CN115209890A - 抑制促炎基因表达的紫草素、芳基萘木酚素以及包含它们的药物组合物 - Google Patents
抑制促炎基因表达的紫草素、芳基萘木酚素以及包含它们的药物组合物 Download PDFInfo
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- CN115209890A CN115209890A CN202180017224.1A CN202180017224A CN115209890A CN 115209890 A CN115209890 A CN 115209890A CN 202180017224 A CN202180017224 A CN 202180017224A CN 115209890 A CN115209890 A CN 115209890A
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Abstract
本发明涉及一种或多种芳基萘木酚素,特别是紫草素A,以及包含其的药物组合物。从紫草(聚合草)根的制备物中分离紫草素A,并且发现其通过干扰促炎基因表达来减少炎症。特别地,其抑制白介素1β(IL‑1β)诱导的HUVEC细胞中的E‑选择素表达。
Description
技术领域
本发明涉及一种或多种芳基萘木酚素,本文称为紫草素或紫草素化合物,以及包含它们的药物组合物。所公开的化合物的示例性实施方案可从紫草(聚合草(Symphytumofficinale L.))根分离。紫草素化合物和包含它们的药物组合物的某些实施方案通过干扰促炎基因表达来减少炎症。
背景技术
消费者正在寻找有效和自然的缓解疼痛和抑制炎症的方法。通常称为紫草的聚合草(紫草科(Boraginaceae))是常见于欧洲、亚洲和北美的多年生草本植物(C.Staiger,Phytother Res 26,1441-1448,2012;A.Trifan等人,Food Chem Toxicol 112,178-187,2018)。紫草已经在民间医学中用于治疗腹泻、支气管炎、肺结核、溃疡和痔疮。现在,临床试验已经证明其局部制剂的功效和安全性。与属于紫草科的其他物种一样,紫草含有肝毒性和致癌的吡咯里西啶生物碱(PA)。因此,PA耗尽的提取物用于非处方局部药物中以减少炎症并且用于治疗断骨、肌腱损伤、疼痛性关节、踝关节变形和肌肉(I.Sowa等人,Nat ProdRes 32,605-609,2018,M.Adams等人,J.Ethnopharmacol.121(2009)343-359)。实际上,紫草根的液体水醇提取物在临床上被证明可有效治疗急性上背部和下背部疼痛、关节炎、膝关节病和钝伤(B.Grube等人,Phytomedicine 14,2-10,2007;R.Koll等人,Phytomedicine11,470-477,2004;H.G.Predel等人,Phytomedicine 12,707-714,2005,S.K.Patwardhan等人Int.J.Pharm.Pharm.Sci.,第21卷,第13号,2020,第4671页)。
据报道,紫草根的主要成分包括尿囊素、多酚类(诸如迷迭香酸、丹酚酸、鞣花酸和咖啡酸)以及丰富的由果糖和葡萄糖单元构成的胶浆和多糖(B.Grabias和L.Swiatek,Pharm.Pharmacol.Lett 8,81-83,1998;I.Sowa等人,Nat Prod Res 32,605-609,2018;C.Staiger Phytother Res 26,1441-1448,2012;A.Trifan等人,Food Chem Toxicol 112,178-187,2018)。此外,紫草根已经产生许多齐墩果酸和双糖链三萜皂苷(V.U.Ahmad等人,Phytochemistry 32,1003-1006,1993;F.V.Mohammad等人,Phytochemistry40,213-218,1995)。最近,报道来自聚合草根的水醇提取物的酚类物质含有丹酚酸异构体(A.Trifan等人,Food Chem Toxicol 112,178-187,2018)。紫草根还含有具有1,2不饱和千里光次碱结构的肝毒性吡咯里西啶生物碱(PA),包括石胺松、印美定碱、它们的乙酰基和N-氧化物衍生物以及聚合草素(R.A.Coulombe,Adv.Food Nutr.Res.45,61-99,2003;F.Liu等人,Talanta80,916-923,2009;A.Trifan等人,Food Chem Toxicol 112,178-187,2018)。
目前,在欧洲市场上商业化的来自紫草根的医用产品仅含有来自吡咯里西啶耗尽的植物材料的提取物(WO2017/068175A1;WO2018/224518A1)或从不合成吡咯里西啶生物碱的特殊载培品种获得(A.Trifan等人,Food Chem Toxicol 112,178-187,2018)。
尽管在临床研究中已经证实紫草的抗炎和止痛性质,但与这些治疗活性相关的生物活性化合物尚未鉴定。因此,本发明的目的是提供对紫草根的化学组成的更好理解,并且初步了解其特定代谢物对抗炎活性的贡献。
发明内容
本发明涉及一种或多种芳基萘木酚素,所述芳基萘木酚素具有如下式I所示的通式结构。
其中每个R1、R2、R3和R4独立地选自氢、羟基、甲基、甲氧基、乙氧基、丙氧基、丁氧基或戊氧基;并且其中R5选自羟基、甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、阿魏酰基、咖啡酰基、香豆酰基、异戊二烯氧基或异戊烯氧基残基。具体地,本发明涉及一种芳基萘木酚素,命名为紫草素A(comfreyn A),其中R1、R2、R3和R4各自为羟基,并且R5为乙氧基,如式II所示
本发明还涉及一种药物组合物,所述药物组合物包含安全有效量的如本文所公开的一种或多种芳基萘木酚素中的至少一者和药学上可接受的载体。特别地,药学上可接受的载体可以是用于局部施用的载体。除此之外或另选地,药学上可接受的载体可以是用于内部施用的载体。
本发明还涉及安全有效量的如本文所公开的一种或多种芳基萘木酚素和包含它们的药物组合物,其用于减少和/或治疗炎症,优选用于治疗断骨、肌腱损伤、疼痛性关节和肌肉、急性上背部和下背部疼痛、膝关节病、钝伤、用于减少关节变形的肿胀、用于改善骨关节炎关节中的关节活动性和/或它们的组合。具体地,通过干扰(阻断或减少)促炎基因表达来实现炎症的减少和/或治疗。
本发明还涉及一种药物组合物,所述药物组合物包含一种或多种称为紫草素的芳基萘木酚素,并且特别是紫草素A,作为药物载体中的活性剂,其中药物制剂还可包括渗透增强剂或任何其他功能性或非功能性赋形剂。在一个优选的实施方案中,药物组合物包含3μg/g组合物至5μg/g组合物的量的紫草素A以及5μg/g组合物至7.5μg/g组合物的量的附加任选的活性咖啡酸乙酯,其中药物载体至少包含功能性和非功能性局部赋形剂。
本发明还涉及通过局部施用和/或内部施用安全有效量的如本文所公开的一种或多种称为紫草素的芳基萘木酚素,并且特别是紫草素A或者安全有效量的一种或多种紫草素,并且特别是紫草素A与安全有效量的咖啡酸乙酯的组合来减少和/或治疗炎症的方法。
在一个实施方案中,公开该方法,该方法用于
·治疗断骨、肌腱损伤、疼痛性关节和肌肉、急性上背部和下背部疼痛、膝关节病、钝伤;
·减少关节变形的肿胀;
·改善骨关节炎关节中的关节活动性;和/或它们的组合,
通过局部施用和/或内部施用安全有效量的一种或多种称为紫草素的芳基萘木酚素,特别是紫草素A或者安全有效量的一种或多种紫草素,特别是紫草素A与安全有效量的咖啡酸乙酯的组合来减少和/或治疗炎症。
在另一个实施方案中,提供通过局部施用和/或内部施用安全有效量的一种或多种紫草素,特别是紫草素A,或者安全有效量的一种或多种紫草素,特别是紫草素A与安全有效量的咖啡酸乙酯和/或如本文所公开的其他附加活性剂的组合,通过干扰(阻断或减少)促炎基因表达来抑制和/或治疗炎症的方法。
本发明还涉及试剂盒,所述试剂盒包含安全有效量以及说明书使用的如本文所公开的药物组合物,所述药物组合物包含如本文所公开的一种或多种芳基萘木酚素,特别是紫草素A,或如本文所公开的一种或多种芳基萘木酚素,特别是紫草素A加上咖啡酸乙酯。
附图说明
图1示出聚合草根的水醇液体提取物在负离子模式下的LC-MS曲线;
图2示出从聚合草根分离的20种主要化合物的结构;
图3示出通过LC-ESI-HR-MS和LC-ESI-HR-MS/MS从聚合草根鉴定的次级代谢物的列表;
图4示出在图2中示出为化合物15的紫草素A的高分辨率MS光谱;并且
具体实施方式
消费者正在寻找有效和自然的缓解疼痛以及抑制和减少炎症的方法。如本文所公开的芳基萘木酚素紫草素A分离自聚合草根,并且显示在用5ng/mL IL-1β刺激90min后抑制内皮细胞中E-选择mRNA的表达。由此,实现炎症反应的减少。因此,本发明涉及一种或多种紫草素、包含它们的药物组合物以及它们在治疗炎性病症和疾病,特别是与促炎基因表达相关的那些中的医学用途。
虽然本说明书通过特别指出并清楚地要求保护本发明的权利要求书作出结论,但据信通过以下实施方案的说明结合附图将更好地理解本发明,其中相同的附图标号表示相同的元件。
本文所用的单位“cm”是指厘米;本文所用的单位“mm”是指毫米;本文所用的单位“μm”或“微米”是指微米;本文所用的单位“nm”是指纳米。本文所用的单位“g”是指克;本文所用的单位“mg”是指毫克。本文所用的单位“mL”或“ml”是指毫升;本文所用的单位“μL”或“μl”是指微升。本文所用的单位“min”是指分钟,本文所用的单位“sec”是指秒。本文所用的单位“mM”是指毫摩尔/升;本文所用的单位“μM”是指微摩尔/升。除非另外指明,否则如本文所用,术语“wt%”和“w/w%”意指按重量计的百分比,并且通常下文所用的所有百分比和比率均按总局部用组合物的重量计。
