CN1233172A - 继发性白内障抑制剂 - Google Patents
继发性白内障抑制剂 Download PDFInfo
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Abstract
一种继发性白内障的抑制剂,它含有右式表示的N-(3,4-二甲氧基肉桂酰)氨茴酸或其药学上可接受的盐作为活性成分:该化合物对白内障手术后发生的后囊层浑浊化有抑制作用,因而可用于预防或治疗继发性白内障。
Description
技术领域
本发明涉及可用作继发性白内障抑制剂的药物组合物。
背景技术
白内障是一种难治的眼科疾病,该病会因多种因素而发病和发展,随后因晶状体浑浊而导致视力下降。绝大多数是与年龄有关的高龄白内障。白内障的发病率在60多岁者中据信为60-70%,在80多岁或更高龄者接近100%。在逐渐迈向由大部分老年人所构成的社会过程中,预防和治疗白内障将会变得更加重要。然而,在目前,还没有对白内障的发展有确实抑制活性的治疗剂。因此,需要开发有效的治疗剂。所以,目前白内障的治疗最终取决于用眼镜、隐性眼镜等来矫正视力,或者用手术治疗,例如在囊外白内障摘除术之后将人工晶体插入到晶状体囊中。
在白内障手术中,已指出手术后的继发性白内障是一大问题。继发性白内障是指在囊外白内障摘除术之后残留的后囊层(posterior capsule)表面的浑浊。继发性白内障的机理基本如下所述。即,在切除了晶状体上皮细胞(前囊层)之后,会因残留晶状体上皮细胞(在摘除晶状体皮质时没有完全被去除)迁移到后囊层并增生而导致后囊层浑浊化,从而导致继发性白内障。此外,继发性白内障可起源于:残留的晶状体上皮细胞在赤道部异常增生,并随后形成Elschnig珠。
在白内障手术中,不可能完全去除晶状体上皮细胞,因此难以完全防止继发性白内障。据称,上述后囊层浑浊化的发生率在无晶状体眼中为40-50%,在人工晶状体眼(pseudophakic eye)中为7-20%。
另一方面,在白内障的药疗法领域,广泛的研究已经积极地进行,以便找到能够抑制继发性白内障的物质。迄今为止,例如已证实代谢拮抗剂如丝裂霉素、柔红霉素、5-氟尿嘧啶和秋水仙素均是有效的。然而,这些药物存在问题,例如严重的副作用[Atarashii Ganka,Vol.12,No.pp451-452(1995);Japanese Journal ofOphthalmic Surgery,Vol.8,No.3,pp439-446(1995)],而且在临床上还不足以应用。此外,已报道,当插入的人工晶体涂有吲哚美辛(indometacin)时,可显著抑制继发性白内障的形成,而且乙二胺四乙酸(EDTA)对继发性白内障也是有效的[Japanese Journal of Ophthalmic Surgery,Vol.8,No.3,pp439-446(1995);IOL&RS,Vol.19 No.2 pp.78-82(1995);日本专利申请出版(公开)No.Hei.8-175984]。然而,还未开发出防止和抑制继发性白内障的在临床上令人满意的药物。
本发明的由上式(Ⅰ)表示的N-(3,4-二甲氧基肉桂酰)氨茴酸(一般名称:曲尼司特(Tranilast)),已经广泛地被用作药物治疗变态反应病如支气管哮喘、过敏性鼻炎、特异反应性皮炎和变态反应性结膜炎,以及治疗皮肤疾病如疤痕疙瘩和肥大性疤痕(hypertrophic scar)。例如,已知道曲尼司特对下列现象有抑制作用:变态反应造成的化学中介物释放,在皮肤组织中成纤维细胞造成的胶原过度堆积,和在冠状动脉血管中平滑肌细胞的过度增生。
然而,没有公开过曲尼司特对继发性白内障形成有抑制活性,而且也根本不知道曲尼司特可用作继发性白内障的抑制剂。
发明公开内容
本发明涉及一种继发性白内障抑制剂,它含有下式表示的N-(3,4-二甲氧基肉桂酰)氨茴酸或其药学上可接受的盐作为活性成分:
本发明涉及一种预防或治疗继发性白内障的方法,它包括施用上式(Ⅰ)所表示的N-(3,4-二甲氧基肉桂酰)氨茴酸或其药学上可接受的盐。
本发明还涉及上式(Ⅰ)所表示的N-(3,4-二甲氧基肉桂酰)氨茴酸或其药学上可接受的盐的用途,它们被用于制造用于预防或治疗继发性白内障的药物组合物。
此外,本发明涉及上式(Ⅰ)所表示的N-(3,4-二甲氧基肉桂酰)氨茴酸或其药学上可接受的盐作为继发性白内障抑制剂的用途。
本发明人进行了广泛研究,以寻找对继发性白内障形成有抑制作用的化合物。结果,发现本发明由上式(Ⅰ)表示的N-(3,4-二甲氧基肉桂酰)氨茴酸对晶状体上皮细胞增生有显著的抑制作用,因而可极为有效地作为继发性白内障抑制剂,由此构成了本发明的基础。
相应地,本发明人证实,在用大鼠晶状体上皮细胞进行体外试验中,证实了曲尼司特可明显地抑制晶状体上皮细胞的增生,从而证实了对细胞增生的抑制活性。
结果,曲尼司特对晶状体上皮细胞增生有优异的抑制作用,因而是极为有用的可用作继发性白内障抑制剂的化合物。
因此,可用作继发性白内障抑制剂的药物组合物可这样制备,即,使其含有曲尼司特或其药学上可接受的盐作为活性成分。
用作活性成分的曲尼司特及其盐的各种制备方法是已知的,这些化合物可方便地根据文献中所述的方法制得(日本专利申请出版物(kokoku)No.Sho.56-40710;同上(ibid)No.Sho.57-36905;同上No.Sho.58-17186;同上No.Sho.58-48545;同上No.Sho.58-55138;同上No.Sho.58-55139;同上No.Hei.01-28013;同上No.Hei.01-50219;同上No.Hei.03-37539等)。
