CN106604730A - 角膜厚度调节剂 - Google Patents
角膜厚度调节剂 Download PDFInfo
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- CN106604730A CN106604730A CN201580045385.6A CN201580045385A CN106604730A CN 106604730 A CN106604730 A CN 106604730A CN 201580045385 A CN201580045385 A CN 201580045385A CN 106604730 A CN106604730 A CN 106604730A
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- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
本发明提供新的角膜厚度调节剂。本发明涉及含有1‑(4‑氟‑5‑异喹啉磺酰基)‑2‑甲基‑1,4‑高哌嗪或其盐或它们的溶剂合物而形成的角膜厚度调节剂。
Description
技术领域
本发明涉及角膜厚度调节剂。更详细而言,本发明涉及含有以1-(4-氟-5-异喹啉磺酰基)-2-甲基-1,4-高哌嗪或其盐或它们的溶剂合物为有效成分而形成的角膜厚度调节剂。
背景技术
角膜是与巩膜一起构成眼球壁的重要组织,同时,角膜作为透明组织,也是将外界影像引入眼内的入口。角膜与其它活体组织不同,没有血管,是透明的,两面形成光滑的球面。角膜外侧的表面由泪液层覆盖,内侧与充满房水的前房连接。
角膜的厚度在中央部约为500μm,从外向内由角膜上皮、Bowman膜(Bowmanmembrane)、基质、Descemet膜(Descemet membrane)和内皮5层构成。角膜上皮层为角膜整体厚度的约10%,由角膜上皮细胞形成。在角膜上皮产生损伤的情况下,周围的上皮细胞移动、增殖,修复损伤部分。角膜基质占据角膜整体厚度的约90%。角膜基质的主要成分是胶原蛋白,另外含有粘多糖。该粘多糖为吸水性的,始终吸收水分膨胀(膨润)。但是,由于角膜内皮的泵功能和屏障功能,角膜基质的含水率总是保持恒定。
角膜内皮由角膜内皮细胞构成,因为人的角膜内皮细胞不进行细胞***,所以一旦脱落不会再生。如果人的角膜内皮细胞受到损伤脱落缺损,则不可能通过增殖修复,结果,周围的内皮细胞移动伸展,形成了新的细胞粘连,修补缺损部。因此,人的角膜内皮细胞的粘附性成为用于损伤部位的修复的重要功能。同时,如果损伤变得严重,那么,通过有限的细胞数的修复变得不可能,可在角膜内皮上形成缺损部位。如果在角膜内皮上形成缺损部位,则成为不可逆性的严重的功能不全。具体而言,如果角膜内皮细胞的密度成为约500个/mm2以下,则不可能修复角膜内皮的缺损部位,在角膜产生水肿(大泡性角膜病变),形成不可逆性的混浊。另外,正常的角膜内皮细胞的密度约为2500~3000个/mm2。
角膜内皮细胞具有从吸收水膨润的角膜基质将水向前房排出的泵功能以及控制水从前房向角膜基质移动的屏障功能。如果角膜内皮细胞的这些功能下降,则角膜基质变为含有过剩的水分,不仅角膜的厚度增加,还会有水肿(大泡性角膜病变)产生,变为不可逆性的浑浊,视力变得极度下降。角膜的膨润使角膜的厚度增加,以至于引起水肿的发生,因此,有必要薄化角膜、防止角膜膨润。
