CN1509462A - NF-κB抑制剂在治疗干眼疾病中的用途 - Google Patents
NF-κB抑制剂在治疗干眼疾病中的用途 Download PDFInfo
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Abstract
NF-κB抑制剂可以用于治疗干眼疾病和其他需要湿润眼睛的疾病。
Description
技术领域
本发明涉及干眼疾病的治疗。具体而言,本发明涉及NF-κB抑制剂在治疗哺乳动物中的干眼和其他需要湿润眼睛的疾病中的用途。
发明背景
干眼,通常也被称作干燥性角结膜炎(keratoconjunctivitis sicca),是一种常见的眼科疾病,每年侵袭数百万美国人。由于绝经后妇女不再具有生殖力导致激素的改变,在她们中间该种病症特别广泛。干眼可以以不同的严重性折磨患者。对于较轻的病例,患者可能经历烧灼一样的干燥感和持续的刺激,如由小物体进入眼睑和眼球表面引起的刺激感。在严重的病例中,视力可以被严重损害。其他疾病,如Sjogren病和疤痕性类天疱疮(cicatricial pemphigoid)是干眼并发症。
尽管干眼似乎产生自许多不相关的病因,但是其并发症的所有表现形式都有共同的结果,即眼前泪膜(pre-ocular tear film)的破坏,从而导致暴露的外表面的脱水和上面列出的许多症状(Lemp,Report of the NationalEye Ittstitute/Industry Workshop on Clinical Trials in Dry Eyes,The
CLAO Journal,第21卷,第4期,第221-231页(1995))。
执业医生已经采用了多种方法治疗干眼。一种常用的方法是周所谓的人造眼泪全天灌注以补充和稳定眼的泪膜。其他方法包括使用眼睛插入物以提供眼泪替代物或者刺激内源的眼泪产生。
眼泪替代物的例子包括使用缓冲等渗盐溶液、水性溶液,该水性溶液含有水溶性聚合物以使得溶液更加粘,这样不容易从眼睛中流出。通过提供一种或多种泪膜组分如磷脂和油,也尝试了眼泪重构。已经证明磷脂组合物对治疗干眼有效;见例如McCulley和Shine,Tear film structure anddry eye,
Contactologia,第20卷(4),第145-49页(1998);及Shine和McCulley,Keratoconjunctivitis sicca associated with meibomian secretionpolar lipid abnormality,
Archives of Ophthalmology,第116卷(7),第849-52页(1998)。治疗干眼的磷脂组合物的例子在美国专利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)中公开。美国专利号5,174,988(Mautone等)公开了包括磷脂、抛射剂和活性物质的磷脂药物递送系统。
另一个方法包括提供润滑物质以替代人造眼泪。例如美国专利号4,818,537(Guo)公开了润滑的、基于脂质体的组合物的应用,美国专利号5,800,807(Hu等)公开了含有甘油和丙二醇的治疗干眼的组合物。
尽管这些方法已经取得了一定的成功,但在治疗干眼中仍然存在许多问题。尽管暂时可能有效,但是眼泪替代物的使用,通常需要患者在醒着的期间内反复施用。患者不得不日间施用人工眼泪溶液10到20次,这并不罕见。这种使用方法不但麻烦和耗时,而且可能非常昂贵。已经报道和屈光手术相关的干眼短期症状在一些病例中手术后持续6周到6个月或更长。
除了主要致力于减轻干眼相关症状的努力外,人们还从事了治疗干眼病症的方法和组合物的研究。例如,美国专利号5,041,434(Lubkin)公开了性类固醇(如轭合雌激素)在治疗绝经后妇女的干眼病症中的用途。美国专利号5,290,572(MacKeen)公开了微粉化钙离子组合物在刺激眼前泪膜产生中的用途;和美国专利号4,966,773(Gressel等)公开了一种或多种视黄醛的微粉颗粒在使进行眼组织的正常化中的用途。
一些最近的文献报道表明,患干眼综合症的患者不成比例的显示出在相关眼组织,如泪腺和睑板腺中过度炎症的特点。已经公开了各种治疗干眼患者的化合物的用途,如类固醇[例如美国专利号5,958,912;Marsh,等,Topical nonpreserved methylprednisolone therapy for keratoconjunctivitissicca in Sjogren syndrome,
Ophthalmology,106(4):811-816(1999);Pfiugfelder等,美国专利号6,153,607],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(Lacrimal Gland,Tear Film,and Dry Eye Syndromes 2),969],和15-HETE(Yanni等,美国专利号5,696,166)。
