脑清乳剂的研制及其性质研究
摘要
脑清乳剂是为治疗缺血性中风而研制的药物,其主要成分为中药麝香、冰片、三七、川芎、石菖蒲等,存在成分复杂,结构多样性的特点。本课题将脂肪乳剂与鼻腔给药结合起来,使乳剂中的药物与鼻粘膜紧密和持续地接触,以提高生物利用度,增加患者用药依从性,特别是利用喷鼻剂具有的剂型特点,加强药物针对脑部的靶向作用,适用于缺血性脑血管机能不全急性期的应急处理。国内尚未见报道使用乳剂作为中药喷鼻给药的剂型。
本论文以药材有效成分含量为指标,通过单因素考察和正交试验优化了麝香、石菖蒲及薄荷的提取工艺。验证试验表明,工艺提取率高,重现性较好。本文研究了冰片的羟丙基-β-环糊精(HP-β-CD)包合物的制备工艺,以包合率和包合物收率为指标评价包合工艺,通过正交设计试验,确定了冰片-HP-β-CD的最佳包合工艺,减少了冰片在制剂中的挥发。
单因素考察了油相比、乳化剂用量、乳化剂HLB值及稳定剂等处方因素对乳剂质量的影响,并以稳定常数Ke为考察指标设计正交试验筛选出脑清乳剂的最佳处方。同时,单因素考察初乳化温度、初乳化时间、搅拌机转速、高压均质机运转压力及循环次数等工艺因素对乳剂质量的影响,后经正交设计试验筛选出脑清乳剂最优工艺。
脑清乳剂的处方工艺为:将注射用大豆磷脂,RH40,油酸,维生素E加入薄荷油、石菖蒲油、大豆油混合油相中,将甘油加入三七、川芎提取物水溶液中,在55℃水浴条件下,将水相缓慢加入到油相,同时以10000rpm的速度搅拌5分钟,得初乳。将冰片与麝香酮醇提液加入初乳中在高压均质机中以1000bar压力循环5次,过0.45μm滤膜得脑清乳剂。
对脑清乳剂中各种药材进行了定性定量检测。建立了川芎、三七、石菖蒲、薄荷及冰片成分的TLC鉴别方法,麝香酮、冰片的GC含量测定方法。为制定脑清乳剂的质量标准提供了依据。
脑清乳剂为淡黄色均匀乳剂,粒径分布为256±22nm,Zeta电位为-23.50mv,粘滞系数为1.367(10-3Pa﹒s),pH值为6.39。脑清乳剂的离心稳定性研究显示在4000rpm离心15min不分层;冷冻加热循环实验说明脑清乳剂具有较好的聚结稳定性;高温和光照实验显示,脑清乳剂对光、热不稳定;30℃加速6个月和室温(25℃)留样6个月,脑清乳剂的各项考察指标变化不大,满足制剂稳定性要求。进行了脑清乳剂安全性初步评价,证明脑清乳剂对大鼠没有毒性。
实验证明脑清乳剂是稳定的,无毒的剂型,提高了脂溶性药物的载药量,减少了用药刺激性,符合外用乳剂的要求。
The main component of Nao-Qing Nasal Spray Emulsion, which is used to treatment of AIS, is Moschus, Notoginseng, Ligustici, Rhizoma, Borneol, et al. The feature is multiplicity compositions and multiplicity constitution. The emulsion formulation and nasal cavity dosage are combined in the research of Nao-Qing Emulsion, to make the drugs and nasal mucosa contact closely and continuously, in order to improve the bioavailability, increase compliance treating patients, especially to utilize the feature of dosage form-nasal spray, to strengthen the target to pars encephalica. It is suitable for the ischemic cerebrovascular inadequacies in the acute phase of the emergency treatment. There is none report about emulsion binding Chinese crude drug nasal spray.
The best extraction tehcnics of muscone, Rhizoma and Mentha haplocalyx were gained by single factor investigation and orthogonal experiment,when effective component contents were as detection index. The result of verification experiment indicated that it was efficient and reproducible.
In this paper, inclusion compound was made by gripping borneol with hydroxypropyl-β-cyclodextrin(HP-β-CD), in order to reduce the volatilization of borneol in the preparation.
