CN102164592A - 可与核黄素一起使用的增强剂用于在圆锥角膜或其它角膜扩张性疾病的治疗中进行角膜交联的用途以及相应眼用组合物 - Google Patents

可与核黄素一起使用的增强剂用于在圆锥角膜或其它角膜扩张性疾病的治疗中进行角膜交联的用途以及相应眼用组合物 Download PDF

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CN102164592A
CN102164592A CN2009801381883A CN200980138188A CN102164592A CN 102164592 A CN102164592 A CN 102164592A CN 2009801381883 A CN2009801381883 A CN 2009801381883A CN 200980138188 A CN200980138188 A CN 200980138188A CN 102164592 A CN102164592 A CN 102164592A
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马尔切洛·斯塔尼
爱德华多·斯塔尼
马西莫·菲利佩洛
乔瓦尼·卡瓦洛
欧金尼奥·索多
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Abstract

本文描述的是增强剂(可与核黄素一起使用)用于通过角膜交联法来治疗圆锥角膜或其它扩张性角膜疾病的用途，以及相应组合物。

Description

可与核黄素一起使用的增强剂用于在圆锥角膜或其它角膜扩张性疾病的治疗中进行角膜交联的用途以及相应眼用组合物
本发明涉及增强剂用于制备可包含核黄素的眼用组合物(尤其是洗眼剂)的用途，所述眼用组合物被设计用于通过交联而在治疗圆锥角膜或其它的扩张性角膜疾病过程中无需去除角膜上皮(去上皮)的处理即可使组合物被吸收进入角膜基质。同时本发明也涉及用于角膜交联技术的相应的眼用组合物。
圆锥角膜是一种严重的角膜疾病，因为它是一种非炎性进行性营养不良，年发病率约为50/100000，通常为10至20岁的年轻人。圆锥角膜是一种遗传性疾病，在女性中高发，并且有时似乎与内分泌腺体(垂体和甲状腺)的功能障碍有关。在85％的病例中，患者的双眼均可发病，其发展过程可能会因人而异。
该病开始发病时，出现曲率不规则，这改变了角膜的折光能力，从而导致像的扭曲以及远、近视觉的混淆。患者都抱怨视力减退，尤其是远距离视力的减退。视力持续发生不可逆的减退，因此需要频繁地更换眼镜，并因此可能被误认为是伴有散光的近视。
由于该病所导致的角膜基质先天性结构脆弱，几年之后，角膜常常进行性地被磨损并朝顶点方向变薄。之后发生角膜曲率不规则，这使其失去球状外形并呈现出特征性的圆锥形(圆锥角膜)。
使用生物显微镜可以观察到圆锥角膜顶端处角膜厚度的明显变薄。随着时间的进展，圆锥角膜的顶端变得不透光，这是因为该部分角膜的营养状况发生改变，在最严重的情况下可以出现超过62D的角膜曲率，而角膜的厚度甚至能够达到446μm。
如果该疾病被忽视的话，则顶端可发生溃疡，随之发生角膜穿孔，并出现疼痛、流泪和眼睑痉挛。这些因圆锥角膜而引发的角膜改变导致角膜蛋白质分布的改变，导致微小的瘢痕，其进一步扭曲视觉图像，在一些病例中还会阻止光的通过，因而产生令人烦恼的眩晕感，尤其是在一天中太阳在地平线上位置较低的时候(日出和日落时)。
正如上文所提到的，为了矫正视力，就必须频繁地更换眼镜。只有在已证明使用眼镜无法取得满意效果后，在较轻微的情况下可以使用刚性的隐形眼镜。
当患圆锥角膜的角膜发生显著变薄时，或者如果在角膜表面撕裂之后形成瘢痕时，就会出现严重的问题，甚至有必要进行角膜移植(角膜移植术)。
2002年，所谓的板层角膜移植术被引入意大利用于治疗圆锥角膜。其中实际上并没有替换整个角膜，而是仅替换外层，即患病的部分。
然而，在德国Dresda的Carl Gustaw Carus大学的眼科诊所中，1997年已经开发出了一种更加安全的并且介入性较小的新技术，被称为“角膜交联(corneal cross-linking)”，这种技术具体使用被紫外激光激发的核黄素；2005年，这一技术也在意大利进行了测试，到现在为止，该技术已经成功地在意大利的许多眼科诊所中广泛使用。
角膜交联是一种低侵入性的方法，其使用被紫外激光(366nm)激发的核黄素；该方法是无痛的，并且可以在日间医院中进行。这种交联通过交织和提高角膜胶原蛋白纤维之间的联系(交联)而使得患圆锥角膜的角膜的结构得以增强。已经进行的临床研究证明，该方法能够减少与圆锥角膜相关的散光，并能够减缓或者阻止圆锥角膜的发展，从而避免进行角膜移植。其它以角膜扩张为特征的疾病也可受益于使用交联法进行的治疗。
角膜交联通过进行角膜局部麻醉以磨除直径为8-9mm的角膜上皮(去上皮)来进行。之后，频繁地滴入基于核黄素的0.1％眼用溶液，15分钟之后，用紫外光(UV-A)发光器照射5分钟；之后再重新滴入，然后再重新照射，总共进行6个循环(共30分钟)。
常用于角膜交联的核黄素(尤其是磷酸核黄素)是一种亲水性、光敏化的和光聚合的分子，透过上皮的能力差，因而到达角膜基质的能力也差。因此，有必要在开始UV-A照射前通过去除角膜上皮(去上皮)来促进其吸收和角膜的完全吸入。这一过程可能(尽管很少见)在角膜水平引发并发症、疼痛，此外，这也是一种使得眼科医生更难完成任务的方法。
