CN105188753B - 角结膜病症的治疗剂 - Google Patents
角结膜病症的治疗剂 Download PDFInfo
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- CN105188753B CN105188753B CN201380069723.0A CN201380069723A CN105188753B CN 105188753 B CN105188753 B CN 105188753B CN 201380069723 A CN201380069723 A CN 201380069723A CN 105188753 B CN105188753 B CN 105188753B
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- conjunctiva
- ester
- gamma agonist
- naphthane
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Abstract
本发明解决了提供用于角结膜病症的新型治疗剂的问题。作为解决该问题的手段,提供了含有RARγ激动剂作为活性成分的用于角结膜病症的治疗剂。治疗剂在角结膜病症模型中显示出极佳的改善作用,并且因此可用作角结膜病症的治疗剂,所述角结膜病症例如角膜溃疡、角膜上皮磨损、角膜炎、干眼症、结膜炎、慢性浅层角膜炎、角膜糜烂、持续性角膜病症、浅层点状角膜病变、角膜上皮缺损、结膜上皮缺损、干燥性角结膜炎、上缘角结膜炎、丝状角结膜炎、传染性角膜炎、非传染性角膜炎、传染性结膜炎和非传染性结膜炎。治疗剂也可用作与角结膜病症相关的角膜结瘢和结膜结瘢两者的治疗剂。
Description
技术领域
本发明涉及含有RARγ激动剂作为有效成分的角结膜病症的治疗剂。
背景技术
角膜是覆盖眼球前表面的直径约1 cm的透明无血管组织。结膜是覆盖眼睑背面和眼球表面的粘膜,其位于角膜缘后方。角膜和结膜在视力中发挥重要作用。已知当在其中发生病症时,视觉功能严重受累。由诸如角膜溃疡、角膜炎和干眼症等多种疾病诱发的角结膜病症是由下述所引起的病症:从诸如外部损伤的某种原因所致的病症中恢复的延迟,或已变成慢性的病症。因为角膜是与结膜相连的组织,所以此类疾病在上皮的正常构成中彼此负面影响,并且在一些情况下会造成伤害角膜基质或内皮的结构或功能。
胶原(尤其是I型胶原)已知为角膜实质组织的代表性基质组分之一。起因于基质降解的功能障碍发生在角结膜病症所致的疾病中。因此,认为胶原(尤其是I型胶原)降解的抑制对于角结膜病症所引起的疾病有效。
在角结膜病症中,通常在炎症已平息后形成的瘢痕组织可能妨碍视觉功能。为此,如上述胶原降解的抑制中那样,认为胶原收缩的抑制(若可能)对于瘢痕的收缩和形成(在下文中统称为“瘢痕形成”)有效。
专利文献1描述了全反式维甲酸(在下文中也称为ATRA)促进角膜再生。然而,它的作用很弱并且它的详细机制尚未阐明。
进一步地,ATRA是维甲酸受体(在下文中也称为RAR)的激动剂。然而,因为ATRA不具有相对于RAR亚型RARα、RARβ和RARγ的选择性,所以各RAR亚型对角膜再生作用的贡献是未知的。
同时,RAR涉及多种作用,例如许多细胞例如炎症细胞、免疫细胞和结构细胞中的生长、形态发生和分化。进一步地,确认到取决于哺乳动物的组织或器官,在RAR亚型的分布中存在差异。
RAR的一些作用是不希望有的,例如RARα所致的甘油三酯的增加。因此,具有RAR激动剂活性的化合物中的相对于亚型的特异性或选择性预期实现副作用风险的降低。
出于上述原因,对于具有强力的抑制角结膜病症的作用并且具有基于亚型选择性的高度安全性的RAR激动剂存在需求。
专利文献2和3公开了RAR激动剂(E)-4-(2-{3-[(1H-吡唑-1-基)甲基]-5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基}乙烯基)苯甲酸及其衍生物。进一步地,专利文献2描述了(E)-4-(2-{3-[(1H-吡唑-1-基)甲基]-5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基}乙烯基)苯甲酸对于肺气肿、癌症和皮肤病是有用的。专利文献3描述了上述激动剂对于神经性疼痛是有用的。
另外,非专利文献1描述了RAR激动剂6-[3-(1-金刚烷基)-4-羟苯基]-2-萘甲酸在肺癌细胞中诱导细胞凋亡。
此外,专利文献4描述了RAR激动剂3-氟-4-[2-羟基-2-(5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基)乙酰基氨基]苯甲酸在肌肉修复或再生中有用。