Effects of oil, emulsifier and stabilizer were studied by single factor test, and based on these we found the best formula by orthogonal design when refining soybean oil, emulsifier and stabilizer were as consideration factors, Ke as investigation index. Effects of emulsification temperature, emulsification time, speed of high-speed mixer, nanomizer working Pressure and cycle times were also investigated by single factor test, and then the orthogonal design was adopted to obtain the optimized preparation procedure.
Gas chromatography(GC)method was set up to determine the concentration of muscone and borneol.TLC method was used to identify Notoginseng, Ligustici, Rhizoma, Borneol and Mentha haplocalyx.
The physiochemical properties of Nao-Qing Nasal Spray Emulsion were studied. Gaussian volume-Wt diameter, zeta-potential, viscosity and pH value is 256±22nm, -23.50mV, 1. 367(10~(-3)Pa﹒s), 6.39 respectively.
The results of accelerating and long-term stability tests indicated that the physical and chemical stability of Nao-Qing Nasal Spray Emulsion were fine and incompliance with the requirement of preparation stability, but it should be tightly preserved form light and heat. There was no creaming after Nao-Qing Nasal Spray Emulsion was centrifugated at speed of 4000 rpm for 15 min, and freezing-heating experiment showed Nao-Qing Nasal Spray Emulsion had better aggregations stability. Meanwhile, preliminary evaluation of the safety of Nao-Qing Nasal Spray Emulsion proved that there was no clear toxicity on mice.
Experiments show that Nao-Qing Nasal Spray Emulsion, which improves the drug loading of fat-soluble drugs and reduces irritation, is stable, non-toxic formulation, in line with the requirements of external emulsion.
本论文以药材有效成分含量为指标,通过单因素考察和正交试验优化了麝香、石菖蒲及薄荷的提取工艺。验证试验表明,工艺提取率高,重现性较好。本文研究了冰片的羟丙基-β-环糊精(HP-β-CD)包合物的制备工艺,以包合率和包合物收率为指标评价包合工艺,通过正交设计试验,确定了冰片-HP-β-CD的最佳包合工艺,减少了冰片在制剂中的挥发。
单因素考察了油相比、乳化剂用量、乳化剂HLB值及稳定剂等处方因素对乳剂质量的影响,并以稳定常数Ke为考察指标设计正交试验筛选出脑清乳剂的最佳处方。同时,单因素考察初乳化温度、初乳化时间、搅拌机转速、高压均质机运转压力及循环次数等工艺因素对乳剂质量的影响,后经正交设计试验筛选出脑清乳剂最优工艺。
脑清乳剂的处方工艺为:将注射用大豆磷脂,RH40,油酸,维生素E加入薄荷油、石菖蒲油、大豆油混合油相中,将甘油加入三七、川芎提取物水溶液中,在55℃水浴条件下,将水相缓慢加入到油相,同时以10000rpm的速度搅拌5分钟,得初乳。将冰片与麝香酮醇提液加入初乳中在高压均质机中以1000bar压力循环5次,过0.45μm滤膜得脑清乳剂。
对脑清乳剂中各种药材进行了定性定量检测。建立了川芎、三七、石菖蒲、薄荷及冰片成分的TLC鉴别方法,麝香酮、冰片的GC含量测定方法。为制定脑清乳剂的质量标准提供了依据。
脑清乳剂为淡黄色均匀乳剂,粒径分布为256±22nm,Zeta电位为-23.50mv,粘滞系数为1.367(10-3Pa﹒s),pH值为6.39。脑清乳剂的离心稳定性研究显示在4000rpm离心15min不分层;冷冻加热循环实验说明脑清乳剂具有较好的聚结稳定性;高温和光照实验显示,脑清乳剂对光、热不稳定;30℃加速6个月和室温(25℃)留样6个月,脑清乳剂的各项考察指标变化不大,满足制剂稳定性要求。进行了脑清乳剂安全性初步评价,证明脑清乳剂对大鼠没有毒性。
实验证明脑清乳剂是稳定的,无毒的剂型,提高了脂溶性药物的载药量,减少了用药刺激性,符合外用乳剂的要求。
The main component of Nao-Qing Nasal Spray Emulsion, which is used to treatment of AIS, is Moschus, Notoginseng, Ligustici, Rhizoma, Borneol, et al. The feature is multiplicity compositions and multiplicity constitution. The emulsion formulation and nasal cavity dosage are combined in the research of Nao-Qing Emulsion, to make the drugs and nasal mucosa contact closely and continuously, in order to improve the bioavailability, increase compliance treating patients, especially to utilize the feature of dosage form-nasal spray, to strengthen the target to pars encephalica. It is suitable for the ischemic cerebrovascular inadequacies in the acute phase of the emergency treatment. There is none report about emulsion binding Chinese crude drug nasal spray.