除非另外指明,否则本文提及成分的所有百分比、比率、水平和浓度均基于该成分的实际量,并且不包括在可商购获得的产品中可与这些成分组合使用的溶剂、填充剂或其他材料。
除非另外指明,否则本文提及的所有测量均在约22℃(即室温)处进行。
如本文所使用,单词“约”指+/-10%。
如本文所用,词语“或”当用作两个或更多个元素的连词时,是指包括单独的所述元素或所述元素的组合;例如X或Y,是指X或Y或两者。
如本文所用,冠词“一个”和“一种”被理解为受权利要求书保护的或描述的一种或多种材料,例如,“活性物质”或“溶剂”。
如本文所用,单词“包含”及其变体旨在是非限制性的,使得列表中条目的叙述不排除其它也可能在本发明的材料、口服组合物、装置和方法中有用的类似条目。该术语包括“由...组成”和“基本上由...组成”。
如本文所用,单词“包括”及其变体旨在是非限制性的,使得列表中条目的叙述不排除其它也可能在本发明的材料、局部用组合物、装置和方法中有用的类似条目。
如本文所使用,单词“优选的”、“优选”和它们的变体是指在特定环境下能够提供特定有益效果的本发明的实施方案。然而,其他实施方案在相同或其它的环境下也可为优选的。此外,一个或多个优选实施方案的表述并不表示其他实施方案是不可用的,并且不旨在从本发明的范围中排除其他的实施方案。
可用于本文中的“活性物质”、“活性剂”和“其他成分”可根据其美容和/或治疗有益效果或其假定的作用或运行模式来在本文中分类或描述。然而应当理解,在一些情况下,可用于本文的活性物质和其他成分可提供多于一种的美容和/或治疗有益效果,或经由多于一种的作用模式起作用或运行。因此,本文的分类只是为了方便起见,而并不旨在将成分限制在所列的具体指定的功能或活性。
如本文所用,“安全有效量”是指在合理的医学判断范围内,组分的量足够高以显著(明确地)改变待治疗的病症或影响期望结果,但又足够低以避免严重副作用(处于合理的效/险比)。组分的安全有效量取决于待处理的具体病症、待处理患者的年龄和生理状态、病症的严重程度、处理周期、协同处理的性质、使用的具体形式和应用组分的具体载体。
如本文所用,术语“施用”、“施予”和“施以”是指在可靠的医学实践中以提供治疗效果的方式向受试者递送组合物的任何方法。
如本文所用,“药物”是指如药剂的药物,包括处方药物、非处方药物、柜台后药物、以及它们的组合。在一些示例中,药物可为补充剂。
紫草素
本发明涉及一种或多种芳基萘木酚素,下文命名为紫草素。如所要求保护的一种或多种紫草素的化学结构如式I所示。
其中每个R1、R2、R3和R4独立地选自氢、羟基、甲基、甲氧基、乙氧基、丙氧基、丁氧基或戊氧基;并且其中R5选自羟基、甲氧基、乙氧基、丙氧基、丁氧基、戊氧基、阿魏酰基、咖啡酰基、香豆酰基、异戊二烯氧基或异戊烯氧基残基。如所要求保护的一种或多种紫草素被确立为带有不寻常δ-内酯环的芳基萘木酚素,对应于香豆素骨架,并且是天然存在的化合物,因为对于R1至R5所要求保护的所有侧基存在天然合成途径。
在一个优选的实施方案中,本发明涉及芳基萘木酚素,下文命名为紫草素A,其中R1、R2、R3和R4中的每一者为羟基,并且其中R5为乙氧基基团。化学结构如式II所示
并且对应于图2的化合物15。
除此之外或另选地,本发明涉及如本文所要求保护的一种或多种紫草素的治疗活性,特别是涉及紫草素A的治疗活性。显示紫草素A通过干扰促炎基因表达,诸如抑制IL-1β刺激的人静脉内皮细胞(HUVEC)中的E-选择素表达来减少炎症(表2)。E-选择素是NF-κB依赖性靶基因,并且IL-1β是充分描述的促炎介质,其在免疫和炎症反应,特别是涉及无菌损伤诸如创伤和钝伤的那些的调节中发挥重要作用。在一个实施方案中,使用如本文所公开的一种或多种紫草素,特别是使用紫草素A,将E-选择素活化抑制至少30%,优选至少40%,更优选至少45%,更优选至少48%,甚至更优选至少50%。除此之外或另选地,如本文所公开的一种或多种紫草素的局部有效浓度,特别是抑制体外E-选择素活化的紫草素A的局部有效浓度低于70μM,优选低于60μM,更优选约50μM。
本发明还涉及使用如本文所公开的一种或多种紫草素的抗炎活性,特别是经由干扰促炎基因表达使用紫草素A的抗炎活性来抑制和/或治疗炎症。不希望受理论束缚,如本文所公开的一种或多种紫草素的抗炎活性,特别是基于抑制促炎基因表达的紫草素A的抗炎活性可通过在需要其的位置处施加一种或多种紫草素,特别是通过施加安全有效量,优选以提供约30μM至约65μM的局部浓度的量,更优选以提供约40μM至约60μM的局部浓度的量,更优选以提供约45μM至约55μM的局部浓度的量,甚至更优选以提供48μM至52μM紫草素A的局部浓度的量的紫草素A来用于治疗断骨、肌腱损伤、疼痛性关节和肌肉、急性上背部和下背部疼痛、膝关节病、钝伤、用于减少关节变形的肿胀、用于改善骨关节炎关节中的关节活动性和/或它们的组合。
在一个优选的实施方案中,合适的组合物包含1μg/g组合物至10μg/g组合物的量,特别是2μg/g组合物至7.5μg/g组合物的量,以及甚至更具体地3μg/g组合物至5μg/g组合物的量的紫草素A,其中合适的单剂量为3g至5g组合物并且建议每天施用至少三次。
附加活性剂
除此之外或另选地并且根据如本文所公开的本发明,一种或多种紫草素活性剂,特别是紫草素A可与附加活性剂组合。根据本发明的合适的附加活性剂优选为止痛药、具有抗炎活性的活性剂、活性增强剂或它们的组合。在一个优选的实施方案中,将经由干扰如本文所公开的促炎基因表达的附加活性剂的抗炎活性抑制至少30%、优选至少40%、更优选至少45%、更优选至少48%、甚至更优选至少50%。除此之外或另选地,抑制促炎基因表达的附加活性剂的有效浓度低于70μM、优选低于60μM、更优选低于50μM、更优选低于40μM、更优选低于30μM以及甚至更优选低于25μM,如通过体外实验所示。
化学止痛药的非限制性示例可包括APAP、布洛芬(ibuprofen)、酮洛芬(ketoprofen)、双氯芬酸(diclofenac)、萘普生(naproxen)、阿司匹林(aspirin)以及它们的组合。在一个示例中按组合物的重量计约0.5%至约3.5%的止痛药可用作附加活性剂,按组合物的重量计,在另一个示例中,可使用约1%至约3%的止痛药,并且在另一示例中,可使用约1.5%至约2%的止痛药。例如,剂量可包含325mg至500mg APAP、200mg布洛芬、200mg萘普生或它们的组合。
在一个优选的实施方案中,附加活性剂是天然止痛药,特别是从聚合草中提取,更具体地从聚合草根中提取的天然止痛药。不希望受理论束缚,据信多于一种活性剂,特别是从聚合草根中提取的多于一种活性剂的组合可增加抗炎活性。在一个优选的实施方案中,将一种或多种紫草素,特别是紫草素A与一种或多种选自以下项的附加活性剂组合:尿囊素、对羟基苯甲酸葡糖苷、5-羟甲基-2-糠醛、原儿茶酸、原儿茶醛、对羟基苯甲酸、咖啡酸、globoidnan B、malaxinic酸、3-羧基-6,7-二羟基-1-(3',4'-二羟基苯基)-萘、(+)-香茶菜素、迷迭香酸、羟基咖啡酸、globoidnan A、咖啡酸乙酯、三叶木酚素D(ternifoliuslignanD)、亚麻酸、亚油酸和羟基棕榈酸。特别地,将紫草素A与一种或多种选自以下项的附加活性剂组合:globoidnan B、malaxinic酸、globoidnan A、咖啡酸乙酯、三叶木酚素D、3-羧基-6,7-二羟基-1-(3',4'-二羟基苯基)-萘和香茶菜素。
在一个优选的实施方案中,将一种或多种紫草素,特别是紫草素A与一种或多种附加活性剂组合,所述附加活性剂包含以下项或由以下项组成:咖啡酸乙酯、malaxinic酸和globoidnan A或它们的组合。更优选地,将紫草素A与咖啡酸乙酯组合。在一个实施方案中,使用咖啡酸乙酯将促炎基因表达抑制至少30%、优选至少40%、更优选至少50%、更优选至少60%、更优选至少65%以及甚至更优选70%。除此之外或另选地,抑制促炎基因表达的咖啡酸乙酯的有效浓度低于80μM、优选低于70μM、更优选低于65μM,如体外实验所示。
咖啡酸乙酯可以安全有效量用作如本文所公开的药物组合物中的活性剂。不希望受理论束缚,咖啡酸乙酯的抗炎活性经由抑制促炎基因表达来实现,并且因此,本发明涉及通过施加安全有效量,优选在需要其的位置处提供约50μM至约80μM咖啡酸乙酯的局部浓度的量,更优选在需要其的位置处提供约55μM至约75μM咖啡酸乙酯的局部浓度的量,更优选在需要其的位置处提供约60μM至约70μM咖啡酸乙酯的局部浓度的量,甚至更优选在需要其的位置处提供62μM至66μM咖啡酸乙酯的局部浓度的量的咖啡酸乙酯来抑制和/或治疗炎症,优选用于治疗断骨、肌腱损伤、疼痛性关节和肌肉、急性上背部和下背部疼痛、膝关节病、钝伤、用于减少关节变形的肿胀、用于改善骨关节炎关节中的关节活动性和/或它们的组合。
在一个优选的实施方案中,合适的组合物包含1μg/g组合物至15μg/g组合物的量,特别是2.5μg/g组合物至10μg/g组合物的量,以及甚至更具体地5μg/g组合物至7.5μg/g组合物的量的咖啡酸乙酯,其中合适的单剂量为3g至5g组合物并且建议每天施用至少三次。
药物组合物
