外用眼膏进入结膜下组织不良反应的实验研究
摘要
目的
眼膏在眼科疾病治疗中的应用十分广泛,能在结膜囊内维持长时间的有效药物浓度。其主要是由药物成分和赋形剂制作而成,赋形剂的选择不同,可能导致眼膏对眼表或药物作用部位的不良反应存在差异。近些年,诸多文献研究指出将眼膏应用于泪道探通术后,能起到支撑泪道和防治泪道再粘连的作用,但也有报道称眼膏通过手术或创伤之假道进入眼结膜下、眶内组织及眼睑和泪囊周围组织时,将引起严重的炎症反应,且治疗比较棘手。
本实验目的：观察不同基质的外用眼膏进入结膜下组织后引起的不良反应情况,筛选出基质可降解吸收、不良反应较少的眼膏,为临床工作中正确选用眼膏提供一定的实验依据,并起到一定的指导作用。
材料与方法
1.动物与分组2-4周龄的健康清洁级豚鼠72只,体重120-150 g,雌雄兼用,无眼部疾患及头面部异常。随机数字表法分为A、B、C三组,每组24只。
2.动物模型制作盐酸奥布卡因滴眼液行豚鼠眼表面麻醉,在显微镜下使用1 ml注射器和7号(22 G)注射针头,A组右眼上方球结膜下注射以凡士林、羊毛脂和液状石蜡为基质的红霉素眼膏0.2 ml,B组右眼上方球结膜下注射以玻璃酸钠和卡波姆为基质的氧氟沙星眼膏0.2ml,C组作为对照组,右眼上方球结膜下注射羟丙基甲基纤维素0.2 ml。
3.观察项目和时间点分别于结膜下注射三种药物后立即观察药物在结膜下聚集情况；注射后1d、3d、7d、14d、21d、28d观察结膜肿胀程度,以0、+、++、+++表示：0为无明显肿胀,+为结膜水肿扁平隆起、无皱褶形成,++为结膜隆起、睑裂区可见,+++为结膜泡状隆起、突出睑裂、部分遮盖角膜上缘；注射后上述六个时间点观察药物扩散与降解吸收情况；以及上述六个时间点的结膜组织病理学变化。
4.统计学分析采用SPSS17.0统计软件进行统计学分析。三组间结膜肿胀程度的有序变量资料采用秩和检验,检验标准a=0.05,P<0.05为差异有统计学意义。
结果
1.三种药物注射到局部的情况注射后立即观察,A组药物在结膜下呈黄白色油质状；B组药物呈淡白色半透明状；C组药物在结膜下呈液状透明。
2.三种药物注射后结膜肿胀程度A组：结膜肿胀以+++为主,14d发生明显变化,0只眼为+++,21 d、28 d结膜仍见肿胀,未见明显消退。B组：结膜肿胀以++为主,14 d结膜肿胀程度明显减轻,范围明显缩小,28 d结膜肿胀完全消退。C组：结膜肿胀以+为主,7d结膜肿胀逐渐消退,14d结膜肿胀已完全消退。三组间结膜肿胀程度在1d、3d、7d比较差异有统计学意义(P<0.05)。
3.药物扩散与降解吸收情况A组：注射眼膏后3d开始,眼膏逐渐向四周球结膜下扩散,但未见明显降解吸收。B组：从3d开始,见眼膏向下方球结膜下扩散,并随着扩散逐渐被降解吸收,28 d眼膏已被完全吸收。C组药物各个时间点均未见扩散,于注射后1d开始逐渐被降解吸收,14d时已被完全降解吸收。
4.组织病理学观察A组：见以中性粒细胞为主的炎症细胞浸润结膜组织,包括淋巴细胞,大量成纤维细胞及纤维组织增生；21d、28d纤维组织增生机化,炎症细胞基本消失。B组：见以中性粒细胞为主的炎症细胞浸润结膜组织,周围血管扩张充血,仅少量纤维组织增生；28 d结膜结构基本恢复正常。C组：仅有少量炎症细胞浸润结膜组织,7d炎症细胞消失,未见纤维组织增生,14d结膜结构恢复正常。
结论
以凡士林、羊毛脂和液状石蜡为基质的眼膏进入组织中将引起严重的炎症反应,建议不要用于有创口的组织表面。
以玻璃酸钠和卡波姆为基质的眼膏进入结膜下组织后仅引起轻度的组织炎症反应,认为用于泪道探通术后可起到支撑管腔和防止组织粘连的作用。
羟丙基甲基纤维素不引起明显的炎症反应,但由于其黏度较低,不用于泪道探通术后注入泪道内。
Purpose
Oculentum is widely used in the treatment of eye disease, and the medicine density can be kept effectively in the conjunctiva sac for a long time. It is mainly manufactured by pharmaceutical ingredients and excipients, if the excipients are different, the adverse reactions caused by eye oculentum to the surface of ocular or the position affected by drugs are different. In recent years, researchs in many documents point out that the oculentum can sustain the lacrimal duct and avoid the lacrimal duct being conglutinated again if it is applied to lacrimal surgery, but the oculentum can also cause severe inflammation and it is hard to be treated if it goes into the subconjunctival tissue, orbital tissues, the tissue surrounding lacrimal sac and the eyelids through the false passage caused by surgery or trauma.
The purpose of the experiment is to observe the adverse reactions caused by the different substrate oculentum when they are going into the subconjunctival tissue. The eye oculentums, which have little side effects and can be degraded and absorbed, are selected. This can provide experimental evidence and plays a role of instruction for the selection of eye oculentums in the clinical work.
