CN105963312B - 从东北婆婆纳中分离的纯化提取物、其制备方法以及包含该提取物的组合物 - Google Patents
从东北婆婆纳中分离的纯化提取物、其制备方法以及包含该提取物的组合物 Download PDFInfo
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Abstract
本发明涉及用于从东北婆婆纳的提取物制备含有比通过在现有技术中公开的传统制备方法制备的提取物更大量的活性成分(例如梓醇衍生物)的纯化提取物的本发明的新的工业化方法,以及含有该纯化提取物的用于治疗和预防炎性、过敏性或哮喘性疾病的治疗剂。通过在OVA致敏/激发小鼠模型中的各种体内试验(例如对于嗜酸性粒细胞繁殖、血浆和支气管肺泡液中免疫球蛋白和炎症趋化因子的释放的抑制试验以及气道高反应性和杯形细胞增生的抑制),所述纯化提取物表现出比通过在现有技术中公开的传统制备方法制备的提取物更有效的抗炎、抗过敏和抗哮喘活性。
Description
本申请是申请日为2013年12月23日,申请号为201380062681.8,发明名称为“从东北婆婆纳中分离的含有大量活性成分的纯化提取物、其制备以及包含该提取物作为活性成分用于预防或治疗炎症、过敏和哮喘的组合物”的发明专利申请(国际申请号:PCT/KR2013/011986)的分案申请。
技术领域
本发明涉及一种从东北婆婆纳(Pseudolysimachion rotundumvar.subintegrum)中分离的含有大量活性成分的纯化提取物、其制备以及包含该提取物作为活性成分用于预防或治疗炎症、过敏和哮喘的组合物。
背景技术
通常,炎症反应是在组织或细胞受到任何侵袭引起组织或细胞中的某些器质性变化的情况下,与水肿、疼痛等有关的人体的正常反应。最近,各种细胞因子已被发现与炎性疾病有关。
过敏反应可以根据反应类型分为四类,即,I型、II型、III型和IV型;或者根据从过敏原引起再致敏时间至反应发作时间的周期的类型分为两类,即,速发型过敏反应(例如I型、II型或III型)和缓发型过敏反应(例如IV型)。
其中,I型过敏与IgE抗体有关且被称为过敏反应型过敏,引起支气管哮喘、特应性疾病(例如皮炎或胃肠炎等)、过敏性鼻炎(例如花粉症)、过敏性结膜炎、食物过敏等。
哮喘被视为一种气道的复杂综合征,其特征在于各种临床症状,例如,咳嗽、由气流阻塞造成的呼吸困难、急性或慢性气道炎症、气道高反应性(AHR)和结构性重塑,并且可以是可逆或不可逆恢复的。大多数哮喘是过敏性疾病,其特征是慢性气道炎症和支气管高反应性(Minoguchi K和Adachi M.,哮喘病理生理学(Pathophysiology of asthma),在:Cherniack NS,Altose MD,Homma I.编辑,呼吸系统疾病患者的康复(Rehabilitation ofthe patient with respiratory disease),纽约:McGraw-Hill,1999年,第97-104页)。
哮喘可分为两种类型,即,外源性哮喘和内源性哮喘。外源性哮喘是由接触抗原引起的,在针对抗原的皮肤试验或支气管激发试验中显示阳性反应。通常发生的年龄趋向年轻化。它主要是由屋尘螨表皮螨属(House Dust Mite Dermatophagoides)和花粉、动物上皮、真菌等引起。内源性哮喘是由上呼吸道感染、运动、情绪不稳定、气候或湿度变化引起的,其常见于成人患者。此外,由于在血清中IgE的增加,可以通过皮肤试验检测外源性哮喘的IgE抗原。
关于病理生理学,哮喘通过T-helper2(Th2)-细胞驱动的慢性炎症识别,并且来自气道中的免疫细胞和结构细胞的各种炎症介质(例如细胞因子、趋化因子、信号分子、粘附分子和生长因子)涉及哮喘的各个阶段(Elias JA等人,J Clin Invest.,111,第291-7页,2003)。患有哮喘的患者支气管中的活化的炎性细胞(例如嗜酸性粒细胞、肥大细胞、肺泡巨噬细胞等),释放各种炎症介质(例如半胱氨酸白三烯、前列腺素等),并且涉及有力的支气管收缩(Maggi E.,Immunotechnology 3,第233-244页,1998;PawankarR.Curr.Opin.Allergy Clin.Immunol.,1,第3-6页,2001;Barnes PJ等人,Phamacol.Rev.50,第515-596页,1998)。
因此,由于涉及炎性细胞活化的各种细胞因子(例如IL-4、IL-5、IL-13等)和IgE的再现,以及从炎性细胞中释放的半胱氨酸白三烯的再现是炎症、过敏性反应和哮喘的主要成因,至今已经进行了许多研究以开发抑制上述物质再现的抑制剂。
本发明人致力于开发源自具有安全性和有效性的天然资源(例如植物、动物等)的具有有效的抑制炎性细胞增殖的活性的有效的治疗剂,最终发现,长叶婆婆纳(Pseudolysimachion longifolium)的提取物显示出有效的抗炎、抗过敏和抗哮喘活性(韩国专利第10-860080号),并且从中分离的各种化合物(例如,毛蕊花甙(verproside)(6-O-3,4-二羟基苯甲酰基梓醇(6-O-3,4-dihydroxybenzoyl catalpol))、胡黄连苷II(picrosideⅡ)(6-O-4-羟基-3-甲氧基苯甲酰基梓醇(6-O-4-hydroxy-3-methoxybenzoylcatalpol))、梓醇6-咖啡酸酯(verminoside)(6-O-3,4-二羟基肉桂酰基梓醇(6-O-3,4-Dihydroxy cinnamoyl catalpol))、6-O-藜芦酰基梓醇(6-O-veratroyl catalpol)(6-O-3,4-二甲氧基苯甲酰基梓醇(6-O-3,4-Dimethoxy benzoyl catalpol))、米内苷(minecoside)(6-O-3-羟基-4-甲氧基肉桂酰基梓醇(6-O-3-hydroxy-4-methoxycinnamoylcatalpol))、梓醇等)也显示出有效的抗炎、抗过敏和抗哮喘活性(韩国专利公开第10-2006-125499号)。
然而,由于长叶婆婆纳的提取物含有非常少的活性成分(例如梓醇(catalopol)衍生物),通过使用该植物提取物进行大量生产和工业化存在困难。
东北婆婆纳是一种分布在韩国、中国、日本、萨哈林岛(Ostrov Sakhalin)和俄罗斯的多年生草本植物。
基于韩国专利第10-860080号中公开的对于长叶婆婆纳的提取物的抗炎、抗过敏和抗哮喘活性的先前研究,本发明人尝试开发从东北婆婆纳的提取物分离的显示抗炎、抗过敏和抗哮喘活性的更有效且更大量的成分的更有效率的制备方法。
然而,尚未有报道或公开有关用于制备从东北婆婆纳的提取物分离的比在上述引用的文献中更有效且更大量的显示抗炎、抗过敏和抗哮喘活性的成分的有效方法,其公开的内容在此通过引用并入本文中。
因此,本发明人发现了用于从东北婆婆纳的提取物制备含有更大量的活性成分(例如梓醇衍生物)的纯化提取物的新的工业化方法,并且通过在OVA致敏/激发小鼠模型中的各种体内试验,例如对于嗜酸性粒细胞繁殖、血浆和支气管肺泡液中免疫球蛋白和炎症趋化因子的释放的抑制试验以及气道高反应性和杯形细胞增生的抑制),所述纯化提取物表现出比通过在现有技术中公开的传统制备方法制备的提取物更有效的抗炎、抗过敏和抗哮喘活性。
发明内容
【技术问题】
本发明提供了一种用于从东北婆婆纳制备含有大量的活性成分(例如梓醇衍生物)的纯化提取物的新方法以及由此制备的提取物。
本发明还提供了一种药物组合物,其含有对治疗和预防炎性、过敏性或哮喘性疾病而言有效量的从东北婆婆纳制备的包含大量的活性成分(例如梓醇衍生物)的纯化提取物作为活性成分。
本发明还提供了一种显示抗炎、抗过敏和抗哮喘活性的从东北婆婆纳制备的含有大量的活性成分(例如梓醇衍生物)的纯化提取物的用途。