本发明涉及一种药物组合物,所述药物组合物包含如本文所公开的一种或多种芳基萘木酚素,特别是如本文所公开的安全有效量的紫草素A和药学上可接受的载体。如本文所用,术语“药学上可接受的载体”包括一种或多种适用于局部或内部施用的相容的固体或半固体或液体赋形剂或稀释剂。如本文所用,“相容的”是指药物组合物的组分能够混合但不会以显著降低组合物的稳定性和/或功效的方式相互作用。
药物赋形剂、载体或稀释剂的选择根据预期的给药途径和标准药学实践来选择。在一些方面,用于本文所述的各种不同组合物的此类合适赋形剂的示例可见于由A Wade和P J Weller编辑的“Handbook of Pharmaceutical Excipients”(第2版,1994年)。在一些方面,可接受的载体描述于例如“Remington's Pharmaceutical Sciences”(MackPublishing Co.,A.R.Gennaro编辑,1985年)中。除了赋形剂、载体或稀释剂之外,此类组合物还可包含附加成分。此类附加成分包括但不限于任何合适的粘结剂、润滑剂、包衣剂、增溶剂、乳化剂、表面活性剂、防腐剂、染料、调味剂、稳定剂、缓冲剂和/或悬浮剂。另外,此类配制物还可包括渗透增强剂或任何其他功能性或非功能性赋形剂。
局部用组合物
如本文所公开的药物组合物可用于局部施用,特别是用于在皮肤处局部施用,即,如本文所用的“局部用组合物”是指在一般使用过程中未用于治疗剂的全身施用目的,但施用于皮肤并在皮肤处保留足够的时间以实现预期目的,例如抑制炎症、缓解疼痛等的产物。
取决于其中成分的类型和量、局部用配制物的所需稠度和预期施用模式,载体材料可包括诸如药理学上可接受的油、水和/或常规地用于局部用配制物,例如用于软膏剂、乳膏和凝胶的常规基质中的此类补充药物佐剂的载体材料。在一些实施方案中,可建议将结构形成剂、增稠剂或凝胶形成剂掺入组合物中。合适的试剂特别是高度分散的硅酸(例如,商业产品“Aerosil”)、膨润土、改性的蒙脱土诸如蒙脱土的烷基铵盐(例如,商业产品“Bentone”)(其中烷基基团可含有1至20个碳原子)(例如二甲基-二烷基铵盐(其中烷基基团含有16至18个碳原子))、有机结构形成剂、增稠剂和悬浮剂,例如黄原胶、角叉菜胶、十八十六醇和/或改性的蓖麻油产品。除此之外或另选地,除了赋形剂、载体或稀释剂之外,此类组合物还可包含附加成分。此类附加成分可包括但不限于任何合适的粘结剂、润滑剂、包衣剂、增溶剂、溶剂、乳化剂、脂质、聚合物、胶凝剂、表面活性剂、渗透增强剂、pH调节剂、缓冲液、防腐剂、染料、调味剂、稳定剂、缓冲剂和/或悬浮剂或芳香剂或螯合剂。
如本文所公开的局部用配制物中单独或作为组合组分施用活性成分的方法将通常涉及施用于受炎症和/或变性影响的区域,或预期受炎症和/或变性影响的区域,或施用于受与所述炎症和/或变性相关的疼痛、肿胀、僵硬和/或活动性缺乏影响或预期受其影响的区域。在某一实施方案中,将活性成分施用于受影响部位周围的区域或预期受影响的区域。例如,活性成分可在本发明的局部用配制物中单独或作为组合组分施用于全部围绕受影响区域或炎症和/或变性的预期区域的区域。局部用配制物将包括但不限于乳膏、凝胶、软膏剂或洗剂,并且可将其涂抹在身体表面上并且轻轻擦入。适用于本发明的方法和用途的炎性和/或退行性病症的类型包括但不限于类风湿性关节炎、脓毒性关节炎、痛风、假痛风、幼年型关节炎、史提尔氏病(Still's disease)、颈椎病、腰椎病、冰冻肩、跟骨骨刺、牛皮癣关节炎、强直性脊柱炎和骨关节炎。
在本发明的某一实施方案中,用于施用的受试者是人。然而,根据本发明的预防性或治疗性治疗的方法还可适用于易患炎性和/或退行性病症的非人受试者,包括但不限于马、狗、猫、兔和/或牛。
剂量方案将取决于许多可容易确定的因素,诸如炎症和/或变性或与所述炎症和/或变性相关的疼痛、肿胀、僵硬和/或活动性缺乏的程度,以及炎症、变性、疼痛、肿胀、僵硬和/或活动性缺乏对治疗的反应性,但通常是每天一个或多个剂量,其中治疗过程持续数天至数月,或者直到实现治愈或受试者经历的炎症、变性、疼痛、肿胀、僵硬和/或活动性缺乏的程度显著降低。普通技术人员可容易地确定最佳剂量、给药方法和重复率。在某一实施方案中,预期局部用配制物将每天施用一次至五次。
如本文所用,“足以提供效果的组合物的量”是指局部用组合物施用于患者、由患者使用或佩戴的量,或者指示患者施用、使用或佩戴每次施用大于约1g、大于约2g、大于约3g、优选约4g、特别是约1、2、3、3.5或4g至约10、8、6、5或4.5g的局部用组合物的量,或任何其他更窄且落入此类更宽数值范围内的数值范围,此类较窄的数值范围似乎都在本文中明确地写出。治疗可根据需要施用并且将取决于期望的效果、所治疗的任何病症的严重程度、使用者的健康状况和年龄及类似考虑因素。通常推荐每天施用三次。在一个实施方案中,一种或多种活性物质,优选一种或多种紫草素活性物质,特别是紫草素A可以1μg/g组合物至10μg/g组合物的量,优选以2μg/g组合物至7.5μg/g组合物的量,以及更优选以3μg/g组合物至5μg/g组合物的量使用。
根据本发明的局部用配制物可以任何常规方式制备,但不限于已知的药物实践。如本文所公开的局部用配制物可以是水性的(即,含有水),或其可以是非水性的并且任选地与封闭覆盖层组合使用,使得在施用于身体表面上之后并且此后从身体表面蒸发的水分保持在配制物内。此外,配制物可在需要或不需要施用绷带或压力垫的情况下直接施用。本发明组合物还可包含例如;免洗型组合物,其中如本文所用,“免洗型”是指旨在施用到并且允许保留在角质组织上的组合物。这些免洗型组合物区别于施用于皮肤并且随后(几分钟内或更短)通过洗涤、淋洗、擦拭等除去的组合物。免洗型组合物不包括洗去型应用,诸如洗发剂、洗面奶、洗手液、沐浴剂或身体沐浴露。
因此,如本文所公开的局部用组合物是“皮肤病学可接受的”,其是指所述组合物或组分适用于与人皮肤组织接触,而没有不适当的毒性、不相容性、不稳定性、变应性应答等。如本文所公开的局部用药物组合物可例如呈软膏剂、油膏剂、糊剂、粘性液体、洗剂、凝胶、乳膏、摩丝、泡沫或任何其他粘合剂产品或它们的组合的形式。
局部用组合物可以是单相组合物或可以是两种或更多种单独组合物的组合,其中两种或更多种单独组合物可包含在分配器的物理分离的隔室中并且并排分配。如本文所用,术语“分配器”是指适于分配局部用组合物的任何泵、管或容器。
局部用组合物还可掺入到递送载体上以用于直接施用或附接到皮肤表面。如本文所用,术语“递送载体”包括用于紧贴皮肤表面保持局部用组合物的材料或器具,但不限于所提及的那些。递送载体可以是例如条带或聚合物膜或背衬膜或贴剂。这些递送载体可以是矩形的、拱形的、弯曲的、半圆形的、具有圆角、具有切入其中的狭缝、具有切入其中的凹口、弯曲成三维形状或它们的组合。它们可以是实心的、半实心的、带纹理的、可塑的、柔性的、可变形的、可永久变形的或它们的组合。条带可例如由包括聚乙烯的塑料片,或蜡片或聚合物载体制成。这些的尺寸根据待治疗的区域进行调整。
除此之外或另选地,本发明的局部用配制物还可使用常规皮肤贴剂通过皮肤或粘膜组织施用,其中活性剂包含在用作待固定到身体表面的递送装置的层压结构内。在此类结构中,局部用配制物包含在上部背衬层下面的层或“贮存器”中。层压结构可含有单个贮存器,或者其可含有多个贮存器。在一个实施方案中,贮存器包括药学上可接受的粘合剂材料的聚合物基体,其用于在局部用配制物的递送期间将系统固定到皮肤。通常,粘合剂材料是适用于长期皮肤接触,并且应该与局部用配制物在物理和化学上相容的压敏粘合剂(PSA)。合适的粘合剂材料的示例包括但不限于:聚乙烯;聚硅氧烷;聚异丁烯;聚丙烯酸酯;聚丙烯酰胺;聚氨酯;增塑的乙烯-乙酸乙烯酯共聚物;以及粘性橡胶,诸如聚异丁烯、聚丁二烯、聚苯乙烯-异戊二烯共聚物、聚苯乙烯-丁二烯共聚物和氯丁橡胶(聚氯丁二烯)。优选的粘合剂是聚异丁烯。背衬层起到透皮系统的主要结构元件的作用,并且为装置提供柔性,以及优选封闭性。用于背衬层的材料应为惰性的并且不能吸收包含在装置内的局部用配制物中包含的任何一种或多种活性剂。背衬优选由柔性弹性体材料构成,该柔性弹性体材料用作保护性覆盖物以防止药物和/或媒剂经由透过贴剂的上表面而损失,并且将优选地赋予系统一定程度的封闭性,使得由贴剂覆盖的身体表面区域在使用期间变得水合。用于背衬层的材料应允许该装置遵循皮肤的轮廓并且舒适地佩戴在皮肤区域上,诸如在通常经受机械应变的关节处或其他弯曲点处,由于皮肤和装置的柔性或回弹性的差异,该装置很少或不可能从皮肤脱离。如上所述,用作背衬层的材料是封闭的或可透过的,尽管封闭背衬是优选的,并且通常衍生自合成聚合物(例如,聚酯、聚乙烯、聚丙烯、聚氨酯、聚偏二氯乙烯和聚醚酰胺)、天然聚合物(例如,纤维素材料)或大孔织造和非织造材料。
除此之外或另选地,含有局部用配制物的贮存器和皮肤接触粘合剂作为单独的和不同的层存在,粘合剂在贮存器下面,其中贮存器可以是如上所述的聚合物基体。另选地,贮存器可由包含在封闭隔室或“袋”中的液体或半固体局部用配制物组成,或者其可以是水凝胶贮存器,或者可采取一些其他形式。
附加层例如中间织物层和/或速率控制膜也可存在于这些递送体系中的任一个递送体系中。织物层可用于促进装置的制造,而速率控制膜可用于控制局部用配制物渗透出装置的速率。
速率控制膜(如果存在)将包括在一个或多个贮存器的皮肤侧上的系统中。通常选择用于形成此类膜的材料以限制包含在局部用配制物中的一种或多种组分的通量。可用于形成速率控制膜的代表性材料包括聚烯烃,诸如聚乙烯和聚丙烯、聚酰胺、聚酯、乙烯-乙基丙烯酸酯共聚物、乙烯-乙酸乙烯酯共聚物、乙烯-乙酸乙烯基甲酯共聚物、乙烯-乙酸乙烯基乙酯共聚物、乙烯-乙酸乙烯基丙酯共聚物、聚异戊二烯、聚丙烯腈、乙烯-丙烯共聚物等。
