CN1185009C - 眼用制剂 - Google Patents
眼用制剂 Download PDFInfo
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- CN1185009C CN1185009C CNB011124849A CN01112484A CN1185009C CN 1185009 C CN1185009 C CN 1185009C CN B011124849 A CNB011124849 A CN B011124849A CN 01112484 A CN01112484 A CN 01112484A CN 1185009 C CN1185009 C CN 1185009C
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Classifications
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- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract
本发明描述了一种水溶液形式的局部眼用制剂,该制剂含有环孢菌素、透明质酸或其一种盐和多乙氧基醚。
Description
本发明涉及含有环孢菌素的局部眼用制剂。
环孢菌素是一类具有许多药效性能的非极性环状寡肽。
更具体地说,已知它们具有免疫抑制和抗炎活性,并且已有报道其在促进或重建患有免疫调节的干性角膜结膜炎患者的泪腺眼泪分泌中是有效的。
大多数含有环孢菌素A和少数含有环孢菌素B到I的天然来源的环孢菌素能够从多孢霉菌(trichoderma polysporum)真菌中得到。
象许多类似物和异构体一样,环孢菌素也能够合成获得。
在环孢菌素中做过最广泛研究和用于药学的环孢菌素是环孢菌素A。
通过改善泪腺中环孢菌素的吸收能够促进环孢菌素特别是环孢菌素A在促进或重建泪腺的眼泪分泌的活性。
由于环孢菌素在水中的溶解度非常低(对环孢菌素A来说20-30μg/mL),所以很难制备含有溶于水介质中的环孢菌素的眼用组合物。
这也正是已知亲脂性的环孢菌素以油为主的制剂使用的原因。
US-A-4,839,342描述了一种局部眼用组合物,它含有环孢菌素,特别是环孢菌素A和赋形剂来增加患有由于泪腺机能障碍而眼睛缺乏眼泪的患者产生眼泪。具体描述的赋形剂是橄榄油、花生油、蓖麻油、聚乙氧基化的蓖麻油、矿物油、凡士林、二甲基亚砜、醇、脂质体、硅酮油或其混合物。
FA-A-2,638,089描述了一种局部眼用组合物,它含有环孢菌素作活性成分和植物油如橄榄油、花生油、蓖麻油、芝麻油和玉米胚油作载体,以及凡士林来治疗影响眼睛的疾病和免疫的或炎性症状,尤其是干性角膜结膜炎(KCS)或眼睛干燥。
尽管如此,以油为基质的眼用局部制剂具有许多缺点,如在眼睛中的不舒服的感觉,或者导致视力模糊。而且,所用的油会增强眼睛干燥的症状。
含有环孢菌素的油为基质的眼用局部制剂的物理形态也是不稳定的,这是因为环孢菌素容易发生形态变化并形成沉淀。
而且,这些制剂的生物利用度很差,眼睛的耐受性低,表现为刺激眼睛。
为了把上述一些缺点如使用的不舒适降到最小,并且改善药剂的生物利用度和耐受性,WO 95/31211建议减少油的用量并且把油相分散到水溶液中形成乳剂,得到一种以水和油为基质的乳剂形式的眼用局部制剂,含有环孢菌素并混有长链脂肪酸的甘油三酯如蓖麻油和多乙氧基醚。该制剂也含有乳化剂如Pemulen。
为了解决环孢菌素的沉淀问题同时改善该制剂的生物利用度和耐受性,US-A-5,951,971建议一种含水的眼用局部制剂,它不含油,含有0.01到0.075%(w/v)浓度的环孢菌素、水和0.1到3%(w/v)用量的表面活性剂,加入表面活性剂是为了改善环孢菌素在水中的溶解度并且选自于聚乙氧基化的烷基酯、多乙氧基化烷基苯基醚、多乙氧基化烷基醚及其混合物。按照US-A-5,951,971,已经发现也称为吐温80的多乙氧基醚不适合作表面活性剂,因为它缺乏可以足够高地把环孢菌素以所需浓度溶于水中的活性。
