CN101242818A - 包含L-肉碱或烷酰基L-肉碱、脂溶性苯醌和ω-3-多不饱和脂肪酸的组合用于制备治疗角膜疾病的膳食补充剂或药物的用途 - Google Patents
包含L-肉碱或烷酰基L-肉碱、脂溶性苯醌和ω-3-多不饱和脂肪酸的组合用于制备治疗角膜疾病的膳食补充剂或药物的用途 Download PDFInfo
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- CN101242818A CN101242818A CNA2006800297238A CN200680029723A CN101242818A CN 101242818 A CN101242818 A CN 101242818A CN A2006800297238 A CNA2006800297238 A CN A2006800297238A CN 200680029723 A CN200680029723 A CN 200680029723A CN 101242818 A CN101242818 A CN 101242818A
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- carnitine
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Abstract
L-肉碱和/或一种或多种烷酰基L-肉碱或它们的可药用盐之一用于制备治疗角膜疾病的膳食补充剂或药物的用途。
Description
本发明涉及L-肉碱和/或一种或多种烷酰基L-肉碱与脂溶性苯醌和多不饱和脂肪酸联合制备用于预防和治疗角膜疾病的膳食补充剂或和药物的用途。
角膜上皮是角膜的最外层,许多疾病可破坏这一精细结构并引起去上皮。角膜上皮结构损伤的主要原因是干眼综合征、角膜擦伤和损伤、由于应用接触镜所致的机械作用和屈光激光手术。
角膜的其它疾病伴随着角膜表面的正常透明度的减退,例如由角膜炎后果损伤,特别是细菌、病毒或真菌性角膜炎;由外伤和屈光激光手术引起的损伤;以及变性或遗传性疾病例如慢性和急性圆锥形角膜引起。
泪液膜,其包裹角膜上皮并且是眼表面稳态所必需的,执行重要的光学功能,充当眼睑和眼球之间的润滑剂,并且作为氧气的载体,保证角膜上皮细胞的新陈代谢;它还执行冲洗功能,确保外部物质的去除。其作为生长因子、神经肽和神经调节剂(调节角膜和结膜上皮细胞的活化、增殖和分化)的载体的功能同样重要。其还转运免疫球蛋白(IgA、IgG、IgE)、补体因子(C3、C4、C5)、金属蛋白酶(MMP-2,4,9)、酶(溶菌酶、乳铁蛋白)和免疫系统细胞(淋巴细胞),由此执行对抗感染的基本防御功能。
如上所述,存在这种体内稳态受到损害的疾病。
干眼综合征特征在于多因素起源的泪液膜的定量(流泪减少(hypolacrimation))和/或定性(流泪障碍(dyslacrimation))缺陷,其可能引起或不引起对眼表面的临床上有意义的损伤。在成年人群中干眼综合征的患病率为10至40%,并且与年龄高度显著相关。
在美国,轻至中度干眼综合征的患病率高达约1千万人(Am.J.Ophthalmol;1997;124:723-728;Arch Ophthalmol,2000;118:1264-1268)。
为了理解在这一疾病中激活的机制的各种研究已经显示,罹患干眼综合征的患者的眼泪呈现:蒸发速率增加,表面张力增加,维生素A浓度降低,渗透压增加,多种蛋白质(溶菌酶、乳铁蛋白)浓度降低,粘液产生不足或粘液产生的性质改变-作为结果粘液层不能适当重建,多种生长因子(EGF、TGF-α、aFGF-bFGF、LG-F、HGF)的减少(Contactologia,1982;4:34-37),无机成分浓度的改变,雄激素减少和T淋巴细胞活性失调(Cornea,2005;24:1-7)。
认为与这一病理情况最为密切相关的临床征象是减少的破裂时间(BUT试验)和希尔默试验结果(Pescosolido N.:Lealterazioni delfilm lacrimale.Stendler P.:″il sistema lacrimale″,Fabianoeditore,Canelli(AT),2000;pag.237-330;在下文中这一参考文献将称为Pescosolido 2000)。
BUT试验涉及泪液膜中的粘蛋白含量,在干眼中,产生仅低于5秒的值。另一方面,希尔默试验涉及泪液膜中的含水量,在干眼中,产生5分钟内低于5毫米的值。
患者呈现以下症状:异物感、烧灼、眨眼困难、睁开眼睑时有杂音、瘙痒、眼疲劳、畏光、视力模糊和内眦粘液外渗。
对这一综合征的治疗基于以下物质的应用:
(1)泪液代用品,其任务是定期润湿角膜,但其对该病的基本原因不起任何作用并且仅具有持续非常短暂的效力;
