CN106232111A - 具有凉爽特性的环丙烷甲酰胺 - Google Patents
具有凉爽特性的环丙烷甲酰胺 Download PDFInfo
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- CN106232111A CN106232111A CN201580020509.5A CN201580020509A CN106232111A CN 106232111 A CN106232111 A CN 106232111A CN 201580020509 A CN201580020509 A CN 201580020509A CN 106232111 A CN106232111 A CN 106232111A
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Abstract
本发明提供了个人护理组合物诸如口服药物组合物,其包含含有一种或多种凉爽剂的风味剂体系。由凉爽剂提供的舒适凉爽感在更快发生、更高强度、影响或更长持续时间方面得到增强,这改善了所述组合物对消费者的吸引力和可接受性。
Description
技术领域
本发明涉及个人护理组合物诸如药物,所述组合物包含具有一种或多种凉爽剂的风味剂体系,其中由所述凉爽剂提供的凉爽感在更快发生、更高强度和/或更长持续时间方面得到增强,从而改善了所述组合物对消费者的吸引力和可接受性。
背景技术
药物,包括液体药物和固体剂型,通常被消费者用于治疗疾病,减轻症状和/或改善他们的健康状态。然而,许多药物具有对消费者而言不可取的感官体验。首先,一些药物味道过苦,这是由制剂中的某些活性物质和赋形剂造成的。此外,在组合物被口服摄入与消费者开始感觉到缓解之间,通常存在滞后。例如,患有感冒症状(包括喉咙痛和鼻充血)的消费者可服用多症状缓解(MSR)感冒/流感药物。然而,她将感受不到感冒症状的即时缓解,相反她必须等待产品被吸收到血液中,并且在她的症状缓解之前成为生物可利用的。
令人不悦的味道和口感已被描述为具有以下方面:苦味、金属腥味、涩味、咸味、麻味、针刺感、灼热感、或刺痛感、甚至是刺激感。为缓解药物的负面美学,药物通常包含风味剂、甜味剂、和感觉剂,以有助于改善消费者的体验。此外,药物中的感觉剂分子可传达功效信号,并且在活性物质成为生物可利用的之前,提供一定的症状缓解。此类功效信号包括凉爽感、麻刺感、麻木感、温热感、甘甜感、和流变感如相变和发泡或起泡。
已描述了大量天然或合成源的凉爽剂化合物。最熟知的化合物为薄荷醇,尤其是l-薄荷醇,其天然存在于薄荷油,特别是野薄荷(Mentha arvensis L)和绿薄荷(Menthaviridis L)中。在薄荷醇异构体中,l-异构体最广泛存在于自然界中,并且是通常被命名为薄荷醇的物质,具有凉爽剂性质。L-薄荷醇具有特征性的胡椒薄荷气味,具有爽口清新的味道,并且当施用到皮肤和黏膜表面上时,产生凉爽的感觉。其它薄荷醇异构体(新薄荷醇、异薄荷醇和新异薄荷醇)部分相似,但是气味和味道不同,即某些具有令人不悦的味道,描述为泥土味、樟脑味、霉味。异构体之间的主要差异在于它们的凉爽效力。L-薄荷醇提供最具效力的凉爽感,即具有约800ppb的凉爽度下限,即可清晰辨识凉爽效果时的浓度。在此含量下,其它异构体无凉爽效果。例如,据报导,d-新薄荷醇具有约25,000ppb的凉爽度阈值,并且l-新薄荷醇具有约3,000ppb的凉爽度阈值。(R.Emberger和R.Hopp,“Synthesis andSensory Characterization of Menthol Enantiomers and Their Derivatives for theUse in Nature Identical Peppermint Oils”,Specialty Chemicals(1987),7(3),193-201)。该研究展示了l-薄荷醇在凉爽和清新方面的优异感官性质以及立体化学对这些分子活性的影响。
在合成的凉爽剂中,许多是薄荷醇的衍生物或者是与薄荷醇结构上相关的,即包含环己烷部分、以及是官能团衍生的,所述官能团包括羧酰胺、缩酮、酯、醚和醇。示例包括对薄荷烷甲酰胺化合物诸如商业上被称为“WS-3”的N-乙基对薄荷烷-3-甲酰胺,以及此系列的其它化合物诸如WS-5(N-乙氧基羰基甲基对薄荷烷-3-甲酰胺)、WS-12[N-(4-甲氧基苯基)-对薄荷烷-3-甲酰胺]和WS-14(N-叔丁基对薄荷烷-3-甲酰胺)。薄荷烷羧基酯的示例包括WS-4和WS-30。结构上与薄荷醇不相关的合成羧酰胺凉爽剂的示例是被称为“WS-23”的N,2,3-三甲基-2-异丙基丁酰胺。合成凉爽剂的其它示例包括醇衍生物,诸如称为TK-10的3-(1-薄荷氧基)-丙-1,2-二醇、异蒲勒醇(商品名为Coolact P)和对薄荷烷-3,8-二醇(商品名为Coolact 38D);称为MGA的薄荷酮甘油缩醛;薄荷酯诸如乙酸薄荷酯、乙酰乙酸薄荷酯、由Haarmarm and Reimer提供的称为的乳酸薄荷酯、和以商品名Physcool得自V.Mane的琥珀酸单薄荷酯。TK-10描述于Amano等人的美国专利4,459,425中。薄荷醇的其它醇和醚衍生物描述于例如GB 1,315,626和美国专利4,029,759;5,608,119和6,956,139中。WS-3和其它甲酰胺凉爽剂描述于例如美国专利4,136,163;4,150,052;4,153,679;4,157,384;4,178,459和4,230,688中。附加的N-取代的对薄荷烷甲酰胺描述于WO 2005/049553A1中,包括N-(4-氰甲基苯基)对薄荷烷甲酰胺、N-(4-氨磺酰苯基)对薄荷烷甲酰胺、N-(4-氰基苯基)对薄荷烷甲酰胺、N-(4-乙酰基苯基)对薄荷烷甲酰胺、N-(4-羟甲基苯基)对薄荷烷甲酰胺和N-(3-羟基-4-甲氧苯基)对薄荷烷甲酰胺。其它N-取代的对薄荷烷甲酰胺包括氨基酸衍生物,如公开于WO 2006/103401以及美国专利4,136,163;4,178,459和7,189,760中的那些,诸如N-((5-甲基-2-(1-甲基乙基)环己基)羰基)甘氨酸乙酯和N-((5-甲基-2-(1-甲基乙基)环己基)羰基)丙氨酸乙酯。包括那些氨基酸如甘氨酸和丙氨酸的薄荷基酯公开于例如EP310 299和美国专利3,111,127;3,917,613;3,991,178;5,5703,123;5,725,865;5,843,466;6,365,215;6,451,844;和6,884,903中。缩酮衍生物描述于例如美国专利5,266,592;5,977,166和5,451,404中。结构上与薄荷醇无关但是已报道具有类似的生理凉爽效果的附加试剂包括α-酮基烯胺衍生物,其描述于美国专利6,592,884中,包括3-甲基-2-(1-吡咯烷基)-2-环戊烯-1-酮(3-MPC)、5-甲基-2-(1-吡咯烷基)-2-环戊烯-1-酮(5-MPC)、和2,5-二甲基-4-(1-吡咯烷基)-3(2H)-呋喃酮(DMPF);icilin(也称为AG-3-5,化学名1-[2-羟基苯基]-4-[2-硝基苯基]-1,2,3,6-四氢吡啶-2-酮),描述于Wei等人,J.Pharm.Pharmacol.(1983),35:110-112中。对薄荷醇和合成凉爽剂的凉爽剂活性的综述包括H.R.Watson等人的J.Soc.Cosmet.Chem.(1978),29,185-200和R.Eccles,J.Pharm.Pharmacol.(1994),46,618-630。
本发明提供包含一种或多种可用于药物中的凉爽剂的药物组合物,其中由所述一种或多种凉爽剂提供的凉爽感和清新感在发生、强度和/或持续时间方面得到增效。
发明内容
提供凉爽感的药物组合物,所述组合物包含具有以下结构的化合物:
R1选自H、烷基、氨基烷基、烷氧基;
Q=H2、O、-OR1、-N(R1)2、-OPO(OR1)x、-PO(OR1)x、-P(OR1)x,其中x=1-2;
V=NR1、O、-OPO(OR1)x、-PO(OR1)x、-P(OR1)x,其中x=1-2;
W=H2、O;
对于n=0,X、Y=独立地选自H、芳基、萘基;
对于n≥1,X、Y=脂族CH2或芳族CH,并且Z选自脂族CH2、芳族CH或杂原子;
A=低级烷氧基、低级烷硫基、芳基、被取代的芳基或稠合芳基;并且立体化学可在标记*的位置处变化。
对于本领域的技术人员来说,通过下面的详细描述,本发明的这些和其它的特征、方面和优点将变得显而易见。
附图说明
图1为溶剂空白注射和化合物28级分1三次平行注射的UV色谱图叠加。相对峰面积百分比示于该混合物中观察到的每种同分异构化合物上方。所有峰出现在QDa质谱的标称m/z 374处,表明这些是同分异构物质。
图2为溶剂空白注射和化合物28级分2三次平行注射的UV色谱图叠加。相对峰面积百分比示于该混合物中观察到的每种同分异构化合物上方。所有峰出现在QDa质谱的标称m/z 374处,表明这些是同分异构物质。级分2具有比级分1更高的同分异构纯度。
图3为化合物28级分1(虚线)和级分2(实线)分离分析期间产生的UV色谱图迹线叠加。这些叠加示出,一些组分包含于两个级分中,而一些组分基本上是独特的,并且这两种级分内的异构体的比率不同。所有峰出现在QDa质谱的标称m/z 374处,表明这些是同分异构物质。
具体实施方式
本发明涉及某些环丙烷甲酰胺结构在低浓度下递送促使凉爽响应的途径的发现。已发现,具有2-氨基-丙酰胺(CAS#4726-84-5)的(1R,2S,5R)-5-甲基-2-(1-甲基乙基)-N-(2-苯乙基)-环丙烷甲酰胺(CAS#824947-52-6)和(1R,2S,5R)-5-甲基-2-(1-甲基乙基)-N-(2-苯乙基)-环丙烷甲酰胺(CAS#847564-71-0)结构具有增强的持久凉爽特性,并且具有氨基乙烷(CAS#75-04-7)部分的(1R,2S,5R)-5-甲基-2-(1-甲基乙基)-N-苯基-环丙烷甲酰胺和(1R,2S,5R)-5-甲基-2-(1-甲基乙基)-N-1-萘基-环丙烷甲酰胺(CAS#863091-95-6)结构递送温热感。两种类型的环丙烷甲酰胺(凉爽和温热)在低使用含量(1-10ppm)下是有效的。上文化合物指定的立体化学基于由薄荷醇原料衍生的主要异构体(1R,2S,5R)。由于从酰胺键构建出另外的手性位点,因此可出现一种或多种附加的异构体和/或对映体。