Materials and methods
1. Animals and Grouping
72 guinea pigs, which are healthy and in clean level,2 to 4 weeks old, weighing 120～150 g, were selected. Male and female was open, and excluded a variety of eye diseases. They were randomly divided into three groups of A, B, C, and 24 in every group.
2. Animal model production
After the ocular surface anesthesia by the eye drops of hydrochloric acid Ao Buka, the erythromycin eye oculentum, which takes vasline, lanolin and liquid paraffin as substrate, was injected into upper subconjunctival tissue of the right eye of guinea pigs in 0.2ml using 1 ml syringes and 7 (22 G) needle under the microscope in group A. The ofloxacin eye oculentum, which takes the sodium hyaluronate and carbomer as substrate, was injected into upper subconjunctival tissue of the right eye of guinea pigs in 0.2ml in group B. The hydroxypropyl methylcellulose was taken as a contrast and was injected into upper subconjunctival tissue of the right eye of guinea pigs in 0.2ml in group C.
3. Project and time points
To observe the accumulative situations after the three drugs were injected into the subconjunctival tissue immediately;the swelling of the conjunctiva on the day of 1d,3d,7d,14 d,21 d,28 d were observed, just as 0,+,++,+++:0 shows it is have no obvious swelling,+shows the conjunctival edema is flat elevation and have no wrinkle,++shows the conjunctiva is upheaved and the area of palpebral fissure is visible,+++shows the conjunctiva is upheaved like the bubble and escaped from palpebral fissure, and the conjunctiva which is severe swelling covered the upper edge of the cornea partially; the diffusion, degradation and absorption of drugs at the above of six time were observed, the histopathological changes of the conjunctiva at the six time above were observed.
4. Statistical analysis
SPSS17.0 statistical software was used for statistical analysis. The method of Rank sum test was used to analyze the difference rates of the conjunctival swelling among the three groups. Inspection standard was 0.05, and P<0.05, so it had statistical significance.
Results
1. The situation of the three drugs injected into the local position
The situations were observed immediately after injection, Group A of drugs looked like the thick oil which was yellow and white under the conjunctiva. Group B of drugs looked pale, white and translucent. Group C of drugs were liquid and transparent under the conjunctiva.
