醋甲唑胺脂质体滴眼剂的研究
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摘要
乙酰唑胺、醋甲唑胺、双氯非那胺等碳酸酐酶抑制剂自1954年起就被应用于青光眼的降眼压治疗。虽然口服碳酸酐酶抑制剂可以降低眼内压,但是全身性副作用限制了其应用,因此开展了醋甲唑胺脂质体滴眼液的研究。
首先建立了醋甲唑胺的紫外测定方法,经方法学验证,该法用于醋甲唑胺体外含量的测定准确可靠;然后用葡聚糖凝胶柱对醋甲唑胺及其脂质体进行洗脱;绘制洗脱曲线并进行洗脱行为的考察,建立了准确可靠的醋甲唑胺脂质体包封率的测定方法,为处方工艺的研究奠定了基础。
通过对常用脂质体制备工艺的筛选,确定采用醋酸钙梯度法对醋甲唑胺脂质体进行研制,并在醋酸钙梯度法基本工艺的基础上进行了醋酸钙浓度、磷脂/胆固醇比例、药脂比和温度等影响因素考察,得到了包封率在80%以上的醋甲唑胺脂质体。通过对搅拌速度与粒径关系的研究,得到了具有优良粒径的脂质体,其平均粒径为182.2±31.1nm。
建立了醋甲唑胺脂质体体外释放行为的测定方法,对脂质体的释放行为进行考察。
在醋甲唑胺脂质体药效学研究中发现,醋甲唑胺脂质体在给药后4h,达到最大降眼压效果为-10.18±4.96mmHg,且降眼压时间持续8h以上。通过1%派立明滴眼液与醋甲唑胺脂质体滴眼液的药效学研究发现,醋甲唑胺脂质体滴眼液有更强的降眼压效果且持续时间更长。
房水药物HPLC分析结果证明了本实验研制的醋甲唑胺脂质体滴眼液能有效进入眼內,具有良好的应用前景。
Carbonic anhydrase inhibitors (CAIs) were first used to lower intraocular pressure (IOP) in glaucoma in 1954, with the introduction of acetazolamide, methazolamide and diclofenamide were subsequently. Although IOP can be controlled by oral administration of CAIs, systemic side effects severely limit this mode of therapy. Methazolamide liposome eye drops were studied to solve this problem.
The UV analysis method of methazolamide was studied and proved to be accurate and reliable for quantitative analysis in vitro through methodology investigation. The encapsulation efficiency (EE%) determination method of methazolamide liposome was created by sephadex column chromatography. It was proved to be accurate and reliable for the detection of encapsulation efficiency of methazolamide liposome through the plot of elution curve and the investigation of elution characteristic.
Calcium acetate gradient method was taken as the basic manufacture of methazolamide liposome by comparative selection of different liposome preparationmethod. Proceeded with the calcium acetate gradient method, the concentration of calcium acetate, the phosphatidylcholine cholesterol ratio, drug lipid ratio and temperature were conducted for influential factor investigation, after that the methazolamide liposome with highest EE% (>80%) was obtained. Furthermore, by studying the correlation between stirring rate and particle size, the methazolamide liposome with finest particle size was gained, with mean PCS particle size of 182.2±31.1 nm.
In order to realize the releasing behavior of methazolamide liposome, its determination method in vitro was created. Effect of topically administered methazolamide liposomes on the change in IOP in NZW rabbits revealed the maximum IOP reduction reached a value of -10.18±4.96mmHg after 4 hours of topical administration methazolamide liposomes and the IOP reduction was sustained during the time of the experiment (8 hours). Comparing the results of both 1% brinzolamide and methazolamide liposomal formulations, it is obvious that methazolamide liposomes produced a more significant lowering in IOP compared with 1% brinzolamide and showed a more sustained action of IOP reduction. Results of HPLC analysis indicated that the methazolamide liposome eye drops can transfer the corneal barrier and penetrate into the anterior humor. The results demonstrated that this preparation was superior to topical administration.
