三嵌段聚合物PLGA-PEG-PLGA的合成及在眼用凝胶中的应用
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摘要
眼部药物传递作为控制释放领域的重要分支近二十年来备受人们的关注。眼睛的有效保护机制与高度敏感性促使人们探索开发安全合理的给药系统,同时又限制了许多药剂学手段的应用,为此类剂型的设计带来了极大的困难。通常情况下,预防和治疗眼部疾病使用最多的是滴眼液和眼膏,但都存在比较明显的缺陷。本课题基于此,以地塞米松(Dexamethasone,DXM)为模型药物,设计了一种新型眼用制剂——温度敏感型的DXM眼用在体(in situ)凝胶剂,对材料的急性毒性和眼部刺激性,制剂的处方设计与质量评价进行了研究,并且初步探讨了制剂在家兔眼部代谢动力学过程。具体内容包括以下4部分:
1.三嵌段温度敏感型聚合物PLGA-PEG-PLGA的合成及表征
根据文献报道,以乳酸、羟基乙酸为起始原料,首先合成了混悬丙交酯(D,L-Lactide,LA)和乙交酯(Glyeolide,GA),在引发剂二乙基己酸亚锡的作用下,采用开环聚合的方式进行三嵌段聚合物PLGA-PEG-PLGA的合成。所得的产物用核磁共振(~1H-NMR)对其进行了结构确证;采用凝胶渗透色谱(Gel Permeation Chromatography,GPC)得到了聚合物材料的分子量及其分布情况;测定了聚合物溶液的相转变温度,粘度及粒径分布等理化性质。结果表明,合成的三嵌段聚合物性质稳定,呈现略带黄色的粘稠状胶体状态;~1H-NMR及GPC测试结果显示,合成产物结构正确,可以根据投入的LA和GA的比例控制聚合物的分子量,分布范围均匀;LA/GA=7∶1,浓度为20%的聚合物溶液在室温(25℃)时,为可以自由流动的透明液体(Sol)状态,随着温度升高至人体生理温度范围附近时,溶液-凝胶转变温度在33～34℃,适合眼部给药后形成凝胶;随着温度的升高,聚合物溶液粘度有一个较为明显的突跃;聚合物的粒径在100nm以下,且分布均匀。
2.三嵌段聚合物PLGA-PEG-PLGA的初步安全性研究
小鼠急性毒性试验表明,该材料安全;眼部刺激性试验结果表明,该材料家兔眼部无明显刺激,可以用于眼用制剂的研究。
3.温度敏感型眼用在体凝胶剂的制备工艺与评价
根据聚合物溶液-凝胶的转变温度,受热形成凝胶的速度及形成凝胶的强度,以LA/GA=7∶1的三嵌段聚合物为基质材料,配制20%的聚合物水溶液,成功制备了温度敏感型地塞米松眼用在体凝胶剂;对温度敏感型眼用凝胶进行了质量评价,考察了凝胶剂的外观,胶凝温度,沉降体积比,渗透压体及pH等指标;建立了地塞米松眼用在体凝胶剂的含量测定方法,准确性及精密性良好。体外释放度实验表明,应用三嵌段聚合物PLGA-PEG-PLGA作为基质,8～12h药物从材料中即可释放90%以上,具有一定的缓释作用,用于眼用制剂可以做到每天给药一次,方便治疗。对眼用制剂的稳定性进行了考察,影响因素试验、加速试验和长期实验结果表明,制剂稳定性良好。
4.温度敏感型眼用在体凝胶剂家兔眼部药物代谢动力学的初步研究
DXM的眼内药物代谢动力学实验的结果表明,DXM眼用凝胶剂组的C_(max),T_(max),T_(1/2),AUC和MRT等药动学参数明显大于滴眼液组,有效作用时间延长。
综上所述,本文采用开环聚合法合成了不同比例的三嵌段聚合物PLGA-PEG-PLGA,~1H-NMR及GPC测试结果显示,合成产物结构正确,可以根据投入的LA和GA的比例控制聚合物的分子量,分布范围均匀;聚合物的粒径在100nm以下,且分布均匀;不同浓度的聚合物水溶液具有温度敏感的特性。初步安全性实验表明,该材料安全,基本无毒副作用,对眼部无明显刺激作用。该制剂的制备简单,工艺参数可控,影响因素试、加速试验及长期实验结果显示,该制剂稳定性良好。地塞米松-聚合物溶液体外释放结果显示,该基质材料可以显著延长药物的释放。眼部药代动力学结果表明,药物在眼部的滞留时间与滴眼液相比明显增加,有效作用时间延长,起到一定的缓释作用。
As one of the important fields of controlled release,ophthalmic drug delivery has received entensive interests during the last two decades.The sensitivity and protection mechanisms of the eye promote more effective drug delivery systems with better compliancy to be developed,however,the applications of numerous pharmaceutical methods are limited simultaneously,which presents great challenge in designing ophthalmic dosage forms.Eye drops and ointments are most usually applicated to prevent and cure kinds of ophthalmopathy,while there are more obvious defects in them.In this dissertation,dexamethasone(DXM) was selected as the model drug,then a thermosensitive in situ gelling ophthalmic drug delivery system for DXM was developed and evaluated in vitro and in vivo,respectively.Five main sections were included in this paper:
1.Synthesis and characterization of triblock copolymers PLGA-PEG-PLGA