本发明还提供了在哺乳动物中治疗或预防炎性、过敏性或哮喘性疾病的方法,包括:给所述哺乳动物施用有效量的从东北婆婆纳制备的含有大量活性成分(例如梓醇衍生物)的纯化提取物及其药学可接受的载体。
【技术方案】
因此,本发明的一个目的是提供从东北婆婆纳的提取物制备的含有大量的梓醇衍生物的新的纯化提取物。
本文公开的术语“梓醇衍生物”包括毛蕊花甙、梓苷、胡黄连苷Ⅱ、异香草酰梓醇(isovanilloyl catalpol)和6-O-藜芦酰梓醇等。
本文公开的术语“东北婆婆纳”包括培养的或天然生长的植物和市售的植物,但不意欲限制到上述范围内。
本文公开的术语“新的纯化提取物”包含:(a)用丁醇分馏的纯化提取物(下文中称为“ATC1”)和(b)二级分馏的纯化提取物(下文中称为“ATC2”)。
具体地,术语“用丁醇分馏的纯化提取物(ATC1)”的特征在于,基于东北婆婆纳的总提取物的重量(100%),含有15-50%(w/w)毛蕊花甙、0.3-10%(w/w)藜芦酸、0.5-10%(w/w)梓苷、0.3-10%(w/w)胡黄连苷II、0.3-10%(w/w)异香草酰梓醇和0.3-10%(w/w)6-O-藜芦酰梓醇;优选地,基于东北婆婆纳的总提取物的重量(100%),含有20-25%(w/w)毛蕊花甙、0.5-5%(w/w)藜芦酸、1-5%(w/w)梓苷、0.5-5%(w/w)胡黄连苷II、0.5-5%(w/w)异香草酰梓醇和1-5%(w/w)6-O-藜芦酰梓醇;
或者其特征在于,在东北婆婆纳的总提取物(100%)中含有12.3-47%(w/w)梓苷衍生物,且各种梓苷衍生物的重量之间具有如下的相对混合比(w/w):15.0-18.0(w/w)毛蕊花甙、2.10-2.60(w/w)梓苷、1(w/w)胡黄连苷II、1.00-1.30(w/w)异香草酰梓醇以及2.00-2.30(w/w)6-O-藜芦酰梓醇;优选地,16.0-17.0(w/w)毛蕊花甙、2.20-2.50(w/w)梓苷、1(w/w)胡黄连苷II、1.10-1.20(w/w)异香草酰梓醇以及2.10-2.20(w/w)6-O-藜芦酰梓醇;更优选地,16.20-16.99(w/w)毛蕊花甙、2.40-2.45(w/w)梓苷、1(w/w)胡黄连苷II、1.10-1.19(w/w)异香草酰梓醇、2.10-2.19(w/w)6-O-藜芦酰梓醇。
更具体地,术语“用丁醇分馏的纯化提取物(ATC1)”的特征在于,通过如下方法制备:在第一步中,向干燥的东北婆婆纳中加入选自水、C1-C4低级醇(例如甲醇、乙醇、丁醇等)或它们的混合物的至少一种提取溶剂,优选水和乙醇的混合物,更优选30-80(w/w)乙醇的水溶液;在第二步中,在10至100℃、优选20至90℃的温度范围内进行选自热水回流提取、冷水提取、超声波处理或常规提取中的至少一种提取方法30分钟至72小时、优选6至48小时的时间,优选冷水提取后,接着回流提取,更优选地,在10至60℃、优选20至50℃的温度范围内进行冷水提取30分钟至72小时、优选6至48小时的时间,然后在40至120℃、优选60至90℃的温度范围内进行回流提取30分钟至72小时、优选6至48小时的时间,反复进行,以获得第一提取物;在第三步中,将所述第一提取物悬浮在约0.5-10倍体积(v/v)、优选约1-5倍体积(v/v)的水中,以得到悬浮提取物;以及加入约0.5-20倍体积(v/v)、优选约1-10倍体积(v/v)的丁醇,分馏为水层和丁醇层并收集丁醇层以得到用丁醇分馏的纯化提取物(ATC1),以治疗和预防炎性、过敏性或哮喘性疾病,基于东北婆婆纳的总提取物的重量(100%),所述用丁醇分馏的纯化提取物含有15-50%(w/w)毛蕊花甙、0.3-10%(w/w)藜芦酸、0.5-10%(w/w)梓苷、0.3-10%(w/w)胡黄连苷II、0.3-10%(w/w)异香草酰梓醇和0.3-10%(w/w)6-O-藜芦酰梓醇。
因此,在本发明的另一个实施方式中,本发明还提供了用于制备从东北婆婆纳中分离出的用丁醇分馏的纯化提取物(ATC1)的方法,包括以下步骤:在第一步中,向干燥的东北婆婆纳中加入选自水、C1-C4低级醇(例如甲醇、乙醇、丁醇等)或它们的混合物的至少一种提取溶剂,优选水和乙醇的混合物,更优选30-80(w/w)乙醇的水溶液;在第二步中,在10至100℃、优选20至90℃的温度范围内进行选自热水回流提取、冷水提取、超声波处理或常规提取中的至少一种提取方法30分钟至72小时,优选6至48小时的时间,优选冷水提取后接着回流提取,更优选地,在10至60℃、优选20至50℃的温度范围内进行冷水提取30分钟至72小时、优选6至48小时的时间,然后在40至120℃、优选60至90℃的温度范围内进行回流提取30分钟至72小时、优选6至48小时的时间,反复进行,以获得第一提取物;在第三步中,将所述第一提取物悬浮在约0.5-10倍体积(v/v)、优选约1-5倍体积(v/v)的水中,以得到悬浮提取物;以及加入约0.5-20倍体积(v/v)、优选约1-10倍体积(v/v)的丁醇,分馏为水层和丁醇层并收集丁醇层以得到用丁醇分馏的纯化提取物(ATC1),以治疗和预防炎性、过敏性或哮喘性疾病,基于东北婆婆纳的总提取物的重量(100%),所述用丁醇分馏的纯化提取物含有15-50%(w/w)毛蕊花甙、0.3-10%(w/w)藜芦酸、0.5-10%(w/w)梓苷、0.3-10%(w/w)胡黄连苷II、0.3-10%(w/w)异香草酰梓醇和0.3-10%(w/w)6-O-藜芦酰梓醇。
具体地,术语“二级分馏的纯化提取物(ATC2)”的特征在于,基于东北婆婆纳的总提取物的重量(100%),含有30-60%(w/w)毛蕊花甙、0.5-10%(w/w)藜芦酸、2-20%(w/w)梓苷、1-10%(w/w)胡黄连苷II、1-10%(w/w)异香草酰梓醇和2-20%(w/w)6-O-藜芦酰梓醇;优选地,基于东北婆婆纳的总提取物的重量(100%),含有40-50%(w/w)毛蕊花甙、1-5%(w/w)藜芦酸、3-10%(w/w)梓苷、2-5%(w/w)胡黄连苷II、2-8%(w/w)异香草酰梓醇和3-8%(w/w)6-O-藜芦酰梓醇;
或者其特征在于,在东北婆婆纳的总提取物(100%)中含有36.5-91%(w/w)梓苷衍生物,且各种梓苷衍生物的重量之间具有如下的相对混合比(w/w):13.0-16.0(w/w)毛蕊花甙、2.20-2.50(w/w)梓苷、1(w/w)胡黄连苷II、1.10-1.40(w/w)异香草酰梓醇以及2.00-2.20(w/w)6-O-藜芦酰梓醇;优选地,14.0-15.0(w/w)毛蕊花甙、2.30-2.45(w/w)梓苷、1(w/w)胡黄连苷II、1.20-1.35(w/w)异香草酰梓醇以及2.00-2.10(w/w)6-O-藜芦酰梓醇;更优选地,14.50-14.99(w/w)毛蕊花甙、2.35-2.43(w/w)梓苷、1(w/w)胡黄连苷II、1.25-1.34(w/w)异香草酰梓醇、2.01-2.09(w/w)6-O-藜芦酰梓醇。
更具体地,术语“二级分馏的纯化提取物(ATC2)”的特征在于,通过如下方法制备:在第一步中,向干燥的东北婆婆纳中加入选自水、C1-C4低级醇(例如甲醇、乙醇、丁醇等)或它们的混合物的至少一种提取溶剂,优选水和乙醇的混合物,更优选30-80(w/w)乙醇的水溶液;在第二步中,在10至100℃、优选20至90℃的温度范围内进行选自热水回流提取、冷水提取、超声波处理或常规提取的至少一种提取方法30分钟至72小时、优选6至48小时的时间,优选冷水提取后,接着回流提取,更优选地,在10至60℃、优选20至50℃的温度范围内进行冷水提取30分钟至72小时、优选6至48小时的时间,然后在40至120℃、优选60至90℃的温度范围内进行回流提取30分钟至72小时、优选6至48小时的时间,反复进行,以获得第一提取物;在第三步中,将所述第一提取物悬浮在约0.5-10倍体积(v/v)、优选约1-5倍体积(v/v)的水中,以得到悬浮提取物;在第三步中,加入约0.5-20倍体积(v/v)、优选约1-10倍体积(v/v)的丁醇,分馏为水层和丁醇层并收集丁醇层以得到用丁醇分馏的纯化提取物(ATC1);以及对用丁醇分馏的纯化提取物(ATC1)进行选自反相分配色谱、正相分配色谱、离子交换色谱以及尺寸排斥色谱的至少一种纯化工艺以得到二级分馏的纯化提取物(ATC2),以治疗和预防炎性、过敏性或哮喘性疾病,基于东北婆婆纳的总提取物的重量(100%),所述二级分馏的纯化提取物含有30-60%(w/w)毛蕊花甙、0.5-10%(w/w)藜芦酸、2-20%(w/w)梓苷、1-10%(w/w)胡黄连苷II、1-10%(w/w)异香草酰梓醇和2-20%(w/w)6-O-藜芦酰梓醇。