如WO 2009/067410中所公开的,由环丙烷甲酰胺主链构建出的结构已被用作抗癌剂。如美国专利4,150,052中所示,仅一些所选环丙烷甲酰胺衍生物具有显著的凉爽感。对WO 2009/067410中所公开的分子进行它们在破坏前列腺癌细胞方面的TRPM8活性的评定。本文所示数据示出,激发TRPM8不一定表示将察觉到凉爽感。因此,凉爽将为不可取的效应,并且有时它们将被避免。
因此,本发明基于以下发现:当配制成消费产品时,可使用所选分子促发凉爽响应。本发明的第二目的示出以下发现:所选环丙烷甲酰胺衍生物在非常低含量下可提供持久凉爽感,获得制剂效率,尤其是凉爽剂化合物(凉爽剂),如下文所述那些。
除非另外指明,下文中所用的所有百分比和比率均按总组合物的重量计。除非另外指明,本文提及的所有成分的百分比、比率和含量均基于该成分的实际含量,并且不包括在市售产品中可与这些成分一起使用的溶剂、填料或其它物质。
除非另外指明,本文所涉及的所有测量均在25℃下进行。
如本文所用,“剂量”是指根据可靠的医学经验,包含一定量适于在单个场合给药的药物活性成分的药物(如液体药物或口服剂量单元)的体积。剂型可口服。在一个示例中,所述剂型可为液体药物,并且可为约30mL,在另一个示例中为约25mL,在另一个示例中为约20mL,在另一个示例中为约15mL,并且在另一个示例中为约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,所述剂型可为固体剂型,并且可为约5g至约25mg,在另一个示例中约3g至约100mg,在另一个示例中约2g至约250mg,在另一个示例中约1.6g至约500mg,并且在另一个示例中约1g至约750mg。在一个示例中,所述剂型可为固体剂型,其中一个剂量为约3g,并且在另一个示例中一个剂量为约1.6g。给定液体剂量大小下,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。
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,其可包含维生素、矿物质和植物药材(VMS)。
药物组合物可为任何适宜形式,包括液体组合物和固体口服剂型。液体组合物的非限制性示例可包括糖浆(包括咳嗽糖浆)、呼吸系统用制剂(包括MSR感冒/流感药物)、饮料、补给水、泡沫组合物、凝胶组合物、悬浮于液体制剂中的颗粒、凝胶或泡沫中的固体、生理盐水洗剂、以及它们的组合。固体口服剂型的非限制性示例可包括片剂、胶囊剂、囊片、小药囊、舌下剂型、颊面剂型、软凝胶(包括LiquiCapsTM和其它液体填充胶囊剂)、可溶性剂型(包括可溶性条)、膜、口香糖(包括中心填充的口香糖)、软糖(包括中心填充的软糖)、锭剂、中心填充的片剂、粉末、颗粒、粒料、微球体、纳米球体、小珠或彩色糖豆、以及它们的组合。片剂可包括压缩片剂、咀嚼片、可溶性片剂等。片剂可包括压缩片剂、咀嚼片、可溶性片剂等。在其它示例中,可将所述药物以膏剂形式施用于皮肤如在其它示例中,所述药物可被吸入如鼻喷剂或吸入剂。在其它示例中,所述药物可存在于饮料中如温热饮料。在其它示例中,所述药物可包含药物活性物质。在其它示例中,所述药物不包含药物活性物质和/或VMS,但是可通过凉爽感,至少部分缓解症状和/或提供健康有益效果。
所述药物可为可直接递送至口腔、喉咙和/或皮肤的形式。在一些示例中,所述药物组合物可经由递送装置递送,所述递送装置选自点滴器、泵、喷涂器、滴液器、经由鼻腔通道递送的生理盐水冲洗器、杯、瓶、罐、加压喷雾器、雾化器、吸气装置、可挤压小袋、电动注射器、泡罩卡、和其它包装和设备、以及它们的组合。喷涂器、雾化器和吸气装置可连有电池或电源。
所谓“个人护理组合物”是指在常规使用过程中被施用至身体表面或与身体表面接触以提供有益效果的产品。身体表面包括皮肤,例如表皮或粘膜;身体表面还包括与身体表面相关联的结构,例如毛发、牙齿、或指/趾甲。个人护理组合物的示例包括被施用于人体以改善外观、清洁、气味控制、整体美观,或用于健康和保健的产品。个人护理组合物的非限制性示例包括药物,包括固体剂型和液体组合物;口腔护理组合物,如牙粉、漱口水、摩丝、泡沫、口喷剂、锭剂、咀嚼片、口香糖、牙齿增白条带、牙线和牙线涂层、口气清新可溶解条带、义齿护理产品、义齿粘合剂产品;剃须后凝胶和霜膏、剃须前准备物、剃须凝胶、霜膏或泡沫、保湿剂和洗剂;咳嗽和感冒组合物、凝胶、胶囊、和咽喉喷剂;免洗型皮肤洗剂和霜膏、洗发剂、沐浴剂、施用于咽喉、胸部以及身体其它部位的膏剂如毛发调理剂、毛发染色和漂白组合物、摩丝、沐浴凝胶、条皂、盥洗室条皂、止汗剂、除臭剂、脱毛剂、口红、粉底、睫毛膏、防晒美黑霜和防晒乳液;女性护理组合物,如涉及吸收制品的洗剂和洗剂组合物;涉及吸收或一次性制品的婴儿护理组合物;以及用于动物如狗和猫的口腔清洁组合物。
在一个示例中,本发明可涉及液体药物,尤其是旨在被患有感冒/流感或过敏症状的人使用的液体药物,所述症状如充血、咽痛、喉痒、鼻痒、咳嗽、以及它们的组合。所述液体药物可按需提供缓解,以减轻鼻腔和咽喉的疼痛和瘙痒,减轻咳嗽,和/或减轻充血。所述制剂可发挥作用以物理涂覆口腔和喉咙,在位于咽喉层的上皮细胞上产生起缓和作用的屏障。此外,所述组合物可形成羽层,其可进一步有助于减轻充血。所述制剂还可减轻炎症,这可有助于缓解与咳嗽和/或咽痛相关的疼痛。在一个示例中,所述液体药物不包含活性物质。在另一个示例中,所述液体药物包含活性物质,所述活性物质可包括止痛剂、减充血剂、和/或镇咳剂。在一个示例中,所述液体药物可被吞咽。在另一个示例中,所述液体药物可被用于洗口和/或漱口,然后吐出。
如本文所用,术语“分配器”是指任何适于分配组合物如药物的泵、管或容器。所述药物可为膏剂、凝胶、泡沫、液体等形式。
本发明组合物的组分描述于以下段落中。
SEQ ID NO | 序列 |
1 | 人TRPV1 DNA序列 |
2 | 人TRPA1 DNA序列 |
3 | 人TRPM8 DNA序列 |
如本文所用,术语“TRPV1”或“TRPV1受体”是指瞬时受体电位香草酸受体亚型1,其是优先表达在小直径的感觉神经元上的配体门控型、非选择性阳离子通道并且检测到有毒物以及其它物质。TRPV1受体以SEQ ID NO:1提供。TRPV1受体响应于,例如,伤害和疼痛刺激。有毒刺激将包括提供辛辣(即辣)感觉的那些。
如本文所用,术语“TRPV1激动剂”是指根据本文所述的FLIPR方法,在1mM的浓度下提供比细胞中存在的基值钙含量高至少1000计数或20%的钙通量计数的任何化合物。术语“计数”定义为细胞系由于钙离子跨细胞膜流入时导致的荧光变化,所述钙离子与细胞内存在的钙离子敏感染料反应。
如本文所用,术语“TRPV1拮抗剂”是指根据在1mM浓度下提供比350μM辣椒素对TRPV1受体的活化低至少1000计数或20%钙通量计数的任何化合物。
如本文所用,术语“TRPV1减敏剂”是指显示激动剂活性并且造成已知TRPV1激动剂所致活化下降的任何化合物。
如本文所用,术语“TRPA1”或“TRPA1受体”是指瞬时受体电位阳离子通道亚家族A成员1,具有包含18个预测的锚蛋白重复的大的富含半胱氨酸的N末端。TRPA1受体以SEQ IDNO:2提供。TRPA1是配体门控型的、非选择性阳离子通道,优先在小直径感觉神经元上表达。
如本文所用,术语“TRPA1激动剂”是指根据本文所述的FLIPR方法,在1mM的浓度下提供比细胞中存在的基值钙含量高至少1000计数或20%的钙通量计数的任何化合物。术语“计数”定义为细胞系由于钙离子跨细胞膜流入时导致的荧光变化,所述钙离子与细胞内存在的钙离子敏感染料反应。
如本文所用,术语“TRPA1拮抗剂”是指根据在1mM浓度下提供比50μM异硫氰酸烯丙酯对TRPV1受体的活化低至少1000计数或20%钙通量计数的任何化合物。
如本文所用,术语“TRPA1减敏剂”是指显示激动剂活性并且造成已知TRPA1激动剂所致活化下降的任何化合物。
如本文所用,术语“TRPM8”或“TRPM8受体”是指对冷-和薄荷醇-敏感的受体(CMR1)或TRPM8。用于所述受体的TRPM8命名来自于其作为瞬时受体电位(TRP)家族的非选择性阳离子通道的特性,其通过刺激包括低温、薄荷醇和其它化学凉爽剂而被活化。TRPM8受体以SEQ ID NO:3提供。
通常称为TRPM8或薄荷醇受体的凉爽受体已被示为区分引发和传播非热性凉爽感觉的有机分子强度和持续时间的途径(D.D.Mckemy,The Open Drug Discovery Journal2:81-88 2010)。McKemy报导了许多TRPM8激动剂的EC50值,所述值在100nM至19mM范围区间内,从而示出,信道可在不同浓度的宽泛结构范围内被活化。该信道还具有CRM1和TRPP8的命名。后者如此命名归因于其对前列腺细胞的辨识,其中它被用作识别以前列腺癌为靶标的分子的途径。
如本文所用,术语“TRPM8激动剂”是指根据本文所述的FLIPR方法,加入到TRPM8受体时,产生相对于背景的任何荧光增加的任何化合物。
如本文所用,术语“TRPM8拮抗剂”是指直接加入时不显示任何激动活性并且抑制已知TRPM8激动剂所致TRPM8受体活化的任何化合物。使用本文所述的FLIPR方法,相对于WS5活化TRPM8受体,钙通量下降>20%的分子被认为是TRPM8拮抗剂。