(2)泪小管中的插入物(塞子);
(3)免疫调节剂如局部用环孢菌素;局部用类固醇;抗炎剂(rumexilone和氯替泼诺);自体血清(细胞因子抑制剂);
(4)局部或全身用雄激素;
(5)粘液(HETE类花生酸)和房水(P2Y2激动剂)促分泌物质;
(6)acquaporins和用于治疗睑炎的药剂例如抗生素和去污剂(Cornea,2005;24:1-7)。
由于其作为还原剂和电子供体的清除剂活性,还使用碘化物离于电渗疗法治疗(Adv.Clin.Path.,2000;4:11-17;Br.J.Ophthalmol,2005;89:40-44)。
甚至这些后面的治疗,尽管发挥可能认为与治疗该疾病原因更相关的作用,未能产生预期的结果。
角膜表面的正常透明度可受到众多获得性、变性或先天性疾病的后果的损伤,所述疾病破坏各种组成成分的精细结构。最常涉及的获得性疾病情况是角膜炎后的损伤,特别是在疱疹性角膜炎之后,以及在外伤和激光屈光手术后果中发生的损伤。最小的共同点是形成角膜浑浊(角膜白斑),其在功能上危害视觉。在感染、腐蚀性损害、损伤和屈光消融手术之后角膜组织中发生的创伤愈合中涉及的事件,对完整性重建过程的最终形态学结果和屈光结果具有极大影响。
于损伤和激光消融术之后立即发生的急性上皮和基质角膜病损,可能涉及随后角膜组织修复事件的调节,且在后面的情况中,角膜细胞的细胞凋亡可能起重要作用(Cornea,2000;19:S7-12)。由于角膜细胞的细胞凋亡是再增殖刺激的原动力,因此这一事件负责角膜修复过程。在初始无细胞基质下面的基质角膜细胞因此代表了介导上皮下表面基质随后愈合的细胞源。作为细胞再生的结果,活化的角膜细胞经历成肌纤维细胞转化(Invest.Ophthalmol.Vis.Sci,1998;39:487-501),由此证明负责胶原纤维和参与完整性重建过程的基本物质的产生。然而,这一过程不是自我控制的,在许多情况下,发生异常、过度的愈合,继而III型胶原更大量产生和片层结构破坏增加(Arch.Ophthalmol,1990;108:665-675)。这些异常情况涉及屈光性角膜切除术(PRK)之后最令人担心的基质再生并发症的发病机理,所述并发症即云雾状混浊,结果损害功能结局。云雾状混浊根据Heitzmann分为5度,基于由角膜透明度降低引起的视力缺损。尽管作为准分子激光领域的技术进展的结果,近年来云雾状混浊的发生率已经显著降低,但是即使是今天其仍旧是相当常见的并发症,在罕见病例中,表现为难以逆转,甚至在可的松治疗数月后。在持续云雾状混浊(超过15-18个月)的病例中,其对药物治疗无反应(可发生于迟发型云雾状混浊的事件,唯一可行的操作是使用准分子激光进行光性治疗性角膜切除术(PTK),这一操作用于激光辅助手术去除浅表的基质不透明。
L-肉碱和烷酰基L-肉碱是已知的化合物,其制备方法描述于美国专利4439438和4254053中。
已知多不饱和脂肪酸(ω-3脂肪酸)的降低甘油三酯的作用,及其在提高高密度脂蛋白(HDL)水平中的作用。这些脂肪酸可通过合成或优选从鱼油中获得。在该情况中,取决于它们的特征,可使用ω-3脂肪酸的各种混合物。优选,ω-3脂肪酸是长链的(20至22个碳原子)。最优选的是5,8,11,14,17-二十碳五烯酸(EPA)和顺式0,13,16,19-二十二碳六烯酸(DHA)。在本发明的一个优选实施方式中,ω-3脂肪酸为顺式4,7,10,13,16,19-二十二碳六烯酸(DHA),最优选比例为1∶1。这些ω-3脂肪酸可能分别利用醇或碱酯化或成盐为药学可接受的衍生物。所述ω-3脂肪酸,或其酯或盐,单独或以其混合物,可在市场上购得,或可由已知方法制备。混合物可以特别配制用于根据本发明的组合。
辅酶Q10在人类中的应用现在已众所周知,无需特别解释,并且该物质可在市场上购得。本领域技术人员可参考本申请提交的专利文件,其中对该物质进行了充分描述。
肉碱在眼科领域的先前用途是已知的。
美国专利5,037,851描述了乙酰基L-肉碱治疗白内障的用途。
US 5,145,871和5,432,199描述了乙酰基D-肉碱治疗青光眼的用途。
US 5,883,127描述了乙酰基L-肉碱治疗黄斑病和黄斑变性的用途。
美国专利4,599,232公开了一种含有L-肉碱或乙酰基L-肉碱和辅酶Q10的药物组合物,适用于治疗性治疗动脉粥样硬化疾病、心肌和冠状动脉功能不全以及源自组织缺氧的病理情况。
肉碱的其它用途也是已知的。
US 5,753,703描述了含有L-肉碱或烷酰基L-肉碱联合ω-3系列多不饱和脂肪酸的药物组合物,用于预防和治疗脂代谢障碍和心血管病症。
在Drugs Exp Clin Res 1992;18(8):355-365中描述了L-肉碱在心脏病学领域中的应用。