因此,在本发明的另一个实施方式中,本发明还提供用于制备从东北婆婆纳中分离出的二级分馏的纯化提取物(ATC2)的方法,包括以下步骤:在第一步中,向干燥的东北婆婆纳中加入选自水、C1-C4低级醇(例如甲醇、乙醇、丁醇等)或它们的混合物的至少一种提取溶剂,优选水和乙醇的混合物,更优选30-80(w/w)乙醇的水溶液;在第二步中,进行在10至100℃、优选20至90℃的温度范围内选自热水回流提取、冷水提取、超声波处理或常规提取的至少一种提取方法30分钟至72小时、优选6至48小时的时间,优选冷水提取后,接着回流提取,更优选地,在10至60℃、优选20至50℃的温度范围内进行冷水提取30分钟至72小时、优选6至48小时的时间,然后在40至120℃、优选60至90℃的温度范围内进行回流提取30分钟至72小时、优选6至48小时的时间,反复进行,以获得第一提取物;在第三步中,将所述第一提取物悬浮在约0.5-10倍体积(v/v)、优选约1-5倍体积(v/v)的水中,以得到悬浮提取物;在第三步中,加入约0.5-20倍体积(v/v)、优选约1-10倍体积(v/v)的丁醇,分馏为水层和丁醇层并收集丁醇层以得到用丁醇分馏的纯化提取物(ATC1);以及对用丁醇分馏的纯化提取物(ATC1)进行选自反相分配色谱、正相分配色谱、离子交换色谱以及尺寸排斥色谱中的至少一种进一步纯化工艺以得到二级分馏的纯化提取物(ATC2),以治疗和预防炎性、过敏性或哮喘性疾病,基于东北婆婆纳的总提取物的重量(100%),所述二级分馏的纯化提取物含有30-60%(w/w)毛蕊花甙、0.5-10%(w/w)藜芦酸、2-20%(w/w)梓苷、1-10%(w/w)胡黄连苷II、1-10%(w/w)异香草酰梓醇和2-20%(w/w)6-O-藜芦酰梓醇。
具体地,术语“进一步纯化工艺”选自(i)反相分配色谱、(ii)正相分配色谱、(iii)离子交换色谱或(iv)尺寸排斥色谱,优选反相分配色谱或者使用能够在洗脱极性物质的同时保留非极性物质的任何树脂作为固定相的任何色谱,例如葡聚糖凝胶树脂(Sephadexresin),例如葡聚糖凝胶(Sephadex),葡聚糖凝胶LH20(Sephadex LH20),葡聚糖凝胶G-25(Sephadex LH20),葡聚糖凝胶G-10(Sephadex LH20),琼脂糖凝胶(Sepharose),Superdex,甲基丙烯酸酯树脂,羧甲基纤维素,磺丙基纤维素,羧甲基葡聚糖凝胶,磺丙基葡聚糖凝胶,羧甲基琼脂糖凝胶,磺丙基琼脂糖凝胶等;使用苯乙烯-二乙烯基苯共聚物(例如聚合物X、HP20、PRP-h1聚合物等)或甲基丙烯酸酯载体树脂等的反向聚合物树脂;正相硅胶,例如BPC(键合相色谱)产品、从YMC有限公司获得的二氧化硅产品、从DAISO有限公司获得的二氧化硅产品、从ASAHI有限公司获得的二氧化硅产品、从COSMOSYL有限公司获得的二氧化硅产品,等;用于HPLC填料的ODS产品,例如从YMC有限公司获得的ODS产品、从DAISO有限公司获得的ODS产品、从ASAHI有限公司获得的ODS产品、从CHEMCO有限公司获得的ODS产品、从Merck有限公司获得的ODS产品、从COSMOSYL有限公司获得的ODS产品、从FUJI有限公司获得的ODS产品等。
在采用(i)反相分配色谱作为本发明的进一步纯化工艺的优选的实施方式中,“在上述反相分配色谱中的固定相”可以是例如可以在洗脱极性物质的同时保留非极性物质的反相物质作为固定相的任何固定相,优选基于硅胶的固定相,基于聚合物的固定相(例如聚苯乙烯等)等,更优选地,硅胶衍生物,例如C2、C4、C6、C8、C10、C12、14、C16、C18等;或基于聚合物的固定相,例如PS-2、Oasis HLB等,更加优选地,反相硅胶(C18(Ⅳ)-D)、来自YMC有限公司的ODS-A/ODS-AQ产品、来自CHEMCO有限公司的SP-C-ODS产品、来自DAISO有限公司的SP-ODS-RPS产品、来自COSMOSYL有限公司的5C18产品、来自FUJI有限公司的Chromatorex产品等。
在采用(i)反相分配色谱作为本发明的进一步纯化工艺的优选的实施方式中,“在上述(i)反相分配色谱中的流动相”可以是选自水、乙腈、低级醇(例如甲醇、乙醇、丁醇等)、四氢呋喃(THF)或它们的混合物的至少一种溶剂;优选是选自水、低级醇(例如甲醇、乙醇、丁醇等)或它们的混合物的至少一种溶剂;更优选水和甲醇的混合溶剂;更加优选,从90:10(v/v)至60:40(v/v)的水和甲醇的混合物溶剂,以洗脱极性物质。
在采用(ii)正相分配色谱作为本发明的进一步纯化工艺的优选的实施方式中,“在上述正相分配色谱中的固定相”可以是例如可以在洗脱非极性物质的同时保留极性物质的正相物质作为固定相的任何固定相;优选基于硅胶、基于Fluorosyl或基于氧化铝的固定相,基于CN,基于二醇(Diol),或基于NH2部分的聚合物的固定相等;更优选基于硅胶、基于Fluorosyl或基于氧化铝的固定相等。
在采用(ii)正相分配色谱作为本发明的进一步纯化工艺的优选的实施方式中,“在上述(ii)正相分配色谱中的流动相”可以是选自己烷、庚烷、乙酸乙酯、乙醇、乙醚、2-丙醇或它们的混合物的至少一种溶剂,优选是选自己烷、庚烷、乙酸乙酯或它们的混合物的至少一种溶剂,以洗脱非极性物质。
在采用(iii)离子交换色谱作为本发明的进一步纯化工艺的优选的实施方式中,“在上述(iii)离子交换色谱中的固定相”可以是作为具有带电的交联部分的固定相的任何高分子固定相,优选阳离子交换树脂、阴离子交换树脂或合成的吸附剂等,更优选强酸性阳离子交换树脂,例如AG 50W-X8、Amberlite IR-120、Dowex 60W-x8,SKIB等;弱酸性阳离子交换树脂,例如Amberlite IRA-67、Dowex 3-x4A等;强碱性阳离子交换树脂,例如DIAIONSKIB、DIAION PK216、DIAION CR20、DIAION UBK555(Mitsubishi Chemical公司)、TRILITESPC 160H、TRILITE SPC 180H、TRILITE SPC400JH(Samyang有限公司)、AMBERLITE 200CNa、AMBERLITE CG50、AMBERLITE CR1310Na、AMBERJET 200H、AMBERLYST 131WET、ALBERLYST232 WET(ROHM和HAAS有限公司))、Lewatit VP OC 1800、Lewatit VP OC 1812、LewatitMDS1368Na、Lewaitit K1221(Bayer有限公司)、PUROLITE PCR833CA、PUROLITE C145(Purolite有限公司)、MFG210、MFG 250(Finex有限公司)等;强碱性阴离子交换树脂,例如SA11A、SA20A、SA21A等;或者CaptoQ(GE Healthcare有限公司)或具有与其类似性质的树脂,例如Toyopearl QEA(Tosoh有限公司)、Q Sepharose FF(GE Healthcare有限公司)、Fractogel EMD、Fractogel TMAE、Fractogel HICAP(Merck KGaA有限公司或Darmstadt有限公司);更优选SA21A;吸附剂,例如SP207、HP20SS、HP20等,更优选HP20。