如Merck Manual定义的术语效能是指,如分级剂量响应曲线如所描绘的,产生50%化学最大效应所需的化合物浓度(EC50)或剂量(ED50)。当占用和响应之间存在线性关系时,EC50等于Kd(解离常数,其为50%的与所述受体结合的所考虑物质的量度)。通常,在受体占用和响应之间存在信号放大,这致使响应的EC50大幅小于(即位于对数剂量响应曲线横坐标的左边)受体占用的KD。效能取决于化合物对其受体的亲和力,以及化合物-受体交互作用与响应相关联的效率。产生效应所需的化合物的剂量与效能负相关。一般来讲,仅在造成施用不可行的大剂量化合物的需要时,低效能才是重要的。量子剂量响应曲线提供化合物效能信息,所述信息不同于由分级剂量响应曲线导出的信息。在量子剂量响应关系中,ED50为50%个体表现出指定量子效应的剂量。
对口腔和其它粘膜表面以及皮肤尤其具有生理凉爽效果的凉爽剂或化合物是多种产品中的常见成分,所述产品包括可食用组合物、个人护理组合物、以及风味剂或香料组合物。可食用组合物的示例包括糖果、蜜饯、巧克力、口香糖、饮料和口服药物。先前已描述了个人护理组合物,包括口腔护理组合物。由凉爽剂提供的舒适凉爽感觉有利于产品的吸引力和可接受性。具体地,药物可用凉爽剂配制,因为它们提供期望的感官体验。具体地,患有感冒/流感的消费者可享受他们口腔和咽喉中的凉爽感觉,以有助于缓解他们的咽痛,并且还可向他们的可因发烧和/或过敏而感觉干热的口腔提供整体凉爽感。此外,施用于皮肤时,如使用膏剂时,凉爽感在可能也是感觉舒适的,尤其是使用者因发烧而发热时。
现在得到确认的是诸如凉爽或寒冷等感觉可归因于在末梢神经纤维处的受体通过刺激如低温或化学凉爽剂的活化,其产生电化学信号,该信号传送至大脑,然后其将进来的信号翻译、组织并且整合成知觉或感觉。在哺乳动物的感觉神经纤维处,不同种类的受体已被涉及到感觉寒冷的温度或化学凉爽剂刺激中。在这些受体中,涉及感觉寒冷的主要候选者已被鉴别并且指定为寒冷和薄荷醇敏感受体(CMR1)或TRPM8。用于所述受体的TRPM8命名来自于其作为瞬时受体电位(TRP)家族的非选择性阳离子通道的特性,其通过刺激包括低温、薄荷醇和其它化学凉爽剂而被活化。然而,感知皮肤或口腔表面上令人愉快的凉爽感觉下的精确机理目前还未被清楚地理解。虽然已证明TRPM8受体被薄荷醇和其它凉爽剂活化,但是未完全理解的是其它哪些受体可能被涉及,并且这些受体需要被刺激或者也许被压制到什么样的程度,以使得总体感觉是愉快、凉爽和清新的。例如,薄荷醇广泛用作凉爽剂,但是薄荷醇还能够产生其它感觉,包括发麻、灼热、刺痛和灼痛以及薄荷气味和苦味。因此,能够推断出的是薄荷醇作用在多种不同的受体上,包括寒冷、温暖、疼痛和味觉受体。
可用于溶解本发明化合物如下文所述化合物28的溶剂示例基于溶解度参数和粘结性能,所述溶解度参数和粘结性能由Charles Hansen在Charles M.Hansen的“HansenSolubility Parameters:A User's Handbook”(CRC Press,2007)和由Allan F.M.Barton(1999)编辑的“The CRC Handbook and Solubility Parameters and CohesionParameters”中进行了解释。每种材料由三维空间中的三个点界定,并且这三个点被称为Hansen溶解度参数(HSP),其可如下定义。
溶解度参数是理论计算出的数值常数,它是预测溶剂材料对特定溶质溶解能力的可用工具。当溶剂的溶解度参数在溶质即待溶解材料的溶解度参数范围内时,可能发生所述溶质的溶解。存在三个Hansen经验和理论导出的溶解度参数:分散力组分(δD)、极性或偶极交互作用组分(δP)和氢键组分(δH)。三个参数(即分散、极性和氢键)中的每一个表示溶解力或溶剂能力的不同特性。将三个参数组合在一起为溶剂总体强度和选择性的量度。总Hansen溶解度参数为前述三个参数平方之和的平方根,其提供了更加综合的溶剂溶解力描述。单独溶解度参数和总溶解度参数单位以MPa0.5示出。然后,可将材料的溶解度参数绘制于正规三维图中。由所述位置(δD、δP、δH),投射半径以形成包围溶解度区域的球体,因此其参数位于此空间内的任何溶剂应能够溶解所关注的溶质。材料(即溶质)的HSP坐标与材料(溶剂)的HSP坐标间的距离在本文中被指定为Ra。三维距离Ra由下式定义:Ra2=4(δD1-δD2)2+(δP1-δP2)2+(δH1-δH2)2。以所选目标分子为中心计算Hansen球体公式,在此情况下,所选目标分子为化合物28和各自的各种异构体(L、D和新)和对映体。目标极性、分散力和氢键HSP是由5.1.9版“Molecular Modeling Pro”软件(ChemSW,Fairfield Calif.,www.chemsw.com)计算出的目标分子的Hansen溶解度参数或是得自Dynacomp软件的Hansen溶解度。在此分析中,同样经由此软件计算出每种溶剂的溶解度参数。半径Ra=14的球体内的是化合物28和异构体物质将溶解于其中的溶剂。为使在所选溶剂中的溶解度>5%,δ分散的优选范围为±3个单位,约15.2至21.2(MPa)0.5。δ极性的优选范围为±6个单位,约0至10.8(MPa)0.5。δ氢键的优选范围为±13个单位,约0至25(MPa)0.5。化合物28的HSP计算为分散=17.8,极性=5.6,并且氢键=9.0。用于溶解所述羧酰胺衍生物的具有适宜Hansen溶解度参数的风味剂和芳香剂原材料的非限制性示例包括薄荷酮、香芹酮、松油、肉桂醛、乙醇、苄醇、桉油精、1,2-丙二醇、1,3-丙二醇、己烷、乙醇胺、环糊精和三醋精。
理想的是,凉爽剂可产生与薄荷醇所产生的类似的凉爽或清新感觉,但是没有与薄荷醇相关的某些缺点,如风味改变、苦的余味、异味、强的气味和灼热或刺激的感觉,尤其是在高浓度下。希望所述凉爽剂化合物仅仅拥有区别性的气味或风味,同时提供持久的令人愉快的清新凉爽的感觉,使得在使用后所述效应仍能够在相当长的时间内被察觉到,例如长于15分钟。薄荷醇一般提供起始高强度的凉爽作用,但是由于凉爽感觉在使用后几分钟内急剧下降,因此其效果是相当短暂的。相反,许多较长持续时间的凉爽剂化合物可能无法提供立即的凉爽感觉,即在施用的几秒钟之内,尤其是当以低含量使用时。因此,有持续的对在以下方面加强凉爽剂化学品的活性的方法的需要:加快凉爽感觉的发生、加强凉爽感觉(尤其是在较低浓度时)并且产生比薄荷醇所提供的更加持久的凉爽和清新的感觉。
如前所述,本发明涉及以下发现:如下所示的特点(1R,2S,5R)-5-甲基-2-(1-甲基乙基)-N-(2-苯乙基)-环丙烷甲酰胺结构在低浓度下递送促使凉爽响应的途径。
如下所示的结构I,包括本发明化合物并且包括化合物28,代表已令人惊奇地发现可用作TRPM8活化调节剂的类属。结构I代表具有下文所示结构的甲醇的杂烷基取代的芳基或杂烷基-芳基取代的烷基酰胺,并且包括其任何可接受的盐或溶剂化物;其中:
结构I
R1选自H、烷基、氨基烷基、烷氧基;
Q=H2、O、-OR1、-N(R1)2、-OPO(OR1)x、-PO(OR1)x、-P(OR1)x,其中x=1-2;
V=NR1、O、-OPO(OR1)x、-PO(OR1)x、-P(OR1)x,其中x=1-2;
W=H2、O;
对于n=0,X、Y=独立地选自H、芳基、萘基;
对于n≥1,X、Y=脂族CH2或芳族CH,并且Z选自脂族CH2、芳族CH或杂原子;
A=低级烷氧基、低级烷硫基、芳基、被取代的芳基或稠合芳基;并且立体化学可在标记*的位置处变化。
上文结构I中设想了多种立体异构体,其中允许取代,并且每个立体中心的相对构型将决定对受体的活性。虽然已知侧链基团的立体化学对分子活性可能是重要的,但是这些化合物的体内活性是高度不可预测的。在一些情况下,相同分子的异构体可具有能与之相比的活性。在其它情况下,相同分子的立体异构体可具有增强或减弱的对受体的活性。在一些情况下,单独的立体异构体可不具有活性。
受关注的特定化合物可衍生自存在于天然(-)-薄荷醇中的1R,2S,5R两者构型。在这些情况下,1R,2S,5R-薄荷基酰胺的立体异构衍生物将存在于所述分子的取代烷基侧链片段中。虽然已知1R,2S,5R构型对活性而言是重要的,但是N-取代的薄荷基酰胺衍生物的1S,2S,5R新-异构体也已示出前途。
新-异构体:
R1选自H、烷基、氨基烷基、烷氧基;
Q=H2、O、-OR1、-N(R1)2、-OPO(OR1)x、-PO(OR1)x、-P(OR1)x,其中x=1-2;
V=NR1、O、-OPO(OR1)x、-PO(OR1)x、-P(OR1)x,其中x=1-2;
W=H2、O;
对于n=0,X、Y=独立地选自H、芳基、萘基;
对于n≥1,X、Y=脂族CH2或芳族CH,并且Z选自脂族CH2、芳族CH或杂原子;
A=低级烷氧基、低级烷硫基、芳基、被取代的芳基或稠合芳基;并且立体化学可在标记*的位置处变化。
在化合物28和776情况下(其将归入结构IA;并且更详细论述于下文中),观察到优异的活性,其中氨基酸衍生的侧链(丙氨酸)包含R(28)和S(776)构型。在这些情况下,虽然不受理论的限制,但是除了确切的立体化学以外,异构体中的特定活性还由分子内独特结构元素确定。虽然已知具有氢键合基团(即-NHR、-OH、-CONHR等)、Log P值和分子量范围的恰当平衡的分子是优选的,但是独特的结构元素可有助于这些优选范围内的活性。受关注的当前化合物在侧链中包含极性基团,所述极性基团能够氢键合,并且平衡整个结构的亲脂性。这些分子内的立体化学特征也向所述结构赋予3D维数,这可增强与特定受体的交互作用。据信,这些独特的结构特征致使对受体的亲和力增强,这转化为已观察到的持久凉爽功效。
已发现,具有2-氨基-丙酰胺(CAS#4726-84-5)的(1R,2S,5R)-5-甲基-2-(1-甲基乙基)-N-(2-苯乙基)-环丙烷甲酰胺(CAS#824947-52-6)和(1R,2S,5R)-5-甲基-2-(1-甲基乙基)-N-(2-苯乙基)-环丙烷甲酰胺(CAS#847564-71-0)结构(上文示出)具有增强的持久凉爽特性,并且具有氨基乙烷(CAS#75-04-7)部分的(1R,2S,5R)-5-甲基-2-(1-甲基乙基)-N-苯基-环丙烷甲酰胺和(1R,2S,5R)-5-甲基-2-(1-甲基乙基)-N-1-萘基--环丙烷甲酰胺(CAS#863091-95-6)结构递送温热感。两种类型的环丙烷甲酰胺(凉爽和温热)在低使用含量(1-10ppm)下是有效的。使用如此低含量的这些材料的优点使得它们能够被配制成含水更高的组合物如漱口水,而无需另外的加工助剂如辅助表面活性剂、油或其它悬浮剂。这些材料也可提供味感减轻,如来自金属盐、过氧化物和CPC的味感。