因此，很期望无需去除角膜上皮就可以改善核黄素的吸收，从而获得一种非侵入性的角膜交联，无需或减少麻醉，并且可以迅速愈合而没有疼痛或可能的并发症。
更加理想的是，设想某些化合物可以易于实现上皮吸收，而在使胶原纤维光敏化和光聚合方面又具有与核黄素相同或更高的活性；所述化合物应该优选地以与可见光接近的光强度所激发，这样就可以避免激活核黄素所需的紫外光重复照射所产生的有害作用。
我们意想不到地发现，通过向角膜施用含有增强剂(可与核黄素一起使用)的眼用组合物，获得了改善的角膜交联，这通过以接近可见光(害处更小)的照射进行激发而无需进行去上皮来实现，所述增强剂选自：
生物增强剂(即这样的物质，其促进核黄素或其它光敏化和光聚合物质透过角膜上皮，使其被角膜基质本身所吸收)，例如，EDTA、EDTA钠、EDTA钾、聚山梨醇酯80、氨基丁三醇、氮酮、氯化苯甲烃铵、西吡氯铵、十六烷基三甲基氯化铵、月桂酸、薄荷醇、甲氧基水杨酸、聚氧乙烯、甘氨胆酸钠、甘氨脱氧胆酸钠、十二烷基硫酸钠、水杨酸钠、牛磺胆酸钠、牛磺脱氧胆酸钠；和/或
光增强剂(即光敏化和光聚合物质，其可以很容易地被上皮所吸收，并且像核黄素一样能够被光激活而形成角膜交联)，例如，染料吖啶黄、奎尼丁黄、亚甲蓝和赤藓红，这些化合物的结构如下：
吖啶黄：
可用吸收：460nm
Figure BPA00001332733000031
奎尼丁黄
Figure BPA00001332733000032
亚甲蓝
可用吸收：668nm
Figure BPA00001332733000041
赤藓红B
2′，4′，5′，7′-四碘荧光素二钠盐
吸收：525nm
Figure BPA00001332733000042
分子式：
C20H6I4Na2O5
分子量：
879.86
因此，本发明考虑上述增强剂(单独使用或是多种混合使用，并可与核黄素一起使用)用于制备眼用组合物的用途，所述眼用组合物用于在圆锥角膜或其它角膜扩张中进行交联。
本发明的增强剂可以直接施用于角膜以用于圆锥角膜或其它角膜扩张中的角膜交联，而没有已证实的细胞毒性。
本发明的另外一个主题是包含上述增强剂(可与核黄素一起使用)的眼用组合物，所述眼用组合物可以根据已知的技术来制备，并可具体包含：
-一种或多种生物增强剂和一种或多种光增强剂，还可包含核黄素；
-一种或多种生物增强剂，还可包含核黄素；
-一种或多种光增强剂，还可包含核黄素。
在眼部施用上述包含一种或多种生物增强剂或者一种或多种光增强剂的组合物之后，可以直接在角膜上施用一种或多种光敏化和光聚合物质(尤其是核黄素)的溶液。
本发明的生物增强剂在上述所有组合物中都以合适的量存在，其选自重量百分比0.001％至5％(相对于组合物)。
特别地，增强剂的能力尤其依赖于EDTA和氨基丁三醇的联合，因为这两种化合物一起在EDTA的未成盐羧基和氨基丁三醇之间形成离子对，该离子对具备显著的膜穿透能力。
在这些研究结果中，值得提到的是：如果氨基丁三醇优选地以0.05wt％至0.5wt％存在，且EDTA优选地以0.05wt％至0.5wt％存在，则核黄素的吸收立即发生。
本发明的光敏化和光聚合物质(光增强剂，其中包括核黄素)以合适的量使用，其选自0.001wt％至1wt％(相对于组合物)
此外，优选用于本发明中的核黄素是磷酸核黄素，在上述所有组合物中均为合适的量，优选为本发明组合物的0.05wt％至0.3wt％。
本发明的眼用组合物可制备成洗眼剂、滴眼液、洗眼液、软膏剂的形式，以及能够根据已知技术进行角膜应用的任何药物形式，下文中以举例的方式提供相关的实施例，这些实施例并不意味着是对发明进行任何的限制。
在每个实施例中，每一种组分的剂量均以重量百分比的形式表示。
实施例1
Figure BPA00001332733000051
Figure BPA00001332733000061
实施例2
Figure BPA00001332733000062
实施例3
Figure BPA00001332733000063
Figure BPA00001332733000071
实施例4
Figure BPA00001332733000072
Figure BPA00001332733000081
实施例5
Figure BPA00001332733000082
实施例6
Figure BPA00001332733000083
Figure BPA00001332733000091
实施例7
Figure BPA00001332733000092
实施例8
Figure BPA00001332733000102
实施例9
Figure BPA00001332733000111
注意，当氨基丁三醇浓度提高时，需要充分增加磷酸二氢钠，以保证pH值为7-7.2。
实施例10
Figure BPA00001332733000112
Figure BPA00001332733000121
实施例11
实施例12
实施例13
Figure BPA00001332733000141
需要指出的是，配方1-13也可以通过加入足量的氯化钠(或其它渗透溶质)而制成等渗或甚至高渗的溶液以达到所述目的。