在采用(iv)尺寸排斥色谱作为本发明的进一步纯化工艺的优选的实施方式中,“在上述(iv)尺寸排斥色谱中的固定相”可以是作为能够通过样品尺寸分离的固定相的任何凝胶型固定相,优选基于葡聚糖的凝胶,例如葡聚糖凝胶(例如葡聚糖凝胶G-25);基于聚丙烯酰胺的凝胶,例如Sephacryl(例如Sephacryl-S400);基于琼脂糖的凝胶,例如Superose或琼脂糖凝胶(Sepharose)(例如琼脂糖凝胶CL-4B)或它们的组合,例如Superdex200组合葡聚糖(例如SephadexTM),或交联的琼脂糖凝胶(SuperoseTM)等,但其不限于此。“在上述(iv)尺寸排斥色谱中的流动相”可以是选自以下的缓冲液:乙酸钠缓冲液、磷酸钠缓冲液、乙酸铵缓冲液、MES(2-(N-吗啉基)乙磺酸)、二-三[2-二(2-羟乙基)氨基-2-(羟甲基)-1,3-丙二醇]、ADA[N-(2-乙酰胺基)亚氨基二乙酸盐)、PIPES[哌嗪-N,N'-二(2-乙磺酸)]、BES[N.N'-二(2-羟乙基)-2-氨基乙磺酸)、MOPS[3-(N-吗啉基)丙磺酸)]、TES(N-三(羟甲基)甲基-2-氨基乙磺酸]、HEPES[N-2-羟乙基-哌嗪-N'-2-乙磺酸)等;优选乙酸钠缓冲液、磷酸钠缓冲液或乙酸铵缓冲液。
在本发明的一个优选实施方式中,作为本文中所公开的进一步纯化工艺,除了(i)反相分配色谱法、(ii)正相分配色谱、(iii)离子交换色谱、(iv)尺寸排斥色谱或它们的组合之外,本发明还可以进行(v)凝胶渗透色谱或凝胶过滤色谱。
本发明还提供由上述制备方法制备的新的纯化提取物,例如(a)用丁醇分馏的纯化提取物(下文中称为“ATC1”)或(b)二级分馏的纯化提取物(下文中称为“ATC2”)。
本发明还提供由上述制备方法制备的用丁醇从东北婆婆纳的提取物分馏的新的纯化提取物(ATC1),其在东北婆婆纳的总提取物(100%)中含有12.3-47%(w/w)梓苷衍生物,其中,基于东北婆婆纳的总提取物的重量(100%),所述梓苷衍生物由15-50%(w/w)毛蕊花甙、0.3-10%(w/w)藜芦酸、0.5-10%(w/w)梓苷、0.3-10%(w/w)胡黄连苷II、0.3-10%(w/w)异香草酰梓醇和0.3-10%(w/w)6-O-藜芦酰梓醇组成;优选地,由20-25%(w/w)毛蕊花甙、0.5-5%(w/w)藜芦酸、1-5%(w/w)梓苷、0.5-5%(w/w)胡黄连苷II、0.5-5%(w/w)异香草酰梓醇和1-5%(w/w)6-O-藜芦酰梓醇组成。
本发明还提供由上述制备方法制备的用丁醇从东北婆婆纳的提取物分馏的新的纯化提取物(ATC1),其显示了各种梓苷衍生物的重量之间的如下的相对混合比(w/w):15.0-18.0(w/w)毛蕊花甙、2.10-2.60(w/w)梓苷、1(w/w)胡黄连苷II、1.00-1.30(w/w)异香草酰梓醇以及2.00-2.30(w/w)6-O-藜芦酰梓醇;优选地,16.0-17.0(w/w)毛蕊花甙、2.20-2.50(w/w)梓苷、1(w/w)胡黄连苷II、1.10-1.20(w/w)异香草酰梓醇以及2.10-2.20(w/w)6-O-藜芦酰梓醇;更优选地,16.20-16.99(w/w)毛蕊花甙、2.40-2.45(w/w)梓苷、1(w/w)胡黄连苷II、1.10-1.19(w/w)异香草酰梓醇、2.10-2.19(w/w)6-O-藜芦酰梓醇。
本发明还提供由上述制备方法制备的从东北婆婆纳的提取物二级分馏的纯化提取物(ATC2),其在东北婆婆纳的总提取物(100%)中含有36.5-91%(w/w)梓苷衍生物,其中,基于东北婆婆纳的总提取物的重量(100%),所述梓苷衍生物由30-60%(w/w)毛蕊花甙、0.5-10%(w/w)藜芦酸、2-20%(w/w)梓苷、1-10%(w/w)胡黄连苷II、1-10%(w/w)异香草酰梓醇和2-20%(w/w)6-O-藜芦酰梓醇组成;优选地,由40-50%(w/w)毛蕊花甙、1-5%(w/w)藜芦酸、3-10%(w/w)梓苷、2-5%(w/w)胡黄连苷II、2-8%(w/w)异香草酰梓醇和3-8%(w/w)6-O-藜芦酰梓醇组成。
本发明还提供由上述制备方法制备的从东北婆婆纳的提取物二级分馏的纯化提取物(ATC2),其显示了各种梓苷衍生物的重量之间的如下的相对混合比(w/w):13.0-16.0(w/w)毛蕊花甙、2.20-2.50(w/w)梓苷、1(w/w)胡黄连苷II、1.10-1.40(w/w)异香草酰梓醇以及2.00-2.20(w/w)6-O-藜芦酰梓醇;优选地,14.0-15.0(w/w)毛蕊花甙、2.30-2.45(w/w)梓苷、1(w/w)胡黄连苷II、1.20-1.35(w/w)异香草酰梓醇以及2.00-2.10(w/w)6-O-藜芦酰梓醇;更优选地,14.50-14.99(w/w)毛蕊花甙、2.35-2.43(w/w)梓苷、1(w/w)胡黄连苷II、1.15-1.24(w/w)异香草酰梓醇、2.01-2.09(w/w)6-O-藜芦酰梓醇。
在本文中公开的术语“纯化提取物”可以以通过真空蒸发法、冷冻干燥法或热空气干燥法等制备的干燥形式使用。
在本文中公开的术语“炎性疾病”包括湿疹、特应性皮炎、结膜炎、牙周病、鼻炎、中耳炎、咽喉炎、扁桃体炎、肺炎、胃溃疡、胃炎、克罗恩病、结肠炎、痔、痛风、强直性脊柱炎、风湿热、系统性红斑狼疮、纤维肌痛、银屑病性关节炎、骨关节炎、风湿性关节炎、肩关节周炎、肌腱炎、腱鞘炎、腱鞘周炎、肌炎、肝炎、膀胱炎、肾炎、干燥综合征(Sjogren’s syndrome)、多发性硬化、慢性炎性疾病、急性炎性疾病等,但本发明并不限于此,优选湿疹、特应性皮炎、风湿性关节炎、慢性炎性疾病、急性炎性疾病等。
在本文中公开的术语“过敏性疾病”包括过敏性鼻炎、过敏性皮炎、接触性皮炎、荨麻疹、昆虫过敏、食物过敏、药物过敏、过敏性结膜炎、超敏反应等,但本发明并不限于此,优选过敏性鼻炎、过敏性皮炎、接触性皮炎、荨麻疹、昆虫过敏、食物过敏、药物过敏,更优选过敏性皮炎、接触性皮炎。
在本文中公开的术语“哮喘性疾病”包括由各种外部因素引起的任何哮喘,例如尘螨、动物的皮毛或皮屑、蟑螂、食物、药物、咳嗽、香烟烟雾、空气污染、食品添加剂、身体活动(例如运动等)、天气变化、黄沙、压力等,但本发明并不限于此。
在本文中公开的术语“预防”包括通过施用本发明组合物以抑制或延迟本文公开的某些疾病或病症的发生的任何行为;以及在本文中公开的术语“治疗”包括通过施用本发明组合物以缓解或有利地改变与本文公开的某些疾病或病症有关的症状的任何行为。
通过各种HPLC分析,本发明人发现,与通过现有技术中公开的常规方法制备的粗提物(其中,梓醇衍生物含量只有8.49%(w/w))相比,用于制备纯化提取物的新的工业化方法可以从东北婆婆纳提供更大量(即36.5%至91.0%(w/w))的活性成分(例如梓醇衍生物),例如,基于东北婆婆纳的总提取物(100%)的重量,本发明的纯化提取物(ATC1)含有17.60%(w/w)毛蕊花甙、0.72%(w/w)藜芦酸、2.62%(w/w)梓苷、1.08%(w/w)胡黄连苷II、1.26%(w/w)异香草酰梓醇和2.36%(w/w)6-O-藜芦酰梓醇(参见实施例2),以及本发明的纯化提取物(ATC2)含有43.83%(w/w)毛蕊花甙、1.80%(w/w)藜芦酸、7.07%(w/w)梓苷、2.93%(w/w)胡黄连苷II、3.85%(w/w)异香草酰梓醇和6.15%(w/w)6-O-藜芦酰梓醇,而由现有技术中公开的常规方法制备的粗提物(CX)只含有5.9%(w/w)毛蕊花甙、0.21%(w/w)藜芦酸、0.82%(w/w)梓苷、0.40%(w/w)胡黄连苷II、0.42%(w/w)异香草酰梓醇和0.74%(w/w)6-O-藜芦酰梓醇;粗提物;以及通过在OVA致敏/激发小鼠模型中各种体内试验(例如对于嗜酸性粒细胞繁殖、血浆和支气管肺泡液中免疫球蛋白和炎症趋化因子的释放的抑制试验以及气道高反应性和杯形细胞增生的抑制),本发明的纯化提取物表现出比通过常规制备方法制备的提取物更有效的抗炎、抗过敏和抗哮喘活性。
