CN104487065A - 包含s-烯丙基-l-半胱氨酸作为活性成分的结肠炎预防或治疗用组合物及包含它的医药制剂 - Google Patents
包含s-烯丙基-l-半胱氨酸作为活性成分的结肠炎预防或治疗用组合物及包含它的医药制剂 Download PDFInfo
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Abstract
本发明涉及结肠炎预防用或治疗用组合物,本发明一实施例的结肠炎预防或治疗用组合物包含S-烯丙基-L-半胱氨酸(S-allyl-L-cysteine)、其药学上可接受的盐或它们的溶剂化物或氢化物作为活性成分,并对结肠炎呈现出抗炎(Anti-inflammation)活性。上述结肠炎或治疗用组合物作为S-烯丙基-L-半胖氨酸的抗炎活性效果及抗氧化活性效果,对结肠炎的预防及改善效果优秀,且S-烯丙基-L-半膀氨酸不会伴随着副作用,因而对结肠炎的应用范围广泛。
Description
技术领域
本发明涉及结肠炎预防用或治疗用组合物。更详细地,涉及包含S-烯丙基-L-半胱氨酸(S-allyl-L-cysteine)为活性成分,且有利于对结肠炎的预防或治疗的组合物及利用它的方法。
背景技术
结肠炎大致分为两种,即,阿米巴痢疾、贾第虫病、肠结核及真菌病等感染性结肠炎和克罗恩病、溃疡性结肠炎等非特异性结肠炎。
尤其,上述溃疡性结肠炎(ulcerative colitis)和克罗恩(crohn's disease)成问题,这是因为与感染性肠道疾病不同,由于病因和病态生理未能得到明确,因而存在治疗难的问题。以往,在慢性结肠炎中的大多数为结肠结核,但随着生活环境的西方化,溃疡性结肠炎、克罗恩病等正处于逐渐增加的趋势。
上述溃疡性结肠炎的特征在于,仅在粘膜和粘膜下层产生炎症,作为其以下的组织的肌层和肠膜层没有炎症。大概在肛门和直肠互发,并呈现出如拧紧般的腹痛、肛门出血、大便带脓或异常粘液排出等症状。在这种症状持续的情况下,可转为结肠癌。
根治上述溃疡性结肠炎的方法到目前为止还未知晓,因此,消除炎症反应,治愈组织的损伤,并缓解腹泻、血便及腹痛等症状是目前为止的内科性的治疗方法。为此,在开始进行治疗之前,需要首先准确地评价具有溃疡性结肠炎的部位、范围及炎症的程度,而治疗的效果以治疗前的状态为基础进行判断。
到目前为止,上述溃疡性结肠炎的原因并不明确,但对于发生过程而言,已积累了某种程度的知识,并基于此来开发出多种药剂并使用。最普遍使用的溃疡性结肠炎的治疗剂可分为抗炎剂、肾上腺皮质激素剂、免疫抑制剂、抗生剂等。例如,作为抗炎剂,可使用柳氮磺胺吡啶(sulfasalazine)及美沙拉嗪(mesalazine)等,作为肾上腺皮质激素剂,可使用泼尼松(prednisone)、泼尼松龙(prednisolone)、氢化可的松(hydrocortisone)及布地奈德(entocort,budesonide)等,作为免疫抑制剂,可使用依木兰(immuran)、6-巯基嘌呤(6-MP,6-mercaptopurine)、环孢霉素(cyclosporine)及氨甲喋呤(methotrexate)等,作为抗生剂,可使用甲硝唑(metronidazole)及环丙沙星(ciprobay)等,作为内腔转化剂,可使用单链脂肪酸及谷氨酰胺等,作为抗氧化剂,可使用别嘌呤醇(allopurinol)及二甲基亚砜等,作为局部麻醉剂,可使用利多卡因(lidocaine)等,作为其他药剂,可使用尼古丁、肝素、酮替芬(ketotifen)、沙利度胺(thalidomide)、集落刺激因子(colony stimulating factor)及表皮生长因子(epidermal growth factors)等。
虽然上述克罗恩病可在消化器官的任何部位产生,但在其中,作为主要在与盲肠相连接的结肠的末段部分产生的炎症性肠道疾病,呈现出腹泻、体重减少、下腹痛、发热及直肠出血等胃肠道症状,而作为胃肠道外症状,伴随着贫血、营养不良、肌肉骨骼及肾功能异常及眼科症状等复合性的症状。可产生肠狭窄、肠脓疮及肠瘘等并发症,且稀少地,会引发肠癌。肠子的炎症的特征在于,慢性,复发率高,且向结肠壁的深处侵犯,从而形成肉芽肿。普遍发病于20~30多岁的年轻阶层,且准确的原因还未明确。治疗需要与其他感染性肠道疾病或缺血性肠道疾病、溃疡性结肠炎、结核性肠道疾病等相区别来进行,需要在通过肠内窥镜组织检查和放射性造影术等进行确切的诊断之后,一同使用输液疗法等保守治疗和药物疗法等来进行治疗。以药物治疗为原则,但在严重的情况下,服用类固醇,若症状得到缓解,则服用柳氮磺胺吡啶或美沙拉嗪等。为了减轻并发症及复发率,几乎一生都要服药。在产生并发症,但无法用药来调节的情况下,可实施手术,但也无法根治,且在手术后也有可能复发。
作为用于治疗实施溃疡性结肠炎及克罗恩病的抗炎剂的柳氮磺胺吡啶为作为硫系抗生剂的硫吡啶分子和与阿司匹林相似的5-氨基水杨酸(5-aminosalicylic acid,5-ASA)分子相结合的药剂,若服用该药,则肠内的细菌分离上述两种分子之间的结合,并由呈现出抗炎作用的5-氨基水杨酸游离。柳氮磺胺吡啶对溃疡性结肠炎和侵犯结肠的克罗恩病及白塞氏病有效,而在溃疡性结肠炎(症状完全消除的状态)中,为了预防重新变差(复发)而使用该药,但在克罗恩病中,复发预防效果并未得到确实的证明。作为柳氮磺胺吡啶的副作用,可发生皮疹、恶心、腹部痛症、肝功能异常,且稀少地,可发生骨髓功能低下。