Claims (11)

1.一种或多种选自生物增强剂和/或光增强剂的增强剂用于制备眼用组合物的用途，所述眼用组合物用于在圆锥角膜或其它角膜扩张性疾病的治疗中进行角膜交联的方法，所述增强剂可与核黄素一起使用。
2.根据权利要求1的用途，其中单独或混合在一起的所述生物增强剂选自EDTA、EDTA钠、EDTA钾、聚山梨醇酯80、氨基丁三醇、氮酮、氯化苯甲烃铵、西吡氯铵、十六烷基三甲基氯化铵、月桂酸、薄荷醇、甲氧基水杨酸、聚氧乙烯、甘氨胆酸钠、甘氨脱氧胆酸钠、十二烷基硫酸钠、水杨酸钠、牛磺胆酸钠、牛磺脱氧胆酸钠。
3.根据权利要求1或权利要求2的用途，其中所述生物增强剂以相对于所述组合物为0.0001-5wt％的量存在，特别地，EDTA为0.001到1wt％，氨基丁三醇为0.001到2wt％，而聚山梨醇酯80为0.001到5wt％。
4.根据权利要求3的用途，其中EDTA以0.05到0.5wt％的量存在和/或氨基丁三醇以0.05到0.5wt％的量存在。
5.根据权利要求1到4中任一项的用途，其中所述光增强剂选自染料：吖啶黄、奎尼丁黄、亚甲蓝、赤藓红。
6.根据权利要求1到5中任一项的用途，其中所述光增强剂以0.001至1wt％的量存在，而磷酸核黄素可以0.05至0.3wt％的量存在。
7.根据权利要求1到6中任一项的用途，其中磷酸核黄素可以0.05至0.3wt％的量存在。
8.用于权利要求1到7中任一项所述用途的组合物，其中存在一种或多种生物增强剂以及一种或多种光增强剂，还可存在核黄素。
9.用于权利要求1到7中任一项所述用途的组合物，其中存在一种或多种生物增强剂，还可存在核黄素。
10.用于权利要求1到7中任一项所述用途的组合物，其中存在一种或多种光增强剂，还可存在核黄素。
11.用于根据权利要求1到7中任一项所述用途的洗眼剂，其用于以角膜交联的方法治疗圆锥角膜或其它角膜扩张性疾病。
CN200980138188.3A 2008-08-28 2009-08-27 可与核黄素一起使用的增强剂制备用于在圆锥角膜的治疗中进行角膜交联的眼用组合物的用途以及相应眼用组合物 Active CN102164592B (zh)

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CN104023706B (zh) * 2011-10-25 2016-11-30 索夫特意大利公司 用于圆锥形角膜治疗的由离子透入法递送的改良的交联组合物
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