US 5,543,556描述了与γ-羟基丁酸的酰基L-肉碱酯类用于抑制神经元变性和在治疗昏迷中的用途。
US 5,811,457描述了丙酰基L-肉碱用于治疗慢性闭塞性动脉病的用途。
如上所述,辅酶Q10和一种ω-3多不饱和脂肪酸的用途是已知的。
WO 00/23069描述了一种含有作为活性成分的辅酶Q10和ω-3多不饱和脂肪酸的组合物,用于预防和/或治疗遗传性线粒体病,在众多引述的病症中提到了慢性进行性外眼肌麻痹综合征和色素性视网膜炎。
上述引用的专利或出版物都没有描述或提示L-肉碱或烷酰基L-肉碱联合脂溶性苯醌和多不饱和脂肪酸用于制备用于治疗角膜疾病的药物的用途。
在医药领域,仍然强烈感受到需要得到用于治疗上述角膜疾病的治疗剂。
现已发现,包含作为活性成分的以下物质的联合组合物可用于制备治疗角膜疾病的膳食补充剂或药物:
(a)L-肉碱和/或一种或多种烷酰基L-肉碱,或它们的可药用盐,
(b)脂溶性苯醌,和
(c)至少一种ω-3多不饱和脂肪酸或其酯。
本发明的一个目的是包含作为活性成分的以下物质的联合组合物的用途:
(a)L-肉碱和/或一种或多种烷酰基L-肉碱(选自乙酰基、丙酰基、戊酰基、异戊酰基、丁酰基和异丁酰基L-肉碱),或它们的可药用盐之一;
(b)脂溶性苯醌,选自辅酶Q10(CoQ10)及其还原形式泛醇-10(CoQ10H2),或其混合物;
(c)ω-3多不饱和脂肪酸,选自二十碳五烯酸(EPA)、二十二碳六烯酸(DHA)和亚麻酸(LNA),或其混合物,LNA、EPA或DHA的优选酯为甘油三酯和乙酯;
用于制备治疗角膜疾病的膳食补充剂或药物,其中所述角膜疾病选自去上皮疾病、干眼综合征、感染性角膜炎、酸或碱腐蚀性损伤、由机械作用或接触镜引起的角膜擦伤和/或损伤、角膜基质的变性疾病例如急性或慢性圆锥形角膜、由屈光激光手术引起的基质损害和营养不良性疾病:
其中:
-L-肉碱(和/或烷酰基L-肉碱)优选存在剂量为0.1-4g,并最优选剂量为0.1g;
-ω-3多不饱和脂肪酸(鱼油)优选存在剂量为0.1-1g,并最优选剂量为0.5g。
-辅酶Q10优选存在剂量为1-100mg,并最优选剂量为10mg。
本发明的另一目的是上述联合组合物的用途,用于制备治疗角膜透明度减退的膳食补充剂或药物,其中所述的透明度减退是由以下情况引起的:各种类型的感染性角膜炎(病毒、细菌和真菌性),或破坏构成角膜的各组成成分的结构的损伤,例如机械、外科手术后和激光屈光手术之后类型的损伤(例如,云雾状混浊);遗传或变性疾病例如慢性和急性圆锥形角膜。
L-肉碱的可药用盐的意思是L-肉碱与不产生毒副作用的酸的任何盐。
这些酸是药理学家和药学专家已知的。这类盐的非限制性实例为:氯化物、溴化物、乳清酸盐、天冬氨酸盐、酸式天冬氨酸盐、酸式柠檬酸盐、柠檬酸镁、磷酸盐、酸式磷酸盐、延胡索酸盐和酸式延胡索酸盐、延胡索酸镁、乳酸盐、马来酸盐和酸式马来酸盐、草酸盐、酸式草酸盐、巴莫酸盐、酸式巴莫酸盐、硫酸盐、酸式硫酸盐、葡萄糖磷酸盐、酒石酸盐和酸式酒石酸盐、甘油磷酸盐、粘酸盐、酒石酸镁、2-氨基-乙磺酸盐、2-氨基-乙磺酸镁、甲磺酸盐、胆碱酒石酸盐、三氯乙酸盐和三氟乙酸盐。
L-肉碱的可药用盐还意指FDA批准的和列于出版物Int.J.ofPharm.33(1986),201-217(通过参考方式并入本文)中的盐。
本发明的组合可以另外含有其他有用成分,例如抗氧化剂如维生素E和/或维生素C;辅酶,矿物质,这不会显著削弱活性。
以下实施例举例说明本发明。
实施例1
进行临床试验,其中招募40名干眼综合征患者。
招募的患者全部为女性,年龄为36至75岁,其中30人患有斯耶格伦综合征,诊断基于Fox等人的标准(Arthritis Rheum,1986;29:577-584;1986)。
基于BUT试验、希尔默试验、荧光素试验和孟加拉玫红试验选择患者(Pescosolido 2000;Arch.Ophthalmol,1969;82:10-14)。
BUT试验必须在≤5秒产生结果,而希尔默试验并不禁忌试验入选。
眼表面的损伤通过孟加拉玫红染色试验和荧光素试验来评估。在孟加拉玫红染色试验中的损伤参照van Bijsterveld评估(Arch.Ophthalmol,1969;82:10-14)来确定,将暴露的表面分为3个区域,每个区域得分0-3。
对于荧光素试验得分的异常,评估受影响的表面(A)和损伤密度(D),基于严重性范围从0至3(低和高)(Jap.Clin.Ophthalmol;1994;48:183-188)。
基于试验得分结果,患者分为三个亚组,即轻度干眼患者(A1D1、A1D2、A2D1)、中度干眼患者(A1D3,A2D2,A3D1)以及重度干眼患者(A2D3,A3D2,A3D3)。
患者每天治疗两次,持续六个月,使用具有以下组成的根据本发明的联合组合物:
