CN1473039A - 含有法呢基乙酸作为活性成分的角膜结膜疾病治疗药物 - Google Patents
含有法呢基乙酸作为活性成分的角膜结膜疾病治疗药物 Download PDFInfo
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Abstract
本发明提供了能促进眼组织中粘蛋白产生和分泌的新物质。本发明的角膜结膜疾病治疗药物含有法呢基乙酸或其盐作为活性成分。这些角膜结膜疾病治疗药物可用于干眼病、角膜炎、结膜炎、角膜上皮脱落、角膜溃疡等。
Description
技术领域
本发明涉及一种含有法呢基乙酸或其盐作为活性成分的角膜结膜疾病治疗药物。
背景技术
生物体具有保护黏膜的防御机制。黏膜的上皮细胞上总是覆盖着粘性外分泌液，这种外分泌液中含有外分泌腺分泌的粘蛋白。在眼睛中，眼泪发挥着这样的作用。泪液层由三层组成，即脂层、水层和粘蛋白层，角膜结膜上皮细胞与粘蛋白层接触。构成粘蛋白层的粘蛋白是由结膜杯型细胞和角膜结膜上皮细胞所分泌的一种糖蛋白，它使泪液能良好保留，保持角膜和结膜湿润。
干眼病是一种具有眼干症状并由于泪液异常造成角膜上皮障碍的疾病。干眼病症状的例子有眼干、角膜充血、痒、异物感等。当干眼病严重时，有时会造成失明。泪液分泌的降少、泪液层的不稳定等被认为是造成干眼病发病的原因，但这些病因还未得到确认。
因此，如果有一种物质能够促进粘蛋白分泌到泪液中，这种物质可望用于治疗角膜结膜上皮上有问题的角膜结膜疾病，例如干眼病、角膜炎、结膜炎、角膜上皮脱落和角膜溃疡。
日本公开的专利申请194363/1997号公开了元白菜素，它是法呢基乙酸与香叶醇的一种酯，它具有促进眼组织中粘蛋白产生和分泌的作用，对治疗角膜结膜疾病如干眼病有效。
但是，没有关于元白菜素游离羧酸法呢基乙酸应用于眼科领域的报道，根本不知道法呢基乙酸如何作用于角膜结膜疾病。
因此，发现法呢基乙酸对角膜结膜疾病的药理作用是一项很有意义的课题。
发明内容
本发明人研究了法呢基乙酸对粘蛋白产生和分泌的促进作用，以发现其新的药理作用，结果发现，法呢基乙酸对粘蛋白的产生和分泌具有显著的促进作用。证明法呢基乙酸甚至在比元白菜素低得多的浓度下也具有与元白菜素同等的效果。
本发明涉及含有下式代表的法呢基乙酸或其盐作为活性成分的角膜结膜疾病治疗药物，所述角膜结膜疾病例如为干眼病、角膜炎、结膜炎、角膜上皮脱落和角膜溃疡。它们的效果将在药理试验部分详细描述。
本发明化合物的盐可以是任何药物可接受的盐，例如与碱金属或碱土金属的盐，如钠盐、钾盐或钙盐，铵盐，和与有机胺如二乙胺或三乙醇胺的盐。
法呢基乙酸或其盐的剂型的例子有眼科制剂如滴眼液和眼膏，以及注射液。法呢基乙酸或其盐可以利用广泛使用的方法配制成这种制剂。例如，滴眼液可以用下列物质制备：任选的等渗剂如氯化钠和浓甘油；缓冲剂如磷酸钠和乙酸钠；表面活性剂如聚山梨酯80、聚氧乙烯氢化蓖麻油60和聚乙二醇4000；稳定剂如柠檬酸钠和乙二胺四乙酸二钠；防腐剂如苯扎氯铵和对羟基苯甲酸酯类；pH调节剂如氢氧化钠和盐酸。最好将pH调节到中性左右，最好将渗透压调节到约1.0。
本发明还涉及一种治疗角膜结膜疾病的方法，其包括给予患者有效量的法呢基乙酸或其盐；还涉及一种促进粘蛋白产生的方法或一种治疗涉及粘蛋白产生的疾病的方法，其包括给予患者有效量的法呢基乙酸或其盐。
可以根据症状、年龄、剂型等适当地选择剂量。对于滴眼液，0.0001％到3(w/v)、优选0.001％到1％(w/v)的溶液，每天可以滴1次到数次。
本发明的最佳实施方式
药理试验：利用泪腺-瞬眼膜-副泪腺摘除的兔干眼病模型研究了法呢基乙酸对干眼病的作用。
兔干眼病模型的制备
参照Girbard等(Invest.Ophthalmol.Vis.Sci.，28：225-228(1987))的方法制备了泪腺-瞬眼膜-副泪腺摘除的兔干眼病模型。即，给兔子以1ml/kg的量注射5％盐酸氯胺酮注射液和2％盐酸赛拉嗪注射液的7∶1混合物，系统麻醉兔子。给兔子滴注0.4％的盐酸奥布卡因滴眼液，沿眶骨将下眼睑皮肤切开约5毫米，然后从结膜袋的外侧摘除泪腺。将切开位置的皮肤用4-0缝线缝合，在切口位置施用氧氟沙星眼膏。然后，摘除副泪腺，将其与瞬眼膜一起拉出。最后，在摘除位置施用氧氟沙星眼膏。
滴眼液的制备
通过用下述载体稀释法呢基乙酸达到0.75、7.5和75μM的浓度，来制备法呢基乙酸滴眼液。通过用同样的载体稀释元白菜素到7.5mM的浓度，制备元白菜素滴眼液。所有获得的滴眼液的pH为7.4，渗透压为1.0。
载体(100毫升中)
聚氧乙烯氢化蓖麻油40 0.3g
NaH2PO4·2HO2 1.0g
乙二胺四乙酸二钠 0.05g
NaCl 0.4g
无菌纯化水 足量给药
将每种法呢基乙酸滴眼液(50μl)滴注给泪腺-瞬眼膜-副泪腺摘除的兔子，每天6次，共2周(每组4只兔子，8只眼)。在对照组和比较组中，分别类似地滴注载体和元白菜素。评价方法
通过测定四氯四碘荧光素的吸收评价对干眼病的效果。给兔子以1ml/kg的量注射5％盐酸氯胺酮注射液和2％盐酸赛拉嗪注射液的7∶1混合物，系统麻醉兔子，然后用开睑器切开眼睑，并在结膜袋中注满含1％四氯四碘荧光素的生理盐水。将这样处理的眼睛保持10秒钟，然后用生理盐水洗涤。给兔子注射5％戊巴比妥注射液进行安乐死，摘下眼球。使用8毫米内径的环钻制备角膜片，将它们放置在1毫升2M氢氧化钠溶液中，然后避光静置一天，以将角膜组织完全溶解。用分光光度计测定所得组织溶解溶液在560纳米波长处的吸光度。
