CN117915889A - 肉毒杆菌神经毒素替代新材料及其制备方法 - Google Patents
肉毒杆菌神经毒素替代新材料及其制备方法 Download PDFInfo
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- CN117915889A CN117915889A CN202280060445.1A CN202280060445A CN117915889A CN 117915889 A CN117915889 A CN 117915889A CN 202280060445 A CN202280060445 A CN 202280060445A CN 117915889 A CN117915889 A CN 117915889A
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- myricetin
- acetylcholine
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- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
- A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
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- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
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- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
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- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
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Abstract
本发明涉及一种肉毒杆菌神经毒素替代新材料及其制备方法。更具体地,涉及一种包括体内稳定性的物质的稳定性显著改善,且具有能够阻碍SNARE复合体形成并最终具有能够阻碍乙酰胆碱分泌能力的杨梅黄酮乙酰基衍生物及其制备方法。
Description
技术领域
本发明涉及一种肉毒杆菌神经毒素(Botulinum neurotoxin)替代新材料及其制备方法,更具体地,涉及一种包括体内稳定性(In vivo stabilit y)的物质的稳定性显著改善的、具有能够阻碍乙酰胆碱(Acetylcholine)分泌的能力的杨梅黄酮(Myricetin)乙酰基衍生物(Acetyl derivative)及其制备方法。
背景技术
肉毒杆菌神经毒素(Botulinum neurotoxin)使神经细胞中干预突触前膜(Presynaptic membrane)与突触小泡(Synaptic vesicle)结合(Docking)的SNARE(可溶性N-乙酰马来酰亚胺敏感因子附着蛋白受体;Soluble N-et hylmaleimide-sensitivefactor attachment protein receptor)蛋白质(Protein)水解,以阻碍乙酰胆碱(Acetylcholine)分泌,最终阻断神经传递,从而不仅可以用于改善皱纹(Treatingwrinkles)等美容施术,而且还可以用于斜视(Crossed eyes)、多汗症(Excessivesweating)等因乙酰胆碱过多分泌引发的100多种疾病的治疗中。
肉毒杆菌神经毒素其本身就是一种毒素,如果处置不当,不仅会导致死亡,还会引发过敏反应,具有说话僵硬、表情不自然、无法闭上眼睛等副作用。一般来说,通常是由于用量控制失败和肉毒杆菌神经毒素扩散到不期望的肌肉等原因造成的,这些副作用需要肉毒杆菌神经毒素在体内分解或形成新的神经,从而恢复正常功能才能消除,这可能会需要几个月的时间。正因为如此,肉毒杆菌神经毒素在用于美容或医学目的时需要相当程度的注意。肉毒杆菌神经毒素是通过培养一种名为“肉毒梭状芽孢杆菌(Clostridiumbotulinum)”的厌氧微生物来生产,这种菌非常致命,因此从培养过程到分离提纯及废弃和杀菌的整个过程都必须严格管理。
