CN1041795C - 眼用组合物 - Google Patents
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- CN1041795C CN1041795C CN93116550A CN93116550A CN1041795C CN 1041795 C CN1041795 C CN 1041795C CN 93116550 A CN93116550 A CN 93116550A CN 93116550 A CN93116550 A CN 93116550A CN 1041795 C CN1041795 C CN 1041795C
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
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Abstract
本发明涉及一种滴眼剂组合物，该组合物由匹罗卡品、β-阻断剂以及一种眼可接受的载体和任意的其它眼可接受的辅剂组成。该组合物特征在于其pH为3.5-5.8，粘度为10-25,000mPas。本发明还涉及上述组合物的制备以及其在制备用于治疗高眼压和青光眼的药物中的用途。
Description
本发明的对象是一种眼用组合物，尤其是一种滴眼液组合物。该组合物由匹罗卡品和另外一种治疗眼压升高的药物，比如一种β-阻断剂象噻吗洛尔组成，该组合物还包括一种眼睛可接受的载体和任选的其它一些眼睛可接受的辅剂。本发明还涉及上述组合物的制备方法以及其治疗高眼压和青光眼的用途。
从欧洲专利申请253717得知，以滴眼剂组合配方形式在眼内同时使用一种β-阻断剂和匹罗卡品，该滴眼剂配方用缓冲剂调pH为6.0-6.8。这种组合配方而非两药分别给药的使用方法，除了有利的治疗效果外还具有使患者更易于接受的优点。
然而，根据欧洲专利253717所提供的配方有其缺点，即所配制的溶液仅在短期内可用，因此必须在首次用药之前的短期内制备，或将一种固体物质与一种溶液组合，或将两种溶液混合。因此根据该欧洲专利提供的配方不能以传统的瓶包装或一种单剂量包装提供给使用者，因为这两种包装形式都要求所装的药液可立即滴眼，而且是足够稳定的。
欧洲专利253717所公开的配方对使用的包装技术和病人的接受都有严格的要求。此外，高度复杂的包装实际上比传统包装贵得多，因为这种包装的结构必须便于在用药前的短时间内配制成组合物。配方中各种成分由非制造者的其他人配制，肯定存在配制错误的风险。为了保证各组分混合后仍无菌，该配方含有抗微生物的防腐剂。
然而，早已所知抗微生物的防腐剂对角膜表现出若干副作用。在眼的治疗中，无防腐剂和以单剂量形式包装的配方已被越来越多使用。多剂量容器被放弃的另一原因是，特别在医院，同一容器给几个病人用药，增加了该药污染的危险性，用这种滴眼剂还增加了传播传染病的危险性。
我们现已意外地发现，根据本发明能够制造一种组合的滴眼剂组合物，该组合物在同一溶液中含有匹罗卡品和一种β-阻断剂，这种滴眼剂很稳定，足以包装在传统的眼药瓶或单剂量容器中以立即可用的形式提供使用。
本发明提供了一种组合物，其pH为3.5-5.8，粘度为10-25,000mPas(毫帕斯卡·秒)，达到了上述目的。
较好的是pH在4.5-5.5，粘度不超过150mPas，特别是在15-50mPas更好。
用Brookfield粘度计(型号为LVDV-Ⅲ)在22℃测量粘度。当粘度范围为100-25,000mPas时，切变粘滞率D=1/秒，粘度范围在10-100mPas时，D=8/秒。
已知在pH接近中性时，匹罗卡品的稳定性减低，在pH为6或6以上时，其稳定性仅能保持几周，甚至几天。然而当pH降至6以下时，匹罗卡品的降解速度明显减低，作为商品药来说是足够稳定的。
然而，当pH降低，与接近中性的溶液相比，活性药物的生物利用度也会降低。依据本发明，生物利用度的降低可通过增加组合物的粘度补偿，这样可在眼表面有较长的接触时间。
依据本发明，与匹罗卡品共同治疗高眼压的药物一般说来是碳酸酐酶抑组合物、前列腺素或任何该领域已知的肾上腺素能受体的阻断剂、兴奋剂，如β-阻断剂，其典型例子是卡替洛尔、苯呋洛尔、美替洛尔、吲哚洛尔、倍他洛尔、左布诺洛尔，特别是噻吗洛尔，还可以是上述药物的眼睛可接受的盐及前体药物。
本发明所指的眼睛可接受的载体赋形剂，较好的是洁净的水或一种水与眼可接受的有机溶剂的混合液，该有机溶剂是该领域已知的。本发明的组合物中还可以含有其它一些眼可接受的辅剂。