乙酰基L-肉碱粘酸盐100mg,鱼油500mg(含有EPA165mg及DHA110mg)和辅酶Q1010mg。
获得的结果列于下表。
表1/1
干眼 | BUT试验(秒) | P<Vs基线(Wilcoxon配对检验) | |
基线 | 治疗结束 | ||
轻度 | 4.6 | 5.1 | <0.01 |
中度 | 3.8 | 4.3 | <0.01 |
表1/2
干眼 | 孟加拉玫红试验(得分) | P<Vs基线 | |
基线 | 治疗结束 | ||
轻度 | 2.4 | 2.9 | <0.05 |
中度 | 1.9 | 2.4 | <0.05 |
重度 | 1.2 | 1.9 | <0.01 |
表1/3
干眼 | 希尔默试验(mm) | P<Vs基线 | |
基线 | 治疗结束 | ||
轻度 | 5.0 | 7.1 | <0.001 |
中度 | 3.8 | 4.8 | <0.001 |
重度 | 2.1 | 3.7 | <0.001 |
实施例2
在该临床试验中登记了20名患者,9男11女,年龄范围从22至31岁,其双眼已经进行屈光激光手术(PRK),近视不超过6屈光度。
将患者分为两组,每组10人(分别为对照组和治疗组)。
患者使用实施例1中所述的本发明的联合组合物治疗,一天两次。
在PRK手术后两组(治疗和对照)的眼均还使用抗生素滴眼剂治疗4天,术后头5天双眼应用水凝胶接触镜。
在治疗前和治疗7天、1和6个月后评估PRK后充分上皮再形成的效力。
由于物体或图像的视觉不能限于最小可分感知(视敏度),评估的一项重要参数是物体对比。为研究这一参数,以逐渐减小的对比对全程各种大小的物体测量感知阈值。所得的评估是空间对比敏感度函数(空间CSF)(Pescosolido 2001)。对于这一函数,主要使用的测试图像由条纹组成,具有正弦式亮度曲线。这些条纹,明暗交替,由其空间频率(每度的循环(CPD)或每度视角的条纹对(黑/白)数)以及其对比度定义。对比度(C)的倒数是对比敏感度(S)(S=1/C)。对比度通常用百分比表示,98%为非常高,3%为非常低(Pescosolido2001)。
对比敏感性试验使用Optec 6500视觉测试器进行,其能够接受ETDRS和FACT试验分值和用于管理和分析对比敏感性数据的软件。该系统能够模拟患者实际上看见物体的方式。而且,它能够比较患者模拟和标准表示。该检查首先在7天后进行,然后在手术后3和6个月进行。患者在PRK之后立即开始治疗。
获得的结果列于表2。
表2
对比敏感性(%) | |||
治疗组 | 对照 | P<Vs对照 | |
基线 | 78 | 77 | ns |
7天 | 52 | 48 | <0.05 |
1个月 | 62 | 56 | <0.01 |
6个月 | 74 | 64 | <0.01 |
实施例3
在该临床试验中招募了14名患者,其双眼已经进行屈光激光手术(PRK),近视不超过10屈光度(3-10屈光度)。
将患者分为两组(每组7人)。
1组(7名患者)接受手术后标准治疗,包括含有皮质激素和抗生素的滴眼剂和含有透明质酸的眼滴剂(人工泪液)。
2组(7名患者)接受与组1相同的治疗,以及描述于实施例1中的本发明组合物,每天两次。
在屈光激光手术前30天开始治疗,并在手术后持续6个月。
在治疗开始时和治疗1个月和6个月后对照以下参数。
(1)刺激症状(由调查表):
刺激症状细分为3组:
(i)感觉迟钝:异物感、干燥、烧灼感、眨眼困难;
(ii)感觉过敏:特别对以下敏感:气流(风、空调、粉末、污浊空气、烟雾);外用药;眼疲劳和疼痛;频繁眨眼;眼泪产生过多;和畏光;
(iii)症状每日变异。
(2)裂隙灯检查的炎症征象:
还记录炎症征象的两个亚组:
(i)结膜充血和乳头肥大,
(ii)排出物(泪液膜中的颗粒物、充填的睑板腺、由于眼表面粘液导致的视力模糊(眨眼后改善)、位于内眦或下穹窿中的粘液线、醒后睁眼困难)。
(3)经修改的希尔默试验(Cornea.2003 May;22(4):285-7)和BUT试验检查的泪流。
(4)每天使用人工泪液治疗的频率。
(5)Cochet-Bonnet estesiometer测试的角膜敏感性(Can JOphthalmol.2004;Dec;39(7):767-71)。
为评估刺激症状和炎症征象,应用以下评分系统:
得分0=无;
得分1=轻度;
得分2=中度;
得分3=重度。
考虑双眼的平均分值。
获得的结果列于下表。
表3/1刺激的症状
治疗组 | 对照组 | P<vs对照 | |
基线 | 0.9 | 0.9 | Ns |
1个月 | 1.8 | 2.3 | <0.01 |
6个月 | 1.2 | 1.7 | <0.001 |