正因为如此,人们正在尝试开发各种材料来替代肉毒杆菌神经毒素。作为其实例存在:想要使用蛋白质或者多肽(Polypeptide)的情况(大韩民国专利公开第10-2012-0001964号;大韩民国专利公开第10-2012-0122999号),想要利用天然多酚(Polyphenol)的情况(大韩民国专利公开第10-2008-0083438号;大韩民国专利公开第10-2008-0091735号;大韩民国专利公开第10-2011-0017599号;大韩民国专利公开第10-2016-0058739号),想要利用杨梅黄酮(Myricetin)衍生物(Derivative)的情况(大韩民国专利公开第10-2017-0015845号;大韩民国专利公开第10-2017-0091554号)等。其中,国外开发出了利用肽的类似肉毒杆菌神经毒素材料,并将其商品化。Lipotec公司开发的阿基瑞林(Argireline)便是其例子。但由于诸多缺点,肉毒杆菌神经毒素替代品的商业成功还处于微乎其微的水平。
因此,需要开发出一种既能够克服现有肉毒杆菌神经毒素替代材料缺点又能够解决肉毒杆菌神经毒素的副作用及问题的新材料。
发明内容
所要解决的技术问题
因此,本发明人着眼于现有肉毒杆菌神经毒素替代材料中杨梅黄酮衍生物降低包括体内稳定性在内的物质稳定性和解决这一问题后可以开发出更有价值的肉毒杆菌神经毒素替代材料,为了解决现有杨梅黄酮衍生物的稳定性问题,经过不懈的努力,最终研发出了与现有公开的杨梅黄酮衍生物比较稳定性显著改善的物质及其制备方法,从而完成了本发明。
因此,本发明的目的在于,提供一种[化学式1]的杨梅黄酮乙酰基衍生物(3-乙酰基-杨梅黄酮;3-Acetyl-Myricetin),其可以用作肉毒杆菌神经毒素替代材料,稳定性显著改善,能够阻碍SNARE复合体形成,最终具有能够阻碍乙酰胆碱分泌的能力。
[化学式1]
本发明的另一个目的在于,提供一种以[化学式1]表示的杨梅黄酮乙酰基衍生物的制备方法。
本发明的又一个目的在于,提供一种以上述[化学式1]表示的杨梅黄酮乙酰基衍生物为有效成分包含的、替代肉毒杆菌神经毒素的美容目的的化妆品组合物。
另外,本发明的又一个目的在于提供一种以上述[化学式1]表示的杨梅黄酮乙酰基衍生物为有效成分包含的、用于治疗因乙酰胆碱过多分泌而产生疾病的药物组合物。
解决技术问题的方法
因此,根据本发明的一种形态,本发明提供一种以[化学式1]表示的杨梅黄酮乙酰基衍生物,其阻碍SNARE复合体形成,从而最终具有能够阻碍乙酰胆碱分泌的能力。
当然,以上述[化学式1]为基本框架,采用额外的衍生化(Derivatizat ion)也可以获得本发明的效果,这在本发明内不言而喻。
根据本发明的另一种形态,本发明提供一种以[化学式1]表示的杨梅黄酮乙酰基衍生物为有效成分包含的美容目的的化妆品组合物。
可以提出的上述美容目的有改善皱纹、缩小毛孔(Reducing pore siz e)、增强皮肤弹性(Improving skin elasticity)等,当然并非仅限定于此。可以提出的上述皱纹的实例有,眉毛下垂(Brow droop)、眼角鱼尾纹(Crow’s-feet)、法令纹(Nasolabial folds)、嘴角皱纹(Mouth frown)、颈部皱纹(Neck wrinkles)、额头皱纹(Forehead lines)、眉间皱纹(Frown lines)、眼底皱纹(Tear troughs)、下巴皱纹(Jowls)等,当然并非仅限定于此。
在本发明的一个方面,“化妆品组合物”是一个包括所有使人体外观变美的组合物的概念。本发明的美容目的的化妆品组合物是指通过抑制根据生物节律的生理现象的皮肤中的负面影响使人体外观变美的组合物的概念,但并非仅限定于此。
在本发明的一个方面,由于化妆品组合物基本上是涂在皮肤上的,因此可以参照本行业的化妆品组合物按照通常制备的任何剂型进行制备。作为一个例子,可以溶液、悬浮液、乳浊液、膏体(paste)、凝胶(gel)、乳霜(cream)、乳液(lotion)、粉饼(powder)、精油(oil)、粉末型粉底、乳浊液型粉底液、蜜蜡液型粉底液(wax foundation)及喷剂(spray)等剂型化,但并非仅限定于此。更具体地,可以制备成柔软化妆水、营养化妆水、营养霜、按摩霜、精华素、眼霜、喷剂或粉饼的剂型等。
在本发明的一个方面,当本发明的剂型为膏体、乳霜或凝胶的情况下,则载体成分可包括动物油、植物油、蜜蜡(wax)、石蜡(paraffin)、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅胶(silicon)、膨润土、二氧化硅、滑石粉(talc)、氧化锌等。
在本发明的一个方面,当本发明的剂型为粉饼或喷剂的情况下,则载体成分可包括乳糖、滑石粉、二氧化硅、氢氧化铝、硅酸钙、聚酰胺粉(pol yamide powder)等,特别是,在喷剂的情况下,可进一步包括含氯氟烃(chlorofluorohydrocarbon)、丙烷/丁烷、二甲醚等推进体。
在本发明的一个方面,当本发明的剂型为溶液或乳浊液的情况下,则载体成分可包括溶剂、增溶剂、乳化剂等,具体地,可包括水、乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇精油(1,3-butyl glycol oil)、甘油脂肪族酯、聚乙二醇、山梨聚糖(sorbitan)的脂肪酸酯等。
