CN109475591A - 用于预防和/或治疗骨关节炎症和疼痛以及软骨损伤的组合物 - Google Patents
用于预防和/或治疗骨关节炎症和疼痛以及软骨损伤的组合物 Download PDFInfo
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- CN109475591A CN109475591A CN201780038357.0A CN201780038357A CN109475591A CN 109475591 A CN109475591 A CN 109475591A CN 201780038357 A CN201780038357 A CN 201780038357A CN 109475591 A CN109475591 A CN 109475591A
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Abstract
本发明涉及组合物,其包含:a)游离形式的或与磷脂的络合物形式的葡萄提取物,或石榴提取物;和b)姜的亲脂性提取物;和c)由含有多不饱和脂肪酸异丁基酰胺的植物获得的亲脂性提取物,其选自紫松果菊属物种提取物或花椒属物种提取物或千日菊(或桂圆菊)提取物;和d)橄榄油和/或玉米油的不皂化级分;或e)N‑乙酰基葡糖胺;或f)双醋瑞因;以及它们在预防和/或治疗骨关节炎症和疼痛以及软骨损伤中的用途。
Description
本发明的技术领域
本发明涉及组合物,其包含游离形式的或与磷脂形成的络合物形式的葡萄(Vitisvinifera)提取物、或者石榴(Punica granatum)提取物;姜(Zingiber officinale)的亲脂性提取物(lipophilic extract);和由含有多不饱和脂肪酸异丁基酰胺的植物获得的提取物;合并有橄榄油和/或玉米油的不皂化级分,或者合并有N-乙酰基葡糖胺或双醋瑞因(diacerein);所述组合物可用于预防和/或治疗骨关节炎症和疼痛,以及软骨损伤(cartilage damage)。
现有技术
外周炎症、特别是与关节磨损有关的那些、骨关节炎、类风湿性关节炎和银屑病关节炎是中年人和老年人残疾的主要原因。
所述病症具有非常不同的病因。在一些情况下,它们是自身免疫性病症,在另一些情况下,它们是由于主要关节受到持续应力产生的机械磨损导致的,尤其是当个体超重时,以及是由于与衰老过程相关的代谢障碍性生物化学变化导致的。生物化学变化涉及改变的蛋白聚糖合成和细胞因子的过量产生,其维持炎症。
骨关节炎(OA)是一种变性疾病,其特征在于滑膜改变以及关节软骨和软骨下骨的破坏。这种病症影响65岁至73岁之间约10%的人口并使其衰弱。
已有类风湿性关节炎和银屑病关节炎的治疗方法,但它们令人不愉快且使人衰弱,并且目前对于骨关节炎没有专门的治疗方法。
一线药物仍然是针对症状起作用的非甾体抗炎药(NSAID),患者常对其耐受性差。
从高剂量阿司匹林到最新一代抗炎药的经典抗炎药必须进行长时间的治疗且具有严重副作用,尤其是在胃水平以及最近发现的在心脏和血管水平的严重副作用。
透明质酸渗透到关节中或自体干细胞的浸润被用于减轻关节损伤,并且从而用于减轻其症状。
近年来OA补充剂的消费呈指数增长。所述补充剂基本上是基于硫酸软骨素、葡糖胺或其衍生物、双醋瑞因和一些油的不皂化级分的制剂,并且始终与减轻疼痛的主要药物组合使用。
使用所有这些产品和许多其它植物来源的产品,但涉及的问题之一是它们的疼痛减轻程度低,迫使患者使用上述止痛药,这在最后的分析中降低了为恢复干骺端软骨而设计的治疗益处。
因此,需要在不损失治疗功效的情况下改善治疗耐受性的新的骨关节炎产品。
局部或全身应用的源自药用植物的亲脂性提取物例如姜、紫松果菊属(Echinacea)物种、青岛花椒(Zanthoxylum bungeanum)、秦椒(Zanthoxylum piperitum)或竹叶花椒(Zanthoxylum armatum)或千日菊(Acmella oleracea)(或桂圆菊(Spilanthesoleracea))的提取物已知具有抗炎和镇痛作用,这与存在多不饱和脂肪酸异丁基酰胺相关,其为大麻素受体CB1和CB2以及香草素(vanilloids)的配体,并且特别是作为TRPV1激动剂起作用。然而,它们的抗炎和镇痛活性不足以解决骨关节问题,因为它们不对导致病症发作的最终原因起作用。