四氯四碘荧光素对角膜结膜中无粘蛋白层的部分染色。如果粘蛋白层存在，四氯四碘荧光素将被阻止不能透入角膜结膜组织，但如果粘蛋白层不存在，四氯四碘荧光素容易到达角膜结膜组织。因此，当粘蛋白层由于干眼病而减少时，角膜组织的四氯四碘荧光素吸收增加，从而所述组织溶解溶液的吸光度增加。结果
吸光度的测定结果显示在表1中。法呢基乙酸给药组中的四氯四碘荧光素吸收显著少于载体对照组，在各法呢基乙酸给药组中，四氯四碘荧光素的吸收大致呈浓度依赖性降低。另外，结果证明，甚至在元白菜素浓度的约1/100的浓度下，法呢基乙酸(75μM给药组)显示与元白菜素(7.5mM给药组)同等的效果。从上述结果可知，因为法呢基乙酸促进粘蛋白的产生和分泌，法呢基乙酸可望用于防治角膜结膜疾病，如干眼病。
| 吸光度 | |
| 对照组(载体) | 0.236 |
| 法呢基乙酸0.75μM7.5μM75μM | 0.1690.1390.093 |
| 比较组(元白菜素7.5mM) | 0.075 |
工业实用性
上述药理试验的结果明确显示，法呢基乙酸对粘蛋白的产生和分泌具有促进作用，可用作角膜结膜疾病的治疗药物，例如对干眼病、角膜炎、结膜炎、角膜上皮脱落和角膜溃疡。
Claims (15)
1.角膜结膜疾病治疗药物，其含有法呢基乙酸或其盐作为活性成分。
2.如权利要求1所述的角膜结膜疾病治疗药物，其中角膜结膜疾病为干眼病、角膜炎、结膜炎、角膜上皮脱落或角膜溃疡。
3.如权利要求1或2所述的角膜结膜疾病治疗药物，其中剂型为眼科制剂。
4.如权利要求3所述的角膜结膜疾病治疗药物，其中法呢基乙酸或其盐的浓度为0.001％到1％(w/v)。
5.一种促进粘蛋白产生的促进剂，其含有法呢基乙酸或其盐作为活性成分。
6.一种治疗角膜结膜疾病的方法，包括给予患者有效量的法呢基乙酸或其盐。
7.如权利要求6所述的治疗角膜结膜疾病的方法，其中角膜结膜疾病为干眼病、角膜炎、结膜炎、角膜上皮脱落或角膜溃疡。
8.一种治疗角膜结膜疾病的方法，包括给患者滴注有效量的法呢基乙酸或其盐。
9.如权利要求8所述的治疗角膜结膜疾病的方法，其中法呢基乙酸或其盐以0.001％到1％(w/v)的浓度滴注。
10.一种促进粘蛋白产生的方法，包括给予患者有效量的法呢基乙酸或其盐。
11.法呢基乙酸或其盐在制造角膜结膜疾病治疗药物中的应用。
12.如权利要求11所述的法呢基乙酸或其盐的应用，其中角膜结膜疾病为干眼病、角膜炎、结膜炎、角膜上皮脱落或角膜溃疡。
13.如权利要求11或12所述的法呢基乙酸或其盐的应用，其中剂型为眼科制剂。
14.如权利要求13所述的法呢基乙酸或其盐的应用，其中法呢基乙酸或其盐的浓度为0.001％到1％(w/v)。
15.法呢基乙酸或其盐在制造粘蛋白产生促进剂中的应用。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP340115/2000 | 2000-11-08 | ||
| JP2000340115 | 2000-11-08 | ||
| JP340115/00 | 2000-11-08 |
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| Publication Number | Publication Date |
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| CN1473039A true CN1473039A (zh) | 2004-02-04 |
| CN1228047C CN1228047C (zh) | 2005-11-23 |
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| CNB018185592A Expired - Fee Related CN1228047C (zh) | 2000-11-08 | 2001-11-08 | 含有法呢基乙酸作为活性成分的角膜结膜疾病治疗药物 |
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| Country | Link |
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| US (1) | US20040014812A1 (zh) |
| EP (1) | EP1338279A1 (zh) |
| KR (1) | KR20030048129A (zh) |
| CN (1) | CN1228047C (zh) |
| AU (1) | AU2002214267A1 (zh) |
| CA (1) | CA2428207A1 (zh) |
| NO (1) | NO20032035L (zh) |
| WO (1) | WO2002038149A1 (zh) |