角膜内皮的功能不全被认为占角膜的功能不全整体的约60%。如果通过物理性的障碍和进行性的角膜内皮营养不良(代表性的有,富克斯角膜内皮营养不良(Fuchscorneal dystrophy))等,产生角膜内皮缺损,则成为产生不可逆的角膜水肿的大泡性角膜病变(bullous keratopathy)。在视力下降显著的情况下,需要角膜移植。
人的角膜内皮细胞在活体内不进行细胞***,是通过体外(In vitro)培养进行了研究(参见非专利文献1和非专利文献2)。因为将在体外(In vitro)培养增殖的人的角膜内皮细胞移植至角膜进行治疗已经成为可能。
由此,不仅期望开发用于促进角膜内皮细胞的粘附性并且修复角膜内皮的损伤部位的药剂以及用于维持和恢复角膜内皮的功能的药剂,而且期望开发用于培养增殖人的角膜内皮细胞的培养液以及用于保存直至移植的角膜内皮细胞和角膜内皮组织的保存液,进一步期望开发调节角膜厚度的药剂等。
Rho激酶(Rho关联含卷曲螺旋蛋白激酶:ROCK)是分子量约160kDa的丝氨酸/苏氨酸磷酸化酶,其基因从线虫和果蝇等低等动物至人等广泛保有。Rho激酶不仅参与平滑肌细胞的收缩,还参与细胞的形态控制、迁移和基因表达的控制等生理功能,开发Rho激酶抑制剂作为循环***疾病等的治疗药正在被推进。
同时,近年来,作为青光眼治疗等的用于眼病的局部给药也被开发出来。进一步地,在角膜内皮细胞的培养方面,有报告称,在Rho激酶抑制剂的1种(+)-反式-4-(1-氨乙基)-1-(4-吡啶氨基羰基)环己烷(以下简称Y-27632)的存在下,可以培养兔角膜内皮细胞(参见非专利文献3和非专利文献4),有报告称,同样可以培养猴角膜内皮细胞(参见专利文献1)。在专利文献1中,报告称1-(5-异喹啉磺酰基)-1,4-高哌嗪(以下,简称法舒地尔)促进兔角膜内皮细胞的粘着性。并且,有报告称,对兔角膜内皮损伤使用Y-27632进行处理(参见非专利文献5)以及在人的富克斯角膜内皮营养不良中使用Y-27632的治疗(参见非专利文献6)。同时,也有报告称,对兔角膜内皮损伤使用(R)-(+)-N-(1H-吡咯并[2,3-b]吡啶-4-基)-4-(1-氨乙基)苯甲酰胺(以下简称Y-39983)进行处理(参见专利文献2和非专利文献7)。根据非专利文献7,Y-39983和Y-27632对Rho激酶的50%抑制浓度(IC50)分别为0.0036μM和0.11μM,具有约30倍的差异,提出该差异是否造成对角膜内皮细胞活性的差异。
这些文献所使用的Y-27632和Y-39983都是N-吡啶酰胺系化合物,而法舒地尔是1-磺酰基-1,4-高哌嗪系化合物。
另一方面,1-(4-氟-5-异喹啉磺酰基)-2-甲基-1,4-高哌嗪(以下简称化合物A)与法舒地尔一样是1-磺酰基-1,4-高哌嗪系化合物,据记载,与法舒地尔相比,其更具有选择性,Rho激酶抑制活性也比法舒地尔强,有报告称,对哮喘的预防和治疗是有用的(参见专利文献3的化合物6)。在专利文献3中指出,化合物A和法舒地尔对Rho激酶的50%抑制浓度(IC50)分别为0.2μM和1.5μM。与前述非专利文献7的记载相比,可以认为,化合物A的对Rho激酶的50%抑制浓度(IC50)比法舒地尔强,而与Y-27632相比为弱或为同等程度。
对于使用化合物A的眼病,有报告称,组合使用化合物A和碳酸酐酶抑制剂对青光眼的预防和治疗是有用的(参见专利文献4),化合物A对眼底疾病的预防和治疗是有用的(参见专利文献5),然而尚无使用化合物A对角膜厚度的作用的报告。
