder which as used a liver-target forming. Limited by the low bioavailability, the bioactivity of ursolic acid can not be fully shown up. Aiming to improving the therapeutic effect and safety, degrading the peak valley phenomenon of blood drug level, being simplify taking medicine, this experiment focous on researching the ursolic acid HPMC hydrophilicity gel matrix sustained-release tablets to increase the clinic preparations of UA.
In this article, we mainly studied several characteristics of UA sustained-release tablets, including formulation and design, quality standard, the influence factors for the in vitro dissolution and its stability.
Selected the formulation of the UA sustained-release tablets by orthogonal design, and took HPMC as main complement, starch and lactose as additives. Firstly investigate the influencing factors of delayed releasing function by preliminary experiments. By the results of this experiment, the main four factors that influence the quality of sustained-release UA included.The dosage of the HPMC, the variety of the binder, the proportion of starch and lactose and the hardness of tabletting. Eventually employ the L9(34)orthogonal table and the parameter of releasing degree to select the best formulation. The optimized prescription of the sustained-release UA was: HPMC (K4M) as hydrophilic gel matrices material; 20% dosage; 2:1 starch and lactose;tablet hardness 5kg/mm2.
Based on the optimized prescription, we studied various factors(such as preparation technology、dissolution media、pH、the methods of dissolution determine、rotational speeds and so on)affected the in vitro dissolution. The technique of amplified production was equivalent incremental classification sift. The dissolution medium was 0.5%SDS (PH=7.00±0.05); the rotational speed was 100rpm; and the dissolution method was rotating basket.
According to the related requirements of the appendices of Chinese pharmacopoeia (2005 edition,Ⅱpart), we definited the feasible quality evaluation, established the quality standard. We checked up the items on the quality standard and investigated the stability of three batches of semi-works production. It lay foundation for a good preclinical research for the application of new drug and industry manufacture.
The analysis of the UA sustained-release tablets including: characters, identification, inspection, quantification, etc. By the groping chromatography condition and studying of methodology, HPLC method was able to determine the contents of the sample precisely, thus was selected to make quantification. Eventually, the quality standard of UA sustained-release tablets had been established. Quality inspection to the three blocks of medium amplified preparations was made according to the standards, and their results satisfied the related regulate. Meanwhile the release of UA sustained-release tablets in vitro fitted the Higuich equation. The 12h accumulating releasing rate was above 90%, which indicated such tablets have desirable sustain-release capability.
We investigated the stability of the three blocks medium amplified preparations, including stress testing (illumination,high temperature and high moisture),accelerated testing,long-term testing. The results of stress testing showed that the sustained-release tablets are stable under illumination,high temperature and high moisture (the release rate increased). Therefore, we selected the packing materials under high moisture. The rest two tests also showed that the sustained-release tablets keep stability.
The results of experiment showed all kinds of index of ursolic acid sustained-release tablets were ideal. It had satisfied delayed release performance in vitro release. Its release nature in vivo depended on a further experiment.
目前,有关熊果酸的制剂研究只有利用β-环糊精制成包合物添加于食物中使用以及制成冻干粉针剂作为肝靶向制剂的相关报道,且受到生物利用度低的限制,熊果酸所具有的生物活性并未得到充分、广泛的应用。本实验从提高其疗效及安全度,降低血浓峰谷现象,方便病人服药考虑,研制熊果酸的亲水凝胶骨架型缓释片,增加其临床剂型。
本论文对UA缓释片的处方工艺,体外释放度影响因素,质量标准和稳定性进行了研究。
采用正交设计法优选熊果酸缓释片,以熊果酸为主药,以HPMC为缓释材料,加入一定比例的淀粉和乳糖作填充剂,首先通过预实验考察影响缓释性能的各项因素,最后确定影响熊果酸缓释片缓释效果的四因素为HPMC用量、粘合剂的种类、淀粉与乳糖比例以及压片硬度。每个因素取三个水平,选用L9(34)表,以熊果酸的释放度为指标进行正交实验,最终确定最佳处方:亲水凝胶骨架材料为HPMC(K4M),用量为20%,淀粉与乳糖的比例为2:1,片剂硬度为5kg/mm2。
最优处方确定后,分别考察了制备工艺、释放介质、pH、不同方法、转速等因素对熊果酸缓释片体外释放度的影响。确定了实验室放大生产工艺为等量递增分级过筛;释放条件:介质为0.5%的十二烷基硫酸钠(磷酸盐调节pH=7.00±0.05),转速为100rpm,方法为转篮法。
依照中国药典2005版二部附录有关要求,确定出可行的质量评价方法进行质量分析,制定出质量标准,并对生产的三批中试制剂进行了质量标准的分析和稳定性考察,为新药申报和工业生产提供了良好的临床前研究基础。
熊果酸缓释片质量分析包括制剂的性状、鉴别、检查、含量测定等方面,其中含量和释放度测定采用高效液相色谱法,经色谱条件摸索和方法学考察,能精密准确地测定样品含量;在此基础上制定了熊果酸缓释片的质量标准;按此质量标准对中试三批制剂进行的质量检查,各项指标均符合要求,体外释放规律拟合符合Higuich方程,12小时累积释放度达90%以上,具有良好的缓释性能。
中试三批制剂稳定性考察包括: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熊果酸缓释片对高温、光照稳定,在高湿条件下释放度略有加快,故在高湿条件下确定包装材料。实验结果显示加速试验和长期试验各项指标均符合要求。