首先建立了醋甲唑胺的紫外测定方法,经方法学验证,该法用于醋甲唑胺体外含量的测定准确可靠;然后用葡聚糖凝胶柱对醋甲唑胺及其脂质体进行洗脱;绘制洗脱曲线并进行洗脱行为的考察,建立了准确可靠的醋甲唑胺脂质体包封率的测定方法,为处方工艺的研究奠定了基础。
通过对常用脂质体制备工艺的筛选,确定采用醋酸钙梯度法对醋甲唑胺脂质体进行研制,并在醋酸钙梯度法基本工艺的基础上进行了醋酸钙浓度、磷脂/胆固醇比例、药脂比和温度等影响因素考察,得到了包封率在80%以上的醋甲唑胺脂质体。通过对搅拌速度与粒径关系的研究,得到了具有优良粒径的脂质体,其平均粒径为182.2±31.1nm。
建立了醋甲唑胺脂质体体外释放行为的测定方法,对脂质体的释放行为进行考察。
在醋甲唑胺脂质体药效学研究中发现,醋甲唑胺脂质体在给药后4h,达到最大降眼压效果为-10.18±4.96mmHg,且降眼压时间持续8h以上。通过1%派立明滴眼液与醋甲唑胺脂质体滴眼液的药效学研究发现,醋甲唑胺脂质体滴眼液有更强的降眼压效果且持续时间更长。
房水药物HPLC分析结果证明了本实验研制的醋甲唑胺脂质体滴眼液能有效进入眼內,具有良好的应用前景。
Carbonic anhydrase inhibitors (CAIs) were first used to lower intraocular pressure (IOP) in glaucoma in 1954, with the introduction of acetazolamide, methazolamide and diclofenamide were subsequently. Although IOP can be controlled by oral administration of CAIs, systemic side effects severely limit this mode of therapy. Methazolamide liposome eye drops were studied to solve this problem.
The UV analysis method of methazolamide was studied and proved to be accurate and reliable for quantitative analysis in vitro through methodology investigation. The encapsulation efficiency (EE%) determination method of methazolamide liposome was created by sephadex column chromatography. It was proved to be accurate and reliable for the detection of encapsulation efficiency of methazolamide liposome through the plot of elution curve and the investigation of elution characteristic.
Calcium acetate gradient method was taken as the basic manufacture of methazolamide liposome by comparative selection of different liposome preparationmethod. Proceeded with the calcium acetate gradient method, the concentration of calcium acetate, the phosphatidylcholine cholesterol ratio, drug lipid ratio and temperature were conducted for influential factor investigation, after that the methazolamide liposome with highest EE% (>80%) was obtained. Furthermore, by studying the correlation between stirring rate and particle size, the methazolamide liposome with finest particle size was gained, with mean PCS particle size of 182.2±31.1 nm.
In order to realize the releasing behavior of methazolamide liposome, its determination method in vitro was created. Effect of topically administered methazolamide liposomes on the change in IOP in NZW rabbits revealed the maximum IOP reduction reached a value of -10.18±4.96mmHg after 4 hours of topical administration methazolamide liposomes and the IOP reduction was sustained during the time of the experiment (8 hours). Comparing the results of both 1% brinzolamide and methazolamide liposomal formulations, it is obvious that methazolamide liposomes produced a more significant lowering in IOP compared with 1% brinzolamide and showed a more sustained action of IOP reduction. Results of HPLC analysis indicated that the methazolamide liposome eye drops can transfer the corneal barrier and penetrate into the anterior humor. The results demonstrated that this preparation was superior to topical administration.
引文
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[4]DeSantis L.,Preclinical overview of brinzolamide.Surv Ophthalmol,2000,44Suppl:1192-1291
[5]Martinez A,Conzalez F,Capeans C,et all.Dorzolamide effect on ocular blood flow.Invest Ophthalmol Vis Sci,1999,40:1270-1275
[6]Hafrun F.,Thorsteinn L.Formulation and testing of methazolamide cyclodextrin eye drop solutions.J Control Release.1997,44:95-99
[7]高正华,沈艺,姜节凯,醋甲唑胺与乙酰唑胺的降眼压疗效比较及其临床意义探讨。中国药业,1999,8:46-47
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[9]Loftsson T,Stefansson E.Effects of cyclodextrins on topical drug delivery to the eye.Drug Dev Ind Pharm.1997,23:473-481
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[1]Lee,V.H.L.and Robinson,J.R.Topical ocular drug delivery:recent development and furore challenges.J.Ocul.Pharmacol.1986,2:67-108.
