葛根及其复方眼用新剂型的研究
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摘要
由于眼部结构复杂并存在许多屏障,传统眼用制剂在疗效和患者顺应性等方面有诸多问题,为了更好地使治疗药物进入眼内发挥疗效,新型眼部给药系统的研究逐渐成为药剂学研究的热点之一。
中药治疗眼部疾病历史悠久,特别是在治疗内眼疾病,如青光眼、白内障、玻璃体出血、糖尿病所致视网膜病变、视网膜动静脉阻塞等方面具有明显的优势特色。常用中药当中,葛根和丹参经药理研究和临床使用证明均有扩张微血管,改善微循环的作用,对眼底病、眼外伤、慢性炎症性眼病等具有很好的疗效。传统给药形式主要为口服,而眼部给药比全身给药对进入眼内达到靶区更具优势与可行性,为了更好地体现与发挥中医药防治眼病的优势,有必要结合现代制药技术与给药系统的理论,对中药眼部给药系统进行研究和开发。
非离子表面活性剂囊泡(non-ionic surfactant vesicles),简称为类脂囊泡(niosomes),是一种与脂质体类似的新型给药系统。其作为眼用制剂载体的优势在于：作为药物的贮库,不仅可以延长药物在角膜和玻璃体内的滞留时间,还可以保护药物分子免受泪液或角膜上皮中代谢酶的破坏,使药物在角膜表面产生缓控释增效作用；并且囊泡对外眼组织,结膜和巩膜具有很强的亲和力,滴眼后可迅速分散,增强了药物对角膜的穿透性。眼用即型凝胶是近来研究较多的一种新型眼部给药载体,其在非生理状态下为自由流动的液体,给药后在眼部生理条件下形成凝胶,能够延长药物在眼内的滞留时间,从而提高生物利用度。
为了改善葛根素滴眼液临床上使用存在眼部滞留时间短患者顺应性差的问题,本课题尝试将葛根素制成非离子囊泡以研究囊泡在眼部应用的可行性；同时选用高分子聚合物泊洛沙姆407与188作为温度敏感型眼用凝胶的基质,对葛根和丹参复方眼用即型凝胶给药系统进行了初步研究,为今后研制开发中药复方眼用新型制剂奠定基础。本课题主要研究内容分为以下四部分：
第一部分葛根及丹参的提取与纯化研究。通过文献资料与预实验,对制剂所用中药葛根及丹参分别进行了提取与纯化。其中葛根以葛根素为指标,采用70%乙醇回流提取然后正丁醇溶解萃取冰醋酸重结晶的方法,得到纯度约89%的葛根素；丹参中有效成分分为丹参总酮和总酚酸两部分,分别以丹参酮II A、丹参总酮和丹酚酸B、丹参总酚酸为指标,对丹参进行醇提和水提,得到有效部位纯度大于50%的丹参总酮和总酚酸提取物。
第二部分葛根素非离子表面活性剂囊泡的制备研究。对葛根素非离子囊泡的制备及理化表征进行了初步研究,实验中对比发现注入法所形成的囊泡外观分散性较好,粒径较小且较为集中。通过比较离心、透析及葡聚糖凝胶柱层析等分离方法,最后优选葡聚糖凝胶柱层析法为葛根素非离子囊泡的有效分离方法。但含量测定结果显示葛根素的包封率很低,是本实验留待解决的一个主要问题。
第三部分丹葛明目即型凝胶的处方筛选及制备研究。以泊洛沙姆溶液经模拟泪液稀释前后的相转变温度为考察指标,采用均匀设计法优选了温度敏感型眼用凝胶基质处方,建立了泊洛沙姆浓度与相变温度的拟合方程,结果表明凝胶相变温度随着泊洛沙姆407的浓度增加而下降；而泊洛沙姆188在一定范围内能够提高泊洛沙姆407的相变温度。在符合条件的结果中选择了3个处方,分别对其在模拟泪液稀释前后的黏度进行了测定,最后确定以浓度较低的19%泊洛沙姆407与1%泊洛沙姆188合用作为温度敏感眼用凝胶的基质。在此基础上,对丹葛明目即型凝胶的处方作进一步筛选,确定处方中需要添加的其它附加剂,包括助溶剂(吐温20)、防腐剂(苯扎氯铵)及pH调节剂(NaOH)等,然后对药物及辅料加入后的胶凝温度及黏度的变化进行了考察,并作了相应调整,最后制备得到符合要求的丹葛明目温度敏感眼用凝胶。
第四部分丹葛明目即型凝胶的体内外初步评价研究。建立了丹葛明目即型凝胶中药物的含量测定方法：以葛根素和丹酚酸B为制剂的指标成分,采用高效液相色谱法进行测定。采用无膜溶出法对制备的丹葛明目即型凝胶进行了体外溶蚀及药物释放的考察。结果表明：凝胶中药物的释放受溶蚀控制,且二者均遵循零级动力学过程。家兔眼部的滞留时间实验显示眼用即型凝胶能显著延长药物在眼部的滞留时间。经兔眼单次给药和多次给药后观察,结果丹葛明目即型凝胶对兔眼无刺激性反应。经豚鼠皮肤多次涂抹给药,也未见皮肤过敏反应。
本课题的创新在于采用新技术新方法对中药眼部给药系统进行了尝试,对葛根素非离子囊泡及丹葛明目即型凝胶进行的相关研究均未见有报道。课题的研究探索结果可以为解决中药眼用制剂一些共性技术问题提供一定的借鉴思路和方法,有助于推动中药眼用新制剂更进一步的发展。
Owing to the complex structure and many barrier in the eye,traditional ophthalmic preparation have a lot of problems in patient compliance,healing effect et al. In order to make therapeutic drugs exert better curative effect on intraocular, novel ophthalmic drug delivery system gradually become the hot spot in pharmaceutics researches.
It has been a long history to treat ocular diseases by using chinese herbal medicine.TCM has obvious characteristic advantage especially in the treatment of interna eye diseases such as glaucoma,cataracts,vitreous hemorrhage,retinopathy caused by diabetes,retinal vein occlusion and retinal artery occlusion.Among the commonly used chinese herbal medicine, By pharmacological research and clinical use,puerarin and Salvia miltiorrhiza are proved that they can expand capillaries and improve microcirculation,have good curative effect in retina,ocular trauma,chronica inflammatory disease.The main administration form of chinese herbal medicine was oral,but ophthamic drug administrtion had more advantages and feasibility to enter in the target areas of eye.In order to better reflect and develop the advantage of preventing ocular disease by TCM,it is necessary to combine the theory of modern pharmaceutical technology and drug delivery system for research and development of TCM ophthamic delivery system.
Non-ionic surfactant vesicles,for short niosomes, is a new drug delivery system similar with liposomes.As ophthalmic drug carrier,its advantage lies in:prolong the drug retention time in cornea and vitreous body as drug storage library, protect the drug molecules from destroy by metabolic enzymes in tears or corneal epithelium, and exert the drug effect in corneal surface slowly; it also has a strong affinity with eyes organization,conjunctiva and sclera, and can disperse rapidly in the eye after droping, hence to enhance the cornea penetrability. In situ forming eye gel is another kind of ophthalmic drug delivery system well-studied recently, in physiological condition it is free flow liquid, in physiological conditions it will form a gel.This can prolong drug residence time in the eye, so as to improve the drug bioavailability.
The aim of this study is to improve low bioavailability and potential risk of clinical pue eyedrops through pue niosomes, and then we study the feasibility of its application in the eye. Meanwhile we choose poloxamer407 and poloxamer188 as temperature sensitive gel matrix, to study pueraria lobata and salvia miltiorrhiza compound in situ forming eye gel, in order to lay foundation for new herbal ophthalmic preparations in the future.In this study,the main investigation focused on four parts as follows:
The first part, the extraction and Pueification of Puerarin and Salvia miltiorrhiza. through the literature material and prediction of preparation,we extract and Pueify pueraria lobata and salvia miltiorrhiza respectively. Among them pueraria lobata with pue for index, the 70% ethanol refluxing extraction and then dissolved n-buoh extraction method of recrystallization glacial acetic acid, get the Pueity of 89% pue; Salvia miltiorrhiza are divided into the extraction and Pueification of total ketone and total phenolic acid two parts, respectively by ketoneⅡA,total and phenolic acids B, total phenolic acids for effective component index to the dan-shen root ethanol-extraction and water extraction, get more than 50% effective parts Pueity of salvia miltiorrhiza total ketone and total phenolic acids extract.
The second part, Puerarin nonionic surfactant vesicles preparation research. After the comparison of the centrifugation, dialysis and glucan gel column chromatography method, we determine glucan gel column chromatography as the effective separation methods. Then the preparation of puerarin niosome and its characterizition is studied, experiment contrast found Injection method formed into law vesicles appearance dispersivity is good, small and is relatively concentrated particle. But the content determination results showed that the puerarin entrapment rate is very low, this is one of the main problems need to be solved.
The third part, the research on prescription and preparation of Dange mingmu in situ forming eye gel. The phase transition temperature before and after diluted by STF is observed as index, we use the uniform design method to optimum the temperature sensitive type ophthalmic gel matrix prescription, established fitting equation between poloxamer concentration and phase-change temperatures, the results showed that the gel phase-change temperatures with concentrations of P407 decreases; And in a certain range P188 can improve the phase-change temperatures. Then we choose three prescription in the results, the viscosity of them before and after diluted by STF are conducted, finally we determine the lower concentration:19% P407 and 1% P188 as temperature sensitive ophthalmic gel matrix. On this basis, the other additional agents in prescription of Dange mingmu in situ eye-gel is screened, including help solvent (tween 20), preservative (benzene pierced ammonium chloride) and pH regulator (NaOH), etc, and then after accession of drug and accessories, gelation temperature and viscosity was investigated, to meet the requirements,we make corresponding adjustment to get Dange mingmu temperature sensitive in situ forming eye gel.