试验结果表明,熊果酸缓释片各项指标均较理想,体外释放具有良好的缓释性能。但是在体内能否得到类似的缓释效果,还有待于进一步试验证明。
Ursolic Acid (UA) is pentacyclic triterpenoid compound, which has wide resources. It has such functions as less poison, against tumour, against oxidate, against hepatitis, against ulcer and diabetes. It also has the functions of protecting liver and reducing hyperlipema. It has rich resource and can be a new medicine against tumour and hepatitis. It can also be used as the product for skin care. It has wide prospects for development. In recent years, the research of ursolic acid had obtained more important findings about basic studies, the methods of extraction and isolation for industry, advanced dosage forms and clinical uses.
At present, the praeparatum of ursolic acid were reported on the itsβ-cyclodextrin inclusion compound which used in foods and the freeze injectable powder which as used a liver-target forming. Limited by the low bioavailability, the bioactivity of ursolic acid can not be fully shown up. Aiming to improving the therapeutic effect and safety, degrading the peak valley phenomenon of blood drug level, being simplify taking medicine, this experiment focous on researching the ursolic acid HPMC hydrophilicity gel matrix sustained-release tablets to increase the clinic preparations of UA.
In this article, we mainly studied several characteristics of UA sustained-release tablets, including formulation and design, quality standard, the influence factors for the in vitro dissolution and its stability.
Selected the formulation of the UA sustained-release tablets by orthogonal design, and took HPMC as main complement, starch and lactose as additives. Firstly investigate the influencing factors of delayed releasing function by preliminary experiments. By the results of this experiment, the main four factors that influence the quality of sustained-release UA included.The dosage of the HPMC, the variety of the binder, the proportion of starch and lactose and the hardness of tabletting. Eventually employ the L9(34)orthogonal table and the parameter of releasing degree to select the best formulation. The optimized prescription of the sustained-release UA was: HPMC (K4M) as hydrophilic gel matrices material; 20% dosage; 2:1 starch and lactose;tablet hardness 5kg/mm2.
Based on the optimized prescription, we studied various factors(such as preparation technology、dissolution media、pH、the methods of dissolution determine、rotational speeds and so on)affected the in vitro dissolution. The technique of amplified production was equivalent incremental classification sift. The dissolution medium was 0.5%SDS (PH=7.00±0.05); the rotational speed was 100rpm; and the dissolution method was rotating basket.
According to the related requirements of the appendices of Chinese pharmacopoeia (2005 edition,Ⅱpart), we definited the feasible quality evaluation, established the quality standard. We checked up the items on the quality standard and investigated the stability of three batches of semi-works production. It lay foundation for a good preclinical research for the application of new drug and industry manufacture.
The analysis of the UA sustained-release tablets including: characters, identification, inspection, quantification, etc. By the groping chromatography condition and studying of methodology, HPLC method was able to determine the contents of the sample precisely, thus was selected to make quantification. Eventually, the quality standard of UA sustained-release tablets had been established. Quality inspection to the three blocks of medium amplified preparations was made according to the standards, and their results satisfied the related regulate. Meanwhile the release of UA sustained-release tablets in vitro fitted the Higuich equation. The 12h accumulating releasing rate was above 90%, which indicated such tablets have desirable sustain-release capability.
We investigated the stability of the three blocks medium amplified preparations, including stress testing (illumination,high temperature and high moisture),accelerated testing,long-term testing. The results of stress testing showed that the sustained-release tablets are stable under illumination,high temperature and high moisture (the release rate increased). Therefore, we selected the packing materials under high moisture. The rest two tests also showed that the sustained-release tablets keep stability.
The results of experiment showed all kinds of index of ursolic acid sustained-release tablets were ideal. It had satisfied delayed release performance in vitro release. Its release nature in vivo depended on a further experiment.