与对照相比,在治疗组中手术后刺激症状减轻得更迅速。在1个月后(p<0.01)和6个月后(p<0.001)差异显著。
表3/2 炎症的征象
治疗组 | 对照组 | P<vs对照 | |
基线 | 0.5 | 0.5 | Ns |
1个月 | 1.1 | 1.9 | <0.01 |
6个月 | 0.6 | 1.0 | <0.01 |
与对照相比,在治疗组中手术后炎症征象减轻得更迅速。在1个月后(p<0.01)和6个月后(p<0.01)差异显著。
表3/3 局部治疗的频率
治疗组 | 对照组 | P<vs对照 | |
基线 | 0.3 | 0.4 | Ns |
1个月 | 3.2 | 3.8 | <0.05 |
6个月 | 1.1 | 3.2 | <0.001 |
在术后期,与对照相比,每天滴注泪液代用品的平均次数在治疗组中显著较低(p<0.05和p<0.001)。
表3/4 角膜敏感性
治疗组 | 对照组 | P<vs对照 | |
基线 | 100 | 100 | Ns |
1个月 | 54 | 48 | <0.01 |
6个月 | 76 | 58 | <0.001 |
在激光手术后,角膜敏感性显著降低。然而,与对照相比,治疗组中的恢复显著提高(p<0.01和0.001)。
如上所述,所得结果显示,本发明的联合组合物改善激光屈光手术后角膜感觉神经的再生,并随后改善术后的干眼症状。
乙酰基L-肉碱、ω-3脂肪酸和辅酶Q10可以是任何适合人类对象口服的形式。
基于各种因素,例如活性成分的浓度和患者状况,本发明的组合物可以作为保健食品补充剂、营养补剂或作为治疗产品上市。
根据本发明的营养补剂可以通过混合活性成分(乙酰基L-肉碱、ω-3脂肪酸和辅酶Q10)与适合将组合物配制成口服的赋形剂来制备。
所述赋形剂是制药技术领域专家众所周知的。
以下报道了本发明组合物的非限制性实例:
-乙酰基L-肉碱粘酸盐100mg;
-鱼油500mg(含EPA165mg和DHA110mg)
-辅酶Q10 10mg。
权利要求书:
1、包含作为活性成分的以下物质的联合组合物用于制备治疗角膜疾病的膳食补充剂或药物的用途:
(a)L-肉碱和/或一种或多种烷酰基L-肉碱,或它们的可药用盐之一;
(b)脂溶性苯醌;
(c)ω-3多不饱和脂肪酸。
2、权利要求1所述的用途,其中所述疾病为角膜透明度的减退。
3、权利要求1或2所述的用途,其中所述烷酰基L-肉碱选自乙酰基、丙酰基、戊酰基、异戊酰基、丁酰基和异丁酰基L-肉碱,或它们的可药用盐之一。
4、权利要求1或2所述的用途,其中L-肉碱或烷酰基L-肉碱的可药用盐选自:氯化物、溴化物、乳清酸盐、天冬氨酸盐、酸式天冬氨酸盐、酸式柠檬酸盐、柠檬酸镁、磷酸盐、酸式磷酸盐、延胡索酸盐和酸式延胡索酸盐、延胡索酸镁、乳酸盐、马来酸盐和酸式马来酸盐、草酸盐、酸式草酸盐、巴莫酸盐、酸式巴莫酸盐、硫酸盐、酸式硫酸盐、葡萄糖磷酸盐、酒石酸盐和酸式酒石酸盐、甘油磷酸盐、粘酸盐、酒石酸镁、2-氨基-乙磺酸盐、2-氨基-乙磺酸镁、甲磺酸盐、胆碱酒石酸盐、三氯乙酸盐和三氟乙酸盐。
5、权利要求1或2所述的用途,其中所述脂溶性苯醌选自辅酶Q10(CoQ10)和泛醇-10(CoQ10H2)或其混合物。
6、权利要求1或2所述的用途,其中所述ω-3多不饱和脂肪酸选自二十碳五烯酸(EPA)、二十二碳六烯酸(DHA)和亚麻酸(LNA)或其混合物。
7、权利要求1或2所述的用途,其中所述角膜疾病选自去上皮疾病、干眼综合征、感染性角膜炎、酸或碱腐蚀性损伤、角膜擦伤和/或损伤、遗传或变性疾病和营养不良性疾病。
8、权利要求7所述的用途,其中所述感染性角膜炎是由于病毒、细菌或真菌感染所致。
9、权利要求7所述的用途,其中所述擦伤和/或损伤是由于机械作用、接触镜、手术后或激光屈光治疗后所致。
10、权利要求7所述的用途,其中所述遗传或变性疾病为急性或慢性圆锥形角膜。
11、权利要求9所述的用途,其中手术后或激光屈光手术后损伤为云雾状混浊。
12、权利要求1所述的用途,其中所述联合组合物包含:乙酰基L-肉碱粘酸盐100mg;鱼油500mg;辅酶Q1010mg。
13、权利要求12所述的用途,其中鱼油含有165mg EPA和110mgDHA。
标题
L-肉碱或烷酰基L-肉碱用于制备治疗角膜疾病的膳食补充剂或药物的用途。
摘要
L-肉碱和/或-种或多种烷酰基L-肉碱或它们的可药用盐之-用于制备治疗角膜疾病的膳食补充剂或药物的用途。
Claims (13)
1、包含作为活性成分的以下物质的联合组合物用于制备治疗角膜疾病的膳食补充剂或药物的用途:
(a)L-肉碱和/或一种或多种烷酰基L-肉碱,或它们的可药用盐之一;
(b)脂溶性苯醌;
(c)ω-3多不饱和脂肪酸。
2、权利要求1所述的用途,其中所述疾病为角膜透明度的减退。