因此,根据本发明的另一个方面,本发明提供一种用于炎性、过敏性或哮喘性疾病的治疗和预防的药物组合物,其包含从东北婆婆纳中通过上述方法制备的含有大量活性成分的纯化提取物作为活性成分。
本发明提供一种用于炎性、过敏性或哮喘性疾病的治疗和预防的药物组合物,其包含从东北婆婆纳通过上述方法制备的含有大量活性成分的纯化提取物作为活性成分,和药学上可接受的载体或赋形剂。
根据本发明的另一个方面,还提供从东北婆婆纳通过上述方法制备的含有大量活性成分的纯化提取物用于制备用于治疗或预防炎性、过敏性或哮喘性疾病的药物的用途。
在本文中限定的术语“药学上可接受的载体或赋形剂”包括“药物添加剂,用于构成药物的非活性成分。它们包括染料、香料、粘合剂、软化剂、填料、润滑剂、防腐剂以及更多种类。常规赋形剂包括玉米淀粉、乳糖、滑石、硬脂酸镁、蔗糖、明胶、硬脂酸钙、二氧化硅、虫胶和釉,这是现有技术中已公知的(参见:食品和药物管理局(Food and DrugAdministration)的主页:www.fda.gov或药品信息在线(drug information online):www.drugs.com)或以前的文献(例如,Rowe、Raymond C等人,药用辅料手册(Handbook ofPharmaceutical Excipients),医药出版社(Pharmaceutical Press),第7版,2012)。
根据本发明的另一个方面,还提供在哺乳动物中治疗或预防炎性、过敏性或哮喘性疾病的方法,其中,该方法包括给患有炎性、过敏性或哮喘性疾病的哺乳动物施用治疗有效量的从东北婆婆纳通过上述方法制备的含有大量活性成分的纯化提取物。
基于组合物的总重量,用于治疗和预防炎性、过敏性或哮喘性疾病的本发明组合物可以包含按重量计0.1至99%、优选0.1至50%的上述提取物。
根据本发明的组合物可以提供为药物组合物,所述药物组合物包含药学上可接受的载体、辅料或稀释剂,例如,乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藓醇、麦芽糖醇、淀粉、阿拉伯胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁和矿物油。制剂可以另外包括填料、抗凝集剂、润滑剂、润湿剂、调味剂、乳化剂、防腐剂等。本发明的组合物可以通过使用本领域公知的任何方法来配制以在给患者施用后提供活性成分的快速、持续或延迟释放。
例如,本发明的组合物可以溶解在油、丙二醇或者常用于制备注射剂的其他溶剂中。所述载体的合适的实例包括生理盐水、聚乙二醇、乙醇、植物油、肉豆蔻酸异丙酯等,但不限于它们。对于局部给药,本发明的提取物可以配制为软膏和乳膏的形式。
可以以任何形式来制备含有本发明组合物的药物制剂,例如口服剂型(散剂、片剂、胶囊剂、软胶囊剂、含水药物、糖浆剂、酏剂、丸剂、散剂、囊剂、颗粒剂),或局部用制剂(乳膏剂、软膏剂、洗剂、凝胶剂、香膏剂、贴剂、糊剂、喷雾溶液、气雾剂等),或注射制剂(溶液、悬浮液、乳液)。
在药物剂型中的本发明的组合物可以以它们药学上可接受的盐的形式使用,并且也可以单独使用或适当联合使用,以及与其他药学上的活性化合物组合使用。
本发明提取物的理想的剂量根据患者的病情和体重、严重性、药物形式、给药途径和时间而不同,并且可以由本领域技术人员来选择。然而,为了获得理想的效果,通常建议以0.0001至1000mg/kg重量/天的量、优选0.001至100mg/kg重量/天的量施用本发明的发明的提取物。所述剂量可以单次施用或分成每天几次。
本发明的药物组合物可以经由各种途径施用给受试动物(例如哺乳动物(大鼠、小鼠、家畜或人))。考虑了给药的所有模式,例如,给药可以通过口服、经直肠或通过静脉内、肌内、皮下、皮内、鞘内、硬膜外或脑室内注射而进行。
本发明的发明提取物没有毒性,因此没有副作用;它们可以安全使用。
对于本领域技术人员来说,在不脱离本发明的精神或范围内,在本发明的组合物、用途和制备中能够进行各种修改和变型是显而易见的。
通过以下实施例对本发明进行更具体地说明。然而,应该理解的是,本发明并不以任何方式限定于这些实施例。
【有益效果】
如本发明中所述,用于从东北婆婆纳的提取物制备含有更大量的活性成分(例如梓醇衍生物)的纯化提取物的本发明的新的工业化方法,以及通过在OVA致敏/激发小鼠模型中各种体内试验(例如对于嗜酸性粒细胞繁殖、血浆和支气管肺泡液中免疫球蛋白和炎症趋化因子的释放的抑制试验以及气道高反应性和杯形细胞增生的的抑制),显示所述纯化提取物比通过在现有技术中公开的传统制备方法制备的提取物更有效的抗炎、抗过敏和抗哮喘活性。
附图说明
结合附图从以下详细描述,可以更清楚地理解本发明的上述和其它目的、特征和其他优点,其中:
图1示出在比较例1中制备的东北婆婆纳的粗提物的HPLC分析;
图2示出实施例1中制备本发明的的东北婆婆纳的纯化提取物(ATC1)的HPLC分析;
图3示出实施例2中制备的本发明的东北婆婆纳的纯化提取物(ATC2)的HPLC分析;
图4示出在OVA致敏/激发小鼠模型中本发明的纯化提取物对气道高反应性的抑制效果;
图5示出本发明的纯化提取物对在支气管肺泡灌洗液中的炎性细胞的聚集的抑制效果;
图6示出本发明的纯化提取物对血清中免疫球蛋白(总IgE)的释放的抑制效果;
图7示出本发明的纯化提取物对血清中OVA特异性IgE的释放的抑制效果;
图8表示本发明的纯化提取物对IL-1β的释放的抑制效果;
图9至11表示本发明的纯化提取物对炎症趋化因子释放的抑制效果;
图12、13表示通过使用支气管肺泡灌洗的组织学检查,本发明的纯化提取物对肺组织细胞中炎性细胞的聚集的抑制效果;
图14、15表示通过使用支气管肺泡灌洗的组织学检查,本发明的纯化提取物对肺组织细胞中粘液分泌的抑制效果。
具体实施方式
对于本领域技术人员来说,在不脱离本发明的精神或范围内,对本发明的组合物、用途和制备进行各种修改和变型是显而易见的。
通过以下实施例对本发明进行更具体地说明。然而,应该理解的是,本发明并不以任何方式限定于这些实施例。
实施例
以下参考实施例、实施例和实验实施例旨在进一步说明本发明而不限制其范围。
比较例1东北婆婆纳的粗提物的制备
1-1粗提物(ATE)的制备
将1kg干东北婆婆纳(按照GAP,在韩国忠清北道阴城郡蘇伊面244号(244,Soi-myeon Eumseong-gun Chungcheongbuk-do)栽培)切成小块,并与10L 40%乙醇混合。将混合物在室温下搅拌24小时,并在78℃下用回流提取进行提取12小时,收集滤液,重复三次。用滤纸过滤提取物以除去碎屑。将收集的滤液在55至65℃下通过旋转蒸发仪(EYELA,N-2100,日本)减压浓缩,并用冷冻干燥机干燥以获得202g干燥粗提物(下文中称为“ACE”),用于作为比较例。
1-2粗提物(ATM)的制备
将1.1kg干东北婆婆纳(按照GAP,在韩国忠清北道阴城郡蘇伊面244号栽培)切成小块,并与5L甲醇混合。将混合物在室温下搅拌24小时,并在78℃用回流提取进行提取12小时,以收集滤液,重复三次。用滤纸过滤提取物以除去碎屑。将收集的滤液在55至65℃下通过旋转蒸发仪(EYELA,N-2100,日本)减压浓缩,并用冷冻干燥机干燥以获得100.5g干燥粗提物(下文中称为“ATM”),用于作为比较例。
1-3成分分析
通过使用HPLC(Agilent 1260型号,USA),根据表1中的条件进行成分分析,其结果示于图1中。
如在图1中所示,已确认,分别在以下时间检测到各个成分:9.548分钟(毛蕊花甙)、10.817分钟(藜芦酸)、16.728分钟(梓苷)、20.346分钟(胡黄连苷II)、21.853分钟(异香草酰梓醇)和30.462分钟(6-O-藜芦酰梓醇)。
