CN1684738A - 细胞因子合成抑制剂用于治疗干眼病的用途 - Google Patents

细胞因子合成抑制剂用于治疗干眼病的用途 Download PDF

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CN1684738A
CN1684738A CNA03822514XA CN03822514A CN1684738A CN 1684738 A CN1684738 A CN 1684738A CN A03822514X A CNA03822514X A CN A03822514XA CN 03822514 A CN03822514 A CN 03822514A CN 1684738 A CN1684738 A CN 1684738A
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D·A·盖玛彻
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Abstract

非免疫驻留眼表细胞中细胞因子合成的抑制剂可用于治疗干眼病和其它需要湿润眼睛的病症。

Description

细胞因子合成抑制剂用于治疗干眼病的用途
本发明涉及干眼病的治疗。特别地，本发明涉及某些细胞因子合成抑制剂在治疗哺乳动物的干眼病和其它需要湿润眼睛的病症中的用途。
发明背景
干眼病，通用名为干燥性角结膜炎，是一种每年侵袭数百万美国人的常见眼科疾病。由于生育能力停止后出现激素改变，该病症在绝经后女性中特别普遍。干眼病以不同的严重程度困扰患者。在轻症病例中，患者会经历烧灼感、干燥感和例如通常由眼睑和眼表面之间的小物体引起的持续刺激。在重症病例中，可严重损害视力。其它疾病如干燥综合征和瘢痕性类天疱疮出现干眼病并发症。
尽管似乎干眼病可由多种不相关的致病因素引起，然而所有并发症均表现出一个共同的结果，即眼前部泪膜的破坏，其导致暴露的外表面失水以及以上所述的多种症状(Lemp，国家眼科研究所/工业研讨会关于干眼病临床试验的报告， The CLAO Journal，21卷，第4期，221-231页(1995))。
医师已经采取多种方法来治疗干眼病。一种常规的方法是全天滴加所谓的人工泪液来补充和稳定眼的泪膜。其它方法包括使用可提供泪液替代物或刺激内源性泪液产生的眼植入剂。
泪液替代方法的实例包括使用缓冲的等张盐水溶液、含有水溶性聚合物的水溶液，所述的聚合物使溶液变得更粘稠，从而更不易从眼中流出。还尝试了通过提供一种或多种泪膜组分如磷脂和油来进行泪膜重构。已经证明磷脂组合物可用于治疗干眼病；参见例如McCulley和Shine，泪膜结构和干眼病， Contactologia，20卷(4)，145-49页(1998)；以及Shine和McCulley，与睑板腺分泌极性脂质异常有关的干燥性角结膜炎， Archives of Ophthalmology，116卷(7)，849-52页(1998)。用于治疗干眼病的磷脂组合物的实例公开于美国专利US 4,131,651(Shah等)、4,370,325(Packman)、4,409,205(Shively)、4,744,980和4,883,658(Holly)、4,914,088(Glonek)、5,075,104(Gressel等)、5,278,151(Korb等)、5,294,607(Glonek等)、5,371,108(Korb等)和5,578,586(Glonek等)中。美国专利US 5,174,988(Mautone等)公开了含有磷脂、抛射剂和活性物质的磷脂药物递送系统。
另一种方法包括提供润滑物质来替代人工泪液。例如，美国专利US4,818,537(Guo)公开了一种基于脂质体的润滑组合物的用途，美国专利US5,800,807(Hu等)公开了用于治疗干眼病的含甘油和丙二醇的组合物。
尽管这些方法已经取得了一些成功，然而在干眼病治疗中仍然存在问题。使用泪液替代物虽然暂时有效，但通常需要在患者清醒时反复应用。要求患者在一天中使用人工泪液10至20次是很常见的。这种方式不仅麻烦费时，而且可能非常昂贵。已经报道，在一些病例中，与屈光手术有关的暂时性干眼病症状在术后持续6周至6个月或更长时间。
除了主要致力于缓解与干眼病相关的症状外，还一直在寻找用于治疗干眼病的方法和组合物。例如，美国专利US 5,041,434(Lubkin)公开了性类固醇如轭合雌激素用于治疗绝经后女性的干眼病的用途；美国专利US5,290,572(MacKeen)公开了细粒钙离子组合物用于刺激眼前部泪膜产生的用途；以及美国专利US 4,966,773(Gressel等)公开了一种或多种类视色素的微细颗粒用于使眼组织正常化的用途。