通常,透皮装置的下表面(即皮肤接触区域)的面积在约0.25cm2至200cm2,优选1cm2至25cm2,更优选2cm2至10cm2的范围内。当然,该区域将随待治疗区域的尺寸而变化。
如本文所公开的递送体系可使用本领域已知的常规涂覆和层压技术制造。例如,粘合剂基质系统可通过将粘合剂和本发明的局部用配制物的流体混合物流延到背衬层上,然后层压剥离衬垫来制备。类似地,可将粘合剂混合物流延到剥离衬垫上,然后层压背衬层。另选地,贮存器可以在不存在局部用配制物的情况下制备,然后通过在局部用配制物中“浸泡”来装载。通常,这些贴剂通过溶剂蒸发、膜流延、熔融挤塑、薄膜层压、模切等制造。
局部用配制物将通常在贴剂制造期间而不是在制备装置之后掺入到装置中。递送体系还可包括粘合剂覆盖层,其也用作递送体系的背衬,用于更好地将贴剂固定到身体表面上。该覆盖层的尺寸使得其延伸超过贮存器,使得覆盖层上的粘合剂与身体表面接触。覆盖层是有用的,因为粘合剂/贮存器可能在施用后几小时由于水合作用而失去其粘附性。通过掺入此类粘合剂覆盖层,递送体系在所需的时间段内保持在适当的位置。
局部用载体
根据本发明的局部用配制物可采取适于局部施用于身体表面的组合物的形式,并且可包括例如乳膏、洗剂、溶液(例如,液体喷雾)、凝胶、膜、软膏剂、糊剂、石膏、油漆、生物粘合剂等。
软膏剂
如本领域所熟知的,软膏剂是通常基于凡士林或其他石油衍生物的半固体制剂。如本领域技术人员将理解的,所使用的特定软膏剂基质是将提供活性剂的最佳递送的软膏剂基质,并且其还可提供其他所需的特性,诸如润肤性等。与其他载体或媒剂一样,软膏剂基质通常是惰性的、稳定的、无刺激性的和非致敏的。软膏剂基质可分为四类:油质基质;可乳化基质;乳液基质;和水溶性基质。油质软膏剂基质包括例如植物油、从动物获得的脂肪和从石油获得的半固体烃。可乳化的软膏剂基质,也称为吸收性软膏剂基质,含有很少或不含水,并且包括例如硫酸羟基甘油三硬脂酸酯、无水羊毛脂和亲水性矿脂。乳液软膏剂基质是油包水(w/o)乳液或水包油(o/w)乳液,并且包括例如鲸蜡醇、单硬脂酸甘油酯、羊毛脂、硬脂酸和不同分子量的聚乙二醇或它们的组合。合适的烃基的其他示例包括但不限于硬、软或液体石蜡、甘油、蜂蜡、金属皂、胶浆、天然来源的油(诸如杏仁油、玉米油、花生油、蓖麻油或橄榄油)、羊毛脂或其衍生物、脂肪酸(诸如硬脂酸或油酸)或它们的组合。有助于制备软膏剂的方法的所有上述成分不限于它们的合成性质,并且可以是天然的或天然来源的或天然衍生的。
乳膏
也在本领域中众所周知的乳膏是粘性液体或半固体水包油乳液。乳膏基质可以是天然的或合成的可水洗的,并且含有油相、乳化剂和水相。油相,也称为“内部”相,可包括凡士林和脂肪醇,诸如鲸蜡基或硬脂醇。水相通常(尽管不是必需的)在体积上超过油相,并且通常含有湿润剂。乳膏配制物中的乳化剂通常是非离子、阴离子、阳离子或两性表面活性剂或它们的组合。此外,掺入乳膏基质中的新型递送技术也可包括在其中。有助于制备乳膏的方法的所有上述成分不限于它们的合成性质,并且可以是天然的或天然来源的或天然衍生的。
凝胶
凝胶或乳液凝胶配制物通常是半固体、悬浮型体系。单相凝胶通常含有基本上均匀地分布在整个载液中的有机大分子,载液通常是水性的,但也可含有醇和任选的油。示例性“有机大分子”(即胶凝剂)是交联的丙烯酸聚合物,诸如“卡波姆”聚合物家族(例如,可根据CarbopolTM商业获得的羧基聚烯烃)。还举例说明亲水性聚合物,诸如聚环氧乙烷、聚氧乙烯-聚氧丙烯共聚物、聚乙烯醇和聚乙烯吡咯烷酮;纤维素聚合物,诸如羟丙基纤维素、羟乙基纤维素、羟丙基甲基纤维素、羧甲基纤维素、邻苯二甲酸羟丙基甲基纤维素和甲基纤维素;树胶,诸如角叉菜胶、黄蓍胶和黄原胶;藻酸钠;和明胶。合适的凝胶形成剂的示例包括羧聚乙烯衍生物,诸如卡波姆和果胶。在本发明的一个实施方案中,胶凝剂是黄原胶和/或角叉菜胶。
在一个实施方案中,增稠剂或胶凝剂可通常以约0.2%至5.0%的w/w%量存在于组合物中。在另一个实施方案中,增稠剂或胶凝剂可通常以约0.1%至1.0%的w/w%量存在于组合物中。在本发明的另一个实施方案中,局部用凝胶配制物可包括至多3.0%w/w的量的胶凝剂(例如,黄原胶)。
为了制备均匀的凝胶,可添加稀释剂诸如醇,或者可通过研磨、机械混合或搅拌或它们的组合来分散胶凝剂。此外,凝胶或乳液凝胶配制物可含有通常用于如防腐剂、抗氧化剂、着色剂、芳香剂、稳定剂等配制物类型的其他辅剂。
水凝胶是吸收水并因此溶胀但不溶于水的大分子网络。即,水凝胶含有提供吸水率的亲水性官能团,但水凝胶由产生水不溶性的交联聚合物构成。通常,然后水凝胶由交联的亲水性聚合物构成,诸如聚氨酯、聚乙烯醇、聚丙烯酸、聚氧乙烯、聚乙烯吡咯烷酮、聚(甲基丙烯酸羟乙酯)(聚(HEMA))或它们的共聚物或混合物。特别优选的亲水性聚合物是HEMA和聚乙烯吡咯烷酮的共聚物。
有助于制备凝胶或乳液凝胶的方法的所有上述成分不限于它们的合成性质,并且可以是天然的或天然来源的或天然衍生的。
洗剂
洗剂通常是在没有摩擦的情况下施用于皮肤表面的制剂,并且通常是液体或半液体制剂,其中固体颗粒(包括活性剂)存在于水或醇基质中。洗剂通常是固体的混悬剂,并且出于本发明的目的,可包含水包油型的液体油性乳液。洗剂可用于处理大的身体区域,因为容易施用更多的流体组合物。通常希望洗剂中的不溶性物质被细分。因此,洗剂将通常含有悬浮剂以产生更好的分散体,以及可用于定位和保持活性剂与皮肤接触的化合物,例如甲基纤维素、羧甲基纤维素钠等。洗剂还可包括加速溶液在皮肤上干燥和冷却的试剂,诸如醇或丙酮。它们还可包括保湿剂,诸如甘油,或油,诸如蓖麻油或花生油。
本发明的局部用配制物还可用脂质体和/或胶束制备。脂质体是具有包含脂质双层的脂质壁的微观囊泡,并且可用作本文的递送体系。通常,脂质体配制物用于难溶性或不溶性试剂。用于本发明的脂质体制剂可包括阳离子(带正电)、阴离子(带负电)和中性制剂。阳离子脂质体可容易获得。例如,N[1-2,3-二油烯氧基)丙基]-N,N,N-三乙基铵(DOTMA)脂质体可以商品名LipofectinTM获得。类似地,阴离子和中性脂质体也可容易获得,或可使用容易获得的材料容易地制备。此类材料包括磷脂酰胆碱、胆固醇、磷脂酰乙醇胺、二油酰磷脂酰胆碱(DOPC)、二油酰磷脂酰甘油(DOPG)、二油酰磷脂酰乙醇胺(DOPE)等。这些材料还可以适当的比率与DOTMA混合。使用这些材料制备脂质体的方法在本领域中是众所周知的。
在水溶液中的胶束在本领域中已知由表面活性剂分子构成,所述表面活性剂分子被排列成使得它们的极性头基形成外部球形壳,而疏水性烃链朝向球体的中心取向,形成核。胶束在含有足够高浓度的表面活性剂的水溶液中形成,使得胶束自然产生。可用于形成胶束的表面活性剂包括但不限于月桂酸钾、辛烷磺酸钠、癸烷磺酸钠、十二烷磺酸钠、月桂基硫酸钠、多库酯钠、癸基三甲基溴化铵、十二烷基三甲基溴化铵、十四烷基三甲基溴化铵、十四烷基三甲基氯化铵、十二烷基氯化铵、聚氧乙烯8十二烷基醚、聚氧乙烯12十二烷基醚、壬苯醇醚10和壬苯醇醚30。胶束配制物可通过掺入局部递送体系的贮存器中或掺入待施用到身体表面的局部用配制物中而与本发明结合使用。本领域技术人员已知的各种添加剂还可包含在本发明的局部用配制物中。
除此之外或另选地,溶剂,包括相对少量的醇可用于溶解某些配制物组分。合适的溶剂包括甘油、SD 40醇、卵磷脂、泊洛沙姆、MiglyolTM和甲基吡咯烷酮或它们的组合。其他合适的溶剂包括甘油、稀醇异丙醇、己二醇和丙二醇。还可将薄荷醇添加到本发明的局部用配制物中。在一个实施方案中,表面活性剂可例如以约0.5%至约5.0%w/w的量用于根据本发明的局部用配制物中。合适的表面活性剂可包括但不限于月桂基硫酸钠、苯扎氯铵、十六烷基氯化吡啶鎓、月桂酸钠、十六烷基三甲基溴化铵、泊洛沙姆(231、182、184)、Tween(20、40、60、80)和SpanTM以及它们的组合。
配制物还可含有减轻刺激的添加剂,以最小化或消除由组合物的药理学活性基质或其他组分产生的皮肤刺激或皮肤损伤的可能性。合适的减轻刺激的添加剂包括例如:a-生育酚;单胺氧化酶抑制剂,特别是苯基醇,诸如2-苯基-1-乙醇;甘油;抗坏血酸和抗坏血酸盐;离子载体,诸如两亲性胺;氯化铵;N-乙酰半胱氨酸;顺式尿刊酸;辣椒碱。
在本发明的另一个实施方案中,递送体系可包括纳米颗粒。纳米颗粒可分散在本发明的配制物中的微乳液中,或作为此类配制物的媒剂的一部分,用于通过皮肤递送活性剂。不希望受理论束缚,此类纳米颗粒将容易地穿透皮肤并且可保留在皮肤的特定层内。在一个实施方案中,纳米颗粒具有由被磁体强烈吸引的铁矿石构成的核。除此之外或另选地,纳米颗粒包括磁铁矿,在一个实施方案中,该磁铁矿是指具有通式Fe3O4的分子。纳米颗粒还可包括化学当量的磁铁矿,例如(Fe M)OFe2O3,其中在一个实施方案中,M可以是Zn、Co、Ni、Mn、Cr、Au或Ag。用于递送体系和根据本发明的方法的纳米颗粒可例如在1nm-100nm的尺寸范围内。聚合物还可通过本领域技术人员熟知的一系列方法与纳米颗粒缀合。活性剂又可与聚合物缀合,与纳米颗粒缀合,或者作为化合物的物理化学性质的函数,可直接固定到纳米颗粒上。所用聚合物的选择可以是所采用的颗粒的函数。在一个实施方案中,聚合物包括聚丙烯酸、聚苯乙烯磺酸、聚乙烯磺酸、聚环氧乙烷、聚环氧丙烷、聚乙烯醇、可光致聚合的大分子单体、可生物降解的聚合物诸如但不限于PLGA,或它们的组合。在另一个实施方案中,聚合物包括表面活性剂、聚乙二醇、木质素磺酸盐、聚丙烯酰胺或生物聚合物。在另一个实施方案中,生物聚合物包括多肽、纤维素和其衍生物(诸如羟乙基纤维素和羧甲基纤维素)、藻酸盐、脱乙酰壳多糖、脂质、葡聚糖、淀粉、结冷胶或其他多糖,或它们的组合。