在本发明的一个方面,当本发明的剂型为悬浮液的情况下,则载体成分可包括:水、乙醇、丙二醇等液态稀释剂;乙氧基化异硬脂醇、聚氧乙烯山梨醇酯、聚氧乙烯山梨聚糖酯等悬浮剂;微晶纤维素、偏氢氧化铝(alumi num metahydroxide)、膨润土、琼脂、黄蓍胶等。
在本发明的一个方面,当本发明的剂型为含有表面活性剂的清洁剂的情况下,则载体成分可利用脂肪族醇硫酸盐、脂肪族醇醚硫酸盐、磺化琥珀酸单酯(sulfosuccinatemonoester)、羟乙基磺酸盐(isethionate)、咪唑啉(imidazolinium)衍生物、甲基牛磺酸盐(methyl taurate)、肌氨酸盐(sarcosinate)、脂肪酸酰胺醚硫酸盐、烷基酰胺甜菜碱(alkyl am ido betaine)、脂肪醇、脂肪酸甘油酯、脂肪酸二乙醇酰胺、植物油、羊毛脂(lanolin)衍生物或乙氧基化甘油脂肪酸酯等。
根据本发明的另一种形态,本发明提供一种以[化学式1]表示的杨梅黄酮乙酰基衍生物为有效成分包含的、用于治疗因乙酰胆碱过多分泌引发疾病的药物组合物。
上述乙酰胆碱过多分泌引发的疾病包括斜视、内耳障碍(Inner ear di sorder)、磨牙(Teeth grinding)、瘢痕疙瘩(Keloid scarring)、多汗症、背部和肩部疼痛(Backpain)、战栗(Tremors)、肛裂(Anal fissure)、臀部畸形(Buttock deformity)、肌肉痉挛(Muscle injuries,twitching)、慢性偏头痛(Chronic migraine)、抑郁症(Depression)、面瘫(Facial nerve disorder)、颈部痉挛(Neck pain,spasms)、甲状腺障碍(Thyroiddisord er)、心肌障碍(Cardiac muscledisorder)、上肢僵硬(Upper limb spast icity)、胰腺障碍(Pancreas disorders)、肠易激综合征(Irritable bowe l syndrome)、膨胀纹(Stretch marks)、小儿脑瘫(Juvenile cerebral pa lsy)等,当然并非仅限定于此。
本发明的药物组合物中包含的药剂学上可接受的载体是在制剂时常用的,包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、洋槐胶、磷酸钙、海藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁及矿物油等,但并非仅限定于此。本发明的药剂学组合物除了上述成分之外,可进一步包括润滑剂、润湿剂、甜味剂、增香剂、乳化剂、悬浮剂、保存剂等。
本发明的将以[化学式1]表示的杨梅黄酮乙酰基衍生物作为有效成分包含在内的药物组合物可以采用口服给药或非口服给药方式给药,在非口服给药的情况下,可以采用静脉内给药、腹腔内给药、肌肉内给药、皮下给药、鼻腔内给药或局部给药来施用,但并非仅限定于此。
本发明的以[化学式1]表示的杨梅黄酮乙酰基衍生物为有效成分的药物组合物可以按照具有本发明所属技术领域一般知识的技术人员能够容易实施的方法利用药学上可接受的载体及/或赋形剂进行制剂化,既可以按照单位用量形态制备,也可以装入大容量容器内进行制备。在这种情况下,剂型既可以是精油或水性介质中的溶液、悬浮液或乳化液形态,也可以是浸膏剂、粉末剂、颗粒剂、片剂或胶囊剂形态,可进一步包括分散剂或稳定剂。
另外,上述药物组合物的合适的涂布、喷雾及给药量根据制剂化方法、给药方式、年龄、体重、姓别、疾病症状的程度、饮食、给药时间、给药途径、排泄速度及反应感应性等因素是多样的,通常,有经验的医生能够针对所期望的治疗容易地确定并处方有效的给药量。
根据本发明的另一种形态,本发明提供一种以[化学式1]表示的杨梅黄酮乙酰基衍生物的制备方法。
具体地,以[化学式1]表示的杨梅黄酮乙酰基衍生物的制备方法,其特征在于,包括:(A)在不会添加外部的空气与水分的氮气环境下向溶解于无水吡啶(Pyridineanhydrous)中的杨梅黄酮添加无水乙酸(Acetic anhydri de)使发生反应的步骤;(B)利用乙酸乙酯(Ethyl acetate;EA)进行提取的步骤;(C)对乙酸乙酯(Ethyl acetate;EA)提取物进行减压干燥的步骤;(D)向减压干燥的样品中添加二甲基亚砜(Dimethyl sulfoxide;DMSO),接着再添加磷酸缓冲生理盐水(Phosphate-buffered saline;PBS;pH 7.0)进行稀释的步骤;(E)使稀释的样品发生反应(Incubation),对副产物进行分解的步骤;以及(F)冷冻干燥的步骤。
发明效果
根据本发明的以[化学式1]表示的杨梅黄酮乙酰基衍生物可以提供改善的物质稳定性,因此以其为有效成分包含的组合物更加易于保管及处理。更重要的是,给药后还能够提供高的体内稳定性,从而可以提供进一步改善且持续的功效。