一些最近的文献报道称患有干眼综合征的患者在相关眼组织如泪腺和睑板腺中不相称地出现过度炎症的特征。已经公开了多种化合物用于治疗干眼病患者的用途，如类固醇[例如美国专利US 5,958,912；Marsh等，在干燥综合征中用于干燥性角结膜炎的不含防腐剂的甲基氢化泼尼松局部治疗，Ophthalmology，106(4)：811-816(1999)；Pflugfelder等，美国专利US6,153,607]、细胞因子释放抑制剂(Yanni，J.M等，WO 0003705 A1)、环孢素A[Tauber，J.Adv.Exp.Med.Biol.1998，438(泪腺、泪膜和干眼综合征2)，969]和15-HETE(Yanni等，美国专利US 5,696,166)。
发明概述
本发明涉及治疗干眼病和包括与屈光手术如LASIK手术有关的干眼病症状在内的其它需要湿润眼睛的病症的方法。根据本发明的方法，对患有干眼病或其它需要湿润眼睛的病症的患者施用某些细胞因子合成抑制剂。优选将细胞因子合成抑制剂局部施用于眼。
附图简述
图1显示了SP-600125和地塞米松对容积渗摩尔浓度过高引起的人角膜上皮细胞中细胞因子的产生的体外抑制作用。
发明详述
根据本发明，对患有干眼病的患者施用包括角膜和结膜上皮细胞和基质细胞在内的非免疫驻留眼表细胞(nonimmune resident ocular surfacecells)细胞因子合成的抑制剂。适用于本发明的化合物通过干扰非免疫驻留眼表细胞中信号级联放大的特定效应子而抑制这些细胞中促炎细胞因子的合成。在干眼病治疗中被靶向抑制的细胞因子合成的效应子包括促分裂原活化激酶(MAP激酶、p38激酶)、c-jun N-末端激酶(JNK)和I-κ激酶(IKK)。同样，将促炎细胞因子IL-1β和TNFα的前体转化为活性形式的酶(分别为ICE，IL-1转化酶和TACE，TNF-α转化酶)的抑制剂或抑制细胞因子mRNA翻译的抑制剂也可用于治疗干眼病。细胞因子通过激活Janus家族酪氨酸激酶(JAK)以及信号转导子和转录激活子(STAT)而进一步促进促炎细胞因子的合成，因此JAK和STAT的抑制剂可用于治疗干眼病。激活蛋白-1(AP-1)抑制剂可抑制眼表细胞中细胞因子的合成，故可用于治疗干眼病。此外，已知类视色素X受体(RXR)的配体可抑制上皮细胞中细胞因子的合成，故适用于本发明。
上述种类的细胞因子合成抑制剂是已知的。MAP激酶(p38)抑制剂包括(5-(2-氨基-4-嘧啶基)-4-(4-氟苯基)-1-(4-哌啶基)咪唑)[“SB-220025”]。JNK抑制剂包括蒽并[1，9-cd]吡唑-6(2H)-酮[“SP-600125”]。ICE抑制剂包括pralnacasan(HMR3480/VX-740)。TNF mRNA翻译抑制剂包括(D)精氨酰-(D)正亮氨酰-(D)正亮氨酰-(D)精氨酰-(D)正亮氨酰-(D)正亮氨酰-(D)正亮氨酰-甘氨酸-(D)酪氨酸-酰胺乙酸盐[“RDP58”]。NFkB抑制剂包括2-氯-N-[3，5-二(三氟甲基)苯基]-4-(三氟甲基)嘧啶-5-甲酰胺[“SP-100030”]和三氟醋柳酸。AP-1抑制剂包括SP-100030。RXR激动剂包括贝沙罗汀。
优选用于本发明的细胞因子合成抑制剂是JNK抑制剂和AP-1抑制剂。
根据本发明的方法，对需要其的哺乳动物施用包含一种或多种所述的细胞因子合成抑制剂和可药用载体的组合物，所述的组合物用于眼睛局部施用或植入眼睛的结膜囊或前房。按照本领域已知的方法配制用于所需的特定施用途径的组合物。
本发明所施用的组合物包含药学有效量的一种或多种所述的细胞因子合成抑制剂。此处所用的“药学有效量”是足以减少或消除干眼病或其它需要湿润眼睛的病症的迹象或症状的量。通常，对于以滴眼剂或眼用软膏剂形式局部施用于眼的组合物，细胞因子合成抑制剂的总量为约0.001％至1.0％(w/w)。
优选将本发明所施用的组合物配制成溶液、混悬液和其它用于局部施用的剂型。通常优选水性溶液，因为其易于配制，并且患者能通过在被侵袭的眼内滴加一至两滴该溶液而容易地施用所述组合物。然而，所述组合物也可以是混悬液、粘稠或半粘稠的凝胶剂或者其它类型的固体或半固体组合物。对于略溶于水的细胞因子合成抑制剂而言，优选混悬液。
本发明所施用的组合物还可包含各种其它成分，所述其它成分包括但不局限于表面活性剂、张力调节剂、缓冲剂、防腐剂、助溶剂和粘度构建剂(viscosity building agent)。
对于眼用组合物，可使用各种张力调节剂调节组合物的张力，优选调节至天然泪液的张力。例如，可向组合物中加入氯化钠、氯化钾、氯化镁、氯化钙、右旋糖和/或甘露醇至近似于生理张力。张力调节剂的量根据所加入的具体张力调节剂变化。然而，通常组合物中张力调节剂的量应足以使最终组合物具有眼可接受的重量渗克分子浓度(通常为约150-450mOsm，优选250-350mOsm)。
可向组合物中加入适宜的缓冲体系(例如磷酸钠、乙酸钠、柠檬酸钠、硼酸钠或硼酸)以防止pH在储藏条件下漂移。具体浓度根据所用的缓冲剂而变化。然而，优选选择可将目标pH维持在pH6-7.5范围内的缓冲剂。
