CN1088361C - 治疗骨关节炎的组合物 - Google Patents

治疗骨关节炎的组合物 Download PDF

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CN1088361C
CN1088361C CN95196816A CN95196816A CN1088361C CN 1088361 C CN1088361 C CN 1088361C CN 95196816 A CN95196816 A CN 95196816A CN 95196816 A CN95196816 A CN 95196816A CN 1088361 C CN1088361 C CN 1088361C
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tribenoside
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diclofenac
treatment
mao
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J·查耶
L·比登斯基
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KS Biomedix Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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Abstract

双氯芬酸钠和三苄糖苷，或更一般来说(i)一种作用在软骨细胞上的化合物和(ii)一种减少软骨细胞基质水含量的化合物，用于治疗骨关节炎。

Description

治疗骨关节炎的组合物
本发明领域
本发明涉及用于治疗骨关节炎(OA)的组合物。
发明背景
已知许多药物用于治疗骨关节炎，但一般来说它们的效果差，尤其是副作用需要避免的情况下。其中一种已知药物是双氯芬酸钠。
在正常关节软骨(人的及鼠的)中，可看到软骨细胞中的单胺氧化酶准确地定位在线粒体中。在鼠自然疾病发展过程中，这些颗粒变大并明显爆裂，单胺氧化酶(MAO)活性遍布软骨细胞浆，甚至进入周围基质。Chambers等人在Int.J.Exp.Path.73：115-123(1992)中对其进行了描述，文章涉及在未治疗鼠和用双氯芬酸治疗的鼠中内侧软骨中MAO活性，并与(正常)边缘软骨中MAO活性对比。
从这些发现推测如下：当循环的药理活性胺和肾上腺素进入正常软骨细胞时，它们被线粒体内的MAO消毒。这种消毒作用要求MAO与辅酶FAD(黄素腺嘌呤二核苷酸)紧密结合以及超氧化酶存在于附近以除去由MAO活性产生的H2O2。当MAO发生在软骨基质中时，它不太可能是功能性的，因为(i)它可能被其辅酶(FAD)破坏，和(ii)如果它有效，它将产生H2O2，而H2O2将损坏基质。
当给鼠双氯芬酸钠时，潜在骨关节软骨中MAO定位有明显改进。在一般血浆或基质中无活性指征。
这暗示双氯芬酸分子可能破裂产生单胺，单胺将成为相关酶的弱底物，并作为MAO活性的竞争性抑制剂。然而，双氯芬酸钠并不使这些鼠内OA停止发展。
双氯芬酸钠与灭酸(芬那酸)有亲联关系。灭酸衍生物一直被用作抗炎剂，尤其影响环氧化酶和/或5-脂氧合酶体系；见US-A-5114958。
本发明概要
本发明基于两种因素(即细胞和细胞外因素)与OA发展有关这一假设。首先由例如双氯芬酸钠或另一种具有相同作用的化合物改进；第二，即基质水肿，由例如三苄糖苷或另一种具有相同作用的化合物改进。无论假设正确与否，实验已发现给予双氯芬酸导致至少9/10的鼠具有严重的OA，但两种药物结合导致7/9的鼠无OA迹象。
本发明的组合物包括分别作用在软骨细胞上和减少软骨细胞基质水含量的化合物。为了预防和治疗OA，可同时或顺序给予这些化合物。本发明描述
用于本发明的两种活性成分可配成混合物或独立地以完整形式用于同时，分别或顺序给予患者。为了口服，非肠道或局部给药，每种化合物可与适当的可药用固体，半固体或液体赋形剂配在一起。取决于所需的给药路线，可使用任何种类的载体。这种材料的实例对本领域技术人员来说是已知的，包括粉末如滑石粉，和含水载体。可再以已知方式将组合物配成片剂，溶液，悬浮液，安瓿，胶囊或其它剂型。例如，已有双氯芬酚钠的25，50和75mg片剂。
每种活性成分给入量为所需治疗的有效量，每种化合物可给1-2000mg/天，但这仅是一种指导原则，在给定情况下，如果合适，照料医生可选择剂量，考虑诸多因素如患者的年龄，健康和体重，治疗疾病的严重程度等。一般来说，可简单地决定活性成分的适当剂量。
本发明的组分物适用于治疗人或动物例如家养及农场动物如狗，猫和马等的骨关节炎。
虽然本发明将具体描述双氯芬酸的用途，但是其它合适的材料包括灭酸衍生物系列，因为它们所有的都在两个苯环之间带有相关的氮原子。Oxicams属于此类，吡罗昔康也是。带有通式R1-NH-R2的几乎任何化合物都是候选者，取决于其毒性和R1或R2在体内容易除去的程度，以产生单胺氧化酶的假底物(“假底物”是能结合到酶上但仅能慢慢被氧化或根本不氧化的一种)。基本上来说，这个概念适用于分子单独或其小碎片能产生芳香胺的任何分子，芳香胺可能是单胺氧化酶的弱底物。
类似地，可以使用三苄糖苷(三苄葡甙)的生物等同物，例如类似地基于糖核并带有大取代基的化合物。
用定量干涉显微镜研究细胞外因素，如Ross在“细胞生物学者的位相干涉显微镜”Arnold：London 36页(1967)中所述。这种形式显微镜能使研究者在切片或细胞的选择区域测量每单位面积的干质(Cs)。然后该测量可评价水含量(Cw)。
Cw＝100-0.75Cs
这种定量显微干涉测量表明在这些鼠受影响的内侧软骨中干质浓度明显低于未受影响的边缘软骨的浓度(Chambers等人，1992)。后者的水含量非常近似于在不易于发生骨关节炎的CBA鼠的内侧和边缘胫软骨中观察到的水含量。
用双氯芬酸钠喂养STR/ORT鼠对每单位面积干质无影响(因此，对水含量无影响)。然而，一方面，用三苄糖苷喂养这种鼠明显增加内侧软骨干质的含量，使甚至内侧软骨的干质/单位面积实际上相当于这些鼠边缘软骨的，或相当于CBA鼠软骨的(表1)。另一方面，这种喂养不能改进MAO活性的定位。然后用双氯芬酸钠和三苄糖苷喂养鼠，这种鼠内侧软骨的水含量和MAO活性均“正常”；即相当于边缘软骨中的活性。在三个分别实验中，这种治疗的结果是以这种方式治疗的鼠仅2/7表现出损伤迹象，而该群体和该鼠龄的STR/ORT鼠的9/10损伤软骨。结果示于表1中，即不同治疗后STR/ORT鼠胫骨平顶软骨基质中每μm的干质。单独用双氯芬酸(Df)治疗3只鼠，单独用三苄糖苷(Tb)治疗四只鼠，用两者(Df+Tb)治疗四只鼠。
                      表1
    治疗              质量pg/单位面积
    内侧软骨     边缘软骨
   4 CBA鼠     2.8-2.97     2.8-2.97
    载体      0.41        -
    Df      0.51        -
    Df      0.50        -
    Df      0.52       2.73
  Df+Tb      2.71     3.18.3.05*
  Df+Tb      2.10       2.93
  Df+Tb      2.52       2.93
  Df+Tb      3.14        -
    Tb    2.54，2.76，2.58，2.77*        -
    Tb      2.29       2.84
    Tb      2.44        -
    Tb      3.14        -
* 双份切片
- 被弯液面覆盖或切片中无边缘部分