附图说明
图1是显示本发明的以[化学式1]表示的3-乙酰基-杨梅黄酮合成过程的概略图。
图2是本发明的以[化学式1]表示的3-乙酰基-杨梅黄酮制备过程中,对冷冻干燥样品采用反相高效液相色谱法(Reversed phase-high performa nce liquidchromatography;RP-HPLC)分析的结果的示意图。
图3是最终提炼的以[化学式1]表示的3-乙酰基-杨梅黄酮的RP-HPLC分析结果的示意图。
图4是对最终提炼的以[化学式1]表示的3-乙酰基-杨梅黄酮采用液体色谱-质谱法(Liquid chromatography-mass spectrometry;LC/MS)分析的结果的示意图。
图5是对最终提炼的以[化学式1]表示的3-乙酰基-杨梅黄酮采用核磁共振分析法(Nuclear magnetic resonance;NMR)分析的结果的示意图。
图6是对根据本发明的以[化学式1]表示的3-乙酰基-杨梅黄酮的抑制乙酰胆碱分泌的程度进行测定的结果的示意图。1是对照组结果,2是采用0.5μM样品的结果,3是采用2μM样品的结果,4是采用10μM样品的结果,5是采用20μM样品的结果。
图7是根据本发明的以[化学式1]表示的3-乙酰基-杨梅黄酮、杨梅黄酮及Myricetin-C4(杨梅黄酮-C4)的稳定性比较实验结果的示意图。
图8是功效比较实验结果的示意图。1是对照组(PBS处理组;无处理组),2是3-乙酰基-杨梅黄酮处理组,3是杨梅黄酮(myricetin)处理组,4是西伯利亚落叶松黄酮(Laricitrin)处理组,5是四角风草子素(Combretol)处理组,6是丁香亭(Syringetin)处理组,7是Myricetin-C4处理组,8是Myricetin-C8处理组,9是Myricetin-C12处理组,10是Myricetin-C16处理组,11是Myricetin-C20处理组,12是Derivative(衍生物)E4-2处理组,13是Derivative E4-4处理组,14是Derivative E4-8处理组,15是Derivative E4-12处理组,16是Derivative E4-16处理组,17是De rivative E4-18处理组,18是Derivative E4-20处理组。功效比较实验将对照组(无处理组)的出汗面积(Sweating area)设定为100%,并将相对值作为结果示出。
具体实施方式
下面,将根据实施例对本发明进行更加详细的说明,但是这些实施例只是本发明的示例,本发明的范围并非仅限定于这些实施例。
实施例1:制备对照物质及杨梅黄酮乙酰基衍生物
在本实施例中,准备了在后续的比较实验需要使用的对照物质。对照物质选定了杨梅黄酮、大韩民国专利公开第10-2017-0015845号及大韩民国专利公开第10-2017-0091554号实施例中作为杨梅黄酮衍生物在实施例中记载的[化学式2]的西伯利亚落叶松黄酮、[化学式3]的四角风草子素、[化学式4]的丁香亭、脂肪酶催化剂下的丁酸乙烯酯(Vinyl butyrate)通过酰化作用制备的杨梅黄酮衍生物(Myricetin-C4)、利用脂肪酶催化剂下的辛酸乙烯酯(Vinyl octanoate)通过酰化作用制备的杨梅黄酮衍生物(Myricetin-C8)、利用脂肪酶催化剂下的月桂酸乙烯酯(Vinyl laurate)通过酰化作用制备的杨梅黄酮衍生物(Myricetin-C12)、利用脂肪酶催化剂下的软脂酸乙烯酯(Vinyl palmitate)通过酰化作用制备的杨梅黄酮衍生物(Myricetin-C16)、利用脂肪酶催化剂下的二十烷酸乙烯酯(Vinyl eicosanoate)通过酰化作用制备的杨梅黄酮衍生物(Myricetin-C20)、利用使用了碱基及草酰氯的乙酸(Acetic acid)通过酰化作用制备的杨梅黄酮衍生物(DerivativeE4-2)、利用使用了碱基及草酰氯的丁酸(Butyric acid)通过酰化作用制备的杨梅黄酮衍生物(Derivative E4-4)、利用使用了碱基及草酰氯的辛酸(Octan oic acid)通过酰化作用制备的杨梅黄酮衍生物(Derivative E4-8)、利用使用了碱基及草酰氯的月桂酸(Lauricacid)通过酰化作用制备的杨梅黄酮衍生物(Derivative E4-12)、利用使用了碱基及草酰氯的软脂酸(Palmitic acid)通过酰化作用制备的杨梅黄酮衍生物(Derivative E4-16)、利用使用了碱基及草酰氯的硬脂酸(Stearic acid)通过酰化作用制备的杨梅黄酮衍生物(Derivative E4-18)、利用使用了碱基及草酰氯的花生酸(Arachidic ac id)通过酰化作用制备的杨梅黄酮衍生物(Derivative E4-20)。
[化学式2]
[化学式3]
[化学式4]