引文
1.陆彬.药物新剂型与新技术[M].北京:人民卫生出版社.1998:1.
2.吕慧侠、周建平缓控释给药系统发展概况机电信息2004.12(7):54-58
3.王建华,陈慧云,杨永,吕正检,徐世荣口服缓/控释药物制剂技术研究进展药学专论2005.14(8):14-15
4.易延逵,邓虹珠,张璐,魏毅,缓释片剂的发展概况中华临床医药2002.3(18):82-84
5.陈慧云,王建华,徐世荣,王琦高分子材料纤维素醚类衍生物在缓释制剂辅料中的应用材料导报2005.19(7):48-51
6.程紫骅,刘燕,朱家璧盐酸雷尼替丁HPMC骨架片药物释放影响因素研究中国药科大学学报1998.29(4):275-277
7.柳晨,王晓黎,陈御石,裴元英阿司匹林HPMC骨架片药物释放因素研究中国药学杂志1999.34(10):673-676
8.董志超.羟丙基甲基纤维素在凝胶骨架片的应用.国外医药合成药、生化药、制剂分册,1993,14:41.
9. XuGj,SunadaH. Influence of formulation change on drug release kinetics from hydroxypropylmethylcellulose maltrix tablets.ChemPharm Bull,1995,43(3):483.
10.董志超,蒋雪涛,张恒弼.卡托普利缓释片的实验研究.中国医药工业杂志,1993,24(2):65.
11.董志超,蒋雪涛.羟丙基甲基纤维素的性质对药物亲水性骨架片溶出度的影响.药学学报,1994,29(12):920.
12.裴元英,戈升荣,陈御石.硫酸奎尼丁HPMC骨架片影响释药因素研究.中国药学杂志,1996,31(12):727.
13.裴元英,陈御石,郑玲妹,等.对乙酰氨基酚HPMC骨架片药物释放影响因素研究.中国药学杂志,1997,32(5):281.
14. BavejaSK, RangaRaoKV, SinghA, etal. Release characteristics of somebronchodilators from compresse dhydrophilic polymericm atrices and their correlation with molecular geometry. Int J Pharma,1988,41:55.
15.高声传,郭涛,陈济民,姜铁夫双氯芬酸赖氨酸盐缓释片制备工艺的研究.解放军药学学报,2000,16(6):303-306
16. Zeng HX, Pan WS, Chen JM, et al. Preparation and release of sustained-release famotidine tablet[J]. Zhongguo Yaoxue Zazhi, 1997,32(4): 213
17.阳长明,候世祥药物溶出度研究进展中成药2000,22(7):511-515
18.吴佩颖,徐莲英,陶建生难溶性药物增溶方法研究进展中成药2005,27(9):附10-13
19.秦冬梅,王恒,李海瑛羟丙甲基纤维素在药剂学中的应用安徽医药2004,8(3):173-174
20.郑俊民药用高分子材料.北京:中国医药科技出版社,2002;7
21.药用辅料手册,上册
22.罗明生,高天惠.药用辅料大全.成都:四川科技出版社,1993
23. Xu Guoiie, Zhan Ruhua, Chu Wei Hisakazu Sunada Water Penetration, Matrix Swell and Drug Release Property Studies of Hvdroxvnronvlmethvl Cellulose Matrix Tablets Journal of Chinese Pharmaceutical Sciences 2000, 9(1):26-29
24.董志超,蒋雪涛,张恒弼.卡托普利缓释片的实验研究.中国医药工业杂志,1993,24(2): 65
25. Baveja SK, RangaRao KV, Singh A, et al. Release Characteristics of some bronchodilators from compressed hydrophilic polymeric matrices and their correlation with molecular geometry. Int J Parm, 1988,41: 55
26.郭波红,程怡乙基纤维素在缓控释制剂中的应用研究中医药学刊2002,20(5):601-603
27.许东航,范辉,叶婷,梁文权稀释剂对HPMC骨架片释药的影响中国现代应用药学杂志2003,20(1):30-32
28. Matsumara M,Nakagami H,Yamao T, etal.Computer optimization for the formulationof controlled release theophylline tablet made of micronized lowsubstitued hydroxypropylcellulose and methylcellulose [J]. Chem Pharm Bull, 1994, 42(9):1902.
29. Richard S,Ramona K.The effects of pH, ionic concentration and ionic species of dissolution media on the release rates of quinidine gluconate sustained release dosage forms [J]. Drug Dev Ind Pharm,1991,17(1):113.