Following references and the conditions we actually had,we decided the way to synthesize copolymers.Details of the synthesis of PLGA-PEG-PLGA from lactic acid, glycolic acid and PEG are described.The synthetic product was characterized by ~1H-NMR and GPC.The phase transition temperature,the viscosity and particle size and other chemical and physical characteristics were determined.The results suggested that it was a kind of transparent gel with achroic or little yellowish.The structures of LA,GA and PLGA-PEG-PLGA were all fight compared with lots of references.The molecular weight can be controlled.At room temperature,the tdblock copolymer PLGA-PEG-PLGA (LA/GA=7:1,20%,w/w,in water) solution can flow freely.While the temperature is raised to about eyes temperature,it turned to be semisolid gel.It was used on eyes drug delivery systems.There is an obvious change of viscosity during the increased temperature.The particle size was below 100 nm.
2.The preliminary safety evaluation of tribloek copolymers PLGA-PEG-PLGA
The results on acute toxicity test of triblock copolymers in rats indicated that the materials were saft enough.The results of irritability study indicated that there was no obvisous stimulus on rabbit eyes.And the study of ophthalmic preparation can last.
3.The preparation and evaluation of DXM thermosensitive eye gels
Denpending on the velocity and strength of the gel,the triblock copolymer solutions (LA/GA=7:1,20%,w/w,in water) were chose to prepare the DXM thermosensitive ophthalmic preparations.The quality evaluation was taken on the preparations.The appearance,pH,and sedimentation ratio of the ophthalmic preparation were good enough. The detection method of DXM in thermosensitive gels was established and it has better sensitivity and specificity.The results of in vitro study showed that the release of DXM from thermosensitive gel last 8h to 12h.This preparation can be used once a day because of its sustaind release.The stablitity of ophthalmic preparation was better after the influencing factor test,accelated test and long term test.
4.The in vivo evaluation of DXM thermosensitive ophthalmic preparation in rabbit eyes
The results of DXM in vivo evaluation indicated that the C_(max),T_(max),T_(1/2),AUC and MRT of DXM thermosensitive ophthalmic in stiu gel were much more obviously better than eye drops.The time of DXM treatment last longer.
In a word,the method of ring-opening polymerization for triblock copolymer PLGA-PEG-PLGA with different LA/GA ratio was described.The results of ~1H-NMR and GPC showed that the structure of the copolymer we had was farmiliar with that reported for years and it was right exactly.The molecular weight of the copolymer could be controlled by LA/GA ratio.The particle size of copolymer in water was all below 100nm. Also the copolymer solution was thermosensitive.Preliminary safety evaluation shows that was a kind of safty preparation and nerely no toxicity.And there was also no irritation after administration.R was simply to prepare the formulation and it was stable after stress testing,accelerated testing and long-term testing.The in virto release results of DXM-copolymer solution indicated there was a long time for DXM to release from the gel. The results of rabbit eye pharmacokinetics showed this kind of preparation can increase the residence time of DXM in aqua oculi.