如化合物28示例的,持久TRPM8活性的其它适宜用途为用于食品应用;皮肤调理,如处理非角质化的多层上皮;止痛应用如疼痛缓解剂;减轻炎症;香烟添加剂;用于肌肉疼痛、用于骨性关节炎慢性疼痛、和用于化疗引起的神经病变的局部用药膏;皮肤屏障恢复促进剂;和止痒或杀菌药物;以及用于扩张血管时的血管收缩。
本发明化合物如化合物28的用量取决于身体靶向TRPM8区域。例如,当本发明化合物用于溶于使用者口腔中的药物组合物如锭剂或可溶性条带中时,用量可为按所述组合物的重量计约0.00001%至约0.1%;按所述组合物的重量计约0.00005%至约0.1%;按所述组合物的重量计约0.0001%至约0.05%;或按所述组合物的重量计约0.001%至约0.01%。在另一个示例中,当本发明化合物用于液体药物组合物中时,使用含量可为按所述组合物的重量计约0.000001%至约0.01%;按所述组合物的重量计约0.00001至约0.005%;按所述组合物的重量计约0.00005%至约0.001%;按所述组合物的重量计约0.0005%至约0.005%;或按所述组合物的重量计约0.0001%至约0.001%。在另一个示例中,当本发明化合物用于吸入组合物如鼻喷剂或蒸气吸入剂中时,使用含量可为按所述组合物的重量计约0.0000001%至约0.010%;按所述组合物的重量计约0.001001至约0.0005%;按所述组合物的重量计约0.000005%至约0.0001%;按所述组合物的重量计约0.00005%至约0.0005%;或按所述组合物的重量计约0.00001%至约0.0001%。在另一个示例中,当本发明化合物为涂层固体剂型时,涂层中的使用含量可为按所述组合物的重量计约0.00001%至约0.1%;按所述组合物的重量计约0.0001至约0.05%;按所述组合物的重量计约0.0005%至约0.01%;按所述组合物的重量计约0.005%至约0.05%;或按所述组合物的重量计约0.001%至约0.01%。当本发明化合物如化合物28以例如局部用膏剂形式局部递送时,含量可为按所述组合物的重量计约0.0001%至约1%;按所述组合物的重量计约0.001%至约0.8%;按所述组合物的重量计约0.005%至约0.7%;按所述组合物的重量计约0.01%至约0.5%;按所述组合物的重量计约0.02%至约0.3%;或按所述组合物的重量计约0.05%至约0.4%。
所述组合物可包含溶剂。溶剂的非限制性示例可包括水、乙醇、甘油、丙二醇、聚乙二醇400、聚乙二醇200、以及它们的混合物。在一个示例中,所述药物包含约40%至约95%的溶剂,在另一个示例中约50%至约80%的溶剂,并且在另一个示例中约55%至约60%的溶剂,并且在另一个示例中约68%的溶剂至约72%的溶剂。
在一个示例中,所述药物可包含水和丙二醇。在一个示例中,所述药物包含约15%至约80%的水,在另一个示例中约25%至约75%的水,在另一个示例中约40%至约70%的水,在另一个示例中约35%至约45%的水,并且在另一个示例中约57%至约66%的水。在另一个示例中,所述药物可包含约1%至约10%的丙二醇,在另一个示例中约2%至约8%的丙二醇,并且在另一个示例中约3%至约6%的丙二醇。在另一个示例中,所述药物可包含约5%至约40%的丙二醇,在另一个示例中约15%至约35%的丙二醇,并且在另一个示例中约20%至约30%的丙二醇。在另一个示例中,所述药物可包含约1%至约15%的乙醇,在另一个示例中约3%至约12%的乙醇,并且在另一个示例中约6%至约10%的乙醇。
所述组合物可包含甜味剂以提供甜味,并且味觉掩蔽提供苦味特征的活性物质和赋形剂。在一个示例中,所述组合物包含约2%至25%的甜味剂,在另一个示例中约5%至20%的甜味剂,在另一个示例中约7%至15%的甜味剂,并且在另一个示例中约8%至12%的甜味剂。甜味剂的非限制性示例包括营养性甜味剂、糖醇、合成糖、高强度天然甜味剂、以及它们的组合。营养性甜味剂的非限制性示例可包括果糖、半乳糖、以及它们的组合。在一个示例中,所述甜味剂可为高果糖玉米糖浆。
糖醇的非限制性示例可包括木糖醇、山梨醇、甘露糖醇、麦芽糖醇、乳糖醇、异麦芽、赤藓醇、甘油、以及它们的组合。在一个示例中,所述组合物可包含约1%至约30%的糖醇,在另一个示例中约5%至约28%的糖醇,在另一个示例中约10%至约25%的糖醇,并且在另一个示例中约15%至约23%的糖醇。在一个示例中,所述组合物包含约5%至约20%的山梨醇,在另一个示例中约7%至约18%的山梨醇,并且在另一个示例中约10%至约15%的山梨醇。在另一个示例中,所述组合物包含约3%至约15%的甘油,在另一个示例中约5%至约10%的甘油,并且在另一个示例中约7%至约9%的甘油。
合成甜味剂的非限制性示例可包括糖精钠、丁磺氨钾、三氯半乳蔗糖、天冬甜素、甘草酸单铵盐、新橙皮苷二氢查耳酮、奇甜蛋白、纽甜、环拉酸盐、以及它们的混合物。在一个示例中,所述组合物可包含约0.01%至约0.5%的人造甜味剂,在另一个示例中约0.1%至约0.3%的人造甜味剂,并且在另一个示例中约0.15%至约0.25%的人造甜味剂。
高强度天然甜味剂的非限制性示例可包括新橙皮甙二氢查尔酮、蛇菊苷、莱鲍迪甙A、莱鲍迪甙C、杜克甙、甘草酸铵、非洲甜果素、以及它们的组合。
所述组合物可包含风味成分。当存在时,风味成分在所述组合物中的使用含量一般为按所述组合物的重量计约0.001%至约8%。
风味成分的其它非限制性示例可包括胡椒薄荷油、玉米薄荷油、留兰香油、冬青油、丁香芽油、桂皮、鼠尾草、欧芹油、牛至属植物、柠檬、酸橙、橙、芒果、顺式-茉莉酮、2,5-二甲基-4-羟基-3(2H)-呋喃酮、5-乙基-3-羟基-4-甲基-2(5H)-呋喃酮、香草醛、乙基香草醛、丙烯基乙基愈创木酚、天芥菜精、4-顺式庚烯醛、联乙酰、对叔丁基苯基乙酸甲酯、薄荷醇、水杨酸甲酯、水杨酸乙酯、乙酸1-薄荷酯、噁烷酮、α-紫罗兰酮、肉桂酸甲酯、肉桂酸乙酯、肉桂酸丁酯、丁酸乙酯、乙酸乙酯、氨茴酸甲酯、乙酸异戊酯、丁酸异戊酯、己酸烯丙酯、丁子香酚、桉叶油素、百里酚、肉桂醇、辛醇、辛醛、癸醇、癸醛、苯乙醇、苄醇、α-萜品醇、里哪醇、柠檬烯、柠檬醛、麦芽糖醇、乙基麦芽糖醇、香芹酮、薄荷酮、β-大马酮、紫罗兰酮、γ-癸内酯、γ-壬内酯、γ-十一烷酸内酯、以及它们的混合物。一般来讲,适宜的风味成分是所包含结构特征和官能团较不倾向于进行氧化还原反应的那些。这些包括是饱和的或包含稳定的芳族环或酯基团的风味成分的衍生物。在一个示例中,所述组合物包含约0.01%至约1%的风味成分,在另一个示例中约0.05%至约0.5%的风味成分,并且在另一个示例中约0.1%至约0.3%的风味成分。
在一个示例中,所述组合物可为局部用膏剂,包含约0%至约2.6%,在另一个示例中约0.5%至约2.0%,在另一个示例中约1.0%至约1.7%,并且在另一个示例中约1.3%至约1.5%的薄荷醇。在另一个示例中,所述组合物不包含薄荷醇。在另一个示例中,所述组合物包含小于2.6%的薄荷醇,并且与至少同等受到消费者偏爱(2015年4月可商购获得)。
在一个示例中,所述组合物可为蒸气吸入剂,包含约0%至约60%,在另一个示例中约20%至约55%,在另一个示例中约27%至约50%,并且在另一个示例中约35%至约45%的薄荷醇。在另一个示例中,所述组合物不包含薄荷醇。在另一个示例中,所述组合物包含小于40%的薄荷醇,并且与可商购获得的蒸气吸入剂(2015年4月可商购获得)至少同等受到消费者偏爱。
所述组合物可为任何颜色。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、碧绿色、以及它们的组合。在一个示例中,所述组合物为绿色。在另一个示例中,所述组合物是透明的。
所述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蓝色1号、FD&C蓝色2号、D&C蓝色4号、D&C蓝色9号、FD&C绿色3号、D&C绿色5号、D&C绿色6号、D&C绿色8号、D&C橙色4号、D&C橙色5号、D&C橙色10号、D&C橙色11号、FD&C红色3号、FD&C红色4号、D&C红色6号、D&C红色7号、D&C红色17号、D&C红色21号、D&C红色22号、D&C红色27号、D&C红色28号、D&C红色30号、D&C红色31号、D&C红色33号、D&C红色34号、D&C红色36号、D&C红色39号、FD&C红色40号、D&C紫罗兰色2号、FD&C黄色5号、FD&C黄色6号、D&C黄色7号、Ext.D&C黄色#7、D&C黄色8号、D&C黄色10号、D&C黄色11号、以及它们的组合。在一个示例中,所述组合物包含约0.001%至约0.1%的染料,在另一个示例中约0.002%至约0.05%的染料,并且在另一个示例中约0.003%至约0.01%的染料。
在一个示例中,所述组合物包含缓冲液。所述缓冲液可有助于保持所述组合物内恒定的pH。在一个示例中,所述组合物包含约0.05%至约2%的缓冲液,在另一个示例中约0.1%至约1%的缓冲液,在另一个示例中约0.15%至约0.5%的缓冲液,并且在另一个示例中约0.18%至约0.25%的缓冲液。缓冲液可包括乙酸盐缓冲液、柠檬酸盐缓冲液、和磷酸盐缓冲液。缓冲液的非限制性示例可包括乙酸、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。
在一个示例中,所述组合物包含防腐剂。在一个示例中,所述组合物包含约0.01%至约1%的防腐剂,在另一个示例中约0.05%至约0.5%的防腐剂,在另一个示例中约0.07%至约0.3%的防腐剂,并且在另一个示例中约0.08%至约0.15%的防腐剂。防腐剂的非限制性示例可包括苯扎氯铵、乙二胺四乙酸(EDTA)、苄醇、山梨酸钾、对羟苯甲酸酯、苯甲酸、苯甲酸钠、以及它们的混合物。