本发明的目的就是通过提供一种含有环孢菌素的水为基质的眼用局部制剂克服上述所有缺点尤其是物理稳定性问题且改善该制剂在结膜、角膜和泪腺中的生物利用度以及眼睛对该制剂的耐受性。
当发明人发现了当把本发明制剂局部给药到眼睛上时,在含有环孢菌素的含水眼用制剂中存在的透明质酸和多乙氧基醚可出人意料地使环孢菌素溶解同时又改善了该制剂在结膜、角膜和泪腺中的生物利用度和眼睛对该制剂的耐受性,从而达到了上述目的。
透明质酸是一种生物原广泛分布在自然的粘多糖。尤其是存在于不同动物组织如脐带、滑液、玻璃体、鸡冠和各种结缔组织如皮肤和软骨中。
从化学上讲,透明质酸是一种糖胺聚糖并且由形成分子量为13×106道尔顿的直链的不同的D-葡糖醛酸和N-乙酰-葡糖胺的重复基团组成。
透明质酸或其盐特别是透明质酸钠的药用已经在文献中进行了广泛的描述。由于透明质酸或其盐是非免疫物质并具有亲水和粘弹性能,它们作为眼睛玻璃体液或者作为眼科手术中的支持介质已经使用了许多年,正如在US-A-4,141,973中所描述的。
透明质酸在眼科中的其他用途也已经有过描述。
这样,EP-A-0,698,388描述了一种含水的眼用组合物,它含有0.05到2%浓度的透明质酸盐作为增加粘度的药剂,用作人工眼泪。
WO-A-89/017772描述了含有环孢菌素的油为基质的局部眼用组合物,目的是提高和重新建立泪腺的眼泪分泌。透明质酸已被加入作为添加剂或额外活性剂列入制剂的产品名单中。
本发明第一方面是一种水为基质的局部眼用制剂,它含有环孢菌素、透明质酸或其一种盐和多乙氧基醚。
本发明第二方面是环孢菌素与透明质酸或其一种盐与多乙氧基醚在制备局部眼用的水为介质的制剂方面的用途。
这样,本发明提供了一种水溶液形式的眼用制剂,其中环孢菌素以胶粒的形式溶解,该制剂稳定并且在结膜、角膜、泪腺和含水体液中具有良好的生物利用度以及眼睛对环孢菌素溶于水-油乳剂中的制剂具有显著改善的耐受性。
本发明的其他优点将从下列详细描述的说明书中逐渐阐明。
在本申请中,应当把术语“环孢菌素”理解为包括环孢菌素类中的任何一个,除非规定特殊的环孢菌素。
也必须注意在本申请中,术语“透明质酸”分别指酸形式或一种盐形式的透明质酸。
按照本发明,本发明制剂含有环孢菌素、透明质酸或其盐中的一种和多乙氧基醚。
本发明的制剂优选含有0.02-2%(重量)环孢菌素、0.01-2%(重量)透明质酸或其盐中的一种和0.5-40%(重量)多乙氧基醚,以该制剂的总重量为准。
本发明制剂中所含的环孢菌素能够是天然来源的或合成的。
按照一个优选的实施方案,制剂中所含的环孢菌素是环孢菌素A。
一种能够用来制备本发明制剂的环孢菌素A是例如由瑞士的SIGMA供应的商用环孢菌素A。
制剂中所含的透明质酸能够是它的酸形式或它的一种盐形式如透明质酸的碱金属盐或碱土金属盐,例如透明质酸钠、透明质酸钾、透明质酸镁、透明质酸钙或其它盐。
透明质酸或其盐优选具有的重均分子量不低于1,000,000道尔顿,更优选在1,300,000-3,000,000道尔顿范围的重均分子量。该分子量优选约1,700,000道尔顿。
透明质酸优选是透明质酸钠。
也称为吐温-80的多乙氧基醚是一种已知可用作表面活性剂的聚乙氧基化的山梨醇单油酸酯。
用于制备本发明制剂的多乙氧基醚是例如由SIGMA供应的商用多乙氧基醚。
在特别优选的实施方案中,该组合物含有0.2%(重量)环孢菌素A、0.1%(重量)透明质酸或其一种盐和5%(重量)多乙氧基醚,以该制剂的总重量为准。
本发明制剂还可包括添加剂如用作等渗剂的山梨糖醇。山梨糖醇具有流体动力学体积大于NaCl的优点。其它可能的添加剂是甘露糖醇、多元醇和氯化钠和氯化钾。
为了本发明制剂在生理上可接受,它优选pH值在6.5到7.5的范围,并且渗透摩尔浓度在290到310mosm/L范围内,优选300mosm/L.