[2]Shehab Ebrahim,MD,Gholam A.Peyman,MD,and Paul J.Lee,MD Applications of Liposomes in Ophthalmology.Surv Ophthalmol 2005,50:167-182.
[3]Niesman,M.R.The use of liposomes as drag carriers in ophthalmology.Crit.Rev.Drag Carriers Syst.1992,9:1-38.
[4]Smolin G.Ikumoto.M,Felies et al,Idoxuridine-liposomes therapy for herps-simplex keratitis Am J ophthalmol,1981,91:220
[5]Dharma, S.K. ,Fishman, P.H. and Peyman, G.A. A preliminary study of corneal penetration of Ilabilled Idoxuridine-liposome. Acta Ophthalmol., 1986,64: 298-301.
[6] McCalden TA, Levy M: Retention of topical liposomal formulations on the cornea. Experientia. 1990,46:713-715.
[7] Velpandian T, Gupta SK, Gupta YK, et al: Ocular drug targeting by liposomes and their corneal interactions. J Microencapsul. 1999,16:243-250.
[8] Schmidt-Erfurth U, Flotte TJ,Gragoudas ES, et al: Benzoporphyrin-lipoprotein-mediated photodestruction of intraocular tumors. Exp Eye Res. 1996,62:1-10.
[9]Singh, K. and Mezei, M., Liposomal ophthalmic drug delivery system. I. Triamcinolone acetonide. Int. J. Pharm. 1983,16:339-344.
[10] Singh. K. and Mezei, M., Liposomal ophthalmic drug delivery system. II. Dihydrostreptomycin sulfate. Int. J. Pharm. 1984,19,:263-269.
[11] Rania M. Hathout,l Samar Mansour,l Nahed D. Mortada,l and Ahmed S. GuinedilLiposomes as an Ocular Delivery System for Acetazolamide: In Vitro and In Vivo Studies. AAPS PharmSciTech. 2007,8 (1):E1-E12.
[12]E1-Gazayerly ON, Hikal AH. Preparation and evaluation of acetazolamide liposomes as an ocular delivery system. Int J Pharm. 1997,158:121-127.
[13]Winum J, Casini A, Mincione F, et al. Carbonic anhydrase inhibitors:N-(p-sulfamoyl phenyl)- α- D- glycopyranosylamines as topically acting antiglaucoma agents in hypertensive rabbits. Bioorg Med Chem Lett. 2004,14:225-229.
[14]Barza, M., Baum, J. and Szoka. F. Pharmacokinetics of subconjunctival liposome-encapsulated gentamicin in normal rabbit eyes. Invest. Ophthalmol. Vis. Sci.1984,25:486-490.
[15]Hirnle. E.. Hirnle. P. and Wright. J.K. Distribution of liposome-incorporated carboxyfluorescein in rabbit eyes. J. Microencapsulation. 1991,8:391-399..
[16] Torres PF, Siegers TP, Peek R, et al: Changes in cytokine mRNA levels in experimental corneal allografts after local clodronate-liposome treatment. Invest Ophthalmol Vis Sci. 1999,40:3194-201.
[17] Siegers TP, van Rooijen N, van Rij G, van der Gaag R:Delayed graft rejection in pre-vascularised corneas after subconjunctival injection of clodronate liposomes. Curr Eye Res 2000,20:322-324.
[18]Van der Veen G, BroersmaL,DijkstraCD, et al: Prevention of corneal allograft rejection in rats treated with subconjunctival injections of liposomes containing dichloromethylene diphosphonate. Invest Ophthalmol Vis Sci 1994,35:3505-3515.
[19]Van der Veen G, Broersma L, Van Rooijen N, et al:Cytotoxic T lymphocytes and antibodies after orthotropic penetrating keratoplasty in rats treated with dichloromethylene diphosphonate encapsulated liposomes. Curr Eye Res 1998,17:1018-1026.
[20]Kim, E.K. and Kim, H.B. Pharmacokinetics of intravitreally injected liposome-encapsulated tobramytin in normal rabbits. Yonsei Med. J. 1990,31: 308-314.
[21]Tremblay. C, Barza, M., Szoka, F., Lahav, M. and Baum, J. Reduced toxicity of liposome-associated amphotericin B injected intravitreally in rabbits. Invest. Ophthalmol. Vis. Sci. 1985,26:711-718.