现有技术文献
专利文献
专利文献1:WO2009/028631号公报
专利文献2:日本特表2013-515676号公报
专利文献3:日本特开平11-349482号公报
专利文献4:WO2007/007737号公报
专利文献5:日本特许第5557408号公报
非专利文献
非专利文献1:小泉范子,医学进展(医学のあゆみ),2012年,第241卷10号,第765~770页
非专利文献2:Y-L.Bi等,Experimental and Therapeutic Medicine,2013,5,433-437
非专利文献3:H.T.Lee等,Molecular Vision,2003,9,624-634
非专利文献4:J.G.Lee等,IOVS,2006,47(4),1376-1386
非专利文献5:N.Okumura等,Br.J.Ophthalmol.,2011,95,1006-1009
非专利文献6:N.Koizumi等,Cornea,2013,32(8),1167-1170
非专利文献7:N.Okumura等,IOVS,2014,55(1),318-329
发明内容
发明要解决的技术问题
本发明涉及提供用于维持和恢复角膜厚度的角膜厚度调节剂以及使用该角膜厚度调节剂维持和恢复角膜厚度的方法,例如角膜薄化的方法。解决技术问题的手段
本发明人发现,为了解决上述技术问题反复深入研究的结果,1-(4-氟-5-异喹啉磺酰基)-2-甲基-1,4-高哌嗪(以下简称化合物A)或其盐或它们的溶剂合物可以维持角膜的厚度为薄,成为对角膜组织较为安全的、有效性优异的药剂。同时,进行滴眼给药也是可能的,进行减少患者负担的制剂化也是可能的。
即,本发明涉及含有1-(4-氟-5-异喹啉磺酰基)-2-甲基-1,4-高哌嗪或其盐或它们的溶剂合物而形成的角膜厚度调节剂。
同时,本发明涉及含有1-(4-氟-5-异喹啉磺酰基)-2-甲基-1,4-高哌嗪或其盐或它们的溶剂合物而形成的角膜薄化剂。
进一步地,本发明涉及含有1-(4-氟-5-异喹啉磺酰基)-2-甲基-1,4-高哌嗪或其盐或它们的溶剂合物而形成的角膜水肿的预防剂。
进一步更详细地说明本发明,则本发明如下:
(1)含有1-(4-氟-5-异喹啉磺酰基)-2-甲基-1,4-高哌嗪或其盐或它们的溶剂合物而形成的角膜厚度调节剂。
(2)如前述(1)所记载的角膜厚度调节剂,其中,1-(4-氟-5-异喹啉磺酰基)-2-甲基-1,4-高哌嗪是(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1,4-高哌嗪(以下,简称化合物B)。
(3)如前述(1)或(2)所记载的角膜厚度调节剂,其中,角膜厚度调节剂是角膜薄化剂。
(4)如前述(1)或(2)所记载的角膜厚度调节剂,其中,角膜厚度调节剂是角膜水肿的预防剂和/或治疗剂。
(5)如前述(1)或(2)所记载的角膜厚度调节剂,其中,角膜厚度调节剂是角膜内皮障碍的预防剂和/或治疗剂。
(6)如前述(5)所记载的角膜厚度调节剂,其中,角膜内皮障碍是大泡性角膜病变或角膜内皮炎等角膜内皮疾病。
(7)如前述(1)至(6)中任意一项所记载的角膜厚度调节剂,其中,角膜厚度调节剂是液体制剂。
(8)如前述(1)至(7)中任意一项所记载的角膜厚度调节剂,其中,角膜厚度调节剂是滴眼剂。
(9)如前述(1)至(8)中任意一项所记载的角膜厚度调节剂,其中,角膜是灵长类的角膜。
(10)如前述(1)至(9)中任意一项所记载的角膜厚度调节剂,其中,角膜是人的角膜。