30. Marcos BP,Ford JL,Armstrong DJ, etal. Influence of pH on the release of propranolol hydrochloride from matrices containing HPMC K4M and carbopol 1974[J]. J Pharm Sci, 1996,85(3):330.
31. Martin-Aragon S, de las He ras B, Sanchez-Reus MI, et al Pharmacological modification of endogenous antioxidant enzymes by ursolic acid on tetrachloride- induced liver damage in rats and primary cultures of rat hepatocytes [J]. Exp Toxicol Pathol 2001, 53(2/3):199-206
32.周小菊.福安特纳米粉针剂研究:[硕士学位论文]:华中科技大学图书馆,2000.
33.刘亚妮.齐墩果酸缓释片的研究: [硕士学位论文]:华中科技大学图书馆,2006.
34.中国药典2005版二部
35. Lapidus H et al: ibid 1968,57: 1292
36. Higuchi T. Mechanism of sustained action medication, Theoretica analysis of rate of release of solid drugs dispersed in solid matrices J Pharm Sci, 1963, 2:1145.
1.李开泉,陈武,熊筱娟,王雪熊果酸的化学、药理及临床应用进展中成药2002.24(9)
2.夏国豪章永红,王瑞平熊果酸抗肿瘤作用研究进展国外医学肿瘤学分册2002.29(6)
3.殷晓东,赵浩如熊果酸研究进展中华实用中西医杂志2004.4(17)
4.徐礼焱,等.中草药有效成分分析法(上册)[M],北京:人民卫生出版社,1984:81
5.陈武,熊筱娟,李开泉,王雪,朱建新,刘传安、冷桂华乌索酸的化学、药理及临床研究宜春医专学报2001.13(2)
6.钟瑞建,郭晓秋,TLC测定白花蛇舌草中熊果酸的含量[J]中药材,1997,20(1):33234.
7.赵春香,章贵杰,张莉,薄层扫描法测定心可舒片中熊果酸的含量[J],中国中药杂志,1999,24(7):4152417.
8.方红玲,戚建中.薄层扫描法测定肝达片中熊果酸的含量[J]中国药科大学学报,1998,29(Suppl):1442146.
9.袁珂,李根林,李俊芝等,车前草中熊果酸齐墩果酸的HPLC测定[J],中草药,1999,30(12):9012903.
10.林巧玲,谢培山,龙广霖.薄层荧光色谱扫描法测定进口药爱活胆通中能果酸的含量[J],中药新药与临床药理,1997,(2)1002102.
11.王旭,周富荣,关晶,等.大山楂口嚼片定性定量的研究[J]中国中药杂志,1999,24(11):6752677.
12.闫花丽,赵陆华,朱丹妮,等.衍生化气相色谱法测定夏枯草中齐墩果酸和熊果酸的含量[J],中国中药杂志,1999.24(12):7442745.
13.熊斌雷志勇,陈虹熊果酸药理学的研究进展国外医学药学分册2004.31(3)
14.熊筱娟、陈武、李开泉、王雪乌索酸药理作用研究进展宜春医专学报2001.13(1)
15. Cha HJ,Bae SK, Lee HY, et al. Anti-invasiveactivity of ursolic acid correlates with thereduced expression of matrix metalloproteinase-9 (MMP-9) in HT 1080 human fibrosarcoma cells [J]. Cancer Res,1996, 56(10) : 2281-2284.
16. Ames BN. Dietary carcinogens and anticarcinogens. Science, 1983, 221:1256
17. Balanehru S. Nagarajan B. Protective effect of oleanloic acid and Ursolic acida ganist lipid peroxidation. Biochem Int, 1991, 24 (5): 9811
18. Young Hs, Chung Hy, Lee Ck, et al Ursolic acid inhibits aflatoxin BI- induced mutagenicity in a Salmonella assay system. Biol Pharm Bull.1994,17(7):990.
19.王春雷,芦柏震,侯桂兰熊果酸抗肿瘤作用研究进展安徽医药2005.9(10):723-725
20.樊明文,王茜,边专.熊果酸对人舌鳞癌细胞株的抑制作用及其机制探讨[J].武汉大学学报(医学版),2004,25(1):1-3.
21.吴其年,黄炜杨凤仪.熊果酸对人乳腺癌细胞增殖、凋亡和细胞内游离Ca2+的影响[J].肿瘤学杂志,2004,10(3):145-147.
22.黄炜,黄济群,张东方.五环三萜类化合物抗人肺癌细胞侵袭和诱导细胞凋亡的研究[J].中国肺癌杂志,2003,6(4):254-257.
23.张秋萍,谢珞琨,邓涛.熊果酸促进562细胞凋亡[J].基础医学与临床,2004,24(4):414-7.
