CN102665708A - 用于治疗骨关节炎的组合 - Google Patents
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Abstract
本发明涉及甘氨酸、脯氨酸和任选的天然或合成粘度控制聚合物和/或赖氨酸和/或亮氨酸的组合在制备用于治疗骨关节炎的组合物中的用途。
Description
本发明涉及治疗骨关节炎、特别是膝盖的髌骨股骨或股骨胫骨的骨关节炎、髋骨的骨关节炎和肩骨关节炎的甘氨酸、脯氨酸和任选的天然或合成粘度控制聚合物和/或赖氨酸和/或亮氨酸的组合。
技术背景
骨关节炎是影响西方世界的风湿病中最常见的关节病。它是可以扩散性或局限性的慢性变性性关节病,从而影响可动关节软骨,其中软骨细胞的正常代谢过程受到损害,导致软骨成骨软化、肌纤维震颤、溃疡和随后的硬化,在最终阶段,导致新骨生成和软骨下囊肿。
主要影响女性的骨关节炎最常见地牵连髌骨股骨关节、腿胫关节、髋关节和肩关节。膝盖的骨关节炎或膝关节炎特别常见且致残。临床图像最初以特性的前或前内侧中央动脉部位机械性痛为主,经休息后减弱。在长期不活动后,例如在早晨或在长期坐后,可能经历痛性的不活动后痉挛。然而,它们是短期的并且通过行走减弱。疼痛可以通过使用楼梯、尤其是下楼行走、蹲坐、尤其是在髌骨股骨骨关节炎的情况中或长期使用交通工具方向舵脚蹬而引起。最初在关节周区域中也可能存在疼痛并且适度积液。疼痛随后可以影响整个关节,变成夜间的并且伴随频繁的关节渗出液。功能缺损仅出现在后期,尽管存在显著的外翻或内翻力线不良。
直到几年前,治疗膝骨关节炎的治疗目的在于控制症状(疼痛和功能限制),传统上使用NSAID(非类固醇抗炎药)和其他止痛药实现。
膝骨关节炎的理想治疗需要药物与其他治疗联用,必须基于局部的危险因素(肥胖、机械因素、体力活动)根据患者的需求、一般风险因素(年龄、同患多病、多药物疗法)、疼痛强度级和伤残程度、炎症征兆(渗出)、结构性损伤的定位和程度定制。
如果必要,膝骨关节炎的非药物治疗应包括康复计划、体育运动、辅助应用(扶杖行走、鞋垫或膝关节支架)和体重减轻。
治疗膝骨关节炎疼痛的一线药物是对乙酰氨基酚,它以低于或等于3gm/天的剂量使用,还使用其他骨关节炎药物。
如果短期使用,则NSAID或辣椒辣素的局部应用可能是有用的治疗,尤其是对拒绝或不能服用口服药物的患者而言。
NSAID被视为针对难以对对乙酰氨基酚起响应的患者和处于胃肠道风险中的患者;在该情况中,使用与质子泵抑制剂相关的常用COXIB或NSAID。
阿片类镇痛药代表有用的在禁忌使用NSAID或COXIB的患者中的可替代选择,因为NSAID或COXIB无效或难以耐受。
所用的其他药物是当通过口服或关节内途径施用时通过不同于止痛药或NSAID的方法减轻临床症状的那些药物。该组药物由两种不同类型组成:针对骨关节炎的缓慢起效的对症药物和能够改变骨关节炎进程的药物。硫酸葡糖胺、硫酸软骨素、大豆和鳄梨提取物、双醋瑞因、透明质酸和S-腺苷蛋氨酸属于第一组。这些药物对软骨细胞和滑膜细胞具有直接作用,由此对软骨结构具有有益效果。其对症状的效力缓慢开始(1-2周),但长期持续:至多中断治疗后2个月。
显示关节内注射具有长效的考地松注射用于急性关节痛,尤其是如果涉及关节内积液更是如此。
近期研究集中于对骨关节炎发病机制具有特殊效应的分子,从而改变症状和关节结构以抵抗该病的发展。
国际专利申请PCT/EP2006/009966描述了伤口愈合药物组合物,其包含甘氨酸、赖氨酸、亮氨酸和脯氨酸和透明质酸钠的组合,该药物组合物特别有效地促进细胞更新过程,这一过程形成了扩散伤口愈合的基础、促进了结缔组织重建,且作为结果是上皮细胞再生。
发明详述
目前已经发现包含甘氨酸、脯氨酸和任选的天然或合成粘度控制聚合、赖氨酸和/或亮氨酸的关节内组合物在有效治疗骨关节炎、尤其是在疼痛控制方面中的用途。
本发明的组合物对疼痛减轻和关节功能改善具有显著效果且由此对患者生活质量具有显著效果。该效果是长效的,甚至在中断治疗后也是如此(至多2个月)。
本发明的组合物的用途由此对骨关节炎、尤其是在疼痛控制、提供快速有效的疼痛减轻方面提供了有用的治疗。
本发明由此涉及一种组合,其包含:
a)甘氨酸;
b)脯氨酸;
和任选的
c)天然或合成粘度控制聚合物;和/或
d)赖氨酸;和/或
e)亮氨酸,
其用于关节内施用以治疗骨关节炎,特别是膝骨关节炎。
根据本发明,天然或合成的粘度控制聚合物选自透明质酸或其盐、聚乙烯吡咯烷酮和纤维素衍生物。
根据一个优选的方面,天然或合成的粘度控制聚合物是透明质酸或其盐。
根据本发明,氨基酸以L型存在。
根据优选的方面,本发明的关节内组合物包含如下重量范围组成的不同活性成分:
a)25-500mg的甘氨酸;
b)40-300mg的脯氨酸;
和任选的
c)5-50mg的透明质酸或其盐;和/或
d)5-100mg的赖氨酸;和/或
e)5-50mg的亮氨酸。
将本发明的组合物配制成适合于关节内施用的再溶解粉末、溶液等形式并且根据制药技术众所周知的常规方法例如那些描述在Remington’s Pharmaceutical Handbook,Mack Publishing Co.,N.Y.,USA中的方法、使用适合于其最终应用的赋形剂进行制备。
药理学试验
本试验的目的在于评价本发明组合物的关节内施用在患有膝盖原发性骨关节炎的患者中中的治疗效力,通过评价软骨厚度、疼痛强度和治疗前后患者的生活质量来进行。
用于本试验的本发明组合物由2瓶组成:A瓶包含透明质酸钠的水溶液;B瓶包含基于甘氨酸(182mg)、L-脯氨酸(150mg)、L-赖氨酸(35mg)和L-亮氨酸(21mg)的冷冻干燥的粉末。在施用前,必须将产品再溶解(将B瓶中的冷冻干燥粉末溶于A瓶中包含的溶液),得到不含颗粒物质的透明溶液。