本发明制剂能够包装成单一剂量。
本发明的局部制剂可以滴液的形式给予眼睛,并且用于提供或重新建立泪腺的眼泪分泌,也可以用于刺激或重新建立泪腺的作用,尤其是对患有干性角膜结膜炎、眼睛干燥症状、斯耶格伦综合征、慢性青春角膜结膜炎患者和作为角膜成形术中的手术预防剂。
下列实施例是为了详细说明本发明及其优点。不能认为它们是用来限定本发明的范围。
实施例
下列表1列出了本发明的制剂例。
对照制剂1是不含环孢菌素的对照制剂。
表1
制剂组分 | 1 | 2 | 3 | 4 | 5 | 对照1 |
环孢菌素A(%) | 0.02 | 0.10 | 0.20 | 0.50 | 2.00 | -- |
透明质酸钠(%) | 0.05 | 0.10 | 0.10 | 0.10 | 0.20 | 0.10 |
吐温80(%) | 0.05 | 2.50 | 5.00 | 10.00 | 20.00 | 5.00 |
Na2HPO4.12H2O(%) | 0.08 | 0.08 | 0.08 | 0.10 | 0.15 | 0.08 |
山梨糖醇(%) | 5.46 | 5.35 | 5.16 | 4.70 | 3.76 | 5.25 |
纯化水加至 | 100mL | 100mL | 100mL | 100mL | 100mL | 100mL |
pH | 7.0-7.4 | 7.0-7.4 | 7.0-7.4 | 7.0-7.4 | 7.3-7.4 | 7.0-7.4 |
mosm/L | 295-305 | 295-305 | 295-305 | 295-305 | 295-305 | 295-305 |
为了评估眼睛的耐受性,把制剂1-5和对照1用于试验,并且制剂1-5用于稳定性试验。
制剂1-5和对照1的眼睛耐受性
用来自新西兰的白化体兔(每组6只,3只雄性和3只雌性)进行了制剂1到5和对照1的局部耐受性的评估,在30分钟的间隔内把12滴0.1mL各种试验制剂给药到右边结膜弓形组织中。
按照Draize试验评估眼睛组织的条件(S.C.Gad和C.P.Chengelis,“眼部刺激试验”,在急性毒性试验,Telford出版社,Caldewell NJ USA,第51-80页)。在最后滴注30分钟后进行试验。由两名完全不知道治疗的观察者进行读数为结膜(睑和眼球)、角膜和虹膜的状况给出独立分数。
按照下列步骤使接受治疗的眼睛也经受荧光素试验。被测制剂的最后滴注40分后,和Draize试验后,把含有2%荧光素的生理盐水溶液滴入测试眼睛中,多余的荧光素用无菌生理盐水冲洗眼睛来去除。然后仔细观察眼部组织来评价已经吸收的荧光素的量。就这种评价来说,用缝隙灯,它显示所有制剂具有良好的耐受性,即,含有环孢菌素A的制剂1到5和不含环孢菌素A的对照制剂1。
在Draize试验中,角膜和虹膜总具有正常外观。发现结膜正常而没有浮肿或分泌物,除了分别用含有0.20、0.5和2%环孢菌素A的制剂3、4和5治疗的三组兔中的每只外,六只治疗眼中的两只在中心区具有血管充血,按照评估试验反映出平均较好的耐受性。
在荧光素的试验中,不同制剂间没有差异;没有一只治疗眼吸收了荧光素。
本发明制剂1到5的稳定性
现已发现室温下所有制剂都是稳定的,在制备制剂12个月内制剂1到5中没有一个出现环孢菌素A的沉淀。
在环孢菌素A在眼部组织中的生物利用度和眼睛耐受性方面,把本发明的制剂3与水包油型乳剂进行了比较。
本发明制剂3和水包油型乳剂的比较
就眼睛耐受性和环孢菌素A在眼部组织中生物利用度方面,把本发明的制剂3与称作CYCLOIL的水包油型乳剂进行了比较,其中CYCLOIL是WO-A-95/31211中的制剂。
下列表2中总结了这两种制剂的组合物。
表2
制剂组成 | 3 | CYCLOIL |
环孢菌素A(%) | 0.20 | 0.20 |
透明质酸钠(%) | 0.10 | -- |
蓖麻油(%) | -- | 1.25 |
吐温80(%) | 5.00 | 1.00 |