24. Sohn KH, Lee HY, Chung HY,et al. Anti-amgio genesis activity of trite rpene acids[J]. Cancer Lett 1995, 94(2):213-217.
25.王兵,王杰军,徐钧.熊果酸对体外血管形成的抑制作用[J].肿瘤防治杂志,2001,8(4):351-2.
26. Lee HY, Chang HY, Kim KH, et al. Induction of differentiation. In the cultured F9 teratocarcinoma stem cells by triterpen acids [J]. Cancer Res Clin Oncol, 1994, 120 (9): 5131
27.宋京、张庆林,熊果酸药理作用研究进展[J],中草药,1999,30(增刊)。
28.白育军,杨小生,康文艺,郝小江,徐筱杰,宋宝安熊果酸的结构修饰物及其抗肿瘤活性华西药学杂志2003.18 (2):87-90
29.张星,潘启超白花蛇舌草提取物-熊果酸的抗肿瘤作用[J]国外医药-植物药分册,1999,14(6):255
30. Philip A. Zoretic, Robert J. Chambers. Sterospecific sythsis of secondary allylic alcohols: selenxide chemistry [J]. J Org Chem, 1985, 50: 2981.
31. GW Cavili, DH Solomon. Organic oxidation pross part IV. The reaction of lead tetra-acetate with some carbonvl compounds [J]. J Chem Soc,1955, 4426
32.江西宜春地区卫生局,陆英研究资料6[M],199
33.陈武,李开泉,熊筱娟,等,陆英抗肝炎活性成分的研究,宜春医专学报,2000,12(4):2391
34.韩德五,等,齐墩果酸防止实验性肝硬变发生的研究,中医杂志,1981,(3):2171
35.张乐之,李新芳,齐墩果酸对大鼠实验性肝损伤作用机理的研究,中药药理与临床,1992,8(2):241
36.马学惠,等,乌索酸对实验性肝损伤的防治作用,药学学报,1986,21:3321
37. Martin-Aragon S, de las He ras B, Sanchez-Reus MI, et al Pharmacological modification of endogenous antioxidant enzymes by ursolic acid on tetrachloride- induced liver damage in rats and primary cultures of rat hepatocytes [J]. Exp Toxicol Pathol 2001, 53(2/3):199-206
38. Saraswat B, Visen PK, Agarwal DP. Ursolic acid isolated from Eucalyptus tereticornis protectsagainst ethanol toxicity in isolated rat hepatocytes [J]. Phytother Res, 2000,14(3):163-6.
39.卞象梅.乌索酸[J].中草药通讯,1976,7(9):15
40.王茜,樊明文,边专,等.熊果酸的提取及其对牙周病原菌的作用[J].中华口腔医学杂志,2002,37(5):388.
41.陈国宝,陈宝田.番石榴叶提取物体外抗轮状病毒的实验研究[J].中国医药学报,2002,17(8):502-504.
42.田英,董俊兴.天然产物中抗艾滋病病毒活性成分的研究进展[J].中国中药杂志,2002,37(6):401~405.
43. Both DM, Goodtzova K, Yarosh DB, et al Liposome encap sulated ursolic acid increases ceramides and collagen in human skin cells [J]. Arch Dermatol Res, 2002, 293 (11): 569-575.
44. Somova LO, NadarA, Rammanan P, et al. Cardiovascular, antihyperlipidemic and antioxidant effects of oleanolic and ursolic acids in experimental hypertension [J]. Phytomedicine, 2003, 10 (2/3): 115-121.
45. Chung YK, Heo HJ, Kim EK, et al. Inhibitory effect of ursolic acid purified from Origanum majorana L on the acetylcholinesterase [J]. MolCells, 2001, 11(2): 137-143.