将待治疗的区域消毒,然后在操作前30分钟用涂布麻醉剂霜麻醉。每周一次重复渗透,持续5周。
已知无超剂量或与其他药物的相互作用。罕见发生因致超敏作用而发生的表现为水肿、温觉和/或瘙痒的局部反应。
检查患有膝骨关节炎的11位患者(7位50-80岁的男性和9位51-72岁的女性)。根据Kellgren和Lawrence评分对骨关节炎程度进行分期(Kellgren JH,Lawrence JS.Radiological assessment ofosteo-arthrosis.Ann Rhem Dis 1957;16:494-502)。
录入标准是:
1)根据ACR(American College of Rheumatology)诊断标准诊断膝骨关节炎
与如下标准的至少三种相关的膝盖疼痛:
a-年龄超过50岁
b-休息30分钟以下后僵硬
c-辗轧声
d-骨痛
e-骨轮廓扩展、触诊无温热
2)使用Kellgren和Lawrence等级在I-II的疾病放射期。
I:关节间隙可疑的减少和可能形成骨赘,
II:界限清楚的骨赘和可能的关节间隙减少,
III:多骨赘和界限清楚的关节间隙减少、硬化和可能的骨轮廓变形,
IV:大骨赘、关节间隙显著减少、严重的硬化和界限清楚的骨轮廓变形。
检查的整个群体除一名女性具有I期外都呈现疾病的放射II期。
在进入本试验时和3和6个月后,通过采集个人和人体测量数据(身高、体重、体重指数(BMI)、血压和心率)得到病史并且评价如下参数:
疼痛强度:使用直观模拟标度尺(VAS),以毫米0(正常)-100(最大疼痛强度)表示,由医生和患者进行;
疾病严重性:使用Womac(Western Ontario和McMaster Universities)骨关节炎指标问卷法,即膝骨关节炎的自我评价等级,由24项组成用于监测该病的进展和确定治疗效力。
膝关节软骨厚度:通过在中心、中间和侧室中超声扫描(使用具有多频线性探头5-13MHz的Philips Envisor 250超声系统进行)。
结果
本发明的组合物是充分耐受的,无局部或全身过敏反应。将临床评价结果列在表I和II中。
将与疼痛强度评价和疾病严重性相关的数据列在下表I中。
a)疼痛强度评价
在本试验开始时由患者评价的平均疼痛值(VAS)为58.03(±8.31);3个月后,平均值为8.07(±8.55),百分比下降为58%(p<0.05);6个月后,平均值已经降至16.20(±9.28)(p<0.05)。在本试验开始时由医生评价的平均疼痛值(VAS)为56.18(±9.66);3个月后,平均值为22.03(±7.32),百分比下降为54%(p<:0.05);6个月后,平均值已经进一步降至9.11mm(±6.97),百分比下降为71%,与基线相比(p<0.05)。
b)疾病严重性评价
在本试验开始时,平均WOMAC值为55.03(±27.04);3个月后,平均值已经降至24.00(±25.44),百分比下降为65%(p<0.001);6个月后,平均值已经进一步降至11.99mm(±10.86),百分比下降为83%,与基线相比(p<0.001)。
表I:试验开始时(基线)和渗透治疗后3和6个月检查的患者的临床评价
*:用于配对数据的Wilcoxon检验:用于配对数据的t-检验
将涉及渗透治疗后3和6个月检查的患者的临床评价中百分比下降的数据列在下表II中。
表II:渗透治疗后3和6个月临床评价中的百分比下降的临床评价
c)关节软骨厚度
软骨的超声评价(列在表III中)显示在基线的中间软骨厚度的平均值为0.13mm(±0.07);3个月后,该厚度已经增加至0.14mm(±0.08),百分比增加为6.5%(p=n/s);6个月后,该厚度进一步增加至0.15mm(±0.08),百分比增加为14.1%,与基线相比(p<0.05)。
在基线的侧软骨厚度的平均值为0.18(±0.06)mm;3个月后,已经增加至0.19(±0.07)mm,百分比增加为2.9%(p=n/s);6个月后,该平均值显示与基线相比具有统计学显著性。
3个月后中心软骨的平均厚度值(0.29mm±0.07)不显著,而6个月后(0.31±0.11mm),与基线值相比具有统计学显著性增加。
表III:试验开始时(基线)和渗透治疗后3和6个月的关节软骨平均厚度
上述展示的结果分析显示在施用本发明的组合物后临床症状确切改善。所述的仅仅3个月后出现的改善可以维持到6个月后,此时观察到对骨关节症状的进一步有益性。3和6个月后的VAS疼痛值与基线相比具有显著下降,显示该药物不仅确切地增加滑液的粘弹性,而且对疼痛症状具有有利的效果,因此,对患者的生活质量具有有利的效果。
Claims (7)
1.用于治疗骨关节炎的关节内制剂,其包含:
a)甘氨酸;
b)脯氨酸;
和任选的
c)天然或合成粘度控制聚合物;和/或
d)赖氨酸;和/或
e)亮氨酸。
2.如权利要求1中所述的制剂,其中骨关节炎是髌骨股骨或股骨胫骨膝骨关节炎、髋骨关节炎和肩骨关节炎。
3.如权利要求1中所述的制剂,其中天然或合成粘度控制聚合物选自透明质酸或其盐、聚乙烯吡咯烷酮和纤维素衍生物。
4.如权利要求3中所述的制剂,其中天然或合成粘度控制聚合物是透明质酸或其盐。
5.如权利要求1中所述的制剂,其中氨基酸是L型。
6.如权利要求1中所述的制剂,其中所述组合中的不同成分以如下重量范围存在:
a)25-500mg的甘氨酸;
b)40-300mg的脯氨酸;
和任选的
c)5-50mg的透明质酸或其盐,和/或
d)5-100mg的赖氨酸;和/或
e)5-50mg的亮氨酸。