2. The swelling degree of conjunctiva after the injection of three drugs
Group A:most swelling degree of the conjunctiva was +++, significant changes occurred on the 14th day,0 eye showed +++. On the 21th,28th day, the swelling of the conjunctiva was still seeing, and there was no significant regression. Group B: most swelling of conjunctiva was ++, the swelling degree of conjunctiva was significantly reduced on the 14th day, and the scope was significantly reduced too. On the 28th day, the swelling of conjunctiva was completely withered up. Group C: most swelling degree of conjunctiva was +, the swelling of the conjunctiva was gradually reduced in 7th day. On the 14th day, the swelling of the conjunctiva was completely subsided.1 d,3 d,7 d the difference rates of the conjunctival swelling among the three groups showed less than 0,05, there was significant difference between the three groups(P<0.05).
3. The situation of drug diffuse and degradation and absorption
Group A:after injection of eye oculentum, on the 3th day, eye oculentum was spreading to the bottom of the ball of the conjunctiva aroudly, but had no significant degradation and absorption. Group B:from the 3th day, eye oculentum was spreading to the blow of subconjunctival tissue, and was gradually degraded and absorbed with the diffusion, on the 28th day, the oculentum was completely absorbed. Group C:the drug was not diffused at each time and was degraded and absorbed at the first day after injection, and it was completely absorbed on 14th day.
4. Histopathological changes
Group A:there were inflammatory cells, which were mainly consisted of neutrophil, could be seen in the conjunctival tissue, including lymphocytes, and a large number of fibrous tissue could be seen. The fibrous tissue proliferated and inflammatory cells disappeared on the 21th and 28th day. Group B:there were also inflammatory cells, which were mainly consisted of neutrophil, could be seen in the conjunctival tissue, peripheral vasodilation, had only a small amount of fibrous tissue; on 28th day, conjunctival structure returned to normal. Group C:there were only a small amount of inflammatory cells infiltrated into the conjunctiva tissue, inflammatory cells disappear on 7th day, and have no hyperplastic fibrous tissue, on 14th day, the structure of conjunctiva returned to normal.
Conclusion
When the erythromycin eye oculentum, which takes the vasline, lanolin and liquid paraffin as substrate, was injected into the conjunctival tissue, it would cause the worst inflammatory reaction, therefore, it was not recommended for the tissue of a wound surface.