The best extraction tehcnics of muscone, Rhizoma and Mentha haplocalyx were gained by single factor investigation and orthogonal experiment,when effective component contents were as detection index. The result of verification experiment indicated that it was efficient and reproducible.
In this paper, inclusion compound was made by gripping borneol with hydroxypropyl-β-cyclodextrin(HP-β-CD), in order to reduce the volatilization of borneol in the preparation.
Effects of oil, emulsifier and stabilizer were studied by single factor test, and based on these we found the best formula by orthogonal design when refining soybean oil, emulsifier and stabilizer were as consideration factors, Ke as investigation index. Effects of emulsification temperature, emulsification time, speed of high-speed mixer, nanomizer working Pressure and cycle times were also investigated by single factor test, and then the orthogonal design was adopted to obtain the optimized preparation procedure.
Gas chromatography(GC)method was set up to determine the concentration of muscone and borneol.TLC method was used to identify Notoginseng, Ligustici, Rhizoma, Borneol and Mentha haplocalyx.
The physiochemical properties of Nao-Qing Nasal Spray Emulsion were studied. Gaussian volume-Wt diameter, zeta-potential, viscosity and pH value is 256±22nm, -23.50mV, 1. 367(10~(-3)Pa﹒s), 6.39 respectively.
The results of accelerating and long-term stability tests indicated that the physical and chemical stability of Nao-Qing Nasal Spray Emulsion were fine and incompliance with the requirement of preparation stability, but it should be tightly preserved form light and heat. There was no creaming after Nao-Qing Nasal Spray Emulsion was centrifugated at speed of 4000 rpm for 15 min, and freezing-heating experiment showed Nao-Qing Nasal Spray Emulsion had better aggregations stability. Meanwhile, preliminary evaluation of the safety of Nao-Qing Nasal Spray Emulsion proved that there was no clear toxicity on mice.
Experiments show that Nao-Qing Nasal Spray Emulsion, which improves the drug loading of fat-soluble drugs and reduces irritation, is stable, non-toxic formulation, in line with the requirements of external emulsion.
引文
[1] Licata G, Tuttolomondo A, Sinagra D, et al. Diabetes mellitus and stroke [J]. Ital Heart J Suppl, 2003, (3):471-477.
[2]李忠.缺血性脑血管疾病[M].北京:北京科学出版社,2002.
[3] Bogousslavsky J, Melle GV, Regli F. The Lausanne Stroke Registry: analysis of 1000consecutive patients with first stroke. Stroke 1988, 19(10): 83-92.
[4]周迎春,邵念方.急性缺血性中风病因病机探讨[J].湖北中医学院学报,1999,1(2) :19-20.
[5] Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. Classification and natural history ofclinically identifiable subtypes of cerebral infarction. Lancet 1991, 7(6):15-21.
[6] Sacco RL, Toni D, Brainin M, and Mohr JP: Classification of Ischemic Stroke. In: Mohr JP, Choi DW, GrottaJC, Weir B, Wolf PA, eds. STROKE: Pathophysiology, Diagnosis, andManagement. (4th Ed) New York: Churchill Livingstone, 2004, (5): 61-74.
[7]张青萍,刘泰.缺血性中风中药治疗研究述要[J].辽宁中医药大学学报,2006,8(4):55-56.
[8]沈光莉.急性缺血性脑卒中溶栓治疗临床新进展[J].中国康复理论与实践, 2006,12(1):23-25.
[9]连立明,陈俊荣.使用组织胞浆素原活化剂静脉注射治疗急性缺血性脑中风之初期经验[J].台湾医学,2000,4(4):379-387.
[10]欧阳海春,吴沃栋,钟冬梅,等.安宫牛黄丸及类方预处理对兔心肌缺血及再灌注损伤保护的作用研究[J].现代医院,2008,8(7) :25-28.