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| US20080153908A1 (en) * | 2006-12-20 | 2008-06-26 | Jani Dharmendra M | Method of Treating Mucin Deficiency with an Active Pharmaceutical and Related Composition |
| JP5758501B2 (ja) * | 2012-08-10 | 2015-08-05 | 三菱重工業株式会社 | 浮体式風力発電装置 |
| JP6760275B2 (ja) * | 2015-05-12 | 2020-09-23 | ライオン株式会社 | 眼科用組成物 |
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| JPS5573642A (en) * | 1978-11-28 | 1980-06-03 | Kuraray Co Ltd | Farnesyl-acetic ester derivative |
| GB8710780D0 (en) * | 1987-05-07 | 1987-06-10 | Scras | Opthalmological application of eicosapentaenoic acid |
| US5567729A (en) * | 1993-10-28 | 1996-10-22 | David L. Bradfute | Farnesyl compounds as farnesyl protein transferase inhibitors to treat ras induced tumor growth |
| JP3136352B2 (ja) * | 1996-01-22 | 2001-02-19 | 参天製薬株式会社 | 角結膜疾患治療剤 |
| JPH10265378A (ja) * | 1997-03-25 | 1998-10-06 | Ofutekusu:Kk | 角膜上皮損傷治療剤 |
| US6303654B1 (en) * | 1998-03-12 | 2001-10-16 | Wisconsin Alumni Research Foundation | Acyclic monoterpenoid derivatives |
| US6432931B1 (en) * | 1998-06-24 | 2002-08-13 | Merck & Co., Inc. | Compositions and methods for inhibiting bone resorption |
-
2001
- 2001-11-08 WO PCT/JP2001/009760 patent/WO2002038149A1/ja active Application Filing
- 2001-11-08 CA CA002428207A patent/CA2428207A1/en not_active Abandoned
- 2001-11-08 AU AU2002214267A patent/AU2002214267A1/en not_active Abandoned
- 2001-11-08 CN CNB018185592A patent/CN1228047C/zh not_active Expired - Fee Related
- 2001-11-08 US US10/415,725 patent/US20040014812A1/en not_active Abandoned
- 2001-11-08 EP EP01982746A patent/EP1338279A1/en not_active Withdrawn
- 2001-11-08 KR KR10-2003-7006263A patent/KR20030048129A/ko not_active Application Discontinuation
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2003
- 2003-05-06 NO NO20032035A patent/NO20032035L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| CA2428207A1 (en) | 2002-05-16 |
| US20040014812A1 (en) | 2004-01-22 |
| EP1338279A1 (en) | 2003-08-27 |
| CN1228047C (zh) | 2005-11-23 |
| NO20032035D0 (no) | 2003-05-06 |
| NO20032035L (no) | 2003-06-20 |
| AU2002214267A1 (en) | 2002-05-21 |
| KR20030048129A (ko) | 2003-06-18 |
| WO2002038149A1 (fr) | 2002-05-16 |
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