已知炎症过程涉及到几个基因产物通过核转录因子即NF-κB的正调节。在静止状态下,NF-κB作为Iκ-Bα蛋白的异二聚体存在,掩盖核定位信号和所述蛋白的DNA结合域。在炎症状态下,Iκ-Bα蛋白被磷酸化,从而引起构象变化,这导致被遍在蛋白的多拷贝标记。遍在蛋白化的Iκ-Bα被蛋白酶体识别、降解,释放NF-κB。游离蛋白易位入核,在此与适当的DNA序列结合,正调节几个炎症介质产物,如COX-2、iNOS、IL-1和TNF-α的产生。因此,抑制NF-κB合成、激活、易位或者DNA结合活性的抑制剂,能减轻炎症并对干眼病患者的治疗有效。
发明概述
本发明涉及治疗干眼和其他需要湿润眼睛的疾病(包括和屈光手术如LASIK手术相关的干眼症状)的方法。根据本发明的方法,对患干眼或其他需要湿润眼睛的疾病的患者施用NF-κB抑制剂。优选NF-κB抑制剂局部施用于眼。
发明详述
在此所用的“NF-κB抑制剂”指阻止NF-κB合成、激活、易位和/或DNA结合活性的化合物。尽管一些类固醇可作为NF-κB抑制剂,但本发明的“NF-κB抑制剂”不包括类固醇。
NF-κB抑制剂被公知。应用于本发明方法的NF-κB抑制剂示例,包括2-氯代-N-[3,5-二(三氟甲基)苯基]-4-(三氟甲基)嘧啶-5-甲酰胺(也称SP-100030);3,4-二氢-4,4-二甲基-2H-1,2-苯并硒嗪(也称BXT-51072);地氯普胺(或称Oxi-104)和dexlipotam。
根据本发明方法,用于局部眼科施用或植入结膜囊或眼前房的含有一种或多种NF-κB抑制剂和药学上可接受的载体的组合物被施用于需要组合物的哺乳动物。根据本领域已知的方法,制备这些组合物以适于所需的特定的给药途径。
根据本发明,所施用的组合物含有药用有效量的一种或多种NF-κB抑制剂。此处所用的“药用有效量”为足够减轻或消除干眼或其他需要湿润眼睛的疾病的迹象或症状的量。通常而言,对于以眼药水或眼药膏的形式局部施用于眼的组合物,其中NF-κB抑制剂的总量将为约0.001到1.0%(w/v”)。
优选,将根据本发明的组合物配制为溶液、混悬液和其他适合局部给药的剂量形式。基于易于制备,以及患者能方便用药(只需在受感染的眼内慢慢滴入一至两滴这种组合物的溶液)的考虑,通常优选水溶液。然而,组合物也可是混悬液、粘性或半粘性凝胶,或者是其他固体或半固体形式的组合物。对不易溶于水的NF-κB抑制剂优选混悬液。
根据本发明所给予的组合物也可以包括各种其他成分,所包括的不仅限于表面活性剂,也包括张力剂、缓冲剂、防腐剂、共溶剂和粘度增加剂。
各种张力剂可用于调节组合物的张力,对于眼科组合物优选调节到天然眼泪的张力。例如,可以将氯化钠、氯化钾、氯化镁、氯化钙、右旋糖和/或甘露糖醇加入到组合物中到接近生理张力。张力剂的量将依赖于所加的特定药物而变化。然而,通常而言,组合物将含有这样的量的张力剂,即其量足以使最终组合物具有眼科可接受的同渗浓度(通常约为150-450mOsm,优选250-350mOsm)。
可向组合物中加入合适的缓冲系统(例如,磷酸钠、乙酸钠、柠檬酸钠、硼酸钠或硼酸)以防止在储藏条件下pH发生变化。特定浓度将取决于所用的药物。然而,优选对缓冲剂加以选择使目的pH保持在6-7.5的范围内。
制备的用于治疗干眼型疾病和紊乱的组合物还可以含有设计的以提供立即的、短期减轻干眼型状况的水性载体。这些载体可以制备成磷脂载体或人造眼泪载体或它们的混合物。此处所用的“磷脂载体”和“人造眼泪载体,,指水性组合物,其(i)含有一种或多种磷脂(对于磷脂载体)或其他化合物,在对眼施用时,这些化合物润滑、“湿润”、使接近内源眼泪的稠度、帮助天然眼泪积累或者提供干眼症状或状况的短暂减轻;(ii)是安全的;并且(iii)提供局部施用有效量的一种或多种NF-κB抑制剂的合适的递送载体。用作人造眼泪载体的例子或人工眼泪组合物包括,但不限于,商业产品,如Tears Naturale、Tears Naturale II、Tears Naturale Free和BionTears(Alcon Laboratories,Inc.,Fort Worth,Texas)。磷脂载体制剂的例子包括美国专利号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)所公开的那些;在此引用前述专利公开的内容用作本发明磷脂载体的磷脂组合物的部分作为参考。
其他当施用于眼时可以润滑、“湿润”、使接近内源泪水的稠度、帮助天然泪水积聚或者提供干眼症状或状况的暂时减轻的化合物在本领域中是已知的。这些化合物可以提高组合物的粘度,包括但不限于:单体多元醇,如甘油、丙二醇、乙二醇;聚合多元醇,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”)、葡聚糖,如葡聚糖70;水溶性蛋白,如明胶;和烯类聚合物,如聚乙烯醇、聚乙烯吡咯烷酮、聚维酮和卡波姆,如卡波姆934P、卡波姆941、卡波姆940、卡波姆974P。