3、权利要求1或2所述的用途,其中所述烷酰基L-肉碱选自乙酰基、丙酰基、戊酰基、异戊酰基、丁酰基和异丁酰基L-肉碱,或它们的可药用盐之一。
4、权利要求1或2所述的用途,其中所述L-肉碱或烷酰基L-肉碱的可药用盐选自:氯化物、溴化物、乳清酸盐、天冬氨酸盐、酸式天冬氨酸盐、酸式柠檬酸盐、柠檬酸镁、磷酸盐、酸式磷酸盐、延胡索酸盐和酸式延胡索酸盐、延胡索酸镁、乳酸盐、马来酸盐和酸式马来酸盐、草酸盐、酸式草酸盐、巴莫酸盐、酸式巴莫酸盐、硫酸盐、酸式硫酸盐、葡萄糖磷酸盐、酒石酸盐和酸式酒石酸盐、甘油磷酸盐、粘酸盐、酒石酸镁、2-氨基-乙磺酸盐、2-氨基-乙磺酸镁、甲磺酸盐、胆碱酒石酸盐、三氯乙酸盐和三氟乙酸盐。
5、权利要求1或2所述的用途,其中所述脂溶性苯醌选自辅酶Q10(CoQ10)和泛醇-10(CoQ10H2)或其混合物。
6、权利要求1或2所述的用途,其中所述ω-3多不饱和脂肪酸选自二十碳五烯酸(EPA)、二十二碳六烯酸(DHA)和亚麻酸(LNA)或其混合物。
7、权利要求1或2所述的用途,其中所述角膜疾病选自去上皮疾病、干眼综合征、感染性角膜炎、酸或碱腐蚀性损伤、角膜擦伤和/或损伤、遗传或变性疾病和营养不良性疾病。
8、权利要求7所述的用途,其中所述感染性角膜炎是由于病毒、细菌或真菌感染所致。
9、权利要求7所述的用途,其中所述擦伤和/或损伤是由于机械作用、接触镜、手术后或激光屈光治疗后所致。
10、权利要求7所述的用途,其中所述遗传或变性疾病为急性或慢性圆锥形角膜。
11、权利要求9所述的用途,其中手术后或激光屈光手术后损伤为云雾状混浊。
12、权利要求1所述的用途,其中所述联合组合物包含:乙酰基L-肉碱粘酸盐100mg;鱼油500mg;辅酶Q1010mg。
13、权利要求12所述的用途,其中鱼油含有165mg EPA和110mgDHA。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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EP05014812 | 2005-07-08 | ||
EP05014812.1 | 2005-07-08 | ||
PCT/EP2006/063769 WO2007006672A1 (en) | 2005-07-08 | 2006-06-30 | Use of a combination comprising l-carnitine or alkanoyl l-carnitine, lipid solubl benzoquinone and omega-3-polyunsaturated fatty acid for the preparation of a dietary supplement or medicament for the treatment of corneal diseases |
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CN101242818A true CN101242818A (zh) | 2008-08-13 |
CN101242818B CN101242818B (zh) | 2011-09-21 |
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CN2006800297238A Expired - Fee Related CN101242818B (zh) | 2005-07-08 | 2006-06-30 | 包含L-肉碱或烷酰基L-肉碱、脂溶性苯醌和ω-3-多不饱和脂肪酸的组合用于制备治疗角膜疾病的膳食补充剂或药物的用途 |
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US (1) | US8349317B2 (zh) |
EP (1) | EP1904044B1 (zh) |
JP (1) | JP5112308B2 (zh) |
KR (1) | KR101262076B1 (zh) |
CN (1) | CN101242818B (zh) |
AU (1) | AU2006268787B2 (zh) |
BR (1) | BRPI0613389A2 (zh) |
CA (1) | CA2611914C (zh) |
CY (1) | CY1114251T1 (zh) |
DK (1) | DK1904044T3 (zh) |
ES (1) | ES2409037T3 (zh) |
HK (1) | HK1118722A1 (zh) |
HR (1) | HRP20130319T1 (zh) |
MX (1) | MX2007016048A (zh) |