[11]赵雍,曹春雨,王秀荣,等.含与不含朱砂和雄黄的安宫牛黄丸对大鼠局灶性脑缺血的影响[J].中国中西医结合杂志,2002,22(9): 684-686.
[12]叶祖光,王金华,梁爱华,等等.安宫牛黄丸及其简化方的药效学比较研究[J].中国中药杂志,2003,28(7): 636-639.
[13]李国菁,严浩成,王行宽.试述肾与脑之关系——也谈缺血性中风从肾论治[J].中医药学刊,2005,23(6),1041-1042.
[14]吴寿荣,程刚.脑靶向给药系统的研究进展[J].中国医药工业杂志,2002,33(5):247-251.
[15]安富荣编译.中枢神经系统给药方法研究进展[J].国外医药-合成药生化药制剂分册,2000,21(4):241-244.
[16]苏德森,王思玲主编.物理药剂学[M].北京:化学工业出版社,2004.
[17]韩璐,胡晋红,朱全刚.经皮给药系统促渗方法研究的新进展[J].中国新药杂志,2007,16(4):274.
[18]李超英,孙丽红.新剂型新技术在中药透皮给药系统中的应用[J].中国中医药信息杂志,2007,14(5):93.
[19]李一龙,金英淑.醒脑静联合乳果糖治疗肝性脑病的疗效分析[J].中国民族民间医药杂志,2010,23,47.
[20]王晓琴,吴潇.醒脑静注射液治疗中风痰热内闭证临床观察[J].湖北中医杂志, 2009,31(7) :39-40.
[21]石森林,徐莲英.脑部疾病的鼻腔给药研究[J].中药新药和临床药理,2004,15(2):145-148.
[22]冉鄂山.鼻用制剂对鼻粘膜的影响[J].贵州医药,1982,16(6):375.
[23]Frey WH, Liu J, Chen X, et al. Delivery of 125I-NGF to the brain via the olfactory route[J]. Drug Del iv-J Deliver Targeting The Agents, 1994, (2):87-89.
[23]Chow HS, Chen Z, Matsuum GT. Direct transport cocaine from the nasal cavity to the brain following intranasal cocaine administration in rats[J].J Pharm Sci,1999,8(8):754.
[24]周迎春.脑脉通方治疗急性缺血性中风的临床与实验研究[J].山东中医学院学报,1996,20(2):94-99.
[25]汪春,陈宏蛙.脑醒喷鼻剂治疗急性缺血性中风的临床观察[J].中药新药与临床药理,2000,11(6) :333.
[26]杨开清,李荣.脑醒喷鼻剂治疗急性缺血性中风66例[J].广州中医药大学学报,2003,20(1):28.
[27]杨帆,潘育方,陈颖.一种脑清喷鼻微乳制剂、其制备方法和应用[P].中国,CN200910036693. 9
[28]脑通滴鼻液抗大鼠脑水肿及对TXB2、6-K-PGF1的影响的实验研究[J].浙江中医药大学学报,2006,30(4):354-355.
[29]邵念方,祝维峰.脑通滴鼻液治疗缺血性脑卒中的临床研究[J].山东中医杂志,1999,18(2):58.
[30]尹士敏,王士贤.麝香的药理作用及临床研究近况[J].天津药学,2002,14(3):42-43
[31]刘亚敏,沈强,徐秋英.麝香保心丸合中医辨证治疗急性缺血性中风的临床疗效分析[J].中成药,2006,8(1),52-55.
[32]南征,南红梅,南劲松,等.麝香抗栓胶囊治疗中风(脑血栓)662例临床与实验研究[J].长春中医学院学报,2005,21(1),11-12.
[33]黄卫东.吕武清.冰片的研究进展[J].中国药业,2008,17(4):64-67.
[34]赵保胜.刘启德.冰片促血脑屏障开放与病理性开放的比较[J].中药新药与临床药理,2002,13(5):287.
[35]柳涌,高蓉.川芎素治疗急性脑梗死临床体会[J].中国中医急症,2008,17(1),104.
[36]杨洁红,白海波,万海同.等.川芎提取物穴位敷贴对大鼠脑缺血再灌注损伤的保护作用[J].中国中医药信息杂志,2004,11(9):778-779.
[37]吴启端,方永奇,李翎,等.石菖蒲醒脑开窍的有效部位筛选[J].时珍国医国药,2002,13(5):260.