上述柳氮磺胺吡啶的副作用大部分缘于硫吡啶分子,因此,除去硫吡啶分子,只具有5-氨基水杨酸分子的药就是美沙拉嗪(或称之为马沙拉嗪(mesalamine)。若直接服用5-氨基水杨酸,则由无病的小肠全部吸收,无法到达真正需要用药的部分,因此,利用多种方法对5-氨基水杨酸进行特殊处理,从而制成能够到达有病的部分,美沙拉嗪的效果与柳氮磺胺吡啶相似,但副作用略少。美沙拉嗪既具有用于口服的药剂,又能以栓剂或灌肠的方式给药,但在栓剂和灌肠的情况下,分别对炎症分布至直肠或左侧结肠为止的情况下有效,且能够为了维持缓解而使用。口服用美沙拉嗪不仅对活动性的溃疡性结肠炎、克罗恩病及白塞氏病有效,而且最近证实,对维持溃疡性结肠炎、克罗恩病及白塞氏病的缓解方面也有效。
为了向小肠的末端部分或结肠传递5-氨基水杨酸,开发并销售多种形态的美沙拉嗪制剂,而代替结合了5-氨基水杨酸的两个分子的奥柳氮钠(dipentum,olsalazine)、硫吡啶来使用没有毒性的其他分子的巴柳氮(colazide)和伊普柳氮(ipsalazide),以使5-氨基水杨酸慢慢游离的方式吸附于纤维素或树脂的颇得斯安(pentasa)及阿扎兰(azalan),以若肠内的酸性度(pH)实现碱化,则使5-氨基水杨酸的游离的方式进行包装的亚沙可(asacol)、氨基水杨酸(rowasa)及马沙拉嗪(salofalk,claversal,mesasal)等就是例子。柳氮磺胺吡啶和奥柳氮钠对结肠的炎症有效,相反,亚沙可、马沙拉嗪及颇得斯安对小肠的炎症也有效。
当前,虽然为了上述溃疡性结肠炎或克罗恩病等炎症性结肠疾病的治疗而广泛使用上述美沙拉嗪制剂,但这些仍旧存在能够引起过敏性皮疹、由药物引起的异常高热症、支气管痉挛及红斑狼疮症之类的过敏反应或作呕、呕吐、头痛等副作用的问题。
因此,正活跃地进行着既对上述炎症性结肠疾病具有预防或改善效果,又不会伴随着如上所述的副作用的新的组合物的研究。
观察与本发明相关的现有技术如下,非专利文献1记载着柳氮磺胺吡啶和类固醇对角叉菜胶-诱导炎症模型有效,且类固醇和免疫抑制剂在T细胞之类的免疫细胞中抑制细胞因子的生成。但在上述柳氮磺胺吡啶和类固醇制剂的情况下,具有如上所述的副作用,在类固醇制剂的情况下,具有体重急剧增加的副作用,因此,存在适用范围大大受限的问题。
(非专利文献1)Cronstein BN,Montesinos MC andWeissman G,Salitylate and sulfasalazine,but notglucocorticoid,inhibit leukocyte accumulation by anadenosinedependent mechanism that is independent ofinhibition of prostaglandinsynthesis and p105 NF-κB,Proc.Natl.Acad.Sci.USA,May 25,1999,96(11):6377-6381
发明内容
发明要解决的技术问题
本发明的目的在于,提供既对结肠炎的预防及改善效果优秀,又不会伴随着副作用的结肠炎预防或治疗用药理学组合物。
本发明的另一目的在于,提供利用上述结肠炎预防或治疗用药理学组合物的方法。
用于解决问题的技术手段
为了实现上述目的,本发明一实施例的结肠炎预防或治疗用组合物包含S-烯丙基-L-半胱氨酸、其药学上可接受的盐或它们的溶剂化物或氢化物作为活性成分,且对结肠炎呈现出抗炎(Anti-inflammation)活性。
上述结肠炎预防或治疗用组合物包含S-烯丙基-L-半胱氨酸、其药学上可接受的盐或它们的溶剂化物或氢化物作为活性成分,且对结肠炎呈现出抗炎活性及抗氧化(Anti-Oxidant)活性。
上述结肠炎预防或治疗用组合物能够包含5至99.9%的上述S-烯丙基-L-半胱氨酸。
上述结肠炎预防或治疗用组合物的上述S-烯丙基-L-半胱氨酸可以为选自由从葱属(Allium genus)植物分离纯化的、合成的及通过发酵来制成的物质及它们的组合组成的组中的一种。
上述结肠炎预防或治疗用组合物可以为针对上述结肠炎预防或治疗用组合物还包含抗炎剂或抗氧化剂的组合物。
上述结肠炎预防或治疗用组合物的上述抗炎剂可以为选自由布洛芬(ibuprofen)、酮洛芬(ketoprofen)、氟比洛芬(flurbiprofen)、非诺洛芬(feno-profen)、萘普生(naproxen)、吡罗昔康(piroxicam)、替诺昔康(tenoxicam)、伊索昔康(isoxicam)、美洛昔康(melo-xicam)、吲哚美辛(indomethacin)、醋氯芬酸(aceclofenac)、双氯芬酸(diclofenac)及它们的组合组成的组中的一种;上述抗氧化剂可以为选自由维生素A、维生素C、维生素E、类胡萝卜素、锌、铜、铁、锰、叶黄素、玉米黄质、硒、谷胱甘肽(GHS)、番茄红素及它们的组合组成的组中的一种。
本发明另一实施例的医药制剂可以为选自由包含上述结肠炎预防或治疗用组合物的口服给药用制剂、粘膜应用制剂、注射剂、吸入剂及外用剂组成的组中的制剂。
以下,对本发明进行更详细的说明。
本发明一实施例的结肠炎预防或治疗用组合物包含S-烯丙基-L-半胱氨酸、其药学上可接受的盐或它们的溶剂化物或氢化物作为活性成分,且对结肠炎呈现出抗炎活性。