然而,对于任意的RAR激动剂,均未讨论或报道关于角结膜病症或角结膜病症所致的瘢痕形成的药理学作用。另外,也不存在暗示此类作用的文献。
引用列表
专利文献
专利文献 1:日本特开2009-235031
专利文献 2:国际公开号WO 2002/028810
专利文献 3:国际公开号WO 2008/057930
专利文献 4:日本特开2013-536855
非专利文献
非专利文献 1:Sun SY等人,Cancer Research 62(8): 2430-2436(2002)。
发明内容
发明概述
技术问题
寻找对于眼科疾病尤其是角结膜病症有效的药物是重要且感兴趣的目标。本发明的目标是提供治疗剂,其具有抑制角结膜病症的作用并且具有基于亚型选择性的高度安全性。
问题的解决方案
在寻找对于角结膜病症有效的药物的辛勤研究中,通过使用兔角膜细胞和结膜下成纤维细胞的药理学测试,本发明人发现:RARγ激动剂(E)-4-(2-{3-[(1H-吡唑-1-基)甲基]-5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基}乙烯基)苯甲酸(R667:在下文中也称为“RARγ激动剂A”)发挥改善角结膜病症以及与角结膜病症相关的瘢痕形成的极佳作用,其中证实了抑制胶原降解的有力作用以及抑制胶原收缩的显著作用。此外,发现其他RARγ激动剂:6-[3-(1-金刚烷基)-4-羟苯基]-2-萘甲酸(CD437:在下文中也称为“RARγ激动剂B”)和3-氟-4-[2-羟基-2-(5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基)乙酰基氨基]苯甲酸(BMS961:在下文中也称为“RARγ激动剂C”),在使用兔角膜细胞的药理学测试中,也显示出抑制胶原降解的显著作用,从而完成了本发明。
具体地,本发明是:[1]角结膜病症的治疗剂,其包含RARγ激动剂作为有效成分,[2]上述[1]的治疗剂,其中所述RARγ激动剂是(E)-4-(2-{3-[(1H-吡唑-1-基)甲基]-5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基}乙烯基)苯甲酸、6-[3-(1-金刚烷基)-4-羟苯基]-2-萘甲酸(naphthalene acid)、3-氟-4-[2-羟基-2-(5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基)乙酰基氨基]苯甲酸、其酯或其盐,[3]上述[1]或[2]的治疗剂,其中所述角结膜病症选自角膜溃疡、角膜上皮磨损(corneal epithelial abrasion)、角膜炎、干眼症、结膜炎、慢性浅层角膜炎、角膜糜烂、持续性角膜病症、浅层点状角膜病变、角膜上皮缺损、结膜上皮缺损、干燥性角结膜炎、上缘角结膜炎、丝状角结膜炎、传染性角膜炎、非传染性角膜炎、传染性结膜炎、非传染性结膜炎、角膜瘢痕和结膜瘢痕,[4]根据上述[1]-[3]中任一项的治疗剂,其中施用形式是滴注(instillative)施用或口服施用,和[5]根据上述[1]-[4]中任一项的治疗剂,其中剂型为滴注剂、眼用软膏、注射剂、片剂、颗粒剂、细粒剂、粉末剂或胶囊剂。
发明的有利作用
作为本发明的角结膜病症治疗剂的有效成分的RARγ激动剂,通过强力抑制角结膜胶原降解,可用作角结膜病症的治疗剂,所述角结膜病症例如为角膜溃疡、角膜上皮磨损、角膜炎、干眼症、结膜炎、慢性浅层角膜炎、角膜糜烂、持续性角膜病症、浅层点状角膜病变、角膜上皮缺损、结膜上皮缺损、干燥性角结膜炎、上缘角结膜炎、丝状角结膜炎、传染性角膜炎、非传染性角膜炎、传染性结膜炎或非传染性结膜炎。
进一步地,作为本发明的角结膜病症治疗剂的有效成分的RARγ激动剂,通过强力抑制角结膜胶原降解,也可用作与角结膜病症相关的角膜瘢痕或结膜瘢痕的治疗剂。
附图说明
[图1]图1是显示RARγ激动剂A(R667)的浓度(nM)和胶原降解(每孔的羟脯氨酸量(µg))之间的关系的图表。纵轴表示当对照羟脯氨酸的量设为100时的数值(%)。
[图2]图2是显示当使用结膜下成纤维细胞时,RARγ激动剂A(R667)的浓度(nM)和胶原收缩(皿中的胶原凝胶直径(mm))之间的关系的图表。其中"★"指示存在统计上的显著差异(p < 0.05)。
[图3]图3是显示当使用角膜细胞时,RARγ激动剂A(R667)的浓度(μM)和胶原收缩(皿中的胶原凝胶直径(mm))之间的关系的图表。其中"★"指示存在统计上的显著差异(p <0.05)。
