CN1864688A - 青光眼的预防或治疗剂 - Google Patents
青光眼的预防或治疗剂 Download PDFInfo
- Publication number
- CN1864688A CN1864688A CNA2006100826303A CN200610082630A CN1864688A CN 1864688 A CN1864688 A CN 1864688A CN A2006100826303 A CNA2006100826303 A CN A2006100826303A CN 200610082630 A CN200610082630 A CN 200610082630A CN 1864688 A CN1864688 A CN 1864688A
- Authority
- CN
- China
- Prior art keywords
- glaucoma
- fluoro
- isoquinolinesulfonylcompounds
- nipradilol
- methyl isophthalic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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Abstract
本发明涉及具有强效降眼压作用，且能延长上述作用持续时间的青光眼或高眼压症的预防或治疗剂。该青光眼预防或治疗剂由(S)－(－)－1－(4－氟－5－异喹啉磺酰基)－ 2－甲基－1，4－高哌嗪或其盐与尼普地洛组合形成。
Description
技术领域
本发明涉及青光眼及高眼压症的预防或治疗剂。
背景技术
青光眼这种疾病由各种病因导致眼压升高、危害视觉神经使其萎缩、导致视野异常、使视力逐渐降低。视觉神经一旦发生萎缩，将不能恢复，因此患上青光眼而置之不理，不仅将导致失明，而且即使治疗成功，也仅是停留在保持现状的程度，而无望恢复，是一种疑难杂症。此外，尽管是未伴有视野异常的眼压高，但如果长期持续，还是很有可能发展成青光眼，所以也蕴含着同样的危险性。
青光眼分为先天性青光眼、继发性青光眼、原发性青光眼三类。先天性青光眼是一种因天生房角结构发育异常，阻塞房水排出而发病的青光眼。继发性青光眼是发炎、受伤等明显原因引发的青光眼，除了葡萄膜炎、眼部受伤等存在于眼部的原因之外，因糖尿病引发的出血、长期使用治疗其它病患时所用的甾类激素也有可能诱发青光眼。原发性青光眼是病因不明的青光眼疾患的总称，中老年人为多发人群，也是青光眼中患者最多的类型。根据房水流动的堵塞状况，原发性青光眼和继发性青光眼还分为房角开放型青光眼和房角闭塞型青光眼两类。此外，尽管存在着大量眼压不升高、眼压正常的青光眼发病患者，但无论如何，青光眼治疗的第一目标是降低眼压。
在药物不能控制眼压的情况下或在房角闭塞型青光眼患者的急性青光眼发病等情况下，尽管青光眼的治疗方法可采用激光治疗法(激光小梁成形术)或手术疗法(小梁切除术、小梁切开术)等，但青光眼的治疗方法的第一选择仍是采用药物疗法。
青光眼药物疗法使用的是交感神经刺激药(肾上腺素等的非选择性刺激药、阿可乐定(Apraclonidine)等α2刺激药、)、交感神经阻断药(噻吗洛尔、苯呋洛尔、卡替洛尔、尼普地洛、贝他洛尔(Betaxolol)、左布诺洛尔(Levobunolol)、美替洛尔(Metipranolol)等β-阻断药，盐酸布那唑嗪等α1阻断药)、拟副交感神经药(匹鲁卡品(pilocarpine)等)、碳酸酐酶抑制剂(乙酰唑胺等)、前列腺素类(异丙基乌诺前列酮、拉坦前列素(Latanoprost)、曲伏前列素(Travoprost)、比马前列素(Bimatoprost)等)。其中，尼普地洛是具有房水产生抑制作用和改善血液循环作用的药物，因此效用很高(非专利文献1)。
另一方面，人们发现Rho激酶抑制剂可根据新发现的作用机理作为青光眼治疗药剂的一种选择(专利文献1)。Rho激酶抑制剂促进房水从小梁流出通路的流出，从而降低眼压(非专利文献2)，并暗示其作用受到小梁细胞中细胞骨架的变化的影响(非专利文献2、非专利文献3)。本发明人等还发现异喹啉衍生物之一的(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪是功效很强的具有降低眼压作用的低分子化合物，并已就此作出了发明专利申请(专利文献2)。
此外，对于青光眼、高眼压症，为达到强化降眼压作用的目的，也与具有降眼压作用的药剂组合使用。例如，有报告表明存在将前列腺素类和交感神经阻断药组合施用(专利文献3)，或将具有降眼压作用的多种药剂组合施用于眼部等的青光眼的治疗方法(专利文献4)等，此外，还有将Rho激活酶抑制剂和β阻断药组合使用的青光眼治疗剂的技术方案(专利文献5)。
但是，上述已知的青光眼、高眼压症的治疗剂、治疗方法很难说可以满足降眼压效果的作用强度、持续时间等方面。特别在正常眼压下的青光眼，降低正常眼压比降低已上升的眼压更困难，上述现有药品或其组合在治疗正常眼压的青光眼方面仍有局限性，因此，从临床医学方面考虑，要求进一步增强降眼压作用。