有报告指出,上述S-烯丙基-L-半胱氨酸作为熟成的大蒜的有效成分中的一种,由于这种抗氧化活性,对动脉硬化也呈现出抑制效果,且对某些癌细胞株也呈现出抗癌活性(Proceedings of the American Association for CancerResearch,30,p181,1989)等多种功效。
如可在以下实施例中确认,8-氧代-脱氧鸟苷可在利用葡聚糖硫酸钠(Dextran sodium sulfate,DSS)来诱导结肠炎的小鼠模型中使用以上述S-烯丙基-L-半胱氨酸为活性成分的结肠炎预防及治疗用组合物的情况下,作为抗炎活性效果,具有对结肠炎的抑制效果。
并且,上述S-烯丙基-L-半胱氨酸或药学上或食品学上可接受的其盐也有以溶剂化物或氢化物方式存在的,因此,作为本发明的治疗剂的活性成分,可利用它们的溶剂化物或氢化物。
在上述结肠炎预防或治疗用组合物中,也可利用作为活性成分来包含的S-烯丙基-L-半胱氨酸的药学上或食品学上可接受的盐。作为这种盐,可以举出酸附加盐或季铵盐等。作为上述酸附加盐,可以举出例如盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐及磷酸盐等无机酸盐或草酸盐、马来酸盐、富马酸盐、乳酸盐、苹果酸盐、琥珀酸盐、酒石酸盐、苯甲酸盐、甲磺酸盐等有机酸盐。但并不局限于此。并且,作为季铵盐,可以举出例如,碘甲烷(methyl iodide)、甲基溴(methyl bromide),碘乙烷(ethyl iodide)、溴乙烷(ethyl bromide)等低级烷基卤化物(alkyl halogenide),甲烷磺酸甲酯(methyl methanesulfonate)、乙基甲磺酸酯(ethyl methane sulfonate)等低级烷基磺酸盐(alkyl sulfonates),对甲基苯磺酸甲酯(methyl-p-toluenesulfonate)等低级烷基芳基磺酸盐(alkylarylsulfonates)等季铵盐。但并不局限于此。
并且,如可在以下实施例中确认,上述S-烯丙基-L-半胱氨酸对上述结肠炎的抗氧化活性也很优秀。
因此,确认了上述结肠炎预防或治疗用组合物包含S-烯丙基-L-半胱氨酸作为活性成分,从而以对结肠炎的抗炎活性和抗氧化活性,即使在不以混用的方式使用两种以上的药剂的情况下,对结肠炎具有优秀的预防及治疗效果。
并且,通常对上述结肠炎使用的柳氮磺胺吡啶因其副作用而可能存在皮疹、恶心、腹部痛症、肝功能异常,且稀少地,可发生骨髓功能的降低,并在维持缓解方面存在困难。但上述结肠炎预防或治疗用组合物包含S-烯丙基-L-半胱氨酸作为活性成分,上述S-烯丙基-L-半胱氨酸没有如柳氮磺胺吡啶之类的副作用,也没有需要一同使用类固醇制剂等的问题,因而在对结肠炎的预防及治疗方面具有其应用范围广泛的优点。
尤其,上述结肠炎预防或治疗用组合物可包含5至99.9%的S-烯丙基-L-半胱氨酸。
在上述S-烯丙基-L-半胱氨酸为上述重量百分比范围的情况下,不仅抗炎活性和抗氧化活性同时出现,具有能够非常有效地治疗结肠炎的特征,而且与柳氮磺胺吡啶等之类的普通的结肠炎治疗剂不同,还具有没有副作用的优点。
上述结肠炎包括感染性结肠炎及炎症性肠道疾病。上述炎症性肠道疾病是指包括特发性慢性持续型的非特异性肠炎,即,溃疡性结肠炎和克罗恩病的典型的疾病。但并不局限于此。
上述结肠炎预防或治疗用组合物的上述S-烯丙基-L-半胱氨酸可以为选自由从葱属植物分离纯化的、合成的及通过发酵来制成的物质组成的组中的一种。具体地,上述S-烯丙基-L-半胱氨酸能够以欧洲公开专利公报EP0429080A1的[0031]所记载的方法,从大蒜(garlic)、象蒜(elephant garlic)、洋葱(onino)及葱(scallion)等葱属植物中制成,除此之外,还能以合成、发酵等本发明所属技术领域公知的多种方法来制成。
作为本发明的组合物的活性成分的S-烯丙基-L-半胱氨酸、药学上或食品学上可接受的其盐或它们的溶剂化物或氢化物将其本身直接向患者给药也很有效,但通常能够制成包含一种或两种以上的这些活性成分的组合物来给药,或者能够与其他有用的抗炎剂或抗氧化剂混合,并以复合制剂形态剂型化来给药。
上述抗炎剂可以为选自由布洛芬、酮洛芬、氟比洛芬、非诺洛芬、萘普生、吡罗昔康、替诺昔康、伊索昔康、美洛昔康、吲哚美辛、醋氯芬酸、双氯芬酸及它们的组合组成的组中的一种;上述抗氧化剂可以为选自由维生素A、维生素C、维生素E、类胡萝卜素、锌、铜、铁、锰、叶黄素、玉米黄质、硒、谷胱甘肽、番茄红素及它们的组合组成的组中的一种。
本发明另一实施例的医药制剂可以为选自由包含上述结肠炎预防或治疗用组合物的口服给药用制剂、粘膜应用制剂、注射剂、吸入剂及外用剂组成的组中的制剂。
上述口服给药用制剂包括硬质或软质胶囊剂、片剂、片剂、悬浮剂、糖浆剂或散剂、缓释剂、肠溶性制剂、颗粒剂、乳糖剂、细粒剂、环剂、浓缩剂、液剂、芳香水剂、乳剂、糖浆剂、酏剂、流动轴剂、沉淀剂、酊剂、酒精剂及药油剂等,但并不局限于此。粘膜应用剂包括片剂、口服片剂、舌下片剂、栓剂及鼻腔喷雾剂,但并不局限于此。注射剂包括皮下注射、肌肉注射、静脉注射及移植片等,但并不局限于此。外用剂包括经鼻剂、点眼剂、点耳剂、眼膏剂、软膏剂、巴布剂、搽剂、洗剂、涂敷剂、撒布剂及外用液剂等,但并不局限于此。