[图4]图4是显示当使用角膜细胞时,RARγ激动剂A(R667)、RARγ激动剂B(CD437)和RARγ激动剂C(BMS961)的浓度(nM)相对于胶原降解的关系的图表。纵轴表示在不添加RARγ激动剂和刺激剂时,每孔的羟脯氨酸量(µg)设为1的情况下,当添加RARγ激动剂和刺激剂时,每孔的羟脯氨酸量(µg)的比率(Ratio),其中"★"指示存在统计上的显著差异(p <0.05)。
[图5]图5显示当使用角膜细胞时,在RARγ激动剂A(R667)的浓度(μM)与基质金属蛋白酶(MMP)的表达和活化之间的关系。图5A的顶部行显示MMP-1的表达和活化,图5A的底部行显示MMP-3的表达和活化,而图5B显示MMP-2和MMP-9的表达和活化。
[图6]图6显示当脂多糖(LPS)和RARγ激动剂A(R667)施用到雄性日本白兔的一只眼中的角膜基质内时的观察结果。顶部行(介质)是仅施用不含本发明的RARγ激动剂A(R667)的溶液的结果,而底部行(0.1% R667)是施用含有RARγ激动剂A(R667)的溶液的结果。
具体实施方式
本发明的角结膜病症治疗剂并无特别限制,并且可以是具有RARγ激动剂作为有效成分的任何治疗剂。本发明的RARγ激动剂是指与RARα受体或RARβ受体相比较,可以通过与RARγ受体结合显著促进RARγ受体的活化的化合物。
此类RARγ激动剂的例子包括由下式(I)表示的(E)-4-(2-{3-[(1H-吡唑-1-基)甲基]-5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基}乙烯基)苯甲酸(R667)、由下式(II)表示的6-[3-(1-金刚烷基)-4-羟苯基]-2-萘甲酸(CD437)、由下式(III)表示的3-氟-4-[2-羟基-2-(5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基)乙酰基氨基]苯甲酸(BMS961)、由下式(IV)表示的(2E)-3-(4-羧基苯基)-1-(5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基)-2-丙烯-1-酮肟(NRX204647:在下文中也称为“RARγ激动剂D”)、 由下式(V)表示的4-[7-(1-金刚烷基)-6-羟基萘-2-基]苯甲酸(CD1530:在下文中也称为“RARγ激动剂E”)、此类化合物(RARγ激动剂A、B、C、D和E)的酯和此类化合物(RARγ激动剂A、B、C、D和E)的盐。RARγ激动剂的优选例子包括RARγ激动剂A、RARγ激动剂B、RARγ激动剂C、此类化合物(RARγ激动剂A、B和C)的酯和此类化合物(RARγ激动剂A、B和C)的盐。
[化学式1]
[化学式2]
[化学式3]
[化学式4]
[化学式5]
。
进一步地,本发明的其他实施方案包括特征在于给对象施用本发明的RARγ激动剂的治疗角结膜病症的方法,用作角结膜病症的治疗剂的本发明的RARγ激动剂,以及本发明的RARγ激动剂在制备用于角结膜病症的治疗剂中的用途。
其为本发明的角结膜病症治疗剂的有效成分之一的RARγ激动剂A、其酯及其盐是专利文献2中所述的已知化合物。它们可以依照专利文献2中所述的方法进行制造,或作为商购可得产品进行购买。商购可得的产品的例子包括下述产品名称:由Shanghai HaoyuanChemexpress制造的帕罗伐汀。
在本发明的角结膜病症治疗剂的有效成分中,RARγ激动剂B是非专利文献1和专利文献4中所述的已知化合物,RARγ激动剂C是专利文献4中所述的已知化合物,而RARγ激动剂D和E是下述文件中所述的已知化合物(Shimono K.等人,Nat Med. 17(4): 454-460(2011))。所述化合物、其酯或其盐可以依照常规方法进行制造,或作为商购可得产品进行购买。商购可得的产品的例子包括下述产品名称:对于RARγ激动剂B,由Abcam制造的CD437(ab141305),以及由Tocris Bioscience制造的CD437;对于RARγ激动剂C,由TocrisBioscience制造的BMS961,以及由Santa Cruz biotechnology制造的CD1530;对于RARγ激动剂E,由Tocris Bioscience制造的CD1530。
其为本发明的角结膜病症治疗剂的有效成分的上述RARγ激动剂A、B、C、D和E的酯中的酯并无特别限制,并且可以是在体内生理条件下在利用酶等的反应中转换为RARγ激动剂A、B、C、D或E的任何酯。此类酯包括:通过与伯醇反应生成的酯,所述伯醇例如甲醇、乙醇、丙醇、己醇或十二烷醇;通过与仲醇反应生成的酯,所述仲醇例如异丙醇、仲丁醇、或1-乙基丙醇;通过与叔醇反应生成的酯,所述叔醇例如叔丁醇或1-甲基-1-乙基丙醇;以及通过与氨基醇例如2-氨基乙醇反应生成的酯。
上述酯可以通过已知方法由上述RARγ激动剂A、B、C、D、E或其合成中间体进行制造。