[38]李翎,邹衍衍,吴启端,等.石菖蒲系列提取物对大鼠脑缺血再灌注损伤的影响[J].中医药学刊,2003,21(2):212.
[39]柯雪红.方永奇.等.石菖蒲挥发油对脑缺血再灌注脑中氨基酸的影响[J].中国老年学杂志,2003,23(5):302.
[40]匡忠生.石菖蒲提取液对脑缺血再灌注诱导的神经细胞凋亡的保护作用[J].广东医学,2002,23(5):459.
[41]许军,王阶,温林军.三七总皂苷干预血栓形成研究概况[J].云南中医中药杂志, 2003,24(5): 46-47.
[42]吉海旺,宗伟,雷鹏,等.血塞通滴丸治疗中风恢复期瘀血阻络证30例[J].陕西中医,2007,8(10):1314-1315.
[43]王北婴,李仪奎.中药新药研制开发技术与方法[M].上海:上海科学技术出版社,2001.
[44]柯瑜,倪健,姚钮成.石菖蒲挥发油提取及包合工艺的优选[J].中成药,2006,8(9):1271-1274.
[45]汤道权.正交法优选固天泉胶囊中石菖蒲挥发油提取工艺[J].时珍国医国药,2001,12(2):125.
[46]王轶伟.β-环糊精及2-羟丙基-β-环糊精与几种药物的包结研究[J].天津:天津大学,2007,35(10) :66-69.
[47]Guomundsdottir E, Stefansson E, Bjarnadottir G. et al. Methazolamide 1% in cyclodextrin solution lowers IOP in human ocular hypertension[J]. Inwestigative Ophthalmology and Visual Science, 2000, 41(11):3552-3554.
[48]蔡双霜,黄华,陈莉.羟丙基-β-环糊精的应用发展[J].中国药业,2008,17(10) :78-80.
[49]Miyake K, Arima H, Hirayama F.et al.Improvement of solubility and oral bioavailability of rutin by complexation with 2-hydroxypropyl-β-cyclodextrin [J].Pharm.Dev.Technol, 2000, 5(3):399-407.
[50]石远,石惠,姜同英等.注射用丹参酮ⅡA包合物的制备及性质考察[J].沈阳药科大学学报,2008,5(10):765-771.
[51] Pitha J, Gerloczy A, Olivi A, Parenteral hydroxypropyl cyclodextrins,Intravenous and intracerebral administration of lipophiles[J].Journal of Pharmaceutical Science, 1994, 3(6):833-837.
[52]欧云国.茴三硫-2-羟丙基-β-环糊精包合物的研究[D].重庆:重庆医科大学,2008.
[53]刘玉雯,余祥彬,吴宏霞.酮洛芬-羟丙基-β-环糊精包合物的制备工艺[J].福建医科大学学报,2005,9(4):437-439.
[54]罗媛,郑林,兰燕宇,等.菊黄上清含片中冰片β-环糊精包合物的制备工艺[J].贵阳医学院学报,2010,35(2),137-139.
[55]李光文,孙媛媛,姚宏.通过与香草醛的显色反应检测冰片成分[J].理化检验-化学分册,2008,44(11):1083-1107.
[56]崔福德.药剂学.第5版.北京:人民卫生出版社,2003.
[57]廖颂明.中/长链脂肪乳注射液制备工艺的研究[J].广东药学院学报,2001,17(3):170.
[58]李少英.正交设计法筛选30%脂肪乳注射液的工艺条件[J].广东药学,1999,9(1):122.
[59]邓大明,朱惠曹,赵剑.脂肪乳剂的工艺研究[J].中国医院药学杂志,2001,21(5): 26.
[60]杜巧云,葛虹.表面活性剂基础及应用[M].北京:中国石化出版社,1996.
[61]中华人民共和国药典委员会.中华人民共和国药典2010版,第一部.
[62]苗明三,李振国.现代实用中药质量控制技术[M].北京:人民卫生出版社.
[63]王宝琴.中成药质量标准与物质研究[ M ] .北京:中国中医药出版社,1994.
[64]刘训红.中药材薄层色谱鉴别[M].天津:天津科学技术出版社,1990:443.
[65]殷金龙,李坤,徐云友.清心安神口服液质量标准的研究[J].长春中医学院学报,2004,20(4) : 39.