在一个示例中,所述组合物包含增稠剂。在一个示例中,所述组合物包含0.01%至3%的增稠剂,在另一个示例中0.05%至1.5%的增稠剂,在另一个示例中0.1%至0.75%的增稠剂,并且在另一个示例中0.12%至0.3%的增稠剂。增稠剂的非限制性示例可包括黄原胶、角叉菜胶、聚丙烯酸、聚乙烯吡咯烷酮、纤维素聚合物(包括羧甲基纤维素、羟乙基纤维素、羟甲基纤维素、和羟丙基甲基纤维素)、以及它们的组合。
所述组合物可包含一种或多种药物活性物质。在一个示例中,所述药物活性物质可为即释型药物活性物质、延释型药物活性物质或缓释型药物活性物质。在一个示例中,所述药物活性物质可被配制成颗粒,并且在另一个示例中,所述活性物质可被配制成涂层小珠。
在一个示例中,所述药物活性物质为MSR感冒/流感活性物质,其可用于治疗一种或多种感冒/流感症状。MSR感冒/流感活性物质可用于治疗多种感冒/流感症状,所述症状包括鼻充血、流涕、打喷嚏、头痛、干咳、喉咙痛、窦压力或疼痛、胸闷、肌肉酸痛/疼痛、湿咳/胸咳、发烧、以及它们的组合。MSR感冒/流感活性物质可包括减充血剂、祛痰剂、抗组胺剂、止咳药、镇痛药、以及它们的组合。
在一个示例中,可配制日用或夜用MSR感冒/流感活性物质。在一个示例中,所述液体药物包括指导使用者在晚上睡前摄入药物的说明书。
祛痰剂的非限制性示例可包括愈创甘油醚、氨溴索、溴己新、以及它们的组合。在一个示例中,所述祛痰剂可为愈创甘油醚。在一个示例中,剂量可包含200mg愈创甘油醚,并且在另一个示例中包含400mg愈创甘油醚。
抗组胺剂的非限制性示例可包括氯苯那敏、地氯雷他定、左西替利嗪、苯海拉明、琥珀酸多西拉敏、曲普利啶、氯马斯汀、非尼拉敏、溴苯那敏、右溴苯那敏、氯雷他定、西替利嗪和非索非那丁、氨来呫诺、烷基胺衍生物、可玛林、阿伐斯汀、异丁司特、巴米品、酮替芬、奈多罗米、奥马珠单抗、二甲茚定、奥沙米特、吡嘧司特、吡咯他敏、喷替吉肽、噻苯哌胺、哌香豆司特、托普帕敏、雷马曲班、瑞吡司特、甲磺司特、氨基烷基醚、他扎司特、溴苯海拉明、卡比沙明、曲呫诺、氯苯沙明、二苯拉林、恩布拉敏、对甲基苯海拉明、莫沙斯汀、奥芬那君、苯托沙敏、赛达斯丁、乙二胺衍生物、氯吡拉敏、氯森、美沙吡林、吡拉明、他拉斯丁、西尼二胺、盐酸桑西胺、曲吡那敏、哌嗪、氯环利嗪、氯西尼嗪、高氯环嗪、羟嗪、三环类、吩噻嗪、美喹他嗪、异丙嗪、甲硫噻丙铵、阿扎他定、赛庚啶、地普托品、地氯雷他定、异西喷地、奥洛他定、卢帕他定、安他唑啉、阿司咪唑、氮卓斯汀、贝他斯汀、克立咪唑、依巴斯汀、依美斯汀、依匹斯汀、左卡巴斯汀、美海屈林、咪唑斯汀、苯茚胺、特非那定、曲托喹啉、苯福林(PE)、伪麻黄碱(PSE)、以及它们的组合。
在一个示例中,所述组合物可包含约0.01%至约0.1%的抗组胺剂,在另一个示例中约0.02%至约0.07%的抗组胺剂,并且在另一个示例中约0.03%至约0.05%的抗组胺剂。在一个示例中,所述抗组胺剂可为琥珀酸多西拉敏,并且一剂液体药物可包含12.5mg的琥珀酸多西拉敏。在另一个示例中,所述抗组胺剂可为氯苯那敏。在一个示例中,剂量可包含2mg氯苯那敏,并且在另一个示例中剂量可包含4mg氯苯那敏。在另一个示例中,所述抗组胺剂可为PE。在一个示例中,剂量可包含5mg PE,在另一个示例中包含10mg PE,并且在另一个示例中包含20mg PE。在另一个示例中,所述抗组胺剂可为PSE。在一个示例中,剂量可包含120mgPSE,并且在另一个示例中包含30mg PSE。
镇咳药的非限制性示例可包括DXM、可待因、氯苯达诺、左羟丙哌嗪、以及它们的组合。在一个示例中,所述液体药物可包含约0.01%至约0.2%的镇咳药,在另一个示例中约0.025%至约0.1%,并且在另一个示例中约0.04%至约0.075%的镇咳药。在一个示例中,所述镇咳药可选自DXM、氯苯达诺、以及它们的组合。在一个示例中,剂量可包含15mg DXM,在另一个示例中包含20mg DXM,并且在另一个示例中包含30mg DXM。在另一个示例中,剂量可包含12.5mg氯苯达诺。
止痛剂的非限制性示例可包括APAP、布洛芬、酮洛芬、双氯芬酸、萘普生、阿司匹林、以及它们的组合。在一个示例中,所述液体药物可包含约0.5%至约3.5%的止痛剂,在另一个示例中约1%至约3%的止痛剂,并且在另一个示例中约1.5%至约2%的止痛剂。在一个示例中,所述止痛剂可包括APAP、布洛芬、萘普生或它们的组合。在一个示例中,剂量可包含325mg至500mg APAP,在另一个示例中包含200mg布洛芬,并且在另一个示例中包含200mg萘普生。
在一个示例中,所述液体药物还可包含兴奋剂如咖啡因。
在一个示例中,所述液体药物可包含一种或多种MSR感冒/流感活性物质,在另一个示例中两种或多种MSR感冒/流感活性物质,在另一个示例中三种或多种MSR感冒/流感活性物质,并且在另一个示例中四种或多种MSR感冒/流感活性物质。在一个示例中,所述液体药物可包含恰好一种MSR感冒/流感活性物质,在另一个示例中恰好两种MSR感冒/流感活性物质,在另一个示例中恰好三种MSR感冒/流感活性物质,并且在另一个示例中恰好四种MSR感冒/流感活性物质。在一个示例中,所述液体药物可包含APAP、琥珀酸多西拉敏、DXM、和PE。
在一个示例中,所述活性物质可为植物来源的材料。如本文所用,植物来源的物质的非限制性示例可包括印第安人的、中国的、阿育吠陀的和日本的传统医学中所使用的那些,包括植物的花、叶、茎和根,以及来自植物的花、叶、茎和根的提取物和分离的活性组分。基于植物和动物的油和酯如ω-3脂肪酸及其烷基酯;维生素(包括但不限于前维生素和维生素C、D、A、B、E的所有形式,以及它们的组合)。纤维:纤维和类似碳水化合物聚合物的非限制性示例可包括果胶、车前子、瓜尔胶、黄原胶、褐藻胶、阿拉伯树胶、低聚果糖、菊粉、琼脂、β-葡聚糖、甲壳质、糊精、木质素、纤维素、非淀粉多糖、角叉菜胶、还原淀粉以及它们的混合物和/或组合;益生元:适合在组合物和方法中使用的益生元的非限制性示例可包括车前子、低聚果糖、菊粉、果寡糖、低聚半乳糖、低聚异麦芽糖、低聚木糖、大豆低聚糖、低聚葡萄糖、甘露寡糖、阿拉伯半乳聚糖、阿拉伯木聚糖、低聚乳果糖、葡甘露聚糖、乳果糖、聚葡萄糖、寡葡聚糖、低聚龙胆糖、果胶寡糖、黄原胶、阿拉伯树胶、半纤维素、抗性淀粉及其衍生物、还原淀粉以及它们的混合物和/或组合。益生元:适用于本文的益生细菌的非限制性示例可包括以下的菌株:乳酸链球菌、乳脂链球菌、双醋酸乳链球菌、嗜热链球菌、保加利亚乳杆菌、嗜酸乳杆菌、瑞士乳杆菌、双歧乳杆菌、干酪乳杆菌、乳酸乳杆菌、植物乳杆菌、鼠李糖乳杆菌、德氏乳杆菌、嗜热乳杆菌、发酵乳杆菌、唾液乳杆菌、罗伊氏乳杆菌、短乳杆菌、类干酪乳杆菌、格氏乳杆菌、啤酒片球菌、长双歧杆菌、婴儿双歧杆菌、青春双歧杆菌、两歧双歧杆菌、动物双歧杆菌、假长双歧杆菌、嗜热双歧杆菌、乳双歧杆菌、保加利亚双歧杆菌、短双歧杆菌、枯草双歧杆菌、大肠杆菌和包括芽孢杆菌属的菌株、拟杆菌属的菌株、肠球菌(例如屎肠球菌)属的菌株和明串球菌属的菌株,以及它们的混合物和/或组合。
矿物质、金属和/或元素;可用于本发明体系中的矿物质、金属、和元素的非限制性示例包括:锌、铁、钙、碘、铜和硒。当存在时,所述矿物、金属和/或元素可以是在适当的载体上或载体中的,并且含量为按包含所述矿物、金属或元素以及载体的组合物的重量计约1重量%至约50重量%,或约2重量%至约30重量%。
在另一个示例中,所述活性物质可为胃肠活性物质。胃肠活性物质的非限制性示例可包括抗腹泻活性物质、泻药、抗恶心和止吐活性物质、抗气胀剂、质子泵抑制剂、抗炎胃肠活性物质、筏运剂、以及它们的组合。
抗腹泻活性物质的非限制性示例可包括洛哌丁胺、含铋组合物、次水杨酸铋、胶态次枸橼酸铋、次枸橼酸铋、高岭土、果胶、粘土如绿坡缕石、活性炭、以及它们的组合。
泻药的非限制性示例可包括纤维、抗性淀粉、抗性麦芽糖糊精、果胶、纤维素、改性纤维素、聚卡波菲、番泻叶、番泻苷、比沙可啶、磷酸钠、多库酯、柠檬酸镁、矿物油、甘油、芦荟、蓖麻油、氢氧化镁、以及它们的组合。
抗恶心和止吐活性物质的非限制性示例可包括含铋组合物(包括次水杨酸铋)、磷酸盐化的碳水化合物、苯海拉明、赛克利嗪、氯苯甲嗪、以及它们的组合;抗酸剂的非限制性示例可包括碳酸氢钠、碳酸钠、碳酸钙、碳酸镁、氢氧化镁、氢氧化铝、硅酸镁、藻酸、藻酸钠、水化铝酸镁、以及它们的组合。
抗气胀剂的非限制性示例可包括二甲基硅油、活性炭、乳糖酶、α-半乳糖苷酶、以及它们的组合;H2受体拮抗剂的非限制性示例可包括法莫替丁、雷尼替丁、西咪替丁、尼扎替丁、以及它们的组合。
质子泵抑制剂的非限制性示例可包括奥美拉唑、南索拉唑、艾美拉唑、泮托拉唑、雷贝拉唑、以及它们的组合。
抗炎胃肠活性物质的非限制性示例可包括氨水杨酸。
筏运剂的非限制性示例可包括藻酸盐、果胶和多糖。
实施例
实施例1
为测定受试化合物(示于表1中)对TRPM8(SEQ ID NO:3)、TRPA1(SEQ ID NO:2)和TRPV1(SEQ ID NO:1)活化所具有的效应(如果有的话),采用下列方案。
TRPM8方案-FLIPR测定
为测定TRPM8是否活化,由具有TRPM8受体序列(SEQ ID NO:3)的转染细胞,测量细胞内钙离子(Ca2+)含量。在设至5%CO2的37℃哺乳动物细胞培养箱中,使采用人TRPM8稳定转染的HEK-293(人胚肾)细胞在75cm2烧瓶内的15mL生长介质[补充有10%FBS(胎牛血清)、100ug/mL青霉素/链霉素、5μg/mL杀稻瘟菌素、和100μg/mL博来霉素的高糖DMEM(Dulbecco's Modification of Eagle's Medium)]内生长3天。在约2-3分钟内加入2mL的胰蛋白酶-EDTA缓冲液(25200,Invitrogen,Grand Island,NY),分离细胞。通过加入8mL生长介质使胰蛋白酶失活。将细胞转移至50mL管中并且以850rpm离心3分钟以除去介质。在离心后,细胞沉淀形成在管子底部,使它们与上层溶液分离。弃去上清液,将细胞沉淀物悬浮在1mL新鲜生长介质中,其中加入5μl(12.5μg)Fluo-4 AM(Molecular Probes,Inc.,Eugene,OR)钙指示剂,并且轻轻振荡培养30分钟。Fluo-4 AM是用于定量在100nM至1微摩尔范围内的细胞Ca2+浓度的荧光染料。在30分钟结束时,加入45mL分析缓冲液(1xHBSS(Hank平衡盐溶液)、20mM HEPES(4-(2-羟基乙基)-1-哌嗪乙磺酸))以洗涤细胞,然后将所得混合物在850rpm下离心3分钟以除去过量的缓冲液和Fluo-4 AM钙指示剂。