The last part, the preliminary evaluation research on Dange mingmu in situ forming eye gel. Established the content determination methods of Dange mingmu in situ forming eye gel:using HPLC to analyse pue and Salvianolic acid B (preparation index component). According to the in vivo characteristic of ocular administration,a memebraneless model was used to study the gel erosion and drug release simultaneously.Correlation analysis demonstrated that drug release,which followed zero-order kinetics,from poloxamer vehicle was completely controlled by gel erosion.The retention time of rabbit eye experiment shows that in situ eye-gel significantly prolong drug retention time in the eye. The rabbit eye single dose and many times experiment demonstrate that Dange mingmu in situ forming eye gel have no irritant reaction to rabbit eyes. There was also no allergic reaction after spraying on the skin of guinea pigs many times.
The novelty in our studies lies in we attemp to use new technology, new method on ophthalmic drug delivery system of TCM,in order to make the drugs and carrier achieve an complementary effection,there are no essays established about relative researches on pue niosomes and Dange mingmu in situ forming eye gel.The study results can provide certain reference and ideas to solve some of the TCM technical issues in common, which is benefit to promote further development on ophthalmic new preparations of TCM and its compounds.
中药治疗眼部疾病历史悠久,特别是在治疗内眼疾病,如青光眼、白内障、玻璃体出血、糖尿病所致视网膜病变、视网膜动静脉阻塞等方面具有明显的优势特色。常用中药当中,葛根和丹参经药理研究和临床使用证明均有扩张微血管,改善微循环的作用,对眼底病、眼外伤、慢性炎症性眼病等具有很好的疗效。传统给药形式主要为口服,而眼部给药比全身给药对进入眼内达到靶区更具优势与可行性,为了更好地体现与发挥中医药防治眼病的优势,有必要结合现代制药技术与给药系统的理论,对中药眼部给药系统进行研究和开发。
非离子表面活性剂囊泡(non-ionic surfactant vesicles),简称为类脂囊泡(niosomes),是一种与脂质体类似的新型给药系统。其作为眼用制剂载体的优势在于：作为药物的贮库,不仅可以延长药物在角膜和玻璃体内的滞留时间,还可以保护药物分子免受泪液或角膜上皮中代谢酶的破坏,使药物在角膜表面产生缓控释增效作用；并且囊泡对外眼组织,结膜和巩膜具有很强的亲和力,滴眼后可迅速分散,增强了药物对角膜的穿透性。眼用即型凝胶是近来研究较多的一种新型眼部给药载体,其在非生理状态下为自由流动的液体,给药后在眼部生理条件下形成凝胶,能够延长药物在眼内的滞留时间,从而提高生物利用度。
为了改善葛根素滴眼液临床上使用存在眼部滞留时间短患者顺应性差的问题,本课题尝试将葛根素制成非离子囊泡以研究囊泡在眼部应用的可行性；同时选用高分子聚合物泊洛沙姆407与188作为温度敏感型眼用凝胶的基质,对葛根和丹参复方眼用即型凝胶给药系统进行了初步研究,为今后研制开发中药复方眼用新型制剂奠定基础。本课题主要研究内容分为以下四部分：
第一部分葛根及丹参的提取与纯化研究。通过文献资料与预实验,对制剂所用中药葛根及丹参分别进行了提取与纯化。其中葛根以葛根素为指标,采用70%乙醇回流提取然后正丁醇溶解萃取冰醋酸重结晶的方法,得到纯度约89%的葛根素；丹参中有效成分分为丹参总酮和总酚酸两部分,分别以丹参酮II A、丹参总酮和丹酚酸B、丹参总酚酸为指标,对丹参进行醇提和水提,得到有效部位纯度大于50%的丹参总酮和总酚酸提取物。
第二部分葛根素非离子表面活性剂囊泡的制备研究。对葛根素非离子囊泡的制备及理化表征进行了初步研究,实验中对比发现注入法所形成的囊泡外观分散性较好,粒径较小且较为集中。通过比较离心、透析及葡聚糖凝胶柱层析等分离方法,最后优选葡聚糖凝胶柱层析法为葛根素非离子囊泡的有效分离方法。但含量测定结果显示葛根素的包封率很低,是本实验留待解决的一个主要问题。
第三部分丹葛明目即型凝胶的处方筛选及制备研究。以泊洛沙姆溶液经模拟泪液稀释前后的相转变温度为考察指标,采用均匀设计法优选了温度敏感型眼用凝胶基质处方,建立了泊洛沙姆浓度与相变温度的拟合方程,结果表明凝胶相变温度随着泊洛沙姆407的浓度增加而下降；而泊洛沙姆188在一定范围内能够提高泊洛沙姆407的相变温度。在符合条件的结果中选择了3个处方,分别对其在模拟泪液稀释前后的黏度进行了测定,最后确定以浓度较低的19%泊洛沙姆407与1%泊洛沙姆188合用作为温度敏感眼用凝胶的基质。在此基础上,对丹葛明目即型凝胶的处方作进一步筛选,确定处方中需要添加的其它附加剂,包括助溶剂(吐温20)、防腐剂(苯扎氯铵)及pH调节剂(NaOH)等,然后对药物及辅料加入后的胶凝温度及黏度的变化进行了考察,并作了相应调整,最后制备得到符合要求的丹葛明目温度敏感眼用凝胶。
第四部分丹葛明目即型凝胶的体内外初步评价研究。建立了丹葛明目即型凝胶中药物的含量测定方法：以葛根素和丹酚酸B为制剂的指标成分,采用高效液相色谱法进行测定。采用无膜溶出法对制备的丹葛明目即型凝胶进行了体外溶蚀及药物释放的考察。结果表明：凝胶中药物的释放受溶蚀控制,且二者均遵循零级动力学过程。家兔眼部的滞留时间实验显示眼用即型凝胶能显著延长药物在眼部的滞留时间。经兔眼单次给药和多次给药后观察,结果丹葛明目即型凝胶对兔眼无刺激性反应。经豚鼠皮肤多次涂抹给药,也未见皮肤过敏反应。
本课题的创新在于采用新技术新方法对中药眼部给药系统进行了尝试,对葛根素非离子囊泡及丹葛明目即型凝胶进行的相关研究均未见有报道。课题的研究探索结果可以为解决中药眼用制剂一些共性技术问题提供一定的借鉴思路和方法,有助于推动中药眼用新制剂更进一步的发展。
Owing to the complex structure and many barrier in the eye,traditional ophthalmic preparation have a lot of problems in patient compliance,healing effect et al. In order to make therapeutic drugs exert better curative effect on intraocular, novel ophthalmic drug delivery system gradually become the hot spot in pharmaceutics researches.
It has been a long history to treat ocular diseases by using chinese herbal medicine.TCM has obvious characteristic advantage especially in the treatment of interna eye diseases such as glaucoma,cataracts,vitreous hemorrhage,retinopathy caused by diabetes,retinal vein occlusion and retinal artery occlusion.Among the commonly used chinese herbal medicine, By pharmacological research and clinical use,puerarin and Salvia miltiorrhiza are proved that they can expand capillaries and improve microcirculation,have good curative effect in retina,ocular trauma,chronica inflammatory disease.The main administration form of chinese herbal medicine was oral,but ophthamic drug administrtion had more advantages and feasibility to enter in the target areas of eye.In order to better reflect and develop the advantage of preventing ocular disease by TCM,it is necessary to combine the theory of modern pharmaceutical technology and drug delivery system for research and development of TCM ophthamic delivery system.
Non-ionic surfactant vesicles,for short niosomes, is a new drug delivery system similar with liposomes.As ophthalmic drug carrier,its advantage lies in:prolong the drug retention time in cornea and vitreous body as drug storage library, protect the drug molecules from destroy by metabolic enzymes in tears or corneal epithelium, and exert the drug effect in corneal surface slowly; it also has a strong affinity with eyes organization,conjunctiva and sclera, and can disperse rapidly in the eye after droping, hence to enhance the cornea penetrability. In situ forming eye gel is another kind of ophthalmic drug delivery system well-studied recently, in physiological condition it is free flow liquid, in physiological conditions it will form a gel.This can prolong drug residence time in the eye, so as to improve the drug bioavailability.
The aim of this study is to improve low bioavailability and potential risk of clinical pue eyedrops through pue niosomes, and then we study the feasibility of its application in the eye. Meanwhile we choose poloxamer407 and poloxamer188 as temperature sensitive gel matrix, to study pueraria lobata and salvia miltiorrhiza compound in situ forming eye gel, in order to lay foundation for new herbal ophthalmic preparations in the future.In this study,the main investigation focused on four parts as follows:
The first part, the extraction and Pueification of Puerarin and Salvia miltiorrhiza. through the literature material and prediction of preparation,we extract and Pueify pueraria lobata and salvia miltiorrhiza respectively. Among them pueraria lobata with pue for index, the 70% ethanol refluxing extraction and then dissolved n-buoh extraction method of recrystallization glacial acetic acid, get the Pueity of 89% pue; Salvia miltiorrhiza are divided into the extraction and Pueification of total ketone and total phenolic acid two parts, respectively by ketoneⅡA,total and phenolic acids B, total phenolic acids for effective component index to the dan-shen root ethanol-extraction and water extraction, get more than 50% effective parts Pueity of salvia miltiorrhiza total ketone and total phenolic acids extract.