[22]Barza, M., Baum, J., Tremblay. C, Szoka, F. and D'Amico, D.J. (1985) Ocular toxicity of intravitreally injected liposomal amphotericin B in rhesus monkeys. Am. J. Ophthalmol. 1985,100:259-263.
[23]Pleyer U, Lutz S, Jusko WJ, et al: Ocular absorption of topically applied FK506 from liposomal and oil formulations in the rabbit eye. Invest Ophthalmol Vis Sci 1993,34: 2737-2742.
[24]Masuda I, Matsuo T, Yasuda T, Matsuo N: Gene transfer with liposomes to the intraocular tissues by different routes of administration. Invest Ophthalmol Vis Sci 1996,37:1914-1920c
[25]Matsuo T, Masuda I, Yasuda T, Matsuo N: Gene transfer to the retina of rat by liposome eye drops. Biochem Biophys Res Commun 1996,219:947-950.
[26] T. Yamashita, S. Sonoda, K. Tachibana, Gene Delivery by Combination of Bubble Liposome and Ultrasound for Corneal Epithelial Cells. Invest. Ophthalmol. Vis. Sci., 2007,48: 2714-2725.
[27] Y. Bao, L. Zhang, G. Chao, D.R. Hinton, and R. Kannan, Efficient Delivery of Human Epidermal Growth Factor (hEGF) in Rabbits With Corneal Alkali Injury .Invest. Ophthalmol. Vis. Sci.,2006,47: 5034-5047.
[1]Lee, V.H.L. and Robinson,J.R. Topical ocular drug delivery: recent development and future challenges. J. Ocul. Pharmacol. 1986,2:67-108.
[2]Shehab Ebrahim, MD, Gholam A. Peyman, MD, and Paul J. Lee, MD Applications of Liposomes in Ophthalmology. Surv Ophthalmol 2005,50:167-182.
[3]Niesman,M.R. The use of liposomes as drug carriers in ophthalmology. Crit. Rev. Drug Carriers Syst. 1992,9:1-38.
[4]Smolin G.Ikumoto.M ,Felies et al , Idoxuridine-liposomes therapy for herps-simplex keratitis Am J ophthalmol ,1981,91:220
[5]Dharma, S.K. ,Fishman, P.H. and Peyman, G.A. A preliminary study of corneal penetration of Ilabilled Idoxuridine-liposome. Acta Ophthalmol., 1986,64: 298-301.
[6] McCalden TA, Levy M: Retention of topical liposomal formulations on the cornea. Experientia. 1990, 46:713-715.
[7] Velpandian T, Gupta SK, Gupta YK, et al: Ocular drug targeting by liposomes and their corneal interactions. J Microencapsul. 1999,16:243-250.
[8] Schmidt-Erfurth U, Flotte TJ,Gragoudas ES, et al: Benzoporphyrin-lipoprotein-mediated photodestruction of intraocular tumors. Exp Eye Res. 1996,62:1-10.
[9]Singh, K. and Mezei, M., Liposomal ophthalmic drug delivery system. I. Triamcinolone acetonide. Int. J. Pharm. 1983,16:339-344.
[10]Singh. K. and Mezei, M., Liposomal ophthalmic drug delivery system. II. Dihydrostreptomycin sulfate. Int. J. Pharm. 1984,19,:263-269.
[11] Rania M. Hathout,l Samar Mansour,l Nahed D. Mortada,l and Ahmed S. GuinedilLiposomes as an Ocular Delivery System for Acetazolamide: In Vitro and In Vivo Studies. AAPS PharmSciTech. 2007,8 (1):E1-E12.
[12]E1-Gazayerly ON, Hikal AH. Preparation and evaluation of acetazolamide liposomes as an ocular delivery system. Int J Pharm. 1997,158:121-127.
[13]Winum J, Casini A, Mincione F, et al. Carbonic anhydrase inhibitors:N-(p-sulfamoyl phenyl)- α - D- glycopyranosylamines as topically acting antiglaucoma agents in hypertensive rabbits. Bioorg Med Chem Lett. 2004,14:225-229.
[14]Barza, M., Baum, J. and Szoka. F. Pharmacokinetics of subconjunctival liposome-encapsulated gentamicin in normal rabbit eyes. Invest. Ophthalmol. Vis. Sci.l984,25:486-490.