本发明的局部用配制物还可包括促进活性成分通过皮肤递送的其他组合物。例如,可使用纳米颗粒将活性剂配制成大分子组件,如例如公布的WO2006/113668、WO2006/129127和US60/671,892(其全部内容以引用方式并入本文)中所述。不希望受理论束缚,该类型的大分子组件通常模拟天然脂蛋白,并且因此据说溶解疏水性活性剂以通过穿透皮肤的角膜间脂质层以及亲水性孔来促进它们的递送(例如透皮递送)。不希望受理论束缚,大分子组件可被捕获在皮肤的角质层内,并且因此充当活性剂的贮存器,以使得能够持续释放到皮肤的较深层中,并由此提供不同的治疗特性。这又可增强活性剂的功效,减少所需的施用次数和活性剂的量,并且因此对于患者来说可更方便。
局部施用的递送体系的这些和其他类型和配置可单独使用或组合使用以促进包括在本发明的配制物中的活性剂的递送,如例如局部药物递送领域的技术人员将理解的。因此,应理解,递送体系可包括本文列出的任何单个实施方案或实施方案的组合。
任何合适的润肤剂或皮肤调理剂可任选地包括在本发明的局部用配制物中。合适的润肤剂包括但不限于胆固醇、甘油、单硬脂酸甘油酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、十八十六醇、羊毛脂醇以及它们的混合物。任选地,聚二甲基硅氧烷、矿物油或白色软石蜡也可以相对少量掺入配制物中以充当皮肤调理剂。润肤剂或皮肤调理剂可以约0.5%至约50%的w/w%量存在于本发明的局部用配制物中。例如,在本发明的凝胶配制物中,润肤剂或皮肤调理剂通常可以至多约50%w/w的量存在。在另一个实施方案中,本发明的乳膏或洗剂配制物可包含约0.5%至约15%w/w量的润肤剂或皮肤调理剂。
本发明的配制物可任选地包括缓冲剂或中和剂。合适的缓冲液的示例包括但不限于柠檬酸、乳酸、油酸、磷酸钠、水、三乙醇胺、柠檬酸钠、盐酸等。缓冲剂可以任何合适的缓冲有效量存在于组合物中。凝胶配制物通常将含有碱,例如氢氧化钠、三乙醇胺等。本发明的凝胶配制物通常还将包括挥发性溶剂,例如乙醇、异丙醇等。
也可向本发明的局部用配制物中添加其他试剂,包括抗微生物剂,以防止储存时的腐败(即抑制微生物诸如酵母和霉菌的生长)。合适的抗微生物剂通常选自由以下项组成的组:对羟基苯甲酸的甲基酯和丙基酯(即,对羟基苯甲酸甲酯和对羟基苯甲酸丙酯)、苯甲酸钠、羟甲基甘氨酸钠、山梨酸、咪脲、碘化钾以及它们的组合。该列表不限于合成材料,但也可以是天然的或天然衍生的或来自天然来源。
本发明的局部用配制物可任选地包括不限于天然或合成来源的防腐剂或抗氧化剂组分。此类防腐剂和抗氧化剂的示例包括但不限于烷基醇、苄醇、丁基化羟基苯甲醚、丁基化羟基甲苯(对羟基苯甲酸甲酯和对羟基苯甲酸丙酯)、对羟基苯甲酸丁酯、依地酸二钠、柠檬酸、葡萄籽果实提取物、芝麻酚等。防腐剂和/或抗氧化剂可以约0.05%至约5.0%w/w的w/w量存在于本发明的配制物中。在另一个实施方案中,防腐剂和/或抗氧化剂可以约0.25%至约0.5%w/w的量存在于本发明的配制物中。
在某些实施方案中,本发明的局部用配制物还可包括其他活性成分,包括但不限于桉树油(例如,蓝桉油、细叶桉油、赤桉)、桉树脑或衍生自桉树油的其他萜烯、乳香酸、甘油、海藻、碘酸钾、褐藻胶、熏衣草、1,8-桉树脑、芳樟醇、乙酸芳樟醇酯、坚果仁提取物、卵磷脂、甘草提取物(例如,甘草根提取物)、光甘草定、甘草酸、甘草酸单铵盐、10-β-甘草次酸、鞣花酸、姜黄、姜黄素、四氢姜黄素(THC)或它们的任何组合。不希望受理论束缚,通过直接或间接在生理学或病理生理学途径上起作用,其他活性成分可至少部分地有助于本发明的配制物的功效。
如本文所公开的局部用组合物中的其他基质载体包含基质载体材料。合适的基质载体材料是无毒油、无毒食用油、饱和或不饱和脂肪醇、脂族烃、长链甘油三酯、脂肪酯以及它们的混合物。除此之外或另选地,疏水相还可包含硅氧烷、聚硅氧烷、以及它们的混合物。
合适的脂族烃可包含约10个、12个、14个或16个至约16个、18个、20个、22个、24个、26个、28个、30个、36个、40个碳原子,诸如癸烷、2-乙基癸烷、十四烷、异十四烷、十六烷、二十烷、以及它们的混合物。长链甘油三酯包括植物油、鱼油、动物脂肪、氢化植物油、部分氢化植物油、半合成甘油三酯、合成甘油三酯以及它们的混合物。还可使用这些类型的分馏、精制或纯化的油。适用于本发明组合物中的合适的含长链甘油三酯的油的具体示例包括杏仁油;巴巴苏油;琉璃苣油;黑醋栗种子油;低芥酸菜子油蓖麻油;椰子油;玉米油;棉籽油;鸸鹋油;月见草油;亚麻籽油葡萄籽油;落花生油;芥子油;橄榄油;棕榈油;棕榈仁油;花生油;油菜籽油;红花油;芝麻油鱼肝油;大豆油;向日葵油;氢化蓖麻油;氢化椰子油氢化棕榈油;氢化大豆油;氢化植物油;氢化棉籽油和氢化蓖麻油的混合物;部分氢化的大豆油;部分氢化的大豆油和部分氢化的棉籽油的混合物;三油酸甘油酯;三亚油酸甘油酯;三次亚麻油酸甘油酯;包含油的Ω3-多不饱和脂肪酸甘油三酯;以及它们的混合物。含长链甘油三酯的油可具体地选自玉米油、橄榄油、棕榈油、花生油、红花油、芝麻油、大豆油、蓖麻油、亚麻籽油、菜油、米糠油、椰子油、氢化蓖麻油;部分氢化的大豆油;三油酸甘油酯;三亚油酸甘油酯;包含油的Ω3-多不饱和脂肪酸甘油三酯;以及它们的混合物。
合适的饱和或不饱和脂肪醇具有约6至约20个碳原子、十六/十八醇、月桂醇以及它们的混合物。例如,由Lipo Chemical供应并制造Lipowax(十六/十八醇和鲸蜡硬脂基聚氧乙烯醚-20)。
合适的矿物油是凡士林和其混合物。凡士林的示例包括得自Calumet SpecialtyProducts(Indianapoli,IN)的Snow White Pet–C、得自Sonneborn(Parsippany,NJ)的G-2191、得自Sonneborn的G-2218、得自Sonneborn的G-1958以及它们的混合物。
关于硅氧烷流体、树胶和树脂的一般信息,以及硅氧烷的制造可见于Encyclopedia of Polymer Science and Engineering,第15卷,第二版,第204-308页,John Wiley&Sons Inc.,1989年和Chemistry and Technology of Silicones,WalterNoll,Academic Press Inc(Harcourt Brue Javanovich,Publishers,New York),1968年,第282-287页和第409-426页。
表面活性剂
可用作如本文所公开的组合物的乳化剂的表面活性剂类型包括非离子乳化剂、阴离子乳化剂、阳离子乳化剂、两性乳化剂、合成乳化剂以及它们的混合物。许多合适的非离子表面活性剂和两性表面活性剂由美国专利3,988,433;美国专利4,051,234公开,并且许多合适的非离子表面活性剂由美国专利3,959,458公开。任选地可用于本文的其他乳化剂包括天然乳化剂,诸如阿拉伯胶、明胶、卵磷脂和胆固醇;精细分散的固体,诸如胶态粘土、膨润土、胶体硅酸镁铝(硅酸镁铝;以及合成乳化剂,诸如脂肪酸的盐、硫酸盐,诸如脱水山梨糖醇三油酸酯、脱水山梨糖醇三硬脂酸酯、蔗糖二硬脂酸酯、单硬脂酸丙二醇酯、单硬脂酸甘油酯、丙二醇单月桂酸酯、脱水山梨醇单硬脂酸酯、脱水山梨糖醇单月桂酸酯、聚氧乙烯-4-月桂基醚、月桂基硫酸钠、磺酸盐诸如二辛基磺基琥珀酸钠、甘油酯、聚氧乙二醇酯和醚、二乙二醇单硬脂酸酯、PEG 200二硬脂酸酯和脱水山梨糖醇脂肪酸酯诸如脱水山梨糖醇单棕榈酸酯,及其聚氧乙烯衍生物、聚氧乙烯乙二醇酯诸如单硬脂酸酯、聚山梨醇酯80(乙氧基化脱水山梨糖醇单油酸酯)(由Spectrum等提供)以及它们的混合物。
水
个人护理组合物还可包含水,优选小于约10%的水,小于约8%的水,小于约5%、小于约3%的水,所有百分比均按组合物的重量计。另选地,个人组合物可包含约0.5%至约10%的水、另选地约0.75%至约8%、另选地约1%至约5%的水,所有百分比均按组合物的重量计。
防腐剂、缓冲剂、染料和调味剂也可包括在组合物的一些实施方案中。
防腐剂的示例包括但不限于苯甲酸钠、苯甲酸、山梨酸和对羟基苯甲酸的酯、对羟基苯甲酸酯,特别是对羟基苯甲酸丙酯、对羟基苯甲酸乙酯、对羟基苯甲酸甲酯、苯扎氯铵、乙二胺四乙酸(EDTA)、苄醇、山梨酸钾或它们的混合物。组合物可包含约0.01%至约1%的防腐剂,约0.05%至约0.5%的防腐剂,约0.07%至约0.3%的防腐剂,以及优选约0.08%至约0.15%的防腐剂。
缓冲剂的示例包括但不限于乙酸、乙酸钠、柠檬酸、柠檬酸钠、磷酸二氢钠、磷酸氢二钠、碳酸钠、碳酸氢钠、琥珀酸、琥珀酸钠、磷酸二氢钾和磷酸,并且有助于建立和维持恒定的pH值。测定缓冲剂的量并且基于待满足的pH要求并且可以由技术人员容易地调整。
本发明组合物还可包含用于增加待处理的消费者的光学接受性的任何染料或颜色。颜色的非限制性示例可包括红色、绿色、琥珀色、橙色、黄色、蓝色、粉红色、紫罗兰色、蓝绿色以及它们的组合。在一个示例中,组合物为透明的。组合物还可包含提供颜色的染料。可用于本发明中的染料的非限制性示例包括FD&C蓝#1、FD&C蓝#2、D&C蓝#4、D&C蓝#9、FD&C绿#3、D&C绿#5、D&C绿#6、D&C绿#8、D&C橙#4、D&C橙#5、D&C橙#10、D&C橙#11、FD&C红#3、FD&C红#4、D&C红#6、D&C红#7、D&C红#17、D&C红#21、D&C红#22、D&C红#27、D&C红#28、D&C红#30、D&C红#31、D&C红#33、D&C红#34、D&C红#36、D&C红#39、FD&C红#40、D&C紫#2、FD&C黄#5、FD&C黄#6、D&C黄#7、Ext.D&C黄#7、D&C黄#8、D&C黄#10、D&C黄#11、以及它们的组合。组合物可包含约0.001%至约0.1%的染料、约0.002%至约0.05%的染料或约0.003%至约0.01%的染料。
