CN107466234A - 药用组合物及其用途 - Google Patents
药用组合物及其用途 Download PDFInfo
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- CN107466234A CN107466234A CN201680019935.1A CN201680019935A CN107466234A CN 107466234 A CN107466234 A CN 107466234A CN 201680019935 A CN201680019935 A CN 201680019935A CN 107466234 A CN107466234 A CN 107466234A
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- indigo
- pharmaceutical composition
- extract
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Abstract
本发明涉及一种药用组合物,以及组合物在医药应用中的用途。
Description
技术领域
本发明涉及一种药用组合物,以及组合物在医药应用中的用途。
背景
对于牛皮癣的常规治疗通常根据患者的年龄、性别、职业和认知能力,损害的类型和分布,患者对先前治疗方法的反应,和患者的其它医疗史而设计。对于牛皮癣的主要治疗方法包括局部疗法、全身疗法、生物制剂注射和光疗。用于局部疗法的组合物包括,例如,皮质类固醇、地蒽酚(可作为Margiton®购得)、煤焦油(可作为Polytar®购得)、骨化三醇(可作为Silkis®购得)、他扎罗汀(可作为Tazorac®购得)、水杨酸,这些组合物适合于治疗具有轻度症状的牛皮癣患者。例如甲氨蝶呤(MTX)、环孢菌素和维甲酸类的口服制剂通常用于全身疗法且适合于治疗具有中度至重度症状的牛皮癣患者。生物制剂包括阿来西普(可作为Amevive®购得)、依法珠单抗(可作为Raptiva®购得)、依那西普(可作为Enbrel®购得)和阿达木单抗(可作为Humira®购得),它们适合于注射到具有中度至重度症状的牛皮癣患者中。光疗,例如,紫外线B (UVB)光疗、光化学疗法例如补骨脂素加紫外线A (PUVA),适合于治疗具有重度症状的牛皮癣患者。
然而,需要另外的治疗方法。
概述
本发明部分涉及一种药用组合物,其包含基于活性成分的总重量的至少65% (w/w)的靛玉红衍生物。
依据本发明的活性成分指包括靛玉红衍生物、靛青衍生物、色胺酮衍生物、靛红衍生物和青黛酮衍生物的一种或多种的成分,或指含有靛玉红衍生物、靛青衍生物、色胺酮衍生物、靛红衍生物和青黛酮衍生物的一种或多种的植物萃取物(例如,青黛(IndigoNaruralis)萃取物或青黛的精制萃取物)。
在一个方面,本发明提供一种药用组合物,其具有基于活性成分的总重量的至少65% (w/w)的靛玉红衍生物(例如,基于活性成分的总重量的至少70%、75%、80%或85% (w/w)),和药学上可接受的载体。
在一些实施方案中,组合物包含基于活性成分的总重量的65-90% (w/w)的靛玉红衍生物和0-15%的靛青衍生物和药学上可接受的载体。例如,靛玉红衍生物(包含一种或多种靛玉红衍生物)可以以基于活性成分总重量的65-90% (w/w),例如,65-70%、65-75%、65-80%、65-85%、65-90%、70-75%、70-80%、70-85%、70-90%、75-80%、75-85%、75-90%、80-85%、80-90%,或85-90% (w/w)的量存在。靛青衍生物(包含一种或多种靛青衍生物)可以以基于活性成分总重量的0-15%,例如,0.05-15%、0.1-15%、0.5-15% (w/w)的量存在。
在一些实例中,靛玉红衍生物(包含一种或多种靛玉红衍生物)可以以基于药用组合物的20-500ppm,例如,20-100ppm、20-200ppm、20-300ppm、20-400ppm、20-500ppm、50-100ppm、50-200ppm、50-300ppm、50-400ppm、50-500ppm、100-200ppm、100-300ppm、100-400ppm、100-500ppm、200-300ppm、200-400ppm、200-500ppm、300-400ppm、300-500ppm或400-500ppm的量存在。
在一些其它实例中,靛青衍生物(包含一种或多种靛青衍生物)可以以基于药用组合物的0.1-40ppm,例如,0.1-5ppm、0.1-10ppm、0.1-20ppm、0.1-30ppm、0.1-40ppm、1-5ppm、1-10ppm、1-20ppm 1-30ppm、1-40ppm、5-10ppm、5-20ppm、5-30ppm、5-40ppm、10-20ppm、10-30ppm、10-40ppm、20-30ppm、20-40ppm或30-40ppm的量存在。
在一些其它实施方案中,组合物还包含色胺酮衍生物。色胺酮衍生物(包含一种或多种色胺酮衍生物)可以以基于活性成分总重量的0.01-5% (w/w),优选0.1-5% (w/w)的量存在,例如,基于活性成分总重量的0.1-1%、0.1-5%、0.5-1%,或0.5-5% (w/w)的量存在。
在一些实例中,色胺酮衍生物(包含一种或多种色胺酮衍生物)可以以基于药用组合物的0.1-10ppm,例如,0.1-1ppm、0.1-5ppm、0.1-10ppm、1-5ppm、1-10ppm,或5-10ppm的量存在。
在一些进一步的实施方案中,组合物还包含作为组分的青黛酮衍生物。青黛酮衍生物(包含一种或多种青黛酮衍生物)可以以基于活性成分的总重量的0.1-5% (w/w)的量存在,例如,基于活性成分的0.1-1%、0.1-3%、0.5-1%,或0.5-5% (w/w)的量存在。
在一些实例中,青黛酮衍生物(包含一种或多种青黛酮衍生物)可以以基于药用组合物的0.1-10ppm,例如,0.1-1ppm、0.1-5ppm、0.1-10ppm、1-5ppm、1-10ppm,或5-10ppm的量存在。
在一些进一步的实施方案中,组合物还包含靛红衍生物作为组分。靛红衍生物(包含一种或多种靛红衍生物)可以以基于活性成分的0.1-5% (w/w)的量存在。
在一些实例中,靛红衍生物(包含一种或多种靛红衍生物)可以以基于药用组合物的0.1-10ppm,例如,0.1-1ppm、0.1-5ppm、0.1-10ppm、1-5ppm、1-10ppm,或5-10ppm的量存在。
在进一步的实施方案中,药用组合物包含:
- 从0.002%至0.077% (w/w)的青黛的精制萃取物,和
- 药学上可接受的载体,
其中青黛的精制萃取物包含从65%至90% (w/w)的靛玉红和一种或多种选自具有以下量的靛青、色胺酮和青黛酮的衍生物:
- 靛青:精制萃取物的0.1-15% (w/w),
- 色胺酮:精制萃取物的0.01-5%,优选0.1-5% (w/w),和
- 青黛酮:精制萃取物的0.1-5% (w/w)。
在特定的实施方案中,本发明的组合物呈现为局部给药或口服给药的形式。
在另一个方面,本发明提供一种上述组合物,其用于治疗或缓解选自牛皮癣、炎性皮肤病况、甲真菌病、皮肤癌、异常角质化诱导的疾病、皮肤老化、脓疱型皮肤病的疾病或病况。
在另一个方面,本发明提供一种抑制角质化细胞的增殖或分化,抑制单核细胞浸润至真皮和表皮,抑制导致增生血管的血管变化,或抑制内皮细胞上粘附分子的上调的方法,其包括使刚刚描述的组合物与需要其的细胞接触。此方法可在体内或体外使用。
在又一个方面,本发明提供上述组合物在制备用于治疗或缓解疾病或病况的产品中的用途,所述疾病或病况选自牛皮癣、炎性皮肤病况、甲真菌病、皮肤癌、异常角质化诱导的疾病、皮肤老化、脓疱型皮肤病和皮肤T细胞淋巴瘤(CTCL)。