The second part, Puerarin nonionic surfactant vesicles preparation research. After the comparison of the centrifugation, dialysis and glucan gel column chromatography method, we determine glucan gel column chromatography as the effective separation methods. Then the preparation of puerarin niosome and its characterizition is studied, experiment contrast found Injection method formed into law vesicles appearance dispersivity is good, small and is relatively concentrated particle. But the content determination results showed that the puerarin entrapment rate is very low, this is one of the main problems need to be solved.
The third part, the research on prescription and preparation of Dange mingmu in situ forming eye gel. The phase transition temperature before and after diluted by STF is observed as index, we use the uniform design method to optimum the temperature sensitive type ophthalmic gel matrix prescription, established fitting equation between poloxamer concentration and phase-change temperatures, the results showed that the gel phase-change temperatures with concentrations of P407 decreases; And in a certain range P188 can improve the phase-change temperatures. Then we choose three prescription in the results, the viscosity of them before and after diluted by STF are conducted, finally we determine the lower concentration:19% P407 and 1% P188 as temperature sensitive ophthalmic gel matrix. On this basis, the other additional agents in prescription of Dange mingmu in situ eye-gel is screened, including help solvent (tween 20), preservative (benzene pierced ammonium chloride) and pH regulator (NaOH), etc, and then after accession of drug and accessories, gelation temperature and viscosity was investigated, to meet the requirements,we make corresponding adjustment to get Dange mingmu temperature sensitive in situ forming eye gel.
The last part, the preliminary evaluation research on Dange mingmu in situ forming eye gel. Established the content determination methods of Dange mingmu in situ forming eye gel:using HPLC to analyse pue and Salvianolic acid B (preparation index component). According to the in vivo characteristic of ocular administration,a memebraneless model was used to study the gel erosion and drug release simultaneously.Correlation analysis demonstrated that drug release,which followed zero-order kinetics,from poloxamer vehicle was completely controlled by gel erosion.The retention time of rabbit eye experiment shows that in situ eye-gel significantly prolong drug retention time in the eye. The rabbit eye single dose and many times experiment demonstrate that Dange mingmu in situ forming eye gel have no irritant reaction to rabbit eyes. There was also no allergic reaction after spraying on the skin of guinea pigs many times.
The novelty in our studies lies in we attemp to use new technology, new method on ophthalmic drug delivery system of TCM,in order to make the drugs and carrier achieve an complementary effection,there are no essays established about relative researches on pue niosomes and Dange mingmu in situ forming eye gel.The study results can provide certain reference and ideas to solve some of the TCM technical issues in common, which is benefit to promote further development on ophthalmic new preparations of TCM and its compounds.
引文
[1]柴田承二,村上孝夫,西川嘉.和汉药成分的研究(第一报)葛根成分的化学的研究[J].药学杂志(日),1959,79(6)：757.
[2]方起程,林茂,孙庆民.葛根黄酮的研究[J].中华医学杂志,1974,54：271-274
[3]Jun-eikinjo,Jun-ichi Furus awa,Junko Baba et al.study on the Constituents of Pueraria lobata,I. Isoflavonids and Compounds in the Roots and the VolublStems,chem.Pharm.Bull,1987,35 (12):4846.
[4]王成,刘玉玲,谷士杰.葛根素的溶解性及其络合助溶的研究[J].中国药学杂志,1993,28(5)：294-296.
[5]马家骅,杨明等.葛根素的提取和含量测定[J].华西药学杂志,2006,21(2)：206-207.
[6]刘敏彦,董超等.中药葛根提取工艺研究[J].中国药业,2008,17(3)：24-25.
[7]贺云,贺武卫.超声提取和超声水解法从野葛根中提取纯化葛根素和大豆苷元[J].天然产物研究与开发,2005,17(3)：328-330.
[8]袁怀波,赵国华,李洪军等.利用大孔吸附树脂纯化葛根异黄酮的研究[J].食品与发酵工业,2003,29(2)：62-65.
[9]白兰莉.葛根总黄酮的微波辅助萃取及其分离纯化的工艺研究[D].南昌：南昌大学,2006.
[10]张建辉,杨代明,吴廷瑞等.HPLC法和紫外分光光度法测定葛根淀粉中葛根素含量的研究[J].食品安全与检测,2006,22(6)：110-112.
[11]王言才,段金廒,华永庆等.不同品种葛根中葛根素及总黄酮的含量测定[J].时珍国医国药,2008,19(1)：132-133.
[12]岳红文,胡小琴等.葛根及葛根素对心血管系统的药用价值[J].中国中西医结合杂志,1996,16(6)：382-384.
[13]孙云翔,栗锦迁.葛根素扩血管作用及其机制初探[J].中草药,2002,33(8)：733-734.
[14]吕欣然,高尔,许兰芝等.葛根素对含B2肾上腺素受体的离体器官和整体动物的阻断作用[J].中国药理学报,2006,7(6)：537-539.
[15]郭晓纲,陈君柱,张雄等.葛根素对大鼠心肌细胞L型钙离子通道的影响[J].中国中药杂志,2004,29(3)：248-251.
[16]宋浩亮,陈士林,梅学仁等.葛根素口服制剂抗心肌缺血及对心肌细胞的保护作用[J].中草药,2003,34(12)：1104-1107.
[17]刘启功,王琳.葛根素对心肌梗塞犬冠脉侧枝循环的影响[J].中国中药杂志,1999,24(5)：304.
[18]周菊芬,万国兰,刘春棋,等.葛根素抗血脂作用的研究[J].赣南医学院学报,2008,28(4)：499-500.
[19]彭少君,陈晓.葛根素对大鼠血脂水平影响的研究[J].时珍国医国药,2006,17(12)：2516.
[20]钟星明,肖海,刘春棋等.葛根素对力竭运动大鼠血脂和血液生化指标的影响[J].赣南医学院学报,2008,28(3)：326-328.
[21]刘亚明,牛欣,刘光珍等.复方葛根胶囊对实验性糖尿病、高脂血症模型血糖和血脂作用的实验研究[J].中国医药学报,2003,18(6)：344-346.
[22]黄兆铨,叶武.葛根素对高血压患者血浆内皮素和一氧化氮的影响[J].中国现代应用药学杂志,1999,16(3)：13.
[23]高唱,王景周,王琳等.葛根素对大鼠局部脑缺血再灌注损伤皮层钙凋磷酸酶和钙蛋白酶活性的影响[J].中国急救医学,2002,22(7)：379-380.
[24]桑韩飞,张英民,徐礼鲜等.葛根素对大鼠局灶性脑缺血再灌注后热休克蛋白70表达的影响[J].中华麻醉学杂志,2003,23(10)：770.
[25]张蕊,曹焕军,高尔.葛根素对家兔脑缺血再灌注损伤的抗自由基作用[J].潍坊医学院学报,2002,24(4)：267-269.
[26]沈炳权,蔡兆斌,徐群红等.葛根素对家兔心肌缺血-再灌注损伤的保护作用[J].中国中西医结合急救杂志,2004,11(6)：361-363.
[27]潘德顺,陈伟强.葛根素对大鼠心肌缺血再灌注损伤的干预作用[J].中国老 年学杂志,2010,30(3)：332-334.
[28]雒光强.葛根素对大鼠肝脏缺血再灌注损伤后NF-κB表达的影响[J].医学研究杂志,2009,38(5)：111-112.
[29]杨硕,娄金丽,王谦等.葛根素治疗2型糖尿病KKAy小鼠肝脏损伤的实验研究[J].中国中西医结合杂志,2009,29(8)：707-710.
[30]钟艺,谭海荣,潘竞锵等.葛根素对D-半乳糖诱导大鼠抑制蛋白非酶糖基化及增强胰岛素敏感性的作用[J].中国药物与临床,2007,7(8)：576-579.
[31]杜艳秋,赵敏.葛根素对敌敌畏中毒大鼠肝脏保护作用的研究[J].中国腹部疾病杂志,2005,5(6)：408-409.
[32]刘淑霞,何宁,刘青娟等.葛根素对糖尿病大鼠肾功能及肾组织MMP-3、TIMP-1表达的影响[J].天然产物研究与开发,2003,15(6)：531-535.
[33]黄彤金,邦荃,孙桂菊等.葛根素对去卵巢大鼠机体骨代谢影响的观察[J].中国老年学杂志,2009,29(17)：2482-2484.
[34]李斌斌,于世凤.葛根素调控骨代谢的体外实验研究[J].北京大学学报(医学版),2003,35(1)：74-77.
[35]邓新国,胡世兴,张清炯等.葛根素经腹腔注射在兔眼房水和玻璃体中的药代动力学结果比较[J].中国药理学通报,2007,23(1)：136-137.
[36]徐新荣,蔡丰英.葛根素对慢性高眼压兔眼视神经轴浆流影响的实验研究[J].中国中医眼科杂志,1997,7(1)：3-6.
[37]吴正红,刘有潜,朱延勤.葛根素滴眼液对家兔眼内压的作用[J].中国药科大学学报,1998,29(5)：387-389.
[38]贺玲,万新顺,韩丽英.葛根素对实验性视网膜缺血-再灌注损伤后视神经的保护作用[J].眼科新进展,2006,26(12)：916-918.
[39]张庆莲,张荷莲,孙玥.葛根素注射液眼科临床应用[J].长春中医学院学报,1999,15(3)：45.
[40]逢曙光,刘艳,孙咏梅,等.葛根素对糖尿病视网膜病变治疗作用的临床研究[J].山东医药,2007,47(10)：5-6.
[41]赵国宏,张荷玲.葛根素治疗糖尿病视网膜病变的疗效观察[J].光明中医,2009,24(12)：2297-2298.
[42]高尔,王金红,李洪军等.乳化葛根素对高脂血症家兔血清NO及PGI2的影响[J].潍坊医学院学报,2001,23(1)：1.
[43]朱晓伟,王林,王升启.葛根素的基础研究与临床应用新进展[J].内蒙古石油化工,2002,27(8)：8.