也可以向本发明眼科组合物中加入其他化合物以增加载体的粘度。粘度增加剂的例子包括,但不限于:多糖,如透明质酸及其盐、硫酸软骨素及其盐、葡聚糖、纤维素家族的各种聚合物;烯类聚合物和丙烯酸聚合物。通常而言,磷脂载体或人工泪水载体组合物的粘度为1到400厘泊(“cps”)。
局部眼科产品通常以多剂量形式包装。因此需要加入防腐剂以防止使用期间的微生物污染。合适的防腐剂包括:苯扎氯铵、氯代丁醇、苯度溴铵、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、苯乙醇、乙二胺四乙酸二钠、山梨酸、阳离子羟乙基纤维基(polyquaternium)-1或其他本领域技术人员已知的试剂。这些防腐剂通常以0.001到1.0%w/v的浓度使用。本发明单位剂量组合物将是无菌的,但通常不保存。因此,这些组合物通常不含防腐剂。
优选将本发明的组合物施用于患干眼或有干眼症状的人类患者。优选将这些组合物局部施用。通常而言,用于上面描述的目的的剂量会发生变化,但是将是消除或改善干眼状况的有效剂量。通常而言,每天施用1到多次、每次1-2滴这样的组合物。
下面的实施例1提供了代表性的眼药水制剂配方。
实施例1
成分 | 用量(%w/v) |
NF-κB抑制剂 | 0.001-1.0 |
聚氧乙烯40硬脂酸酯 | 0.1 |
硼酸 | 0.25 |
氯化钠 | 0.75 |
乙二胺四乙酸二钠 | 0.01 |
阳离子羟乙基纤维基-1 | 0.001 |
NaOH/HCI | q.s.,pH=7.4 |
纯化水 | q.s.100% |
通过下面的方法制备上面的组合物。称量批量的硼酸、氯化钠、乙二胺四乙酸二钠和阳离子羟乙基纤维基-1并通过搅拌溶于90%的批量纯化水,用NaOH和/或HCI调节pH到7.4±0.1。测量并加入批量的作为储液的NF-κB抑制剂。加入纯化水q.s.到100%。搅拌混合物5分钟使其均匀然后通过除菌滤膜过滤到无菌容器内。
已经通过引用某些优选的实施方案对本发明进行了描述;然而,应该理解,可以以其他特定形式或进行某些变化来实施本发明而不脱离其特定的或本质的特征。因此,上面描述的实施方案是用于说明本发明,而非用于限制本发明,本发明的范围由所附的权利要求加以限定而不是由前面的描述加以限定。
Claims (5)
1.一种治疗干眼或其他需要湿润眼睛的疾病的方法,该方法包括对哺乳动物施用含有药学可接受的载体和一种或多种药用有效量的NF-κB抑制剂的组合物。
2.权利要求1的方法,其中所述一种或多种NF-κB抑制剂的药用有效量为0.001-1.0%(w/v)。
3.权利要求1的方法,其中所述NF-κB抑制剂选自:2-氯代-N-[3,5-二(三氟甲基)苯基]-4-(三氟甲基)嘧啶-5-甲酰胺、3,4-二氢-4,4-二甲基-2H-1,2-苯并硒嗪、地氯普胺和dexlipotam。
4.权利要求1的方法,其中所述组合物用于眼部局部给药。
5.权利要求1的方法,其中所述干眼或其他需要湿润眼睛的疾病为与屈光手术相关的干眼症状。
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US (1) | US6696453B2 (zh) |
EP (1) | EP1393277B1 (zh) |
JP (1) | JP2004527578A (zh) |
CN (1) | CN1509462A (zh) |
AT (1) | ATE333273T1 (zh) |
AU (1) | AU2002309963B2 (zh) |
BR (1) | BR0209965A (zh) |
CA (1) | CA2447883A1 (zh) |
CY (1) | CY1105220T1 (zh) |
DE (1) | DE60213230T2 (zh) |
DK (1) | DK1393277T3 (zh) |
ES (1) | ES2263785T3 (zh) |
MX (1) | MXPA03010632A (zh) |
PL (1) | PL367286A1 (zh) |
PT (1) | PT1393277E (zh) |
WO (1) | WO2002095704A1 (zh) |
ZA (1) | ZA200308769B (zh) |
Families Citing this family (1)
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EP1542768A1 (en) * | 2002-09-20 | 2005-06-22 | Alcon, Inc. | Use of cytokine synthesis inhibitors for the treatment of dry eye disorders |
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2002