在更进一步的另一个方面,本发明提供一种用于治疗皮肤疾病或病况的方法,其包括给予有效量的上述组合物至有需要的受试者(例如,人)。疾病或病况选自牛皮癣、炎性皮肤病况、甲真菌病、皮肤癌、异常角质化诱导的疾病、皮肤老化、脓疱型皮肤病和CTCL。在一些实施方案中,炎性皮肤病况可以是特应性皮炎(AD)、湿症或重复感染的皮肤。皮肤老化可以是皮肤年轻化,疤痕的组织再生或皮肤衰老(skin senescence)。异常角质化可以是痤疮、鱼鳞病和掌跖角化病。皮肤癌可以是癌前期皮肤癌,例如,光化性角化病(AK)、鲍恩病(Bowen’s diseace);皮肤癌,例如SCC、BCC、NMSC;黑素瘤和HPV诱发的皮肤癌。
附图描述
本发明的以上和其它特征和优点将参照以下详细描述和附图而变得显而易见。
图1:靛青(A)和靛玉红(B)的示例性HPLC色谱图。
图2:色胺酮(A)、青黛(B)和实施例2的精制萃取物(C)的示例性HPLC色谱图。
图3:在IL-22诱发的牛皮癣模型中对得自青黛的萃取物的体内评估的分组和剂量。设计了5组研究并分别在研究1-5中概述。在研究1中,在20µL中的100ng和500ng的IL-22,经i.d.用于诱导。在研究2-5中,在20µL盐水中的500ng的IL-22,经i.d.用于诱导。
图4:图说明在皮内注射IL-22后的耳部炎症。在研究中,小鼠的耳朵经皮内注射并在注射之间的天数测量耳部厚度。
图5:图说明在皮内注射IL-22后青黛萃取物对耳部炎症的作用。
详细描述
青黛(Indigo Naturalis),例如青黛(Qingdai),是一种从含靛青植物或产靛青植物的叶子制备的深蓝色粉末。所述植物优选选自木蓝(Indigofera tinctoria L.)、马蓝(Baphicacanthus cusia (Nees) Bremek (syn. Strobilanthes cusia (Nees)、蓼蓝(Persi、caria tinctoria (Aiton) Spach. (syn. Polygonum tinctorium Aiton, P. tinctorium Lour.))和菘蓝(Isatis tinctoria L. (syn. Isatis indigotica Fort.))。
青黛(Qingdai)是青黛(Indigo Naturalis)的俗名。它用NaOH或KOH水溶液从含靛青植物或产靛青植物萃取,且相当于约5-15%有机化合物(包括生物碱类,其中存在靛青和靛玉红)和85-95%无机化合物(例如碳酸钙和氢氧化钙)的混合物。
如本文所用的,靛玉红、靛青、色胺酮、靛红和青黛酮具有以下结构。
如本文所用的,靛玉红衍生物指靛玉红及其衍生物,例如由式I表示,
式I
其中,X是选自N、O和S的任一个的杂原子;在X=N的情况下,N被连接于羟基,或用羟基、卤素或NH2取代的烷基;R1和R2是选自氢、烷基、OH、卤素、NH2、SO3H、NO2的一或多个取代基;且前述烷基是例如具有1-6个碳原子的烷基。
如本文所用的,靛青衍生物指靛青及其衍生物,例如由式II表示,
式II
X、R1和R2如在式I中的那些所定义。
靛青衍生物和靛玉红衍生物的例子如下:
- N-甲基异靛青(甲异靛);
- N-乙酰基-靛玉红;和
- 如下表示的化合物:
如本文所用的,色胺酮衍生物指色胺酮及其衍生物。色胺酮的衍生物指含有色胺酮核心,即稠合于吲哚部分的喹唑啉环的化合物。色胺酮的衍生物的一个例子是PhaitanthrinA、B、C、D或E;Methylisatoid,或Orphiuroidin,如于Ashli M. Tucker和Peter Grundt,Thechemistry of tryptanthrin and its derivatives, ARKIVOC 2012 (i) 546-569中所示的。
如本文所用的,靛红衍生物指靛红及其衍生物。靛红的衍生物指得自靛红的化合物,例如,在Yun Mi Chung等, Synthesis of ortho-Acetamidomandelic AcidDerivatives from Isatins, Bull. Korean Chem. Soc. 2002, Vol. 23, No. 10 1363;Ankur Patel等, Synthesis and Antimicrobial Activity of Some New IsatinDerivatives, Iranian Journal of Pharmaceutical Research (2006) 4: 249-254;或Olcay Bekircan等, Synthesis of Schiff and Mannich Bases of Isatin Derivativeswith 4-Amino-4,5-Dihydro-1H-1,2,4-Triazole-5-Ones, Molecules 2008, 13, 2126-2135中公开的那些化合物。
青黛酮衍生物指青黛酮本身及其衍生物。青黛酮的衍生物指得自青黛酮的化合物。
术语“有效量”指对患者平均产生治疗益处(例如,疾病、病症或症状的改善、缓解或治愈)的药用组合物的剂量水平。
上述活性成分可通过本领域技术人员已知的方法经化学合成,或从含靛青植物,例如青黛萃取物萃取。
用于从青黛制备精制萃取物的方法在下文描述。
青黛从含靛青植物或产靛青植物(优选地选自木蓝、马蓝、蓼蓝和菘蓝)的叶子和茎获得。当青黛(Indigo Naturalis)或青黛(Qingdai)是可市售获得的(可市售获得的青黛的例子(植物/供应商):马蓝(Baphicacanthus cusia)/Delong;木蓝(Indigoferatinctoria)/KMA出口商品或SAM VEGETABLE COLOURS PVT LTD或SICHUAN XIELI;菘蓝(Isatis tinctoria)/ANDREA PRIMAVERA或Bleu de Lectoure;蓼蓝(Polygonumtinctorium) /Couleur Garance或EARL 4 saisons)时,其可通过本领域通常已知的方法从一种或多种以上植物的叶子和/或茎生产。这些方法可概述如下:将新鲜收获的蓼蓝(Persicaria Tinctoria)和/或马蓝的茎和叶子加入到露天的池中,将水加入池中以覆盖茎/叶子。在浸泡数天(26-30℃)后,茎/叶子将变得腐烂。然后添加石灰碱(lime soda)同时搅拌。当浸泡混合物的颜色从绿色变成深紫色时,收集沉淀物,洗涤(通常用水洗2-3次),然后干燥,得到青黛粉末。
精制萃取物可通过包括以下步骤的方法制备:
a) 萃取步骤:用第一极性溶剂或中度极性溶剂萃取青黛或以上选择的一种或多种植物的叶子和/或茎,以获得萃取混合物;
b) 过滤步骤:过滤该萃取混合物,以获得滤液;
c) 浓缩步骤:浓缩该滤液,以获得粗萃取物;
d) 洗涤步骤:用非-极性溶剂和任选地用第二极性溶剂洗涤粗萃取物,以获得洗涤混合物;和
e) 过滤步骤:过滤洗涤混合物,任选地在干燥步骤(例如,依据用于干燥的常规方法)后,获得精制萃取物。
在特定的实施方案中,从浓缩步骤c)获得的粗萃取物经历以下程序至少一个循环直至获得精制萃取物:粗萃取物用溶剂洗涤(步骤d)),并过滤(步骤(e)),得到精制萃取物,任选地随后进行干燥步骤。依据特定的实施方案,洗涤步骤d)和过滤步骤e)仅执行一个循环,以获得精制萃取物。当应用一个以上的循环时,可使用相同或不同的溶剂用于洗涤。此外,该粗萃取物可在回流下用溶剂洗涤,混合物可冷却至室温且接着过滤,得到精制萃取物,任选地随后进行干燥步骤。
在优选的实施方案中,进行两个循环。特别地,通过浓缩步骤c)获得的粗萃取物在非- 极性溶剂,优选在己烷中洗涤(步骤d)并过滤(步骤e),任选地随后进行干燥步骤。然后,己烷萃取物用有机极性溶剂,优选用乙醇洗涤(步骤d)且接着过滤(步骤e),以获得精制萃取物,任选地随后进行干燥步骤。