为了调整或稳定pH，可以使用某些常规的pH调节剂，如酸、碱或合适的缓冲剂，象磷酸盐缓冲剂、硼酸盐缓冲剂、醋酸盐缓冲剂和柠檬酸盐缓冲剂。为了调整产品的张力，可用一些常规使用的物质，如氯化钠、氯化钾、甘油、甘露糖醇、山梨醇、硼酸钠、醋酸钠或诸如此类的物质。
在组合物中用一种合适的粘度增加剂调节粘度，用适当的量调节至所需粘度。典型的例子是纤维素类衍生物，例如羟丙基甲基纤维素(HPMC，如英国Colorcon公司的Methocel)、羧甲基纤维素钠(如英国Aqualon公司的Blanose)、甲基纤维素(如英国Colorcon公司的Methocel A)、聚乙烯吡咯烷酮(如英国GAF公司的Plasdone)、聚乙烯醇(如英国Wacker化学品公司的Polyviol)、右旋糖酐(如美国Sigma公司的Dextran)、聚丙烯酸(如英国Goodrich公司的Carbopol)等等。所加的聚合物用量除决定于所需的粘度，还取决于所用的聚合物，这个量的确定对该领域的普通技术人员是很容易的。除了提高组合物的粘度，使用上述聚合物还有其它优点，如对眼睛的润滑作用以及对泪膜的稳定作用，这些作用对某些患者如患眼干症者是有益的。
在需要抗微生物剂的情况下，如在以多剂量而非单剂量容器包装组合物的情况下，可以使用一些已知的抗微生物剂，象季铵化合物类如洁尔灭，还可用苯甲醇、汞盐、硫柳汞、洗必泰、三氯叔丁醇或其类似物，单用或并用。
根据本发明制备的一种有效的滴眼剂组合物是用无菌水作为载体赋形剂，其组成如下(％重量/体积)：盐酸匹罗卡品1-5％，最好为2-4％，与一种β-阻断剂配伍，特别是噻吗洛尔，其含量为0.1-1％，最好在0.25-0.5％，羟丙基甲基纤维素作为增稠剂，含量0.3-1％，使粘度达10-150mPas，最好为15-50mPas，柠檬酸缓冲液调pH达4.5-5.5。此外配方中可含有一种可接受的微生物防腐剂，如洁尔灭，典型用量为0.04-0.2mg/ml。
本发明也涉及如上定义的一种滴眼剂组合物的制备工艺，包括组合匹罗卡品和一种其它治疗高眼压的药物及一种眼可接受的载体、调节pH值至3.5-5.8，粘度值10-25,000mPas，或者还加入其它眼可接受的辅剂。
本发明还涉及这种治疗高眼压和青光眼的滴眼剂组合物的应用。
本发明在下述例子中得到说明，这些例子并不能限定本发明。实施例1：多剂量组合物
组分(mg) A B盐酸匹罗卡品 20.0 40.0马来酸噻吗洛尔 6.84 6.84柠檬酸·H2O 1.12 0.88柠檬酸钠·2H2O 5.79 6.13洁尔灭 0.1 0.1羟丙基甲基纤维素 5.0 5.0无菌水 加至 1.0ml 1.0ml
实施例1提供的滴眼液以三步制备。第一步将羟丙基甲基纤维素在无菌水中搅匀，将该溶液置于高压灭菌器中灭菌，然后在搅拌下使高压灭菌的溶液冷却至室温。
第二步将洁尔灭、柠檬酸、柠檬酸钠、盐酸匹罗卡品和马来酸噻吗洛尔在室温下溶于无菌水，将该溶液用孔径为0.2μm的滤器过滤灭菌。
第三步即最后一步，将上两步制备的熔液在无菌操作下混合直至成为均一的溶液。所得到的溶液的pH为5.3，粘度为25mPas，该溶液被包装在传统的眼药瓶中。实施例2：单剂量组合物
组分(mg) A B盐酸匹罗卡 20.0 40.0马来酸噻吗洛尔 6.84 6.84柠檬酸·H2O 1.12 0.88柠檬酸钠·2H2O 5.79 6.13羟丙基甲基纤维素 5.0 5.0无菌水 加至 1.0ml 1.0ml
该溶液依照实施例1的方法制备，所得溶液的pH为5.3，粘度为25mPas，该溶液被包装在单剂量容器中。实施例3：单剂量组合物
组分(mg)盐酸匹罗卡品 20.0噻吗洛尔·1/2H2O 5.12柠檬酸·H2O 2.40柠檬酸钠·2H2O 4.00羟丙基甲基纤维素 5.0无菌水 加至 1.0ml
该溶液依照实施例1的方法制备，所得溶液的pH为5.3，粘度为25mPas，该溶液被包装在单剂量容器中。在配方中加入洁尔灭0.10mg/ml，可得到相应的多剂量组合物。实施例4：
组分(mg)盐酸匹罗卡品 20.0马来酸噻吗洛尔 6.84柠檬酸·H2O 1.12柠檬酸钠·2H2O 5.79洁尔灭 0.10聚乙烯醇 115000 40.00无菌水 加至 1.0ml
该溶液依照实施例1的方法制备，所得溶液的pH为5.3，粘度为25mPas。实施例5：
组分(mg)盐酸匹罗卡品 20.0mg盐酸倍他洛尔 5.6mg羟丙基甲基纤维素 5.0mg氢氧化钠/盐酸 加至pH 5.3无菌水 加至 1.0ml
该溶液依照实施例1的方法制备，所得溶液的pH为5.3，粘度为25mPas。实施例6：
下面描述两种高粘度产品的制备