[44]GABETTA E,BOMBAROELLI E,PIFFERL G.Complexes of flavanolignanes with phospholipids,preparation there of and associated pharmaceutical composition. Patent No.0209038 [P].119872012211.
[45]WU J M,CHEN D W,ZHANG R H, et al. The review of the pharmaceutical study on the natural active component phospholipid complex[J].Chin Pharm J(中国药学杂志),1998,33(1)：9211.
[46]盂庆国,高尔,王汝琴等.葛根素磷脂复合物的制备及核磁共振和薄层层析研究[J].潍坊医学院学报,2001,32(1)：4.
[47]李颖,潘卫三,陈士林等.葛根素磷脂复合物的制备及其固体分散体研究[J].中国药学杂志,2006,41(15)：1162-1167.
[48]马云淑,赵浩如,林以宁.葛根素及其磷脂复合物的体外透皮实验研究[J].中国中药杂志,2000,25(5)：274-276.
[49]周毅生,贾永艳,申小清等.葛根素固体分散体的制备及其体外研究[J].中国药学杂志,2003,38(11：42-44.
[50]王曙宾,黄兰芷.葛根素缓释固体分散体制备及其体外释放度评价[J].中成药,2007,29(9)：1285-1288.
[51]龚显峰,李述溪,赵学玲等.葛根素固体分散体的制备及大鼠体内生物利用度研究[J].黑龙江医药,2009,22(2)：157-160.
[52]董祥玉,任勇,马学琴等.葛根素/β-环糊精包合物的初步研究[J].中国新药杂志,2006,15(7)：528-532.
[53]尤思路,高秀蓉,廖昌军.饱和水溶液法制备葛根素的β-环糊精包合物研究[J].西南军医,2008,10(4)：17-19.
[54]吴纯洁,齐红艺,黄春燕,等.羟丙基-β-环糊精对葛根素溶解性与角膜渗透性的影响[J].中国药学杂志,2006,41(20)：1565-1568.
[55]Wu W, Wang Y, Que L. Enhanced bioavailability of silymarin by self-microemulsifying drug delivery system [J]. Eur J Pharm Biopharm,2006, 63：288.
[56]于爱华,翟光喜,崔晶等.葛根素微乳的制备及质量评价[J].中国医药工业杂志,2006,37(7)：471-473.
[57]韩静,崔升淼.葛根素自微乳化释药系统的处方筛选与体外评价[J].中南药学,2009,7(10)：731-734.
[58]周红义,杨今祥.新型凝胶给药系统研究进展[J].中国药师,1999,2(3)：121.
[59]宋成君.葛根素眼部传递系统的研究[D].沈阳：沈阳药科大学,2006.
[60]齐红艺.葛根素温度敏感与生物粘附型眼用原位凝胶的研究[D].成都.成都中医药大学,2007.
[61]吴纯洁.葛根素眼用新型给药系统的研究[D].成都：四川大学,2005.
[62]王丹,石力夫,胡晋红等.一种葛根素经皮给药系统体外透皮性能的初步考察[J].药学服务于研究,2009,9(2)：104-106.
[63]顾一珠,周文,翟光喜.葛根素脂质体的研制及其大鼠口服吸收[J].中药材,2007,30(8)：970-973.
[64]邓赞,徐金库,李新松.葛根素脂质体滴眼液的制备及其药动学研究[J].中国中药杂志,2010,35(3)：301-304.
[65]平其能主编.现代药剂学[M].第1版.北京：中国医药科技出版社,1998：599-600.
[66]陆彬.药物新剂型与新技术.北京：人民卫生出版社,2005.
[67]宋金春,刘薇芝；黄岭.葛根素前体脂质体的制备及体外性质研究[J].中国药学杂志,2007,42(15)：1155-1158.
[68]宋金春,刘薇芝,黄岭.葛根素前体脂质体的质量考察[J].中国医院药学杂志,2007,27(9)：1244-246.
[69]宋金春,刘薇芝,黄岭.葛根素前体脂质体药动学和生物利用度研究[J].中国医院药学杂志,2008,28(24)：2075-2077.
[1]Schoenwald RD.Ocular Pharmacokinetics. In:Zimmerman TJ. Textbook of Ocular Pharmacology[M].New York:Lippincott-Raven Publishers,1997:119-138.
[2]Yasmin Sultana,M Aqil,Asgar Ali, et al.Advances in the topical ocular drug delivery [J].Expert Rev.Ophthalmol,2007,2(2):309-323.
[3]Baillie A J, Florence A T, Hμme L R, et al. The preparation and properties of niosomes:non-ionic surfactant vesicles[J]. J Pharm Pharmacol,1985,37(12):863-868.
[4]Yongmei Hao, Fenglin Zhao, Na Li,et al.Studies on a high encapsulation of colchicine by a niosome system[J]. Int. J. Pharm,2002,244:73-80.
[5]Ijeoma F Uchegbu,Suresh P Vyas.non-ionic surfactant based vesicles(niosomes) in drug delivery[J]. Int. J. Pharm,1998,172:33-70.
[6]M.Carafa,E Santucci,and G Lucania. Lidocaine-loaded non-ionic surfactant vesicles:characterization and in vitro permeation studies[J]. Int.J.Pharm,2002,231: 21-32.
[7]Indu P Kaur, Alka Garg, Anil K Singla, et al. Vesicular systems in ocular drug delivery:an overview[J]. Int. J. Pharm,2004,269:1-14.
[8]Ahmed S Guinedi,Nashed D Mortada,Samar Mansour,et al.Preparation and evaluation of reverse-phase evaporation and multilamellar niosomes as ophthalmic carriers of Acetazolamide [J].Int.J.Pharm,2000,306(1-2):71-82.
[9]Anil Vangala Vangala,Shehzad Rasul Rasul. Incorporation of acetazolamide into niosome using a novel pH gradient technique[J]. Pharm. Chem. J,2006,26:66-73.
[10]Aranya Manosroi, Paveena Wongtrakul, Jiradej Manosroi,et al. Characterization of vesicles prepared with various non-ionic surfactants mixed with cholesterol[J]. Colloids Surf, B:Biointerfaces,2003,30:129-138.
[11]Jim Jiao.Polyoxyethylated nonionic surfactants and their applications in topical ocular drug delivery[J]. Adv Drug Deliv Rev,2008,60:1663-1673.
[12]Ghada Abdelbary and Nashwa El-gendy. Niosome-Encapsulated Gentamicin for Ophthalmic Controlled Delivery[J]. AAPS PharmSciTech,2008,9(3):740-747.
[13]Perini G, Saettone MF, Niosome as carrier for ophthalmic drugs in vitro/in vivo evaluation[J]. Boll Chim Farm,1996,135(2):145-146.
[14]Deepika Aggarwal, Indu P Kaur. Improved pharmacodynamics of timolol maleate from a mucoadhesive niosomal ophthalmic drug delivery system[J]. Int.J.Pharm,2005, 290(1-2):155-159.
[15]Deepika Aggarwal, Dhananjay Pal, Ashim K Mitra, et al.Study of the extent of ocular absorption of acetazolamide from a developed niosomal formulation, by microdialysis sampling of aqueous humor[J]. Int.J.Pharm,2007,338:21-26.
[16]Saettone MF, Perini G, Carafa M, et al, Non-ionic surfactant vesicles as ophthalmic carriers for cyclopentolate.A preliminary evaluation[J]. S.T.P. Pharm.Sci,1996,6(1)：94-98.
[17]Schaffer HE, Brietieller JM, Krohn D L,Lectin-mediated attachment of liposomes to cornea:influence on transcorneal drug flux[J]. Investig Ophthalmol Vis Sci,1983,23:530-533.
[18]Uchegbu IF, Bouwstra JA, Florence AT.Large disk-shaped structures (discomes) in nonionic surfactant vesicle to micelle transitions[J]. Phys.Chem.1992,96:10548-10553.
[19]S.P. Vyas, N. Mysore, V. Jaittley, et al. Discoidal niosome based controlled ocular delivery of timolol maleate[J].Pharmazie.1998,53:466-469.
[1]Chien YW.Ocular drug delivery and delivery systems.In:Novel drug delivery systems [A]. New York:Marcel Dekker Inc,1992.269-300.
[2]Lee VHL. Ophthalmic drug delivery systems.In:Mitra AK.Ophthalmic drug delivery systems [A]. New York:Marcel Dekker Inc,1993.59-81.
[3]张强,武凤兰.药剂学[M].北京：北京大学医学出版社,2008.
[4]Herrero-Vanrell R,Fernandez-Carballidoa,Frutos G,et al. Enhancement of the mydriatic response to tropicamide by bioadhesive polymers[J].J Ocul Pharmacol Ther,2000,16(5):419-428.
[5]W. D. Ma, H.Xu, C.Wang, et al.Pluronic F127-g-poly(acrylic acid) copolymers as in situ gelling vehicle for ophthalmic drug delivery system[J]. Int.J.Pharm. 2008.350:247-256.
[6]徐晖,王绍宁,周力民,等.丙烯酸—泊洛沙姆407共聚物的合成及其原位凝胶性质[J].沈阳药科大学学报,2006,23(7)：421-424.
[7]齐红艺,吴纯洁.葛根素温度敏感与生物粘附型眼用原位凝胶的研究[D].成都：成都中医药大学,2007.
[8]Edsman K, Carlfors J, Pertsson R.Rheological evaluation of poloxamer as an in situ gel for ophthalmic use[J].Eur J pharm Sci,1998,6(2):105.
[9]Hong-Ru Lin, K.C.Sung, Carbopol/Pluronic phase change solutions for ophthalmic drug delievery[J].Joμmal of controlled release,2000, 69(3):379-388.