[15]Hirnle. E.. Hirnle. P. and Wright. J.K. Distribution of liposome-incorporated carboxyfluorescein in rabbit eyes. J. Microencapsulation. 1991,8:391-399..
[16] Torres PF, Siegers TP, Peek R, et al: Changes in cytokine mRNA levels in experimental corneal allografts after local clodronate-liposome treatment. Invest Ophthalmol Vis Sci. 1999,40:3194-201.
[17] Siegers TP, van Rooijen N, van Rij G, van der Gaag R:Delayed graft rejection in pre-vascularised corneas after subconjunctival injection of clodronate liposomes. Curr Eye Res 2000,20:322-324.
[18] Van der Veen G, BroersmaL,DijkstraCD, et al: Prevention of corneal allograft rejection in rats treated with subconjunctival injections of liposomes containing dichloromethylene diphosphonate. Invest Ophthalmol Vis Sci 1994,35:3505-3515.
[19]Van der Veen G, Broersma L, Van Rooijen N, et al:Cytotoxic T lymphocytes and antibodies after orthotropic penetrating keratoplasty in rats treated with dichloromethylene diphosphonate encapsulated liposomes. Curr Eye Res 1998,17:1018-1026.
[20]Kim, E.K. and Kim, H.B. Pharmacokinetics of intravitreally injected liposome-encapsulated tobramytin in normal rabbits. Yonsei Med. J. 1990,31:308-314.
[21]Tremblay. C, Barza, M, Szoka, F., Lahav, M. and Baum, J. Reduced toxicity of liposome-associated amphotericin B injected intravitreally in rabbits. Invest. Ophthalmol. Vis. Sci. 1985,26:711-718.
[22]Barza, M., Baum, J., Tremblay. C, Szoka, F. and D'Amico, D.J. (1985) Ocular toxicity of intravitreally injected liposomal amphotericin B in rhesus monkeys. Am. J. Ophthalmol. 1985,100:259-263.
[23]Pleyer U, Lutz S, Jusko WJ, et al: Ocular absorption of topically applied FK506 from liposomal and oil formulations in the rabbit eye. Invest Ophthalmol Vis Sci 1993,34:2737-2742.
[24]Masuda I, Matsuo T, Yasuda T, Matsuo N: Gene transfer with liposomes to the intraocular tissues by different routes of administration. Invest Ophthalmol Vis Sci 1996,37:1914-1920。
[25]Matsuo T, Masuda I, Yasuda T, Matsuo N: Gene transfer to the retina of rat by liposome eye drops. Biochem Biophys Res Commun 1996,219:947-950.
[26] T. Yamashita, S. Sonoda, K. Tachibana, Gene Delivery by Combination of Bubble Liposome and Ultrasound for Corneal Epithelial Cells. Invest. Ophthalmol. Vis. Sci., 2007,48:2714-2725.
[27] Y. Bao, L. Zhang, G. Chao, D.R. Hinton, and R. Kannan, Efficient Delivery of Human Epidermal Growth Factor (hEGF) in Rabbits With Corneal Alkali Injury .Invest. Ophthalmol. Vis. Sci.,2006,47: 5034-5047.
[2]胡尔玮编译,青光眼治疗药物的疗效和安全性。世界临床药物,2003,20:750-755
[3]Grunwald J E,Zinn H,The acute effect of oral acetazolamide on macular blood flow.Invest Ophthalmol Vis Sci,1993,7:697-7021
[4]DeSantis L.,Preclinical overview of brinzolamide.Surv Ophthalmol,2000,44Suppl:1192-1291
[5]Martinez A,Conzalez F,Capeans C,et all.Dorzolamide effect on ocular blood flow.Invest Ophthalmol Vis Sci,1999,40:1270-1275
[6]Hafrun F.,Thorsteinn L.Formulation and testing of methazolamide cyclodextrin eye drop solutions.J Control Release.1997,44:95-99
[7]高正华,沈艺,姜节凯,醋甲唑胺与乙酰唑胺的降眼压疗效比较及其临床意义探讨。中国药业,1999,8:46-47
[8]T.J.Zimmerman,Acetazolamide and methazolamide.Ann.Ophthalmol.1978,10:509-510
[9]Loftsson T,Stefansson E.Effects of cyclodextrins on topical drug delivery to the eye.Drug Dev Ind Pharm.1997,23:473-481
[10]Angela C.P.,Stable Ophethalmic Composition Comprising Methazolamide.UK Pat.2223166 A.1990.