【专利文献1】国际公开WO00/09162号小册子
【专利文献2】国际公开WO99/20620号小册子
【专利文献3】日本专利第2726672号公报
【专利文献4】国际公开WO02/38158号小册子
【专利文献5】日本特开2004-182723号公报
【非专利文献1】新眼科，16(4)，529-535
【非专利文献2】IOVS，42(1)，137-144(2001)
【非专利文献3】IOVS，42(5)，1029-1037(2001)
发明内容
本发明的目的在于，提供一种具有强效降眼压作用，且能延长作用的持续时间的青光眼或高眼压症的预防或治疗剂。
本发明人为解决上述问题而反复研究后，结果发现，(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪或其盐与尼普地洛组合施用，将可发挥出强效降眼压作用，并能延长上述作用的持续时间。
即，本发明涉及(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪或其盐与尼普地洛组合形成的青光眼的预防或治疗剂。
此外，本发明还涉及(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪或其盐与尼普地洛组合形成的高眼压症的预防或治疗剂。
发明效果
根据本发明，可提供具有强效降眼压作用，且能延长上述作用的持续时间的青光眼或高眼压症的预防或治疗剂。
附图说明
图1为各投药组的眼压随时间变化的示意图。眼压用相对于眼压初值的变化值(平均值±标准偏差)表示。
○：单独施用尼普地洛组
□：单独施用(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪组
△：尼普地洛与(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪混合施用组
*：p＜0.05vs.0小时
#：p＜0.05vs.尼普地洛滴眼组
$：p＜0.05vs.(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪滴眼组
具体实施方式
本发明所用的(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪是一种公知的具有P物质拮抗作用、白三烯D4拮抗作用以及Rho激酶抑制作用的化合物(日本特开平11-349482号公报)，可采用公知方法，例如国际专利公开第99/20620号公报所述的方法制造。
(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪盐可举出制药方面许可使用的盐，例如盐酸、硫酸、硝酸、氢氟酸、氢溴酸等无机酸的盐；或乙酸、酒石酸、乳酸、柠檬酸、富马酸、马来酸、琥珀酸、甲基磺酸、乙基磺酸、苯磺酸、甲苯磺酸、萘磺酸、樟脑磺酸等有机酸的盐，特别优选为盐酸盐。
该(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪或其盐不仅可以未溶剂化物的形态存在，也可以水合物或溶剂化物的形态存在。在本发明中，包括所有的结晶型和水合物或溶剂化物。
本发明所用的尼普地洛具有优异的β阻断作用，是一种已知的有效的高血压、心绞痛等循环系统疾病的治疗剂(日本特公昭60-54317号公报、日本特公平01-53245号公报)，可按照公知的方法，例如日本特公昭60-54317号公报所述的方法制造。此外，作为滴眼用制剂，可使用青光眼/高眼压症治疗剂“Hypadil兴和眼药水”(兴和株式会社)。
将(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪或其盐与尼普地洛组合使用的情况下，如后述实施例所述，确认其即使在正常眼压下也具有强效且持续时间得到延长的降眼压作用。因此，含有该组合物的医药品是一种有效的青光眼、高眼压症的预防或治疗剂。在此可举出的青光眼类型有，例如原发性房角开放型青光眼、正常眼压型青光眼、房水产生过多型青光眼、高眼压症、急性房角闭塞性青光眼、慢性房角闭塞性青光眼、高褶虹膜性症候群、混合型青光眼、类固醇性青光眼、水晶体囊肿性青光眼、色素性青光眼、淀粉样青光眼、血管增生性青光眼、恶性青光眼等。此外，高眼压症也被称为眼部高血压症，是指无论视神经是否被确认有明确的病变，都表现出异常高的眼压的症状，包括手术后表现出的高眼压等多种高眼压状态。
本发明的(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪或其盐与尼普地洛组合使用制成的青光眼以及高眼压症的预防或治疗剂，可以是按照适当的配比以其各自的有效配合量与配合剂配合制成的某种剂型，也可以是同时或空出一段时间间隔分别使用的含有各种有效量配合剂的药剂单独制成的制剂的套装品。