1.三嵌段温度敏感型聚合物PLGA-PEG-PLGA的合成及表征
根据文献报道,以乳酸、羟基乙酸为起始原料,首先合成了混悬丙交酯(D,L-Lactide,LA)和乙交酯(Glyeolide,GA),在引发剂二乙基己酸亚锡的作用下,采用开环聚合的方式进行三嵌段聚合物PLGA-PEG-PLGA的合成。所得的产物用核磁共振(~1H-NMR)对其进行了结构确证;采用凝胶渗透色谱(Gel Permeation Chromatography,GPC)得到了聚合物材料的分子量及其分布情况;测定了聚合物溶液的相转变温度,粘度及粒径分布等理化性质。结果表明,合成的三嵌段聚合物性质稳定,呈现略带黄色的粘稠状胶体状态;~1H-NMR及GPC测试结果显示,合成产物结构正确,可以根据投入的LA和GA的比例控制聚合物的分子量,分布范围均匀;LA/GA=7∶1,浓度为20%的聚合物溶液在室温(25℃)时,为可以自由流动的透明液体(Sol)状态,随着温度升高至人体生理温度范围附近时,溶液-凝胶转变温度在33～34℃,适合眼部给药后形成凝胶;随着温度的升高,聚合物溶液粘度有一个较为明显的突跃;聚合物的粒径在100nm以下,且分布均匀。
2.三嵌段聚合物PLGA-PEG-PLGA的初步安全性研究
小鼠急性毒性试验表明,该材料安全;眼部刺激性试验结果表明,该材料家兔眼部无明显刺激,可以用于眼用制剂的研究。
3.温度敏感型眼用在体凝胶剂的制备工艺与评价
根据聚合物溶液-凝胶的转变温度,受热形成凝胶的速度及形成凝胶的强度,以LA/GA=7∶1的三嵌段聚合物为基质材料,配制20%的聚合物水溶液,成功制备了温度敏感型地塞米松眼用在体凝胶剂;对温度敏感型眼用凝胶进行了质量评价,考察了凝胶剂的外观,胶凝温度,沉降体积比,渗透压体及pH等指标;建立了地塞米松眼用在体凝胶剂的含量测定方法,准确性及精密性良好。体外释放度实验表明,应用三嵌段聚合物PLGA-PEG-PLGA作为基质,8～12h药物从材料中即可释放90%以上,具有一定的缓释作用,用于眼用制剂可以做到每天给药一次,方便治疗。对眼用制剂的稳定性进行了考察,影响因素试验、加速试验和长期实验结果表明,制剂稳定性良好。
4.温度敏感型眼用在体凝胶剂家兔眼部药物代谢动力学的初步研究
DXM的眼内药物代谢动力学实验的结果表明,DXM眼用凝胶剂组的C_(max),T_(max),T_(1/2),AUC和MRT等药动学参数明显大于滴眼液组,有效作用时间延长。
综上所述,本文采用开环聚合法合成了不同比例的三嵌段聚合物PLGA-PEG-PLGA,~1H-NMR及GPC测试结果显示,合成产物结构正确,可以根据投入的LA和GA的比例控制聚合物的分子量,分布范围均匀;聚合物的粒径在100nm以下,且分布均匀;不同浓度的聚合物水溶液具有温度敏感的特性。初步安全性实验表明,该材料安全,基本无毒副作用,对眼部无明显刺激作用。该制剂的制备简单,工艺参数可控,影响因素试、加速试验及长期实验结果显示,该制剂稳定性良好。地塞米松-聚合物溶液体外释放结果显示,该基质材料可以显著延长药物的释放。眼部药代动力学结果表明,药物在眼部的滞留时间与滴眼液相比明显增加,有效作用时间延长,起到一定的缓释作用。
As one of the important fields of controlled release,ophthalmic drug delivery has received entensive interests during the last two decades.The sensitivity and protection mechanisms of the eye promote more effective drug delivery systems with better compliancy to be developed,however,the applications of numerous pharmaceutical methods are limited simultaneously,which presents great challenge in designing ophthalmic dosage forms.Eye drops and ointments are most usually applicated to prevent and cure kinds of ophthalmopathy,while there are more obvious defects in them.In this dissertation,dexamethasone(DXM) was selected as the model drug,then a thermosensitive in situ gelling ophthalmic drug delivery system for DXM was developed and evaluated in vitro and in vivo,respectively.Five main sections were included in this paper:
1.Synthesis and characterization of triblock copolymers PLGA-PEG-PLGA
Following references and the conditions we actually had,we decided the way to synthesize copolymers.Details of the synthesis of PLGA-PEG-PLGA from lactic acid, glycolic acid and PEG are described.The synthetic product was characterized by ~1H-NMR and GPC.The phase transition temperature,the viscosity and particle size and other chemical and physical characteristics were determined.The results suggested that it was a kind of transparent gel with achroic or little yellowish.The structures of LA,GA and PLGA-PEG-PLGA were all fight compared with lots of references.The molecular weight can be controlled.At room temperature,the tdblock copolymer PLGA-PEG-PLGA (LA/GA=7:1,20%,w/w,in water) solution can flow freely.While the temperature is raised to about eyes temperature,it turned to be semisolid gel.It was used on eyes drug delivery systems.There is an obvious change of viscosity during the increased temperature.The particle size was below 100 nm.