甘油(%) | -- | 2.00 |
PemulenTR-2(%) | -- | 0.05 |
Na2HPO4.12H2O(%) | 0.08 | -- |
山梨糖醇(%) | 5.16 | -- |
纯化水加至 | 100mL | 100mL |
pH | 7.0-7.4 | 7.0-7.4 |
mosm/L | 295-305 | 290-310 |
眼部生物利用度
在该试验中,把两种制剂即,本发明的制剂3和CYCLOIL局部给药后,测定结膜、角膜、含水体液和泪腺中的环孢菌素A的浓度。
用来自新西兰的雄性白化体兔进行试验。把兔分为两组,每组15只并用试验的两种制剂每只眼50μL治疗双眼。在滴注后1、3、6、12和24小时后杀死动物,取结膜、角膜、含水体液和泪腺作为样本,每次从两组中取三只兔。摘出眼睛并在取出含水体液(大约400μL)、角膜(大约120mg)、结膜(大约120mg)和泪腺(约800mg)前用生理盐水冲洗。
通过使用isocratic洗脱液的反相HPLC和UV-光谱检测得到环孢菌素A的定量测定。色谱层析是Varian仪器,色谱层析条件如下:
- 柱:C18.60×4.6mm,3μm(Alltech)
- 流动相:乙腈/异丙醇/H2O(66/2/32)
- 流速:0.7mL/分钟
- 柱温度:72℃
- 测定:UV205nm(0.1-0.002AUFS)
- 注射量:25-50μL
- 保留时间:9.1分钟
如下制备色谱层析的样本:
含水体液
向300μL含水体液中加入150μL乙腈,把这样得到的溶液涡式搅拌大约1分钟,然后以3000g离心3分钟分离。把上清液转入瓶中,用15mg ZnSO4和15mg CdSO4处理,涡式搅拌1分钟,并以2000g离心2分钟分离。把有机相滤过0.45μm,并向柱中注射50到75μL。
角膜、结膜和泪腺
把组织精确称量,在低温下用甲醇(大约1.0mL)搅匀,以3000g离心分离15分钟,用甲醇(大约1mL)提取上清液并在大约40℃真空干燥,用乙腈(150μL)萃取残余物,用无水(NH4)2SO4处理,涡式搅拌1分钟,并以2000g离心分离2分钟。把有机相滤过0.45μm,并向柱上注射50到75μL。
分析方法
环孢菌素A在兔的结膜、角膜。泪腺和含水液体中的浓度列在表3到6。
环孢菌素A在结膜中的浓度
下列表3显示了在把本发明的制剂3和CYCLOIL滴注50μL到治疗兔两眼的结膜囊中1、3、6、12和24小时后结膜中环孢菌素A的浓度(ng/g)。
表3
制剂3(本发明) | CYCLOIL(对照) | |
滴注1小时后的浓度(ng/g) | 1170±170 | 820±155 |
滴注3小时后的浓度(ng/g) | 900±215 | 713±187 |
滴注6小时后的浓度(ng/g) | 616±102 | 370±78 |
滴注12小时后的浓度(ng/g) | 502±95 | 250±70 |
滴注24小时后的浓度(ng/g) | 198±40 | 75±25 |
AUC0-24(ng g-1 h-1) | 12483±234 | 7378±1891 |
Cmax(ng/g) | 1170±170 | 820±155 |
Tmax(小时) | 1 | 1 |
人们从上表3能够看出本发明的制剂3与制剂CYCLOIL相比,保证了给样后所有时间点结膜中的环孢菌素有更好的生物利用度。
尽管人们可以假设在滴注后马上可以发现环孢菌素在结膜中的最高浓度,但是只有在1小时后才能发现最大浓度。
本发明水为基质的制剂3与油包水型乳剂CYCLOIL相比保证环孢菌素A的浓度在所有样本中都是较高的。
本发明制剂3的AUC(曲线下的面积)是12483±234ng g-1 h-1,水包油型乳剂CYCLOIL是7378±1891ng g-1 h-1。
在角膜中得到相同结果。
在角膜中环孢菌素A的浓度
表4显示了在把本发明的制剂3和CYCLOIL滴注50μL到治疗兔两眼的结膜囊中1、3、6、12和24小时后角膜中环孢菌素A的浓度(ng/g)。