作为曲尼司特的药学上可接受的盐的例子,可以例举的有与无机碱形成的盐如钠盐和钾盐,与有机胺(如吗啉、哌嗪和吡咯烷)形成的盐,以及与氨基酸形成的盐。
当本发明的药物组合物被用于实际治疗时,可根据使用情况而采用各种不同剂型的药物组合物。较佳地,可以例举的有眼药水、针剂、眼药膏,或者例如在掺入药丸或微囊后进行植入(plantation),以及在预先涂于人工晶体之后再插入晶体的方法。
这些药物组合物可根据常规方法通过混合、稀释或溶解而进行配制,并且偶尔添加合适的药物添加剂,如赋形剂、崩解剂、粘合剂、润滑剂、稀释剂、缓冲剂、等渗剂(isotonicities)、防腐剂、润湿剂、乳化剂、分散剂、稳定剂和助溶剂,而且该配制过程可根据剂型用惯常方式进行。
例如,眼药水的配制可这样进行:将曲尼司特或其药学上可接受的盐与碱性物质(basic substance)一起通过加热溶解于无菌水(在无菌水中溶解有表面活性剂)中,加入聚乙烯吡咯烷酮,并可任意地加入合适的药物添加剂如防腐剂、稳定剂、缓冲剂和等渗剂、抗氧化剂和增粘剂,然后使其完全溶解。
可通过细针,将针剂直接注射入病理组织如角膜、晶状体和玻璃质中,或它们相邻的组织中。针剂还可被用作眼内灌注液。
本发明的药物组合物可以缓释剂形式给药。例如,曲尼司特或其盐可被掺入以缓释聚合物为载体的药丸或微囊中,然后将该药丸或微囊通过手术植入待治疗的组织。此外,曲尼司特或其盐还可通过插入预先涂有药物的人工晶体而得以应用。作为缓释聚合物的例子,可例举的有乙烯-乙烯基乙酸酯共聚物、聚羟基甲基丙烯酸酯(polyhydrometaacrylate)、聚丙烯酰胺、聚乙烯吡咯烷酮、甲基纤维素、乳酸聚合物、乳酸-乙醇酸共聚物等,较佳地可例举的是可生物降解的聚合物如乳酸聚合物和乳酸-乙醇酸共聚物。
当本发明的药物组合物被用于实际治疗时,作为活性成分的曲尼司特或其药学上可接受的盐的剂量,可根据待治疗的每个病人的体重、年龄、性别、症状程度而合理地加以确定。例如,当滴注入眼内时,这些化合物的给药量约为每个成人10微克-50毫克/天。
取决于待治疗病人的症状程度和治疗效果,曲尼司特或其药学上可接受盐的剂量可以适当地增加或减少。
实施例
接着,通过以下实施例更详细地阐述本发明。
实施例
对晶状体上皮细胞增生的抑制活性
(1)培养大鼠晶状体上皮细胞
采集大鼠晶状体,将其切成细长条。将细长条粘附于培养皿上并在含10%胎牛血清(FBS)的Dulbecco改进的Eagle培养基(DMEM)上,在含5%二氧化碳的空气中,于37℃继代培养4天。在第4天时(在晶状体上皮细胞从晶状体组织中迁移出并增生时),培养基被吸去,用磷酸盐缓冲液(PBS(-))轻柔地洗涤细胞。然后,吸去PBS(-),将一份含0.02%EDTA的0.25%胰蛋白酶溶液加至培养皿,在相差显微镜下观察细胞形态。当细胞变圆时,将等量的含10%FBS的DMEM加至胰蛋白酶溶液中以终止胰蛋白酶的作用。通过用细长的巴氏吸管吸取培养基,将贴壁细胞(attached cell)从培养皿上收集下来。细胞悬浮液被转移至一锥形容器(spit),然后向该锥形容器中加入培养基,通过用巴氏吸管吸取而剧烈地混合细胞悬浮液约20次,然后100-110×g离心1分钟。在弃去上清液之后,向沉淀物加入新鲜的培养基,然后通过用巴氏吸管吸取而制备晶状体上皮细胞的悬浮液。该悬浮液在含10%FBS的DMEM中进一步进行继代培养,以备试验之用。
(2)制备测试药物
将曲尼司特加至1%碳酸氢钠水溶液中,在70℃下加温溶解而制备成1.0%溶液。溶液通过微孔滤器过滤而灭菌,并用含10%FBS的DMEM培养基稀释至最终的规定浓度。
(3)实验方法
将细胞悬浮液(2×104细胞/0.1毫升)以及含有各种浓度曲尼司特和10%FBS的DMEM培养基(1.9毫升)加至培养皿(60毫米)中,在含5%二氧化碳的空气中,于37℃进行培养。4天后,吸去培养基,用PBS(-)洗涤细胞,然后将1毫升含0.02%EDTA的0.25%胰蛋白酶溶液加至培养皿中。在通过巴氏吸管吸取而从培养皿收获细胞之后,用血细胞计数器对活细胞的数目进行计数。
(4)结果评估
计算每组的平均值和标准差数值。用单向方差分析方法进行显著性的统计分析,证实了统计显著性。之后,用Dunnett氏多重测试法对组之间的显著性进行分析。
(5)结果
如图1所示,曲尼司特以依赖于浓度的方式显著地抑制晶状体上皮细胞的增生。
附图简述
图1阐述了曲尼司特对大鼠晶状体上皮细胞增生的抑制活性。纵坐标显示了大鼠晶状体上皮细胞的数目(×104细胞),横坐标显示了加入的曲尼司特浓度(微克/毫升)。在图中,符号*和**分别表示差异显著性为p<0.05和p<0.01。
工业应用性
含有曲尼司特或其药学上可接受盐作为活性成分的药物组合物,对晶状体上皮细胞增生有显著的抑制活性,因而适合用作继发性白内障的抑制剂。
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JP306952/1996 | 1996-10-14 | ||
JP30695296 | 1996-10-14 | ||
JP306952/96 | 1996-10-14 |
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CN1233172A true CN1233172A (zh) | 1999-10-27 |
CN1111403C CN1111403C (zh) | 2003-06-18 |
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CN97198769A Expired - Fee Related CN1111403C (zh) | 1996-10-14 | 1997-10-09 | 继发性白内障抑制剂 |