其为本发明的角结膜病症治疗剂的有效成分的上述RARγ激动剂A、B、C、D和E的盐中的盐并无特别限制,并且可以是任何药学可接受的盐。此类盐包括(1)作为酸加成盐的无机酸盐例如盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐和磷酸盐;以及有机酸盐例如乙酸盐、三氟乙酸盐、苯甲酸盐、草酸盐、丙二酸盐、琥珀酸盐、马来酸盐、富马酸盐、酒石酸盐、柠檬酸盐、甲磺酸盐、乙磺酸盐、三氟甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、谷氨酸盐和天冬氨酸盐,和(2)作为碱性盐的金属盐例如钠盐、钾盐、钙盐和镁盐;无机盐例如铵盐;和有机胺盐例如三乙胺盐和胍盐。
在本发明中,角结膜病症指其中角膜或结膜由于多种因素而受损的状况,所述多种因素例如异常泪液、代谢异常或外部损伤。角结膜病症的例子包括角膜溃疡、角膜上皮磨损、角膜炎、干眼症、结膜炎、慢性浅层角膜炎、角膜糜烂、持续性角膜病症、浅层点状角膜病变、角膜上皮缺损、结膜上皮缺损、干燥性角结膜炎、上缘角结膜炎、丝状角结膜炎、传染性角膜炎、非传染性角膜炎、传染性结膜炎和非传染性结膜炎。对胶原降解的抑制作用发挥极佳的改善作用。进一步地,在本发明中,与角结膜病症相关的角膜瘢痕(角膜上的瘢痕形成)和结膜瘢痕(结膜上的瘢痕形成)也是角结膜病症的例子。对胶原收缩的抑制作用发挥极佳的改善作用。
本发明的角结膜病症治疗剂可以以通过在合适的药理学可接受的添加剂中混合进行制造的下述形式经口或肠胃外施用(静脉内施用、肌内施用、腹膜内施用、经皮施用、气管内施用、皮内施用或皮下施用):片剂、胶囊剂、粉末剂、糖浆剂、颗粒剂、细粒剂、丸剂、液体制剂、悬浮剂、乳液剂、经皮吸收剂、栓剂、软膏剂(优选眼用软膏)、洗剂、吸入剂或注射剂。
这些制剂通过众所周知的方法经由使用添加剂进行制造,所述添加剂例如赋形剂、润滑剂、粘合剂、崩解剂、乳化剂、稳定剂、调味剂或稀释剂。
赋形剂的例子包括有机赋形剂和无机赋形剂。有机赋形剂的例子包括:糖衍生物例如乳糖、蔗糖、葡萄糖、甘露醇和山梨糖醇;淀粉衍生物例如玉米淀粉、马铃薯淀粉、α淀粉和糊精;纤维素衍生物例如结晶纤维素;阿拉伯胶;右旋糖酐;和支链淀粉。无机赋形剂的例子包括:轻质无水硅酸;和硫酸盐例如硫酸钙。
润滑剂的例子包括:硬脂酸;硬脂酸的金属盐例如硬脂酸钙和硬脂酸镁;滑石;胶体二氧化硅;蜡例如蜂蜡和鲸蜡;硼酸;己二酸;硫酸盐例如硫酸钠;乙二醇;富马酸;苯甲酸钠;D,L-亮氨酸、月桂基硫酸钠;硅酸例如二氧化硅和硅酸水合物;和上述赋形剂中的淀粉衍生物。
粘合剂的例子包括羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、聚乙二醇和上述赋形剂中示出的化合物。
崩解剂的例子包括:纤维素衍生物例如具有低取代度的羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钙和内部交联的羧甲基纤维素钙;交联聚乙烯吡咯烷酮;和化学修饰的淀粉或纤维素衍生物,例如羧甲基淀粉和羧甲基淀粉钠。
乳化剂的例子包括:胶质粘土例如皂粘土和硅酸镁铝;阴离子表面活性剂例如月桂基硫酸钠;阳离子表面活性剂例如苯扎氯铵;和非离子表面活性剂例如聚氧乙烯烷基醚、聚氧乙烯脱水山梨糖醇脂肪酸酯和蔗糖脂肪酸酯。
稳定剂的例子包括:对羟基苯甲酸酯例如对羟基苯甲酸甲酯和对羟基苯甲酸丙酯;醇例如三氯叔丁醇、苄醇和苯乙醇;苯扎氯铵;酚例如苯酚和甲酚;硫柳汞;乙酸酐;和山梨酸。
调味剂的例子包括:甜味剂例如糖精钠和阿斯巴甜;酸化剂例如柠檬酸、苹果酸和酒石酸;和调味料例如柠檬提取物和橙提取物。
稀释剂是一般用作稀释剂的化合物。稀释剂的例子包括乳糖、甘露醇、葡萄糖、蔗糖、硫酸钙、羟丙基纤维素、微晶纤维素、水、乙醇、聚乙二醇、丙二醇、丙三醇、淀粉、聚乙烯吡咯烷酮及其混合物。
本发明的角结膜病症治疗剂包括除上述剂型之外,采取滴注剂形式的那些。试剂可以使用众所周知的方法,通过在作为添加剂的等渗剂、缓冲剂、pH调节剂、增溶剂、增稠剂、稳定剂、防腐剂(抗菌剂)等中适当掺和进行配制。进一步地、还能够通过添加pH调节剂、增稠剂、分散剂等制备药物悬浮液,来获得稳定滴注剂。
等渗剂的例子包括丙三醇、丙二醇、氯化钠、氯化钾、山梨糖醇和甘露糖醇。
缓冲剂的例子包括磷酸、磷酸盐、柠檬酸、乙酸和ε-氨基己酸。
pH调节剂的例子包括盐酸、柠檬酸、磷酸、乙酸、氢氧化钠、氢氧化钾、硼酸、硼砂、磷酸氢二钠、磷酸二氢钠、碳酸钠和碳酸氢钠。
增溶剂的例子包括聚山梨醇酯80、聚氧乙烯氢化蓖麻油60和聚乙二醇4000。
增稠剂和分散剂的例子包括:纤维素高分子例如羟丙基甲基纤维素和羟丙基纤维素;聚乙烯醇;和聚乙烯吡咯烷酮。进一步地,稳定剂的例子包括依地酸和依地酸钠。