When the ofloxacin eye oculentum, which takes the sodium hyaluronate and carbomer as substrate, was injected into the conjunctival tissue, it would cause slight inflammatory reaction, and it could be used in the lacrimal surgery to play a part in supporting and preventing the tissue to adhesion.
The hydroxypropyl methylcellulose did not cause significant inflammatory reaction, but it was not used to inject to the lacrimal because of its low viscosity.
眼膏在眼科疾病治疗中的应用十分广泛,能在结膜囊内维持长时间的有效药物浓度。其主要是由药物成分和赋形剂制作而成,赋形剂的选择不同,可能导致眼膏对眼表或药物作用部位的不良反应存在差异。近些年,诸多文献研究指出将眼膏应用于泪道探通术后,能起到支撑泪道和防治泪道再粘连的作用,但也有报道称眼膏通过手术或创伤之假道进入眼结膜下、眶内组织及眼睑和泪囊周围组织时,将引起严重的炎症反应,且治疗比较棘手。
本实验目的：观察不同基质的外用眼膏进入结膜下组织后引起的不良反应情况,筛选出基质可降解吸收、不良反应较少的眼膏,为临床工作中正确选用眼膏提供一定的实验依据,并起到一定的指导作用。
材料与方法
1.动物与分组2-4周龄的健康清洁级豚鼠72只,体重120-150 g,雌雄兼用,无眼部疾患及头面部异常。随机数字表法分为A、B、C三组,每组24只。
2.动物模型制作盐酸奥布卡因滴眼液行豚鼠眼表面麻醉,在显微镜下使用1 ml注射器和7号(22 G)注射针头,A组右眼上方球结膜下注射以凡士林、羊毛脂和液状石蜡为基质的红霉素眼膏0.2 ml,B组右眼上方球结膜下注射以玻璃酸钠和卡波姆为基质的氧氟沙星眼膏0.2ml,C组作为对照组,右眼上方球结膜下注射羟丙基甲基纤维素0.2 ml。
3.观察项目和时间点分别于结膜下注射三种药物后立即观察药物在结膜下聚集情况；注射后1d、3d、7d、14d、21d、28d观察结膜肿胀程度,以0、+、++、+++表示：0为无明显肿胀,+为结膜水肿扁平隆起、无皱褶形成,++为结膜隆起、睑裂区可见,+++为结膜泡状隆起、突出睑裂、部分遮盖角膜上缘；注射后上述六个时间点观察药物扩散与降解吸收情况；以及上述六个时间点的结膜组织病理学变化。
4.统计学分析采用SPSS17.0统计软件进行统计学分析。三组间结膜肿胀程度的有序变量资料采用秩和检验,检验标准a=0.05,P<0.05为差异有统计学意义。
结果
1.三种药物注射到局部的情况注射后立即观察,A组药物在结膜下呈黄白色油质状；B组药物呈淡白色半透明状；C组药物在结膜下呈液状透明。
2.三种药物注射后结膜肿胀程度A组：结膜肿胀以+++为主,14d发生明显变化,0只眼为+++,21 d、28 d结膜仍见肿胀,未见明显消退。B组：结膜肿胀以++为主,14 d结膜肿胀程度明显减轻,范围明显缩小,28 d结膜肿胀完全消退。C组：结膜肿胀以+为主,7d结膜肿胀逐渐消退,14d结膜肿胀已完全消退。三组间结膜肿胀程度在1d、3d、7d比较差异有统计学意义(P<0.05)。
3.药物扩散与降解吸收情况A组：注射眼膏后3d开始,眼膏逐渐向四周球结膜下扩散,但未见明显降解吸收。B组：从3d开始,见眼膏向下方球结膜下扩散,并随着扩散逐渐被降解吸收,28 d眼膏已被完全吸收。C组药物各个时间点均未见扩散,于注射后1d开始逐渐被降解吸收,14d时已被完全降解吸收。
4.组织病理学观察A组：见以中性粒细胞为主的炎症细胞浸润结膜组织,包括淋巴细胞,大量成纤维细胞及纤维组织增生；21d、28d纤维组织增生机化,炎症细胞基本消失。B组：见以中性粒细胞为主的炎症细胞浸润结膜组织,周围血管扩张充血,仅少量纤维组织增生；28 d结膜结构基本恢复正常。C组：仅有少量炎症细胞浸润结膜组织,7d炎症细胞消失,未见纤维组织增生,14d结膜结构恢复正常。
结论
以凡士林、羊毛脂和液状石蜡为基质的眼膏进入组织中将引起严重的炎症反应,建议不要用于有创口的组织表面。
以玻璃酸钠和卡波姆为基质的眼膏进入结膜下组织后仅引起轻度的组织炎症反应,认为用于泪道探通术后可起到支撑管腔和防止组织粘连的作用。
羟丙基甲基纤维素不引起明显的炎症反应,但由于其黏度较低,不用于泪道探通术后注入泪道内。
Purpose
Oculentum is widely used in the treatment of eye disease, and the medicine density can be kept effectively in the conjunctiva sac for a long time. It is mainly manufactured by pharmaceutical ingredients and excipients, if the excipients are different, the adverse reactions caused by eye oculentum to the surface of ocular or the position affected by drugs are different. In recent years, researchs in many documents point out that the oculentum can sustain the lacrimal duct and avoid the lacrimal duct being conglutinated again if it is applied to lacrimal surgery, but the oculentum can also cause severe inflammation and it is hard to be treated if it goes into the subconjunctival tissue, orbital tissues, the tissue surrounding lacrimal sac and the eyelids through the false passage caused by surgery or trauma.