[10]Hong-Ru Lin, K. C. Sung, In Situ Gelling of Alginate/Pluronic Solutions for Ophthalmic Delivery of Pilocarpine[J].Biomacro-molecules,2004,5(6): 2358-2365.
[11]Jeong B, Kim S W, Bae Y H.Thermosensitive sol-gel reversible hydrogels[J]. Adv Drug Del Rev,2002,54:37-51.
[12]Kμmar S, Himmelstein KJ. Modification of in Situ gelling behavior of carbopol solutions by hydroxypropyl methylcellulose[J]. J Pharm Sci,1995,84(3): 344-348.
[13]郑俊民.药用辅料手册[M].北京：化学工业出版社,2004,107.
[14]张治强,张玮,陈光,等.pH敏感型盐酸左氧氟沙星眼用即型凝胶的制备及其体外释放考察[J].药学实践杂志,2010,28(2)：122-125.
[15]夏苗芬,梁文权,李士敏.复方甲硫酸新斯的明眼用原位凝胶的研究[D].杭州：浙江大学,2008.
[16]Chanrasekaran R, Puigjaner LC, Joyce KL, et al. Cation interaction in gellan:an X-ray study of the potassiμm salt[J].CarbohydrRes,1988,181(1):23-40.
[17]Lindell K, Engstrom S. In vitro release of timolol maleate from an in situ gelling polymer system[J].Int J pharm,1993,95:219.
[18]Grant GT, Morris E R, Rees D A, et al. Biological interactions between polys-accharides and divalent cations:The egg box model[J]. Febs Lett,1973,32: 195-198.
[19]Cohen S, Lobel E, Trevgoda A, et al. A novel in situ forming ophthalmic drug delivery systems form alginates undergoing gelation in the eye[J]. J Controlled Release,1997,44 (223):201.
[1]叶淑静.中药葛根研究进展[J].浙江中医学院学报,2003,27(6)：94-96.
[2]白海波,李波,宋子荣.葛根提取工艺研究[J].中国实验方剂学杂志,2002,8(6)：14-15.
[3]崔九成,宋小妹,张培芳,等.葛根总黄酮提取工艺研究[J].西北药学杂志,1999,14(5)：202.
[4]徐新刚,路富玉,隋晓春,等.正交试验优选葛根提取工艺[J].时珍国医国药,2000,11(9)：780-781.
[5]王翊臻,潘洪平.优选葛根提取工艺的实验研究[J].医学文选,2004,23(1)：4-6.
[6]王美东,等.葛根提取工艺的正交设计试验[J].齐鲁药事,2005,24(2)：45-46.
[7]梅林,石开云,杨元娟,等.葛根中葛根素的分离纯化技术进展[J].广州化学,2007,32(1)：73-76.
[8]郭延生,魏彦明,梁剑平,等.野葛根中提取分离葛根素的研究甘肃农业大学学报,2004,39(2)：199-202.
[9]徐华东.葛根素的提取及纯化新工艺研究[D].南宁：广西大学,2007.
[1]张丽琼,崔浩.丹参在眼科的应用[J].中国中医眼科杂志,2005,15(4)：242-244.
[2]简洋辉,徐国钧,金蓉鸾,等.中药丹参类的质量研究[J].中国药科大学学报,1989,20(1)：5-9.
[3]陈少兵.丹参有效部位的制备工艺与稳定性研究[D].安徽：合肥工业大学,2007.
[4]杨筠,古卓俍,印仁昌,等.用分光光度法测定丹参制剂中水溶性酚酸[J].中成药研究,1986,12：10-11.
[5]郑胜国,郭俊.分光光度法测定注射用丹参川芎嗪中丹参总酚酸的含量[J].中药研究与信息、,2005,7(11)：16-17.
[6]杨小宁,唐星,柳玉石.丹参中总酚酸的分离纯化工艺研究[J].中草药,2007,38(6)：843-846.
[7]王秀丽,张志荣,聂宇,等.从丹参中提取高纯度的丹参酚酸B[J].华西药学杂志,2008,23(3)：280-282.
[1]陆彬主编.药物新剂型与新技术[M].北京：人民卫生出版社.1998,第一版.
[2]杨继红,,蒋学华等.HPLC测定葛根素长循环脂质体中葛根素的含量和包封率[J].华西药学杂志,2006,21(1)：6668.
[3]周莉玲,王岩,刘清飞,等.青藤碱脂质体包封率的测定[J].中国中药杂志,2006,31(9)：731-734.
[4]鞠静红,张志荣,韩静,等.穿琥宁脂质体包封率的测定[J].中国医药工业杂志,2008,39(7)：514-516.
[5]郑杭生,张亚军,徐真,等.全缘千里光碱脂质体包封率测定方法的研究[J].中国药学杂志,2007,42(14)：1075-1078.
[6]高晓黎,季兴梅.葡聚糖凝胶柱色谱法测定脂质体包封率的条件筛选[J].中国药学杂志,2003,38(7)：515-517.
[7]王海刚,翟光喜.壳聚糖包覆葛根素脂质体的制备及理化性质考察[J].中药材,2007,30(1)：89-91.
[8]邓赟,徐金库等.葛根素脂质体滴眼液的制备及其药动学研究[J].2010,35 (3):301-304.
[9]Ahmed S. Guinedi, Nahed D. Mortada et al.Preparation and evaluation of reverse-phase evaporation and multilamellar niosomes as ophthalmic carriers of acetazolamide[J]. International Journal of Pharmaceutics,2005 (306):71-82.
[10]Francis szoka, jr., and Demetrios Papahadjopoulos.Procedure for preparation of liposomes with large internal aqueous space and high capture by reverse-phase evaporation[J].1978,75(9):4194-4198.
[11]刘丹,胡海洋.芹菜素囊泡的制备及理化性质考察[J].沈阳药科大学学报,2009,26(6)：423-428.
[12]孙娟,龙晓英.辣椒碱表面活性剂泡囊处方设计[J].广东药学院学报,2007,23(1)：21-24.
[13]奚菊群,郭荣.葛根素与卵磷脂囊泡的相互作用[J].科学通报,2007,52(17)：1997-2002.
[14]宋金春,陈佳丽,黄岭.葛根素环糊精包合物脂质体的制备及体外性质研究[J].中国药学杂志,2008,43(23)：17921797.
[1]魏刚,徐晖,郑俊民.原位凝胶的形成机制及在药物控制释放领域的应用[J].中国药学杂志,2003,38(8)：5642-5671.
[2]Sambhaji SP, Anant RP, Kakasaheb RM, et al. Pluronic gels for nasal delivery of Vitamin B12[J].Int J Pharm,2004,270(1):37-45.
[3]鞠凤阁,朱照静,王丽娟,等.双氯芬酸钠眼用温敏凝胶的处方优化及体外释放[J].中国医院药学杂志,2009,29(7)：541-545.
[4]高斐,王东凯,罗立,等.左氧氟沙星热敏型眼用凝胶的研制及体外释放研究[J].中国药房,2005,16(14)：1057-1059.
[5]Choi HG, Jung JH, Ryu JM.et al. Development of in situ-gelling and mucoadhesive acetaminophen liquid supposity [J]. Int J Pharm,1998,165 (1):33-44.
[6]马廉正.复方阿奇霉素地塞米松眼用即型凝胶的研究[D].武汉：湖北中医学院,2009.
[7]Helene Hagerstrom, Mattias Paulsson, Katarina Edsman. Evaluation of mucoadhesion for two polyelectrolyte gels in simulated physiological conditions using a rheological method.Eur J Pharma Sci.2000,9:301-309.
[8]Wei Gang, Xu Hui, Ding Pingtian, et al. Thermosetting gels with modulated gelation temperature for ophthalmic use:the rheological and gamma scintigraphic studies[J].J Controlled Release,2002,83 (1):65-74.
[9]方开泰.均匀设计与均匀设计表[M].北京：科学出版社,1994.
[10]Mansoor M Amiji, Phung-Kim Lai, Dinesh B, et al. Intratumoral Administration of Paclitaxel in an In Situ Gelling Poloxamer 407 Formulation[J]. Pharmaceutical Development and Technology,2002,7(2): 195-202.
[1]张兆旺.中药药剂学[M].北京：中国中医药出版社,2006.
[2]姚建国,周卯星,冯瑜,等.表面活性剂对丹参酮增溶作用的研究[J].日用化学工业,2003,33(1)：12-14.
[3]宁黎丽.眼用制剂研发过程中应关注抑菌剂的合理使用和质量控制[J].中国药学杂志,2007,42(23)：1836-1838.
[4]张新妹,胡昌勤,姜彩辉,等.滴眼剂中防腐剂的合理应用[J].广东医学院学报,2003,21(3)：268-269.
[5]陈钢,侯世祥,秦凌浩.动态流变实验评价温敏凝胶的方法研究[J].中国药学杂志.2008,43(6)：444-447.
[6]郭永学.丹酚酸B的降解机理及纯化工艺研究[D].大连：大连理工大学,2007.
[1]Pawar PK, Majumdar DK.Effect of formulation factors on in vitro permeation of moxifloxacin from aqueous drops through excised goat, sheep, and buffalo corneas [J].AAPS Pharm SciTech,2006,7(1):13.
[2]Srividya B,Cardoza RM,Amin PD.Sustained ophthalmic delivery of ofloxacin from a pH triggered in situ gelling system[J].J Control Rel.2001,73(2):205-211.
[3]EL-Kamelah.In vitro and in vivo evaluation of Pluronic F-127 based ocular delivery system for timolol maleate [J].Int JPharm,2002,241(1):47-55.
[4]Liu Y, Lu WL,Wang JC,et al.Controlled delivery of recombinant hirudin based on thermo-sensitive Pluronic P407 hydrogel for subcuntaneous administration:In vitro and in vivo characterization[J].J Control Release,2007,117(3):387-395.