[11]L.M.Hurvitz,P.L.Kaufman,A.L.Robin,R.N.Weinreb,K.Crawford and B.Shaw,New developments in drug treatmentof glaucoma.Drugs,1991,41:514-532
[12]Kaur IP,Garg A,Singla AK,et al.Vesicular systems in ocular delivery:an overview.Int J Pharm.2004,269:1-14
[13]S.Weiner and H.D.,Wagner,Annu.Rev.Mater.,Sci.,1998,28,271
[14]S.V.Dorozhkin and M.Eapple,Angew.,Chem.Int.Ed.,2002,41:3130
[15]Paul W,Sharma CP.,Ceramic drug delivery:a perspective.J Biomater Appl 2003,17:253-264
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[1]Lee,V.H.L.and Robinson,J.R.Topical ocular drug delivery:recent development and furore challenges.J.Ocul.Pharmacol.1986,2:67-108.
[2]Shehab Ebrahim,MD,Gholam A.Peyman,MD,and Paul J.Lee,MD Applications of Liposomes in Ophthalmology.Surv Ophthalmol 2005,50:167-182.
[3]Niesman,M.R.The use of liposomes as drag carriers in ophthalmology.Crit.Rev.Drag Carriers Syst.1992,9:1-38.
[4]Smolin G.Ikumoto.M,Felies et al,Idoxuridine-liposomes therapy for herps-simplex keratitis Am J ophthalmol,1981,91:220
[5]Dharma, S.K. ,Fishman, P.H. and Peyman, G.A. A preliminary study of corneal penetration of Ilabilled Idoxuridine-liposome. Acta Ophthalmol., 1986,64: 298-301.
[6] McCalden TA, Levy M: Retention of topical liposomal formulations on the cornea. Experientia. 1990,46:713-715.
[7] Velpandian T, Gupta SK, Gupta YK, et al: Ocular drug targeting by liposomes and their corneal interactions. J Microencapsul. 1999,16:243-250.
[8] Schmidt-Erfurth U, Flotte TJ,Gragoudas ES, et al: Benzoporphyrin-lipoprotein-mediated photodestruction of intraocular tumors. Exp Eye Res. 1996,62:1-10.
[9]Singh, K. and Mezei, M., Liposomal ophthalmic drug delivery system. I. Triamcinolone acetonide. Int. J. Pharm. 1983,16:339-344.
[10] Singh. K. and Mezei, M., Liposomal ophthalmic drug delivery system. II. Dihydrostreptomycin sulfate. Int. J. Pharm. 1984,19,:263-269.
[11] Rania M. Hathout,l Samar Mansour,l Nahed D. Mortada,l and Ahmed S. GuinedilLiposomes as an Ocular Delivery System for Acetazolamide: In Vitro and In Vivo Studies. AAPS PharmSciTech. 2007,8 (1):E1-E12.
[12]E1-Gazayerly ON, Hikal AH. Preparation and evaluation of acetazolamide liposomes as an ocular delivery system. Int J Pharm. 1997,158:121-127.
[13]Winum J, Casini A, Mincione F, et al. Carbonic anhydrase inhibitors:N-(p-sulfamoyl phenyl)- α- D- glycopyranosylamines as topically acting antiglaucoma agents in hypertensive rabbits. Bioorg Med Chem Lett. 2004,14:225-229.
[14]Barza, M., Baum, J. and Szoka. F. Pharmacokinetics of subconjunctival liposome-encapsulated gentamicin in normal rabbit eyes. Invest. Ophthalmol. Vis. Sci.1984,25:486-490.
[15]Hirnle. E.. Hirnle. P. and Wright. J.K. Distribution of liposome-incorporated carboxyfluorescein in rabbit eyes. J. Microencapsulation. 1991,8:391-399..
[16] Torres PF, Siegers TP, Peek R, et al: Changes in cytokine mRNA levels in experimental corneal allografts after local clodronate-liposome treatment. Invest Ophthalmol Vis Sci. 1999,40:3194-201.