如本文所公开的组合物还可包含消费者可接受的芳香剂材料。在一个示例中,适用于本文的芳香剂材料可包括白千层油、茴香油、天竺葵油、柠檬油、留兰香油、桉树油、桃金娘油、牛至油、松油、风轮菜油、百里香油、雪松木油、雪松叶油、肉豆蔻以及它们的混合物。另外或另选地,芳香剂材料可包含精油的化学组分,诸如香草醛、乙基香草醛、麝香、二氢茉莉酮酸甲酯、茴香脑、儿茶酚、樟脑、莰烯、阿魏酸、金合欢醇、桧木醇、环庚三烯酚酮、薄荷醇、左薄荷脑、水杨酸甲酯、香芹醇、萜品醇、马鞭草烯酮、拉坦尼根(ratanhia)提取物、石竹烯氧化物、香茅酸、姜黄素、橙花叔醇、松脂、百里酚或它们的混合物。这些材料可以混合用于个人护理组合物的芳香剂材料领域的技术人员已知的水平和比率使用。
内部施用
另选地,一种或多种紫草素活性物质,特别是紫草素A和/或包含其的药物组合物也可通过全身药物组合物内部施用。如本文所用,“全身药物组合物”是指在一般使用过程中用于全身施用治疗剂的目的的产品,其通过口服、胃肠外、栓剂的使用或以足以实现预期目的(例如抑制炎症、缓解疼痛等)的剂型和剂量的其他内部和全身施用来施用。组合物可包括多种内部施用的剂型。剂型的非限制性示例可包括液体药物、悬浮在液体配制物中的颗粒、明胶或泡沫中的固体、或呈片剂、胶囊、粉末、颗粒剂、球剂、微球、纳米球、珠粒或丸粒的形式的固体剂量,以及它们的组合。
可口服施用的剂型可立即吞咽、缓慢溶解于口中或咀嚼。在一些方面,组合物可被配制成可通过任何合适的途径施用给受试者的粉末、片剂、胶囊、包肠溶衣剂型(例如,用于递送到回肠/结肠)或丸剂。冻干制剂可在施用之前与盐水或其他溶液混合。
在一些方面,如本文所公开的药物组合物可以是联合肠溶的。肠溶衣可保护组合物的活性物质例如免受胃酸影响,并提供向回肠和/或上部结肠区域的递送。肠溶衣的非限制性示例可包括pH敏感性聚合物(例如FS30D)、丙烯酸甲酯-甲基丙烯酸共聚物、乙酸琥珀酸纤维素、羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素乙酸琥珀酸酯(例如乙酸琥珀酸羟丙甲纤维素)、聚乙酸乙烯苯二甲酸酯(PVAP)、甲基丙烯酸甲酯-甲基丙烯酸共聚物、紫胶、偏苯三酸乙酸纤维素、藻酸钠、玉米醇溶蛋白、其他聚合物、脂肪酸、蜡、紫胶、塑料以及植物纤维。在一些方面,肠溶衣由pH敏感性聚合物(例如使用FS30D)形成。溶衣内的组合物可与如本文所公开的局部用组合物类似地配制,前提是仅使用预期和登记用于内部施用的载剂材料,诸如植物油(例如花生油)或被接受用于营养的乳化剂,诸如卵磷脂。
除此之外或另选地,如本文所公开的药物组合物也可以片剂的形式提供。用于片剂的组合物是技术人员已知的,并且通常包含填充剂,诸如淀粉、葡萄糖、甘露糖醇和/或山梨糖醇;粘结剂,诸如微晶纤维素、淀粉、淀粉糊剂、纤维素醚和/或明胶、崩解剂、润滑剂和/或任选的涂料。可将活性剂干燥并与片剂材料直接混合。
如本文所用,“剂量”是指一定体积的药物,诸如液体或固体药物,根据可靠的医学实践,其含有适于在单个场合施用的药物活性物质量。剂量可口服。在一个示例中,剂量可为约30mL,在另一个示例中约25mL,在另一个示例中约20mL,在另一个示例中约15mL,并且在另一个示例中约10mL。在另一个示例中,液体药物的剂量可为约10mL至约75mL,在另一个示例中约15mL至约50mL,在另一个示例中约25mL至约40mL,并且在另一个示例中约28mL至约35mL。在另一个示例中,剂量可为半个片剂或胶囊,在另一个示例中可为一个片剂或胶囊,在另一个实施方案中可为1.5个片剂或胶囊,并且在另一个实施方案中可为2个片剂或胶囊。在另一个示例中,固体药物的剂量可为约1mg至约100mg,在另一个示例中约5mg至约50mg,在另一个示例中约10mg至约40mg,在另一个示例中约15mg至约30mg,并且在另一个示例中约50mg至约90mg,在另一个示例中为约55mg至约80mg,并且在另一个示例中为约60mg至约75mg。给定剂量大小下,可调节活性成分的浓度以提供适当的活性物质剂量。在一个示例中,所述剂量旨在每4小时,在另一个示例中每6小时,在另一个示例中每8小时,并且在另一个示例中每12小时服用。
本文公开的活性剂,包括但不限于一种或多种紫草素(特别是紫草素A)、紫草素A与咖啡酸乙酯的组合以及本文提及的其他活性物质和包含所述活性物质的药物组合物可特别用于治疗疼痛、炎症、肿胀、运动受限、挫伤、拉伤、扭伤、关节病、背痛、肌肉不适和/或关节不适。不希望受理论束缚,特别是经由NF-κB途径,通过抑制E-选择素转录来实现治疗效果。
因此,本发明还涉及通过局部施用和/或内部施用安全有效量的一种或多种紫草素,特别是紫草素A,或者安全有效量的紫草素A与安全有效量的咖啡酸乙酯和/或如本文所公开的其他附加活性剂的组合来抑制和/或治疗炎症的方法。
本发明还涉及通过在例如用白介素1β(IL-1β)活化后至少部分阻断NF-κB途径的活化,通过局部施用和/或内部施用安全有效量的一种或多种紫草素,特别是紫草素A,或者安全有效量的紫草素A与安全有效量的咖啡酸乙酯和/或如本文所公开的其他附加活性剂的组合来抑制和/或治疗炎症的方法。
药物组合物可局部施用和/或可内部施用。局部施用需要以足够的量施用药物组合物以实现对需要治疗的区域的效果,其中组合物在那里保持足够的时间段以实现效果。
本发明还涉及试剂盒,所述试剂盒包含安全有效量以及说明书使用的如本文所公开的药物组合物,所述药物组合物包含一种或多种芳基萘木酚素,特别是紫草素A,或紫草素A加上咖啡酸乙酯。使用说明将描述如本文所述的一些示例性施用场景,但是施用的最佳量、持续时间和频率将取决于期望的效果、任何待治疗病症的严重程度、使用者的健康和年龄以及类似的考虑因素。
另一个优选的实施方案基于从属专利权利要求。组合物权利要求的特征可对应地与此处使用权利要求组合,反之亦然,以任何期望的组合。下文将更详细地描述本发明。
实施例
一般实验程序
IR测量在Bruker IFS-48光谱仪上进行。在Beckman DU 670光谱仪上获得UV光谱。NMR实验在甲醇-d4(99.95%,Sigma-Aldrich)中在配备有Bruker 5mm TCI CryoProbe的Bruker DRX-600光谱仪(Bruker BioSpin GmBH,Rheinstetten,Germany)上在300K处获得。用Topspin 3.2软件进行数据处理。用tmix=400ms获得ROESY光谱。在Sephadex LH-20(GEHealthcare,Sigma Aldrich,Milan,Italy)上进行尺寸排阻色谱法。
化合物分离
从Merck KGaA&Co Werk Spittal,Austria获得紫草根(DER 1:2)的PA耗尽的水醇(20%EtOH w/w)液体提取物。为了除去胶浆,蒸发500g液体提取物的乙醇含量,并且用乙酸乙酯(1:1)分配水相,获得50g乙酸乙酯提取物。将3g乙酸乙酯提取物在Sephadex LH-20(GEHealthcare,Sigma Aldrich,Milan,Italy)柱(100×5cm)上分馏,使用甲醇作为流动相,得到80个级分(8mL),通过LC-ESI-HR-MS分析监测。
LC-ESI/LTQ轨道阱/MS分析
通过LC-ESI/HR/MS使用“数据依赖性扫描”模式(其中选择对应于最强峰的前体离子)来分析显示在20μg/mL的浓度处抑制HUVEC细胞中白介素-1β诱导的E-选择素表达的紫草根的胶浆和PA耗尽的提取物的LC-MSn指导的分馏。如下所示进行该程序:
通过使用与混合型质谱仪耦合的HPLC方法获得紫草根的水醇提取物的次级代谢物谱,该质谱仪结合了线性阱四极杆(LTQ)和轨道阱质量分析器。所有实验均使用Thermoscientific液相色谱系统进行,该系统由连接到具有电喷雾电离(ESI)的线性阱-轨道阱混合型质谱仪(LTQ-Orbitrap XL,Thermo Fisher Scientific,Bremen,Germany)的四元Accela 600泵和Accela自动进样器组成。在Kinetex EVO C185μm(150mm×2.10mm)柱(Phenomenex Aschaffenburg,Germany)上,使用0.2mL/min的流速和由A(0.1%甲酸/水,v/v)和B(0.1%甲酸/乙腈,v/v)的组合组成的流动相进行分离。使用线性梯度程序,在5min内以5%B的等度开始,然后在5min内从5%至23%B,在23%B处保持5min,在7min内从23%至55%B,在5min内从55%至95%B,在95%B处保持5min。质谱仪以负离子模式操作。ESI源参数如下:毛细管电压-48V;筒镜电压-176.47;毛细管温度280℃;护套和辅助气流(N2),15(任意单位)和5(任意单位),吹扫气体0喷雾电压5kV。质量范围为120m/z至1600m/z,分辨率为30000。对于碎片化研究,进行数据依赖性扫描,选择对应于LC-MS分析中最强峰的前体离子。Xcalibur软件版本2.1用于仪器控制、数据采集和数据分析。
初步代谢物谱显示对应于不同结构类别(图2)的20种主要化合物(图1)。这些代谢物中的一些通过将它们的准确质量、特征碎片化模式和保留时间与真实标准物的那些进行比较来鉴定。基于上述方法,鉴定了尿囊素(1)、原儿茶酸(4)、原儿茶醛(5)、对羟基苯甲酸(6)、咖啡酸(7)以及其乙酯衍生物(16)、迷迭香酸(12)以及脂肪酸亚麻酸(18)、亚油酸(19)和羟基棕榈酸(20)的存在。剩余的化合物(2、3、8-11、13-15和17)不能由HR-ESI-MS明确指定,因为它们的准确质量与文献中由聚合草所报告的任何化合物不匹配,或者因为它们的初步NMR数据不支持在具有相同分子量的聚合草中所报告的化合物。