从药理学可知,具有抗自由基和蛋白酶抑制活性的分子例如透明质酸酶、胶原酶和弹性蛋白酶以及白细胞介素1和6抑制剂改善关节功能,条件是它们到达靶器官。
临床文献中报道的数据表明,如果服用足够长的时间,则一些物质可能在预防关节损伤方面起作用,条件是一般的疼痛治疗条件允许它们使用足够长的时间,而不必由于副作用的发作过早地中断治疗。
因此,仍然需要鉴定可用于预防和/或治疗骨关节炎症和疼痛以及关节软骨损伤的替代产品。
发明概述
本发明涉及组合物,其包含:
a)游离形式的或与磷脂的络合物形式的葡萄提取物,或石榴提取物;和
b)姜的亲脂性提取物;和
c)由含有多不饱和脂肪酸异丁基酰胺的植物获得的亲脂性提取物,其选自紫松果菊属物种提取物或花椒属(Zanthoxylum)物种提取物或千日菊(或桂圆菊)提取物;和
d)橄榄油和/或玉米油的不皂化级分;或
e)N-乙酰基葡糖胺;或
f)双醋瑞因。
本发明还涉及所述组合物在预防和/或治疗骨关节炎症和疼痛以及软骨损伤中的用途。
发明详述
现在已经令人惊讶地发现,包含以下成分的组合物可有效预防和/或治疗骨关节炎症和疼痛以及由关节臼、尤其是特别暴露的骨骼部分的磨损引起的损伤:游离形式的或与磷脂的络合物形式的葡萄提取物,或石榴提取物;姜的亲脂性提取物;和由含有多不饱和脂肪酸异丁基酰胺的植物获得的提取物;合并有橄榄油和/或玉米油的不皂化级分,或合并有N-乙酰基葡糖胺或双醋瑞因。
本发明涉及组合物,其包含:
a)游离形式的或与磷脂的络合物形式的葡萄提取物,或石榴提取物;和
b)姜的亲脂性提取物;和
c)由含有多不饱和脂肪酸异丁基酰胺的植物获得的亲脂性提取物,其选自紫松果菊属物种提取物或花椒属物种提取物或千日菊(或桂圆菊)提取物;和
d)橄榄油(油橄榄(Olea europaea))和/或玉米油的不皂化级分;或
e)N-乙酰基葡糖胺;或
f)双醋瑞因。
石榴提取物优选通过用乙醇提取成熟果实并且在吸附树脂上纯化获得。该提取物还可以特征在于40%w/w安石榴苷(punicalagin)含量。
葡萄提取物优选由籽获得,如GB 15441469、EP 2189062或EP 1909750中所述。
根据本发明,“与磷脂的络合物形式的葡萄提取物”意指根据EP 0275224制备的产物。
姜的亲脂性提取物优选由根和根茎获得。该提取物还优选具有高的姜辣素和姜烯酚含量;含有30%w/w姜辣素和姜烯酚、优选25%w/w姜辣素的姜提取物是特别优选的。
紫松果菊属物种、花椒属物种或千日菊(或桂圆菊)提取物可以通过用非质子溶剂从通常用于提取的相应植物的果实或部位中提取获得。
紫松果菊属物种、花椒属物种、姜和千日菊的亲脂性提取物可以通过用醇、酮或脂肪族醚或者优选地用二氧化碳在超临界条件下从根或根茎中提取获得。紫松果菊属物种提取物可以根据EP0464298 A1(第2页第1-52行,以及第5页第45行—第6页第7行)制备。花椒属物种的亲脂性提取物可以根据WO 00/02570 A1(第1页第26行—第2页第13行,以及第4页第28行—第7页第21行)制备。花椒属物种的亲脂性提取物优选是青岛花椒或秦椒提取物,更优选是含有25%w/w异丁基酰胺的标准化的提取物。
橄榄油的不皂化级分可以通过以下方法制备:皂化橄榄-渣油,还含有可以从核果中提取的油,和从三萜、甾醇、长链的支链或无支链的醇和角鲨烯中分离不皂化级分。优选使用油橄榄生产的副产物。萜烯和多元醇含量在40%w/w至90%w/w之间,优选60%w/w。
根据本发明的一个优选的方面,所述组合物包含:
a)游离形式的或与磷脂的络合物形式的葡萄提取物,或石榴提取物;
b)姜的亲脂性提取物;
c)紫松果菊属物种、花椒属物种或千日菊(或桂圆菊)的亲脂性提取物,优选花椒属物种提取物,甚至更优选青岛花椒提取物;和
d)橄榄油(油橄榄)的不皂化级分。
用于口服施用的本发明的组合物可以在每个剂量单位中包含:
a)游离形式的或与磷脂的络合物形式的葡萄提取物,或石榴提取物,量为50-1000mg,优选200mg;
b)姜的亲脂性提取物,量为10-80mg,优选50mg;