任选地,微粉化步骤在步骤e)之后执行,从而提供具有粒径介于25和35 µm之间,优选约30 µm的精制萃取物。
在优选的实施方案中,精制萃取物可通过包括由下列组成的以下步骤的方法制备:a) (i) 将萃取溶剂,极性或中度极性溶剂(例如醇或乙酸乙酯)加入青黛粉末,得到混合物;(ii) 加热并搅拌混合物一段时间(例如,30 min、1小时、2小时);b) (iii) 过滤经加热的混合物,同时趁热除去不溶性副产物,得到滤液;c) (iv) 浓缩该滤液以得到粗萃取物;d) (v) 将洗涤溶剂(例如,水,非-极性,或极性溶剂,或其混合物)加入粗萃取物中,以得到洗涤混合物;(vi) 加热并搅拌洗涤混合物一段时间(例如,30 min、1小时、2小时);e)(vii) 例如在室温(例如18℃-35℃)过滤洗涤混合物,以收集精制萃取物;任选地(viii)重复步骤(v)-(vii),直至精制萃取物中的靛玉红的量(% w/w)超过55% (w/w),优选地超过65% (w/w),如通过在实施例8A中公开的HPLC方法所测定的,且任选地(ix) 根据常规方法(例如,风干、冷冻干燥)干燥残留物,以获得干燥萃取物。在步骤(v)和(viii)中的洗涤溶剂可以是相同或不同的。
在更优选的实施方案中,精制萃取物通过包括以下步骤的方法制备:
a) 用乙醇回流2-8小时萃取青黛,
b) 在不低于65℃的温度下过滤混合物,以获得滤液,
c) 浓缩滤液,以获得粗萃取物,任选地过滤所述粗萃取物(加入水),以完全除去溶剂和仍存在于溶剂中的最后组分并干燥,
d) (i) 用己烷在不低于50℃的温度下洗涤粗萃取物15-60 min,
(ii) 在室温下过滤在步骤d) (i)中获得的混合物,以获得产物,任选地用乙醇和水冲洗之
(iii) 用乙醇在回流下洗涤在步骤d) (ii)中获得的产物,和
e) 在室温下过滤在步骤d)中获得的洗涤混合物并在低于80℃的温度下干燥生成的产物,以获得萃取物,其任选地被微粉化。
在另一个优选的实施方案中,当精制萃取物在最后步骤中被微粉化时,颗粒大小是在25-35 µm范围内,优选约30 µm。
在另一个优选的实施方案中,当精制萃取物在最后步骤中被微粉化时,获得的颗粒的99%小于或等于30 µm。
如本文所用的,“约”或“大约”将被本领域普通技术人员所理解,并且在某种程度上根据使用该术语的上下文而变化。如果鉴于使用该术语的上下文,本领域普通技术人员对该术语的使用不明白,则“约”或“大约”将意味着至多加或减特定术语的20%,优选10%。
如本文所用的,术语“精制萃取物”指固体、半-固体或油性萃取物,优选固体萃取物,其含有少于10% (w/w)的在制备所述精制萃取物的方法中所用的水和/或溶剂。精制萃取物更优选的特征为增加量的活性成分,包括生物碱类,其中存在靛青、靛玉红、色胺酮和/或青黛酮,优选地与青黛(Qingdai)或青黛(Indigo Naturalis)相比富含靛玉红。更特别地,根据本发明的精制萃取物包含至少60%,或更优选地超过65 % (w/w)的活性成分,包括靛青、靛玉红、色胺酮和/或青黛酮。
如本文所用的术语“粗萃取物”指固体、半-固体或油性萃取物,优选固体或半-固体萃取物,其含有少于15% (w/w) (例如,5-15%、5-10%)的在制备精制萃取物的方法中所用的水和/或溶剂。与青黛(Qingdai)或青黛(Indigo Naturalis)比较,粗萃取物含有的靛玉红比精制萃取物少。粗萃取物通过根据本发明的浓缩步骤c)获得。浓缩步骤更特别地通过将滤液送至浓缩器(例如在减压下)执行,以除去用于该方法中的水和/或溶剂,从而浓缩萃取物中存在的活性成分,包括靛青、靛玉红、色胺酮、靛红和/或青黛酮衍生物。
如本文所用的“一次循环”指按顺序执行一次的洗涤步骤d)和过滤步骤e)的两个步骤。如本文所用的“两次循环”指按顺序执行两次的洗涤步骤d)和过滤步骤e)的两个步骤。
成分例如靛青、靛玉红、色胺酮和青黛酮的含量可通过如在实施例8中公开的HPLC方法定量。
来自青黛的上述精制萃取物或来自含靛青植物或产靛青植物(优选选自木蓝、马蓝、蓼蓝和菘蓝)的叶子和/或茎的精制萃取物包括作为组分的靛玉红,其量为精制萃取物的至少65% (w/w)。萃取物呈固体形式且可通过上述方法或任何其它合适的方法制备。萃取物还可包含靛青、色胺酮、青黛酮,和/或这些化合物的任何衍生物,其可与靛玉红一起被共同萃取。尤其是,含有多成分的萃取物可提供协同效应。
在由以上方法获得的精制萃取物中,靛玉红衍生物和靛青、色胺酮和青黛酮衍生物的至少一种或多种以以下量存在:
- 靛青衍生物:精制萃取物的0.1%-15% (w/w),
- 靛玉红衍生物:精制萃取物的65%-90% (w/w),
- 色胺酮衍生物:精制萃取物的0.01-5 % (w/w),优选0.1%-5% (w/w),
- 青黛酮衍生物:精制萃取物的0.1%-5% (w/w)。
在优选的实施方案中,在由以上方法获得的精制萃取物中,靛玉红和靛青、色胺酮和青黛酮的至少一种或多种以以下量存在:
- 靛青:精制萃取物的0.1%-15% (w/w),
- 靛玉红:精制萃取物的65%-90% (w/w),
- 色胺酮:精制萃取物的0.01-5 % (w/w),优选地从0.1%至5% (w/w),
- 青黛酮:精制萃取物的0.1%-5% (w/w)。
本发明还提供一种药用组合物,其可使用本领域技术人员熟知的技术配制成用于局部或口服给予的合适的剂型。药用组合物可另外地包含药学上可接受的载体例如在药物制造领域中广泛采用的那些载体。例如,药学上可接受的载体可包括一种或多种以下试剂:溶剂例如橄榄油、精制橄榄油、棉籽油、芝麻油、葵花籽油、花生油、小麦胚芽油、大豆油、希蒙得木油、月见草油、椰子油、棕榈油、甜杏仁油、芦荟油、杏仁油、鳄梨油、琉璃苣油、大麻子油、澳大利亚坚果油、玫瑰果油、核桃油、榛子油、油茶油、米糠油、牛油树脂、玉米油、山茶油、葡萄籽油、菜籽油、蓖麻油,及其组合,优选精制橄榄油,乳化剂、助悬剂、分解剂、结合剂、赋形剂、稳定剂、螯合剂、稀释剂、胶凝剂、增稠剂例如蜂蜡和/或凡士林,防腐剂、润滑剂、吸收延缓剂、脂质体、抗氧化剂例如丁羟甲苯或丁羟茴醚等。优选地,药用组合物被配制成局部制剂,其可直接应用于皮肤,例如,罹患牛皮癣的皮肤。适合于药用组合物的局部制剂可以是乳剂、凝胶剂、软膏剂、霜剂、贴剂、擦剂、气溶胶、喷雾剂、洗剂、精华液、糊剂、泡沫剂,或滴剂。在本发明的一个实施方案中,药用组合物通过使依据本发明的萃取物与基质例如本领域熟知的和通常使用的那些基质混合,配制成外用制剂。
在一些实施方案中,如上所述的药用组合物可包含0.002%和0.077% (w/w)之间的青黛的精制萃取物,和药学上可接受的载体,其中,青黛的精制萃取物包含从65%至90% (w/w)的靛玉红衍生物和一种或多种选自具有以下量的靛青、色胺酮和青黛酮的衍生物:
- 靛青衍生物:精制萃取物的0.1-15% (w/w),
- 色胺酮衍生物:精制萃取物的0.01-5% (w/w),优选0.1-5% (w/w),和
- 青黛酮衍生物:精制萃取物的0.1-5% (w/w)。
在一些优选的实施方案中,如上所述的药用组合物可包含0.002%和0.077% (w/w)之间的青黛的精制萃取物,和药学上可接受的载体,其中,青黛的精制萃取物包含从65%至90% (w/w)的靛玉红和一种或多种选自具有以下量的靛青、色胺酮和青黛酮的衍生物:
- 靛青:精制萃取物的0.1-15% (w/w),
- 色胺酮:精制萃取物的0.01-5% (w/w),优选0.1-5% (w/w),和
- 青黛酮:精制萃取物的0.1-5% (w/w)。
在一些实施方案中,给予依据本发明的药用组合物的剂量和频率可取决于以下因素而变化:待治疗的疾病的严重性,给药途径,和待治疗的受试者的体重、年龄、身体状况和反应。在进一步的或另外的实施方案中,药用组合物中的活性成分的量是在约0.001-约1000 mg/kg体重/天范围内,例如,约0.01-约500、300或100mg/kg体重/天。