(11)制造如前述(1)至(10)中任意一项所记载的角膜厚度调节剂的制剂的方法,其中,所述方法包括将1-(4-氟-5-异喹啉磺酰基)-2-甲基-1,4-高哌嗪或其盐或它们的溶剂合物和制药上可容许的载体混合的工序。
发明效果
本发明提供用于预防和/或治疗导致角膜厚度调整的角膜障碍的角膜厚度调节剂。本发明的角膜厚度调节剂可以预防和/或治疗大泡性角膜病变、角膜内皮炎等角膜内皮疾病以及由角膜移植等引起的角膜内皮异常等各种角膜内皮障碍。并且,本发明的角膜厚度调节剂即使有效成分为低浓度也是有效的,可以作为能够维持角膜的厚度为薄的、副作用小的、安全且有效性高的医药组合物使用。
同时,本发明的角膜厚度调节剂可以作为患者负担小的滴眼剂提供。
附图说明
图1是将化合物B对人进行滴眼给药时的角膜的厚度变化以箱线图表示的图。
具体实施方式
以下较详细地说明本发明。
本发明中的化合物A具有一个不对称碳原子,存在(R)型和(S)型。在本发明中,可以使用(R)型、(S)型或它们的混合物的任意一种。作为医药有效成分,优选(R)型或(S)型的高纯度的光学活性体。在(R)型和(S)型中,从活性方面来看,优选(S)型。在本说明书中,单独将(S)型标记为化合物B。
本发明的有效成分1-(4-氟-5-异喹啉磺酰基)-2-甲基-1,4-高哌嗪是公知作为脑血管治疗剂和哮喘治疗剂并具有P物质拮抗作用、白三烯D4拮抗作用和Rho激酶抑制作用的化合物(参见专利文献3),可以通过公知的方法,例如,在国际专利公开第99/20620号小册子中所记载的方法制造。
作为化合物A的盐,可以列举例如:盐酸、硫酸、硝酸、氢氟酸、氢溴酸等无机酸的盐,或者与醋酸、酒石酸、乳酸、柠檬酸、富马酸、马来酸、琥珀酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、萘磺酸、樟脑磺酸等有机酸形成的盐,特别优选盐酸盐。
化合物A或其盐不仅能够以未溶剂化型存在,也能够以水合物或溶剂合物存在。优选水合物,然而,在本发明中,化合物A或其盐包括所有结晶型以及水合物或溶剂合物。
在本发明中,“角膜厚度调节剂”是指调节角膜的厚度、维持正常角膜的功能的药剂。角膜的厚度主要依赖于角膜内皮的功能,可以认为,本发明的“角膜厚度调节剂”是在角膜内皮功能亢进或低下等角膜内皮发生功能障碍的情况下,可以通过调节该功能成为较正常的状态,从而调节角膜的厚度。也就是说,可以认为,角膜内皮具有泵功能和屏障功能等用于维持视力的重要功能,在这些功能亢进时,通过抑制这种功能,同时,在这些功能低下时,通过促进这种功能,使角膜厚度成为较正常。
通过给予本发明的“角膜厚度调节剂”,调节角膜内皮的功能,可以对角膜的厚度进行薄化,因此,本发明的“角膜厚度调节剂”可以作为角膜薄化剂、角膜水肿的预防和治疗剂和/或角膜内皮障碍的预防和治疗剂使用。
本发明的“角膜厚度调节剂”可以通过该领域普遍使用的常规的制剂化技术进行制剂化成为用于向眼局部给药的剂型。作为剂型,例如优选前房内注射液、眼灌流液或滴眼液等液体制剂,但不限于此。作为优选的制剂,从治疗效果方面来看,前房内注射液和眼灌流液是优选的剂型,然而,患者的负担大;从给药的容易程度来看,可以列举滴眼剂。
本发明的滴眼药是含有本发明的有效成分化合物A(优选化合物B)或其盐或它们的溶剂合物以及在滴眼药中容许的载体的滴眼药。