2.The preliminary safety evaluation of tribloek copolymers PLGA-PEG-PLGA
The results on acute toxicity test of triblock copolymers in rats indicated that the materials were saft enough.The results of irritability study indicated that there was no obvisous stimulus on rabbit eyes.And the study of ophthalmic preparation can last.
3.The preparation and evaluation of DXM thermosensitive eye gels
Denpending on the velocity and strength of the gel,the triblock copolymer solutions (LA/GA=7:1,20%,w/w,in water) were chose to prepare the DXM thermosensitive ophthalmic preparations.The quality evaluation was taken on the preparations.The appearance,pH,and sedimentation ratio of the ophthalmic preparation were good enough. The detection method of DXM in thermosensitive gels was established and it has better sensitivity and specificity.The results of in vitro study showed that the release of DXM from thermosensitive gel last 8h to 12h.This preparation can be used once a day because of its sustaind release.The stablitity of ophthalmic preparation was better after the influencing factor test,accelated test and long term test.
4.The in vivo evaluation of DXM thermosensitive ophthalmic preparation in rabbit eyes
The results of DXM in vivo evaluation indicated that the C_(max),T_(max),T_(1/2),AUC and MRT of DXM thermosensitive ophthalmic in stiu gel were much more obviously better than eye drops.The time of DXM treatment last longer.
In a word,the method of ring-opening polymerization for triblock copolymer PLGA-PEG-PLGA with different LA/GA ratio was described.The results of ~1H-NMR and GPC showed that the structure of the copolymer we had was farmiliar with that reported for years and it was right exactly.The molecular weight of the copolymer could be controlled by LA/GA ratio.The particle size of copolymer in water was all below 100nm. Also the copolymer solution was thermosensitive.Preliminary safety evaluation shows that was a kind of safty preparation and nerely no toxicity.And there was also no irritation after administration.R was simply to prepare the formulation and it was stable after stress testing,accelerated testing and long-term testing.The in virto release results of DXM-copolymer solution indicated there was a long time for DXM to release from the gel. The results of rabbit eye pharmacokinetics showed this kind of preparation can increase the residence time of DXM in aqua oculi.
引文
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[2]Lin HR,Sung KC.Carbopol/pluronic phase change solutions for ophthalmic drug delivery[J].Journal of Controlled Release,2000,69(2):379-388.
[3]崔福德 主编.药剂学实验指导(第2版)[M].北京:人民出版社,2007.
[4]Ocak F,Robinson JR.An investigation of theological,mucoadhesive and release properties of pluronic F-127 gel and pluronic F127/polycarbophil mixed gel system[J].Proceed.Int'l Syrup.Control Rel.Bioact.Mater.,Pads,27(2000),7144.