PL (1) | PL1904044T3 (zh) |
PT (1) | PT1904044E (zh) |
RS (1) | RS52735B (zh) |
SG (1) | SG162836A1 (zh) |
SI (1) | SI1904044T1 (zh) |
WO (1) | WO2007006672A1 (zh) |
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US8343753B2 (en) | 2007-11-01 | 2013-01-01 | Wake Forest University School Of Medicine | Compositions, methods, and kits for polyunsaturated fatty acids from microalgae |
TWI474817B (zh) * | 2008-07-04 | 2015-03-01 | Sigma Tau Ind Farmaceuti | 用於預防或治療調節性眼疲勞之化合物類 |
AU2011204795A1 (en) * | 2010-07-15 | 2012-02-02 | Brien Holden Vision Institute | Composition and method for improved lens comfort |
CN103221041B (zh) * | 2010-11-19 | 2016-08-03 | 日本水产株式会社 | 用于角膜上皮病变和/或结膜上皮病变的治疗剂或预防剂 |
EP2716167A1 (en) * | 2012-10-02 | 2014-04-09 | Lunamed AG | Non-pharmaceutical composition comprising short chain fatty acids |
JP7474598B2 (ja) * | 2020-02-03 | 2024-04-25 | 小林製薬株式会社 | 経口組成物 |
JP7474599B2 (ja) * | 2020-02-03 | 2024-04-25 | 小林製薬株式会社 | 経口組成物 |
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IT1235153B (it) | 1988-11-15 | 1992-06-22 | Sigma Tau Ind Farmaceuti | Uso dell'acetil l-carnitina nel trattamento terapeutico della cataratta e composizioni farmaceutiche utili in tale trattamento |
IT1277953B1 (it) * | 1995-12-21 | 1997-11-12 | Sigma Tau Ind Farmaceuti | Composizione farmaceutica contenente l-carnitina o una alcanoil l- carnitina e un acido poliinsaturo della serie 3-omega utile per |
IT1299191B1 (it) * | 1998-06-23 | 2000-02-29 | Sigma Tau Healthscience Spa | Composizione atta a prevenire e trattare l'osteoporosi e le alterazioni legate alla menopausa |
IT1307281B1 (it) | 1999-11-25 | 2001-10-30 | Simonelli Giuseppe | Uso di ubichinone q10 per il trattamento locale e la prevenzione dipatalogie oftalmologiche secondarie alla terapia fotorefrattiva, |
CA2291959A1 (en) | 1999-12-08 | 2001-06-08 | Alex P. Korn | A nutriceutical composition of l-carnitine, ubiquinone, n-3 polyunsaturated fatty acids and vitamins specifically formulated at pharmacological doses for the amelioration of the risk factors and symptoms of atherosclerosis-related illnesses |