根据数学式1,基于HPLC图谱(保留时间),计算样品中每种成分的含量(%)。
[数学式1]
每种成分的含量=标准的浓度(mg/ml)/测试样品的浓度(mg/ml)×At/As×标准的纯度(%)
其中,“At”表示在测试样品中的成分面积,“As”表示在标准中的成分面积,条件是测试样品和标准的采样体积彼此相同。
表1
[表1]
HPLC条件
如在表2中所示,在结果中,已经证实,东北婆婆纳的粗提物仅包含8.49%(w/w)梓苷衍生物,即分别为5.9%(w/w)毛蕊花甙、0.21%(w/w)藜芦酸、0.82%(w/w)梓苷、0.40%(w/w)胡黄连苷II、0.42%(w/w)异香草酰梓醇和0.74%(w/w)6-O-藜芦酰梓醇。
表2
[表2]
HPLC结果(粗提物:ATM)
实施例1东北婆婆纳的纯化提取物(ATC1)的制备
将根据比较例1的常规方法制备的东北婆婆纳的粗提物(ACE)悬浮于2L蒸馏水中,在悬浮液中加入2L丁醇,分馏成可溶于丁醇的馏分和水溶性馏分。收集可溶于丁醇的馏分,减压浓缩并干燥,得到82g本发明的用丁醇分馏的纯化提取物(ATC1)用作实验例。
通过使用HPLC(Agilent 1260型号,USA),根据表1中的条件进行成分分析,其结果示于图2中。
如在图2中所示,已确认,分别在以下时间检测到各个成分:9.545分钟(毛蕊花甙)、10.821分钟(藜芦酸)、16.727分钟(梓苷)、20.345分钟(胡黄连苷II)、21.853分钟(异香草酰梓醇)和30.462分钟(6-O-藜芦酰梓醇)。
根据数学式1,基于HPLC图谱(保留时间),计算样品中每种成分的含量(%)。
如在表3中所示,在结果中,已经证实,东北婆婆纳的本发明的用丁醇分馏的纯化提取物(ATC1)包含25.64%(w/w)梓苷衍生物,即分别为17.60%(w/w)毛蕊花甙、0.72%(w/w)藜芦酸、2.62%(w/w)梓苷、1.08%(w/w)胡黄连苷II、1.26%(w/w)异香草酰梓醇和2.36%(w/w)6-O-藜芦酰梓醇。
表3.
表3
[表3]
HPLC结果(纯化提取物:ATC1)
实施例2东北婆婆纳的纯化提取物(ATC2)的制备
将根据实施例1的东北婆婆纳的本发明的用丁醇分馏的纯化提取物(ATC1)溶解于75ml混合溶剂(蒸馏水:甲醇=1:0.003),并将75g该溶液装载在反相柱色谱(C18(Ⅳ)-D-75-120nm,AGCSi-Tech有限公司,日本,450g),通过使用洗脱溶剂(蒸馏水:甲醇=90:10→60:40)洗脱该悬浮液。收集在初始洗脱溶剂系统(蒸馏水:甲醇=90:10)中运行的8.4L洗脱溶液,并减压浓缩。收集在晚期洗脱溶剂系统(蒸馏水:甲醇=60:40)中运行的5.6L洗脱溶液,减压浓缩并干燥,得到33g本发明的二级分馏的纯化提取物(ATC2)用作实验例。
通过使用HPLC(Agilent 1260型号,USA),根据表1中的条件进行成分分析,其结果示于图3中。
如在图3中所示,已确认,分别在以下时间检测到各个成分:9.525分钟(毛蕊花甙)、10.818分钟(藜芦酸)、16.721分钟(梓苷)、20.346分钟(胡黄连苷II)、21.857分钟(异香草酰梓醇)和30.462分钟(6-O-藜芦酰梓醇)。
根据数学式1,基于HPLC图谱(保留时间),计算样品中每种成分的含量(%)。
如在表4中所示,在结果中,已经证实,东北婆婆纳的本发明的二级分馏的纯化提取物(ATC2)包含65.63%(w/w)梓苷衍生物,即分别为43.83%(w/w)毛蕊花甙、1.80%(w/w)藜芦酸、7.07(w/w)梓苷、2.93%(w/w)胡黄连苷II、3.85%(w/w)异香草酰梓醇和6.15%(w/w)6-O-藜芦酰梓醇。
表4
[表4]
HPLC结果(纯化提取物:ATC2)
实验例1在OVA致敏/激发小鼠模型中总血清IgE水平的初步判定。
为了发现纯化提取物显示出比比较例中制备的粗提物药理学上更有效的活性,通过文献(Elias,J.A.等人,J.Clin.Invest.,111,第297-297页,2003)中公开的方法进行下面的初步试验。
1-1.动物致敏和气道激发
经相关呼吸道病原体常规血清学筛选的无特定病原体的6周龄雌性BALB/c小鼠(约20g),购自ORIENT公司(韩国首尔)并在实验环境驯化1周。
简言之,通过每两周一次腹膜内注射20μg OVA(卵清蛋白;A5503,Sigma,St.Louis,MO)使小鼠致敏,所述OVA在200μl PBS缓冲液(pH 7.4)中的2mg氢氧化铝中乳化。从初次致敏后第28天至34天,使用超声喷雾器(NE-U12;Omron公司,东京,日本)通过气道以OVA(1%,在PBS中)激发小鼠30分钟。抗原处理后24小时,确定气道高反应性并在最后激发后48小时处死小鼠。最后激发后24小时用过量戊巴比妥( Hanrim Pharm.有限公司)处死小鼠,并进行气管切开术。1.2ml生理盐水溶液(PBS)滴入肺后,通过经由气管插管抽吸三次(共1.5ml)获得支气管肺泡灌洗液(BALF)。
分为若干组,即,(a)正常对照组(NC):用OVA处理或不处理的组;(b)哮喘诱发组(OVA):用OVA处理以诱发哮喘的组;以及(c)比较组:吸入OVA之前1小时以阳性对照组(M30,孟鲁司特;30mg/kg,PO,Sigma-Aldrich有限公司,SML-0101)处理的组。
试验组每组由6只小鼠组成,吸入OVA之前1小时,给小鼠口服施用各种浓度的测试样品(ATC1(30mg/kg和100mg/kg)和ATM(30和100mg/kg))。
如表5所示,在哮喘诱发组(OVA)中血清中的IgE的总水平显著增加,而口服施用各种浓度的测试样品(ATC1,330mg/kg和100mg/kg)的测试样品组的血清中的IgE的总水平比用东北婆婆纳的粗提物(ATM,30和100mg/kg)处理的组的血清中的IgE的总水平降低的更多。(见表5)
表5
[表5]
血清中的总IgE水平
实验例2.在OVA致敏/激发小鼠模型中使用气道高反应性测试的抗哮喘效果
为了证实实施例中制备的测试样品在OVA致敏/激发小鼠模型中使用气道高反应性测试的抗哮喘效果,通过文献(Elias,J.A.等人,J.Clin.Invest.,111,第297-297页,2003)中公开的方法进行下面的试验。
1-1.动物致敏和气道激发
经相关气道病原体常规血清学筛选的无特定病原体的6周龄雌性BALB/c小鼠(约20g),购自ORIENT公司(韩国首尔)并在实验环境驯化1周。
简言之,通过每两周一次腹膜内注射20μg OVA(卵清蛋白;A5503,Sigma,St.Louis,MO)使小鼠致敏,所述OVA在200μl PBS缓冲液(pH 7.4)中的2mg氢氧化铝中乳化。初次致敏后从第28天至34天,使用超声喷雾器(NE-U12;Omron公司,东京,日本)通过气道以OVA(1%,在PBS中)激发小鼠30分钟。抗原处理后24小时,确定气道高反应性并在最后激发后48小时处死小鼠。最后激发后24小时用过量戊巴比妥(Entobal,Hanrim Pharm.有限公司)处死小鼠,并进行气管切开术。1.2ml生理盐水溶液(PBS)滴入肺后,通过经由气管插管抽吸三次(总共1.5ml)获得支气管肺泡灌洗液(BALF)。
研究小鼠组(n=6);它们受到以下处理:(1)以OVA的非处理组作为正常对照组(NC);(2)处理并吸入OVA的对照组作为哮喘诱发组(OVA);(3)吸入OVA之前1小时以已知的哮喘治疗剂处理的阳性对照组(孟鲁司特;30mg/kg,PO,韩国Sigma-Aldrich,SML-0101,M30);(4)吸入OVA之前1小时,口服施用不同浓度的测试样品(即,5mg/kg、10mg/kg、25mg/kg和50mg/kg的纯化提取物(ATC2))的测试样品组。
1-2气道高反应性的评价