[5]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.
[6]Higuchi WI.Analysis of data on medicament release from ointments[J].J Pharm.Sci.,1962,51(8):802-804.
[7]Suh H,Jun HW.Physicochemical and release studies of naproxen in poloxamer gels[J].Int.J Pharm.,1996,129(1-2):13-20.
[8]Chi sC,Jun HW.Release rates of ketoprofen from poloxamer gels in a membraneless diffusion cell[J].J Pharm.Sci.,1991,80(3):280-283.
[9]Bhardwaj R,Blanchard J.Controlled release delivery system for the a-MSH analog Melanotan-Ⅰusing poloxamer 407[J].JPharm.Sci.,1996,85(9):915-919.
[10]Desal SD,Blanchard J.In vitro evaluation ofpluronic F127-based controlled release ocular delivery systems for pilocarpine[J].J Pharm Sci.,1998,87(2):226-230.
[11]Lavasanifar A,Samuel J,Kwon GS.Micelles self-assembled from poly(ethylene oxide)-block-poly(N-hexyl stearate L-aspartamide) by a solvent evaporation method:effect on the solubilization and haemolytic activity of amphotericin B[J].J.Control.Rel.,77(1-2):155-160.
[12]Ronald FP(戴干策,方图南等译).物理化学流体动力学导论[M].上海:华东化工学院出版社,1992,107-152.
[1]Burngay PM,Morrison PF,Dedrick RL.Steady-state theory for quantitative microdialysis of solutes and water in vivo and in vitro[J].Life Sci,1990,46(2):105-119.
[2]Urtti A,Salminen L.Minimizing systemic absorption of topically administered ophthalmic drugs[J].Surv Ophthalmol,1993,37(6):435-456.
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[4]Sehoenwald RD.Ocular drug delivery:,pharmacokinetie consideratious[J].Clin Pharmacokinet,1990,18(4):255-269.
[5]Miller MH,Madu A,Samathjanam G,et aL Fleroxaein pharmacokineties in aqueous and vitreous humors determined by using complete concentration-time data from individual rabbits[J].Antimic Agents Chemother,1992,36(1):32-38.
[6]Rittenhouse KD,Peiffer Jr RL,Pollack GM.Mierodialiysis evaluation of the ocular pharmacokineties of propranolol in the conscious rabbit[J].Pharm Res,1999,16(5):736-742.
[7]Lange ECM,Boer AC,Breimer DD.Methodological issues in mierodialysis sampling for pharmacokinetie studies[J].Adv Drug Delivery Rev,2000,4.5(2-3):125-148.
[8]Ritterthouse KD,Pollack GM.Mierodialysis and drug delivery to the eye[J].Adv.Drug Delivery Res.,2000,45(2-3):229-241.
[9]Schoenwald,RD.Ocular pharmacokinetics/pharmacodynamics,ophthalmic drug delivery systems,Marcel Dekker,Inc.,New York,1993,pp.83-110.
[10]Lee YC,Simamora P,Yalkowsky SH.Systemic delivery of insulin via an enhancer-free ocular device[J].J Pharm.Sci.,1997,86(12):1361-1364.
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[7]Saettone MF,Salminen L.Ocular inserts for topical delivery[J].Adv Drug Delivery Rev,1995,16(1):95-106.
[8]Hui HW,Robinson JR.Ocular delivery of progesterone using a bioadhesive polymer[J].Int J Pharm,1985,26(3):203-213.
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[7]Saettone MY,Salminen L.Ocular inserts for topical delivery[J].Adv Drug Delivery Rev,1995,16(1):95-106.
[8]Hui HW,Robinson JR.Ocular delivery of progesterone using a bioadhesive polymer[J].Int J Pharm,1985,26(3):203-213.
[9]Burgalassi S,Chetoni P,Saettone MF.Hydrogels for ocular delivery of pilocarpine:Preliminary evaluation in rabbits of the influence of viscosity and of drug solubility[J].Eur.J Pharm.Biopharm.,1996,42(6):385-392.