上述制剂优选用作眼科用制剂，特别优选用作滴眼剂。这类滴眼剂可以是水性滴眼剂、非水性滴眼剂、悬浊性滴眼剂、乳浊性滴眼剂、眼软膏中的任一种。本领域技术人员可采用公知的制造方法根据需要配合制药业允许使用的载体，例如等渗剂、螯合剂、稳定剂、pH值调节剂、防腐剂、抗氧化剂、助溶剂、增稠剂等，将这些制剂制成与施用状况相应的组合物。
等渗剂可举出葡萄糖、海藻糖、乳糖、果糖、甘露糖醇、木糖醇、山梨糖醇等糖类；甘油、聚乙二醇、丙二醇等多元醇类；氯化钠、氯化钾、氯化钙等无机盐类，其配合量优选为相对于组合物总量为0～5重量％。
螯合剂可举出乙二胺四乙酸二钠、乙二胺四乙酸钙二钠、乙二胺四乙酸三钠、乙二胺四乙酸四钠、乙二胺四乙酸钙等乙二胺四乙酸盐类；乙二胺四乙酸盐、氨三乙酸或其盐、六偏磷酸钠、柠檬酸等，其配合量优选为相对于组合物总量为0～0.2重量％。
稳定剂可举出亚硫酸氢钠等，其配合量优选为相对于组合物总量为0～1重量％。
pH值调节剂可举出盐酸、碳酸、乙酸、柠檬酸、磷酸、硼酸等酸类；以及氢氧化钠、氢氧化钾等碱金属氢氧化物，碳酸钠等碱金属碳酸盐或碳酸氢盐，乙酸钠等碱金属乙酸盐，柠檬酸钠等碱金属柠檬酸盐，氨丁三醇等碱类，其配合量优选为相对于组合物总量为0～20重量％。
防腐剂可举出山梨酸、山梨酸钾、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、对羟基苯甲酸丁酯等对羟基苯甲酸酯类；葡糖酸氯乙定(ダルコン酸クロルヘキシジン gluconic acidchlorhexidine)、氯化苄烷铵、苄索氯铵、氯化十六烷基吡啶鎓等季铵盐烷基聚氨基乙基甘氨酸、氯代丁醇、POLYQUAD(ポリクオ-ド)、聚六亚甲基双胍、氯已定(Chlorhexidine)等，其配合量优选为相对于组合物总量为0～0.2重量％。
抗氧化剂可举出亚硫酸氢钠、干燥亚硫酸氢钠、焦亚硫酸钠、浓缩混合生育酚等，其配合量优选为相对于组合物总量为0～0.4重量％。
助溶剂可举出苯甲酸钠、甘油、D-山梨糖醇、葡萄糖、丙二醇、羟丙基甲基纤维素、聚乙烯基吡咯烷酮、聚乙二醇(Macrogol)、D-甘露糖醇等，其配合量优选为相对于组合物总量为0～3重量％。
增稠剂可举出聚乙二醇、甲基纤维素、乙基纤维素、羧甲基纤维素钠、黄原胶、软骨素硫酸钠、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯基吡咯烷酮、聚乙烯醇等，其配合量优选为相对于组合物总量为0～70重量％。
调制滴眼剂时，可通过例如将预期的上述组分溶解或悬浊在杀菌后纯净水、生理食盐水等水性溶剂中；或棉籽油、大豆油、芝麻油、花生油等植物油等非水性溶剂中，调节到规定的渗透压，实施过滤杀菌等杀菌处理进行调制。而在调制滴眼软膏时，除上述各种成分之外，还可含有软膏基剂。上述软膏基剂没有特别限定，优选物可举出凡士林、液体石蜡、聚乙烯等油性基剂；用表面活性剂等将油相与水相乳化的乳剂性基剂；羟丙基甲基纤维素、羧甲基纤维素、聚乙二醇等水溶性基剂。
在将本发明的青光眼或高眼压症的预防或治疗剂制成套装剂时，可设计成将含有如上所述制成制剂的(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪或其盐的药剂与含有尼普地洛的药剂分别包装，施用时从各包装中取出各医药品制剂使用的形态。此外，各医药品制剂也可包装成适用于每次并用的形态。
在施用本发明的青光眼或高眼压症的预防或治疗剂时，其施用量因患者的体重、年龄、性别、症状、剂型以及服用次数等而异，通常，就成人而言，(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪或其盐的剂量范围可举出每日0.025～2000μg、优选为0.1～1000μg，尼普地洛的剂量范围可举出每日10～1250μg、优选为50～250μg。
对于服用次数没有特别限定，优选为1次或分成多次服用，在眼药水的形态下，每次可向眼部滴1滴～数滴。在套装剂的情况下，可同时施用各单独制剂，也可在间隔5分钟～24小时的间隔施用。
下面，对本发明进行更详细的说明，但本发明并不限于此。
【实施例】
实施例1
为研究(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪与尼普地洛组合的有效性，单独或两者并用向实验动物施用这两种药物，比较研究各情况下的降眼压效果。
1.受验化合物溶液的调制
A.(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪溶液的调制
将(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪一盐酸盐·二水合物溶解于生理盐水后，加入磷酸二氢钠、氢氧化钠，中和溶液(pH＝6.0)，调制成期望浓度的(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪溶液。
B.尼普地洛溶液的调制