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US (1) | US6376543B1 (zh) |
EP (1) | EP0958815A4 (zh) |
KR (1) | KR20000049136A (zh) |
CN (1) | CN1111403C (zh) |
AU (1) | AU745028B2 (zh) |
BR (1) | BR9712308A (zh) |
CA (1) | CA2267320A1 (zh) |
CZ (1) | CZ127999A3 (zh) |
EA (1) | EA001745B1 (zh) |
HU (1) | HUP9904617A3 (zh) |
IL (1) | IL129421A0 (zh) |
NO (1) | NO991627L (zh) |
NZ (1) | NZ335042A (zh) |
WO (1) | WO1998016214A1 (zh) |
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AU6748398A (en) * | 1997-04-18 | 1998-11-13 | Kissei Pharmaceutical Co. Ltd. | Preventives or remedies for diseases affecting excessive proliferation of retinal pigment epithelial cells |
US20060172972A1 (en) * | 2002-12-20 | 2006-08-03 | Chakshu Research Inc | Formulation and method for administration of ophthalmologically active agents |
US20060177430A1 (en) * | 2002-12-20 | 2006-08-10 | Chakshu Research Inc | Treatment of ocular disorders with ophthalmic formulations containing methylsulfonylmethane as a transport enhancer |
US20060166879A1 (en) * | 2002-12-20 | 2006-07-27 | Chakshu Research Inc | Treatment of conditions associated with the presence of macromolecular aggregates, particularly ophthalmic disorders |
JP5583310B2 (ja) * | 2002-12-20 | 2014-09-03 | チャクシュ・リサーチ・インコーポレーテッド | 眼球の症状の予防及び治療のための眼科用製剤 |
US20050106230A1 (en) * | 2003-11-17 | 2005-05-19 | Young Janel E. | Drug-enhanced adhesion prevention |
WO2006073126A1 (ja) * | 2005-01-06 | 2006-07-13 | Kissei Pharmaceutical Co., Ltd. | 慢性移植片対宿主症におけるドライアイの予防および治療剤 |
US20070021505A1 (en) * | 2005-07-15 | 2007-01-25 | Chakshu Research, Inc | Prevention and treatment of ophthalmic complications of diabetes |
CA2670590C (en) * | 2006-12-01 | 2018-06-12 | Wake Forest University Health Sciences | Medical devices incorporating collagen inhibitors |
WO2008144933A1 (en) | 2007-05-29 | 2008-12-04 | Université de Montréal | Cinnamoyl inhibitors of transglutaminase |
WO2011003080A1 (en) * | 2009-07-02 | 2011-01-06 | Oxigene, Inc. | Combretastatins for prevention of posterior capsule opacification |
US9844556B2 (en) | 2015-03-25 | 2017-12-19 | Megumi Honjo | Preventive/therapeutic method and preventive/therapeutic agent for complications after cataract surgery |