[5]魏刚.体温敏感眼用凝胶的研究[D].沈阳：沈阳药科大学,2002.
[6]高斐,王东凯,罗立,等.左氧氟沙星热敏型眼用凝胶的研制及体外释放研究[J].中国药房,2005,16(14)：1057-1059.
[1]Grass GR,Robinson JR.Relationship of chemical structure to cornel penetration and influence of low viscosity solution on ocular bioavailability[J].J Pharm Sci, 1984,73:1021.
[2]Vinardell MP,Garcia L.The quantitive chlofioallantoic membrane test using typan blue stain to predict the eye irritancy of liquid sciatillation cocktails[J].Toxicol vitro,2000,14:551
[3]Mochizuki H,Yamada M,Hato S,et al.Fluorophotometric measurement of the precorneal residence time of topically applied hyaluronic acid[J].Br J Ophthalmol,2008,92:108-111.
[4]国家食品药品监督管理局药品审评中心.眼用药物(改剂型改途径)临床前安全性评价的一些考虑[S].北京,2004.
[1]国家食品药品监督管理局药品审评中心.化学药物刺激性、过敏性和溶血性研究技术指导原则[S].北京,2005.
[2]方起程,林茂,孙庆民.葛根黄酮的研究[J].中华医学杂志,1974,54：271-274
[3]Jun-eikinjo,Jun-ichi Furus awa,Junko Baba et al.study on the Constituents of Pueraria lobata,I. Isoflavonids and Compounds in the Roots and the VolublStems,chem.Pharm.Bull,1987,35 (12):4846.
[4]王成,刘玉玲,谷士杰.葛根素的溶解性及其络合助溶的研究[J].中国药学杂志,1993,28(5)：294-296.
[5]马家骅,杨明等.葛根素的提取和含量测定[J].华西药学杂志,2006,21(2)：206-207.
[6]刘敏彦,董超等.中药葛根提取工艺研究[J].中国药业,2008,17(3)：24-25.
[7]贺云,贺武卫.超声提取和超声水解法从野葛根中提取纯化葛根素和大豆苷元[J].天然产物研究与开发,2005,17(3)：328-330.
[8]袁怀波,赵国华,李洪军等.利用大孔吸附树脂纯化葛根异黄酮的研究[J].食品与发酵工业,2003,29(2)：62-65.
[9]白兰莉.葛根总黄酮的微波辅助萃取及其分离纯化的工艺研究[D].南昌：南昌大学,2006.
[10]张建辉,杨代明,吴廷瑞等.HPLC法和紫外分光光度法测定葛根淀粉中葛根素含量的研究[J].食品安全与检测,2006,22(6)：110-112.
[11]王言才,段金廒,华永庆等.不同品种葛根中葛根素及总黄酮的含量测定[J].时珍国医国药,2008,19(1)：132-133.
[12]岳红文,胡小琴等.葛根及葛根素对心血管系统的药用价值[J].中国中西医结合杂志,1996,16(6)：382-384.
[13]孙云翔,栗锦迁.葛根素扩血管作用及其机制初探[J].中草药,2002,33(8)：733-734.
[14]吕欣然,高尔,许兰芝等.葛根素对含B2肾上腺素受体的离体器官和整体动物的阻断作用[J].中国药理学报,2006,7(6)：537-539.
[15]郭晓纲,陈君柱,张雄等.葛根素对大鼠心肌细胞L型钙离子通道的影响[J].中国中药杂志,2004,29(3)：248-251.
[16]宋浩亮,陈士林,梅学仁等.葛根素口服制剂抗心肌缺血及对心肌细胞的保护作用[J].中草药,2003,34(12)：1104-1107.
[17]刘启功,王琳.葛根素对心肌梗塞犬冠脉侧枝循环的影响[J].中国中药杂志,1999,24(5)：304.
[18]周菊芬,万国兰,刘春棋,等.葛根素抗血脂作用的研究[J].赣南医学院学报,2008,28(4)：499-500.
[19]彭少君,陈晓.葛根素对大鼠血脂水平影响的研究[J].时珍国医国药,2006,17(12)：2516.
[20]钟星明,肖海,刘春棋等.葛根素对力竭运动大鼠血脂和血液生化指标的影响[J].赣南医学院学报,2008,28(3)：326-328.
[21]刘亚明,牛欣,刘光珍等.复方葛根胶囊对实验性糖尿病、高脂血症模型血糖和血脂作用的实验研究[J].中国医药学报,2003,18(6)：344-346.
[22]黄兆铨,叶武.葛根素对高血压患者血浆内皮素和一氧化氮的影响[J].中国现代应用药学杂志,1999,16(3)：13.
[23]高唱,王景周,王琳等.葛根素对大鼠局部脑缺血再灌注损伤皮层钙凋磷酸酶和钙蛋白酶活性的影响[J].中国急救医学,2002,22(7)：379-380.
[24]桑韩飞,张英民,徐礼鲜等.葛根素对大鼠局灶性脑缺血再灌注后热休克蛋白70表达的影响[J].中华麻醉学杂志,2003,23(10)：770.
[25]张蕊,曹焕军,高尔.葛根素对家兔脑缺血再灌注损伤的抗自由基作用[J].潍坊医学院学报,2002,24(4)：267-269.
[26]沈炳权,蔡兆斌,徐群红等.葛根素对家兔心肌缺血-再灌注损伤的保护作用[J].中国中西医结合急救杂志,2004,11(6)：361-363.
[27]潘德顺,陈伟强.葛根素对大鼠心肌缺血再灌注损伤的干预作用[J].中国老 年学杂志,2010,30(3)：332-334.
[28]雒光强.葛根素对大鼠肝脏缺血再灌注损伤后NF-κB表达的影响[J].医学研究杂志,2009,38(5)：111-112.
[29]杨硕,娄金丽,王谦等.葛根素治疗2型糖尿病KKAy小鼠肝脏损伤的实验研究[J].中国中西医结合杂志,2009,29(8)：707-710.
[30]钟艺,谭海荣,潘竞锵等.葛根素对D-半乳糖诱导大鼠抑制蛋白非酶糖基化及增强胰岛素敏感性的作用[J].中国药物与临床,2007,7(8)：576-579.
[31]杜艳秋,赵敏.葛根素对敌敌畏中毒大鼠肝脏保护作用的研究[J].中国腹部疾病杂志,2005,5(6)：408-409.
[32]刘淑霞,何宁,刘青娟等.葛根素对糖尿病大鼠肾功能及肾组织MMP-3、TIMP-1表达的影响[J].天然产物研究与开发,2003,15(6)：531-535.
[33]黄彤金,邦荃,孙桂菊等.葛根素对去卵巢大鼠机体骨代谢影响的观察[J].中国老年学杂志,2009,29(17)：2482-2484.
[34]李斌斌,于世凤.葛根素调控骨代谢的体外实验研究[J].北京大学学报(医学版),2003,35(1)：74-77.
[35]邓新国,胡世兴,张清炯等.葛根素经腹腔注射在兔眼房水和玻璃体中的药代动力学结果比较[J].中国药理学通报,2007,23(1)：136-137.
[36]徐新荣,蔡丰英.葛根素对慢性高眼压兔眼视神经轴浆流影响的实验研究[J].中国中医眼科杂志,1997,7(1)：3-6.
[37]吴正红,刘有潜,朱延勤.葛根素滴眼液对家兔眼内压的作用[J].中国药科大学学报,1998,29(5)：387-389.
[38]贺玲,万新顺,韩丽英.葛根素对实验性视网膜缺血-再灌注损伤后视神经的保护作用[J].眼科新进展,2006,26(12)：916-918.
[39]张庆莲,张荷莲,孙玥.葛根素注射液眼科临床应用[J].长春中医学院学报,1999,15(3)：45.
[40]逢曙光,刘艳,孙咏梅,等.葛根素对糖尿病视网膜病变治疗作用的临床研究[J].山东医药,2007,47(10)：5-6.
[41]赵国宏,张荷玲.葛根素治疗糖尿病视网膜病变的疗效观察[J].光明中医,2009,24(12)：2297-2298.
[42]高尔,王金红,李洪军等.乳化葛根素对高脂血症家兔血清NO及PGI2的影响[J].潍坊医学院学报,2001,23(1)：1.
[43]朱晓伟,王林,王升启.葛根素的基础研究与临床应用新进展[J].内蒙古石油化工,2002,27(8)：8.
[44]GABETTA E,BOMBAROELLI E,PIFFERL G.Complexes of flavanolignanes with phospholipids,preparation there of and associated pharmaceutical composition. Patent No.0209038 [P].119872012211.
[45]WU J M,CHEN D W,ZHANG R H, et al. The review of the pharmaceutical study on the natural active component phospholipid complex[J].Chin Pharm J(中国药学杂志),1998,33(1)：9211.
[46]盂庆国,高尔,王汝琴等.葛根素磷脂复合物的制备及核磁共振和薄层层析研究[J].潍坊医学院学报,2001,32(1)：4.
[47]李颖,潘卫三,陈士林等.葛根素磷脂复合物的制备及其固体分散体研究[J].中国药学杂志,2006,41(15)：1162-1167.
[48]马云淑,赵浩如,林以宁.葛根素及其磷脂复合物的体外透皮实验研究[J].中国中药杂志,2000,25(5)：274-276.
[49]周毅生,贾永艳,申小清等.葛根素固体分散体的制备及其体外研究[J].中国药学杂志,2003,38(11：42-44.
[50]王曙宾,黄兰芷.葛根素缓释固体分散体制备及其体外释放度评价[J].中成药,2007,29(9)：1285-1288.