除了一种或一种以上的活性成分之外,本发明的制剂还能包含一种或一种以上的作为非活性的通常的载体,例如,淀粉、乳糖、羧甲基纤维素、高岭土等赋形剂、水、明胶、乙醇、葡萄糖、阿拉伯树胶、黄蓍胶等结合剂、淀粉、糊精、藻酸钠等崩解剂、滑石、硬脂酸、硬脂酸镁,液体石蜡等滑剂、溶解辅助剂之类的追加的添加剂成分。
本发明的组合物为食品组合物的情况下,活性成分的混合量能够根据其使用目的来适当地决定。通常,当制作食品或饮料等时,相对于原料,能够包含0.0001至90重量百分比的S-烯丙基-L-半胱氨酸,优选地,能够天机0.1至50重量百分比的S-烯丙基-L-半胱氨酸。但在以健康及卫生为目的或以健康调节为目的的长期摄取的情况下,上述量可以为上述范围以下,但由于活性成分在安全性方面没有任何问题,因而能够使用上述范围以上的量,这是显而易见的。作为本发明的使用食品组合物的食品,具有包括肉类、火腿、面包、巧克力、糖类、快餐类、饼干类、比萨饼类、拉面类、其他面类、口香糖类、冰淇淋类的酪农制品、各种黏粥、饮料、茶、口服液、酒精饮料及维生素复合剂等,但并不局限于此。
发明的效果
本在本发明一实施例的结肠炎预防或治疗用药理学组合物的情况下,作为S-烯丙基-L-半胱氨酸的抗炎活性效果及抗氧化活性效果,S-烯丙基-L-半胱氨酸既对结肠炎的预防及改善效果优秀,又不会伴随着副作用,因此,对结肠炎的应用范围广泛。
本发明的另一实施例提供利用结肠炎预防或治疗用药理学组合物的方法。
附图说明
图1为涉及露出于葡聚糖硫酸钠的小鼠的体重变化的图表。
图2为对利用实施例、比较例及对照例进行处理的小鼠进行验尸之后的结肠(colon)的照片。
图3为对各组小鼠的疾病活动指数(Disease ActivityIndex,DAI)评分(Score)图表。
图4为表示各组的结肠长度的平均的图表。
图5至图6为表示实施例、比较例及对照例的苏木精-伊红(Hematoxylin&Eosin)染色(H&E stain)的病理学观察结果的照明(图5)及图表(图6)。
图7至图10作为表示实施例、比较例及对照例的炎症性细胞因子(Inflammatory cytokine)的测定结果的图表,分别为IL-1β、IL-6、TNF-α及IL-12的结果图表。
图11至图12作为表示实施例、比较例及对照例的抗氧化作用的测定结果的图表,分别为丙二醛(MDA)浓度图表(图11)及抗氧化浓度(图12)图表。
图13为实施例、比较例及对照例的基于抑制效果的免疫荧光法的COX-2的表达的照片。
具体实施方式
以下,以使本发明所属技术领域的普通技术人员能够容易地实施本发明的方式对本发明的实施例进行详细说明。但本发明能够以多种不同的形态体现,并不局限于在此说明的实施例。
制备例:实施例、比较例及对照例的制备
制备了包含以下表1的组成比的混合物的实施例及比较例。并且,为了与现有的结肠炎治疗剂之间比较效果及副作用,也为了结肠炎的治疗,作为对照例,将瑞巴派特按以下表1的组成比进行了制备。
表1
-S-烯丙基-L-半胱氨酸:韩亚制药(株)
-瑞巴派特:大冢制药(Ostuka pharmaceutical)公司产品
实验例1:基于葡聚糖硫酸钠的炎症性肠道疾病的诱导
(1)准备实验动物
本实验所使用的C57BL6为全世界普遍使用的模型,是适合有效性评价实验的实验动物,该动物对多个疾病木星积累有丰富的实验基础资料,能够将这种细聊利用于实验结果的解释及评价,因而被选定。实验动物由(株)东方生物所提供,供给时,以18g±20%的动物供给。实验动物的饲养条件以最少10次/小时进行了换气,以12小时点灯/熄灯的方式进行了照明,且光照度维持了150~300Lux。
当开始实验时,各组的平均体重为G1:20.8±1.4g,G2:21.0±0.5g,G3:20.9±1.5g,G4:20.2±0.9g,G5:20.7±1.1g,G6:20.5±0.9g,G7:20.7±0.7g,各组并未呈现出较大的差异。
(2)结肠炎的诱发
为了确认对实施例、比较例及对照例的结肠炎的治疗效果,使小鼠(G1至G7)应用2.5重量百分比的葡聚糖硫酸钠水溶液,从而诱导了炎症性肠道疾病。
在上述炎症性诱导疾病的诱导当日,并未观察出死亡或临死动物。
实验例2:确认基于S-烯丙基-L-半胱氨酸的结肠炎治疗效果
实验例2-1:实施例1、比较例及对照例的处理
根据以下表2,使用上述实施例1、比较例及对照例对小鼠进行预处理,并在实验开始的两周后,根据诱导模型,使用葡聚糖硫酸钠对上述结肠炎诱导了结肠炎疾病。
表2
实验例2-2:基础性观察结果
对于上述实验组而言,当利用葡聚糖硫酸钠进行处理时,初始体重为G1:23.4±1.5,G2:23.1±1.2,G3:22.1±2.4,G4:22.8±0.8,G5:22.9±1.1,G6:22.2±1.3,G7:23.2±1.2,而当验尸时,体重为G1:24.2±1.7,G2:21.9±1.2,G3:20.3±2.2,G4:20.5±0.9,G5:21.4±0.8,G6:21.6±0.7,G7:21.1±0.9。
按不同的实验日期测定各处理组的体重的结果如以下表3及表1所示。此时,体重意味着平均±标准偏差。
表3