防腐剂(抗菌剂)的例子包括常用的山梨酸、山梨酸钾、苯扎氯铵、苄索氯铵、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、和三氯叔丁醇。还能够将这些防腐剂组合使用。
滴注剂可以具有在眼科制剂可接受范围内的任何pH,但pH期望地设为4.0-8.5。
对于软膏剂(优选眼用软膏),常用基质例如白凡士林或液体石蜡可以用于制备。
依照剂型、试剂施用于其的患者的症状严重性、年龄、重量、医生判断等,本发明的角结膜病症治疗剂的剂量可以适当地加以改变。对于口服试剂,对于成人每天一般能够按照1次或数次给药施用0.01-5000 mg、优选0.1-2500 mg且更优选0.5-1000 mg。对于滴注剂,能够以0.000001-10%(W/V)、优选0.00001-3%(W/V)且更优选0.0001-1%(W/V)的有效成分浓度按照每天1次或数次给药施用这些。对于眼用软膏,能够以0.00001-10%(W/W)、优选0.0001-3%(W/W)且更优选0.001-1%(W/W)的有效成分浓度按照每天1次或数次给药施用这些。
在下文中,本发明在提供实施例(测试实施例和制剂实施例)的同时更详细地加以说明。然而,本发明的范围并不限于其。
(实施例1)
(测试实施例)通过RARγ激动剂A抑制正常兔原代角膜细胞中的三维胶原凝胶降解的测试
依照Nishida等人(Investigative Ophthalmology & Visual Science 42:1247-1253(2001))的方法,将正常兔角膜细胞用于评价测试化合物对三维胶原凝胶降解的抑制作用。
由正常兔眼球收集的原代角膜细胞生长至汇合状态,并且用0.05%胰蛋白酶-EDTA与培养载玻片脱离。在无血清培养基(产品编号11095;Gibco)中洗涤后,计数细胞数目。将所获得的原代角膜细胞与I型胶原溶液Cellmatrix Type I-A(产品编号637-00653;NittaGelatin Inc.)和重构缓冲液(产品编号635-00791;Nitta Gelatin Inc.)混合,并且分配到24孔板内,使得最终浓度为1 × 105细胞/孔以制备胶原凝胶。
在制备凝胶后,通过将含RARγ激动剂A(R667)的二甲亚砜溶液(R667浓度:0.1nM、1 nM、10 nM、100 nM或1000 nM)或作为对照的无RARγ激动剂二甲亚砜溶液,以及作为刺激剂的10 ng(最终浓度10 ng/ml)IL-1β(产品编号201-LB-005;R&D Systems)和60 µg(最终浓度60 µg/ml)纤溶酶原(产品编号P9156;Sigma)加入MEM培养基中,并且在先前制备的胶原凝胶上叠加培养基,开始培养(在37℃和5% CO2的条件下)。
在培养48小时后,将上清液超滤,加入100 μl浓盐酸且加热,并且使胶原水解。通过使用Dry Thermo Uni(DTU-2C,Taitec Co. Ltd.)和蒸发头(E1-20 Taitec Co. Ltd.),使在水解后的反应溶液在氮气大气下干燥,并且随后溶解于500 μl超纯水中。依照Bergman等人的方法(Analytical Chemistry 35(12): 1961-1965(1963))测量溶液中的羟脯氨酸量,所述羟脯氨酸是胶原降解产物,以评价RARγ激动剂A抑制胶原降解的作用。结果显示于图1中。
在该测试中,RARγ激动剂A显示出抑制角结膜胶原降解的剂量依赖性作用。
(制剂实施例)
(药物制剂实施例1)滴注剂
在100 ml中
RARγ激动剂A 100 mg
氯化钠 800 mg
聚山梨醇酯80 适量
磷酸氢二钠 适量
磷酸二氢钠 适量
灭菌纯净水 适量。
将RARγ激动剂A和上文描述的其他组分加入灭菌纯净水中。将溶液充分混合以制备滴注剂。通过改变添加的RARγ激动剂A等的量,能够制备浓度为0.05%(W/V)、0.3%(W/V)、0.5%(W/V)或1%(W/V)的滴注剂。
(药物制剂实施例2)眼用软膏
在100 g中
RARγ激动剂A 0.3 g
液体石蜡 10.0 g
白凡士林 适量。
将RARγ激动剂A加入均匀熔化的白凡士林和液体石蜡中。将混合物充分混合且随后逐渐冷却,以制备眼用软膏。通过改变添加的RARγ激动剂A等的量,能够制备浓度为0.05%(W/W)、0.1%(W/W)、0.5%(W/W)或1%(W/W)的眼用软膏。
(药物制剂实施例3)片剂
在100 mg中
RARγ激动剂A 1 mg
乳糖 66.4 mg
玉米淀粉 20 mg
羧甲基纤维素钙 6 mg
羟丙基纤维素 6 mg
硬脂酸镁 0.6 mg。