表4
制剂3(本发明) | CYCLOIL(对照) | |
滴注1小时后的浓度(ng/g) | 2995±750 | 2070±1115 |
滴注3小时后的浓度(ng/g) | 3350±920 | 1991±630 |
滴注6小时后的浓度(ng/g) | 2520±870 | 2420±870 |
滴注12小时后的浓度(ng/g) | 2228±490 | 1825±690 |
滴注24小时后的浓度(ng/g) | 1590±220 | 450±190 |
AUC0-24(ng g-1 h-1) | 53800±13070 | 38097±1397 |
Cmax(ng/g) | 3350±920 | 2420±870 |
Tmax(小时) | 3 | 6 |
从上表4中可以看出本发明制剂3是3小时后得到药物最大浓度(3350±920ng/g),CYCLOIL是6小时后得到最大药物浓度(2420±870ng/g)。
本发明水为基质的制剂3保证了环孢菌素A的浓度在所有样本中总是比用水包油型乳剂CYCLOIL高。
泪腺中环孢菌素A的浓度
表5显示了在把本发明的制剂3和CYCLOIL滴注50μL到治疗兔两眼的结膜囊中1、3、6、12和24小时后泪腺中环孢菌素A的浓度(ng/g)。
表5
制剂3(本发明) | CYCLOIL(对照) | |
滴注1小时后的浓度(ng/g) | 88±29 | 22±10 |
滴注3小时后的浓度(ng/g) | 149±45 | 42±16 |
滴注6小时后的浓度(ng/g) | 135±33 | 53±18 |
滴注12小时后的浓度(ng/g) | 54±22 | 21±10 |
滴注24小时后的浓度(ng/g) | 38±19 | 17±10 |
AUC0-24(ng g-1 h-1) | 1826±616 | 668±286 |
Cmax(ng/g) | 149±45 | 53±18 |
Tmax(小时) | 3 | 6 |
本发明水为基质的制剂3第3小时显示了环孢菌素A的最大浓度(149±45ng/g),而CYCLOIL第6小时显示了环孢菌素A的最大浓度(53±16ng/g)。
正如所期望的,表5中所报导的泪腺中环孢菌素A的浓度明显低于结膜和角膜中所得到的,但仍然总是超过该方法敏感度的界限(15ng/g)。
从以上可以看出,本发明制剂3的生物利用度远远高于CYCLOIL的,而且在滴注24小时后环孢菌素A仍然以低浓度但可以测出的低浓度存在。表示生物利用度之比的AUCAN-023/AUCcycloil大约是3。
环孢菌素A在含水体液中的浓度
表6显示了在把本发明的制剂3和CYCLOIL滴注50μL到治疗兔两眼的结膜囊中1、3、6、12和24小时后含水体液中环孢菌素A的浓度(ng/g)。
表6
制剂3(本发明) | CYCLOIL(对照) | |
滴注1小时后的浓度(ng/g) | 40±12 | 12±13 |
滴注3小时后的浓度(ng/g) | 41±14 | 18±7 |
滴注6小时后的浓度(ng/g) | 31±8 | 22±11 |
滴注12小时后的浓度(ng/g) | 27±9 | 16±4 |
滴注24小时后的浓度(ng/g) | 16±5 | 14±2 |
AUC0-24(ng g-1 h-1) | 641±14 | 390±119 |
Cmax(ng/g) | 41±14 | 22±11 |
Tmax(小时) | 3 | 6 |
在第3小时出现了所滴注的含水制剂(本发明的制剂3)的环孢菌素的最大浓度(41±14ng/mL),而油为基质的乳剂CYCLOIL在第6小时出现了最大浓度(22±11ng/mL)。
通过滴注50μL的两种试验制剂治疗的兔的含水体液中环孢菌素A的浓度证实其比组成眼睛表面的两种组织(角膜和结膜)中的相对低。对含水体液来说,象其他眼睛组织一样,作为含水制剂的给药环孢菌素的生物利用度高于油包水型乳剂所滴注的环孢菌素生物利用度。