配制用于治疗干眼病类疾病和病症的组合物还可包含水性载体，其被设计用于即时、短期缓解干眼病类病症。所述载体可配制成磷脂载体或人工泪液载体，或两者的混合物。此处所用的“磷脂载体”和“人工泪液载体”是指水性组合物，其：(i)包含一种或多种磷脂(当为磷脂载体时)或其它化合物，眼部施用后，其可润滑、“湿润”眼睛，使粘度近似于内源性泪液，并有助于天然泪液的构建，或暂时缓解干眼病症状和病情；(ii)是安全的；和(iii)为局部施用有效量的一种或多种所述的细胞因子抑制剂提供适宜的递送载体。可用作人工泪液载体的人工泪液组合物的实例包括但不局限于市售产品，如Tears Naturale、Tears Naturale II、Tears NaturaleFree和Bion Tears(Alcon Laboratories，Inc.，Fort Worth，得克萨斯)。磷脂载体制剂的实例包括美国专利US 4,804,539(Guo等)、4,883,658(Holly)、4,914,088(Glonek)、5,075,104(Gressel等)、5,278,151(Korb等)、5,294,607(Glonek等)、5,371,108(Korb等)、5,578,586(Glonek等)中公开的那些；在它们公开可用作本发明的磷脂载体的磷脂组合物的范围内，将前述专利在此引入作为参考。
设计用于眼部施用后润滑、“湿润”眼睛、使粘度近似于内源性泪液、有助于天然泪液的构建或暂时缓解干眼病症状和病情的其它化合物是本领域公知的。所述化合物可增加组合物的粘度，其包括但不局限于：单体多元醇，例如甘油、丙二醇、乙二醇；聚合多元醇，例如聚乙二醇、羟丙基甲基纤维素(“HPMC”)、羧甲基纤维素钠、羟丙基纤维素(“HPC”)、右旋糖酐如右旋糖酐70；水溶性蛋白，例如明胶；以及乙烯基聚合物，例如聚乙烯醇、聚乙烯吡咯烷酮、聚维酮和卡波姆例如卡波姆934P、卡波姆941、卡波姆940、卡波姆974P。
也可在本发明的眼用组合物中加入其它化合物以增加载体的粘度。粘度增强剂的实例包括但不局限于：多糖，例如透明质酸及其盐、硫酸软骨素及其盐、右旋糖酐、纤维素家族的各种聚合物、乙烯基聚合物以及丙烯酸聚合物。通常，磷脂载体或人工泪液载体组合物的粘度为1至400厘泊(“cps”)。
局部眼用制品通常被包装成多剂量形式。因此需要添加防腐剂以防止使用过程中的微生物污染。适宜的防腐剂包括：苯扎氯铵、氯代丁醇、溴化苄基十二烷基二甲铵(benzododecinium bromide)、尼泊金甲酯、尼泊金丙酯、苯乙醇、依地酸二钠、山梨酸、聚季铵盐-1或本领域技术人员已知的其它防腐剂。所述防腐剂通常以0.001至1.0％w/v的浓度使用。本发明的单位剂量组合物是无菌的，但通常无防腐剂。因此，所述组合物通常不含有防腐剂。
本发明的优选组合物旨在施用于患有干眼病或干眼病症状的人类患者。优选局部施用该组合物。通常，用于上述目的的剂量可以变化，但应当是消除或改善干眼病病症的有效量。通常，所述组合物每天施用一次至多次，每次1-2滴。
以下实施例1中给出了代表性的滴眼剂制剂。
                 实施例1
  成分   量(％w/w)
  细胞因子合成抑制剂   0.001-1.0
  硬脂酸40聚烃氧基酯   0.1
  硼酸   0.25
  氯化钠   0.75
  依地酸二钠   0.01
  聚季铵盐-1   0.001
  NaOH/HCl   适量，pH＝7.4
  纯化水   适量100％
用以下方法制备上述组合物。称取批次量的硼酸、氯化钠、依地酸二钠和聚季铵盐-1，通过搅拌将其溶解在90％批次量的纯化水中。用NaOH和/或HCl调节pH至7.4±0.1。量取并加入储备液形式的批次量的细胞因子合成抑制剂。加适量纯化水至100％。将混合物搅拌5分钟以进行匀化，然后经除菌滤膜过滤至无菌容器中。
实施例2：对容积渗摩尔浓度过高引起的人角膜上皮细胞中细胞因子的产生的体外抑制作用
在干眼病中，眼的泪膜是异常高渗的，其对眼表细胞形成刺激。用高张介质处理人结膜上皮细胞引起促炎细胞因子的产生。评价选择性JNK抑制剂蒽并[1，9-cd]吡唑-6(2H)-酮对容积渗摩尔浓度过高引起的转化人角膜上皮细胞系CEPI-17中细胞因子分泌的抑制作用。在等张的完全角质细胞生长培养基(iso KGM)中生长CEPI-17细胞，并将其置于48孔板上不含氢化可的松的iso KGM(iso KGM-HC)中。当细胞达到融合时，将其在isoKGM-HC中用指定浓度的化合物预处理1小时。然后，在化合物存在下，用高张KGM-HC(在iso KGM-HC中另外加入80mM NaCl)刺激细胞6小时。用ELISA测定上清液等分试样中的IL-6、IL-8。用由细胞中提取的双链DNA(dsDNA)的量标化细胞因子的释放。通过与赋形剂处理的细胞中的细胞因子水平相比较计算细胞因子产生的抑制百分数。结果如图1所示。在所述条件下，容积渗摩尔浓度过高显著引起CEPI-17细胞中IL-6和IL-8的产生。在100nM下地塞米松显著抑制每种细胞因子的分泌。蒽并[1，9-cd]吡唑-6(2H)-酮(SP-600125)剂量依赖性地抑制IL-6(IC50＝12.6μM)和IL-8(IC50＝3.7μM)的产生。
已经根据某些优选实施方案对本发明进行了描述；然而应当理解的是，可不背离本发明的特定或基本特征而形成本发明的其它具体形式或变体。因此，上述实施方案被认为是在各个方面的举例说明，而非对本发明范围的限制，其中本发明的范围通过所附的权利要求而非上述说明来确定。