杨梅黄酮、西伯利亚落叶松黄酮、四角风草子素、丁香亭购买并使用了商业销售的产品,其余用作对照物质的衍生物按照大韩民国专利公开第10-2017-0015845号及大韩民国专利公开第10-2017-0091554号的实施例中提出的方法进行了制备。本发明人开发的[化学式1]的杨梅黄酮乙酰基衍生物(3-乙酰基-杨梅黄酮)按照以下方法进行制备。向圆底烧瓶(Round bottom flask;RBF)中放入搅拌棒(Stirring bar)和杨梅黄酮(1当量),用氮气置换后,为了防止外部的空气与水分添加进来,用橡皮塞堵住后,再向RBF中添加无水吡啶(Pyridine anhydrous;0.5当量),然后在冰槽(Ice bath)中使杨梅黄酮全部溶解。利用注射器向溶解的杨梅黄酮中一滴一滴地添加无水乙酸(Acetic anhydride)。在冰槽中搅拌(Stirring)一夜。向反应了一夜的溶液中添加冷蒸馏水结束反应。将结束反应后的反应物全部放入分液漏斗(Separating funnel)中,然后再添加乙酸乙酯(Ethyl acetate;EA)。为了不使反应物留在RBF上,将EA添加到RBF中后,再向分液漏斗转移。为了确保合成的3-乙酰基-杨梅黄酮能够充分溶解于EA中,将分液漏斗进行多次摇晃后,将其静置于架台(stand)上,以便使水与EA层能够分开。当水与EA层分开后,仅将水层去除(EA的密度为比水低的0.9,所以水层在下面)。向分液漏斗中添加饱和盐水(Brine)后,为了确保合成的3-乙酰基-杨梅黄酮能够充分溶解于EA中,将分液漏斗进行多次摇晃后,将其静置于架台上,以便使水与EA层能够分开。当水与EA层分开后,仅将水层去除。向分液漏斗中添加蒸馏水后,为了确保合成的3-乙酰基-杨梅黄酮能够充分溶解于EA中,将分液漏斗进行多次摇晃后,重复实施3次为了使水和EA层分开而将分液漏斗静置于架台上的过程和水与EA层分开后仅将水层去除的过程。将EA层转移到新的RBF中后,实施减压干燥。通过这一过程,向经减压干燥的样品中放入DMSO,按照10mg/ml浓度进行溶解。向10mg/ml的合成混合物中添加PBS(pH 7.0)稀释至1mg/ml浓度。将这样准备的样品在37℃条件下按照200rpm进行搅拌,使其反应(Incubation)一夜。接着,使反应一夜的样品冷冻干燥。经冷冻干燥的样品使用DMSO进行溶化。针对这样准备的样品按照表1中的条件实施RP-HPLC,只取16分钟左右的峰值部分(Peakfraction)。
【表1】
图1中简要显示了以[化学式1]表示的3-乙酰基-杨梅黄酮的合成过程,RP-HPLC结果如图2,对于最终提炼的以[化学式1]表示的3-乙酰基-杨梅黄酮(纯度99%以上)的RP-HPLC分析结果如图3所示。另外,为了对结构进行确认,按照常用的方法实施了LC/MS分析和1H-NMR分析[在进行NMR分析时,参考了杨梅黄酮的NMR分析论文(Molecules 2014;19:13643)],其结果如图4和图5所示。
实施例2:神经传递抑制功效调查
在本实施例中,调查了实施例1中制备的以[化学式1]表示的3-乙酰基-杨梅黄酮是否能够如预期的那样提供抑制神经传递的功效。调查采用常规的基于细胞的(Cell-based)有效性评价法即乙酰胆碱分泌分析法(Acetylch oline release assay)实施,研究是否能够抑制神经递质即乙酰胆碱的分泌。乙酰胆碱分泌分析法作为一种对乙酰胆碱性神经细胞(Acetylcholiner gic neuron)分泌的乙酰胆碱在细胞水平上进行定量分析的试验法,其是一种通过对传递骨骼肌的收缩、松弛运动信号的信使即乙酰胆碱进行定量分析,从而可以确认神经递质是否分泌的试验法。
具体地,首先使用T75烧瓶(Flask)每3天一次利用全血清培养基[Ful l serummedia:84%Dulbecco’s modified eagle’s media(Hyclone),10%Horse serum(Gibco),5%Fetal bovine serum(Gibco),1%Antibiot ic antimycotic solution(Hyclone)]实施PC12细胞的继代培养。在不继代期间,每天用新的全血清培养基实施培养基更换。与此同时,在实验的第1天制作了胶原蛋白包被板(Collagen-coated plate)。胶原蛋白包被板的制作采用以下方法实施。利用经过0.2μm过滤器(Filter)过滤的灭菌水制备20mM的乙酸(Acetic acid)溶液。然后再利用其制备50μg/ml浓度的胶原蛋白溶液50ml。将通过上述方法制备的胶原蛋白溶液按照每孔(Well)1ml的标准添加后,在常温条件下静置(Incubation)3小时。静置后,小心地将各个孔的胶原蛋白溶液清除。并且利用1ml的PBS小心地进行清洗。然后,在超净工作台(Clean bench)上进行自然干燥(Air drying),从而完成胶原蛋白包被板的制作。在实验第2天,在前面制作的胶原蛋白包被板上接种(Seedin g)细胞。细胞接种采用以下方法实施。