上述组合物可用于疾病或病况的治疗或缓解。所谓治疗意味着至少缓解与受试者罹患的病理状况有关的症状,其中广义上使用的缓解指至少减少参数的量值,例如与待治疗的病理状况,例如皮炎、牛皮癣等有关的症状。因此,治疗还包括以下情况,其中病理状况,或至少与其相关的症状,被完全抑制,例如,避免发生,或停止,例如终止,以致宿主不再罹患病理状况,或至少为病理状况特征的症状。因此,治疗包括治愈和控制疾病状况两者。因此,上述组合物可用于治疗或缓解选自牛皮癣、炎性皮肤病况、甲真菌病、皮肤癌、异常角质化诱导的疾病、皮肤老化和脓疱型皮肤病的疾病或病况。
本发明还提供一种抑制角质化细胞的增殖或分化,抑制单核细胞浸润至真皮和表皮,抑制导致增生血管的血管变化,或抑制内皮细胞上粘附分子的上调的方法,其包括给予上述组合物至有需要的受试者。
关于其抑制增殖或分化,或炎症的活性,组合物的功效可通过体外模型进行评估。例如,体外测试可在细胞因子信号传导,STAT-3/STAT-1、MAPK、NFĸB参与的途径上执行。
关于其在治疗疾病或病症中的活性,组合物的功效可通过体内模型进一步评估。例如,可测试基因工程改造的小鼠,包括转基因和敲除模型。
本申请的新特征在所附权利要求书中具体阐述。本申请的特征和优点的更好的理解将通过参考以下阐明其中利用本申请原理的示例性实施方案的详细描述而获得。
虽然本文已显示和描述了本申请的优选的实施方案,但这样的实施方案仅通过实例的方式提供。应该理解,本文描述的本申请的实施方案的各种代替方案可用于实施本申请。本领域普通技术人员将意识到,许多变化、改变和取代是可能的而不背离本申请。意欲使以下权利要求限定本申请的诸方面的范围,并且从而覆盖这些权利要求及其等价物的范围内的方法和结构。
应理解的是,如果本文提及任何先有技术出版物,则这样的参考文献不构成承认出版物形成本领域普通常识的一部分。本申请引用的所有文件,或文件的部分(包括,但不限于,专利、专利申请、文章、书籍、手册和论文)为了任何目的,通过引用以其整体明确结合到本文中。
本文的百分比通过相对于萃取物或指定产物的重量的重量来表示,除非另外指明。
本发明的其它方面和优点将在以下示例性的实验部分中公开。
实施例
1. 精制青黛萃取物的制备和用于分析的分析方法
实施例1:精制青黛萃取物的制备
用于以下制备的青黛购自Delong Pharmaceutical (靛青2.62%和靛玉红0.284% (在实施例7A中描述的HPLC方法)和色胺酮0.0046% (在实施例8B中描述的HPLC方法))。
使500g青黛悬浮于10L乙酸乙酯中。在回流中搅拌该混合物2小时,且接着于75℃过滤。在减压下浓缩滤液,得到黑色固体。将粗萃取物在250mL己烷中搅拌并加热至回流1小时。冷却至室温后,过滤悬浮液以得到黑色残留物。
将0.50g黑色残留物在25mL己烷中再次回流1小时,并冷却至室温,接着过滤以得到精制萃取物,为深红色固体452mg。HPLC: 62.9%靛玉红,12.9%靛青,和0.53%色胺酮。
实施例2:精制青黛萃取物的制备
将用于实施例1的500g青黛悬浮于10L醇(乙醇)中。在回流中搅拌该混合物2小时,且接着于75℃过滤。在减压下浓缩滤液,得到黑色固体,将其在260mL己烷中搅拌并加热至回流1小时。冷却至室温后,过滤悬浮液以得到黑色残留物。
使0.80g黑色残留物在24mL醇(乙醇)中回流另外1小时,然后冷却至室温,接着过滤以得到精制萃取物,为深红色固体(538mg)。HPLC: 83.6%靛玉红,6.35%靛青,和0.75%色胺酮。
实施例3:精制青黛萃取物的制备
将用于实施例1的500g青黛悬浮于10L乙酸乙酯中。在回流中搅拌该混合物2小时,接着趁热过滤。在减压下浓缩滤液,得到黑色固体。将粗萃取物在250mL己烷中搅拌并加热至回流1小时。冷却至室温后,过滤悬浮液以得到黑色残留物。
使0.75g黑色残留物在22.5mL乙醇中回流1小时,并冷却至室温,接着过滤以得到精制萃取物,为深红色固体(538mg)。HPLC: 77.9%靛玉红,15.9%靛青,和0.56%色胺酮。
实施例4:精制青黛萃取物的制备
将用于实施例1的500g青黛悬浮于2.1L DMF中。于50℃搅拌混合物40分钟。冷却至20℃后,过滤悬浮液。在减压下浓缩滤液,得到黑色固体,将其在130mL己烷中搅拌并加热至回流1小时。冷却至20℃后,过滤悬浮液以得到黑色残留物。
用46.8 ml乙醇洗涤1.56g黑色残留物,并加热至回流1小时,然后冷却至20℃,接着过滤,得到精制萃取物(766mg)。HPLC: 66.3%靛玉红,9.76%靛青。
实施例5:精制青黛萃取物的制备
将用于实施例1的500g青黛悬浮于3L DMF中。于30℃搅拌该混合物1小时,且接着过滤。在减压下浓缩滤液,得到黑色固体,将其在230mL己烷中搅拌并加热至回流1小时。冷却至20℃后,过滤悬浮液以得到黑色残留物。
用59mL 85%乙醇(85% aq.醇)洗涤1.96g黑色残留物,并加热至回流1小时,接着趁热过滤,得到精制萃取物(1.02g)。HPLC: 69.4%靛玉红,18.7%靛青,和0.62%色胺酮。
实施例6:精制青黛萃取物的制备
在回流条件下,用2L乙醇92% (92%含水乙醇)萃取100g青黛2小时。完成后,在AF6滤器(Buchner)上趁热过滤混合物,以获得作为滤液的深蓝-红色溶液。将这种滤液在真空下浓缩至干燥,得到2.4 g干燥残留物。这种残留物用120 mL己烷在回流下洗涤1h。完成后,将该混合物冷却至室温22h,然后在真空下过滤,得到312.9mg深红色精制萃取物。
280mg的这种精制萃取物用15 mL乙醇92% (92%含水乙醇)在回流下洗涤1h。完成后,使该溶液冷却至室温,且接着过滤,在烘箱(80℃)中干燥1h30后,得到159 mg深红色/深紫红色精制萃取物(0.18%);HPLC: 82.31%靛玉红,8.99%靛青,和0.81%色胺酮。
实施例7:微粉化步骤
在先前实施例获得的精制青黛萃取物的微粉化步骤用以下设备进行:
- 微粉磨机:螺旋喷射式粉碎机Diameter 200
- 进料器:该设备被用于粉末剂量给微粉磨机进料。该剂量由两个螺杆制得。该系统允许有规律的流动。
微粉化包括以空气射流射出粉末微粒。微粒的接触使其炸裂。
在微粉化期间,记录微粉化的以下参数:
- 环压力:6巴
- 注射器压力:3巴
- 粉末进料速度:25 kg/h
微粉磨机允许为圆柱形外壳-外壳周围的孔用于空气注入。
粉末被导入微粉磨机;微粒由于空气射流被推进。当微粒具有良好的尺寸时,它们被集中在微粉磨机的中心且它们被吸出。为避免被异物颗粒或设备的破片的任何污染,执行另外的筛分(筛子:700 μm)。
该步骤在微粉化之后和包装之前手动进行。
获得的匀质产物的粒度分析根据粒度分布(PSD)方法进行[分析规格:D99 ≤ 30μm]。
实施例8:用于分析的分析方法
A –反相HPLC方法:
一种同时定量靛青和靛玉红的新的反相HPLC方法基于欧洲药典(PharmacopoeiaVol.20, No.1, 2008年1月, P118-119.)、中国药典(2010版, P185)和文献(Chen LW,Liao W, Yang M. Jia DY, He P, Chen SM, Fu CM. Determination of indigo andindirubin in Indigo Naturalis by HPLC. West China Journal of PharmaceuticalSciences, 2008, 23(6), 714-715;Liu ZY, Su ZT, Gao YN, Yang M. Simultaneouslydetermination of indigo and indirubin in Indigo Naturalis by HPLC. ChinaPharmacist 2010, 13(3), 324-326)建立。