46.颜玲,陈会敏熊果酸的免疫学活性湖北民族学院学报医学版2005. 22(1):51-53
47. You HJ, Chou CY, Kim JY, et al Ursolic acid enhances nitric oxide and tum or necrosis factor-alpha production via nuclear factor-kappaB activation in the resting macrophages [J]. FEBS Lett 2001, 509(2):156-160
48. Raphael TJ, Kuttan G, Effect of naturally occurring triterpenoids glycyrrhizic acid, ursolic acid, oleanolic acid and nomilin on the immune system [J]. Phytomedicine. 2003, 10(6-7):483-489
49.熊筱娟、陈武、李开泉,等.乌索酸毒性实验研究[J].宜春医专学报,2001,13(1):541
50.陈武、熊筱娟、李开泉,等.乌索酸治疗急性病毒性肝炎的临床研究[J].宜春医专学报,2001,13(1):1-3
2.吕慧侠、周建平缓控释给药系统发展概况机电信息2004.12(7):54-58
3.王建华,陈慧云,杨永,吕正检,徐世荣口服缓/控释药物制剂技术研究进展药学专论2005.14(8):14-15
4.易延逵,邓虹珠,张璐,魏毅,缓释片剂的发展概况中华临床医药2002.3(18):82-84
5.陈慧云,王建华,徐世荣,王琦高分子材料纤维素醚类衍生物在缓释制剂辅料中的应用材料导报2005.19(7):48-51
6.程紫骅,刘燕,朱家璧盐酸雷尼替丁HPMC骨架片药物释放影响因素研究中国药科大学学报1998.29(4):275-277
7.柳晨,王晓黎,陈御石,裴元英阿司匹林HPMC骨架片药物释放因素研究中国药学杂志1999.34(10):673-676
8.董志超.羟丙基甲基纤维素在凝胶骨架片的应用.国外医药合成药、生化药、制剂分册,1993,14:41.
9. XuGj,SunadaH. Influence of formulation change on drug release kinetics from hydroxypropylmethylcellulose maltrix tablets.ChemPharm Bull,1995,43(3):483.
10.董志超,蒋雪涛,张恒弼.卡托普利缓释片的实验研究.中国医药工业杂志,1993,24(2):65.
11.董志超,蒋雪涛.羟丙基甲基纤维素的性质对药物亲水性骨架片溶出度的影响.药学学报,1994,29(12):920.
12.裴元英,戈升荣,陈御石.硫酸奎尼丁HPMC骨架片影响释药因素研究.中国药学杂志,1996,31(12):727.
13.裴元英,陈御石,郑玲妹,等.对乙酰氨基酚HPMC骨架片药物释放影响因素研究.中国药学杂志,1997,32(5):281.
14. BavejaSK, RangaRaoKV, SinghA, etal. Release characteristics of somebronchodilators from compresse dhydrophilic polymericm atrices and their correlation with molecular geometry. Int J Pharma,1988,41:55.
15.高声传,郭涛,陈济民,姜铁夫双氯芬酸赖氨酸盐缓释片制备工艺的研究.解放军药学学报,2000,16(6):303-306
16. Zeng HX, Pan WS, Chen JM, et al. Preparation and release of sustained-release famotidine tablet[J]. Zhongguo Yaoxue Zazhi, 1997,32(4): 213
17.阳长明,候世祥药物溶出度研究进展中成药2000,22(7):511-515
18.吴佩颖,徐莲英,陶建生难溶性药物增溶方法研究进展中成药2005,27(9):附10-13
19.秦冬梅,王恒,李海瑛羟丙甲基纤维素在药剂学中的应用安徽医药2004,8(3):173-174
20.郑俊民药用高分子材料.北京:中国医药科技出版社,2002;7
21.药用辅料手册,上册
22.罗明生,高天惠.药用辅料大全.成都:四川科技出版社,1993
23. Xu Guoiie, Zhan Ruhua, Chu Wei Hisakazu Sunada Water Penetration, Matrix Swell and Drug Release Property Studies of Hvdroxvnronvlmethvl Cellulose Matrix Tablets Journal of Chinese Pharmaceutical Sciences 2000, 9(1):26-29
24.董志超,蒋雪涛,张恒弼.卡托普利缓释片的实验研究.中国医药工业杂志,1993,24(2): 65
25. Baveja SK, RangaRao KV, Singh A, et al. Release Characteristics of some bronchodilators from compressed hydrophilic polymeric matrices and their correlation with molecular geometry. Int J Parm, 1988,41: 55
26.郭波红,程怡乙基纤维素在缓控释制剂中的应用研究中医药学刊2002,20(5):601-603
27.许东航,范辉,叶婷,梁文权稀释剂对HPMC骨架片释药的影响中国现代应用药学杂志2003,20(1):30-32
28. Matsumara M,Nakagami H,Yamao T, etal.Computer optimization for the formulationof controlled release theophylline tablet made of micronized lowsubstitued hydroxypropylcellulose and methylcellulose [J]. Chem Pharm Bull, 1994, 42(9):1902.
29. Richard S,Ramona K.The effects of pH, ionic concentration and ionic species of dissolution media on the release rates of quinidine gluconate sustained release dosage forms [J]. Drug Dev Ind Pharm,1991,17(1):113.
30. Marcos BP,Ford JL,Armstrong DJ, etal. Influence of pH on the release of propranolol hydrochloride from matrices containing HPMC K4M and carbopol 1974[J]. J Pharm Sci, 1996,85(3):330.