将RARγ激动剂A、玉米淀粉和乳糖在混合器中进行混合。将羧甲基纤维素钙和羟丙基纤维素加入混合物中用于造粒。在干燥后调整所得到的颗粒的粒子大小。将硬脂酸镁加入且与调整的颗粒混合,并且用压片机将混合物制备成片剂。进一步地,通过改变添加的RARγ激动剂A等的量,能够制备100 mg中的含量为0.1 mg、10 mg或50 mg的片剂。
实施例2
(测试实施例)通过RARγ激动剂A抑制衍生自正常兔的多种原代细胞中的三维胶原凝胶收缩的测试
依照Nishida等人的方法,原代结膜下成纤维细胞和原代角膜细胞用于评价测试化合物对三维胶原凝胶收缩的抑制作用。
如实施例1中,使原代结膜下成纤维细胞生长且与培养载玻片脱离。在洗涤后,制备细胞悬浮液。将所得到的悬浮液(1.1 × 107细胞/孔MEM)、I型胶原溶液(5 mg/ml)、10× MEM重构缓冲液和水在冰上以0.2:7:1:1:1.8(体积比)进行混合。用0.5 ml该混合物接种涂布有1% BSA的培养皿,所述培养物在37℃下温育一小时,以制备胶原凝胶。
随后,将0.5 ml无血清培养基各自加入上述凝胶上,向所述无血清培养基中添加一定量(1 ng/ml)的TGF-β1(R&D Systems)和浓度各自为1 nM、10 nM和100 nM的RARγ激动剂。凝胶连同向其中添加无试剂无血清培养基的凝胶一起在37℃下继续进行温育。从经过24小时的时间开始测量凝胶直径。48小时后的凝胶直径的测量结果显示于图2中。
以与原代结膜下成纤维细胞相似的方式,对于原代角膜细胞测量凝胶直径。结果显示于图3中。
由图2和3可见,使用结膜下成纤维细胞或角膜细胞,RARγ激动剂A不仅可以抑制胶原降解,还可以抑制TGF所致的胶原凝胶收缩。这证实RARγ激动剂有助于胶原周转(turnover),并且具有抑制眼组织中的炎症、出血、感染、手术或损伤后发生的组织重塑,即纤维化或瘢痕化的作用。
实施例3
(测试实施例)通过RARγ激动剂A、B或C抑制衍生自正常兔的原代角膜细胞中的三维胶原凝胶降解的测试
依照Nishida等人的方法,通过与实施例1中相同的方法,将原代角膜细胞用于评价测试化合物对三维胶原凝胶降解的抑制作用。
如实施例1中,使原代角膜细胞生长且与培养载玻片脱离。在洗涤后,制备细胞悬浮液。将所得到的悬浮液(1.1 × 107细胞/孔MEM)、I型胶原溶液(5 mg/ml)、10 × MEM重构缓冲液和水在冰上以0.2:7:1:1:1.8(体积比)进行混合。用0.5 ml该混合物接种涂布有1% BSA的培养皿,所述培养物在37℃下温育一小时,以制备胶原凝胶。
在制备凝胶后,通过将含RARγ激动剂A(R667)的二甲亚砜溶液(1 nM)、含RARγ激动剂B(CD437)的二甲亚砜溶液(1 nM、10 nM)、含RARγ激动剂C(BMS961)的二甲亚砜溶液(10 nM)或作为对照的无RARγ激动剂二甲亚砜溶液,以及作为刺激剂的10 ng(最终浓度10ng/ml)IL-1β(产品编号201-LB-005;R&D Systems)和60 µg(最终浓度60 µg/ml)纤溶酶原(产品编号P9156,Sigma Aldrich)加入MEM培养基中,并且在先前制备的胶原凝胶上叠加培养基,开始培养(在37℃和5% CO2的条件下)。
在培养48小时后,使胶原水解,并且通过与实施例1相同的方法测量羟脯氨酸量,所述羟脯氨酸是胶原降解产物,以评价每种RARγ激动剂抑制胶原降解的作用。结果显示于图4中。
在该测试中,不仅RARγ激动剂A,而且RARγ激动剂B和C均显示出抑制角结膜胶原降解的作用。
实施例4
(测试实施例)通过RARγ激动剂抑制MMP-1、2、3和9的表达和活化的测试
认为蛋白酶即基质金属蛋白酶(MMP)的分泌或表达与I型胶原的降解相关。在这点上,研究通过RARγ激动剂的MMP-1、2、3和9的表达和活化抑制。
由正常兔眼球收集的原代角膜细胞在无血清MEM培养基中培养24小时。将RARγ激动剂(R667)(R667浓度:1 × 10-6 µM、1 × 10-5 µM、1 × 10-4 µM、1 × 10-3 µM、1 × 10-2 µM)加入所获得的培养溶液中,并且执行12小时的预处理。作为阳性对照,添加10 nM其为合成类固醇的地塞米松(Dex),并且类似地执行预处理。随后,加入IL-1β(0.1 ng/ml)用于刺激,并且在24小时后收集上清液。对收集的培养溶液使用下述蛋白质印迹分析和明胶酶谱分析。
(蛋白质印迹分析)
在使用10%聚丙烯酰胺凝胶的SDS-PAGE中,使收集的培养溶液的上清液展开后,将分离的蛋白质转移到硝酸纤维素滤器上。随后,将硝酸纤维素滤器上的非特异性位点阻断,并且在4℃下与抗人MMP-1抗体(R&D Systems)或抗兔MMP-3抗体(Daiichi Fine ChemicalCo.,Ltd)一起温育24小时。使用ECL®试剂(GE Healthcare)进行检测。