耐受性的评价
按照如前所述的改良的Draize试验已经评价了本发明制剂3的耐受性。
把两组动物,每组6只,各含有来自新西兰的3织雄性和3织雌性白化体的兔子。通过在6小时每隔30分钟进行2种试验制剂0.1mL 12滴的给药治疗眼睛。
最后滴注后30分钟开始评价耐受性的Draize试验。该试验后,滴注后40分钟,进行荧光素试验。这两种试验的结果报告在表7和8中。
在下列表7中,按照Draize试验报导了把本发明制剂3和CYCLOIL滴注到右眼治疗的兔子结膜的红肿程度。
表7
兔编号 | 性别 | 制剂 | 结膜变红的程度 |
123456 | 雄性雄性雄性雌性雌性雌性 | 333333 | 011000 |
平均 | 0.33±0.52 | ||
频率 | 2/6 | ||
789101112 | 雄性雄性雄性雌性雌性雌性 | CYCLOILCYCLOILCYCLOILCYCLOILCYCLOILCYCLOIL | 112110 |
平均 | 1.00±0.63 | ||
频率 | 5/6 |
可以看出本发明制剂3在6只中仅有2只出现红肿,并伴有中心区的某些充血,同时油为基质的CYCLOIL显示出6只兔子有5只的频率。用CYCLOIL红肿程度在4只兔子中较弱,但滴注1小时后,一只兔子出现绯红色的分散性充血,各血管很难分辨。
没有一只兔子出现浮肿或高于结膜正常分泌物。
下列表8中报导了把本发明制剂3和CYCLOIL滴注到右眼治疗的兔子虹膜的充血程度。用独立刻度帮助评价虹膜的充血。以30分钟的间隔给药治疗12次。最后滴注30分钟开始评价。
表8
兔编号 | 性别 | 制剂 | 结膜变红的程度 |
123456 | 雄性雄性雄性雌性雌性雌性 | 333333 | 001000 |
平均 | 0.17±0.41 | ||
频率 | 1/6 | ||
789101112 | 雄性雄性雄性雌性雌性雌性 | CYCLOILCYCLOILCYCLOILCYCLOILCYCLOILCYCLOIL | 011010 |
平均 | 0.50±0.55 | ||
频率 | 3/6 |
用本发明制剂3治疗组中只有一只兔子在虹膜的第二血管表现出非常轻度的充血并且在第四血管上没有出现。
用CYCLOIL治疗组中6只中有3只出现非常轻度的充血。
表9中显示了用本发明制剂3和CYCLOIL滴注到右眼治疗的兔子角膜的混浊程度。按照独立刻度评价混浊。每隔30分钟给药治疗12次。最后滴注后30分钟开始评价。
表9
兔编号 | 性别 | 制剂 | 结膜变红的程度 |
123456 | 雄性雄性雄性雌性雌性雌性 | 333333 | 000000 |
平均 | 0 | ||
频率 | 0/6 | ||
789101112 | 雄性雄性雄性雌性雌性雌性 | CYCLOILCYCLOILCYCLOILCYCLOILCYCLOILCYCLOIL | 001000 |
平均 | 0.17±0.41 | ||
频率 | 1/6 |
用CYCLOIL治疗组中仅有一只兔子显示了角膜分散的混浊区,但是虹膜仍然有良好的可见性。
下列表10报导了用本发明制剂3和CYCLOIL滴注到右眼治疗的兔子角膜上皮吸收荧光素的程度。按照独立刻度评价吸收。每隔30分钟给药治疗12次。最后滴注后40分钟开始评价。
表10
兔编号 | 性别 | 制剂 | 结膜变红的程度 |
123456 | 雄性雄性雄性雌性雌性雌性 | 333333 | 010010 |
平均 | 0.33±0.52 | ||
频率 | 2/6 | ||
789101112 | 雄性雄性雄性雌性雌性雌性 | CYCLOILCYCLOILCYCLOILCYCLOILCYCLOILCYCLOIL | 012100 |
平均 | 0.67±0.82 | ||
频率 | 3/6 |
可以看出在荧光素试验中本发明制剂3也有更好地耐受。实际上用CYCLOIL治疗组的三个角膜已经吸收了荧光素,其中之一,第9号兔出现了恶化的荧光素的斑点,即使各种组织的结构仍然可以分辨,如果使用适当的光照,忽略了损失细节。