组分(mg)盐酸匹罗卡品 20.0马来酸噻吗洛尔 6.84柠檬酸·H2O 1.12柠檬酸钠·2H2O 5.79洁尔灭 0.10Carbopol(聚丙烯酸)941 9.0NaOH 适量 加至 pH5.0-5.5无菌水 加至 1.0g
该溶液依照实施例1的方法制备，所得溶液的pH为5.2，粘度为24000mPas。盐酸匹罗卡品 20.0噻吗洛尔·1/2H2O 5.12柠檬酸·H2O 1.12柠檬酸钠·2H2O 5.79洁尔灭 0.10Carbopol(聚丙烯酸)941 7.5NaOH适量加至 pH5.0-5.5无菌水 加至 1.0g
该溶液依照实施例1的方法制备，所得溶液的pH为5.5，粘度为13700mPas。
Claims (17)
1．一种滴眼剂组合物，由匹罗卡品、一种β-阻断剂以及一种眼可接受的载体和任意的其它眼可接受的辅剂组成，其特征在于该组合物的pH为3.5-5.8，粘度为10-25,000mPas。
2．权利要求1的组合物，其特征为该pH值为4.5-5.5。
3．权利要求1或2的组合物，其特征在于该组合物的粘度为10-150mPas。
4．权利要求3的组合物，其特征在于该组合物的粘度为15-50mPas。
5．权利要求1或2的组合物，其特征在于该组合物用一种合适的缓冲剂调节pH值。
6．权利要求5的组合物，其特征在于该组合物用柠檬酸盐缓冲剂调节pH值。
7．权利要求3的组合物，其特征在于使用羟丙基甲基纤维素作为增稠剂。
8．权利要求4的组合物，其特征在于使用羟丙基甲基纤维素作为增稠剂。
9．权利要求1的组合物，其特征在于该β-阻断剂的浓度为0.1-1％(重量/体积)，匹罗卡品的浓度为1-5％(重量/体积)。
10．权利要求9的组合物，其特征在于该β-阻断剂的浓度为0.25-0.5％(重量/体积)，匹罗卡品的浓度为2-4％(重量/体积)。
11．权利要求1、9或10的组合物，其特征在于该β-阻断剂是一个噻吗洛尔化合物。
12．权利要求11的组合物，其特征在于该噻吗洛尔化合物选自噻吗洛尔碱、噻吗洛尔半水合物或一种药物上可接受的噻吗洛尔盐。
13．权利要求12的组合物，其特征在于该药物上可接受的噻吗洛尔盐是噻吗洛尔马来酸盐。
14．权利要求1的组合物，其特征在于该组合物以一种单剂量形式包装。
15．权利要求1的滴眼液组合物的制备方法，其特征在于该方法包括组合匹罗卡品和一种β-阻断剂，用一种眼可接受的载体，调节pH值至3.5-5.8，粘度值10-25,000mPas，以及还任选加入其它一些眼可接受的辅剂。
16．权利要求15的滴眼液组合物的制备方法，其中该组合物是根据权利要求2-14中任一权利要求所限定的。
17．匹罗卡品和一种β-阻断剂在制备用于治疗高眼压和青光眼的权利要求1-14的滴眼液组合物中的组合应用。
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| SE92023985 | 1992-08-20 | ||
| SE9202398-5 | 1992-08-20 | ||
| SE9202398A SE512871C2 (sv) | 1992-08-20 | 1992-08-20 | Oftalmologisk beredning innehållande pilokarpin och ytterligare medel för behandling av okular hypertension |
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| CN1089837A CN1089837A (zh) | 1994-07-27 |
| CN1041795C true CN1041795C (zh) | 1999-01-27 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| AU721273B2 (en) * | 1996-09-20 | 2000-06-29 | Bausch & Lomb Incorporated | Method and composition for rewetting contact lenses and relieving eye dryness |
| US6335335B2 (en) | 1997-11-05 | 2002-01-01 | Senju Pharmaceutical Co., Ltd. | Prolonged-action eye drop |