结果显示于图5A中。无活性PRO-MMP-1、PRO-MMP-3以及活性MMP-1、MMP-3各自的条带均减弱,其中其量依赖于RARγ激动剂A的浓度。因此,揭示RARγ激动剂A浓度依赖性地抑制MMP-1和MMP-3的表达和活化。
(明胶酶谱分析)
在使用含有0.1%明胶的10%聚丙烯酰胺凝胶的SDS-PAGE上,使收集的培养溶液的上清液展开后,将它与含有2.5% Triton X-100的TBS溶液一起在室温下温育一小时。温育后的凝胶用考马斯亮蓝(Wako Pure Chemical Industries,Ltd)溶液染色,并且用5%甲醇-7.5%乙酸溶液(Nacalai Tesque,Inc)脱色。
结果显示于图5B中。无活性PRO-MMP-2、PRO-MMP-9以及活性MMP-2、MMP-9各自的条带均减弱,其中其量依赖于RARγ激动剂A的浓度。因此,揭示RARγ激动剂A浓度依赖性地抑制MMP-2和MMP-9的表达和活化。
实施例5
(测试实施例)用RARγ激动剂A抑制角膜混浊和溃疡的测试
通过氯胺酮和赛拉嗪的混合物溶液的肌内施用,将全身麻醉应用于雄性日本白兔(体重2.5-3.5 kg,27只兔)。随后,通过0.4%盐酸奥布卡因滴注剂实施局部麻醉。此外,将30µl 1% LPS(Sigma Aldrich)注射到一只眼的角膜基质内,而另一只眼则不注射。
通过使用微量吸管,在LPS注射当天的注射后,将50 µl含有RARγ激动剂A(R667:0.1%,24 mM)的0.1% PBS/0.1%聚山梨醇酯80溶液滴注施用于用LPS注射了的兔两次,并且其后每天四次直至第10天。作为对照,类似地施用不含RARγ激动剂A的0.1% PBS/0.1%聚山梨醇酯80溶液(介质)。图6显示对照和其中施用RARγ激动剂A的情况的代表性例子。
在图6中,在顶部行中所示的对照(介质)中,观察到角膜混浊和溃疡。然而,在底部行中所示的其中施用RARγ激动剂A(0.1% R667)的情况下,未观察到角膜混浊和溃疡。因此,揭示RARγ激动剂A抑制角膜混浊和溃疡。
工业可应用性
其为本发明的角结膜病症治疗剂的有效成分的RARγ激动剂,通过强力抑制胶原降解,可用于预防角结膜病症或用作角结膜病症的治疗剂,所述角结膜病症例如为角膜溃疡、角膜上皮磨损、角膜炎、干眼症、结膜炎、慢性浅层角膜炎、角膜糜烂、持续性角膜病症、浅层点状角膜病变、角膜上皮缺损、结膜上皮缺损、干燥性角结膜炎、上缘角结膜炎、丝状角结膜炎、传染性角膜炎、非传染性角膜炎、传染性结膜炎和非传染性结膜炎。进一步地,所述RARγ激动剂通过强力抑制胶原收缩,也可用作与角结膜病症相关的角膜瘢痕或结膜瘢痕的治疗剂。
Claims (37)
1.(E)-4-(2-{3-[(1H-吡唑-1-基)甲基]-5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基}乙烯基)苯甲酸、或其酯或其盐在制备用于在有干眼病的对象的眼中预防或减少瘢痕形成的药物中的用途。
2.权利要求1的用途,其中所述药物是液体制剂的形式。
3.权利要求1的用途,其中所述药物是粉末剂、糖浆剂、颗粒剂、悬浮剂、乳液剂、软膏剂、或滴注剂的形式。
4.权利要求3的用途,其中所述软膏剂是眼用软膏。
5.权利要求4的用途,其中眼用软膏中的所述(E)-4-(2-{3-[(1H-吡唑-1-基)甲基]-5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基}乙烯基)苯甲酸、或其酯或其盐浓度为0.0001%至3%(w/v)。
6.权利要求5的用途,其中眼用软膏中的所述(E)-4-(2-{3-[(1H-吡唑-1-基)甲基]-5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基}乙烯基)苯甲酸、或其酯或其盐浓度为0.001%至1%(w/v)。
7.权利要求3的用途,其中所述药物是滴注剂的形式。
8.权利要求7的用途,其中滴注剂中的所述(E)-4-(2-{3-[(1H-吡唑-1-基)甲基]-5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基}乙烯基)苯甲酸、或其酯或其盐浓度为0.00001%至3%(w/v)。
9.权利要求8的用途,其中滴注剂中的所述(E)-4-(2-{3-[(1H-吡唑-1-基)甲基]-5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基}乙烯基)苯甲酸、或其酯或其盐浓度为0.0001%至1%(w/v)。
10.权利要求9的用途,其中滴注剂中的所述(E)-4-(2-{3-[(1H-吡唑-1-基)甲基]-5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基}乙烯基)苯甲酸、或其酯或其盐浓度为0.3%(w/v)、0.5%(w/v)或1%(w/v)。