像这样,自2012.01.12饮用2.5重量百分比的葡聚糖硫酸钠水溶液开始,进行了7天的葡聚糖硫酸钠饮水的结果可以确认,由于利用葡聚糖硫酸钠来诱导的腹泻或血便等,在G2至G7的小鼠的情况下,与刚开始进行葡聚糖硫酸钠的饮水处理时相比,体重减少。
并且,在进行葡聚糖硫酸钠饮水第七天时,在醚麻醉条件下牺牲动物来摘除结肠,并对此进行了观察。结果如图2所示,可以确认由于利用葡聚糖硫酸钠来诱导的腹泻或血便等,在G2至G7的小鼠的情况下,发生了炎症。
当实验结束时,以反映血便(hematochezia)和腹泻(diarrhea)的程度来拟定了疾病活动指数评分,并将此呈现于图3中。并且,结肠从盲肠至结肠末端为止测定了长度,并将其结果呈现于图4中。在图4中,#意味着与正常组G1相比,具有显著性差异(p<0.0001),*意味着与结肠炎模型动物组相比,具有显著性差异(p<0.05)。
表4
疾病活动指数的分数及基准
参照图3,与正常组相比,当利用葡聚糖硫酸钠诱导炎症性结肠炎时,优于结肠内粘膜组织的验证而以腹泻和血便之类的临床表现(clinical sign)的变化,使疾病活动指数评分增加,但通过G3至G6的处理,结肠内粘膜组织的炎症得到减少,从而使腹泻和血便减少,这种临床表现以疾病活动指数评分的减少呈现。并且,如图4所示,确认了在被葡聚糖硫酸钠诱导的结肠炎症状中,与正常组相比较,结肠的长度因炎症而变短,通过G3至G6的处理,结肠的长度与葡聚糖硫酸钠处理组相比,统计性地得到有利的恢复,而这与作为对照组的G7相比,呈现出同等以上的效果。
实验例2-3:通过苏木精-伊红染色的病理学观察结果
将所采取的结肠固定于10%普尔马林溶液,并实施苏木精-伊红染色,从而将此呈现于图5中。并且,通过盲试验(blindtest)来观察了共计6种炎症的组织病理学所见(炎症(inflammation),卵泡聚集(follicle aggregation),水肿(oedema),侵蚀/溃疡(erosion/ulceration),肠隐窝(cryptloss),单和多形核细胞的侵润(Infiltration of mono-andpolymorphonuclear cells))并进行了评分。将对各项目的各实验组的分数和对6种项目的分数合计后的总病理学分数如图6所示。
参照以下的图5至图6,可以确认对肠粘膜组织进行苏木精-伊红染色结果,在利用葡聚糖硫酸钠来诱导炎症的肠粘膜组织的情况下,因由发炎(inflammation)、卵泡聚集(follicleaggregation),水肿(oedema)等作用引起的组织病理学变化而使肠粘膜组织与正常组不同。但确认了通过G3至G6的处理,肠粘膜组织得到回复,并基于这种结果,将组织病理学所见的评价进行图示化的结果,在病理评分(pathologic score)方面,与正常组相比,在葡聚糖硫酸钠处理组中增加,且因G3至G6处理,使病理评分减少。这与作为对照组的G7相比,呈现出同等或同等以上的效果。
实验例2-4:炎症性细胞因子的测定结果
对作为诱导炎症反应的代表性的细胞因子IL-1β、IL-6、IL-12及TNF-α的水平(level)进行测定的结果,可在被葡聚糖硫酸钠诱导的炎症性肠病(IBD)组中观察到炎症性细胞因子的表达显著增加,并观察到通过G3至G6的处理,其表达程度有益地减少。将上述观察结果呈现于以下的图5中。
参照以下的图7自图10,借助被葡聚糖硫酸钠诱导的炎症反应,如IL-1β(图7)、IL-6(图8)、TNF-α(图9)、IL-12(图12)之类的炎症性细胞因子增加,由此,如图4的苏木精-伊红染色结果,肠粘膜因炎症反应而丧失粘膜的功能,从而呈现出腹泻及血便之类的病变现象。通过G3至G6的处理,炎症性细胞因子的表达减少,炎症性细胞因子的表达的减少诱导了向正常粘膜组织的恢复,而这与作为对照组的G7相比,呈现出同等的效果。
实验例2-5:抗氧化作用的测定结果
对用于测定作为氧化应激(Oxidative stress)的代表性标记(marker)的脂质过氧化(lipid peroxidation)的丙二醛(malondialdehyde,MDA)的浓度进行了测定。
结果,观察出在作为S-烯丙基-L-半胱氨酸的低浓度的G3和G4中统计性地得到有利的抑制,并且,作为与其相应的结果,观察出与葡聚糖硫酸钠处理组相比,G3中的抗氧化剂(antioxidant)的浓度统计性低得到有利的增加。将上述观察结果呈现于以下的图10(丙二醛浓度)至图11(总抗氧化剂浓度)中。
参照以下图10至图11,由于被葡聚糖硫酸钠诱导的氧化应激,作为脂质过氧化的代表性指标的丙二醛与正常组相比增加,且这种脂质过氧化如同图5的苏木精-伊红染色结果般诱导肠粘膜的炎症反应,从而诱导了粘膜功能的丧失。通过G3至G6的处理,丙二醛的水平得到减少,且丙二醛水准的减少因基于氧化应激的炎症反应得到减少而诱导了向正常粘膜组织的恢复,而这与作为对照组的G7相比,呈现出了同等以上的效果。尤其,在G3处理组中呈现出最佳的效果,这是因为细胞内的抗氧化剂的浓度越增加,越呈现出好的效果,并且,可知如图6的总的病例评分(total pathologic score)所示,在G3处理组中的粘膜组织的恢复最为突出。
实验例2-6:测定炎症性基因的表达
在G2至G3的实验组中可以观察到,作为代表性炎症酶的COX-2的表达得到显著增加,在用实验物质进行处理的组中,上述COX-2的表达减少。虽然执行了多次的蛋白质印迹(Western blot),但由于难以获得结果,因而在动物组织的石蜡为未染色切片(unstained slide)中执行了COX-2的免疫荧光(immunofluorescence)。