| JP4377052B2 (ja) * | 1997-11-05 | 2009-12-02 | 千寿製薬株式会社 | 持続性点眼剤 |
| MY116782A (en) | 1997-12-22 | 2004-03-31 | Otsuka Pharma Co Ltd | Water-soluble eye drop |
| JP2005247875A (ja) * | 2000-07-21 | 2005-09-15 | Rohto Pharmaceut Co Ltd | 点眼剤 |
| JP2002097129A (ja) * | 2000-07-21 | 2002-04-02 | Rohto Pharmaceut Co Ltd | 点眼剤 |
| JP5364658B2 (ja) * | 2000-07-21 | 2013-12-11 | ロート製薬株式会社 | 点眼剤 |
| AU2002245134A1 (en) * | 2000-12-21 | 2002-08-06 | Alcon Universal Ltd. | Artificial tear composition adapted to be used with contact lenses |
| CN100483106C (zh) * | 2002-09-29 | 2009-04-29 | 天津市先石光学技术有限公司 | 可分离介质表层与深层信息的光学检测方法 |
| US7862552B2 (en) | 2005-05-09 | 2011-01-04 | Boston Scientific Scimed, Inc. | Medical devices for treating urological and uterine conditions |
| JP2011513393A (ja) * | 2008-03-07 | 2011-04-28 | サン、ファーマ、アドバンスト、リサーチ、カンパニー、リミテッド | 眼用組成物 |
| RU2402316C2 (ru) * | 2009-01-11 | 2010-10-27 | Пшеничников Виталий Георгиевич | Фармацевтическая антиглаукомная композиция |
| MY168643A (en) | 2011-09-20 | 2018-11-27 | Allergan Inc | Compositions and methods for treating presbyopia, mild hyperopia, and irregular astigmatism |
| PT3681500T (pt) | 2018-04-24 | 2022-06-27 | Allergan Inc | Utilização do cloridrato de pilocarpina para o tratamento da presbiopia |
| CN119300821A (zh) * | 2022-06-03 | 2025-01-10 | Amd治疗有限责任公司 | 利福霉素的眼用组合物及其用途 |
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| WO1991019481A1 (en) * | 1990-06-15 | 1991-12-26 | Allergan, Inc. | Reversible gelation compositions and methods of use |
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| FR2601247A1 (fr) * | 1986-07-09 | 1988-01-15 | Merk Sharp Dohme Chibret Labor | Combinaison d'agents beta-bloquants et de pilocarpine. |
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| WO1991019481A1 (en) * | 1990-06-15 | 1991-12-26 | Allergan, Inc. | Reversible gelation compositions and methods of use |
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