31. Martin-Aragon S, de las He ras B, Sanchez-Reus MI, et al Pharmacological modification of endogenous antioxidant enzymes by ursolic acid on tetrachloride- induced liver damage in rats and primary cultures of rat hepatocytes [J]. Exp Toxicol Pathol 2001, 53(2/3):199-206
32.周小菊.福安特纳米粉针剂研究:[硕士学位论文]:华中科技大学图书馆,2000.
33.刘亚妮.齐墩果酸缓释片的研究: [硕士学位论文]:华中科技大学图书馆,2006.
34.中国药典2005版二部
35. Lapidus H et al: ibid 1968,57: 1292
36. Higuchi T. Mechanism of sustained action medication, Theoretica analysis of rate of release of solid drugs dispersed in solid matrices J Pharm Sci, 1963, 2:1145.
1.李开泉,陈武,熊筱娟,王雪熊果酸的化学、药理及临床应用进展中成药2002.24(9)
2.夏国豪章永红,王瑞平熊果酸抗肿瘤作用研究进展国外医学肿瘤学分册2002.29(6)
3.殷晓东,赵浩如熊果酸研究进展中华实用中西医杂志2004.4(17)
4.徐礼焱,等.中草药有效成分分析法(上册)[M],北京:人民卫生出版社,1984:81
5.陈武,熊筱娟,李开泉,王雪,朱建新,刘传安、冷桂华乌索酸的化学、药理及临床研究宜春医专学报2001.13(2)
6.钟瑞建,郭晓秋,TLC测定白花蛇舌草中熊果酸的含量[J]中药材,1997,20(1):33234.
7.赵春香,章贵杰,张莉,薄层扫描法测定心可舒片中熊果酸的含量[J],中国中药杂志,1999,24(7):4152417.
8.方红玲,戚建中.薄层扫描法测定肝达片中熊果酸的含量[J]中国药科大学学报,1998,29(Suppl):1442146.
9.袁珂,李根林,李俊芝等,车前草中熊果酸齐墩果酸的HPLC测定[J],中草药,1999,30(12):9012903.
10.林巧玲,谢培山,龙广霖.薄层荧光色谱扫描法测定进口药爱活胆通中能果酸的含量[J],中药新药与临床药理,1997,(2)1002102.
11.王旭,周富荣,关晶,等.大山楂口嚼片定性定量的研究[J]中国中药杂志,1999,24(11):6752677.
12.闫花丽,赵陆华,朱丹妮,等.衍生化气相色谱法测定夏枯草中齐墩果酸和熊果酸的含量[J],中国中药杂志,1999.24(12):7442745.
13.熊斌雷志勇,陈虹熊果酸药理学的研究进展国外医学药学分册2004.31(3)
14.熊筱娟、陈武、李开泉、王雪乌索酸药理作用研究进展宜春医专学报2001.13(1)
15. Cha HJ,Bae SK, Lee HY, et al. Anti-invasiveactivity of ursolic acid correlates with thereduced expression of matrix metalloproteinase-9 (MMP-9) in HT 1080 human fibrosarcoma cells [J]. Cancer Res,1996, 56(10) : 2281-2284.
16. Ames BN. Dietary carcinogens and anticarcinogens. Science, 1983, 221:1256
17. Balanehru S. Nagarajan B. Protective effect of oleanloic acid and Ursolic acida ganist lipid peroxidation. Biochem Int, 1991, 24 (5): 9811
18. Young Hs, Chung Hy, Lee Ck, et al Ursolic acid inhibits aflatoxin BI- induced mutagenicity in a Salmonella assay system. Biol Pharm Bull.1994,17(7):990.
19.王春雷,芦柏震,侯桂兰熊果酸抗肿瘤作用研究进展安徽医药2005.9(10):723-725
20.樊明文,王茜,边专.熊果酸对人舌鳞癌细胞株的抑制作用及其机制探讨[J].武汉大学学报(医学版),2004,25(1):1-3.
21.吴其年,黄炜杨凤仪.熊果酸对人乳腺癌细胞增殖、凋亡和细胞内游离Ca2+的影响[J].肿瘤学杂志,2004,10(3):145-147.
22.黄炜,黄济群,张东方.五环三萜类化合物抗人肺癌细胞侵袭和诱导细胞凋亡的研究[J].中国肺癌杂志,2003,6(4):254-257.
23.张秋萍,谢珞琨,邓涛.熊果酸促进562细胞凋亡[J].基础医学与临床,2004,24(4):414-7.