Claims (9)

1.一种组合物，其包含(i)抗炎药和(ii)三苄糖苷或其生物等同物，其作为联合制剂同时，分别或顺序用于治疗骨关节炎。
2.权利要求1的组合物，其还含有生理上可接受载体。
3.按照权利要求1或2的组合物，其中化合物(ii)为三苄糖苷。
4.权利要求1-3中任一项的组合物，其中抗炎药为芬那酸或其衍生物。
5.权利要求1-4中任一项的组合物，其中抗炎药为双氯芬酸钠。
6.抗炎药和三苄糖苷或其生物等同物在制备用于治疗骨关节炎的药物中的用途。
7.权利要求6的用途，其中抗炎药为芬那酸或其衍生物。
8.权利要求6或7的用途，其中抗炎药为双氯芬酸钠。
9.权利要求6-8中任一项的用途，其中化合物(ii)为三苄糖苷。
CN95196816A 1994-12-16 1995-12-18 治疗骨关节炎的组合物 Expired - Fee Related CN1088361C (zh)

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GBGB9425487.7A GB9425487D0 (en) 1994-12-16 1994-12-16 Osteoarthritis treatment

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EP (1) EP0796100A1 (zh)
JP (1) JPH10510528A (zh)
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GB9425487D0 (en) * 1994-12-16 1995-02-15 Res Inst Osteoarthritis treatment
GB9608133D0 (en) * 1996-04-19 1996-06-26 Gemini International Holdings Diagnostic method and apparatus
US6197776B1 (en) * 1999-03-17 2001-03-06 Ernest L. Bonner, Jr. Method for treatment of reactive arthritis or bursitis
US6765000B2 (en) * 1999-03-17 2004-07-20 Bonner Jr Ernest L Treatment for reactive arthritis or bursitis
US20050137181A1 (en) * 1999-03-17 2005-06-23 Bonner Ernest L. Method for treatment of reactive arthritis or bursitis
US7691831B2 (en) * 1999-03-17 2010-04-06 Ernest L. Bonner, Jr. Pharmaceutical combination and method for treatment of reactive arthritis or bursitis
US7884090B2 (en) * 1999-03-17 2011-02-08 Ernest L. Bonner, Jr. Compositions and methods for the treatment of arthritis
GB0104571D0 (en) * 2001-02-23 2001-04-11 Ks Biomedix Holdings Plc Composition
AU2014267299B2 (en) 2013-05-14 2019-07-18 Mars, Incorporated Joint care composition
GB201414910D0 (en) * 2014-05-23 2014-10-08 Mars Inc Composition
CN112138015B (zh) * 2020-10-22 2022-08-05 合肥博思科创医药科技有限公司 三苄糖苷在治疗微循环障碍引起的皮肤疾病中的应用

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US4464376A (en) 1982-07-22 1984-08-07 Richardson-Vicks, Inc. Analgesic and anti-inflammatory compositions comprising caffeine and methods of using same
CH662505A5 (it) * 1985-04-30 1987-10-15 Seuref Ag Composizioni farmaceutiche ad azione protettiva vascolare.
GB9425487D0 (en) * 1994-12-16 1995-02-15 Res Inst Osteoarthritis treatment

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Publication number Priority date Publication date Assignee Title
US5095037A (en) * 1989-12-21 1992-03-10 Nissho Corporation Combined anti-inflammatory agent
US5095037B1 (en) * 1989-12-21 1995-12-19 Nissho Kk Combined anti-inflammatory agent

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福建中医药1983,(4) 1983.4.30 林毅宏，扛板归制剂在痔瘘术后的应用 *

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CN1170366A (zh) 1998-01-14
MX9704409A (es) 1998-07-31
AU697425B2 (en) 1998-10-08
EP0796100A1 (en) 1997-09-24
JPH10510528A (ja) 1998-10-13
AU4266996A (en) 1996-07-03
GB9425487D0 (en) 1995-02-15
CA2207911A1 (en) 1996-06-20
US6034122A (en) 2000-03-07
US6369107B1 (en) 2002-04-09

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