7.如权利要求1中所述的制剂,其为再溶解粉末或在生物相容性溶剂中的粘性溶液形式。
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ITMI2009A002256A IT1397522B1 (it) | 2009-12-21 | 2009-12-21 | Uso di una combinazione per il trattamento dell'osteoartrosi |
ITMI2009A002256 | 2009-12-21 | ||
PCT/EP2010/069451 WO2011076596A1 (en) | 2009-12-21 | 2010-12-13 | A combination for the treatment of osteoarthritis |
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CN102665708A true CN102665708A (zh) | 2012-09-12 |
CN102665708B CN102665708B (zh) | 2014-11-05 |
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US (2) | US20120316217A1 (zh) |
EP (1) | EP2515897B1 (zh) |
JP (1) | JP2013515024A (zh) |
KR (1) | KR20120095451A (zh) |
CN (1) | CN102665708B (zh) |
BR (1) | BR112012015124B1 (zh) |
CA (1) | CA2785116C (zh) |
ES (1) | ES2447829T3 (zh) |
IT (1) | IT1397522B1 (zh) |
PL (1) | PL2515897T3 (zh) |
RS (1) | RS53197B (zh) |
RU (1) | RU2560844C2 (zh) |
WO (1) | WO2011076596A1 (zh) |
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RU2549436C1 (ru) * | 2014-06-06 | 2015-04-27 | Государственное бюджетное образовательное учреждение высшего профессионального образования "Ростовский Государственный медицинский университет" Министерства здравоохранения Российской Федерации (ГБОУ ВРО РостГМУ Минздрава России) | Способ лечения больных плечелопаточным периартрозом |
WO2020009191A1 (ja) * | 2018-07-04 | 2020-01-09 | 味の素株式会社 | 高齢動物の疼痛緩和用アミノ酸含有組成物 |
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EP1161945A2 (en) * | 2000-06-07 | 2001-12-12 | Solartium Establishment | Pharmaceutical composition based on proline, glycine and lysine used in the therapy for the healing of tendon lesions and open wounds |
WO2006067608A1 (en) * | 2004-12-22 | 2006-06-29 | Laboratoire Medidom S.A. | Aqueous formulations based on sodium hyaluronate for parenteral use |
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KR20040073559A (ko) * | 2002-01-11 | 2004-08-19 | 라쓰 마티아스 | 폴리페놀을 포함하는 영양성 제약 제제 및 암 치료에서의용도 |
US20060029647A1 (en) * | 2004-02-09 | 2006-02-09 | Friesen Kim G | Composition and method for use in cartilage affecting conditions |
US20050176807A1 (en) * | 2004-02-09 | 2005-08-11 | Friesen Kim G. | Composition and method for use in cartilage affecting conditions |
ITMI20051230A1 (it) * | 2005-06-29 | 2006-12-30 | Pharmaperoducts Uk Ltd | Composizioni farmaceutiche e cosmetiche contenenti colostro tocoferoli ossido di zinco e acido ialuronico |