将正在T75烧瓶中培养的PC12细胞的培养基去除后,添加2ml的无血清培养基[Serum free media:99%Dulb ecco’s modified eagle’s media(Hyclone),1%Antibiotic antimycot ic solution(Hyclone)],然后轻轻地用滴管吸取(Pipetting),将细胞吸取下来之后,转移到15ml圆锥形管中实施离心分离(2,500rpm,3分钟)。完成离心分离后,去除上清液,使用无血清培养基1ml使细胞再悬浮(Resusp ension)后,实施细胞计数(Cell counting)。然后,使用无血清培养基准备2×105cell/ml的PC12细胞悬浮液,接着将其在准备好的胶原蛋白包被板上按照每孔1ml的标准喷注后,再以将板培养24小时(CO2 incubator,37℃)的方式实施了细胞接种。在实验开始的第3天,从培养中的板上将培养基去除后,采取用NGF培养基[98.6%Dulbecco’s modified eagle’s me dia(Hyclone),1%Antibiotic antimycotic solution(Hyclone),0.4%(25μg/ml)NGF(Nervegrowth factor-2.5S from murine submaxillary glan d;Sigma)]更换的方式实施NGF处理。完成NGF处理后,再追加培养5天(CO2 incubator,37℃)板。在实验的第8天,按照以下方法实施了样品处理及分析。从培养了5天的PC12细胞的板上将培养基去除,添加无血清培养基各995μl,然后使用DMSO将准备的0.5μM、2μM、10μM、20μM的3-乙酰基-杨梅黄酮样品按照每孔5μl的标准进行添加,接下来培养18小时(CO2incubator,37℃)。对照组添加了5μl的DMSO。培养18小时后,利用乙酰胆碱分泌分析试剂盒(Acetylcholine release assay kit;Cell Biolabs)按照产品说明实施了定量分析。其结果如图6所示。
通过上述结果可以确认,本发明的以[化学式1]表示的杨梅黄酮衍生物(3-乙酰基-杨梅黄酮)也可以阻碍SNARE复合体形成,最终能够阻碍乙酰胆碱分泌。这表明,本发明的以[化学式1]表示的杨梅黄酮衍生物(3-乙酰基-杨梅黄酮)能够提供阻断神经传递的效果。
实施例3:物质稳定性的比较
在本实施例中,实施了稳定性比较实验。为了极端的条件比较,按照放置一天的条件实施。作为参考,现有的杨梅黄酮或者杨梅黄酮衍生物即使仅放置约2小时,大部分也会分解消失。稳定性实验通过以下方法实施。在使用DMSO以10mg/ml的浓度准备的样品中添加PBS(pH7.0),从而稀释为1mg/ml浓度(1/10稀释)。将通过上述方法准备的样品按照200rpm进行搅拌,然后在37℃下放置(Incubation)1天。将放置的样品进行冷冻干燥之后,将其溶化在DMSO中,以与前面提出的条件相同的条件实施RP-HPLC分析,从而对稳定性进行比较。其结果如表2所示。
【表2】
为了帮助理解,在图7中给出了具有代表性的实验结果(杨梅黄酮、My ricetin-C4及3-乙酰基-杨梅黄酮)。
通过以上结果可以确认,本发明的以[化学式1]表示的杨梅黄酮衍生物(3-乙酰基-杨梅黄酮)可以提供现有已报告的杨梅黄酮衍生物无法提供的程度的改善稳定性。这种改善的稳定性可以在采用以[化学式1]表示的杨梅黄酮衍生物(3-乙酰基-杨梅黄酮)制备的最终产品的保管及流通方面发挥巨大的优势。另外,由于本实施例的实验条件也与体内的条件类似,因此可以推定,本发明的以[化学式1]表示的杨梅黄酮衍生物(3-乙酰基-杨梅黄酮)还能够提供改善的体内稳定性,并由此提供更加增强的功效。
实施例4:制备组合物
在本实施例中,制备了捕集包括杨梅黄酮在内的多种杨梅黄酮衍生物的纳米颗粒(Nanoparticle)。由于想要按照大韩民国专利公开10-2017-0091554的实施例中提出的方法完成实施例5的功效比较实验,因此制备了可用于经皮传输(Transdermal drugdelivery)的纳米颗粒。具体地,按照(1)制备脂质层(Lipid phase)、(2)制备水溶液层(Water phase)及(3)制备脂质-纳米颗粒(Lipid-nanoparticle formation)的顺序实施,详细的制备方法如下。
4.1制备脂质层
首先,按照以下方法制备脂质层。定量称出三硬脂酸甘油酯(Tristear in)70mg和三辛酸甘油酯(Tricaprylin)30mg,放入玻璃反应容器(Glass re action vial)中进行混合后,在实施以下步骤之前一直将其保管在85℃恒温槽(水槽;Water bath)中。将2mg杨梅黄酮或杨梅黄酮衍生物溶解于1ml丙酮(Acetone)中,完成准备工作之后,将其与前面准备好保管的脂质混合液(Lipid mixture)混合,保持85℃的温度,搅拌(Stirring)30分钟。完成30分钟搅拌之后,为了将混入的丙酮去除,实施减压干燥(Evaporation),将这样准备的脂质层保管在85℃恒温槽中。