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[10]王晶,周庆颂,袁悦,莫凤奎.生物降解聚合物PLGA-PEG-PLGA的合成及表征[J].沈阳药科大学学报,2005,22(5):348-351.
[1]王顺耳,刘煊波主编.实用新药研究手册[M].北京:人民军医出版社,1991,174-176.
[2]国家食品药品监督管理局.化学药物研究技术指导原则.北京:中国医药科技出版社,2005.
[3]秦伯益主编.新药评价概论.北京:人民卫生出版社,1999.
[4]王玉祥主编.药理学实验.北京:医药科技出版社,1998,77-80.
[5]袁伯俊主编.新药评价基础.上海:第二军医大学出版社,2002,62-65.
[1]崔福德 主编.药剂学[M].北京:中国医药群技出版社,2002.
[2]Lin HR,Sung KC.Carbopol/pluronic phase change solutions for ophthalmic drug delivery[J].Journal of Controlled Release,2000,69(2):379-388.
[3]崔福德 主编.药剂学实验指导(第2版)[M].北京:人民出版社,2007.
[4]Ocak F,Robinson JR.An investigation of theological,mucoadhesive and release properties of pluronic F-127 gel and pluronic F127/polycarbophil mixed gel system[J].Proceed.Int'l Syrup.Control Rel.Bioact.Mater.,Pads,27(2000),7144.
[5]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.
[6]Higuchi WI.Analysis of data on medicament release from ointments[J].J Pharm.Sci.,1962,51(8):802-804.
[7]Suh H,Jun HW.Physicochemical and release studies of naproxen in poloxamer gels[J].Int.J Pharm.,1996,129(1-2):13-20.
[8]Chi sC,Jun HW.Release rates of ketoprofen from poloxamer gels in a membraneless diffusion cell[J].J Pharm.Sci.,1991,80(3):280-283.
[9]Bhardwaj R,Blanchard J.Controlled release delivery system for the a-MSH analog Melanotan-Ⅰusing poloxamer 407[J].JPharm.Sci.,1996,85(9):915-919.
[10]Desal SD,Blanchard J.In vitro evaluation ofpluronic F127-based controlled release ocular delivery systems for pilocarpine[J].J Pharm Sci.,1998,87(2):226-230.
[11]Lavasanifar A,Samuel J,Kwon GS.Micelles self-assembled from poly(ethylene oxide)-block-poly(N-hexyl stearate L-aspartamide) by a solvent evaporation method:effect on the solubilization and haemolytic activity of amphotericin B[J].J.Control.Rel.,77(1-2):155-160.
[12]Ronald FP(戴干策,方图南等译).物理化学流体动力学导论[M].上海:华东化工学院出版社,1992,107-152.
[1]Burngay PM,Morrison PF,Dedrick RL.Steady-state theory for quantitative microdialysis of solutes and water in vivo and in vitro[J].Life Sci,1990,46(2):105-119.
[2]Urtti A,Salminen L.Minimizing systemic absorption of topically administered ophthalmic drugs[J].Surv Ophthalmol,1993,37(6):435-456.
[3]Tang-Liu DDS,Burke PJ.The effect of atone on ocular levobunolol absorption:calculating the area under the curve and its standard error using tissue sampling compartments[J].Pharm Res,1988,5(4):238-241.
[4]Sehoenwald RD.Ocular drug delivery:,pharmacokinetie consideratious[J].Clin Pharmacokinet,1990,18(4):255-269.
[5]Miller MH,Madu A,Samathjanam G,et aL Fleroxaein pharmacokineties in aqueous and vitreous humors determined by using complete concentration-time data from individual rabbits[J].Antimic Agents Chemother,1992,36(1):32-38.
[6]Rittenhouse KD,Peiffer Jr RL,Pollack GM.Mierodialiysis evaluation of the ocular pharmacokineties of propranolol in the conscious rabbit[J].Pharm Res,1999,16(5):736-742.
[7]Lange ECM,Boer AC,Breimer DD.Methodological issues in mierodialysis sampling for pharmacokinetie studies[J].Adv Drug Delivery Rev,2000,4.5(2-3):125-148.