在配制滴眼剂的情况下,例如,可以通过以下步骤进行。将所要求的上述成分溶解或悬浮于以下溶剂中:无菌纯净水、生理盐水等水性溶剂,或棉籽油、大豆油、芝麻油、花生油等植物油等的非水性溶剂;调节至规定的渗透压;实施过滤灭菌等灭菌处理。另外,在配制眼软膏剂的情况下,除了前述各种成分以外,可以含有软膏基质。作为前述软膏基质,不受到特别限定,可以优选列举:凡士林、液体石蜡、聚乙烯等油性基质;通过表面活性剂等使油相和水相乳化而成的乳剂型基质;由羟丙基甲基纤维素、羧甲基纤维素、聚乙二醇等组成的水溶性基质等。
在将化合物A(优选化合物B)或其盐或它们的溶剂合物用于本发明的“角膜厚度调节剂”的情况下,其给药量根据患者的体重、年龄、性别、症状、给药方式和给药次数等而不同,然而,通常对于成人,作为化合物A(优选化合物B),可以列举:每天0.025~10000μg,优选0.025~2000μg,较优选0.1~2000μg,进一步优选0.025~200μg、0.025~100μg的范围。
在作为滴眼剂使用的情况下,可以在有效成分为约0.0001~5w/v%、优选在约0.01~4w/v%的浓度使用。
同时,给药次数不受到特别限定,优选一次或分数次给药;在液体滴眼剂的情况下,每次一至数滴滴眼即可。
作为本发明的“角膜厚度调节剂”的给药对象,可以列举,哺乳动物(例如,人、小鼠、大鼠、仓鼠、兔、猫、狗、牛、马、羊、猴等)。作为优选的哺乳动物,可以列举人、猴等灵长类。特别优选为人。
实施例1
人的角膜厚度的变化:
在化合物B对患有眼科疾病的对象的长期给药试验中,调查对角膜的影响(27-34例)。即,在化合物B 0.4%滴眼液的1天2次给药52周的滴眼组中,使用测厚仪测定给药开始前(0周)、给药2周后、给药4周后、以后每4周的角膜厚度。测定进行5次,采用5次的平均值。测定日9点滴眼,11点测定。另外,28周后、52周后、跟踪(从最终给药日开始7~28日后)时,在9点(28周后、52周后为滴眼前)和11时进行两次测定。
结果显示于图1。图1上是右眼的结果,图1下是左眼的结果。纵轴表示从0周开始的变化值(μm),横轴表示给药周数。同时,就28周、52周以及跟踪(f/u)而言,将9点的测定以(0)表示,11点的测定以(2)表示。另外,给药开始前(0周)的角膜厚度为:右眼531.6±28.0μm,左眼530.9±27.9μm(皆为平均值±标准偏差)。
可知,在本发明的化合物B的给药期间中,角膜的厚度减小。即使继续给药,角膜的厚度大体上维持为一定值。同时,在28周后以及52周后,在滴眼前(0)的角膜的厚度具有回到化合物B给药开始前(0周)的值的倾向,然而,在滴眼2小时后(2),角膜的厚度减小。
Claims (6)
1.含有1-(4-氟-5-异喹啉磺酰基)-2-甲基-1,4-高哌嗪或其盐或它们的溶剂合物而形成的角膜厚度调节剂。
2.如权利要求1所记载的角膜厚度调节剂,其中,1-(4-氟-5-异喹啉磺酰基)-2-甲基-1,4-高哌嗪是(S)-(-)-1-(4-氟-5-异喹啉磺酰基)-2-甲基-1,4-高哌嗪。
3.如权利要求1或2所记载的角膜厚度调节剂,其中,角膜厚度调节剂是角膜薄化剂。
4.如权利要求1或2所记载的角膜厚度调节剂,其中,角膜厚度调节剂是角膜水肿的预防和/或治疗剂。
5.如权利要求1至4中任意一项所记载的角膜厚度调节剂,其中,角膜厚度调节剂是液体制剂。
6.如权利要求1至5中任意一项所记载的角膜厚度调节剂,其中,角膜是灵长类的角膜。
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