[17] Siegers TP, van Rooijen N, van Rij G, van der Gaag R:Delayed graft rejection in pre-vascularised corneas after subconjunctival injection of clodronate liposomes. Curr Eye Res 2000,20:322-324.
[18]Van der Veen G, BroersmaL,DijkstraCD, et al: Prevention of corneal allograft rejection in rats treated with subconjunctival injections of liposomes containing dichloromethylene diphosphonate. Invest Ophthalmol Vis Sci 1994,35:3505-3515.
[19]Van der Veen G, Broersma L, Van Rooijen N, et al:Cytotoxic T lymphocytes and antibodies after orthotropic penetrating keratoplasty in rats treated with dichloromethylene diphosphonate encapsulated liposomes. Curr Eye Res 1998,17:1018-1026.
[20]Kim, E.K. and Kim, H.B. Pharmacokinetics of intravitreally injected liposome-encapsulated tobramytin in normal rabbits. Yonsei Med. J. 1990,31: 308-314.
[21]Tremblay. C, Barza, M., Szoka, F., Lahav, M. and Baum, J. Reduced toxicity of liposome-associated amphotericin B injected intravitreally in rabbits. Invest. Ophthalmol. Vis. Sci. 1985,26:711-718.
[22]Barza, M., Baum, J., Tremblay. C, Szoka, F. and D'Amico, D.J. (1985) Ocular toxicity of intravitreally injected liposomal amphotericin B in rhesus monkeys. Am. J. Ophthalmol. 1985,100:259-263.
[23]Pleyer U, Lutz S, Jusko WJ, et al: Ocular absorption of topically applied FK506 from liposomal and oil formulations in the rabbit eye. Invest Ophthalmol Vis Sci 1993,34: 2737-2742.
[24]Masuda I, Matsuo T, Yasuda T, Matsuo N: Gene transfer with liposomes to the intraocular tissues by different routes of administration. Invest Ophthalmol Vis Sci 1996,37:1914-1920c
[25]Matsuo T, Masuda I, Yasuda T, Matsuo N: Gene transfer to the retina of rat by liposome eye drops. Biochem Biophys Res Commun 1996,219:947-950.
[26] T. Yamashita, S. Sonoda, K. Tachibana, Gene Delivery by Combination of Bubble Liposome and Ultrasound for Corneal Epithelial Cells. Invest. Ophthalmol. Vis. Sci., 2007,48: 2714-2725.
[27] Y. Bao, L. Zhang, G. Chao, D.R. Hinton, and R. Kannan, Efficient Delivery of Human Epidermal Growth Factor (hEGF) in Rabbits With Corneal Alkali Injury .Invest. Ophthalmol. Vis. Sci.,2006,47: 5034-5047.
[1]Lee, V.H.L. and Robinson,J.R. Topical ocular drug delivery: recent development and future challenges. J. Ocul. Pharmacol. 1986,2:67-108.
[2]Shehab Ebrahim, MD, Gholam A. Peyman, MD, and Paul J. Lee, MD Applications of Liposomes in Ophthalmology. Surv Ophthalmol 2005,50:167-182.
[3]Niesman,M.R. The use of liposomes as drug carriers in ophthalmology. Crit. Rev. Drug Carriers Syst. 1992,9:1-38.
[4]Smolin G.Ikumoto.M ,Felies et al , Idoxuridine-liposomes therapy for herps-simplex keratitis Am J ophthalmol ,1981,91:220
[5]Dharma, S.K. ,Fishman, P.H. and Peyman, G.A. A preliminary study of corneal penetration of Ilabilled Idoxuridine-liposome. Acta Ophthalmol., 1986,64: 298-301.
[6] McCalden TA, Levy M: Retention of topical liposomal formulations on the cornea. Experientia. 1990, 46:713-715.
[7] Velpandian T, Gupta SK, Gupta YK, et al: Ocular drug targeting by liposomes and their corneal interactions. J Microencapsul. 1999,16:243-250.
[8] Schmidt-Erfurth U, Flotte TJ,Gragoudas ES, et al: Benzoporphyrin-lipoprotein-mediated photodestruction of intraocular tumors. Exp Eye Res. 1996,62:1-10.
[9]Singh, K. and Mezei, M., Liposomal ophthalmic drug delivery system. I. Triamcinolone acetonide. Int. J. Pharm. 1983,16:339-344.