将沉淀的细胞重新悬浮在10mL分析缓冲液中,并且将90μL等分试样(约50,000个细胞)/孔递送至96-孔的包含10μL受试化合物(1mM,在分析缓冲液中,最终浓度100μM)或者缓冲液对照物的检测板上,并且在室温下温育30分钟。在30分钟后,将板置于荧光成像读板仪(FLIPR384,得自Molecular Devices,Sunnyvale,CA)中,并且记录基底的荧光(激发波长488nm,并且发射波长510nm)。然后加入溶于检测缓冲液中的20μL的100mM的TRPM8激动剂WS5凉爽剂,并且记录荧光。为了确定受试化合物对TRPM8的直接影响,在添加每种化合物(表2和3)之后立即测量荧光。FLIPR方法的附加讨论可见于Smart等人的“Characterization using FLIPR of human vanilloid VR1 receptor pharmacology”(European Journal of Pharmacology 417,51-58,2001)和Liu等人的“Development andvalidation of a platelet calcium flux assay using a fluorescent imaging platereader”(Analytical Biochemistry 357,216-224,2006)。
TRPA1方案--FLIPR测定
为测定TRPA1是否活化,由具有TRPA1受体序列(SEQ ID NO:2)的转染细胞来测量细胞内钙离子(Ca2+)含量。在设至5%CO2的37℃哺乳动物细胞培养箱中,使采用人TRPA1稳定转染的HEK-293细胞在75cm2烧瓶内的15mL生长介质[补充有10%FBS(胎牛血清)、100μg/mL青霉素/链霉素、100μg/mL G418的高糖DMEM(Dulbecco's Modification of Eagle'sMedium)]内生长3天。加入10mL PBS(磷酸盐缓冲盐水溶液),通过手动轻摇使细胞分离,并转移至50mL管中,并以850rpm离心3分钟,以除去PBS。在离心后,细胞沉淀形成在管子底部,使它们与上层溶液分离。弃去上清液,并将细胞沉淀物悬浮在1mL新鲜生长介质中,其中加入5μL(12.5μg)Fluo-4 AM(Molecular Probes,Inc.)钙指示剂,并且轻轻振荡培养30分钟。在30分钟结束时,加入45mL分析缓冲液(1xHBSS(Hank平衡盐溶液)、20mM HEPES(4-(2-羟基乙基)-1-哌嗪乙磺酸))以洗涤细胞,并且然后将所得混合物在850rpm下离心3分钟以除去过量的缓冲液和Fluo-4 AM钙指示剂。
将沉淀的细胞重新悬浮在10mL分析缓冲液中,并且将递送至96-孔检测板的90μL等分试样(~50,000个细胞)/孔置于荧光成像板阅读器(FLIPR TETRA,得自MolecularDevices)上,并且记录基底的荧光(激发波长488nm,并且发射波长510nm)。然后加入20μL待测试的受试化合物,并且记录荧光(表2和3)。
为了确定化合物是否为激动剂,测定受试化合物的直接效应。如果记录到高于背景的任何荧光的升高,则认为该化合物是激动剂。激动剂活性相对于用基准激动剂如针对TRPA1的50μM异硫氰酸烯丙酯所观察到的来表示。
TRPV1方案--FLIPR测定
为测定TRPV1是否活化,由用TRPV1受体序列(SEQ ID NO:1)转染的细胞,来测量细胞内钙离子(Ca+2)含量。在设至5%CO2的33℃哺乳动物细胞培养箱中,使采用人TRPV1稳定转染的HEK-239细胞在75cm2烧瓶内的15mL生长介质[补充有10%FBS(胎牛血清)、100μg/mL青霉素/链霉素、100μg/mL G418的高糖DMEM(Dulbecco's Modification of Eagle'sMedium)]内生长3天。加入10mL的PBS(磷酸盐缓冲液),轻轻手摇振荡分离细胞。将细胞转移至50mL管中并且以850rpm离心3分钟以除去PBS。在离心后,细胞沉淀形成在管子底部,使它们与上层溶液分离。弃去上清液,将细胞沉淀物悬浮在1ml新鲜生长培养基中,其中加入5μl(12.5μg)Fluo-4AM(Molecular Probes,Inc.,Eugene,OR)钙指示剂并轻轻振荡温育30分钟。在30分钟结束时,加入45mL分析缓冲液(1xHBSS(Hank平衡盐溶液)、20mM HEPES(4-(2-羟基乙基)-1-哌嗪乙磺酸))以洗涤细胞,并且然后将所得混合物在850rpm下离心3分钟以除去过量的缓冲液和Fluo-4 AM钙指示剂。
将沉淀的细胞重新悬浮在10mL分析缓冲液中,并且将递送至96-孔检测板的90μL等分试样(~50,000个细胞)/孔置于荧光成像板阅读器(FLIPR TETRA,得自MolecularDevices)上,并且记录基底的荧光(激发波长488nm,并且发射波长510nm)。然后加入20μL待测试的受试化合物作为TRPV1受体激活剂,并且记录荧光。将用化合物预处理的细胞的观测值与缓冲液对照物比较;二者之间的差值表示受试化合物对激动剂的效应的量度(表2和3)。
如果记录到高于背景的任何荧光的升高,则认为该化合物是激动剂。激动剂活性相对于用基准激动剂如针对TRPV1的350 nM辣椒素所观测到的表示。
表1
表2:对HEK 293受体表达细胞测得的浓度
每种受试化合物的浓度 | TRPM8 | TRPA1 | TRPV1 |
180 | 0.001% | 0.001% | 0.001% |
773 | 0.004% | 0.02% | 0.02% |
776 | 0.004% | 0.02% | 0.02% |
777 | 0.004% | 0.02% | 0.02% |
28 | 5.2E-6% | 5.2E-5% | 5.2E-5% |
30 | 5.2E-5% | 5.2E-5% | 5.2E-5% |
WS5 | 30微摩尔 | - | - |
异硫氰酸烯丙酯(AITC) | - | 50微摩尔 | - |
辣椒素 | - | - | 350纳摩尔 |
表2示出对包含HEK 293受体的细胞测试时,每种受试化合物的浓度。
表3:受体活性
受试的化合物 | TRPM8 | TRPA1 | TRPV1 |
180 | 108.80% | 68.02% | 0.01% |
773 | 141.07% | 198.79% | 92.07% |
776 | 139.41% | 112.99% | 94.61% |
777 | 139.37% | 173.88% | 60.5% |
28 | 130.42% | 242.50% | 104.50% |
30 | 109.70% | 38.18% | 16.24% |
WS5 | 100% | - | - |
异硫氰酸烯丙酯(AITC) | - | 100% | - |
辣椒素 | - | - | 100% |
表3示出基于细胞的受体对三种受体(TRPM8、TRPA1和TRPV1)的活性。化合物28对所有三种受体具有令人惊奇地高的活性,表明在体内测试时,它可根据浓度递送多种感觉。
表3示出每种结构对以下受体的影响:TRPM8(凉爽);TRPA1(灼热、麻木、麻刺、刺激);和TRPV1(温热)。将所期望的受试化合物对三种受体(TRPM8、TRPA1和TRPV1)的强度与对照受试化合物(用于TRPM8的WS5,用于TRPA1的异硫氰酸烯丙酯,和用于TRPV1的辣椒素)的强度进行比较。化合物773和777上的氨基乙烷部分朝向下面的苯基环丙烷甲酰胺,以从感知的凉爽感转变成灼热感(来自777的高TRPA1活性)和温热感(来自773的高TRPV1活性)。另外,化合物28相对于其它酰胺结构的效能由表2和3示出。例如,在0.0000052%筛选含量下,化合物28递送130%的WS5活性,并且在0.003%下测试WS5。在0.001%下测试N-(4-氰基甲基苯基)-对薄荷烷甲酰胺,以获得109%的WS5活性。因此,在单个浓度下,化合物28的质量效率比类别中的下一个最佳凉爽剂N-(4-氰基甲基苯基)-对薄荷烷甲酰胺高100倍。如下文所述,EC50值示出,在稀释时其质量效率更高,因为它在非常低的使用含量下保持高活性。
化合物28和30示出另外的结构,具有提供凉爽感的邻近苯环的上述部分2-氨基丙酰胺;和提供温热和/或灼热感的邻近苯环的乙醇胺。当氨基乙烷背离苯环时,分子的感觉组分似乎减少,如由来自受试化合物30的凉爽或温热感觉减少所示。萘部分上的氨基乙烷(受试化合物777)递送灼热感。如表3中和由专门小组成员报导的凉爽感中所示,化合物28对TRPM8受体活化是高度强效的。
实施例2:化合物28的异构体表征
收集克数量的如下所述的化合物28的两种级分。这两种化合物28级分的异构体含量通过使用Waters Acuity H Class超高效液相色谱仪(UPLC),由LC-UV-MS来表征,所述色谱仪配备样本管理器、四元溶剂管理器、可调紫外(TUV)检测器和QDa质量选择性单四极杆质量分析器(Waters Corporation,Milford,MA)。为准备进行分析和表征,将每种级分的固体样品称重并且以约100μg/mL溶解于由50%去离子水/50%甲醇(MeOH,HPLC等级,得自EMDMillipore Corporation,Billerica,MA)组成并且还包含0.1%三氟乙酸(TFA,SigmaAldrich Corporation,St.Louis,MO)的溶液中。