c)花椒属物种的亲脂性提取物,量为1-50mg,优选20mg,或者紫松果菊属物种或千日菊(或桂圆菊)的亲脂性提取物,量为5-50mg,优选10mg;
d)橄榄油(油橄榄)的不皂化级分,量为50-500mg,优选150mg。
根据本发明的另一个方面,组合物中的不皂化级分可以被量为50-500mg、优选150mg的N-乙酰基葡糖胺或量为20-200mg、优选50mg的双醋瑞因替代。
根据一个特别优选的方面,用于口服施用的组合物在每个剂量单位中包含200mg与磷脂络合的葡萄提取物;50mg含有30%w/w姜辣素和姜烯酚的姜的亲脂性提取物;10mg花椒属物种的亲脂性提取物;和100mg橄榄油(油橄榄)的不皂化级分或150mg N-乙酰基葡糖胺或50mg双醋瑞因。
根据一个优选的方面,用于局部施用的本发明的组合物可以包含:
a)量为0.1-2.5%w/w、优选1%w/w的与磷脂络合的葡萄提取物;
b)量为0.1-1%w/w、优选0.5%w/w的姜的亲脂性提取物;
c)量为0.1-1%w/w、优选0.5%w/w的花椒属物种的亲脂性提取物;
d)量为0.1-1w/w、优选0.5w/w的橄榄油(油橄榄)的不皂化级分。
本发明还涉及所述组合物在预防和/或治疗骨关节炎症和疼痛以及软骨损伤中的用途。
已经证明所述组合物可用于预防和/或治疗骨关节炎症和疼痛。它们作用于干骺端软骨和滑液中蛋白聚糖水解的合成和抑制。
已经证明本发明的组合物可用于预防和/或治疗所有类型的外周疼痛,例如糖尿病性神经病、化疗诱导的、特别是铂衍生物引起的神经性疼痛、各种起因的肌肉疼痛、和炎症状态,例如各种起因的皮肤炎症。
已经证明所述组合物可特别有效地治疗骨关节炎症和疼痛,特别是外周和全身性疼痛,尤其是在小关节和大关节中。它们对行走所必需的大关节例如膝盖和股骨臼的影响特别重要。
与甾体和非甾体抗炎药不同,本发明的组合物已经表现出了强有效的、长时间持续的镇痛和抗炎活性,甚至在停止治疗后也如此。
本发明的组合物恢复关节基质的生理恢复,因此可用于减少侵入性治疗,例如润滑剂或甾体渗入关节。
当单个使用时,本发明的组合物的成分表现出不大的功效,而当适当地根据本发明组合时,它们在耐受性和功效方面产生了完全不同的特性,表现出协同作用。本发明的组合物对患者非常有利,因为它们具有镇痛和抗炎作用,没有主要的长期副作用。
包含本发明的组合物的制剂可以通过常规技术获得,例如如在“Remington'sPharmaceutical Handbook”,Mack Publishing Co.,N.Y.,USA中所述。特别地,本发明的组合物可以通过常规用于配制基于植物的成分的技术配制。
本发明的组合物可以口服或局部施用。
口服制剂的实例有片剂、糖锭剂(dragée)、软和硬明胶胶囊、和纤维素胶囊。
本发明的组合物可以优选配制成软明胶胶囊或乳剂的形式。
以下实施例进一步举例说明了本发明。
实施例1
制备含有以下成分的软明胶胶囊:
实施例2
制备含有以下成分的软明胶胶囊:
实施例3
制备含有以下成分的软明胶胶囊:
实施例4
制备含有以下成分的软明胶胶囊:
实施例5–在人体中的活性测试
将本发明的组合物的镇痛活性与吡罗昔康和安慰剂的活性进行比较,所述组合物包含与磷脂络合的葡萄提取物、姜的亲脂性提取物、秦椒的亲脂性提取物和油橄榄的不皂化级分。
在对180名骨关节炎患者(主要位于膝盖)进行的盲性研究中,通过在随机化后进行3个月的治疗并在停止治疗后检查关节功能6个月,将实施例1的组合物与吡罗昔康和安慰剂进行比较。
开始时,在用实施例1的组合物的两粒胶囊/天VS两粒600mg吡罗昔康或安慰剂胶囊治疗7天后,评价用Western Ontario and McMaster University Osteoarthritis(WOMAC)量表测量的镇痛作用。第一个7天后,治疗持续3个月,每月测量一次镇痛作用。
用实施例1的组合物和吡罗昔康治疗的两组具有相当的镇痛作用,但是实施例1的组合物证明具有更好的耐受性,因为用吡罗昔康治疗的组中一些患者的治疗由于明显的副作用而不得不停止。在安慰剂组中,没有改善,并且有恶化趋势。
在第三个月的治疗期间,实施例1的组合物的结果VS含有吡罗昔康的制剂的结果为-76%+/-28.6%VS-72%+/-31.4%(P ns),而安慰剂的结果为-25%+/-21%。