The purpose of the experiment is to observe the adverse reactions caused by the different substrate oculentum when they are going into the subconjunctival tissue. The eye oculentums, which have little side effects and can be degraded and absorbed, are selected. This can provide experimental evidence and plays a role of instruction for the selection of eye oculentums in the clinical work.
Materials and methods
1. Animals and Grouping
72 guinea pigs, which are healthy and in clean level,2 to 4 weeks old, weighing 120～150 g, were selected. Male and female was open, and excluded a variety of eye diseases. They were randomly divided into three groups of A, B, C, and 24 in every group.
2. Animal model production
After the ocular surface anesthesia by the eye drops of hydrochloric acid Ao Buka, the erythromycin eye oculentum, which takes vasline, lanolin and liquid paraffin as substrate, was injected into upper subconjunctival tissue of the right eye of guinea pigs in 0.2ml using 1 ml syringes and 7 (22 G) needle under the microscope in group A. The ofloxacin eye oculentum, which takes the sodium hyaluronate and carbomer as substrate, was injected into upper subconjunctival tissue of the right eye of guinea pigs in 0.2ml in group B. The hydroxypropyl methylcellulose was taken as a contrast and was injected into upper subconjunctival tissue of the right eye of guinea pigs in 0.2ml in group C.
3. Project and time points
To observe the accumulative situations after the three drugs were injected into the subconjunctival tissue immediately;the swelling of the conjunctiva on the day of 1d,3d,7d,14 d,21 d,28 d were observed, just as 0,+,++,+++:0 shows it is have no obvious swelling,+shows the conjunctival edema is flat elevation and have no wrinkle,++shows the conjunctiva is upheaved and the area of palpebral fissure is visible,+++shows the conjunctiva is upheaved like the bubble and escaped from palpebral fissure, and the conjunctiva which is severe swelling covered the upper edge of the cornea partially; the diffusion, degradation and absorption of drugs at the above of six time were observed, the histopathological changes of the conjunctiva at the six time above were observed.
4. Statistical analysis
SPSS17.0 statistical software was used for statistical analysis. The method of Rank sum test was used to analyze the difference rates of the conjunctival swelling among the three groups. Inspection standard was 0.05, and P<0.05, so it had statistical significance.
Results
1. The situation of the three drugs injected into the local position
The situations were observed immediately after injection, Group A of drugs looked like the thick oil which was yellow and white under the conjunctiva. Group B of drugs looked pale, white and translucent. Group C of drugs were liquid and transparent under the conjunctiva.
2. The swelling degree of conjunctiva after the injection of three drugs
Group A:most swelling degree of the conjunctiva was +++, significant changes occurred on the 14th day,0 eye showed +++. On the 21th,28th day, the swelling of the conjunctiva was still seeing, and there was no significant regression. Group B: most swelling of conjunctiva was ++, the swelling degree of conjunctiva was significantly reduced on the 14th day, and the scope was significantly reduced too. On the 28th day, the swelling of conjunctiva was completely withered up. Group C: most swelling degree of conjunctiva was +, the swelling of the conjunctiva was gradually reduced in 7th day. On the 14th day, the swelling of the conjunctiva was completely subsided.1 d,3 d,7 d the difference rates of the conjunctival swelling among the three groups showed less than 0,05, there was significant difference between the three groups(P<0.05).
3. The situation of drug diffuse and degradation and absorption
Group A:after injection of eye oculentum, on the 3th day, eye oculentum was spreading to the bottom of the ball of the conjunctiva aroudly, but had no significant degradation and absorption. Group B:from the 3th day, eye oculentum was spreading to the blow of subconjunctival tissue, and was gradually degraded and absorbed with the diffusion, on the 28th day, the oculentum was completely absorbed. Group C:the drug was not diffused at each time and was degraded and absorbed at the first day after injection, and it was completely absorbed on 14th day.