结果,观察到在所有组中抑制基于葡聚糖硫酸钠的COX-2的表达。将上述观察结果呈现于以下的图13(COX-2(绿色),DAPI(蓝色)及合并图形(merged image))中。
参照以下的图13,确认了COX-2作为炎症反应的代表性指标,在呈现出被基于葡聚糖硫酸钠的氧化应激诱导的炎症反应的结肠粘膜组织中,COX-2的表达与正常组相比,得到显著增加,而这种COX-2的表达如图4的苏木精-伊红染色结果般诱导肠粘膜的炎症反应,从而诱导了粘膜功能的丧失。通过G3至G6的处理,粘膜组织内的COX-2的表达得到减少,且COX-2的表达的减少因基于氧化应激的炎症反应得到减少而诱导了向正常粘膜组织的恢复,而这与作为对照组的G7相比,呈现出了同等以上的效果。尤其,确认了在作为对照组的G7的情况下,虽然抑制了在粘膜组织中的COX-2的表达,但并未有效地抑制粘膜组织的下部的肌膜组织的COX-2的表达,相反,在G4至G6处理组中,还抑制了肌膜组织的COX-2的表达。
实验例2-7:确认S-烯丙基-L-半胱氨酸的副作用效果
作为免疫抑制效果,在使用于结肠炎治疗剂的环孢霉素或波尼松龙的情况下,作为类固醇,呈现出体重增加的副作用。但在使用包含S-烯丙基-L-半胱氨酸作为活性成分的实施例1的实验组G3至G6的情况下,并未表达基于上述实施例1的处理的体重增加,因而可以知道没有体重增加之类的副作用。
众所周知,在上述马沙拉嗪或美沙拉嗪制剂或NSAIDs类抗炎的情况下,存在过敏反应、作呕、呕吐、头痛等副作用。但在包含S-烯丙基-L-半胱氨酸的上述G3至G6的情况下,在将实验时间增加至12周的期间内,未确认出使用包含上述美沙拉嗪的对照组的G7的副作用的症状。
用于实施发明的方式
剂型例:包含S-烯丙基-L-半胱氨酸的制剂
制剂例1:片剂的制备
S-烯丙基-L-半胱氨酸200mg
乳糖50mg
淀粉10mg
制剂例2:散剂的制备
S-烯丙基-L-半胱氨酸250mg
乳糖30mg
淀粉20mg
硬脂酸镁适量
将上述成分紧密混合之后,填充于涂敷有聚乙烯的布,并通过密封来制备了散剂。
制剂例3:胶囊剂的制备
S-烯丙基-L-半胱氨酸500mg
乳糖30mg
淀粉28mg
滑石2mg
硬脂酸镁适量
将上述成分相混合,并根据通常的胶囊剂的制备方法来填充于明胶硬胶囊,从而制备了胶囊剂。
制剂例4:悬浮剂的制备
S-烯丙基-L-半胱氨酸50mg
异构酶10g
砂糖30mg
羧甲基纤维素钠100mg
柠檬香适量
添加适量的纯化水,整体成为100ml
混合上述成分,并根据通常的悬浮剂的制备方法来制备悬浮剂之后,填充于100ml容量的棕色瓶,并通过灭菌来制备了悬浮剂。
制剂例5:软质胶囊剂的制备(软质胶囊剂的一净重含量)
S-烯丙基-L-半胱氨酸500mg
聚乙二醇400mg
浓甘油55mg
纯化水35mg
将在混合聚乙二醇和浓甘油之后,添加纯化水的混合物以约60℃的温度维持的状态下,放入黄铜,并利用搅拌器以约1500rpm的速度进行搅拌,并进行了均匀的混合。将上述混合液慢慢搅拌,并利用常温进行冷却,利用真空泵除去气泡,从而准备软质胶囊的内容物。软质胶囊的的皮膜以所属领域公知的明胶、增塑剂的软处方,每一胶囊使用132mg的明胶、52mg的浓甘油、6mg的70%脱山梨糖醇液以及使用适量的乙基香兰素作为着香剂,使用巴西棕榈树蜡作为涂料基剂,从而以通常的制备方法进行了制备。
制剂例6:注射剂的制备
S-烯丙基-L-半胱氨酸200mg
甘露醇180mg
注射用灭菌蒸馏水2974mg
Na2HPO412H2O 26mg
根据通常的注射剂的制备方法,以每安瓿按上述的成分含量进行制备。
制剂例7:饮料的制备
S-烯丙基-L-半胱氨酸0.01g
柠檬酸8.5g
白砂糖10g
葡萄糖2.5g
DL-苹果酸0.3g
纯化水适量
在上述的成分含量中适量低配合纯化水,以成为共100mL的方式进行搅拌,并以通常的饮料制备方法进行了制备。
以上,对本发明的优选实施例进行了详细说明,但本发明的保护范围并不局限于此,由发明要求保护范围所定义,且由利用本发明的基本概念的所属领域技术人员的多种变形及改良形态同样属于本发明的保护范围。
产业上的可利用性
本发明涉及结肠炎预防用或治疗用组合物,更详细地,包含S-烯丙基-L-半胱氨酸作为活性成分,且作为有利于结肠炎的预防或治疗的组合物及利用这种组合物的方法,在产业上具有可利用性。
Claims (5)
1.一种结肠炎预防或治疗用组合物,其特征在于,包含S-烯丙基-L-半胱氨酸、其药学上可接受的盐或它们的溶剂化物或氢化物作为活性成分。
2.根据权利要求1所述的结肠炎预防或治疗用组合物,其特征在于,上述S-烯丙基-L-半胱氨酸为选自由从葱属植物分离纯化的、合成的及通过发酵来制成的物质组成的组中的一种。
3.根据权利要求1所述的结肠炎预防或治疗用组合物,其特征在于,还包含抗炎剂或抗氧化剂。
4.根据权利要求3所述的结肠炎预防或治疗用组合物,其特征在于,
上述抗炎剂为选自由布洛芬、酮洛芬、氟比洛芬、非诺洛芬、萘普生、吡罗昔康、替诺昔康、伊索昔康、美洛昔康、吲哚美辛、醋氯芬酸、双氯芬酸及它们的组合组成的组中的一种;