色谱系统(Agilent 1200系列)由G1322A除气器、G1211A泵、G1367B自动取样器、G1316A柱式加热炉和G1315B DAD检测器组成。其它设备包括SK7200H超声波装置(中国)和Milli-Q水纯化系统(USA)。
6批青黛从中国的3个供应商收集。靛青标准品购自Tokyo Chemical IndustryCo. (日本, >98%)。色胺酮购自Accela Co. (中国, 97%)。靛玉红在HutchisonMedipharma (HMP)合成和重结晶(>99%,HPLC)。
有机滤膜(0.45μm, 中国)、二甲基甲酰胺(DMF, 分析级)、甲醇(HPLC级)、甲酸(FA, HPLC级)、三乙胺(TEA, 分析级)和用Milli-Q水纯化系统纯化的超纯水用于实验。
DMF溶液的预处理:用干燥N2吹入500 mL DMF中半小时,然后加入0.5 mL TEA并混合,得到DMF溶液(含有0.1%TEA, 无氧)。这种DMF溶液被用于样品制备。
使50mg青黛悬浮于50mL DMF溶液中。在超声萃取10min后,通过0.45µm注射器滤器过滤悬浮液,以生成青黛的试验溶液。
使20mg青黛干燥萃取物(获自实施例2)悬浮于200mL DMF溶液。在超声萃取后,通过0.45 µm注射器滤器过滤悬浮液,以生成青黛萃取物的试验溶液。
在Waters Symmetry C18柱(5μm, 3.9×150mm)上执行分离。流动相为65%甲醇(含有0.05% FA)。流速是1.0mL/min,持续15min且柱温度是25℃。注射体积是4μL。检测波长是289nm,以致靛青和靛玉红可同时测定。靛青和靛玉红可在一次注射中同时分析。靛青和靛玉红的典型的HPLC色谱图示于图1中。
B - 定量色胺酮的HPLC分析方法:
一种定量色胺酮的新的HPLC分析方法也已建立。样品浓度由于在青黛及其富集产物,干燥萃取物两者中的低浓度的色胺酮而相应调整。分析于25℃,在Waters Symmetry C18柱(5μm, 3.9×150mm)上进行。流动相为甲醇(含有0.05% FA, 洗脱液B)和水(含有0.05% FA,洗脱液A)。梯度洗脱模式如下:50% B等度(12min), 50%-100% B (1min), 100% B等度(6min)和100%-50% B (1min)。流速是1.0mL/min且柱温度是25℃。注射体积是10μL。检测波长是254nm。
使400mg青黛悬浮于20mL DMF溶液中。在超声萃取20min后,通过0.45 µm注射器滤器过滤悬浮液,以提供青黛的试验溶液。
使15mg干燥萃取物(获自实施例2)悬浮于20mL DMF溶液中。在超声萃取后,通过0.45 µm注射器滤器过滤悬浮液,以提供干燥萃取物的试验溶液。
色胺酮、青黛和精制萃取物的典型的HPLC色谱图示于图2中。
2.精制青黛萃取物在生物化学和细胞测定中的体外评价
实施例9:体外测定和结果
A. 一般试剂:
DMSO, Sigma-Aldrich, St. Louis, MO, Cat. No. D2650 Janus激酶1(JAK1), LifetechnologiesTM, Cat. No. PV4774 Janus激酶1(JAK2), Life technologiesTM, Cat.No. PV4210 Janus激酶1(JAK3), Life technologiesTM, Cat. No. PV3855 CDK1, LifetechnologiesTM, Cat. No. PV3292 CDK2, Life technologiesTM, Cat. No. PV3267CDK5, Life technologiesTM, Cat. No. PV3000 Z'-LYTE®激酶测定试剂盒 - 酪氨酸6肽, Life technologiesTM, Cat. No. PV4122 Z'-LYTE®激酶测定试剂盒 - Ser/Thr 12肽, Life technologiesTM, Cat. No. PV3673 Dulbecco改良Eagle培养基(DMEM), LifetechnologiesTM, Cat. No. C11965 RMPI-1640, Life technologiesTM, Cat. No.A10491 胎牛血清(FBS), Life technologiesTM, Cat. No. 10099141 EpiLife ®Medium, Life technologiesTM, Cat. No. M-EPI-500-CA HKGS, Life technologiesTM,Cat. No. S-001-5 重组人IL-2, Peprotech Inc, Cat. No. 200-02 重组人IL-6,Peprotech Inc, Cat. No. 200-06
重组人IL-3, Peprotech Inc, Cat. No. 200-03
重组人GM-CSF, Peprotech Inc, Cat. No. 300-03
重组人IL-22, Peprotech Inc, Cat. No. 200-22 重组人TNFα, R&D, Cat. No.210-TA-010 脂多糖(LPS), Calbiochem, Cat. No. 437650 抗-人CD3功能级® Purified(aCD3) (克隆:OKT3) eBioscience, Cat. No. 16-0037-85 抗-人CD28功能级®Purified (aCD28) (克隆:CD28.2), eBioscience, Cat. No. 16-02897-85 磷酸-STAT3(Y705)抗体(兔-抗-人), Cell Signaling Technology, Cat. No. 9145 磷酸-STAT5(Y694)抗体(兔-抗-人), Cell Signaling Technology, Cat. No. 9359 肌动蛋白抗体(小鼠-抗-人) Sigma-Aldrich, Cat. No. A1978 山羊抗-兔IgGAlexa 488, LifetechnologiesTM, Cat. No. A11034 山羊-抗-兔IROYE 800CW, Li-COR Bioscience, Cat.No. 926-32211 山羊-抗-小鼠IROYE 800CW, Li-COR Bioscience, Cat. No. 926-32210人IFNγ ELISA试剂盒, R&D, Cat. No. DY285 人TNFα ELISA试剂盒, R&D, Cat. No.DY210 人IL-1β ELISA试剂盒, R&D, Cat. No. DY201 人IL-6 ELISA试剂盒, R&D, Cat.No. DY206 噻唑基蓝四唑鎓蓝(MTT), Sigma-Aldrich, Cat. No. M2128 CellTiter-Glo®发光细胞存活测定, Promega, Cat. No. G7572 CytoTox-ONE™均质膜完整性测定,Promega, Cat. No. G7891 萤光素酶测定, Promega, Cat. No. E4550 iBlot®Transfer Stack, Regular (硝化纤维素), Life technologiesTM, Cat. No. IB3010-01碘化丙锭, Sigma-Aldrich, Cat. No. P4170 核糖核酸酶A, Sigma-Aldrich, Cat. No.R6513 1XPBS缓冲液(1L): NaCl 8.0g, KCl 0.2g, Na2HPO4-12H2O 3.58g, KH2PO4 0.24g,溶于1L MilliQ ddH2O, pH调整至7.4 1xSDS加样缓冲液:50 mM Tris-HCl/pH8.8, 2%SDS, 10%甘油, 0.1%溴酚蓝,100 mM DTT。