[66]聂明华,黄淑君.中风康复胶囊中黄芪、红花、丹参的薄层色谱鉴别[J].中国药业,2006,15(8):29.
[67]次旦扎西,刘松青,林彩.脑伤泰颗粒剂中红花和桃仁的薄层色谱鉴别[J].中国药业,2003,12(9):57.
[68]邹巧根,苏建俊.气相色谱法测定序香保心丸中麝香酮的含量[J].中国中药杂质,1994,9(7):418.
[69]魏晓舒.玉清安液中冰片的含量测定研究[J].中草药,1995,6(4):183.
[70]袁劲松,汤翠娥.气相色谱法测定紫金胶囊中麝香酮含量[J].中国医院药学杂质,2003,23(2):8-9.
[71]王强,毕开顺,陈金泉,等.六神丸中麝香酮含量的GC法测定[J].中国药科大学学报,1995,5(6):87.
[72]《中药、天然药物稳定性研究技术指导原则》课题研究组.中药、天然药物急性毒性研究技术指导原则[M].北京:国家食品药品监督管理局药品审评中心,2005.
[73]《中药、天然药物急性毒性试验技术指导原则》课题研究组.中药、天然药物急性毒性研究技术指导原则[M].北京:国家食品药品监督管理局药品审评中心,2005.
[2]李忠.缺血性脑血管疾病[M].北京:北京科学出版社,2002.
[3] Bogousslavsky J, Melle GV, Regli F. The Lausanne Stroke Registry: analysis of 1000consecutive patients with first stroke. Stroke 1988, 19(10): 83-92.
[4]周迎春,邵念方.急性缺血性中风病因病机探讨[J].湖北中医学院学报,1999,1(2) :19-20.
[5] Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. Classification and natural history ofclinically identifiable subtypes of cerebral infarction. Lancet 1991, 7(6):15-21.
[6] Sacco RL, Toni D, Brainin M, and Mohr JP: Classification of Ischemic Stroke. In: Mohr JP, Choi DW, GrottaJC, Weir B, Wolf PA, eds. STROKE: Pathophysiology, Diagnosis, andManagement. (4th Ed) New York: Churchill Livingstone, 2004, (5): 61-74.
[7]张青萍,刘泰.缺血性中风中药治疗研究述要[J].辽宁中医药大学学报,2006,8(4):55-56.
[8]沈光莉.急性缺血性脑卒中溶栓治疗临床新进展[J].中国康复理论与实践, 2006,12(1):23-25.
[9]连立明,陈俊荣.使用组织胞浆素原活化剂静脉注射治疗急性缺血性脑中风之初期经验[J].台湾医学,2000,4(4):379-387.
[10]欧阳海春,吴沃栋,钟冬梅,等.安宫牛黄丸及类方预处理对兔心肌缺血及再灌注损伤保护的作用研究[J].现代医院,2008,8(7) :25-28.
[11]赵雍,曹春雨,王秀荣,等.含与不含朱砂和雄黄的安宫牛黄丸对大鼠局灶性脑缺血的影响[J].中国中西医结合杂志,2002,22(9): 684-686.
[12]叶祖光,王金华,梁爱华,等等.安宫牛黄丸及其简化方的药效学比较研究[J].中国中药杂志,2003,28(7): 636-639.
[13]李国菁,严浩成,王行宽.试述肾与脑之关系——也谈缺血性中风从肾论治[J].中医药学刊,2005,23(6),1041-1042.
[14]吴寿荣,程刚.脑靶向给药系统的研究进展[J].中国医药工业杂志,2002,33(5):247-251.
[15]安富荣编译.中枢神经系统给药方法研究进展[J].国外医药-合成药生化药制剂分册,2000,21(4):241-244.
[16]苏德森,王思玲主编.物理药剂学[M].北京:化学工业出版社,2004.
[17]韩璐,胡晋红,朱全刚.经皮给药系统促渗方法研究的新进展[J].中国新药杂志,2007,16(4):274.
[18]李超英,孙丽红.新剂型新技术在中药透皮给药系统中的应用[J].中国中医药信息杂志,2007,14(5):93.
[19]李一龙,金英淑.醒脑静联合乳果糖治疗肝性脑病的疗效分析[J].中国民族民间医药杂志,2010,23,47.