- 2002-05-17 MX MXPA03010632A patent/MXPA03010632A/es active IP Right Grant
- 2002-05-17 US US10/150,219 patent/US6696453B2/en not_active Expired - Lifetime
- 2002-05-17 BR BR0209965-9A patent/BR0209965A/pt not_active IP Right Cessation
- 2002-05-17 CA CA002447883A patent/CA2447883A1/en not_active Abandoned
- 2002-05-17 DE DE60213230T patent/DE60213230T2/de not_active Expired - Lifetime
- 2002-05-17 CN CNA028102061A patent/CN1509462A/zh active Pending
- 2002-05-17 WO PCT/US2002/015859 patent/WO2002095704A1/en active IP Right Grant
- 2002-05-17 PL PL02367286A patent/PL367286A1/xx not_active Application Discontinuation
- 2002-05-17 PT PT02736994T patent/PT1393277E/pt unknown
- 2002-05-17 AU AU2002309963A patent/AU2002309963B2/en not_active Ceased
- 2002-05-17 DK DK02736994T patent/DK1393277T3/da active
- 2002-05-17 AT AT02736994T patent/ATE333273T1/de active
- 2002-05-17 ES ES02736994T patent/ES2263785T3/es not_active Expired - Lifetime
- 2002-05-17 EP EP02736994A patent/EP1393277B1/en not_active Expired - Lifetime
- 2002-05-17 JP JP2002592087A patent/JP2004527578A/ja active Pending
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2003
- 2003-11-11 ZA ZA2003/08769A patent/ZA200308769B/en unknown
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2006
- 2006-09-14 CY CY20061101314T patent/CY1105220T1/el unknown
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ES2263785T3 (es) | 2006-12-16 |
US20030008854A1 (en) | 2003-01-09 |
DK1393277T3 (da) | 2006-10-30 |
MXPA03010632A (es) | 2004-03-09 |
DE60213230D1 (de) | 2006-08-31 |
US6696453B2 (en) | 2004-02-24 |
AU2002309963B2 (en) | 2007-03-01 |
CY1105220T1 (el) | 2010-03-03 |
EP1393277A1 (en) | 2004-03-03 |
ZA200308769B (en) | 2005-01-26 |
DE60213230T2 (de) | 2006-11-23 |
JP2004527578A (ja) | 2004-09-09 |
ATE333273T1 (de) | 2006-08-15 |
BR0209965A (pt) | 2004-04-06 |
PT1393277E (pt) | 2006-09-29 |
WO2002095704A9 (en) | 2003-02-27 |
CA2447883A1 (en) | 2002-11-28 |
PL367286A1 (en) | 2005-02-21 |
WO2002095704A8 (en) | 2003-09-18 |
EP1393277B1 (en) | 2006-07-19 |
WO2002095704A1 (en) | 2002-11-28 |
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