RU2622606C1 (ru) * | 2016-08-11 | 2017-06-16 | Федеральное государственное автономное учреждение "Межотраслевой научно-технический комплекс "Микрохирургия глаза" имени академика С.Н. Федорова" Министерства здравоохранения Российской Федерации | Способ медикаментозного лечения вторичной катаракты |
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FR2693107B1 (fr) * | 1992-07-01 | 1994-09-23 | Chauvin Laboratoire | Moyens pour la prévention de la cataracte secondaire. |
EP0735895B1 (en) * | 1993-11-19 | 2006-01-18 | The University Of Sydney | A method for preventing or controlling cataract |
WO1997029744A1 (fr) * | 1996-02-15 | 1997-08-21 | Kissei Pharmaceutical Co., Ltd. | Inhibiteur de la neoformation de vaisseaux sanguins |
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1997
- 1997-10-09 EP EP97943164A patent/EP0958815A4/en not_active Withdrawn
- 1997-10-09 CN CN97198769A patent/CN1111403C/zh not_active Expired - Fee Related
- 1997-10-09 AU AU44718/97A patent/AU745028B2/en not_active Ceased
- 1997-10-09 US US09/269,200 patent/US6376543B1/en not_active Expired - Fee Related
- 1997-10-09 IL IL12942197A patent/IL129421A0/xx unknown
- 1997-10-09 KR KR1019990703223A patent/KR20000049136A/ko not_active Application Discontinuation
- 1997-10-09 CA CA002267320A patent/CA2267320A1/en not_active Abandoned
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- 1997-10-09 EA EA199900374A patent/EA001745B1/ru not_active IP Right Cessation
- 1997-10-09 WO PCT/JP1997/003630 patent/WO1998016214A1/ja not_active Application Discontinuation
- 1997-10-09 BR BR9712308-0A patent/BR9712308A/pt not_active Application Discontinuation
- 1997-10-09 NZ NZ335042A patent/NZ335042A/xx unknown
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Publication number | Publication date |
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AU4471897A (en) | 1998-05-11 |
CZ127999A3 (cs) | 1999-07-14 |
AU745028B2 (en) | 2002-03-07 |
WO1998016214A1 (fr) | 1998-04-23 |
HUP9904617A3 (en) | 2000-07-28 |
EP0958815A1 (en) | 1999-11-24 |
NO991627L (no) | 1999-06-03 |
IL129421A0 (en) | 2000-02-17 |
US6376543B1 (en) | 2002-04-23 |
EA199900374A1 (ru) | 1999-12-29 |
EA001745B1 (ru) | 2001-08-27 |
NZ335042A (en) | 2001-01-26 |
BR9712308A (pt) | 1999-08-31 |
HUP9904617A2 (hu) | 2000-05-28 |
KR20000049136A (ko) | 2000-07-25 |
CA2267320A1 (en) | 1998-04-23 |
NO991627D0 (no) | 1999-04-06 |
CN1111403C (zh) | 2003-06-18 |
EP0958815A4 (en) | 2001-02-07 |
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