[20]王晓琴,吴潇.醒脑静注射液治疗中风痰热内闭证临床观察[J].湖北中医杂志, 2009,31(7) :39-40.
[21]石森林,徐莲英.脑部疾病的鼻腔给药研究[J].中药新药和临床药理,2004,15(2):145-148.
[22]冉鄂山.鼻用制剂对鼻粘膜的影响[J].贵州医药,1982,16(6):375.
[23]Frey WH, Liu J, Chen X, et al. Delivery of 125I-NGF to the brain via the olfactory route[J]. Drug Del iv-J Deliver Targeting The Agents, 1994, (2):87-89.
[23]Chow HS, Chen Z, Matsuum GT. Direct transport cocaine from the nasal cavity to the brain following intranasal cocaine administration in rats[J].J Pharm Sci,1999,8(8):754.
[24]周迎春.脑脉通方治疗急性缺血性中风的临床与实验研究[J].山东中医学院学报,1996,20(2):94-99.
[25]汪春,陈宏蛙.脑醒喷鼻剂治疗急性缺血性中风的临床观察[J].中药新药与临床药理,2000,11(6) :333.
[26]杨开清,李荣.脑醒喷鼻剂治疗急性缺血性中风66例[J].广州中医药大学学报,2003,20(1):28.
[27]杨帆,潘育方,陈颖.一种脑清喷鼻微乳制剂、其制备方法和应用[P].中国,CN200910036693. 9
[28]脑通滴鼻液抗大鼠脑水肿及对TXB2、6-K-PGF1的影响的实验研究[J].浙江中医药大学学报,2006,30(4):354-355.
[29]邵念方,祝维峰.脑通滴鼻液治疗缺血性脑卒中的临床研究[J].山东中医杂志,1999,18(2):58.
[30]尹士敏,王士贤.麝香的药理作用及临床研究近况[J].天津药学,2002,14(3):42-43
[31]刘亚敏,沈强,徐秋英.麝香保心丸合中医辨证治疗急性缺血性中风的临床疗效分析[J].中成药,2006,8(1),52-55.
[32]南征,南红梅,南劲松,等.麝香抗栓胶囊治疗中风(脑血栓)662例临床与实验研究[J].长春中医学院学报,2005,21(1),11-12.
[33]黄卫东.吕武清.冰片的研究进展[J].中国药业,2008,17(4):64-67.
[34]赵保胜.刘启德.冰片促血脑屏障开放与病理性开放的比较[J].中药新药与临床药理,2002,13(5):287.
[35]柳涌,高蓉.川芎素治疗急性脑梗死临床体会[J].中国中医急症,2008,17(1),104.
[36]杨洁红,白海波,万海同.等.川芎提取物穴位敷贴对大鼠脑缺血再灌注损伤的保护作用[J].中国中医药信息杂志,2004,11(9):778-779.
[37]吴启端,方永奇,李翎,等.石菖蒲醒脑开窍的有效部位筛选[J].时珍国医国药,2002,13(5):260.
[38]李翎,邹衍衍,吴启端,等.石菖蒲系列提取物对大鼠脑缺血再灌注损伤的影响[J].中医药学刊,2003,21(2):212.
[39]柯雪红.方永奇.等.石菖蒲挥发油对脑缺血再灌注脑中氨基酸的影响[J].中国老年学杂志,2003,23(5):302.
[40]匡忠生.石菖蒲提取液对脑缺血再灌注诱导的神经细胞凋亡的保护作用[J].广东医学,2002,23(5):459.
[41]许军,王阶,温林军.三七总皂苷干预血栓形成研究概况[J].云南中医中药杂志, 2003,24(5): 46-47.
[42]吉海旺,宗伟,雷鹏,等.血塞通滴丸治疗中风恢复期瘀血阻络证30例[J].陕西中医,2007,8(10):1314-1315.
[43]王北婴,李仪奎.中药新药研制开发技术与方法[M].上海:上海科学技术出版社,2001.
[44]柯瑜,倪健,姚钮成.石菖蒲挥发油提取及包合工艺的优选[J].中成药,2006,8(9):1271-1274.
[45]汤道权.正交法优选固天泉胶囊中石菖蒲挥发油提取工艺[J].时珍国医国药,2001,12(2):125.