Claims (7)

1.治疗干眼病和其它需要湿润眼睛的病症的方法，该方法包括对哺乳动物施用包含可药用载体和药学有效量的细胞因子合成抑制剂的组合物，所述的细胞因子合成抑制剂选自促分裂原活化激酶抑制剂、c-jun N-末端激酶抑制剂、I-κ激酶抑制剂、IL-1β合成抑制剂、TNFα合成抑制剂、Janus家族酪氨酸激酶抑制剂、信号转导子和转录激活子抑制剂和类视色素X受体的配体。
2.权利要求1的方法，其中的细胞因子合成抑制剂选自MAP激酶抑制剂和p38激酶抑制剂。
3.权利要求1的方法，其中的细胞因子合成抑制剂选自(5-(2-氨基-4-嘧啶基)-4-(4-氟苯基)-1-(4-哌啶基)咪唑)、蒽并[1，9-cd]吡唑-6(2H)-酮、pralnacasan、(D)精氨酰-(D)正亮氨酰-(D)正亮氨酰-(D)精氨酰-(D)正亮氨酰-(D)正亮氨酰-(D)正亮氨酰-甘氨酸-(D)酪氨酸-酰胺乙酸盐、2-氯-N-[3，5-二(三氟甲基)苯基]-4-(三氟甲基)嘧啶-5-甲酰胺、三氟醋柳酸和贝沙罗汀。
4.权利要求1的方法，其中的细胞因子合成抑制剂选自c-jun N-末端激酶抑制剂和激活蛋白-1抑制剂。
5.权利要求1的方法，其中细胞因子合成抑制剂的药学有效量是0.001-1.0％(w/w)。
6.权利要求1的方法，其中组合物局部施用于眼。
7.权利要求1的方法，其中干眼病和其它需要湿润眼睛的病症是与屈光手术有关的干眼病症状。
CNA03822514XA 2002-09-20 2003-08-26 细胞因子合成抑制剂用于治疗干眼病的用途 Pending CN1684738A (zh)

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US20060189541A1 (en) 2006-08-24
US7026296B2 (en) 2006-04-11
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TW200404534A (en) 2004-04-01
WO2004026406A1 (en) 2004-04-01
MXPA05003063A (es) 2005-05-27
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