上述抗氧化剂为选自由维生素A、维生素C、维生素E、类胡萝卜素、锌、铜、铁、锰、叶黄素、玉米黄质、硒、谷胱甘肽、番茄红素及它们的组合组成的组中的一种。
5.一种医药制剂,其特征在于,选自由包含权利要求1至4中任一项所述的结肠炎预防或治疗用组合物的口服给药用制剂、粘膜应用制剂、注射剂、吸入剂及外用剂组成的组中。
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Application Number | Priority Date | Filing Date | Title |
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KR10-2012-0072080 | 2012-07-03 | ||
KR20120072080A KR101320945B1 (ko) | 2012-07-03 | 2012-07-03 | 에스-알릴-엘-시스테인을 유효성분으로 포함하는 대장염 예방 또는 치료용 조성물 및 이를 포함하는 의약제제 |
PCT/KR2013/005922 WO2014007549A2 (ko) | 2012-07-03 | 2013-07-03 | 에스-알릴-엘-시스테인을 유효성분으로 포함하는 대장염 예방 또는 치료용 조성물 및 이를 포함하는 의약제제 |
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CN104487065A true CN104487065A (zh) | 2015-04-01 |
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US (1) | US20150147411A1 (zh) |
EP (1) | EP2870964A4 (zh) |
JP (1) | JP2015521657A (zh) |
KR (1) | KR101320945B1 (zh) |
CN (1) | CN104487065A (zh) |
BR (1) | BR112014033088A2 (zh) |
RU (1) | RU2015100897A (zh) |
WO (1) | WO2014007549A2 (zh) |
Cited By (1)
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CN117503745A (zh) * | 2024-01-04 | 2024-02-06 | 潍坊现代农业山东省实验室 | 脱氧蒜氨酸作为肥大细胞活化抑制剂的应用 |
Families Citing this family (2)
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KR101811440B1 (ko) * | 2014-12-16 | 2017-12-21 | 경희대학교 산학협력단 | 에스-알릴-엘-시스테인을 유효성분으로 함유하는 위장관 운동 촉진용 약학적 조성물 |
US20190380986A1 (en) * | 2017-01-26 | 2019-12-19 | Canvax Biotech, S.L | Method for producing extracts enriched with sulfoxide-free organosulfur compounds, s-alkenyl-lcysteine and s-alkyl-lcysteine, from plant raw materials, and uses thereof in the treatment of inflammatory diseases |
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WO2011037411A2 (en) * | 2009-09-23 | 2011-03-31 | Pharmaking Co., Ltd. | Composition comprising s-allyl-l-cysteine as active ingredient for preventing or treating gastrointestinal disorders |
CN102316730A (zh) * | 2008-05-09 | 2012-01-11 | 天雅瑞药业有限公司 | 用于减轻全身性炎症和/或血管炎症的n-乙酰半胱氨酸(nac)的控释 |
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JP2005306831A (ja) * | 2004-04-20 | 2005-11-04 | Sakamoto Yakusoen:Kk | 皮膚外用剤 |
EP1753734A1 (en) * | 2004-05-05 | 2007-02-21 | Renopharm Ltd. | Nitric oxide donors and uses thereof |
KR100530386B1 (ko) | 2005-08-03 | 2005-11-22 | (주)코스트플러스코리아 | 숙성 마늘의 제조방법 |