[46]王轶伟.β-环糊精及2-羟丙基-β-环糊精与几种药物的包结研究[J].天津:天津大学,2007,35(10) :66-69.
[47]Guomundsdottir E, Stefansson E, Bjarnadottir G. et al. Methazolamide 1% in cyclodextrin solution lowers IOP in human ocular hypertension[J]. Inwestigative Ophthalmology and Visual Science, 2000, 41(11):3552-3554.
[48]蔡双霜,黄华,陈莉.羟丙基-β-环糊精的应用发展[J].中国药业,2008,17(10) :78-80.
[49]Miyake K, Arima H, Hirayama F.et al.Improvement of solubility and oral bioavailability of rutin by complexation with 2-hydroxypropyl-β-cyclodextrin [J].Pharm.Dev.Technol, 2000, 5(3):399-407.
[50]石远,石惠,姜同英等.注射用丹参酮ⅡA包合物的制备及性质考察[J].沈阳药科大学学报,2008,5(10):765-771.
[51] Pitha J, Gerloczy A, Olivi A, Parenteral hydroxypropyl cyclodextrins,Intravenous and intracerebral administration of lipophiles[J].Journal of Pharmaceutical Science, 1994, 3(6):833-837.
[52]欧云国.茴三硫-2-羟丙基-β-环糊精包合物的研究[D].重庆:重庆医科大学,2008.
[53]刘玉雯,余祥彬,吴宏霞.酮洛芬-羟丙基-β-环糊精包合物的制备工艺[J].福建医科大学学报,2005,9(4):437-439.
[54]罗媛,郑林,兰燕宇,等.菊黄上清含片中冰片β-环糊精包合物的制备工艺[J].贵阳医学院学报,2010,35(2),137-139.
[55]李光文,孙媛媛,姚宏.通过与香草醛的显色反应检测冰片成分[J].理化检验-化学分册,2008,44(11):1083-1107.
[56]崔福德.药剂学.第5版.北京:人民卫生出版社,2003.
[57]廖颂明.中/长链脂肪乳注射液制备工艺的研究[J].广东药学院学报,2001,17(3):170.
[58]李少英.正交设计法筛选30%脂肪乳注射液的工艺条件[J].广东药学,1999,9(1):122.
[59]邓大明,朱惠曹,赵剑.脂肪乳剂的工艺研究[J].中国医院药学杂志,2001,21(5): 26.
[60]杜巧云,葛虹.表面活性剂基础及应用[M].北京:中国石化出版社,1996.
[61]中华人民共和国药典委员会.中华人民共和国药典2010版,第一部.
[62]苗明三,李振国.现代实用中药质量控制技术[M].北京:人民卫生出版社.
[63]王宝琴.中成药质量标准与物质研究[ M ] .北京:中国中医药出版社,1994.
[64]刘训红.中药材薄层色谱鉴别[M].天津:天津科学技术出版社,1990:443.
[65]殷金龙,李坤,徐云友.清心安神口服液质量标准的研究[J].长春中医学院学报,2004,20(4) : 39.
[66]聂明华,黄淑君.中风康复胶囊中黄芪、红花、丹参的薄层色谱鉴别[J].中国药业,2006,15(8):29.
[67]次旦扎西,刘松青,林彩.脑伤泰颗粒剂中红花和桃仁的薄层色谱鉴别[J].中国药业,2003,12(9):57.
[68]邹巧根,苏建俊.气相色谱法测定序香保心丸中麝香酮的含量[J].中国中药杂质,1994,9(7):418.
[69]魏晓舒.玉清安液中冰片的含量测定研究[J].中草药,1995,6(4):183.
[70]袁劲松,汤翠娥.气相色谱法测定紫金胶囊中麝香酮含量[J].中国医院药学杂质,2003,23(2):8-9.
[71]王强,毕开顺,陈金泉,等.六神丸中麝香酮含量的GC法测定[J].中国药科大学学报,1995,5(6):87.
[72]《中药、天然药物稳定性研究技术指导原则》课题研究组.中药、天然药物急性毒性研究技术指导原则[M].北京:国家食品药品监督管理局药品审评中心,2005.
[73]《中药、天然药物急性毒性试验技术指导原则》课题研究组.中药、天然药物急性毒性研究技术指导原则[M].北京:国家食品药品监督管理局药品审评中心,2005.
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