US20040076695A1 (en) * | 2002-07-08 | 2004-04-22 | Advanced Vision Research | EPA and DHA enriched omega-3 supplement for the treatment of dry eye, meibomianitis and xerostomia |
WO2004006801A2 (en) * | 2002-07-17 | 2004-01-22 | Biosyntrx, Inc. | Treatment for dry eye syndrome |
US9192586B2 (en) * | 2003-03-10 | 2015-11-24 | Zeavision Llc | Zeaxanthin formulations with additional ocular-active nutrients, for protecting eye health and treating eye disorders |
US20050074443A1 (en) * | 2003-10-03 | 2005-04-07 | Treadwell Benjamin V. | Methods of attenuating autoimmune disease and compositions useful therefor |
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- 2006-06-30 AU AU2006268787A patent/AU2006268787B2/en not_active Ceased
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- 2006-06-30 WO PCT/EP2006/063769 patent/WO2007006672A1/en active Application Filing
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Also Published As
Publication number | Publication date |
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KR101262076B1 (ko) | 2013-05-08 |
CN101242818B (zh) | 2011-09-21 |
KR20080036077A (ko) | 2008-04-24 |
HRP20130319T1 (hr) | 2013-05-31 |
CA2611914A1 (en) | 2007-01-18 |
PL1904044T3 (pl) | 2013-08-30 |
AU2006268787A1 (en) | 2007-01-18 |
US20100034795A1 (en) | 2010-02-11 |
HK1118722A1 (en) | 2009-02-20 |
CA2611914C (en) | 2013-11-19 |
JP2009500374A (ja) | 2009-01-08 |
SI1904044T1 (sl) | 2013-05-31 |
PT1904044E (pt) | 2013-04-26 |
CY1114251T1 (el) | 2016-08-31 |
ES2409037T3 (es) | 2013-06-24 |
EP1904044A1 (en) | 2008-04-02 |
DK1904044T3 (da) | 2013-05-13 |
MX2007016048A (es) | 2008-03-10 |
EP1904044B1 (en) | 2013-03-27 |
SG162836A1 (en) | 2010-07-29 |
JP5112308B2 (ja) | 2013-01-09 |
AU2006268787B2 (en) | 2012-02-02 |
US8349317B2 (en) | 2013-01-08 |
WO2007006672A1 (en) | 2007-01-18 |
BRPI0613389A2 (pt) | 2011-01-11 |
RS52735B (en) | 2013-08-30 |
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