B. 细胞和细胞系
HepG2,人肝细胞癌细胞系,购自上海生命科学研究院(SIBS) (上海,中国, Cat. No.TCHu 72),在含有10% FBS的DMEM中培养。
于37℃、5% CO2下,将TF1,人红白血病细胞系,购自美国组织培养物保藏中心(American Tissue Culture Collection) (ATCC) (Manassas, VA, Cat. No. CRL-2003™),在含有10% FBS和2ng/mL GM-CSF的RMPI-1640中培养。
PBMC:在肝素化管中收集来自健康成人供体的正常人血样。每个独立的实验使用来自单个健康供体的血液。单核细胞(PBMC)依据生产商建议的方案,使用Ficoll-PaquePlus试剂(Amersham Pharmacia Biotech, Sweden, Cat. No. 17-1440-02)分离,并于37℃、5% CO2下,在含有10% FBS的RMPI-1640中培养。
原代T细胞:单核细胞(PBMC)依据生产商建议的方案,使用Ficoll-Paque Plus试剂(Amersham Pharmacia Biotech, Sweden, Cat. No. 17-1440-02)分离。然后细胞通过使用抗-CD3 (1µg/mL)和抗-CD28 (5µg/mL)激活3天,并在进行实验之前,于37℃、5% CO2下,每2-3天在含有10% FBS和10ng/mL IL-2的RMPI-1640中扩增,持续2周。
HaCaT,一种人表皮角质化细胞系,由YuYiZhi教授(第二军医大学(The SecondMilitary Medical University) (SMMU), 中国)友好馈赠,在含有10% FBS的DMEM中培养。
HEKa,从成人皮肤分离的人表皮角质化细胞,购自Life technologiesTM(Carlsbad, CA, USA, Cat. No. C-005-5C),并于37℃、5% CO2下,在含有HKGS的EpiLife®培养基中培养。
293/NFkB-Luc细胞系购自Panomics (Fremont, CA, Cat. No. RC0014)。其通过用pNFĸB-Luc和pHyg共转染至人胚胎肾293细胞中,接着由潮霉素选择而获得。细胞在含有10% FBS和100µg/mL潮霉素B (Life technologiesTM, Cat. No. 10687-010)的DMEM中培养。
C. 激酶测定
JAK1/2/3激酶测定使用重组人JAK1/2/3和Z'-LYTE®激酶测定试剂盒-酪氨酸6肽在体外进行。CDK1/2/5激酶测定使用重组人CDK1/2/5和Z'-LYTE®激酶测定试剂盒-Ser/Thr 12肽在体外进行。所有反应(20µL)通过加入在4% DMSO溶液中的2.5µL阳性对照品(CP-690550,用于JAK激酶测定,而星孢菌素(Staurosporine)用于CDK激酶测定)或试验物品(即,样品)、5µL激酶/肽底物混合物或磷酸-肽溶液、2.5µL ATP溶液(100µM)或1.33 x激酶缓冲液启动。混合384-孔测定板(Corning, Cat. No. 3575)并在室温孵育1小时。然后将5µL的显色溶液加入各孔,混合并在室温下孵育另外1小时。然后通过加入5µL终止试剂停止激酶反应,接着使用Perkin-Elmer Victor III (Perkin-Elmer Life Sciences, Boston,MA)板读出仪记录450nm和520nm的荧光。
D. Acumen测定
对于IL-6诱发的STAT3磷酸化,将HepG2以每孔5.4x103个细胞接种到96孔板中,在无血清DMEM培养基中于37℃, 5% CO2下过夜。在与CP-690550或试验物品孵育30分钟后,通过加入100ng/mL人重组IL-6 (1:10)至各孔刺激细胞15分钟。
对于IL-3诱发的STAT5磷酸化,于37℃、5% CO2,将TF-1以每孔1x104个细胞接种于96-孔板3小时。在与CP-690550或试验物品孵育30分钟后,通过加入100ng/mL人重组IL-3(1:10)至各孔刺激细胞30分钟。
然后于室温下,将HepG2或TF1细胞在2%多聚甲醛中固定45分钟并在冰冷的甲醇中孵育30分钟。用PBS洗涤后,将细胞分别用抗-磷酸-STAT3 (Y705)或抗-磷酸-STAT5 (Y694)抗体于4℃下孵育过夜。加入山羊抗-兔IgG Alexa 488第二抗体90分钟,然后PBS洗涤。在含有7.5µM碘化丙锭和100µg/mL核糖核酸酶A的PBS中,在黑暗中孵育60分钟后,对细胞计数。在Acumen X3仪器(TPP Labtech, Hertfordshire SG8, UK)上读板。
E. 蛋白质印迹法
于37℃、5% CO2下,将HEKa以2x105个细胞/孔接种到6-孔板过夜。与试验物品一起孵育30分钟后,用100ng/mL IL-22刺激细胞30分钟。
处理后,在1xSDS加样缓冲液中收集样品。煮沸蛋白样品15分钟并于4℃以14,000离心10 min收集。使用上清液或于-80℃立即贮存。对于蛋白质印迹法分析,样品在10%Tris-HCL梯度电泳凝胶(Bio-Rad Laboratories)上分离。将凝胶印迹至iBlot® TransferStack, Regular (硝化纤维素)上,后者以5%脱脂奶粉封闭,且于4℃分别用抗-磷酸-STAT3(Y705)抗体或抗-肌动蛋白抗体探测过夜。然后将膜与适当的IDRye 800CW第二抗体一起孵育,接着使用Odyssey红外成像系统(Li-COR Bioscience, Lincoln, NE, USA)检测。
F. 报道基因测定
对于报道基因测定,将293/NFĸB-Luc以每孔4x104个细胞接种于96-孔板过夜。在与穿心莲内酯(LGT)或试验物品一起孵育30分钟后,通过加入100ng/mL TNFα (1:10)至各孔刺激细胞6小时。细胞溶胞产物通过除去培养基并加入裂解缓冲液制备。将5x体积的萤光素酶测定试剂加入各孔,然后读板。使用Perkin-Elmer Victor III板读出仪(Perkin-ElmerLife Sciences, Boston, MA, USA)记录发光。
G. ELISA测定
原代T细胞以8x104个细胞/孔接种于96-孔板。将试验物品加入到培养物中并于37℃、5% CO2下孵育。30分钟后,将各孔中的细胞悬浮液转移至另一个用CD3 (1µg/mL)和CD28 (5µg/mL)包被的96-孔板中,并于37℃、5% CO2下孵育22小时。除去培养基并于-80℃贮存直至被测定。按照制造商的指示,使用市售的ELISA试剂盒(R & D Systems)测定IFNγ浓度。
将PBMC以每孔3x104个细胞接种到96-孔板。然后将试验物品加入培养物中并于37℃、5% CO2下孵育。30分钟后,将1µg/mL LPS (1:10)加入培养物中。为了定量蛋白水平,将板孵育18小时。除去培养基并于-80℃贮存直至被测定。按照制造商的指示,使用市售的ELISA试剂盒(R & D Systems)测定TNFα、IL-1β和IL-6浓度。
H. MTT测定
将HaCaT以4x104个细胞/孔接种到96-孔板过夜。然后将星孢菌素或试验物品加入培养物中并于37℃、5% CO2孵育72小时。除去培养基后,使在96-孔板中的细胞暴露于100µL MTT(每孔0.5mg/mL,在含有10% FBS的DMEM中),并于37℃、5% CO2下孵育3小时。随后,移去上清液并将150µL DMSO加入各孔。在暗处孵育板10分钟并立即使用Multiskan MK3微板读出仪(Thermo Life Sciences, HK, 中国)记录在492 nm的吸光度。