JP4564471B2 (ja) * | 2006-07-06 | 2010-10-20 | 株式会社コーセー | 外用に適する組成物 |
US20100069319A1 (en) | 2007-03-02 | 2010-03-18 | Talia Miron | Mercaptopurine derivatives and uses thereof |
JP2010531811A (ja) * | 2007-06-29 | 2010-09-30 | ノボゲン リサーチ ピーティーワイ リミテッド | 2−置換イソフラボノイド化合物、医薬及び使用 |
KR20090068560A (ko) * | 2007-12-24 | 2009-06-29 | 덕성여자대학교 산학협력단 | 항염증 활성을 갖는 산마늘 추출물 |
DK2303330T4 (da) * | 2008-06-06 | 2021-09-13 | Pharma Two B Ltd | Farmaceutiske sammensætninger til behandling af parkinsons sygdom |
KR20100026597A (ko) * | 2008-09-01 | 2010-03-10 | 경남도립남해대학 산학협력단 | 흑마늘 추출물을 유효성분으로 함유하는 염증성 질환의 예방 및 치료용 조성물 |
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2013
- 2013-07-03 CN CN201380035480.9A patent/CN104487065A/zh active Pending
- 2013-07-03 WO PCT/KR2013/005922 patent/WO2014007549A2/ko active Application Filing
- 2013-07-03 RU RU2015100897A patent/RU2015100897A/ru not_active Application Discontinuation
- 2013-07-03 JP JP2015520061A patent/JP2015521657A/ja active Pending
- 2013-07-03 EP EP13813180.0A patent/EP2870964A4/en not_active Withdrawn
- 2013-07-03 BR BR112014033088A patent/BR112014033088A2/pt not_active IP Right Cessation
- 2013-07-03 US US14/412,674 patent/US20150147411A1/en not_active Abandoned
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WO2002041837A2 (en) * | 2000-11-22 | 2002-05-30 | Rxkinetix, Inc. | Treatment of mucositis |
CN102316730A (zh) * | 2008-05-09 | 2012-01-11 | 天雅瑞药业有限公司 | 用于减轻全身性炎症和/或血管炎症的n-乙酰半胱氨酸(nac)的控释 |
WO2011037411A2 (en) * | 2009-09-23 | 2011-03-31 | Pharmaking Co., Ltd. | Composition comprising s-allyl-l-cysteine as active ingredient for preventing or treating gastrointestinal disorders |
Cited By (1)
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CN117503745A (zh) * | 2024-01-04 | 2024-02-06 | 潍坊现代农业山东省实验室 | 脱氧蒜氨酸作为肥大细胞活化抑制剂的应用 |
Also Published As
Publication number | Publication date |
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KR101320945B1 (ko) | 2013-10-23 |
WO2014007549A2 (ko) | 2014-01-09 |
WO2014007549A3 (ko) | 2014-02-20 |
EP2870964A2 (en) | 2015-05-13 |
JP2015521657A (ja) | 2015-07-30 |
BR112014033088A2 (pt) | 2017-06-27 |
RU2015100897A (ru) | 2016-08-20 |
US20150147411A1 (en) | 2015-05-28 |
EP2870964A4 (en) | 2015-11-25 |
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