4.2制备水溶液层
制备水溶液层按照以下方法实施,分别定量称出布里杰(S100,0.9735g)和普朗尼克(/>P-123,0.9735g)添加到玻璃反应容器中之后,再加入10ml的水(蒸馏水;Distilled water),然后保持85℃,搅拌12小时。
4.3制备脂质-纳米颗粒
将脂质层(体积比0.5)与水溶液层(体积比9.5)放入50ml圆锥形管(Co nicaltube)中混合。这时,脂质层与水溶液层应当继续保持85℃的温度。将这样准备的混合液保持85℃,利用高速混合器(High speed blender)在8,000rpm下进行1分钟的均质化(Homogenizing),然后在10,000rpm下再进行1分钟的均质化(Homogenizing)。接着,利用尖头型超声波仪(Tip-type sonicator)保持85℃采用启动1秒再停止1秒的方式按照60%强度(Amplit ude)实施超声波混合(Sonication)4分钟。将装有这么准备的样品的圆锥管浸入装满25℃水的烧杯中进行搅拌,使其冷却至45℃,然后,使用尖头型超声波仪采用启动1秒再停止1秒的方式按照60%强度实施超声波混合4分钟。将制备的样品冷藏(4℃)保管。
实施例5::功效比较实验1
利用实施例4中制备的组合物进行功效比较实验。功效比较实验按照大韩民国专利公开第10-2017-0091554号的实施例中提出的方法采用对多汗症的效果进行测定的方式实施。具体地,将实施例4中准备的组合物按照1mg浓度混入1ml市售的防晒霜中,由此准备试验样品。对照组(无处理组)仅对不包含组合物的防晒霜进行处理,处理组对包含各自组合物的防晒霜进行处理。双手上处理试验样品,然后让受试者双手握着已称重的化妆棉5分钟,回收后再测定化妆棉的重量,计算增加的重量。对于每个处理组,以10人的平均值作为结果列出在表3中。将对照组(无处理组)的平均汗液的重量设定为100%,将其比例值作为结果示出。
【表3】
通过以上结果可知,本发明的以[化学式1]表示的杨梅黄酮衍生物(3-乙酰基-杨梅黄酮)能够提供现有报告的杨梅黄酮衍生物无法提供的程度的改善效果。这可以解释为是改善的体内稳定性引发的。
实施例6:功效比较实验2
实施了利用小鼠的追加功效比较实验。也利用了实施例4中制备的组合物。提出具体的实施方法如下。将180只6周龄的雄性ICR小鼠(体重:25-35g)随机分成18组后(每组10只小鼠),采用涂抹皮肤的方法进行处置。具体地,将混合有80mg/kg的阿法沙龙(Alfaxan)及10mg/kg的隆朋(Rompu n)的溶液注射到腹腔内,使小鼠麻醉1小时以上。然后,在被麻醉的小鼠的右后脚掌上涂抹样品。阴性对照组按照0.8ml/kg的用量涂布PBS(pH7.4),处置组将实施例4中制备的各种组合物(悬浮在PBS中制备)按照0.8mg/kg的用量进行涂布。为了使涂布的样品充分被吸收,将涂布有样品的小鼠按照涂布后的状态保持30分钟。然后,将脚掌上的样品擦去,接着再涂布溶解在乙醇中的3.5%碘溶液(w/v)。干燥1分钟后,追加涂布溶解在蓖麻油(Cas tor oil)中的10%淀粉溶液(w/v)。涂布淀粉溶液之后,利用1200万像素的数码相机按照相同的条件(距离、倍率及曝光)对所有小鼠的脚掌进行拍照。然后,对拍摄的照片通过图像分析,对出汗面积(Sweating area)进行了分析。其结果如图8所示。
通过这一结果也可以确认,本发明的以[化学式1]表示的杨梅黄酮衍生物(3-乙酰基-杨梅黄酮)能够提供现有报告的杨梅黄酮衍生物无法提供的程度的改善效果。这也可以解释为是改善的体内稳定性所致。
实施例7:功效比较实验3
实施了针对皮肤皱纹改善的功效比较实验。将72名30~50岁的女性每4名分成1组进行实验。在实验开始之前,采用常规的方法采集眼底的复制品(Replica),在从采集复制品经过1小时的时间点,将实施例4中准备的组合物使用PBS按照1mg/ml的浓度配制成的试验样品(5ml)区分各个实验组涂抹在面部。对照组涂抹PBS。在从涂抹经过6小时的时间点,在眼底的相同部位重新采集复制品。通过对采集的复制品进行影像分析,采用对皮肤皱纹实施二维分析的方式对皮肤皱纹的密度(Dermal density of skin wrinkle)进行比较测定。通过影像分析获得的皮肤皱纹密度的测定结果如[表4]所示,上述结果是将相对于试验样品涂抹前皮肤皱纹密度的涂抹后的皮肤皱纹密度的比进行平均后得出的。
【表4】
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通过这一结果也可以确认,本发明的以[化学式1]表示的杨梅黄酮衍生物(3-乙酰基-杨梅黄酮)能够提供现有报告的杨梅黄酮衍生物无法提供的改善效果。
下面,列举了本发明化妆品组合物的剂型例及制剂例。但是,下述剂型例及制剂例仅是为了对本发明进行示例性说明,本发明的内容并非限定于以下剂型例及制剂例。