4. Histopathological changes
Group A:there were inflammatory cells, which were mainly consisted of neutrophil, could be seen in the conjunctival tissue, including lymphocytes, and a large number of fibrous tissue could be seen. The fibrous tissue proliferated and inflammatory cells disappeared on the 21th and 28th day. Group B:there were also inflammatory cells, which were mainly consisted of neutrophil, could be seen in the conjunctival tissue, peripheral vasodilation, had only a small amount of fibrous tissue; on 28th day, conjunctival structure returned to normal. Group C:there were only a small amount of inflammatory cells infiltrated into the conjunctiva tissue, inflammatory cells disappear on 7th day, and have no hyperplastic fibrous tissue, on 14th day, the structure of conjunctiva returned to normal.
Conclusion
When the erythromycin eye oculentum, which takes the vasline, lanolin and liquid paraffin as substrate, was injected into the conjunctival tissue, it would cause the worst inflammatory reaction, therefore, it was not recommended for the tissue of a wound surface.
When the ofloxacin eye oculentum, which takes the sodium hyaluronate and carbomer as substrate, was injected into the conjunctival tissue, it would cause slight inflammatory reaction, and it could be used in the lacrimal surgery to play a part in supporting and preventing the tissue to adhesion.
The hydroxypropyl methylcellulose did not cause significant inflammatory reaction, but it was not used to inject to the lacrimal because of its low viscosity.
引文
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[14]Wictorin A, Hansson C. Allergic contact dermatitis from a bismuth compound in an eye ointment [J]. Contact Dermatitis,2001,45(5):318
[15]Wong J G, Bank A. Surgical removal of intraocular antibiotic ointment after routine cataract PHacoemulsification[J]. Cataract Refract Surg,2006,32:890-892
[16]Tilley H. A series of consecutive cases in which the mastoid has been operated on for acute suppurative inflammation, B.I.P. (bismuth, iodofonn, and liquid paraffin) inserted, and the external wound sutured in its entire length at the close of the Operation[J]. Proc R Soc Med, 1918,11:69-76
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[21]Brauninger G E. Kaufman H E. Tear film surface[J]. Ophthalmol,1972,73:132-134
[22]Kahook M Y. Developments in dosing aids and adherence devices for glaucoma therapy: current and future perspectives [J]. Expert Rev. Med. Dev,2007,4:261-266
[23]Ryser J E, Tabatabay C, Martenet M, et al. Precornealresidence time in humans of sodium hyaluronate as measured by gamma scintigraphy[J]. Graefes Arch Clin Exp Ophthalmol, 1990,228(6):510-512
[24]Laurent U B, Dahl L B, Liljia K. Hyaluronan injected in the anterior chamber of the eye is catabolized in the liver[J]. Exp Eye Res,1993,57:435-440
[25]Islam M T, Rodriguez Hornedo N, Ciotti S, et al. Rheological characterization of topical carbomer gels neutralized to different PH[J]. Pharm Res,2004,21(7):1192-1199
[26]Llabot J M, Manzo R H, Allemandi D A. Drug release from carbomencarbomer sodium salt matrices with potential use as mucoadhesive drug delivery system[J]. Int J Pharm,2004, 276(1-2):59-66
[27]Viriden A, Wittgren B, Andersson T, et al. Influence of substitution pattern on solution behavior of hydroxypropyl methylcellulose biomacromolecules[J].2009,10(3):522-529
[28]Aron Rosa D, Cohn H C, Aron J J, et al. Methylcellulose instead of healon in extracapsular surgery with intraocular lens implantation[J]. Ophthalmology,1983,90 (10):1235-1238
[29]Warshaw E M, Nelsen D D, Maibach H I, et al. Positive patch test reactions to lanolin: cross-sectional data from the north american contact dermatitis group,1994 to 2006[J]. Dermatitis,2009,20 (2):79-88