24. Sohn KH, Lee HY, Chung HY,et al. Anti-amgio genesis activity of trite rpene acids[J]. Cancer Lett 1995, 94(2):213-217.
25.王兵,王杰军,徐钧.熊果酸对体外血管形成的抑制作用[J].肿瘤防治杂志,2001,8(4):351-2.
26. Lee HY, Chang HY, Kim KH, et al. Induction of differentiation. In the cultured F9 teratocarcinoma stem cells by triterpen acids [J]. Cancer Res Clin Oncol, 1994, 120 (9): 5131
27.宋京、张庆林,熊果酸药理作用研究进展[J],中草药,1999,30(增刊)。
28.白育军,杨小生,康文艺,郝小江,徐筱杰,宋宝安熊果酸的结构修饰物及其抗肿瘤活性华西药学杂志2003.18 (2):87-90
29.张星,潘启超白花蛇舌草提取物-熊果酸的抗肿瘤作用[J]国外医药-植物药分册,1999,14(6):255
30. Philip A. Zoretic, Robert J. Chambers. Sterospecific sythsis of secondary allylic alcohols: selenxide chemistry [J]. J Org Chem, 1985, 50: 2981.
31. GW Cavili, DH Solomon. Organic oxidation pross part IV. The reaction of lead tetra-acetate with some carbonvl compounds [J]. J Chem Soc,1955, 4426
32.江西宜春地区卫生局,陆英研究资料6[M],199
33.陈武,李开泉,熊筱娟,等,陆英抗肝炎活性成分的研究,宜春医专学报,2000,12(4):2391
34.韩德五,等,齐墩果酸防止实验性肝硬变发生的研究,中医杂志,1981,(3):2171
35.张乐之,李新芳,齐墩果酸对大鼠实验性肝损伤作用机理的研究,中药药理与临床,1992,8(2):241
36.马学惠,等,乌索酸对实验性肝损伤的防治作用,药学学报,1986,21:3321
37. Martin-Aragon S, de las He ras B, Sanchez-Reus MI, et al Pharmacological modification of endogenous antioxidant enzymes by ursolic acid on tetrachloride- induced liver damage in rats and primary cultures of rat hepatocytes [J]. Exp Toxicol Pathol 2001, 53(2/3):199-206
38. Saraswat B, Visen PK, Agarwal DP. Ursolic acid isolated from Eucalyptus tereticornis protectsagainst ethanol toxicity in isolated rat hepatocytes [J]. Phytother Res, 2000,14(3):163-6.
39.卞象梅.乌索酸[J].中草药通讯,1976,7(9):15
40.王茜,樊明文,边专,等.熊果酸的提取及其对牙周病原菌的作用[J].中华口腔医学杂志,2002,37(5):388.
41.陈国宝,陈宝田.番石榴叶提取物体外抗轮状病毒的实验研究[J].中国医药学报,2002,17(8):502-504.
42.田英,董俊兴.天然产物中抗艾滋病病毒活性成分的研究进展[J].中国中药杂志,2002,37(6):401~405.
43. Both DM, Goodtzova K, Yarosh DB, et al Liposome encap sulated ursolic acid increases ceramides and collagen in human skin cells [J]. Arch Dermatol Res, 2002, 293 (11): 569-575.
44. Somova LO, NadarA, Rammanan P, et al. Cardiovascular, antihyperlipidemic and antioxidant effects of oleanolic and ursolic acids in experimental hypertension [J]. Phytomedicine, 2003, 10 (2/3): 115-121.
45. Chung YK, Heo HJ, Kim EK, et al. Inhibitory effect of ursolic acid purified from Origanum majorana L on the acetylcholinesterase [J]. MolCells, 2001, 11(2): 137-143.
46.颜玲,陈会敏熊果酸的免疫学活性湖北民族学院学报医学版2005. 22(1):51-53
47. You HJ, Chou CY, Kim JY, et al Ursolic acid enhances nitric oxide and tum or necrosis factor-alpha production via nuclear factor-kappaB activation in the resting macrophages [J]. FEBS Lett 2001, 509(2):156-160
48. Raphael TJ, Kuttan G, Effect of naturally occurring triterpenoids glycyrrhizic acid, ursolic acid, oleanolic acid and nomilin on the immune system [J]. Phytomedicine. 2003, 10(6-7):483-489
49.熊筱娟、陈武、李开泉,等.乌索酸毒性实验研究[J].宜春医专学报,2001,13(1):541
50.陈武、熊筱娟、李开泉,等.乌索酸治疗急性病毒性肝炎的临床研究[J].宜春医专学报,2001,13(1):1-3