直接使用市售尼普地洛眼药水。
2.试验方法
研究了并用(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪和尼普地洛时的降眼压效果。为进行比较对照，还研究了单独施用尼普地洛或单独施用(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪时的降眼压效果。
A.试验使用的药剂和动物
(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪溶液：1％溶液(滴眼剂量：50μl)
尼普地洛溶液：尼普地洛眼药水(商品名：Hypadil兴和，0.25％，滴眼剂量：50μl)
实验动物：日本白兔(系统：JW，性别：雄性，一组6～8只)
B.施用方法和测定方法
(1)两种药剂并用
1)将4％盐酸奥布卡因(Oxybuprocaine Hydrochloride)滴眼剂(商品名：ベノキシ一ル0.4％溶液)滴一滴到实验动物的两眼内，实施局部麻醉(仅取滴入眼的数据)。
2)在即将施用受验化合物溶液之前测量眼压，作为眼压初值。
3)将尼普地洛溶液滴入实验动物的某只眼内，然后将(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪溶液溶液滴入同一只眼内。
4)分别在向眼内滴加了两种药剂1小时、2小时、3小时、4小时、5小时后，向两眼中滴加一滴0.4％盐酸奥布卡因滴眼剂实施局部麻醉后，然后测量眼压。
(2)单独施用(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪
单独将(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪滴入眼内，在与上述同时施用试验相同的测量时间下进行试验。
(3)单独施用尼普地洛
不采用单独施用(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪作为受验溶液，而是采用单独施用尼普地洛溶液作为受验溶液，其它则按照与上述单独施用试验同样的方法进行试验。
3.结果及考察
试验结果如图1所示。显示出眼压从眼压初值的变化值。
根据图1所示可知，并用(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪和尼普地洛的试验组与单独施用药剂组，即单独施用(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪组或单独施用尼普地洛组相比，显示出更优异的降眼压作用，且显示出提高该作用的持久性的效果。
综上可知，通过将(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪和尼普地洛组合，就可得到更强的降眼压效果以及提高其持久性的效果。
Claims (6)
1.一种青光眼预防或治疗剂，其特征在于，由(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪或其盐与尼普地洛组合形成。
2.如权利要求1所述的青光眼预防或治疗剂，其特征在于，是一种配合剂。
3.如权利要求1所述的青光眼预防或治疗剂，其特征在于，是含有(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪或其盐的药剂与含有尼普地洛的药剂形成的套装剂。
4.一种高眼压症预防或治疗剂，其特征在于，由(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪或其盐与尼普地洛组合形成。
5.如权利要求4所述的高眼压症预防或治疗剂，其特征在于，是一种配合剂。
6.如权利要求4所述的高眼压症预防药剂或治疗剂，其特征在于，是含有(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1，4-高哌嗪或其盐的药剂与含有尼普地洛的药剂形成的套装剂。
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| CN106310285A (zh) * | 2015-06-15 | 2017-01-11 | 江苏吉贝尔药业股份有限公司 | 一种新的盐酸利舒地尔滴眼液及其制备方法 |
| CN107106570A (zh) * | 2014-12-12 | 2017-08-29 | 兴和株式会社 | 水性组合物 |
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| JP5530483B2 (ja) | 2014-06-25 |
| KR101333970B1 (ko) | 2013-11-27 |
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