剂型例1:柔软化妆水(柔肤水)的制备
将捕集有以[化学式1]表示的杨梅黄酮衍生物(3-乙酰基-杨梅黄酮)的纳米颗粒0.1重量%、1,3-丁二醇5.2重量%、油醇1.5重量%、乙醇3.2重量%、聚山梨酯20(polysorbate 20)3.2重量%、二苯甲酮-92.0重量%、羧乙烯基聚合物1.0重量%、甘油3.5重量%、微量的香、微量的防腐剂及余量的纯净水混合,采用常规的方法制备柔软化妆水。
剂型例2:润肤乳(milk lotion)的制备
将捕集以[化学式1]表示的杨梅黄酮衍生物(3-乙酰基-杨梅黄酮)的纳米颗粒0.1重量%、甘油5.1重量%、丙二醇4.2重量%、生育酚乙酸酯3.0重量%、流动石蜡4.6重量%、三乙醇胺1.0重量%、角鲨烷3.1重量%、澳洲坚果油2.5重量%、聚山梨酯601.6重量%、山梨糖醇酐倍半油酸酯1.6重量%、对羟基苯甲酸丙酯0.6重量%、羧乙烯基聚合物1.5重量%、微量的香、微量的防腐剂、余量的纯净水混合,采用常规的方法制备润肤乳。
剂型例3:营养霜的制备
将[化学式1]表示的杨梅黄酮衍生物(3-乙酰基-杨梅黄酮)捕集纳米颗粒0.5重量%、甘油4.0重量%、凡士林3.5重量%、三乙醇胺2.1重量%、流动石蜡5.3重量%、角鲨烷3.0重量%、蜜蜡2.6重量%、生育酚乙酸酯5.4重量%、聚山梨酯603.2重量%、羧乙烯基聚合物1.0重量%、山梨糖醇酐倍半油酸酯3.1重量%、微量的香、微量的防腐剂及余量的纯净水混合,采用常规的方法制备营养霜。
以上,对本发明的特定部分进行了详细描述,具有本领域一般知识的技术人员都明白,以上具体描述仅是本发明的优选实现例,本发明的范围并非仅限定于此。因此,本发明的实际范围应当根据后附权利要求书与其等价物进行定义。
Claims (5)
1.一种提供阻碍乙酰胆碱(Acetylcholine)分泌效果的组合物,其特征在于,
将以下述[化学式1]表示的杨梅黄酮衍生物,即3-乙酰基-杨梅黄酮(3-Acetyl-Myricetin)作为有效成分包含,
[化学式1]
2.根据权利要求1所述的提供阻碍乙酰胆碱(Acetylcholine)分泌效果的组合物,其特征在于,
所述组合物是美容目的的化妆品组合物或用于治疗因乙酰胆碱过多分泌引发的疾病的药物组合物。
3.根据权利要求2所述的提供乙酰胆碱(Acetylcholine)分泌效果的组合物,其特征在于,
所述美容目的是从包含皱纹改善(Treating wrinkles)、毛孔缩小(Red ucing poresize)及增强皮肤弹性(Improving skin elasticity)的组中选择的任意一种。
4.根据权利要求2所述的提供阻碍乙酰胆碱(Acetylcholine)分泌效果的组合物,其特征在于,
所述因乙酰胆碱过多分泌引发的疾病是从包含斜视(Crossed eyes)、内耳障碍(Innerear disorder)、磨牙(Teeth grinding)、瘢痕疙瘩(Keloid scarring)、多汗症(Excessivesweating)、背部和肩部疼痛(Back pain)、战栗(Tremors)、肛裂(Anal fissure)、臀部畸形(Buttock deformity)、肌肉痉挛(Muscle injuries,twitching)、慢性偏头痛(Chronicmigraine)、抑郁症(Depression)、面瘫(Facial nerve disorder)、颈部痉挛(Neck pa in,spasms)、甲状腺障碍(Thyroid disorder)、心肌障碍(Cardiac muscl e disorder)、上肢僵硬(Upper limb spasticity)、胰腺障碍(Pancreas disorders)、肠易激综合征(Irritable bowel syndrome)、膨胀纹(Stretch marks)、小儿脑瘫(Juvenile cerebralpalsy)的组中选择的任意一种。
5.一种以[化学式1]表示的杨梅黄酮衍生物3-乙酰基-杨梅黄酮(3-Ac etyl-Myricetin)的制备方法,其特征在于,包括:
(A)在不会添加外部的空气与水分的氮气环境下,向溶解于无水吡啶(Pyridineanhydrous)中的杨梅黄酮添加无水乙酸(Acetic anhydride)使发生反应的步骤;
(B)利用乙酸乙酯(Ethyl acetate;EA)进行提取的步骤;
(C)对乙酸乙酯(Ethyl acetate;EA)提取物进行减压干燥的步骤;
(D)向减压干燥的样品中添加二甲基亚砜(Dimethyl sulfoxide;DMSO),接着再添加磷酸缓冲生理盐水(Phosphate-buffered saline;PBS;pH 7.0)进行稀释的步骤;
(E)使稀释的样品发生反应(Incubation),对副产物进行分解的步骤;以及
(F)冷冻干燥的步骤。
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