[8]Ritterthouse KD,Pollack GM.Mierodialysis and drug delivery to the eye[J].Adv.Drug Delivery Res.,2000,45(2-3):229-241.
[9]Schoenwald,RD.Ocular pharmacokinetics/pharmacodynamics,ophthalmic drug delivery systems,Marcel Dekker,Inc.,New York,1993,pp.83-110.
[10]Lee YC,Simamora P,Yalkowsky SH.Systemic delivery of insulin via an enhancer-free ocular device[J].J Pharm.Sci.,1997,86(12):1361-1364.
[1]Lang JC.Ocular drug delivery conventional ocular formulations[J].Adv Drug Delivery Rev,1995,16(1):39-43.
[2]Chien YW.Ocular Drug Delivery and Delivery Systems[M].In:Novel drug delivery Systems.(2nd)Marcel Dekker Inc.,New York,1992:269-300.
[3]Lee VHL.Ophthalmic drug delivery systems[M].In:Mitra AK.Ophthalmic drug delivery systems.Marcel Dekker Inc.,New York,1993:59-81.
[4]Ludwig A,Van Ooteghem M.The evaluation of viscous ophthalmic vehicles by slit lamp fluorophotometry in humans[J].Int J Pharm,1989,54(2):95-102.
[5]Meisner D,Mezei M.Liposome ocular delivery systems[J].Adv Drug Delivery Rev,1995,16(1):75-93.
[6]Zimmer A,Krenter J.Microspheres and nanoparticles used in ocular delivery systems[J].Adv Drug Delivery Rev,1995,16(1):61-73.
[7]Saettone MF,Salminen L.Ocular inserts for topical delivery[J].Adv Drug Delivery Rev,1995,16(1):95-106.
[8]Hui HW,Robinson JR.Ocular delivery of progesterone using a bioadhesive polymer[J].Int J Pharm,1985,26(3):203-213.
[9]Burgalassi S,Chetoni P,Saettone MF.Hydrogels for ocular delivery of pilocarpine:Preliminary evaluation in rabbits of the influence of viscosity and of drug solubility[J].Eur.J Pharm.Biopharm.,1996,42(6):385-392.
[10]张卫,钟华玉,唐瑞嫦.氟啶酸眼用缓释凝胶的制备及释药研究[J].广东药学,2005,15(4):28-30.
[11]Annouk R,Cloude M,Jeffrey C,et al.Functionality testing of gellan gum,a polymeric excipient material for ophthalmic dosage forms[J].Int J Pharm,1997,153(2):191-198.
[12]Rozier A,Mazuel C,Grove J,et al.Gelrite~(TM):a novel,ion-activated,in sire gelling polymer for ophthalmic vehicles.Effect on bioavailability of timolol[J].Int JPharm,1989,57(2):163-168.
[13]Paulsson M,Hagerstrom H,Edsman K.Rheological.Studies of the gelation of deacetylated gellan gum(Gelrite~(?)) in physiological conditions[J].Eur.J Pharm.Sci.,1999,9(1):99-105.
[14]Carfors J,Edsman K,Petersson R,et al.Rheological evaluation of Gelrite~(?) in sire gels for ophthalmicuse[J].Eur.J Pharm.Sci.,1998,6(2):113-119.
[15]Them D,Grant GT,Morris ER,et al.Characterization of cation binding and gelation of polyuronates by circular dichroism[J].Carbohydr Res,1982,100(3):29-42.
[16]Cohen S,Lobel E,Trevgoda A,et al.A novel in situ forming ophthalmic drug delivery systems from alginates undergoing gelation in the eye[J].J Control Rel.,1997,44(2-3):201-208.
[17]魏刚.温度敏感眼用原位凝胶的研究[D].沈阳:沈阳药入大学,2002.
[18]Edsman K,Carlfors J,Pctersson R.Rheological evaluation of poloxamer as an in situ gel for ophthalmic use[J].Eur.JPharm.Sci.,1998,6(1):105-112.
[19]Gurny R,Ibrahim H,Aebi A,et al.Design and evaluation of controlled release systems for the eye[J].J Control Rel.,1987,6(3):367-373.
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