使用具有1.7μm颗粒(Waters Corporation,Milford,MA)的2.1×100mm AcuityUPLC BEH Shield RP18柱,实现包含于化合物28各级分中的异构体的分离。使用移动相梯度,移动相(A)由水和0.1%的得自Sigma Aldrich的TFA组成,并且移动相(B)由得自EMD的MeOH组成。注入前使移动相组成平衡至75%(A)/25%(B),然后进行5μl样品注入,在10分钟时使移动相组成线性阶升至100%(B)。使100%移动相(B)保持3分钟,然后在2分钟内阶降回至初始条件。始终保持0.4mL/min的移动相流量。通过监测215nm处的检测器吸光度,获得UV迹线。给定化合物28的结构,示于图1至3中的UV迹线中的QDa正离子质谱峰按预期在m/z 374处显示强的质子化分子离子,并且表明图1至3中凸显的组分是化合物28的异构体物质。
化合物28-级分1和2的UV分析分别示于图1和2中,表明优异的保留时间重复性和非常好的存在于这些混合物中的异构体的分离。图3提供级分1和级分2的代表性分析的UV叠加,凸显化合物28的这两种级分的异构组成的差异。
图3示出化合物28的异构体的HPLC。标记为级分1的在7.4至7.5分钟收集的级分对应于递送强烈凉爽感和由TRPM8活性测得的低EC50的主要异构体和次要异构体,如下表7、8和9中所示。标记为级分2的在7.20至7.38分钟收集的级分对应于具有低得多的TRPM8值的化合物28的异构体,其在所测试剂量下不提供凉爽响应,如表7、8和9中所示。
如实施例1中所述,由用TRPM8受体基因转染的细胞测量细胞内钙离子(Ca2+)含量,确定TRPM8活化,其结果示于表4和5中
表4:化合物28的TRPM8时间进程活化
表5:化合物28的异构体的TRPM8时间进程活化
表4和5中所示的TRPM8数据(其中表4对应于级分1,并且表5对应于级分2)比较化合物28的异构体(级分1、级分2)的两个HPLC分离的剂量响应。如表4和5中所示,两个级分各自在781nM下快速活化TRPM8。然而,级分1在与级分2相比越来越低的剂量下持续活化。在由12.2nM剂量活化5分钟时,级分1为对照物的103.8%;而相同时间点和剂量下,级分2为对照物的65.7%。活化10分钟时,12.2nM剂量级分1为对照物的115.5%,而12.2nM剂量级分2为对照物的71.1%。异构体的这些差异进一步由如下表6所示的EC50值示出。
表6:异构体级分的EC50计算
TRPM8中的EC50(μM) | 50秒 | 3分钟 | 5分钟 | 10分钟 |
级分2 | 0.1972 | 0.05548 | 0.04567 | 0.0374 |
级分1 | 0.3306 | 0.001476 | ~5.235E-008 | ~1.148E-007 |
在本发明组合物如液体药物和固体口服剂量单元中,当将化合物28分离成异构体或混合的异构体时,使用含量可为约10%至约70%的级分1和约10%至约70%的级分2,或约30%至约60%的级分1和约30%至约60%的级分2。当为异构体或混合的异构体的化合物28与TRPA1激动剂、TRPV1激动剂或二者混合时,TRPA1或TRPV1激动剂的使用含量将在按所述组合物的重量计约0.001%至约0.5%,或约0.01%至约0.2%的TRPA1或TRPV1激动剂范围内,其中TRPA1激动剂和/或TRPV1激动剂可分别或同时加入到包含化合物28的组合物中。当除了化合物28以外,还使用另一种TRPM8激动剂时,附加TRPM8激动剂的使用含量可为按所述组合物的重量计约0.001%至约0.5%,或约0.005%至约0.3%。如果除了化合物28以外,还使用TRPM8增强剂,则它可以按所述组合物的重量计约0.001%至约0.2%,或约0.005%至约0.1%的范围加入。本发明的组合物可包含上文所公开范围内的多种TRPA1和TRPV1激动剂,以由化合物28递送增强的感觉信号。
在以例如局部用膏剂和喷剂以及吸入剂形式局部施用本发明化合物中,当化合物28分离成异构体或混合的异构体时,使用含量可为约10%至约70%的级分1和约10%至约70%的级分2,或约30%至约60%的级分1和约30%至约60%的级分2。当为异构体或混合的异构体的化合物28与TRPA1和/或TRPV1激动剂混合时,TRPA1或TRPV1激动剂的使用含量可在按所述组合物的重量计约0.001%至约0.5%,或约0.01%至约0.2%的TRPA1或TRPV1激动剂范围内,其中TRPA1激动剂和TRPV1激动剂可分别或同时加入到包含化合物28的组合物中。当除了化合物28以外,还使用另一种TRPM8激动剂时,附加TRPM8激动剂的使用含量可为按所述组合物的重量计约0.001%至约0.5%,或约0.005%至约0.3%。如果除了化合物28以外,还使用TRPM8增强剂,则它可以按所述组合物的重量计约0.001%至约0.2%,或约0.005%至约0.1%的含量使用。所述组合物可包含所述范围内的多种TRPA1和TRPV1激动剂,以由化合物28递送增强的感觉信号。
实施例4:化合物28溶解度
表7:溶解度参数计算
如前所述,表7概述了化合物28及其异构体(级分1、级分2)的Hansen溶解度参数。这些参数有助于识别将用于形成>5%原液的良好候选物的溶剂。由于口腔护理产品中的低使用含量,~1%的典型原液将足以递送1至10ppm。较高(>5%)的溶剂将采用Hansen球体计算,并且5-6范围内的球体半径将足以识别用于较高原液的溶剂。在1-5%范围内的原液的口腔护理用途范围内,通常用于口腔护理产物中的溶剂如乙醇、薄荷醇、香芹酮、茴香脑、苄醇、和多元醇可用于制备原液。
以下实施例进一步描述和展示了在药物组合物中使用本文所述的凉爽剂化合物。所给出的这些实施例仅仅是为了举例说明目的,不可理解为是对本发明的限制,因为在不脱离本发明的实质和范围的条件下,其许多变型是可能的。除非另外指明,所有示例的量均为按总组合物的重量计的浓度,即w/w百分比。
实施例5:具有活性物质的液体药物
表8:液体药物
*适量是指术语足够量的,是指多达足够,其中该配方的剩余部分用这种物质补足。
可根据以下方法制备实施例5A-5N。可通过在适当速率下混合至少五分钟,将DXM、APAP和琥珀酸多西拉敏(如果存在)加入到丙二醇中。如果五分钟后所述活性物质不溶解,则可将所述溶液稍微加热并且搅拌,直至活性物质溶解。适当的搅拌速率是指将溶液快速混合,但是它不飞溅出容器。接着,可将可包括凉爽化合物(化合物776,化合物28级分1,或化合物28级分2)的风味剂加入到溶液中,并且可混合至少五分钟或直至分散,以较迟者为准。接着,如果存在醇,则它可作为溶剂加入以形成二醇预混物。如果不存在醇,则可将黄原胶加入到溶液中并且混合不小于五分钟,直至分散,以形成二醇预混物。
接着,可将二醇预混物加入到水中。然后,可将以下组分按以下顺序加入到溶液中:缓冲液(包括柠檬酸和柠檬酸钠)、苯甲酸钠、染料、氯化钠、PE和甜味剂(可包括糖精钠、乙酰磺胺酸钾、甘油、和山梨醇)。可将每种组分在加入下一组分之前加入并且掺入到所述溶液中。可将所述溶液混合,直至所有成分均溶解,并且溶液均匀。
在某些实施例中,实施例5中的组合物可提供某些感冒/流感症状的按需缓解。这可能是尤其有用的,因为在使用者摄入药物的时间和活性物质起作用的时间之前可存在滞后。接触后,所述组合物可降低咳嗽量和/或缓解咽痛和/或提供至少部分减轻鼻充血。所述组合物还可使口腔凉爽,这可能是非常令人愉悦的,尤其是使用者发烧时。所述组合物可口服施用,并且可被吞服。
实施例6:没有活性物质的液体药物
表9:液体药物
可根据实施例5中所述的方法,制备实施例6A至6E。实施例6中的组合物可降低咳嗽量和/或缓解咽痛和/或提供至少部分减轻鼻充血。所述组合物还可使口腔凉爽,这可能是非常令人愉悦的,尤其是使用者发烧时。在其它实施例中,所述组合物可被吞服,并且在其它实施例中,所述组合物可被吐出。
实施例7:包含凉爽剂的涂层
以下实施例进一步描述,在固体剂型的涂层制剂中包含这些凉爽剂化合物,其可包括压片。
表10:包含凉爽剂的涂层
可通过在连续搅拌下混合指定量的成分,制备涂层溶液。然后可根据具体片剂所制定的涂层方法,使用所得悬浮液。所述涂层可用于将多种片剂(包括压片)涂敷至可接受的重量增益。口腔施用后,所述片剂可在口腔和/或咽喉中提供凉爽感。在一个示例中,可将该涂层施用于MSR感冒/流感药物。在另一个示例中,可将该涂层施用于旨在用于治疗胃灼热的药物。在另一个示例中,可将该涂层施用于旨在用于治疗过敏的药物。
实施例8:局部用膏剂
表11:抚慰性局部用膏剂
表12:局部用膏剂
8G | 8H | 8I | 8J | 8K | |
樟脑(合成的) | 4.8 | 4.8 | 4.8 | 4.8 | 4.8 |
桉树油 | 1.2 | 1.2 | 1.2 | 1.2 | 1.2 |
薄荷醇 | 2.6 | 2.6 | 2.6 | 2.6 | 2.6 |
雪松叶油 | 0.44 | 0.44 | 0.44 | 0.44 | 0.44 |
肉豆蔻油 | 0.54 | 0.54 | 0.54 | 0.54 | 0.54 |
百里酚 | 0.09 | 0.09 | 0.09 | 0.09 | 0.09 |
松脂油 | 2.00 | 2.00 | 2.00 | 2.00 | 2.00 |
凡士林 | 适量 | 适量 | 适量 | 适量 | 适量 |
化合物28–级分1 | 0.02% | 0.01% | - | 0.005% | |
化合物28–级分2 | - | 0.01% | - | - | |
化合物776 | - | - | 0.02% | - | 0.001% |
可使用本领域技术人员已知的技术制备实施例8A-8K,其可包括将成分以指定的量混合,并且搅拌直至组合物均匀。可将实施例8中的组合物施用于胸部和咽喉,并且可暂时缓解因与感冒和/或流感相关联的咽喉和/或支气管刺激造成的咳嗽。还可将实施例8中的组合物施用于肌肉和关节,以缓解肌肉和关节的轻微疼痛和疼痛。