I. 细胞存活测定
CellTiter-Glo®发光细胞存活测定试剂盒被用来研究细胞存活。将HEKa以1x104个细胞/孔接种到96-孔不透明壁板过夜。然后将地蒽酚或试验物品加入培养物中并于37℃、5%CO2下孵育48小时。用等于在各孔中存在的细胞培养基的体积的CellTiter-Glo®试剂裂解细胞,并混合内含物2分钟以诱导细胞裂解。在室温下孵育板10分钟以稳定发光信号。使用Perkin-ElmerVictor III板读出仪(Perkin-Elmer Life Sciences, Boston, MA, USA)记录发光。
J. LDH释放测定
乳酸脱氢酶(LDH)释放测定试剂盒被用来研究细胞毒性。将HEKa以4x104个细胞/孔接种到96-孔不透明壁板过夜。然后将地蒽酚或试验物品加入培养物中并于37℃、5% CO2下孵育24小时。制备上清液和细胞溶胞产物。将等于上清液或细胞溶胞产物体积的1x体积的CytoTox-ONE™试剂加入各孔,接着混合30秒并于25℃孵育10分钟。将等于上清液或细胞溶胞产物的50%体积的终止溶液加入各孔以终止反应,并使用SpectraMax M2 (MolecularDevices, Sunnyvale, CAL, USA)记录具有560nm的激发波长和590nm的发射波长的荧光。
K. TNFα-诱导的NFκB激活(hmp 2.3.2.1, table 22)
促炎细胞因子和趋化因子在牛皮癣的发病机理中起着重要作用。NFκB清楚地为促炎细胞因子和趋化因子基因表达的最重要的调节子之一。因此,青黛(Qing Dai)及其精制萃取物对TNFα-依赖的NFκB激活的抑制效力在HEK 293/NFκB-Luc中研究。如于表1中所示,TNFα刺激NFκB-依赖的萤光素酶表达和用雷公藤糖苷(Tripterygium Glycoside)预处理细胞以浓度依赖性方式阻断NFκB激活。青黛精制萃取物在实验条件下对TNFα-依赖的NFκB激活具有微克/g活性(见表1)。
L. IC
50
测定
所有的IC 50 值通过使用得自ID Business Solutions (Guildford, UK)的Xlfit™软件(2.0版本)测定。背景在仅用DMSO处理的细胞的培养物中定义,并对于IC50的计算将其减去。
M. 结果
一些青黛精制萃取物的一些体外测定结果示于下表1中,其中青黛A获自DelongPharmaceutical: (靛青2.62%、靛玉红0.284%;色胺酮0.0046%)。
表1
** 青黛A:来自Delong Pharmaceutical的青黛:靛青2.62%、靛玉红0.284%;色胺酮0.0046%
3.精制青黛萃取物在动物模型中的体内评价
实施例10:体内测定和结果
A. 材料和方法
动物
BABL/c小鼠,雄性,体重19~22g,购自上海SLC动物中心 室温:24±1℃ 室内相对湿度:40-70% 光循环:12-小时光照(8:00-20:00) 12-小时黑暗的荧光灯 动物收养:4只小鼠/笼食物:自由接近食物(经照射,Shanghai SLAC Laboratory Animal Co. Ltd., 中国) 水:自由接近当地供应的自来水(首先通过Molanimal超纯水处理机自市政府自来水过滤)
仪器
MJ Research PTC-200 Peltie热循环仪(Alpha UnitTM Block Assembly,用于PTCDNA EngineTM Systems) Applied BioSystems 7500实时PCR系统 数显千分卡尺:Mitutoyo, 日本。精度:0.001mm
试剂
重组小鼠IL-22 (rmIL-22), Novoprotein (sinobio), Cat. C047, Lot. 0375351高容量cDNA逆转录试剂盒, Applied BioSystems, Part no.:4368813, Lot:0909069Thermo Scientific ABsolute SYBR Green Rox Mix, Thermo Scientific, Cat: AB-1163/A, Lot:0911/16
阳性对照
Protopic® (他克莫司, FK506), 0.1%软膏剂, Astellas Toyama Co., Ltd.Toyama Plant,H20100079, Lot:028680。
剂量方案
在诱发模型后1小时,将不同的浓度的试验样品、媒介,或0.1% FK506软膏剂以1%局部给予,然后从第1天至第11天每天给予,每天两次。给予试验物品的第一天被视为第0天。
给药途径
局部应用,b.i.d。
IL-22诱发的牛皮癣-样小鼠模型的建立
将20µL PBS,单独或者含有100或500ng重组小鼠IL-22 (eBiosience),使用30-号针,每隔一天皮内注射给予麻醉小鼠的耳朵,持续11天。在第0天注射之前和此后没有注射的天数,测量耳的厚度。耳部测量在耳朵的中部使用数显千分卡尺(Mitutoyo)进行。
在最后IL-22处理后24小时,处死小鼠,并收集耳朵供进一步的分析。
组织学检查
在尸体解剖时收集耳朵,在10%缓冲的福尔马林磷酸盐中固定,以石蜡包埋,切片,并用苏木精/伊红(H&E)染色。显微镜切片通过损伤的数量和严重性分级。
统计方法
耳部厚度数据的结果表示为均值 ± S.E.M。耳部肿胀的AUC用从第0天至第11天的耳部厚度数据计算,并用JMP®软件通过重复-测量的ANOVA方法分析。细胞因子蛋白和基因表达数据用单向ANOVA评估,接着student’s t-检验用于事后分析(显著性水平设定为p <0.05)。
分组和剂量
见图3。
结果
一些青黛精制萃取物的一些体内测定结果示于表2。
表2
*青黛B:来自Qingfeng Pharmaceutical的青黛:靛青2.02%、靛玉红0.216%;色胺酮0.0032%
4. 含有精制青黛萃取物的药用组合物的制备
实施例11:制剂A (青黛软膏剂)
相 | 组成 | % w/w |
A | Olea Europaea果油(橄榄油) | 81.873 |
A | 丁羟甲苯(BHT) | 0.10 |
A | 依据实施例6制备的精制青黛萃取物* | 0.027 |
B | 蜂蜡(白色) | 9 |
B | 白凡士林 | 9 |
* HPLC:79.26%靛玉红,6.15%靛青,和0.62%色胺酮。
制备方法:
步骤1:精制青黛萃取物、橄榄油和BHT被搅拌并于90℃加热至少20分钟,以获得匀质制备物。该混合物构成相A。
步骤2:蜂蜡(白色)和白凡士林于90℃被加入相A并搅拌至少20分钟,直至混合物被匀化。
步骤3:将来自步骤2的匀质混合物冷却至55℃,同时搅拌。
步骤4:将步骤3的内容物维持于55℃且成品被填充至包装中。
初始(T=0)规格:
宏观方面:匀质化和粘性紫红色软膏剂
物理稳定性:
化学稳定性:
青黛软膏剂的化学稳定性已通过靛玉红的化学测定来评估。
青黛软膏剂中的靛玉红使用反相高效液相色谱(HPLC)测定,结果表示为靛玉红在青黛软膏剂中的mg/g。
结果显示青黛软膏剂在RT、30℃和40℃下是物理和化学稳定3个月的。
化学稳定性被定义为≥90% T0值的测定值。
物理稳定性被定义为与初始观察没有显著变化。
实施例12:制剂B
相 | 组成 | % w/w |
A | 辛酸/癸酸三甘油酯 | 69.973 |
A | 依据实施例6制备的精制青黛萃取物* | 0.027 |
A | 甘油二山嵛酸酯(和)三山嵛精(和)甘油山嵛酸酯 | 6 |
A | 氢化蓖麻油 | 3 |
A | 甘油硬脂酸酯 | 6 |
B | PPG-15硬脂基醚 | 15 |
* HPLC:79.26%靛玉红,6.15%靛青,和0.62%色胺酮。
制备方法:
步骤1:精制青黛萃取物被加入到辛酸/癸酸三酸甘油酯中,于90℃加热并混合至少20分钟,以获得匀质化制备物。