[10]Singh. K. and Mezei, M., Liposomal ophthalmic drug delivery system. II. Dihydrostreptomycin sulfate. Int. J. Pharm. 1984,19,:263-269.
[11] Rania M. Hathout,l Samar Mansour,l Nahed D. Mortada,l and Ahmed S. GuinedilLiposomes as an Ocular Delivery System for Acetazolamide: In Vitro and In Vivo Studies. AAPS PharmSciTech. 2007,8 (1):E1-E12.
[12]E1-Gazayerly ON, Hikal AH. Preparation and evaluation of acetazolamide liposomes as an ocular delivery system. Int J Pharm. 1997,158:121-127.
[13]Winum J, Casini A, Mincione F, et al. Carbonic anhydrase inhibitors:N-(p-sulfamoyl phenyl)- α - D- glycopyranosylamines as topically acting antiglaucoma agents in hypertensive rabbits. Bioorg Med Chem Lett. 2004,14:225-229.
[14]Barza, M., Baum, J. and Szoka. F. Pharmacokinetics of subconjunctival liposome-encapsulated gentamicin in normal rabbit eyes. Invest. Ophthalmol. Vis. Sci.l984,25:486-490.
[15]Hirnle. E.. Hirnle. P. and Wright. J.K. Distribution of liposome-incorporated carboxyfluorescein in rabbit eyes. J. Microencapsulation. 1991,8:391-399..
[16] Torres PF, Siegers TP, Peek R, et al: Changes in cytokine mRNA levels in experimental corneal allografts after local clodronate-liposome treatment. Invest Ophthalmol Vis Sci. 1999,40:3194-201.
[17] Siegers TP, van Rooijen N, van Rij G, van der Gaag R:Delayed graft rejection in pre-vascularised corneas after subconjunctival injection of clodronate liposomes. Curr Eye Res 2000,20:322-324.
[18] Van der Veen G, BroersmaL,DijkstraCD, et al: Prevention of corneal allograft rejection in rats treated with subconjunctival injections of liposomes containing dichloromethylene diphosphonate. Invest Ophthalmol Vis Sci 1994,35:3505-3515.
[19]Van der Veen G, Broersma L, Van Rooijen N, et al:Cytotoxic T lymphocytes and antibodies after orthotropic penetrating keratoplasty in rats treated with dichloromethylene diphosphonate encapsulated liposomes. Curr Eye Res 1998,17:1018-1026.
[20]Kim, E.K. and Kim, H.B. Pharmacokinetics of intravitreally injected liposome-encapsulated tobramytin in normal rabbits. Yonsei Med. J. 1990,31:308-314.
[21]Tremblay. C, Barza, M, Szoka, F., Lahav, M. and Baum, J. Reduced toxicity of liposome-associated amphotericin B injected intravitreally in rabbits. Invest. Ophthalmol. Vis. Sci. 1985,26:711-718.
[22]Barza, M., Baum, J., Tremblay. C, Szoka, F. and D'Amico, D.J. (1985) Ocular toxicity of intravitreally injected liposomal amphotericin B in rhesus monkeys. Am. J. Ophthalmol. 1985,100:259-263.
[23]Pleyer U, Lutz S, Jusko WJ, et al: Ocular absorption of topically applied FK506 from liposomal and oil formulations in the rabbit eye. Invest Ophthalmol Vis Sci 1993,34:2737-2742.
[24]Masuda I, Matsuo T, Yasuda T, Matsuo N: Gene transfer with liposomes to the intraocular tissues by different routes of administration. Invest Ophthalmol Vis Sci 1996,37:1914-1920。
[25]Matsuo T, Masuda I, Yasuda T, Matsuo N: Gene transfer to the retina of rat by liposome eye drops. Biochem Biophys Res Commun 1996,219:947-950.
[26] T. Yamashita, S. Sonoda, K. Tachibana, Gene Delivery by Combination of Bubble Liposome and Ultrasound for Corneal Epithelial Cells. Invest. Ophthalmol. Vis. Sci., 2007,48:2714-2725.
[27] Y. Bao, L. Zhang, G. Chao, D.R. Hinton, and R. Kannan, Efficient Delivery of Human Epidermal Growth Factor (hEGF) in Rabbits With Corneal Alkali Injury .Invest. Ophthalmol. Vis. Sci.,2006,47: 5034-5047.