用本发明制剂3治疗的6只兔子中仅有2只具有稀有的少量的荧光斑点,但在瞳孔外周见不到着色。
这样上述结果清楚地证实本发明的含水制剂比水包油型乳剂不仅有更好的耐受性,而且有更高的生物利用度,水包油型乳剂基于蓖麻油、吐温80(多乙氧基醚)、甘油和PemulenTR-2(CYCLOIL)。
Claims (21)
1.水溶液形式的局部眼用制剂,它含有环孢菌素、透明质酸或其盐中的一种和多乙氧基醚。
2.按照权利要求1所述的制剂,其特征在于它含有0.02-2%(重量)环孢菌素、0.01-2%(重量)透明质酸或其一种盐和0.5-40%(重量)多乙氧基醚,以制剂的总重量为准。
3.按照权利要求1所述的制剂,其特征在于环孢菌素是环孢菌素A。
4.按照权利要求1所述的制剂,其特征在于透明质酸或其盐重均分子量不低于1,300,000道尔顿。
5.按照权利要求4所述的制剂,其特征在于透明质酸或其盐具有重均分子量在1,300,000-3,000,000道尔顿之间。
6.按照权利要求1所述的制剂,其特征在于透明质酸是以透明质酸的碱金属或碱土金属盐的形式存在的。
7.按照权利要求6所述的制剂,其特征在于透明质酸是以透明质酸钠的形式存在的。
8.按照权利要求2所述的制剂,其特征在于它含有0.2%(重量)环孢菌素A、0.1%(重量)透明质酸或其一种盐和5%(重量)多乙氧基醚,以制剂的总重量为准。
9.按照权利要求1所述的制剂,其特征在于它还含有添加剂。
10.环孢菌素与透明质酸或其一种盐和多乙氧基醚用于制备水溶液形式的局部眼用制剂的用途。
11.按照权利要求10所述的用途,其中该制剂含有0.02-2%(重量)环孢菌素、0.01-2%(重量)透明质酸或其一种盐和0.5-40%(重量)多乙氧基醚,以制剂的总重量为准。
12.按照权利要求10所述的用途,其特征在于环孢菌素是环孢菌素A。
13.按照权利要求10所述的用途,其特征在于透明质酸或其盐重均分子量不低于1,300,000道尔顿。
14.按照权利要求13所述的用途,其特征在于透明质酸或其盐重均分子量在1,300,000-3,000,000道尔顿之间。
15.按照权利要求10所述的用途,其特征在于透明质酸是以透明质酸的碱金属或碱土金属盐的形式存在的。
16.按照权利要求15所述的用途,其特征在于透明质酸是以透明质酸钠的形式存在的。
17.按照权利要求10所述的用途,其特征在于该制剂用于治疗干性角膜结膜炎(KCS)。
18.按照权利要求10所述的用途,其特征在于该制剂用于治疗斯耶格伦综合征。
19.按照权利要求10所述的用途,其特征在于该制剂用于治疗眼睛干燥综合征。
20.按照权利要求10所述的用途,其特征在于该制剂用于治疗慢性青春角膜结膜炎。
21.按照权利要求10所述的用途,其特征在于该制剂用作角膜成形术中手术后的预防剂。
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US592048A (en) * | 1897-10-19 | Drill-press | ||
DE3851152T2 (de) * | 1987-09-03 | 1995-01-26 | Univ Georgia | Cyclosporin-augenmittel. |
CA1340994C (en) * | 1989-09-21 | 2000-05-16 | Rudolf Edgar Dr. Falk | Treatment of conditions and disease |
JPH0558906A (ja) * | 1991-09-06 | 1993-03-09 | Sankyo Co Ltd | シクロスポリン点眼製剤 |
EP0642332B1 (en) * | 1992-05-13 | 1997-01-15 | Sandoz Ltd. | Ophthalmic compositions containing a cyclosporin |