[51]龚显峰,李述溪,赵学玲等.葛根素固体分散体的制备及大鼠体内生物利用度研究[J].黑龙江医药,2009,22(2)：157-160.
[52]董祥玉,任勇,马学琴等.葛根素/β-环糊精包合物的初步研究[J].中国新药杂志,2006,15(7)：528-532.
[53]尤思路,高秀蓉,廖昌军.饱和水溶液法制备葛根素的β-环糊精包合物研究[J].西南军医,2008,10(4)：17-19.
[54]吴纯洁,齐红艺,黄春燕,等.羟丙基-β-环糊精对葛根素溶解性与角膜渗透性的影响[J].中国药学杂志,2006,41(20)：1565-1568.
[55]Wu W, Wang Y, Que L. Enhanced bioavailability of silymarin by self-microemulsifying drug delivery system [J]. Eur J Pharm Biopharm,2006, 63：288.
[56]于爱华,翟光喜,崔晶等.葛根素微乳的制备及质量评价[J].中国医药工业杂志,2006,37(7)：471-473.
[57]韩静,崔升淼.葛根素自微乳化释药系统的处方筛选与体外评价[J].中南药学,2009,7(10)：731-734.
[58]周红义,杨今祥.新型凝胶给药系统研究进展[J].中国药师,1999,2(3)：121.
[59]宋成君.葛根素眼部传递系统的研究[D].沈阳：沈阳药科大学,2006.
[60]齐红艺.葛根素温度敏感与生物粘附型眼用原位凝胶的研究[D].成都.成都中医药大学,2007.
[61]吴纯洁.葛根素眼用新型给药系统的研究[D].成都：四川大学,2005.
[62]王丹,石力夫,胡晋红等.一种葛根素经皮给药系统体外透皮性能的初步考察[J].药学服务于研究,2009,9(2)：104-106.
[63]顾一珠,周文,翟光喜.葛根素脂质体的研制及其大鼠口服吸收[J].中药材,2007,30(8)：970-973.
[64]邓赞,徐金库,李新松.葛根素脂质体滴眼液的制备及其药动学研究[J].中国中药杂志,2010,35(3)：301-304.
[65]平其能主编.现代药剂学[M].第1版.北京：中国医药科技出版社,1998：599-600.
[66]陆彬.药物新剂型与新技术.北京：人民卫生出版社,2005.
[67]宋金春,刘薇芝；黄岭.葛根素前体脂质体的制备及体外性质研究[J].中国药学杂志,2007,42(15)：1155-1158.
[68]宋金春,刘薇芝,黄岭.葛根素前体脂质体的质量考察[J].中国医院药学杂志,2007,27(9)：1244-246.
[69]宋金春,刘薇芝,黄岭.葛根素前体脂质体药动学和生物利用度研究[J].中国医院药学杂志,2008,28(24)：2075-2077.
[1]Schoenwald RD.Ocular Pharmacokinetics. In:Zimmerman TJ. Textbook of Ocular Pharmacology[M].New York:Lippincott-Raven Publishers,1997:119-138.
[2]Yasmin Sultana,M Aqil,Asgar Ali, et al.Advances in the topical ocular drug delivery [J].Expert Rev.Ophthalmol,2007,2(2):309-323.
[3]Baillie A J, Florence A T, Hμme L R, et al. The preparation and properties of niosomes:non-ionic surfactant vesicles[J]. J Pharm Pharmacol,1985,37(12):863-868.
[4]Yongmei Hao, Fenglin Zhao, Na Li,et al.Studies on a high encapsulation of colchicine by a niosome system[J]. Int. J. Pharm,2002,244:73-80.
[5]Ijeoma F Uchegbu,Suresh P Vyas.non-ionic surfactant based vesicles(niosomes) in drug delivery[J]. Int. J. Pharm,1998,172:33-70.
[6]M.Carafa,E Santucci,and G Lucania. Lidocaine-loaded non-ionic surfactant vesicles:characterization and in vitro permeation studies[J]. Int.J.Pharm,2002,231: 21-32.
[7]Indu P Kaur, Alka Garg, Anil K Singla, et al. Vesicular systems in ocular drug delivery:an overview[J]. Int. J. Pharm,2004,269:1-14.
[8]Ahmed S Guinedi,Nashed D Mortada,Samar Mansour,et al.Preparation and evaluation of reverse-phase evaporation and multilamellar niosomes as ophthalmic carriers of Acetazolamide [J].Int.J.Pharm,2000,306(1-2):71-82.
[9]Anil Vangala Vangala,Shehzad Rasul Rasul. Incorporation of acetazolamide into niosome using a novel pH gradient technique[J]. Pharm. Chem. J,2006,26:66-73.
[10]Aranya Manosroi, Paveena Wongtrakul, Jiradej Manosroi,et al. Characterization of vesicles prepared with various non-ionic surfactants mixed with cholesterol[J]. Colloids Surf, B:Biointerfaces,2003,30:129-138.
[11]Jim Jiao.Polyoxyethylated nonionic surfactants and their applications in topical ocular drug delivery[J]. Adv Drug Deliv Rev,2008,60:1663-1673.
[12]Ghada Abdelbary and Nashwa El-gendy. Niosome-Encapsulated Gentamicin for Ophthalmic Controlled Delivery[J]. AAPS PharmSciTech,2008,9(3):740-747.
[13]Perini G, Saettone MF, Niosome as carrier for ophthalmic drugs in vitro/in vivo evaluation[J]. Boll Chim Farm,1996,135(2):145-146.
[14]Deepika Aggarwal, Indu P Kaur. Improved pharmacodynamics of timolol maleate from a mucoadhesive niosomal ophthalmic drug delivery system[J]. Int.J.Pharm,2005, 290(1-2):155-159.
[15]Deepika Aggarwal, Dhananjay Pal, Ashim K Mitra, et al.Study of the extent of ocular absorption of acetazolamide from a developed niosomal formulation, by microdialysis sampling of aqueous humor[J]. Int.J.Pharm,2007,338:21-26.
[16]Saettone MF, Perini G, Carafa M, et al, Non-ionic surfactant vesicles as ophthalmic carriers for cyclopentolate.A preliminary evaluation[J]. S.T.P. Pharm.Sci,1996,6(1)：94-98.
[17]Schaffer HE, Brietieller JM, Krohn D L,Lectin-mediated attachment of liposomes to cornea:influence on transcorneal drug flux[J]. Investig Ophthalmol Vis Sci,1983,23:530-533.
[18]Uchegbu IF, Bouwstra JA, Florence AT.Large disk-shaped structures (discomes) in nonionic surfactant vesicle to micelle transitions[J]. Phys.Chem.1992,96:10548-10553.
[19]S.P. Vyas, N. Mysore, V. Jaittley, et al. Discoidal niosome based controlled ocular delivery of timolol maleate[J].Pharmazie.1998,53:466-469.
[1]Chien YW.Ocular drug delivery and delivery systems.In:Novel drug delivery systems [A]. New York:Marcel Dekker Inc,1992.269-300.
[2]Lee VHL. Ophthalmic drug delivery systems.In:Mitra AK.Ophthalmic drug delivery systems [A]. New York:Marcel Dekker Inc,1993.59-81.
[3]张强,武凤兰.药剂学[M].北京：北京大学医学出版社,2008.
[4]Herrero-Vanrell R,Fernandez-Carballidoa,Frutos G,et al. Enhancement of the mydriatic response to tropicamide by bioadhesive polymers[J].J Ocul Pharmacol Ther,2000,16(5):419-428.
[5]W. D. Ma, H.Xu, C.Wang, et al.Pluronic F127-g-poly(acrylic acid) copolymers as in situ gelling vehicle for ophthalmic drug delivery system[J]. Int.J.Pharm. 2008.350:247-256.
[6]徐晖,王绍宁,周力民,等.丙烯酸—泊洛沙姆407共聚物的合成及其原位凝胶性质[J].沈阳药科大学学报,2006,23(7)：421-424.
[7]齐红艺,吴纯洁.葛根素温度敏感与生物粘附型眼用原位凝胶的研究[D].成都：成都中医药大学,2007.
[8]Edsman K, Carlfors J, Pertsson R.Rheological evaluation of poloxamer as an in situ gel for ophthalmic use[J].Eur J pharm Sci,1998,6(2):105.
[9]Hong-Ru Lin, K.C.Sung, Carbopol/Pluronic phase change solutions for ophthalmic drug delievery[J].Joμmal of controlled release,2000, 69(3):379-388.
[10]Hong-Ru Lin, K. C. Sung, In Situ Gelling of Alginate/Pluronic Solutions for Ophthalmic Delivery of Pilocarpine[J].Biomacro-molecules,2004,5(6): 2358-2365.
[11]Jeong B, Kim S W, Bae Y H.Thermosensitive sol-gel reversible hydrogels[J]. Adv Drug Del Rev,2002,54:37-51.
[12]Kμmar S, Himmelstein KJ. Modification of in Situ gelling behavior of carbopol solutions by hydroxypropyl methylcellulose[J]. J Pharm Sci,1995,84(3): 344-348.
[13]郑俊民.药用辅料手册[M].北京：化学工业出版社,2004,107.
[14]张治强,张玮,陈光,等.pH敏感型盐酸左氧氟沙星眼用即型凝胶的制备及其体外释放考察[J].药学实践杂志,2010,28(2)：122-125.
[15]夏苗芬,梁文权,李士敏.复方甲硫酸新斯的明眼用原位凝胶的研究[D].杭州：浙江大学,2008.
[16]Chanrasekaran R, Puigjaner LC, Joyce KL, et al. Cation interaction in gellan:an X-ray study of the potassiμm salt[J].CarbohydrRes,1988,181(1):23-40.