紫草素A(化合物15)的分离程序
为了完全表征化合物2-3、8-11和13-17,首先通过用乙酸乙酯分配液体提取物来除去提取物的胶浆级分。然后,将有机相在Sephadex Lh-20柱上进行尺寸排阻色谱法,并且通过半制备型HPLC-UV进一步纯化。实际上,将获得的干燥级分在乙腈中稀释(浓度为10mg干燥残余物/100μL),并且通过在配备有二元泵(G-1312C)和UV检测器(G-1314B)的Agilent1260Infinity系统(Agilent Technologies,Palo Alto,CA,USA)上使用Phenomenex C18 Synergi-Hydro-RP(250mm×10mm,10μm)柱进行半制备型HPLC UV分离。流动相由溶剂A(H2O+0.1%甲酸)和溶剂B(CH3CN+0.1%甲酸)组成。分析在没有恒温的情况下在室温处进行。在HPLC-UV处收集的峰在真空中蒸发至干,并且在NMR分析之前也冷冻干燥。化合物结构通过广泛的1D-和2D-NMR实验以及MS/MS分析完全表征。
级分23-26(10mg)对应于化合物12,即迷迭香酸。
级分40-42(10mg)对应于化合物14,其被鉴定为globoidnan A(C26H20O10)。
级分19-22(51.6mg)使用线性梯度程序以2mL/min的流速在254nm的波长处纯化(在15min内从0%至20%B;在10min内从20%至40%B;在10min内从40%至60%B;在11min内从60%至100%B,然后在100%B下进行6min,得到化合物2(1.2mg,Rt=10.3min),3(1.3mg,Rt=13.5min),6(1.5mg,Rt=11.2min,对羟基苯甲酸)和9(2.2mg,Rt=27.3)。NMR分析分别证实化合物2为对-羟基苯甲酸葡糖苷以及化合物3为5-羟甲基-2-糠醛。化合物9在m/z 367.1384[M-H]-处显示主峰,支持分子式C18H24O8。其MS/MS光谱在m/z 205.09[M-H-162]-处显示碎片离子,表明存在己糖单元。9的NMR数据允许推导其结构为糖基化和异戊二烯化的酚酸malaxinic酸,其首次描述为存在于本文的聚合草中。
级分27-39(42.3mg)、级分43-54(7.1mg)和级分55-80(22.2mg)在相同的洗脱条件下以2mL/min的流速以及在280nm的波长处纯化:(在5%B处保持0min-5min,在15min内从5%至20%B;在20min内从20%至50%B,在10min内从50%至100%B,以及在100%B处保持5min)。
在这些条件下,从级分27-39中分离化合物4(1.1mg原儿茶酸,Rt=22.60min)、5(1.2mg原儿茶醛,Rt=27.9min)、7(1.5mg咖啡酸,Rt=29.4min)、8(1.3mg,Rt=31.7min)、11(1.6mg,Rt=34.3)、13(1.7mg,Rt=35.1min)和10(4.4mg,Rt=35.3)。
8、11和14的HR-ESI-MS光谱支持分子式分别为C27H22O12、C36H30O16和C26H20O10。它们的NMR和MS/MS数据的分析允许分别鉴定化合物14为globoidnan A以及化合物8为globoidnan B。化合物11被确定为(+)-香茶菜素,其中这些木酚素首次在聚合草根中描述。化合物13的分子式被确定为C9H10O5,并且通过NMR分析提供的结构说明允许将化合物13鉴定为羟基咖啡酸。尽管MS/MS碎片化模式表明与化合物10的globoidnan A的结构框架类似的结构框架,但NMR数据的解释证实了这种假设,将10的结构确定为3-羧基-6,7-二羟基-1-(3',4'-二羟基苯基)-萘。
从级分43-54中分离化合物15(1.6mg Rt=41.10)。
化合物16(1.2mg,Rt=42.2)被鉴定为咖啡酸乙酯,并且从级分55-80中分离17(1.0mg,Rt=43.3)。尽管MS/MS碎片化模式表明与化合物17的globoidnan A的结构框架类似的结构框架,但NMR数据的解释确定了化合物17的结构为化合物10的乙酯衍生物,三叶木酚素D。
此外,用50mL甲醇提取3g原料以获得甲醇提取物,以便通过LC-MS分析证明紫草中乙酯15-17的天然发生。由此表明,由于使用乙醇作为提取溶剂,化合物15、16和17不是假象,而是天然存在的。
化合物15的鉴定;命名为紫草素A:
紫草素A(化合物15)表现为无定形黄色固体。化合物15的HR-ESI-MS光谱(m/z381.0601[M-H]-,C20H13O8的计算值,381.0610)支持C20H14O8的分子式(图4)。化合物15的ESI/MS/MS光谱在m/z 353.02([M-H-28]-)处显示强离子,表明存在乙基基团。在m/z 353.02处的离子峰的MS显示在m/z 309.10([M-H-44]-)和265.10([M-H-44-44]-)处的碎片离子,对应于两个CO2分子的损失。1H和13C NMR(甲醇-d4,600MHz和150MHz)数据示于下表1中;ESI-HR-MS m/z 381.0601[M-H]-(C20H13O8的计算值,381.0610)。
表1:化合物15的13C(150MHz)和1HNMR(600MHz)数据。
对化合物15的13C和HSQC NMR数据的分析表明带有16个芳族碳的高度不饱和分子,而其1H NMR光谱在δ8.30(H-8),8.02(H-6'),7.67(H-4),7.34(H-5),6.91(H-3')处显示五个芳族单峰。另外,化合物15的1HNMR在δ4.43(2H,q,J=7.0Hz)和1.41(3H,t,J=7.0Hz)处显示乙氧基基团的特征信号。此外,HMBC光谱的详细分析证实存在两个主要片段(图5)。具体地,在芳族质子H-4与在δ172.2(C-9),130.5(C-3),113.4(C-2),133.7(C-4a),112.4(C-5)和124.5(C-8a)处的碳共振、H-5与在δ133.7,151.3(C-6),150.3(C-7)和124.5处的碳共振以及H-8与在δ136.1(C-1),151.3和133.7处的碳共振之间的关键长程相关性确定1,2-二取代的6,7-二羟基-萘-3-羧酸的存在。基于从质子H-3'和H-6'到在δ111.5(C-1'),143.8(C-2'),149.6(C-4')和147.1(C-5')处的碳共振的HMBC相关性,第二片段的结构被确定为1-取代的苯-2,4,5-三醇。继而,从H-6'到C-1的HMBC相关性推导出这两个碎片之间的连接性。另外,δ4.43(H-1”)处的当量亚甲基与δ172.2处的羰基的HMBC相关性将乙氧基残基连接至萘部分。对该部分结构的检测揭示其含有所需的14个不饱和度中的13个,并且仅指定两个羰基中的一个。因此,酚环和6,7-二羟基-萘-3-羧酸残基必须通过形成内酯环来连接以满足不饱和指数和分子式。进行长程延迟范围为2.75Hz至10Hz的HMBC实验。对于5Hz的nJ(C,H)耦合优化的HMBC光谱,对应于延迟时间Δ2=100ms,显示出四键长程相关性和更强的双键长程相关性。最后,如下组装化合物15的结构。H-4与δ162.5(C-10)处的碳共振的4JCHHMBC相关性允许推导羰基基团与C-2的连接,而H-6'与H-8之间的ROE相关性连同H-6'与C-2的4JCH HMBC相关性指示C-2处的酯化位点(图3)。因此,紫草素A(15)被确定为带有不寻常的δ-内酯环(对应于香豆素骨架)的芳基萘木酚素。
紫草素A的药物活性
J.Seigner等人(Frontiers in Pharmacology 10.3389/fphar.2019.00289)最近报道,在20μg/ml的起始浓度下,紫草提取物抑制白介素-1β(IL-1β)诱导的E-选择素mRNA水平约70%。E-选择素是NF-κB依赖性靶基因,并且IL-1β是充分描述的促炎介质,其在调节免疫和炎症应答,特别是涉及无菌损伤诸如创伤和钝伤的那些中发挥重要作用。测试的提取物显示包含尿囊素(1)、原儿茶酸(5)、对羟基苯甲酸(6)、咖啡酸(7)、迷迭香酸(12)和globoidnan A(14)。因此,使用IL-1刺激的HUVEC细胞测试单个化合物1、5、12和14的抗炎活性,并且通过实时PCR分析,确定E-选择素的mRNA表达的倍数变化。将这些与新的芳基萘木酚素紫草素A(15)和globoidnan B(8)、malaxinic酸(9)和咖啡酸乙酯(16)的抑制活性进行比较,后三者在如本文所公开的聚合草中第一次鉴定。