在第4个月停止治疗后,用吡罗昔康治疗的组疼痛加重了-41%+/-38%,在第5个月结果进一步降至-24%+/-23%,与安慰剂组具有非常相似的得分。实施例1的组合物在第4个月的评分为-68%+/-26%,在第5个月的评分为-70.06%+/-31%。
在本病案中,吡罗昔康/安慰剂与实施例1的组合物之间的差异高度显著。该结果清楚地表明,实施例1的组合物对干骺端软骨的分解代谢具有保护作用,或者无论如何都使软骨恢复。在X射线上显示的损伤(其中在病理情况下平均关节内厚度为2mm)定性地下降,但实验困难使得无法进行统计学评估。
事实上,对于本发明的组合物,在双盲试验中改善患者滑膜软骨表面恢复后,其疗效在停止治疗后继续维持了6个月,而使用参比化合物吡罗昔康治疗的患者则需要继续治疗。
实施例6–在人中的镇痛活性评价
患有伴有持续疼痛的膝关节疾病的40名患者被随机分组并且每天用实施例4的组合物或者安慰剂(仅由载体组成)或者按照与实施例4的组合物中存在的量相等的量将实施例1的组合物中的成分各自加入到安慰剂制剂中的两个片剂进行治疗,一片早晨给予,一片晚上给予。
用国际模拟疼痛量表对疗效进行评分,评分为0-10,10分表示最大疼痛,0表示疼痛消失。在施用片剂后第二天,在早晨于治疗后60分钟和120分钟对效果进行评估。
结果列于下面的表1中。
表1
实施例7–在人中的镇痛活性评价
表2显示了用实施例3的组合物治疗长达三个月后以及在治疗结束后长达六个月中根据Karnofsky量表进行选择和功效评价所获得的对招募的患者的骨关节炎的整体作用的结果(J.Clin.Oncology 1984;2:187-193)。
通过在设定为3Km/h和10%倾斜度的跑步机上测量没有疼痛的和具有不同程度的疼痛的行进距离来进行评估。
将患有膝骨关节炎的80名患者分成两组。随机分组后,一组用安慰剂治疗,另一组用实施例3的组合物治疗。在治疗期间,每周一次用WOMAC评估疼痛,每月一次评估表明炎症参数的体液参数,发现它们均被改善。
表2–在跑步机上行进的距离结果
治疗结束后6个月行进的距离为320米。
xx:患者因伦理原因离开试验并接受其它药物治疗。
Claims (16)
1.组合物,包含:
a)游离形式的或与磷脂的络合物形式的葡萄提取物,或石榴提取物;和
b)姜的亲脂性提取物;和
c)由含有多不饱和脂肪酸异丁基酰胺的植物获得的亲脂性提取物,其选自紫松果菊属物种提取物或花椒属物种提取物或千日菊(或桂圆菊)提取物;和
d)橄榄油(油橄榄)和/或玉米油的不皂化级分;或
e)N-乙酰基葡糖胺;或
f)双醋瑞因。
2.根据权利要求1所述的组合物,其包含:
a)游离形式的或与磷脂的络合物形式的葡萄提取物,或石榴提取物;和
b)姜的亲脂性提取物;和
c)由含有多不饱和脂肪酸异丁基酰胺的植物获得的亲脂性提取物,其选自紫松果菊属物种提取物或花椒属物种提取物或千日菊(或桂圆菊)提取物;和
d)橄榄油(油橄榄)的不皂化级分。
3.根据权利要求1或2所述的组合物,其用于口服施用,在每个剂量单位中包含:
a)游离形式的或与磷脂的络合物形式的葡萄提取物,或石榴提取物,量为50-1000mg;
b)姜的亲脂性提取物,量为10-80mg;
c)花椒属物种的亲脂性提取物,量为1-50mg,或者紫松果菊属物种或千日菊(或桂圆菊)的亲脂性提取物,量为5-50mg;
d)橄榄油(油橄榄)的不皂化级分,量为50-500mg。
4.根据权利要求3所述的组合物,其中不皂化级分d)被量为50-500mg的N-乙酰基葡糖胺或量为20-200mg的双醋瑞因替代。
5.根据权利要求3所述的组合物,其包含:
a)游离形式的或与磷脂的络合物形式的葡萄提取物,或石榴提取物,量为200mg;
b)姜的亲脂性提取物,量为50mg;
c)花椒属物种的亲脂性提取物,量为20mg,或者紫松果菊属物种或千日菊(或桂圆菊)的亲脂性提取物,量为10mg;
d)橄榄油(油橄榄)的不皂化级分,量为150mg。
6.根据权利要求5所述的组合物,其中不皂化级分d)被量为150mg的N-乙酰基葡糖胺或量为50mg的双醋瑞因替代。
7.根据权利要求3-5所述的组合物,其包含:
a)与磷脂络合的葡萄提取物,量为200mg;