JP2007161688A (ja) * | 2005-12-16 | 2007-06-28 | Hiroshima Univ | 軟骨生成促進剤 |
ITPD20060219A1 (it) * | 2006-05-31 | 2007-12-01 | Fidia Farmaceutici | Composizioni farmaceutiche contenenti acido ialuronico solfatato nel trattamento dell'osteoartrosi |
JP2009120512A (ja) * | 2007-11-13 | 2009-06-04 | Nitta Gelatin Inc | 関節軟骨再生促進剤 |
-
2009
- 2009-12-21 IT ITMI2009A002256A patent/IT1397522B1/it active
-
2010
- 2010-12-13 PL PL10796334T patent/PL2515897T3/pl unknown
- 2010-12-13 RS RS20140061A patent/RS53197B/en unknown
- 2010-12-13 EP EP10796334.0A patent/EP2515897B1/en active Active
- 2010-12-13 CN CN201080058090.XA patent/CN102665708B/zh active Active
- 2010-12-13 CA CA2785116A patent/CA2785116C/en active Active
- 2010-12-13 BR BR112012015124-0A patent/BR112012015124B1/pt active IP Right Grant
- 2010-12-13 KR KR1020127016043A patent/KR20120095451A/ko not_active Application Discontinuation
- 2010-12-13 RU RU2012125823/15A patent/RU2560844C2/ru active
- 2010-12-13 WO PCT/EP2010/069451 patent/WO2011076596A1/en active Application Filing
- 2010-12-13 US US13/517,307 patent/US20120316217A1/en not_active Abandoned
- 2010-12-13 JP JP2012545214A patent/JP2013515024A/ja active Pending
- 2010-12-13 ES ES10796334.0T patent/ES2447829T3/es active Active
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2013
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CN1845729A (zh) * | 2003-09-05 | 2006-10-11 | 马赛厄斯·拉思 | 包括i.a.维生素c,镁,绿茶提取物的延缓心血管疾病的药物组合物 |
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Also Published As
Publication number | Publication date |
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BR112012015124A2 (pt) | 2017-06-20 |
US20130310437A1 (en) | 2013-11-21 |
ES2447829T3 (es) | 2014-03-13 |
CN102665708B (zh) | 2014-11-05 |
US20120316217A1 (en) | 2012-12-13 |
BR112012015124A8 (pt) | 2017-12-26 |
RU2560844C2 (ru) | 2015-08-20 |
KR20120095451A (ko) | 2012-08-28 |
CA2785116A1 (en) | 2011-06-30 |
CA2785116C (en) | 2017-09-05 |
US9040575B2 (en) | 2015-05-26 |
PL2515897T3 (pl) | 2014-05-30 |
WO2011076596A1 (en) | 2011-06-30 |
ITMI20092256A1 (it) | 2011-06-22 |
EP2515897B1 (en) | 2013-12-04 |
RU2012125823A (ru) | 2013-12-27 |
EP2515897A1 (en) | 2012-10-31 |
IT1397522B1 (it) | 2013-01-16 |
RS53197B (en) | 2014-06-30 |
BR112012015124B1 (pt) | 2021-06-15 |
JP2013515024A (ja) | 2013-05-02 |
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