为了评价小鼠的气道高反应性,通过用仪器(单室全身体积描记系统(Onechamber whole body plethymography),OCP3000,All Medicus,首尔,韩国)测定气道阻力,通过表现气道阻塞程度的Pehn值(增强暂停)来进行统计学计算所侧定的值。通过测定在正常呼吸阶段的基值以及测定用超声雾化器(NE-U12,IMRON公司,东京,日本)吸入PBS 3分钟后的Pehn值的过程,测定Pehn值3分钟。
此后,随着浓度增加吸入各种浓度(12、25和50mg/ml)的乙酰甲胆碱(A2251,Sigma,St.Louis,MO),以测定Pehn值。Pehn值的增加表示为吸入乙酰甲胆碱后的百分比(%),Pehn值的基线设定为100%。Pehn的值根据数学式2计算,结果在图4中示出。
[数学式2]
Pehn=(Te/RT-1)×PEF/PIF
TE:呼气时间(从吸气到下一次吸气的时段);
RT:松弛时间(呼气期间呼出体积达到一次呼气体积的30%的程度的时段)
PEF:呼气流量峰
PIF:吸气流量峰
在结果中,已经证实,随着乙酰甲胆碱的浓度增加,在作为哮喘诱发组(OVA)的处理并吸入OVA的对照组中,Penh值急剧增加,而在作为正常对照组(NC)的OVA的非处理组中,Penh值逐渐增加。
在一段时间,不管乙酰甲胆碱的浓度如何,在以孟鲁司特(MO)处理的阳性对照组中以及以不同浓度(ATC-10、ATC-25和ATC-50)的测试样品口服施用的测试样品组中,Penh值显著降低。(见表6)
表6
[表6]
已经证实,Penh值的这种变化在高剂量乙酰甲胆碱处理组而不是在低剂量乙酰甲胆碱处理组中显著,对于相同浓度的乙酰甲胆碱,测试样品中的Penh值以剂量依赖方式显著地降低。
因此,已经证实,本发明的纯化的提取物有效地抑制气道高反应性,因此,它们可用于治疗或预防气道中的哮喘性疾病、过敏性疾病。
实验例3对于BALF中嗜酸性粒细胞和炎性细胞的水平的影响
为了证实实施例制备的测试样品对于支气管肺泡液(BALF)中嗜酸性粒细胞和炎性细胞的水平的抑制效果,通过文献(Chen M.等人,Immunolgy,第376-384页,2011)中公开的方法进行下面的试验。
回收实验例1中制备的支气管肺泡灌洗液(BALF),以测定炎性细胞的水平。
通过用锥虫蓝(trypan blue)染色排除死细胞后,在血细胞计数器的至少五个正方形中计数细胞以评估总炎性细胞数目(Daigle I.等人,Swiss Med Wkly,131,第2317页,2001)。将100μl BALF加到载玻片上并使用Cellspin机(Cyto12.5+clip5,Hanil ScienceIndustrial,韩国)离心(200×g,4℃,10分钟)以将细胞固定在载玻片上。根据制造商的说明,用染色试剂(Sysmex,Cat No.38721,瑞士)给细胞染色。对独立的平均值通过Student氏双尾t-检验确定统计学显著性,并将显著性的临界水平设定在P<0.05。
如图5中所示,与作为正常对照组(NC)的OVA的非处理组中的嗜酸性粒细胞和炎性细胞的总数目相比,作为哮喘诱发组(OVA)的处理并吸入OVA的对照组中的嗜酸性粒细胞和炎性细胞的总数目显著增加。
在以孟鲁司特(MO)处理的阳性对照组中以及以不同浓度(ATC-5、ATC-10、ATC-25和ATC-50)的测试样品口服施用的测试样品组中,嗜酸性粒细胞和炎性细胞的总数目显著降低。(见表7)
表7
[表7]
BALF中嗜酸性粒细胞和炎性细胞的总数目
实验例4对血清中IgE和OVA特异性IgE的水平的影响
为了证实实施例制备的测试样品对血清中IgE和OVA特异性IgE的水平的抑制效果,通过文献(Kay,A.B.,The New England Journal of Medicine,344,第30-37页,2001)中公开的方法进行下面的试验。
回收实验例1中制备的血清和支气管肺泡灌洗液(BALF),以确定血清中IgE和OVA特异性IgE的水平。
将血清和支气管肺泡灌洗液(BALF)加入到96孔板(ELISA板),并在4℃下用含20μg/ml OVA(Sigma,MO,USA)的0.1M碳酸氢钠缓冲液(pH 8.3)包被过夜。通过使用含有1%牛血清白蛋白的PBS抑制非特异性反应后,将用于测试的血清稀释至1:400,并在室温下共同反应2小时。洗涤后,在室温下,使血清与稀释的(x 300)抗小鼠IgE单克隆抗体(MCA419,Serotec,Oxford,UK)反应2小时,再与稀释的(x4000)结合HRP的山羊抗大鼠IgG多克隆A(STAR110P,Serotec,UK)反应1小时。洗涤后,用3,3',5,5'-四甲基联苯胺(52-00-02,KPL)底物对溶液进行染色,用2N H2SO4停止反应,使用分光光度计(VersaMax,MolecularDevices,US)在450nm处测定吸光度。
如图6和图7所示,作为哮喘诱发组(OVA)的处理并吸入OVA的对照组中的血清中的IgE和OVA特异性IgE水平显著增加,而在以孟鲁司特(MO)处理的阳性对照组中以及以不同浓度(ATC-5、ATC-10、ATC-25和ATC-50)的测试样品口服施用的测试样品组中,血清中的IgE和OVA特异性IgE水平显著降低。(见表8)
表8
[表8]
血清中IgE和OVA特异性IgE的水平
因此,已经证实,本发明的纯化提取物有效地抑制血清中的IgE和OVA特异性IgE的水平,因此,它们可以用于治疗或预防过敏性疾病和哮喘性疾病。
实验例5对BALF中炎性细胞因子的水平的影响
为了证实实施例中制备的测试样品对于支气管肺泡灌洗液(BALF)中Th2细胞因子(IL-4、IL-5和IL-13)和IL-1β的水平的抑制效果,通过在文献(Renz H.等人,J.Exp.Med.,1777,第1175-1180页,1993)中公开的夹心酶免疫吸附测定法(sandwich enzymeimmunosorbent assay method)进行以下试验。
在室温下将血清和支气管肺泡灌洗液(BALF)加入到以细胞因子抗体包被的96孔板(ELISA板)以诱导抗原抗体反应进行2小时。根据制造商的说明书,使用与每种细胞因子特异性反应的ELISA试剂盒(Biosource Int.CA,USA)测定支气管肺泡灌洗液(BALF)中的Th2细胞因子(IL-4,IL-5和IL-13)和IL-1β的水平。
如图8和图9-11中所示,OVA处理后48小时,与作为正常对照组(NC)的OVA的非处理组中的Th2细胞因子(IL-4,IL-5和IL-13)和IL-1β水平相比,作为哮喘诱发组(OVA)的处理并吸入OVA的对照组中Th2细胞因子(IL-4,IL-5和IL-13)和IL-1β的水平显著增加。
在以孟鲁司特(MO,30mg/kg)处理的阳性对照组中以及以不同浓度(ATC-10、ATC-25和ATC-50)的测试样品口服施用的测试样品组中Th2细胞因子(IL-4,IL-5和IL-13)和IL-1β的增加水平显著降低。(见表9)
表9
[表9]
Th2细胞因子(IL-4,IL-5和IL-13)和IL-1β的水平
因此,已经证实,本发明的纯化提取物有效地抑制BALF中Th2细胞因子(IL-4、IL-5和IL-13)和IL-1β的水平,因此,它们可用于治疗或预防过敏性疾病和哮喘性疾病。
实验例6肺组织学
为了证实实施例中制备的测试样品的抗哮喘效果,通过在文献(Kwak YG.等人,J.Clin.Invest.,111,第1083-1092页,2003)中所公开的方法进行以下对支气管肺泡组织的组织病理学分析。
将没有进行支气管肺泡灌洗的BALB/c小鼠的交付(delivered)肺组织固定于10%中性缓冲的福尔马林中24小时。包埋在石蜡中之后,然后制成4-厚切片,用H&E溶液(苏木精;Sigma MHS-16和曙红,Sigma HT110-I-32)将组织染色,测定以随机的方式选择的每个切片中的五个区域中的炎症评分(炎症评分0:支气管周围没有发现发炎细胞,炎症评分1:支气管周围零星地发现发炎细胞,炎症评分2:在大多数支气管周围发现薄发炎细胞层,炎症评分3:在大多数支气管周围发现厚发炎细胞层)。