[30]Debbasch C, De La Salle S B, Brignole F, et al. Cytoprotective effects of hyaluronic acid and carbomer 934P in ocular surface epithelial cells[J]. Invest Ophthalmol Vis Sci,2002,43(11): 3409-3415
[31]Bu H Z, Gukasyan H J, Goulet L, et al. Ocular disposition, pharmacokinetics, efficacy and safety of nanoparticle formulated ophthalmic drugs[J]. Curr Drug Metab,2007,8(2):91-107
[32]Walker G F, Ledger R, Tucker I G. Carbomer inhibits tryptic proteolysis of luteinizing hormone-releasing hormone and N-alPHa-benzoyl-L-arginine ethyl ester by binding the enzyme[J]. Pharm Res,1999,16(7):1074-1080
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[35]Park W S, Chung Y S, Lee K E, et al. Anti-adhesive effect and safety of sodium hyaluronate and sodium carboxy methylcellulose solution in thyroid surgery[J]. Asian J Surg,2010,33(1): 25-30
[36]杨惠英,窦宏亮,王梅英2%HPMC对兔眼内压及角膜内皮影响的实验研究[J].眼科研究,1992,10(3)：164-166
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[1]谢立信.角膜移植学[M].北京：人民卫生出版社2000,35-36
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[8]Liu K R, Peyman G A, Khoobehi B. Efficacy of liposome-bound amphotericin B for the treatment of experimental fungal endophthalmitis in rabbits[J]. Invest Ophthalmol Vis Sci, 1989,30(7):1527-1534
[9]Nagarwal R C, Singh P N, Kant S, et al. Chitosan coated PLA nanoparticles for ophthalmic delivery:characterization, in-vitro and in-vivo study in rabbit eye[J]. J Biomed Nanotech-nol,2010,6(6):648-657
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[11]Zaupa A, Neffe AT, Pierce BF, et al.A molecular dynamic analysis of gelatin as an amorphous material: Prediction of mechanical properties of gelatin systems[J]. Int J Artif Organs,2011,34(2):139-151.
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[13]Malhotra M, Majumdar D K. Aqueous, oil, and ointment formulations o ketorolac:efficacy against prostaglandin E2-induced ocular inflammation and safety:a technical note[J]. AAPS Pharm Sci Tech,2006,7(4):96
[14]Wictorin A, Hansson C. Allergic contact dermatitis from a bismuth compound in an eye ointment [J]. Contact Dermatitis,2001,45(5):318
[15]Wong J G, Bank A. Surgical removal of intraocular antibiotic ointment after routine cataract PHacoemulsification[J]. Cataract Refract Surg,2006,32:890-892
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[1]谢立信.角膜移植学[M].北京：人民卫生出版社2000,35-36
[2]Li Y, Liu J, Pan D, et al. A study of the relationship between cornea permeability and eye irritation using membrane-interaction QSAR analysis[J]. Toxicological sciences,2005, 88(2):434-446
[3]Bishop A G, Tallon J M. Anticholinergic visual hallucinosis from atropine eye drops[J]. CJEM,1999,1(2):115-116
[4]Schoenwald R D, Zhu J. The ocular pharmacokinetics of ketanserin and its metabolite, ketanserinol, in albino rabbits[J]. Ocul Pharmacol Ther,2000,16(5):481-495
[5]Shin S H, Kim D S. Studies on the interfacial characterization of O/W emulsion for the optimization of its treatment[J]. Environ Sci Technol,2001,35(14):3040-3047
[6]Ji H, Yang Z, Jiang W, et al. Antiviral activity of nano carbon fallerene lipidosome against influenza virus in vitro[J]. Huazhong Univ Sci Technolog Med Sci,2008,28(3):243-246
[7]Singh K, Mezei M. Liposomal ophthalmic drug delivery system[J].Triamcinolone Acetoni-de Pharm,1983,16:339-344
[8]Liu K R, Peyman G A, Khoobehi B. Efficacy of liposome-bound amphotericin B for the treatment of experimental fungal endophthalmitis in rabbits[J]. Invest Ophthalmol Vis Sci, 1989,30(7):1527-1534
[9]Nagarwal R C, Singh P N, Kant S, et al. Chitosan coated PLA nanoparticles for ophthalmic delivery:characterization, in-vitro and in-vivo study in rabbit eye[J]. J Biomed Nanotech-nol,2010,6(6):648-657
[10]Meng Z X, Xu X X, Zheng W. et al. Preparation and characterization of electrospun PLGA/gelatin nanofibers as a potential drug delivery system[J]. Colloids Surf B Biointerfaces,2011,84(1):97-10 2.