实施例9:蒸汽吸入剂
表13:蒸汽吸入剂组合物
9A | 9B | 9C | 9D | 9E | 9F | |
左旋甲基苯丙胺 | 20.8 | 24.0 | 33.0 | - | - | - |
左旋薄荷醇 | 40.0 | 35.0 | 30.0 | 50.6 | 46.1 | 44.7 |
樟脑 | 30.0 | 35.0 | 28.0 | 37.9 | 46.0 | 41.7 |
熏衣草油 | 2.0 | - | 3.0 | 2.5 | - | 4.5 |
水杨酸甲酯 | 7.0 | 6.0 | 6.0 | 8.8 | 7.9 | 8.9 |
乙酸冰片酯 | 0.1 | - | 0.1 | 0.12 | - | 0.15 |
化合物28–级分1 | 0.0001 | 0.00005 | - | 0.0001 | 0.00005 | - |
化合物28–级分2 | - | 0.00005 | - | - | 0.00005 | - |
化合物776 | - | - | 0.0001 | - | - | 0.0001 |
可将实施例9A-9F中的成分一起混合于不锈钢槽罐中,直至溶解并且均匀。然后可将制剂吸收在纤维素吸芯中,将所述吸芯包封于吸入器主体内。吸入器主体可以是刚性注塑管口件和覆盖物。吸入时,实施例9中的组合物可提供因感冒和/或花粉过敏或上呼吸道过敏而造成的鼻充血缓解。
实施例10:鼻喷剂
表14:鼻喷剂
可将实施例10A-10H中的成分混合在一起,直至存在均匀的溶液。鼻喷剂可有助于缓解感冒、花粉过敏或上呼吸道过敏所伴随的鼻充血。它可为有效的鼻腔减充血剂,其可有助于缓解窦压,并且还可有助于使肿胀的鼻膜收缩,以有助于使用者更自由地呼吸。所述液体组合物可经由喷雾瓶施用。可将两个或三个喷剂施用于每个鼻孔并且引入。在一个实施例中,与没有凉爽剂的鼻喷剂相比,如果鼻喷剂包含本发明的凉爽剂,则它可能是较小刺激性的。
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值。相反,除非另外指明,否则每个这样的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”。
除非明确排除或换句话讲有所限制,将本文引用的每篇文献,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。任何文献的引用均不是对其作为与本发明任何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其它参考文献或多个参考文献的组合提出、建议或公开了此发明任何方面的认可。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件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。
虽然已经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,在不脱离本发明实质和范围的情况下可作出多个其它改变和变型。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改变和变型。
Claims (13)
1.一种提供凉爽感的药物组合物,其中所述组合物包含具有以下结构的化合物:
R1选自H、烷基、氨基烷基、烷氧基;
Q=H2、O、-OR1、-N(R1)2、-OPO(OR1)x、-PO(OR1)x、-P(OR1)x,其中x=1-2;
V=NR1、O、-OPO(OR1)x、-PO(OR1)x、-P(OR1)x,其中x=1-2;
W=H2、O;
对于n=0,X、Y=独立地选自H、芳基、萘基;
对于n≥1,X、Y=脂族CH2或芳族CH,并且Z选自脂族CH2、芳族CH或杂原子;
A=低级烷氧基、低级烷硫基、芳基、被取代的芳基或稠合芳基;并且立体化学可在标记*的位置处变化。
2.根据权利要求1所述的组合物,其中所述化合物活化TRPA1、TRPV1或TRPM8中的至少一种,优选地,其中所述化合物在约5.2E-5%的浓度下提供:a)比约30mM浓度的WS5更大的TRPM8活化;b)比约50mM浓度的异硫氰酸烯丙酯更大的TRPA1活化;和c)比约350nM浓度的辣椒素更大的TRPV1活化。
3.根据权利要求2所述的组合物,其中所述化合物在约5.2E-5%的浓度下提供:
a)比约30mM浓度的WS5更大的TRPM8活化;
b)比约50mM浓度的异硫氰酸烯丙酯更大的TRPA1活化;和
c)比约350nM浓度的辣椒素更大的TRPV1活化。
4.根据权利要求2所述的组合物,其中所述化合物在约5.2E-5%的浓度下提供:
a)与约30mM浓度的WS5相比时,至少约110%的TRPM8活化;
b)与约50mM浓度的异硫氰酸烯丙酯相比时,至少约180%的TRPA1活化;和
c)与约350nM浓度的辣椒素相比时,至少约100%的TRPV1活化。
5.根据权利要求2至4所述的组合物,其中所述化合物在约5.2E-5%的浓度下提供比约30mM浓度的WS5更大的TRPM8活化。
6.一种权利要求1至5中任一项所述的化合物的异构体HPLC级分,其中与约10μm浓度的WS 5相比,约12.2nM浓度的所述异构体HPLC级分在10分钟下具有更高的TRPM8活化。
7.根据权利要求1所述的组合物,其中所述结构包括:
R1选自H、烷基、氨基烷基、烷氧基;
Q=H2、O、-OR1、-N(R1)2、-OPO(OR1)x、-PO(OR1)x、-P(OR1)x,其中x=1-2;
V=NR1、O、-OPO(OR1)x、-PO(OR1)x、-P(OR1)x,其中x=1-2;
W=H2、O;
对于n=0,X、Y=独立地选自H、芳基、萘基;
对于n≥1,X、Y=脂族CH2或芳族CH,并且Z选自脂族CH2、芳族CH或杂原子;
A=低级烷氧基、低级烷硫基、芳基、被取代的芳基或稠合芳基;并且立体化学可在标记*的位置处变化。
8.根据权利要求7所述的组合物,其中所述结构包括:
9.根据权利要求1所述的组合物,其中所述结构包括:
R1选自H、烷基、氨基烷基、烷氧基;
Q=H2、O、-OR1、-N(R1)2、-OPO(OR1)x、-PO(OR1)x、-P(OR1)x,其中x=1-2;
V=NR1、O、-OPO(OR1)x、-PO(OR1)x、-P(OR1)x,其中x=1-2;
W=H2、O;
对于n=0,X、Y=独立地选自H、芳基、萘基;
对于n≥1,X、Y=脂族CH2或芳族CH,并且Z选自脂族CH2、芳族CH或杂原子;
A=低级烷氧基、低级烷硫基、芳基、被取代的芳基或稠合芳基;并且立体化学可在标记*的位置处变化。
10.根据权利要求1至9中任一项所述的组合物,其中所述组合物为液体组合物。
11.根据权利要求1至10中任一项所述的组合物,其中所述组合物还包含活性物质。
12.根据权利要求11所述的组合物,其中所述活性物质选自对乙酰氨基酚、布洛芬、萘普生、右美沙芬、去氧肾上腺素、伪麻黄碱、愈创甘油醚、琥珀酸多西拉敏、以及它们的组合。
13.根据权利要求1至10中任一项所述的组合物,其中所述组合物不包含药物活性物质。
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CN201580021015.9A Expired - Fee Related CN106458861B (zh) | 2014-04-23 | 2015-04-23 | 具有凉爽性质的环丙烷甲酰胺 |
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AU2015312408A1 (en) | 2016-10-27 |
AU2015312408B2 (en) | 2018-02-01 |
US20180228746A1 (en) | 2018-08-16 |
WO2015164553A1 (en) | 2015-10-29 |
US20150306050A1 (en) | 2015-10-29 |
WO2016036423A3 (en) | 2016-06-09 |
CN106458861B (zh) | 2020-05-19 |
CA2946383A1 (en) | 2016-03-10 |
RU2016138746A3 (zh) | 2018-05-24 |
US20150307447A1 (en) | 2015-10-29 |
JP2017518963A (ja) | 2017-07-13 |
US9974761B2 (en) | 2018-05-22 |
MX2016013617A (es) | 2017-02-28 |
WO2016036423A2 (en) | 2016-03-10 |
RU2016138746A (ru) | 2018-05-24 |
BR112016024691A2 (pt) | 2017-08-15 |
EP3134081B1 (en) | 2020-04-22 |
US9492411B2 (en) | 2016-11-15 |
EP3134080A1 (en) | 2017-03-01 |
US20170119639A1 (en) | 2017-05-04 |
AU2015249706A1 (en) | 2016-11-03 |
CN106458861A (zh) | 2017-02-22 |
EP3134081A2 (en) | 2017-03-01 |
BR112016024573A2 (pt) | 2017-08-15 |
US20170079939A1 (en) | 2017-03-23 |
CA2944160A1 (en) | 2015-10-29 |
MX2016013618A (es) | 2017-02-28 |
KR20160136383A (ko) | 2016-11-29 |
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