步骤2:将甘油二山嵛酸酯(和)三山嵛精(和)甘油山嵛酸酯、氢化蓖麻油,和甘油硬脂酸酯加入步骤1的内容物中。使混合物维持于90℃并搅拌至少10分钟直至匀化。
步骤3:使步骤2的内容物(相A)在搅拌下冷却至55℃。
步骤4:于55℃下,将相B (PPG-15硬脂基醚)加入到相A中,同时于55℃下搅拌至少10分钟直至匀化。
步骤5:冷却步骤4的内容物,同时搅拌直至混合物达到室温。
5. 依据实施例11的软膏剂制剂(制剂A)的体外经皮肤吸收
本研究比较了以两种含有青黛萃取物的不同软膏剂配制的靛玉红在离体人皮肤中的皮肤吸收和分布。
一种软膏剂(软膏剂1)公开于本发明的实施例11 (制剂A),而另一种软膏剂(软膏剂2)依据现有技术US 2012/213868制备,其含有也依据US 2012/213868制备的青黛萃取物(制剂C)。
两种软膏剂制剂在下表3中说明。
表3
成分(%) | 软膏剂1 (制剂A) | 软膏剂2 (制剂C) |
精制青黛萃取物(实施例6) | 0.027 | - |
青黛萃取物(依据US 2012/213868) | - | 0.02 |
橄榄油 | - | 83.28 |
精制橄榄油 | 81.873 | - |
BHT (抗氧化剂) | 0.1 | - |
蜂蜡 | 9 | 16.7 |
凡士林 | 9 | 0 |
实验程序
体外吸收研究使用安装在扩散池上的分开-厚度人皮肤(厚度范围在0.59和0.91 mm之间)执行。每个条件在4个不同的供体上重复测试4次,每一条件得出总共16个值。
各制剂的10 mg/cm²的剂量以施用面积2 cm²施用于皮肤表面和用含有0.1% (v/v) Tween-80的3 mL磷酸盐缓冲液盐水填充受体隔室。试验系统用设定于37℃的水循环浴维持热稳定,且受体液体以350 rpm连续地搅拌。在静态条件和非光化光下,处理持续时间是24小时。
靛玉红的浓度在包含角质层(stratum corneum)的表皮、真皮、受体液体和制剂过量样品中,使用LC-MS/MS方法测量。定量的限制在所有的基质中是0.05 ng/mL。
结果
靛玉红在皮肤隔室中的释放的结果在表4中呈现,并显示靛玉红的质量平衡对于在软膏剂1和软膏剂2分别表示靛玉红施用的剂量的102%和105%。
无论施用何制剂,靛玉红分布于表皮(包括角质层)、真皮和受体液体。
表4:在24-小时处理期后,靛玉红在分开厚度人皮肤中的释放
(算术均值和SEM;N = 16)
总渗透:在表皮+角质层;真皮和受体液体中回收的总量
括号中的值对应于SEM值。
*几何均值“试验组相对参照组”的比率,其中试验组为软膏剂1和参照组为软膏剂2。
至于软膏剂1,靛玉红在表皮(包含角质层)、真皮和受体液体中分别表现为靛玉红施用剂量的1.60%、0.93%和0.29%。靛玉红的总渗透表现为靛玉红施用剂量的2.82%。
至于软膏剂2,靛玉红在表皮(包含角质层)、真皮和受体液体中分别表现为靛玉红施用剂量的1.51%、0.63%和0.18%。靛玉红的总渗透表现为靛玉红施用剂量的2.32%。
使用生物等效性方式进行统计学分析,且总渗透获得的几何均值比率在上表4中提供。两个几何均值比率超出可接受的区间[80.00% - 125.00%],从而显示出软膏剂1相较于软膏剂2的更高的靛玉红皮肤吸收(基于总渗透的分析(以ng/cm²表示),由软膏剂1递送的靛玉红多49%,见下表5)。
表5
*试验 = 软膏剂1
参照 = 软膏剂2
总之,本发明人令人惊奇地证明靛玉红分布于表皮(包含角质层)、真皮和受体液体(见表4),并且与依据US 2012/213868制剂比较,使用本发明制剂的靛玉红的皮肤吸收显著更高。
Claims (10)
1.一种药用组合物,且包含以下组分:
靛青衍生物:基于活性成分的总重量的0-15% (w/w),
靛玉红衍生物:基于活性成分的总重量的65-90% (w/w),和
药学上可接受的载体。
2. 权利要求1的药用组合物,其还包含基于活性成分的总重量的0.01-5% (w/w),优选0.1-5% (w/w)的量的色胺酮衍生物。
3. 权利要求2的药用组合物,其还包含各自基于活性成分的总重量的0.1-5% (w/w)的量的青黛酮衍生物和/或靛红衍生物。
4. 一种药用组合物,其包含:
- 从0.002%至0.077% (w/w)的青黛的精制萃取物,和
- 药学上可接受的载体,
其中青黛的精制萃取物包含从65%至90% (w/w)的靛玉红和一种或多种选自具有以下量的靛青、色胺酮和青黛酮的衍生物:
- 靛青:精制萃取物的0.1-15% (w/w),
- 色胺酮:精制萃取物的0.01-5% (w/w),优选0.1-5% (w/w),和
- 青黛酮:精制萃取物的0.1-5% (w/w)。
5.前述权利要求的任一项的药用组合物,其中组合物呈现为局部给药或口服给药的形式。
6.前述权利要求的任一项的药用组合物,其用于治疗选自牛皮癣、炎性皮肤病况、甲真菌病、皮肤癌、异常角质化诱导的疾病、皮肤老化、脓疱型皮肤病的疾病或病况。
7.权利要求6使用的药用组合物,其中所述炎性皮肤选自特应性皮炎(AD)、湿症和重复感染的皮肤。
8. 权利要求6使用的药用组合物,其中所述皮肤老化选自皮肤年轻化、疤痕的组织再生和皮肤衰老(skin senescence)。
9.权利要求6使用的药用组合物,其中所述异常角质化诱导的疾病选自痤疮、鱼鳞病和掌跖角化病。
10.权利要求6使用的药用组合物,其中所述皮肤癌选自癌前期皮肤癌,例如,光化性角化病(AK)、鲍恩病;皮肤癌,例如SCC、BCC、NMSC;黑素瘤和HPV诱发的皮肤癌。
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US10668120B2 (en) | 2015-04-09 | 2020-06-02 | Galderma Sa | Antibacterial indigo naturalis or indigo-producing plant extract and use thereof |
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CA2980667A1 (en) | 2016-10-13 |
AU2016245204A1 (en) | 2017-10-12 |
US20190160128A1 (en) | 2019-05-30 |
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EP3209314B1 (en) | 2021-11-10 |
US20170304381A1 (en) | 2017-10-26 |
BR112017021190A2 (pt) | 2018-09-25 |
KR20170132880A (ko) | 2017-12-04 |
BR112017021190B1 (pt) | 2021-12-21 |
TW201701893A (zh) | 2017-01-16 |
AU2016245204B2 (en) | 2021-07-29 |
JP2018510889A (ja) | 2018-04-19 |
US10555985B2 (en) | 2020-02-11 |
WO2016162485A1 (en) | 2016-10-13 |
US20200147163A1 (en) | 2020-05-14 |
TWI737602B (zh) | 2021-09-01 |
US11116811B2 (en) | 2021-09-14 |
JP6749935B2 (ja) | 2020-09-02 |
EP3209314A1 (en) | 2017-08-30 |
MX2017012596A (es) | 2018-01-09 |
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