[17]Lindell K, Engstrom S. In vitro release of timolol maleate from an in situ gelling polymer system[J].Int J pharm,1993,95:219.
[18]Grant GT, Morris E R, Rees D A, et al. Biological interactions between polys-accharides and divalent cations:The egg box model[J]. Febs Lett,1973,32: 195-198.
[19]Cohen S, Lobel E, Trevgoda A, et al. A novel in situ forming ophthalmic drug delivery systems form alginates undergoing gelation in the eye[J]. J Controlled Release,1997,44 (223):201.
[1]叶淑静.中药葛根研究进展[J].浙江中医学院学报,2003,27(6)：94-96.
[2]白海波,李波,宋子荣.葛根提取工艺研究[J].中国实验方剂学杂志,2002,8(6)：14-15.
[3]崔九成,宋小妹,张培芳,等.葛根总黄酮提取工艺研究[J].西北药学杂志,1999,14(5)：202.
[4]徐新刚,路富玉,隋晓春,等.正交试验优选葛根提取工艺[J].时珍国医国药,2000,11(9)：780-781.
[5]王翊臻,潘洪平.优选葛根提取工艺的实验研究[J].医学文选,2004,23(1)：4-6.
[6]王美东,等.葛根提取工艺的正交设计试验[J].齐鲁药事,2005,24(2)：45-46.
[7]梅林,石开云,杨元娟,等.葛根中葛根素的分离纯化技术进展[J].广州化学,2007,32(1)：73-76.
[8]郭延生,魏彦明,梁剑平,等.野葛根中提取分离葛根素的研究甘肃农业大学学报,2004,39(2)：199-202.
[9]徐华东.葛根素的提取及纯化新工艺研究[D].南宁：广西大学,2007.
[1]张丽琼,崔浩.丹参在眼科的应用[J].中国中医眼科杂志,2005,15(4)：242-244.
[2]简洋辉,徐国钧,金蓉鸾,等.中药丹参类的质量研究[J].中国药科大学学报,1989,20(1)：5-9.
[3]陈少兵.丹参有效部位的制备工艺与稳定性研究[D].安徽：合肥工业大学,2007.
[4]杨筠,古卓俍,印仁昌,等.用分光光度法测定丹参制剂中水溶性酚酸[J].中成药研究,1986,12：10-11.
[5]郑胜国,郭俊.分光光度法测定注射用丹参川芎嗪中丹参总酚酸的含量[J].中药研究与信息、,2005,7(11)：16-17.
[6]杨小宁,唐星,柳玉石.丹参中总酚酸的分离纯化工艺研究[J].中草药,2007,38(6)：843-846.
[7]王秀丽,张志荣,聂宇,等.从丹参中提取高纯度的丹参酚酸B[J].华西药学杂志,2008,23(3)：280-282.
[1]陆彬主编.药物新剂型与新技术[M].北京：人民卫生出版社.1998,第一版.
[2]杨继红,,蒋学华等.HPLC测定葛根素长循环脂质体中葛根素的含量和包封率[J].华西药学杂志,2006,21(1)：6668.
[3]周莉玲,王岩,刘清飞,等.青藤碱脂质体包封率的测定[J].中国中药杂志,2006,31(9)：731-734.
[4]鞠静红,张志荣,韩静,等.穿琥宁脂质体包封率的测定[J].中国医药工业杂志,2008,39(7)：514-516.
[5]郑杭生,张亚军,徐真,等.全缘千里光碱脂质体包封率测定方法的研究[J].中国药学杂志,2007,42(14)：1075-1078.
[6]高晓黎,季兴梅.葡聚糖凝胶柱色谱法测定脂质体包封率的条件筛选[J].中国药学杂志,2003,38(7)：515-517.
[7]王海刚,翟光喜.壳聚糖包覆葛根素脂质体的制备及理化性质考察[J].中药材,2007,30(1)：89-91.
[8]邓赟,徐金库等.葛根素脂质体滴眼液的制备及其药动学研究[J].2010,35 (3):301-304.
[9]Ahmed S. Guinedi, Nahed D. Mortada et al.Preparation and evaluation of reverse-phase evaporation and multilamellar niosomes as ophthalmic carriers of acetazolamide[J]. International Journal of Pharmaceutics,2005 (306):71-82.
[10]Francis szoka, jr., and Demetrios Papahadjopoulos.Procedure for preparation of liposomes with large internal aqueous space and high capture by reverse-phase evaporation[J].1978,75(9):4194-4198.
[11]刘丹,胡海洋.芹菜素囊泡的制备及理化性质考察[J].沈阳药科大学学报,2009,26(6)：423-428.
[12]孙娟,龙晓英.辣椒碱表面活性剂泡囊处方设计[J].广东药学院学报,2007,23(1)：21-24.
[13]奚菊群,郭荣.葛根素与卵磷脂囊泡的相互作用[J].科学通报,2007,52(17)：1997-2002.
[14]宋金春,陈佳丽,黄岭.葛根素环糊精包合物脂质体的制备及体外性质研究[J].中国药学杂志,2008,43(23)：17921797.
[1]魏刚,徐晖,郑俊民.原位凝胶的形成机制及在药物控制释放领域的应用[J].中国药学杂志,2003,38(8)：5642-5671.
[2]Sambhaji SP, Anant RP, Kakasaheb RM, et al. Pluronic gels for nasal delivery of Vitamin B12[J].Int J Pharm,2004,270(1):37-45.
[3]鞠凤阁,朱照静,王丽娟,等.双氯芬酸钠眼用温敏凝胶的处方优化及体外释放[J].中国医院药学杂志,2009,29(7)：541-545.
[4]高斐,王东凯,罗立,等.左氧氟沙星热敏型眼用凝胶的研制及体外释放研究[J].中国药房,2005,16(14)：1057-1059.
[5]Choi HG, Jung JH, Ryu JM.et al. Development of in situ-gelling and mucoadhesive acetaminophen liquid supposity [J]. Int J Pharm,1998,165 (1):33-44.
[6]马廉正.复方阿奇霉素地塞米松眼用即型凝胶的研究[D].武汉：湖北中医学院,2009.
[7]Helene Hagerstrom, Mattias Paulsson, Katarina Edsman. Evaluation of mucoadhesion for two polyelectrolyte gels in simulated physiological conditions using a rheological method.Eur J Pharma Sci.2000,9:301-309.
[8]Wei Gang, Xu Hui, Ding Pingtian, et al. Thermosetting gels with modulated gelation temperature for ophthalmic use:the rheological and gamma scintigraphic studies[J].J Controlled Release,2002,83 (1):65-74.
[9]方开泰.均匀设计与均匀设计表[M].北京：科学出版社,1994.
[10]Mansoor M Amiji, Phung-Kim Lai, Dinesh B, et al. Intratumoral Administration of Paclitaxel in an In Situ Gelling Poloxamer 407 Formulation[J]. Pharmaceutical Development and Technology,2002,7(2): 195-202.
[1]张兆旺.中药药剂学[M].北京：中国中医药出版社,2006.
[2]姚建国,周卯星,冯瑜,等.表面活性剂对丹参酮增溶作用的研究[J].日用化学工业,2003,33(1)：12-14.
[3]宁黎丽.眼用制剂研发过程中应关注抑菌剂的合理使用和质量控制[J].中国药学杂志,2007,42(23)：1836-1838.
[4]张新妹,胡昌勤,姜彩辉,等.滴眼剂中防腐剂的合理应用[J].广东医学院学报,2003,21(3)：268-269.
[5]陈钢,侯世祥,秦凌浩.动态流变实验评价温敏凝胶的方法研究[J].中国药学杂志.2008,43(6)：444-447.
[6]郭永学.丹酚酸B的降解机理及纯化工艺研究[D].大连：大连理工大学,2007.
[1]Pawar PK, Majumdar DK.Effect of formulation factors on in vitro permeation of moxifloxacin from aqueous drops through excised goat, sheep, and buffalo corneas [J].AAPS Pharm SciTech,2006,7(1):13.
[2]Srividya B,Cardoza RM,Amin PD.Sustained ophthalmic delivery of ofloxacin from a pH triggered in situ gelling system[J].J Control Rel.2001,73(2):205-211.
[3]EL-Kamelah.In vitro and in vivo evaluation of Pluronic F-127 based ocular delivery system for timolol maleate [J].Int JPharm,2002,241(1):47-55.
[4]Liu Y, Lu WL,Wang JC,et al.Controlled delivery of recombinant hirudin based on thermo-sensitive Pluronic P407 hydrogel for subcuntaneous administration:In vitro and in vivo characterization[J].J Control Release,2007,117(3):387-395.
[5]魏刚.体温敏感眼用凝胶的研究[D].沈阳：沈阳药科大学,2002.
[6]高斐,王东凯,罗立,等.左氧氟沙星热敏型眼用凝胶的研制及体外释放研究[J].中国药房,2005,16(14)：1057-1059.
[1]Grass GR,Robinson JR.Relationship of chemical structure to cornel penetration and influence of low viscosity solution on ocular bioavailability[J].J Pharm Sci, 1984,73:1021.
[2]Vinardell MP,Garcia L.The quantitive chlofioallantoic membrane test using typan blue stain to predict the eye irritancy of liquid sciatillation cocktails[J].Toxicol vitro,2000,14:551
[3]Mochizuki H,Yamada M,Hato S,et al.Fluorophotometric measurement of the precorneal residence time of topically applied hyaluronic acid[J].Br J Ophthalmol,2008,92:108-111.
[4]国家食品药品监督管理局药品审评中心.眼用药物(改剂型改途径)临床前安全性评价的一些考虑[S].北京,2004.
[1]国家食品药品监督管理局药品审评中心.化学药物刺激性、过敏性和溶血性研究技术指导原则[S].北京,2005.