b)含有30%w/w姜辣素和姜烯酚的姜的亲脂性提取物,量为50mg;
c)花椒属物种的亲脂性提取物,量为10mg;
d)橄榄油(油橄榄)的不皂化级分,量为100mg;或
e)N-乙酰基葡糖胺,量为150mg;或
f)双醋瑞因,量为50mg。
8.根据权利要求1或2所述的组合物,用于局部施用,其包含:
a)与磷脂络合的葡萄提取物,量为0.1-2.5%w/w;
b)姜的亲脂性提取物,量为0.1-1%w/w;
c)花椒属物种的亲脂性提取物,量为0.1-1%w/w;
d)橄榄油(油橄榄)的不皂化级分,量为0.1-1%w/w。
9.根据权利要求7所述的组合物,其包含:
a)与磷脂络合的葡萄提取物,量为1%w/w;
b)姜的亲脂性提取物,量为0.5%w/w;
c)花椒属物种的亲脂性提取物,量为0.5%w/w;
d)橄榄油(油橄榄)的不皂化级分,量为0.5%w/w。
10.根据权利要求1-6所述的组合物,其中石榴提取物特征在于40%w/w的安石榴苷含量。
11.根据权利要求1-10所述的组合物,其中所述的姜的亲脂性提取物特征在于30%w/w的姜辣素和姜烯酚含量,优选25%w/w的姜辣素。
12.根据权利要求1-3、5和7-11所述的组合物,其中所述的橄榄油(油橄榄)的不皂化级分特征在于萜烯和多元醇的含量为40%-90%w/w,优选60%w/w。
13.根据权利要求1-12所述的组合物,用于在预防和/或治疗炎症和疼痛。
14.根据权利要求13所述的具有所述用途的组合物,用于预防和/或治疗骨关节炎症和疼痛以及软骨损伤。
15.根据权利要求13所述的具有所述用途的组合物,用于预防和/或治疗小关节和大关节例如膝和股骨臼的外周疼痛以及全身性疼痛。
16.根据权利要求15所述的具有所述用途的组合物,用于预防和/或治疗外周疼痛,例如由糖尿病性神经病导致的疼痛、由化疗诱导的、特别是铂衍生物引起的神经病所导致的疼痛、各种起因的肌肉疼痛、和炎症状态,例如各种起因的皮肤炎症。
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CN115515614A (zh) * | 2020-02-06 | 2022-12-23 | 尤尼根公司 | 用于改进关节健康和治疗关节炎的包含山姜属和其它植物提取物的组合物 |
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RU2019100779A (ru) | 2020-07-29 |
SG11201811680VA (en) | 2019-01-30 |
US20190151396A1 (en) | 2019-05-23 |
JP7100593B2 (ja) | 2022-07-13 |
KR20190021333A (ko) | 2019-03-05 |
IL263988B (en) | 2021-05-31 |
KR102398013B1 (ko) | 2022-05-13 |
US10583162B2 (en) | 2020-03-10 |
ITUA20164757A1 (it) | 2017-12-29 |
DK3478310T3 (da) | 2022-04-11 |
RU2019100779A3 (zh) | 2020-09-14 |
HUE058969T2 (hu) | 2022-09-28 |
BR112018077128A2 (pt) | 2019-04-30 |
PL3478310T3 (pl) | 2022-06-20 |
WO2018002144A1 (en) | 2018-01-04 |
CA3026476A1 (en) | 2018-01-04 |
SI3478310T1 (sl) | 2022-06-30 |
EP3478310B1 (en) | 2022-03-30 |
MX2019000161A (es) | 2019-05-30 |
RU2750993C2 (ru) | 2021-07-07 |
ES2912123T3 (es) | 2022-05-24 |
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