US5474979A (en) * | 1994-05-17 | 1995-12-12 | Allergan, Inc. | Nonirritating emulsions for sensitive tissue |
RU2119351C1 (ru) * | 1994-06-01 | 1998-09-27 | Юхан Корпорейшн | Иммуносупрессорная композиция, содержащая циклоспорин, и способ ее получения |
JPH1160505A (ja) * | 1997-05-20 | 1999-03-02 | Senju Pharmaceut Co Ltd | 防腐組成物 |
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- 2001-03-23 AT AT01107223T patent/ATE250924T1/de active
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- 2001-04-04 CZ CZ20011229A patent/CZ294385B6/cs not_active IP Right Cessation
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IL142268A (en) | 2007-08-19 |
PT1142566E (pt) | 2004-02-27 |
SK4602001A3 (en) | 2001-11-06 |
JP2001316284A (ja) | 2001-11-13 |
US6953776B2 (en) | 2005-10-11 |
US20040106546A1 (en) | 2004-06-03 |
PL201055B1 (pl) | 2009-03-31 |
CZ294385B6 (cs) | 2004-12-15 |
AU3340401A (en) | 2001-10-11 |
CN1317342A (zh) | 2001-10-17 |
ZA200102769B (en) | 2001-10-05 |
CA2342133A1 (en) | 2001-10-07 |
IL142268A0 (en) | 2002-03-10 |
US6677304B2 (en) | 2004-01-13 |
DK1142566T3 (da) | 2004-02-09 |
AU778858B2 (en) | 2004-12-23 |
EP1142566A1 (fr) | 2001-10-10 |
CA2342133C (en) | 2011-02-01 |
ATE250924T1 (de) | 2003-10-15 |
EP1142566B1 (fr) | 2003-10-01 |
TR200302105T4 (tr) | 2004-02-23 |
DE60100866T2 (de) | 2004-07-29 |
PL346926A1 (en) | 2001-10-08 |
BR0101332A (pt) | 2001-11-06 |
DE60100866D1 (de) | 2003-11-06 |
US20010041671A1 (en) | 2001-11-15 |
CZ20011229A3 (cs) | 2001-11-14 |
AR028291A1 (es) | 2003-04-30 |
ES2206363T3 (es) | 2004-05-16 |
SK285220B6 (sk) | 2006-09-07 |
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