[11]Zaupa A, Neffe AT, Pierce BF, et al.A molecular dynamic analysis of gelatin as an amorphous material: Prediction of mechanical properties of gelatin systems[J]. Int J Artif Organs,2011,34(2):139-151.
[12]Hui H W, Robinson J R. Ocular delivery of progesterone using a bioadhesive polymer[J]. Inter J PHarm,1985,26(3):203-213
[13]Dai L. Development of ion-sensitivity in-situ gel[R]. Zhongguo Zhong Yao Za Zhi,2009, 34 (5):515-518
[14]Gupta H, Velpandian T, Jain S. Ion- and pH-activated novel in-situ gel system for sustained ocular drug delivery[J]. Drug Target,2010,18(7):499-505
[15]Gupta H, Jain S, Mathur R, et al. Sustained ocular drug delivery from a temperature and pH triggered novel in situ gel system[J]. Drug Deliv,2007,14(8):507-515
[16]Sharp J, Hanna C. Use of a spray to delever drugs to the eyes[J]. Arkansas.med. soc,1997, 73:462-463
[17]Kang S W, Seo S K, Hill J M, et al. Changes in gene expression in latent HSV-1-infected rabbit trigeminal ganglia following epinephrine iontophoresis[J]. Curr Eye Res,2003,26: 225-229
[18]Harderger R E, Hanna.C, Goodart R. Effects of drug vehicles on ocular uptake of tetracycline[J]. Am.J.Ophthal,1975,80:133-138
[19]Scheie H G, Rubenstein A, Katowitz J A. Ophthalmic ointment bases in the anterior chamber[J]. Archs Ophthal,1965,73:36-42
[20]Robin J S, Ellis P P. Ophthalmic ointment[J]. Snee.Ophthal,1978,22:335-340
[21]Ralph R A, Doane M G, Dohlman C H. Clinical experience with a mobile ocular perfusion pump[J].Archs.Ophthal,1975,93:1039-1043
[22]Birmingham A T, Galloway N R, Spencer S A, et al. Continuous infusion of the conjunctival sac with pilocarpine in normal subjects and in patients with chronic glaucoma[J]. Trans ophthal Soc.U.K,1976,96:322-324
[23]Waltman S R, Kaufman H E. Use of hydrophilic contact lenses to increase ocular penetration of topical drugs[J]. Invest.Ophthal,1970,9:250-255
[24]Podos S M, Beckfr B, Assiff C, et al. Pilocarpine therapy with soft contact lenses[J]. Am. J.Ophthal,1972,73:336-341
[25]Friedlander P, Zimny M L. Effects of soft contacts of differing thickness on corneal wound healing in rabbits[J]. Invest Ophthalmol Vis Sci,1989,30(10):2138-2147
[26]Mizutani Y, Miwa Y. On the uptake and release of drugs by soft contact lenses[J]. Contact intraocular Lens med,1975,1:177-183
[27]Hillman J S. Management of acute glaucoma with pilocarpine-soaked hydrophilic lens[J]. Br. J.OPHthal,1974,58:674-679
[28]Kaufman H E, Votila M H, Casset A R, et al. The medical uses of soft contact lense[J]. Trans. Am.Acad.Ophthal.Otolar,1971,75:361-373
[29]Jasik-Slezak J, Slezak A. Relation between effective and real solute permeability coeffi-cients through polymeric membrane[J]. Polim Med,2010,40(2):29-36
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