因此,如M.Hoeth等人,Guidance Molecules in Human Endothelial Cells,PlosOne 7,2012所描述,从脐带中分离原代HUVEC细胞,并且维持在补充有20%FCS(Sigma)、2mML-谷氨酰胺(Sigma)、青霉素(100单位/mL)、链霉素(100mg/mL)、5单位/mL肝素和25mg/mLECGS(Promocell)的M199培养基(Lonza)中,直到第5代。在用5ng/mL IL-1β(R&D Systems)刺激90min后,将HUVEC细胞与各种浓度的纯化化合物(1、5、8、9、12、14、15和16)一起预温育30分钟。然后分析细胞的E-选择素(SELE)mRNA表达的变化。因此,根据制造商的说明书,使用PeqGold总RNA分离试剂盒(VWR International)分离总RNA。使用随机六聚体(Fermentas)和鼠白血病病毒逆转录酶(Thermo Scientific Fisher)对1μg RNA进行逆转录。使用软件“Primer3”设计引物。以下引物序列用于qPCR:3-磷酸甘油醛脱氢酶(GAPDH)正向,5′-AGAAGGCTGGGGCTCATTT-3′和反向,5′-CTAAGCAGTTGGTGGTGCAG-3′;E-选择素(SELE)正向,5′-CCTGTGAAGCTCCCACTGA-3′和反向,5′-GGCTTTTGGTAGCTTCCATCT-3′。用SsoAdvanced Universal SYBR Green Supermix(BioRad)使用StepOnePlus仪器(AppliedBiosystems)进行实时PCR,并且将相对mRNA表达标准化为GAPDH。根据2-ΔΔCT方法计算mRNA表达的倍数变化。结果表示为一式三份的平均Ct值的平均诱导倍数,并且在表2中示出:
表2:1、5、8、9、12、14、15和16对IL-1β诱导的E-选择素表达的抑制作用。
有效浓度(EC)至少基于三个独立实验。
令人惊讶地,显示尿囊素(化合物1)和迷迭香酸(化合物12)对E-选择素表达不显示任何抑制剂活性。用40μM有效浓度的globoidnan A(化合物14)可实现35%抑制的小效果,其中先前已知的globoidnan B(化合物8)未显示任何抑制活性。发现紫草素A(化合物15)在E-选择素抑制中更有效,在50μM的EC下抑制50%。咖啡酸乙酯(化合物16)代表在64μM的浓度下将E-选择素表达抑制70%的最具活性的抑制剂。已知的原儿茶酸(化合物5)以及新鉴定的malaxinic酸(化合物9)也显示高于50%的抑制作用,但仅在更高的有效浓度下。与后两种化合物相比,紫草素A(15)和咖啡酸乙酯(16)在半浓度下有效。
实施例组成
在以下学术实施例中,指定了组合物,其仅旨在是示例性的,并且不应限制本发明的范围。
本文所公开的量纲和值不应理解为严格限于所引用的精确数值。相反,除非另外指明,否则每个此类量纲旨在表示所述值以及围绕该值功能上等同的范围。例如,公开为“40mm”的量纲旨在表示“约40mm”。
除非明确排除或以其它方式限制,本文中引用的每一篇文献,包括任何交叉引用或相关专利或专利申请以及本申请对其要求优先权或其有益效果的任何专利申请或专利,均据此全文以引用方式并入本文。对任何文献的引用不是对其作为与本发明的任何所公开或本文受权利要求书保护的现有技术的认可,或不是对其自身或与任何一个或多个参考文献的组合提出、建议或公开任何此类发明的认可。此外,当本发明中术语的任何含义或定义与以引用方式并入的文献中相同术语的任何含义或定义矛盾时,应当服从在本发明中赋予该术语的含义或定义。
虽然已举例说明和描述了本发明的具体实施方案,但是对于本领域技术人员来说显而易见的是,在不脱离本发明的实质和范围的情况下可作出各种其他变化和修改。因此,本文旨在于所附权利要求中涵盖属于本发明范围内的所有此类变化和修改。
<110> 宝洁公司(The Procter & Gamble Company)
<120> 抑制促炎基因表达的紫草素、芳基萘木酚素
以及包含它们的药物组合物
<130> CM05167FQ
<160> 4
<170> PatentIn版本3.5
<210> 1
<211> 19
<212> DNA
<213> 3-磷酸甘油醛脱氢酶(GAPDH)
<400> 1
agaaggctgg ggctcattt 19
<210> 2
<211> 20
<212> DNA
<213> 3-磷酸甘油醛脱氢酶(GAPDH)
<400> 2
ctaagcagtt ggtggtgcag 20
<210> 3
<211> 19
<212> DNA
<213> E-选择素(SELE)
<400> 3
cctgtgaagc tcccactga 19
<210> 4
<211> 21
<212> DNA
<213> E-选择素(SELE)
<400> 4
ggcttttggt agcttccatc t 21
Claims (15)
2.根据权利要求1或2所述的芳基萘木酚素,其中R1、R2、R3和R4各自为羟基,并且R5为乙氧基。
3.一种药物组合物,所述药物组合物包含
a)活性剂,所述活性剂包含一种或多种根据权利要求1或2中任一项所述的芳基萘木酚素;以及
b)药学上可接受的载体。
4.根据权利要求3所述的药物组合物,所述药物组合物还包含附加活性剂,其中所述附加活性剂优选为止痛药、具有抗炎活性的活性剂、活性增强剂或它们的组合,更优选地其中所述附加活性剂为天然止痛药,更优选地其中所述附加活性剂为从聚合草中提取的天然止痛药。
5.根据权利要求4所述的药物组合物,其中所述附加活性剂包括咖啡酸乙酯、malaxinic酸、globoidnanA、原儿茶醛、聚合草根提取物或它们的组合,优选地其中所述附加活性剂包括咖啡酸乙酯、malaxinic酸、globoidnanA或它们的组合。
6.根据权利要求4或5所述的药物组合物,其中所述附加活性剂还包括尿囊素、对羟基苯甲酸葡糖苷、5-羟甲基-2-糠醛、原儿茶酸、对羟基苯甲酸、咖啡酸、globoidnanB、3-羧基-6,7-二羟基-1-(3',4'-二羟基苯基)-萘、(+)-香茶菜素、迷迭香酸、α-羟基氢咖啡酸、三叶木酚素D、亚麻酸、亚油酸、羟基棕榈酸或它们的组合,优选地包括globoidnanB、三叶木酚素D、3-羧基-6,7-二羟基-1-(3',4'-二羟基苯基)-萘、香茶菜素和/或它们的组合。
7.根据权利要求3至6中任一项所述的药物组合物,其中所述组合物包含药学上安全有效量,优选在需要其的位置处提供30μM至65μM活性剂的局部浓度的量,更优选在需要其的位置处提供40μM至60μM活性剂的局部浓度的量,更优选在需要其的位置处提供45μM至约55μM活性剂的局部浓度的量,更优选在需要其的位置处提供48μM至52μM活性剂的局部浓度的量的所述一种或多种芳基萘木酚素活性剂,更优选地其中所述组合物包含1μg/g组合物至10μg/g组合物的量,更优选2μg/g组合物至7.5μg/g组合物的量,以及甚至更优选3μg/g组合物至5μg/g组合物的量的所述一种或多种芳基萘木酚素活性剂。
8.根据权利要求5至7中任一项所述的药物组合物,其中所述组合物包含安全有效量,优选在需要其的位置处提供50μM至80μM咖啡酸乙酯的局部浓度的量,更优选在需要其的位置处提供55μM至75μM咖啡酸乙酯的局部浓度的量,更优选在需要其的位置处提供60μM至约70μM咖啡酸乙酯的局部浓度的量,更优选在需要其的位置处提供62μM至66μM咖啡酸乙酯的局部浓度的量的咖啡酸乙酯,更优选地其中所述组合物包含更多的1μg/g组合物至15μg/g组合物的量,更优选2.5μg/g组合物至10μg/g组合物的量,以及甚至更优选5μg/g组合物至7.5μg/g组合物的量的所述咖啡酸乙酯。
9.根据权利要求3至8中任一项所述的药物组合物,其中所述组合物在用白介素1β活化后将E-选择素转录抑制至少30%、优选至少40%、更优选至少45%、更优选至少48%、甚至更优选至少50%。
10.根据权利要求3至9中任一项所述的药物组合物,其中所述组合物是局部用组合物或用于内部施用的组合物,优选地其中所述局部用组合物呈软膏剂、油膏剂、糊剂、粘性液体、洗剂、凝胶、乳膏、摩丝、泡沫、涂料或施用于条带或能够溶解的条带的任何其他粘合剂产品或它们的组合的形式,并且/或者其中所述用于内部施用的组合物优选地呈胶囊、片剂、锭剂、咀嚼片、口香糖、糖浆、液体、摩丝或它们的组合的形式。
11.根据权利要求10所述的药物组合物,其中所述药学上可接受的载体是包含至少一种载体基质材料、表面活性剂和水的油包水乳液,优选地其中所述载体基质材料选自无毒油、无毒食用油、饱和或不饱和脂肪醇、脂族烃、长链甘油三酯、脂肪酯以及它们的混合物,更优选地其中所述载体基质材料是花生油。
12.根据权利要求3至11中任一项所述的药物组合物,其中所述组合物还包含防腐剂、染料、芳香剂、稳定剂、缓冲剂或它们的组合中的至少一者。
13.根据权利要求3至12中任一项所述的药物组合物,其中所述组合物在药学上可接受的载体中至少包含根据权利要求3所述的芳基萘木酚素紫草素A、咖啡酸乙酯、malaxinic酸和globoidnanA,所述药学上可接受的载体包含至少一种无毒食用油、至少一种乳化剂、至少一种缓冲剂、水和防腐剂,优选地其中所述组合物包含在需要其的位置处提供局部浓度约50μM紫草素A的量的紫草素A和在需要其的位置处提供局部浓度约65μM咖啡酸乙酯的量的咖啡酸乙酯,更优选地其中所述组合物在药物载体中包含3μg/g组合物至5μg/g组合物的量的紫草素A和5μg/g组合物至7.5μg/g组合物的量的咖啡酸乙酯,所述药物载体优选地至少包含花生油、至少一种乳化剂、至少一种缓冲剂、水、芳香剂和防腐剂。
14.根据权利要求1或2中任一项所述的一种或多种芳基萘木酚素和根据权利要求3至13中任一项所述的药物组合物,其用于抑制和/或治疗炎症,优选用于治疗断骨、肌腱损伤、疼痛性关节和肌肉、急性上背部和下背部疼痛、膝关节病、钝伤、用于减少关节变形的肿胀、用于改善骨关节炎关节中的关节活动性和/或它们的组合。
15.根据权利要求2所述的芳基萘木酚素紫草素A作为标记物质用于定量分析使用紫草根和/或从紫草根提取的产品中的活性物质的用途。
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