11.权利要求1-10任一项的用途,其中所述药物配制为每天一次或多次的剂量。
12.RARγ激动剂、或其酯或其盐在制备用于预防或降低对象的眼中的瘢痕形成的药物中的用途,其中所述RARγ激动剂是(E)-4-(2-{3-[(1H-吡唑-1-基)甲基]-5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基}乙烯基)苯甲酸、6-[3-(1-金刚烷基)-4-羟苯基]-2-萘甲酸、3-氟-4-[2-羟基-2-(5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基)乙酰基氨基]苯甲酸、(2E)-3-(4-羧基苯基)-1-(5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基)-2-丙烯-1-酮肟,4-[7-(1-金刚烷基)-6-羟基萘-2-基]苯甲酸、其酯或其盐。
13.权利要求12的用途,其中所述眼中的瘢痕形成是在结膜和/或角膜上。
14.权利要求12的用途,其中所述眼中的瘢痕形成是由外部损伤引起。
15.权利要求14的用途,其中所述外部损伤是手术。
16.RARγ激动剂、或其酯或其盐在制备用于抑制对象的眼中的胶原降解和/或胶原收缩的药物中的用途,其中所述RARγ激动剂是(E)-4-(2-{3-[(1H-吡唑-1-基)甲基]-5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基}乙烯基)苯甲酸、6-[3-(1-金刚烷基)-4-羟苯基]-2-萘甲酸、3-氟-4-[2-羟基-2-(5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基)乙酰基氨基]苯甲酸、(2E)-3-(4-羧基苯基)-1-(5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基)-2-丙烯-1-酮肟,4-[7-(1-金刚烷基)-6-羟基萘-2-基]苯甲酸、其酯或其盐。
17.权利要求12-16任一项的用途,其中所述对象患有角结膜病症。
18.权利要求17的用途,其中所述角结膜病症选自角膜炎、结膜炎。
19.权利要求17的用途,其中所述角结膜病症选自角膜溃疡、角膜上皮磨损、干眼症、慢性浅层角膜炎、角膜糜烂、持续性角膜病症、浅层点状角膜病变、角膜上皮缺损、结膜上皮缺损、干燥性角结膜炎、上缘角结膜炎、丝状角结膜炎、传染性角膜炎、非传染性角膜炎、传染性结膜炎、非传染性结膜炎、角膜瘢痕和结膜瘢痕。
20.权利要求19的用途,其中所述角结膜病症是干眼症。
21.权利要求19的用途,其中所述角结膜病症是干燥性角结膜炎。
22.权利要求19的用途,其中所述角结膜病症是角膜瘢痕。
23.权利要求19的用途,其中所述角结膜病症是结膜瘢痕。
24.权利要求12或16的用途,其中所述RARγ激动剂是(E)-4-(2-{3-[(1H-吡唑-1-基)甲基]-5,5,8,8-四甲基-5,6,7,8-四氢萘-2-基}乙烯基)苯甲酸、其酯或其盐。
25.权利要求24的用途,其中所述药物是液体制剂的形式。
26.权利要求24的用途,其中所述药物是粉末剂、糖浆剂、颗粒剂、悬浮剂、乳液剂、软膏剂或滴注剂的形式。
27.权利要求26的用途,其中所述软膏剂是眼用软膏。
28.权利要求27的用途,其中眼用软膏中的所述RARγ激动剂、或其酯或其盐浓度为0.0001%至3%(w/v)。
29.权利要求28的用途,其中眼用软膏中的所述RARγ激动剂、或其酯或其盐浓度为0.001%至1%(w/v)。
30.权利要求26的用途,其中所述药物为滴注剂的形式。
31.权利要求30的用途,其中在滴注剂中的所述RARγ激动剂、或其酯或其盐浓度为0.00001%至3%(w/v)。
32.权利要求31的用途,其中在滴注剂中的所述RARγ激动剂、或其酯或其盐浓度为0.0001%至1%(w/v)。
33.权利要求32的用途,其中在滴注剂中的所述RARγ激动剂、或其酯或其盐浓度为0.3%(w/v)、0.5%(w/v)或1%(w/v)。
34.权利要求1、12或16中任一项的用途,其中所述药物配制为每天一次或多次的剂量。
35.权利要求1、12或16中任一项的用途,其中所述药物包含增溶剂。
36.权利要求35的用途,其中所述增溶剂选自聚山梨醇酯80、聚氧乙烯氢化蓖麻油60和聚乙二醇4000。
37.权利要求36的用途,其中所述增溶剂是聚山梨醇酯80。
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