如图12、13中所示,在作为哮喘诱发组(OVA)的处理并吸入OVA的对照组中,在细支气管周围发现许多包括嗜酸性粒细胞的炎性细胞,并且也发现了上皮细胞的增生以及气管肌的肥大,而在以孟鲁司特(MO,30mg/kg)处理的阳性对照组中以及以不同浓度(ATC-10、ATC-25和ATC-50)的测试样品口服施用的测试样品组中发炎细胞的入侵显著减少。(见表10)
表10
[表10]
细支气管上皮细胞中的炎性评分和杯形细胞的比例
实验例7杯形细胞生长的评估
为了证实实施例中制备的测试样品的抗哮喘效果,通过在文献(Lee KS.等人,FASEB J.,20,第455-465页,2006)中所公开的方法进行以下对支气管肺泡组织的杯形细胞生长分析。
将没有进行支气管肺泡灌洗的BALB/c小鼠的交付肺组织固定于10%中性缓冲的福尔马林中24小时。包埋在石蜡中之后,然后制成4-厚切片,用高碘酸-希夫(PAS染色试剂盒,T-K7308,IMEB,CA,USA)将组织染色,以测定在细支气管上皮细胞中杯形细胞的比率。
如图14、15所示,与正常对照组(Nc)相比,在作为哮喘诱发组(OVA)的处理并吸入OVA的对照组中的细支气管上皮细胞中的杯形细胞的比率显著增加,而在以孟鲁司特(MO,30mg/kg)处理的阳性对照组中以及以不同浓度(ATC-10、ATC-25和ATC-50)的测试样品口服施用的测试样品组中在细支气管上皮细胞中杯形细胞的比率显著减少。(见表9)
实验例8在大鼠中口服给药的急性毒性试验
通过给6周龄的SPF Sprague-Dawley大鼠施用本发明提取物以进行急性毒性试验。
给每组由2只大鼠组成的各组口服施用250mg/kg、500mg/kg、1000mg/kg、5000mg/kg的本发明的提取物,观察大鼠的症状进行14天。施用该提取物后,观察所有的临床变化(即死亡率、临床症状、体重变化),并进行血液检测(例如血液病学检测和血液生化检测)。尸体解剖后观察腹腔脏器和胸部器官的异常变化。
在任何组或任一性别中没有显示出死亡率、临床症状、体重变化和总体结果上的任何变化。此外,以5000mg/kg的本发明提取物处理的试验组中表现出一些毒性。
因此,已经证实的是,本发明中制备的发明提取物为在口服给药中显示LD50(超过5000mg/kg)的有效且安全的物质。
【发明方式】
在下文中,将对配制方法和赋形剂的种类进行说明,但本发明并不限定于此。代表性的制备实施例描述如下。
注射剂的制备
ATC1提取物…………………….100mg
焦亚硫酸钠………………………3.0mg
对羟基苯甲酸甲酯……………0.8mg
对羟基苯甲酸丙酯……………0.1mg
注射用蒸馏水…………………适量
注射制剂是通过常规注射制备方法通过溶解活性组分,控制pH至约7.5,然后将所有组分装入2ml的安瓿瓶中并灭菌。
散剂的制备
ATC2提取物……………………500mg
玉米淀粉………………………100mg
乳糖………………………100mg
滑石………………………10mg
散剂是通过混合上述成分并填充密封的包装而制备。
片剂的制备
ATC1提取物………………………200mg
玉米淀粉………………………100mg
乳糖………………………100mg
硬脂酸镁…………………适量
片剂通过混合上述成分并压片而制备。
胶囊的制备
ATC2提取物………………………100mg
乳糖………………………50mg
玉米淀粉………………………50mg
滑石………………………2mg
硬脂酸镁………………………适量
片剂制剂是通过常规明胶制备方法通过混合上述成分并填充于明胶胶囊中制备。
液体的制备
ATC1提取物………………………1000mg
糖……………………………20g
多糖…………………………20g
柠檬香料………………………20g
液体制剂是通过常规液体制备方法通过将活性成分溶解,然后将所有成分填充在1000ml安瓿瓶中并灭菌而制备。
尽管如此描述本发明,但很明显的是可以在许多方面进行改变。这些变化不应被视为背离本发明的精神和范围,并且对于本领域技术人员来讲将是显而易见的所有这样的修改都旨在包括在以下权利要求的范围之内。
【工业实用性】
如本发明中所述,本发明提供用于从东北婆婆纳的提取物制备含有更大量的活性成分(例如梓醇衍生物)的纯化提取物的本发明的新的工业化方法,并且通过在OVA致敏/激发小鼠模型中各种体内试验(例如对于嗜酸性粒细胞(eosinolphil)繁殖、血浆和支气管肺泡液中免疫球蛋白和炎症趋化因子的释放的抑制试验以及气道高反应性和杯形细胞增生的抑制),所述纯化提取物表现出比通过在现有技术中公开的传统制备方法制备的提取物更有效的抗炎、抗过敏和抗哮喘活性。因此,其可以用作用于治疗和预防炎性、过敏性或哮喘性疾病的治疗剂。
Claims (3)
1.一种用于治疗和预防炎性、过敏性或哮喘性疾病的从东北婆婆纳的提取物二级分馏的纯化提取物(ATC2),其由以下方法制得:在第一步中,向干燥的东北婆婆纳中加入含30-80重量%的乙醇的水;在第二步中,在20至50℃的温度范围内进行冷水提取6至48小时的时间,然后在60至90℃的温度范围内进行回流提取6至48小时的时间,反复进行,以获得第一提取物;在第三步中,将所述第一提取物悬浮在1-5倍体积(v/v)的水中,以得到悬浮提取物;在第三步中,加入1-10倍体积(v/v)的丁醇,分馏为水层和丁醇层并收集丁醇层以得到用丁醇分馏的纯化提取物(ATC1);以及对用丁醇分馏的纯化提取物(ATC1)进行反相分配色谱以得到二级分馏的纯化提取物(ATC2),所述反相分配色谱使用选自基于硅胶的固定相或基于聚合物的固定相的固定相,以及选自水、乙腈、甲醇、乙醇、丁醇、四氢呋喃(THF)和其混合物的流动相,
基于东北婆婆纳的总提取物的重量(100%),其含有30-60%(w/w)毛蕊花甙、0.5-10%(w/w)藜芦酸、2-20%(w/w)梓苷、1-10%(w/w)胡黄连苷II、1-10%(w/w)异香草酰梓醇和2-20%(w/w)6-O-藜芦酰梓醇。
2.一种用于制备权利要求1所述的二级分馏的纯化提取物(ATC2)的方法,其包括:在第一步中,向干燥东北婆婆纳中加入含30-80重量%的乙醇的水;在第二步中,在20至50℃的温度范围内进行冷水提取6至48小时的时间然后在60至90℃的温度范围内进行回流提取6至48小时的时间,反复进行以获得第一提取物;在第三步中,将所述第一提取物悬浮在1-5倍体积(v/v)的水中,以得到悬浮提取物;在第三步中,加入1-10倍体积(v/v)的丁醇,分馏为水层和丁醇层并收集丁醇层以得到用丁醇分馏的纯化提取物(ATC1);以及对所述用丁醇分馏的纯化提取物(ATC1)进行反相分配色谱以得到二级分馏的纯化提取物(ATC2),以治疗和预防炎性、过敏性或哮喘性疾病,基于东北婆婆纳的总提取物的重量(100%),该二级分馏的纯化提取物(ATC2)含有30-60%(w/w)毛蕊花甙、0.5-10%(w/w)藜芦酸、2-20%(w/w)梓苷、1-10%(w/w)胡黄连苷II、1-10%(w/w)异香草酰梓醇和2-20%(w/w)6-O-藜芦酰梓醇,所述反相分配色谱使用选自基于硅胶的固定相或基于聚合物的固定相的固定相,以及选自水、乙腈、甲醇、乙醇、丁醇、四氢呋喃(THF)和其混合物的流动相。
3.一种用于治疗和预防炎性、过敏性或哮喘性疾病的药物组合物,其包含:
作为活性成分的从东北婆婆纳中分离的权利要求1所述的二级分馏的纯化提取物(ATC2),以及药学上可接受的载体或赋形剂,所述炎性、过敏性或哮喘性疾病选自湿疹,特应性皮炎,风湿性关节炎,慢性炎性疾病,急性炎性疾病,过敏性皮炎,接触性皮炎,由尘螨、食物、药物、咳嗽、香烟烟雾、空气污染、食品添加剂、天气变化或黄沙引起的哮喘。
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